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1. UNIT I A). Diabetes, and antidiabetic drugs By: Muhammad Aurangzeb Lecturer-INS/KMU

2. Objectives By the completion of this section the learners will be able to: Discuss the role of Insulin in metabolic process. Discuss different types of anti-diabetic agents with their mode of action, side effects and care. List the principles of therapy for all anti-diabetic agents. State reasons for combinations of insulin and oral hypoglycemic agents. Calculate drug dosage accurately.

3. Diabetes Mellitus Diabetes mellitus is a chronic metabolic disorder characterized by a high blood glucose concentration (hyperglycemia). Diabetes develops when the level of blood sugar increases due to insufficient or ineffective insulin . Fasting plasma glucose of 126 mg/ dL (7.0 mmol/L ) or more, documented on more than one occasion. What is metabolic disorder? Metabolic disorder occurs when the metabolism process fails and causes the body to have either too much or too little of the essential substances needed to stay healthy. Disease in the liver, pancreas, endocrine glands or other organs involved in metabolism lead to metabolic disorder. Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to the hormone insulin

4. Types Type 1 diabetes: In type 1 there is selective beta cell (B cell) destruction and severe or absolute insulin deficiency Type 2 diabetes: it is characterized by tissue resistance to the action of insulin combined with a relative deficiency in insulin secretion

5. New risk factors for obesity and diabetes: Environmental chemicals

6. BPA stands for  bisphenol A. BPA is an industrial chemical that has been used to make certain plastics Further reading: https://www.ncbi.nlm.nih.gov/pubmed/27650850

7. Pesticide Use Can Cause Diabetes: Scientists Sound Warning www.ndtv.com › Health Jan 24, 2017 - A team of scientists have found links between use of  pesticides  and the high prevalence of  diabetes  in India. They have suggested that view of ...

8. New-onset diabetes after transplantation (NODAT)

9. Glucose transporters

10. Classification of Anti diabetic drugs Parenteral 1. Insulin 2. Glucagon-like Polypeptide-1 (GLP-1) Receptor agonists Exenatide Liraglutide Oral antidiabetic drugs A. Sulfonylurea's Tolbutamide Chlorpropamide Tolazamide Glimepiride Glipizide B. Miglitinides /Glinides Repaglinide Nateglinide C. Biguanides Metformin D . Thiazolidinediones Rosiglitazone Pioglitazone E. α- Glucosidase inhibitors Acarbose Miglitol F. Dipeptidyl peptidase-4 inhibitors (DPP-4) Sitagliptin Saxagliptin Linagliptin G. Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors Canagliflozin Ipragliflozin Dapagliflozin

11. Classification Enhance Insulin secretion (sectertogagus) Sulfonylureas First generation: Tolbutamide Second generation: Glibenclamide, Glipizide , Meglitinide analogues Repaglinide, Nateglinide Gluc a g o n- li k e pe p ti d e - 1 (GL P- 1) r ece p t or a g o n i s ts ( Injec t able drugs) Exenatide, Liraglutide Dipeptidyl peptidase-4 (DPP-4) inhibitors Sitagliptin, Vildagliptin.

12. Classification Overcome Insulin resistance (insulin sensitizer) 1. Biguanide Metformin 2. Thiazolidinediones (PPAR  activator) Pioglitazone

13. Miscellaneous antidiabetic drugs α- Glucosidase inhibitors Acarbose, Miglitol, Voglibose Sodium-glucose cotransport-2 (SGLT-2) Inhibitor : Dapagliflozin

14. Insulin Insulin is a peptide hormone produced by beta cells of the pancreatic islets. It is a protein containing 51 amino acids. Insulin Secretion: Insulin is released from pancreatic beta cells in response to a variety of stimuli, especially glucose and incretin hormones. Basal insulin values of 30–90 pmol/L ) are found in normal humans.

15. Insulin Secretion Insulin is released from pancreatic beta cells in response to Glucose, Certain peptide hormones (incretin) such as glucagon-like polypeptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP.

16. Cell Organization in Pancreas Exocrine acinar cells surround a small duct Endocrine cells secrete near a capillary

17. Cell Types in the Pancreatic Islets Alpha cells (20%) produce glucagon Beta cells (70%) produce insulin Delta cells (5%) produce somatostatin Daily pancreatic production of insulin in the adult individual is approximately 50 units ( 0.7–1.3 mg).

18. Produced within the pancreas by β cells, islets of Langerhans – identified by Paul Langerhans in 1869.
Islets of Langerhans –
α cells – secrete glucagons , delta cells – somatostatin PP cells – pancreatic polypeptide.
Insulin is an anabolic hormone. Insulin is a polypeptide (built from 51 amino acids: Chain A consists of 21, chain B of 30 amino acids. 2 chains linked by disulfide bonds)

19. Insulin discovery Insulin was discovered in 1921 by Banting and Best who demonstrated the hypoglycemic action of an extract of pancreas.

20. Release of insulin from beta cells Glucose enters the β-cells through the glucose transporters,  GLUT2. Glucose goes into glycolysis and the Krebs cycle, where multiple, high-energy ATP molecules are produced. An increased intracellular ATP closes the ATP-sensitive potassium channel preventing potassium ions (K + ) from leaving the cell. As a result, the inside of the cell becomes less negative(depolarization) Upon depolarisation, voltage-gated calcium ion (Ca 2+ ) channels open, which allows calcium ions to move into the cell. Then, increased amounts of calcium ions in the cells causes the release of stored insulin from secretory vesicles.

21. How Insulin act ? After insulin enter the circulation, it diffuses into tissues, where it is bound by receptors. The insulin receptor consists an α subunit, which is entirely extracellular having a recognition site, and a β subunit that cross the membrane contains a tyrosine kinase. The binding of an insulin molecule to the α subunits activates the receptor by phosphorylation followed by several reactions occurring within the cell representing insulin’s second message and exert multiple effects on glucose regulating organs.

22. Mechanism of insulin

23. Effect on liver Inhibits glycogenolysis Inhibits Gluconeogenesis Promotes glycogen synthesis Increases triglyceride synthesis (lipogenesis) Effect on muscle Promotes protein synthesis. Increased glycogen synthesis Increases glucose transport and glycogen synthesis. Effect on adipose tissue Lipogenesis as promotes the storage of fat Increases glucose uptake

24. Various insulin preparations for details please read Lippincott self study Rapid-acting insulin preparations (lispro, aspart) Short-acting insulin preparations (humulin R) Intermediate-acting insulin (Humulin N) Long-acting insulin preparations (lantus, levemir) Insulin combinations (premixed) eg. Humulin 30/70

25. Adverse reactions to insulin Hypoglycemia Weight gain

26. Reactions to insulin Hypoglycemia can occur following unintentional injection of large dose, by missing a meal after injection or by performing vigorous exercise. Hypoglycemia symptoms are palpitation, tremor, dizziness, headache, behavioral changes, fatigue. Treatment : Glucose must be given orally or i.v. (for severe cases)—reverses the symptoms rapidly.

27. Glucagon-like Polypeptide-1 (GLP-1) Receptor agonists Incretin mimetics Incretins are hormones produced by intestines in response to food. Orally administered glucose stimulate greater release of insulin than the same amount of glucose delivered by injection. Some signal is produced from the gastrointestinal tract (or “gut”) that increases insulin release whenever food is consumed. These signals are incretins  (peptide hormones) Incretins increase insulin secretion and decrease glucagon Furthermore, people with Type 2 diabetes have diminished insulin release in response to meals.

28. Examples: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 is made in the small intestine and colon GIP is made by cells in the upper small intestine

29. Dipeptidyl peptidase-IV (DPP-IV) is an enzyme which cause the degradation of GLP-1 leading to termination of action. What is Dipeptidyl peptidase-IV (DPP-IV) ?

30. What is incretin effect? Incretin effect is defined as the increased stimulation of insulin secretion after oral ingestion of glucose as compared with intravenous administration of glucose. Incretin hormones are responsible for 60% to 70% of postprandial insulin secretion . Patients with type 2 diabetes exhibit loss of incretin effect. 

31. Incretin mimetics are agents that act like incretin hormones. Examples; Glucagon-like Polypeptide-1 or (GLP-1) Receptor agonists Exenatide Liraglutide Incretin mimetics

32. The incretin mimetics are agonists of GLP-1 receptors. Insulin secretion Slow gastric emptying time Reduce food intake Decrease postprandial glucagon secretion Promote β-cell proliferation Mechanism of action

33. Exenatide ( Byetta ®) Exenatide approved in 2005) is a peptide GLP-1 receptor agonist that was originally isolated from lizard venom (exendin). Liraglutide is more effective than exenatide because it is more stable: it is resistant to degradation by DPP-4. Moreover, anti- exentide antibodies  formation led to decrease efficacy exenatide. Pharmacokinetics and fate: Being polypeptides, exenatide and liraglutide must be administered subcutaneously. Liraglutide is highly protein bound and has a long half-life, allowing for once-daily dosing without regard to meals.

34. Nausea Vomiting Constipation Pancreatitis decreased gastric motility weight loss Adverse effects

35. Oral Anti-diabetic Drugs

36. GLP-1 and GIP are the known substrates of DPP4, it is important for drugs to selectively inhibit this enzyme in order to prolong the action of incretins. Drugs: Sitagliptin Vildagliptin Alogliptin Linagliptin The first agent of the class sitagliptin  was approved by the FDA in 2006 Dipeptidyl peptidase 4 inhibitors (DPP-4)

37. Mechanism of action DPP-4 Inhibitors DPP-4 inhibitors inhibit the enzyme DPP-4, prolonging the activity of incretin hormones, increases insulin release in response to meals. Pharmacokinetics: The DPP-4 inhibitors are well absorbed after oral administration. Food does not affect the extent of absorption. Alogliptin and sitagliptin are mostly excreted unchanged in the urine. All DPP-4 inhibitors except linagliptin require dosage adjustments in renal dysfunction.

38. Adverse effects Most common adverse effects are Nasopharyngitis and Headache. Although infrequent, pancreatitis has occurred with use of all DPP-4 inhibitors.

39. Sulfonylureas Sulfonylureas are also know as insulin secretagogues, because they promote insulin release from the β cells of the pancreas. Sulfonylureas were among the first oral medicines available for the treatment of Type 2diabetes . They were discovered by accident in France by a researcher who was working on drugs for typhoid fever. Animals that were given sulfonylureas displayed unusual behaviors and were found to have hypoglycemia (low blood glucose). It was quickly recognized that these drugs could be used for the treatment of diabetes. Since sulfonylureas work by stimulating the pancreas to release insulin, they are only useful in people with Type 2 diabetes whose beta cells still produce insulin.

40. Mechanism of action of sulfonylureas These drugs exert their hypoglycemic effects by stimulating insulin secretion from the pancreatic beta-cell.

41. Sulfonylureas mechanism of action Sulfonylureas bind sulf onylurea receptor present on ATP-sensitive potassium channel inhibiting the efflux of potassium ions causing depolarization. Depolarization opens a voltage-gated calcium channel and results in calcium influx and the release of preformed insulin. Voltage-gated ion channel: any ion channel that opens and closes in response to changes in electrical potential across the cell membrane.

42. Adverse effects of sulfonylureas Weight gain Hypoglycemia They should be used with caution in hepatic or renal insufficiency as accumulation of sulfonylurea's may cause hypoglycemia.

43. Meglitinides / Glinides This class of agents includes repaglinide and nateglinide . Glinides are also considered insulin secretagogues. Mechanism of action: Like the sulfonylureas, the glinides stimulate insulin secretion. They bind to β cell, closing ATP-sensitive K+ channels, and initiating a series of reactions that results in the release of insulin. In contrast to the sulfonylureas, the glinides have a rapid onset and a short duration of action. They are particularly effective in the early release of insulin that occurs after a meal and are categorized as postprandial glucose regulators. Glinides should not be used in combination with sulfonylureas due to overlapping mechanisms of action. This would increase the risk of serious hypoglycemia.

44. Meglitinides (glinides) make up a class of drugs used to treat diabetes type 2. They bind to an ATP-dependent K+ (KATP) channel on the cell membrane of pancreatic beta cells in a similar manner to sulfonylureas

45. Meglitinides / Glinides Pharmacokinetics and fate: Glinides should be taken prior to a meal and are well absorbed after oral administration. Both glinides are metabolized to inactive products by cytochrome P450 3A4 in the liver and are excreted through the bile. Adverse effects: Although glinides can cause hypoglycemia and weight gain, the incidence is lower than that with sulfonylureas. These agents should be used with caution in patients with hepatic impairment.

46. Biguanides Metformin, the only biguanide, is classified as an insulin sensitizer. It increases glucose uptake and use by target tissues, thereby decreasing insulin resistance.

47. Biguanides Mechanism of action: The main mechanism of action of metformin is reduction of hepatic gluconeogenesis. Metformin also slows intestinal absorption of sugars and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Weight loss may occur because metformin causes loss of appetite. The American Diabetic Association recommends metformin as the initial drug of choice for type 2 diabetes. Metformin may be used alone or in combination with other oral agents or insulin.

48. [Note: Excess glucose produced by the liver is a major source of high blood glucose in type 2 diabetes, accounting for high fasting blood glucose.]

49. Biguanides Unwanted effects : Dose-related gastrointestinal disturbances Lactic acidosis is a rare but potentially fatal toxic effect Long-term use may interfere with absorption of vitamin B 12 Contra indications: metformin should not be given to patients with Renal failure Hepatic disease Hypoxic pulmonary disease Heart failure or s hock

50. Thiazolidinedione's The thiazolidinediones (TZDs) are also insulin sensitizers. The two members of this class are pioglitazone and rosiglitazone . Although insulin is required for their action, the TZDs do not promote its release from the β cells, so hyperinsulinemia is not a risk.

51. Cont.. Mechanism of action: The TZDs lower insulin resistance by acting as agonists for the peroxisome proliferator–activated receptor-γ (PPARγ), a nuclear hormone receptor. Activation of PPARγ regulates the transcription of several genes with products that are important in insulin signaling , resulting in increased insulin sensitivity in adipose tissue, liver, and skeletal muscle.

52. Cont.. Unwanted effects TZDs : Weight gain fluid retention, Headache Fatigue Gastrointestinal disturbances.

53. α-Glucosidase inhibitors Acarbose and miglitol are oral agents used for the treatment of type 2 diabetes. Mechanism of action: Located in the intestinal brush border, α- glucosidase enzymes break down carbohydrates into glucose and other simple sugars that can be absorbed . Acarbose and miglitol reversibly inhibit α- glucosidase enzymes . When taken at the start of a meal, these drugs delay the digestion of carbohydrates, resulting in lower postprandial glucose levels.

54. Cont… Unwanted effects : Flatulence Loose stools or diarrhea Abdominal pain Bloating

55. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of diabetic medications indicated only for the treatment of type 2 diabetes. Canagliflozin Dapagliflozin Mechanism of action : by inhibiting SGLT2, canagliflozin , dapagliflozin decrease reabsorption of glucose, increase urinary glucose excretion, and lower blood glucose . Sodium–glucose cotransporter 2 inhibitors

56. Sodium–glucose cotransporter 2 inhibitors

57. Adverse effects Genital mycotic infections (candidiasis) Urinary tract infections Osmotic diuresis Increase urinary frequency Hypotension Gliflozins can increase the diuretic effect of thiazides, loop diuretics and related diuretics and therefore increase the risk of dehydration and hypoten sion

58. Principles of treatment with antihyperglycemic agents Metformin is the preferred initial oral antihyperglycemic agent [A]. If metformin is contraindicated or intolerable as the initial treatment, then another class of antihyperglycemic agent can be used, depending on the clinical situation [E]. If monotherapy fails to achieve the glycemic goal, then combination therapy using a second agent with a different mechanism of action should be initiated [A]. Dual combination therapy can be used as the initial management strategy, depending on the patient [B].

59. Principles of treatment with antihyperglycemic agents Although the maximal dosage of a single oral agent may be prescribed, early initiation of combination therapy is suitable after considering the glucose-lowering efficacy and side-effects of the drug [B]. When selecting a class of antihyperglycemic agents for combination therapy, the glucose-lowering efficacy, risk of hypoglycemia, body weight gain, and cardiovascular benefits associated with the drugs are preferentially considered [E]. The different mechanisms of action, drug interactions, and patient preferences for combination therapy with more than two classes of antihyperglycemic agents should be considered [C].

60. References Lippincott Illustrated Reviews: Pharmacology Sixth Edition

61. Unit-VI B Corticosteroids By: Muhammad Aurangzeb Lecturer-INS/KMU

62. Objectives By the completion of this section the learners will be able to: Discuss the action, indication, side effects and contraindication of exogenous corticosteroids. Discuss the action, indication, side effects and contraindication of exogenous androgen therapy. Discuss the consequences of abusing anabolic steroids. Identify few names of anabolic steroids. Calculate drug dosage accurately.

63. Adrenal glands The adrenal gland consists of the cortex and the medulla. The medulla secretes catecholamines, whereas the cortex, secretes two types of corticosteroids The adrenal cortex has three zones, and each zone synthesizes a different type of steroid hormone from cholesterol. The outer zona glomerulosa produces mineralocorticoids-aldosterone) The middle zona fasciculata synthesizes glucocorticoids-cortisol The inner zona reticularis secretes adrenal androgens. Secretion is controlled by pituitary adrenocorticotropic hormone (ACTH; also called corticotropin), which is released in response to hypothalamic corticotropin-releasing hormone (CRH). Glucocorticoids serve as feedback inhibitors of ACTH and CRH secretion.

64. Corticosteroids Betamethasone ( Celestone ) Cortisone ( Cortone ) Dexamethasone ( Decadron ) Hydrocortisone ( Cortef ) Methylprednisolone (Medrol) Prednisolone ( Prelone ) Prednisone ( Deltasone ) Triamcinolone ( Kenacort , Kenalog )

65. Corticosteroids Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as Stress response, Immune response and regulation of inflammation, Carbohydrate metabolism, Protein catabolism, blood electrolyte levels,

66. Glucocorticoids Cortisol is the principal human glucocorticoid. Normally, its production is diurnal, with a peak early in the morning followed by a decline and then a secondary, smaller peak in the late afternoon. Factors such as stress and levels of the circulating steroid influence secretion.

67. Cont… Glucocorticoids such as cortisol control carbohydrate, fat and protein metabolism and are anti-inflammatory by preventing phospholipid release, decreasing eosinophil action and a number of other mechanisms. Mineralocorticoids such as aldosterone control electrolyte and water levels, mainly by promoting sodium retention in the kidney.

68. Biosynthesis The corticosteroids are synthesized from cholesterol within the adrenal cortex . Aldosterone and corticosterone share the first part of their biosynthetic pathway. The last part is either mediated by the aldosterone synthase (for aldosterone) or by the 11β-hydroxylase (for corticosterone).

69. Regulation of Synthesis Synthesized and released under influence of ACTH - Ant. Pituitary (HPA axis) Regulated by CRH from hypothalamus and by feedback levels of blood concentrations

70. Control by circadian rhythm (Diurnal rhythm) – morning rise Stress: hypoglycaemia, physical stress etc. Regulation of Synthesis - Others

71. Glucocorticoids - MOA Not stored: rate of synthesis = rate of release Synthesize rhythmically influenced by light and major pulses occur early in the morning and after meals Glucocorticoids act via their receptors located in nucleus (GR) GRs are widely distributed and located almost in all cells of the body

72. Glucocorticoids - MOA GR receptors are located in the cytoplasm One GR receptor has a DNA binding domain This receptor is incapable of activating transcription Binding of free steroid molecule to GR forms an unstable compound The S+GR complex enters the nucleus and binds to gene and regulate transcription by RNA polymerase II and others The resulting mRNA is transported to cytoplasm for production of protein and bring about final response

73. Some conditions which affect level of corticosteroids Primary adrenocortical deficiency (Addison’s disease) Secondary adrenocortical deficiency (due to inadequate secretion from pituitary gland) Surgical removal of gland, prolonged use of glucocorticoids in non endocrine disorders i.e. iatrogenic disease) Tertiary adrenocortical deficiency (Releasing factor deficiency) Cushing syndrome Adrenal glands tumors

74. Stress & Stressors “the non specific response of the body to any demand” “A stressor is an agent which attempts to alter the internal environment”. Physical injury Infection, High or low temperature Radiation therapy neuromuscular fatigue emotions, Noise and environmental pollutants. Note: Body usually tend to adapt with situation. The negative feed back fails in stress and there is continuous secretion of ACTH

75. Physiological actions 1. Increase CHO metabolism---gluconeogenesis i.e.. break down of protein to Amino acids. 2. Cortisol inhibits glucose uptake by tissues . 3. Anti insulin secretion 4. Inhibits glycogenolysis 5. Protein metabolism --- catabolic in nature. 6. Negative nitrogen balance 7. Lipid metabolism--- triglycerides----fatty acids 8. However, happens in the trunk “buffalo hump ”

76. Physiological actions Anti-inflammatory (migration and activity of PMNs) Anti-allergic (delayed Hypersensitivity) delay the immune response. Immunosuppressant (antibody production) Suppresses the DNA dependent RNA polymerases in lymphocytes. Lympholysis - helps in management of tissue graft rejection

77. Anti-inflammatory action: The most important therapeutic properties of the glucocorticoids are their potent anti-inflammatory and immunosuppressive activities. These therapeutic effects of glucocorticoids are the result of a number of actions. The lowering of circulating lymphocytes is known to play a role. In addition, these agents inhibit the ability of leukocytes and macrophages to respond to antigens. Glucocorticoids also decrease the production and release of proinflammatory cytokines.

78. Cont… They inhibit phospholipase A2, which blocks the release of arachidonic acid (the precursor of the prostaglandins and leukotriene) from membrane-bound phospholipid. The decreased production of prostaglandins and leukotriene is believed to be central to the anti-inflammatory action. Lastly, these agents influence the inflammatory response by stabilizing mast cell and basophil membranes, resulting in decreased histamine release.

79. Effects on CVS Positive inotropic Shorten PR interval Increases sensitivity of Vascular response to adrenaline and N. Adrenaline. Blood volume is increased (aldosterone effects) Steroid induced hypertension.

80. Effects on blood Decrease in lymphatic tissues and in circulating lymphocytes. Increase in neutrophils, platelets and RBCs. Clotting time shortened presumably due to increase in platelets count .

81. Effects on growth Large doses retard the growth of children Systems affected are: 1. Musculoskeletal system 2. Teeth 3. Cellular activity at epiphyseal cartilage suffers.

82. Pharmacokinetics/Metabolism Plasma protein bound (90%) to plasma proteins, mostly corticosteroid-binding globulin or albumin Half life 90-110 min. Conjugation in liver-----dihydr-ocortisol----tetrahydro-cortisol.-------- excretion via urine. Synthetic steroids (prednisone & prednisolone) are more potent antiinflammatory.

83. Routes of administration of Corticosteroids Topical steroid for use topically on the skin, eye, and mucous membranes. Inhaled steroids for use to treat the nasal mucosa, sinuses, bronchi, and lungs. Oral forms - such as prednisone and prednisolone. Parenteral forms - available in injectibles for use intravenously

84. Therapeutic Uses 1. Endocrine disorders Primary adrenocortical insufficiency Secondary adrenocortical insufficiency Tertiary adrenocortical insufficiency Congenital adrenal hyperplasia Adrenocortical hyper function

85. Contd. Autoimmune diseases & Allergic disorders : ( Systemic lupus erythematous, Anaphylactic shock, blood transfusion reaction, stevens jhonson syndrome, hay fever, angioneurotic edema. Management of graft rejection. Dermatological ( pruritis vulvi , psoriasis, seborrhoic dermatitis). Ophthalmic disorders, iritis, corneal ulcers. Respiratory diseases (Asthma) Neoplastic diseases. Acute infectious diseases (antistress, anti toxic effects, endotoxic shock,

86. Cont…. Diagnosis of Cushing syndrome: hypersecretion of glucocorticoids that results from excessive release of ACTH by the anterior pituitary or an adrenal tumor. Cortisol levels (urine, plasma, and saliva) and the dexamethasone suppression test are used to diagnose Cushing syndrome. The synthetic glucocorticoid dexamethasone suppresses cortisol release in normal individuals, but not those with Cushing syndrome. Acceleration of lung maturation: Respiratory distress syndrome is a problem in premature infants. Fetal cortisol is a regulator of lung maturation. Consequently, a regimen of betamethasone or dexamethasone administered intramuscularly to the mother within the 48 hours proceeding premature delivery can accelerate lung maturation in the fetus.

87. Anti-inflammatory Uses For suppression of inflammatory components in Rheumatoid arthritis – as adjuvant with NSAIDs in severe cases Osteoarthritis – NSAIDs, intra-articular injection Rheumatic fever – severe cases with carditis and CHF Gout – NSAID failed cases and colchicine failed cases – intra-articular injection

88. Cont… Synthetic glucocorticoids are used in the treatment of dermatitis, inflammatory bowel disease ( ulcerative colitis and Crohn's disease), sarcoidosis and for glucocorticoid replacement in Addison's disease or other forms of adrenal insufficiency.

89. Organ Transplant Combined with other immunosuppressants – cyclosporine, azathioprine For prolonged use: Prednisolone or methylprednisolone are used Intermediate duration of action Can be easily tapered Can be converted to an alternate regime

90. Contraindications 1. Peptic ulcer 2. HTN with congestive heart failure 3. Psychosis 4. Diabetes mellitus 5. Glaucoma 6. Pregnancy

91. Adverse Effects Precipitation of Diabetes mellitus – hyperglycemia Increased susceptibility to infections – immune response suppression Peptic ulceration – bleeding & perforation Osteoporosis – flat spongy bones Myopathy – weakness of muscles Cataract – posterior sub capsular Glaucoma – prolonged topical therapy Growth retardation – in children Increased appetite and weight gain Deposits of fat in chest, face, upper back, and stomach Water and salt retention leading to swelling and edema High blood pressure

92. Discontinuation Sudden discontinuation of these drugs can be a serious problem if the patient has suppression of the HPA axis. In this case, abrupt removal of corticosteroids causes acute adrenal insufficiency that can be fatal. This risk, coupled with the possibility that withdrawal might cause an exacerbation of the disease, means that the dose must be tapered slowly according to individual tolerance. The patient must be monitored carefully.

93. Tappering off the dose of steroids Side effects are minimized by taking the lowest doses possible (that still yields positive results) and following doctor's orders. It is important to avoid self regulation of the dosage, either by adding more or stopping the drug without a schedule.

94. Cont.. Steroids must be gradually reduced to permit the adrenal glands to resume natural cortisol production. Eliminating doses too quickly can result in adrenal crisis (a life-threatening state caused by insufficient levels of cortisol). Another possible complication to coming off steroids is withdrawal syndrome, or rebound

95. Anabolic steroids According to the National Institute on Drug Abuse, anabolic steroids are synthetic substances related to the male sex hormones (androgens). They promote growth of skeletal muscle (anabolic effect) and the development of male sexual characteristics (androgenic effects) .

96. Cont.. The proper term for these compounds actually is "anabolic / androgenic" steroids: “anabolic” refers to muscle-building “androgenic” refers to increased masculine characteristics “steroids” refers to the class of drugs

97. Anabolic steroids Anabo lic steroids are available legally only by prescription, to treat conditions that occur when the body produces abnormally low amounts of testosterone, such as delayed puberty and some types of impotence.

98. Anabolic steroids They are also prescribed to treat Body wasting in patients with AIDS and Other diseases that result in loss of lean muscle mass.

99. Anabolic Steroids Synthetic androgens – higher anabolic but lower androgenic activity (1: 3 ratio) – decreased virilizing effect Examples: Nandrolone propionate 10-25 mg/ml (10 – 50 mg IM/week) – inj. Durabolin Nandrolone decanoate 25-100 mg/ml (25- 100mg/week) – inj. Decadurabolin Stanazolol ( 2 mg tablets (2-6 mg/day)

100. Anabolic Steroids – Therapeutic uses Catabolic states: Acute illness, severe trauma, major surgery Osteoporosis Suboptimal growth in boys Performance enhancement

101. A b us e Anabolic steroids are being abused by some athletes and others to enhance performance or improve physical appearance. Abuse of anabolic steroids can lead to serious health problems, some of which are irreversible. Major side effects can include: Liver tumors Cancer Jaundice High blood pressure Kidney tumors Severe acne Trembling

102. Cont… In males, side effects may include shrinking of the testicles and breast development. In females, side effects may include growth of facial hair, menstrual changes, and deepened voice. In teenagers, growth may be halted prematurely and permanently.

103. Androgens – Adverse Effects Virilization/ masculinization : may occur in women receiving relatively high doses for prolonged periods, such as for estrogen-dependent mammary carcinoma Cholestatic Jaundice Priapism (sustained erection) Oligospermia Edema--via promotion of salt and water retention Acne Hepatic carcinoma````` Gynaecomastia

104. References Lippincott Illustrated Reviews: Pharmacology Sixth Edition

105. Unit-VI C Thyroid and Anti-Thyroid Drugs\ By: Muhammad Aurangzeb Lecturer-INS/KMU

106. Objectives By the completion of this section the learners will be able to: Review the physiologic effects of thyroid hormone. Identify effects of hypo and hyper secretions of thyroid hormone. Discuss actions, indications, side effects of thyroid and anti-thyroid drugs. Integrate the influence of thyroid and anti-thyroid drugs on the metabolism of other drugs. Calculate drug dosages accurately.

107. Thyroid Gland Thyroid is an endocrine gland. It has two lobes, which are connected in the middle by an isthmus. Thyroid gland facilitates normal growth and maturation by maintaining a level of metabolism in the tissues that is optimal for their normal function.

108. Thyroid gland secretes three hormones: 1. Tetraiodothyronine or T4 (thyroxine) 2. Tri- iodothyronine or T3 3. Calcitonin T4 is otherwise known as thyroxine and it forms about 80% of the total secretion, whereas T3 is only 20%. Hormones of thyroid gland

109. Synthesis of thyroid hormones Synthesis of thyroid hormones takes place in thyroglobulin Substances needed for hormone: Iodine and tyrosine are essential for the formation of thyroid hormones. Iodine is consumed through diet. It is converted into iodide and absorbed from GI tract. Tyrosine is also consumed through diet and is absorbed from the GI tract . For the synthesis of normal quantities of thyroid hormones, approximately 1 mg of iodine is required per week or about 50 mg per year.

110. Synthesis of thyroid hormones occurs in five stages: 1. Thyroglobulin synthesis 2. Iodide trapping 3. Oxidation of iodide 4. Transport of iodine into follicular cavity 5. Iodination of tyrosine 6. Coupling reactions. Synthesis of thyroid hormones

111. Synthesis of thyroid hormones thyroid peroxidase

112. Synthesis of Thyroid Hormones Thyroid hormones are synthesized by iodination of tyrosine residues on thyroglobulin within the lumen of the thyroid follicle. The thyroglobulin is endocytosed and thyroxin (T4) and triiodothyronine (T3) are secreted. Synthesis and secretion of T3 and T4 are regulated by thyroid-stimulating hormone (TSH; thyrotrophin ) and influenced by plasma iodide.

113. The effect of thyroid hormones on metabolism Stimulate metabolism generally causing increased oxygen consumption increased metabolic rate Influence growth and development. Within cells, the T4 is converted to T3, which interacts with a nuclear receptor, and activates transcription of mRNA and synthesis of different types of proteins.

114. Hormone Loop ↓Metabolic rate  Detected by hypothalamus  Stimulates anterior pituitary  Secretes TSH  Blood stream  target organ  thyroid Stimulate Thyroid to secrete T3/T4  Blood stream  target organs  adrenal medulla  Secretes Epinephrine & Norepinephrine  ↑Metabolic rate

115. The thyroid gland is influenced by hormones produced by two other organs: The pituitary gland, located at the base of the brain, produces thyroid stimulating hormone (TSH) The hypothalamus produces thyrotropin releasing hormone (TRH). Low levels of thyroid hormones in the blood are detected by the hypothalamus and the pituitary. TRH is released, stimulating the pituitary to release TSH. Increased levels of TSH, in turn, stimulate the thyroid to produce more thyroid hormone, thereby returning the level of thyroid hormone in the blood back to normal. The three glands and the hormones they produce make up the "Hypothalamic - Pituitary - Thyroid axis. Thyroid Axis

116. Regulation of thyroid hormone synthesis

117. Transport of Thyroid Hormones T 4 and T 3 in plasma - bound to protein - thyroxine- binding globulin (TBG) – Reversibly Only about 0.04% of total T 4 & 0.4% of T 3 exist in the free form.

118. Functions of thyroid hormone Metabolic function CHO metabolism:  glycogenolysis Increase gluconeogenesis  glucose absorption from GIT Enhance glycolysis – rapid uptake of glucose by the cell. Net result -  blood glucose level On protein metabolism:  protein catabolism On fat metabolism:  mobilization of fat, oxidation of FA   FFA On BMR:  BMR Action on blood: Thyroxine accelerates erythropoietic activity and increases blood volume.

119. Cont… Growth :  growth On GIT:  appetite & food intake.  rate of secretion of digestive juice.  motility of GIT  diarrhea often result in hyperthyroidism On CVS: Enhance tissue sensitivity to catecholamines  cardiac output On nervous system: excitable effect, inability to sleep Has role on development of brain in fetal & 1 st few weeks of postnatal life Muscle weakness due to protein catabolism

120. Normal Hyperthyroidis m Hypothyroidism/Deficiency States I nt er m ed i a r y Metabolism Lipid: indirectly enhances lipolysis; elevated plasma free fatty acid; Hy p e r c hole s t e r ol emia Carbohydrate: metabolism stimulated; tissue utilization of sugar increased; glycogenolysis and gluconeogenesis increased, faster absorption of glucose from intestine Hyperglycaemia, diabetic like stale, insulin resistance Protein: overall catabolic, prolong action: negative nitrogen balance and tissue wasting. Weight loss

121. Normal Hyperthyroidism Hypothyroidism/Deficiency states Calorigenesis Increase BMR; Metabolic rates in brain, gonads, uterus, spleen, lymph nodes, not significantly affected. Ca r di o v ascular System Hyperdynamic state of circulation due: increased peripheral demand, direct cardiac actions. Fast bounding pulse Atrial fibrillation, arrhythmias Congestive Heart Failure, angina Reduced Myocardial O 2 demand Nervous System Profound functional effects Anxious, nervous, excitable, tremors, hyperreflexia Mental Retardation (Cretinism) Sluggishness, behavioural symptoms (Myxedema) Skeletal Muscle Increased Muscle tone, tremor, weakness due to myopathy Flaccid and weak (Myxedema) Gastrointestinal Increases propulsive activity Diarrhoea Constipation

122. Normal Hyperthyroidism Hypothyroidism/Deficiency State Hematopoiesis Facilitates erythropoiesis Anaemia G r o wth a n d Development Maturation of nervous system Muscle wasting, weight loss Co ng e ni t al d e fici e n c y l e ad i n g to Cretinism Delayed developmental milestones Retardation and nervous deficit A d ul t: I m pai r ed i nt e l l i g ence a n d slow movements

123. Disease of Thyroid gland Hyp e rt h y r oid i s m / T h y r o t o xi c osi s /G r a v e ’ s disease Increased secretion of thyroid hormones Hypothyroidism – Too little thyroid hormone production Cretinism (in children) Myxedema (in adult)

124. Hypothyroidism is usually treated by oral administration of L-thyroxine 75-200 micrograms daily Other drug is liothyronine (T3) and liotrix (T3 plus T4) Levothyroxine (T4) is preferred over T3 (liothyronine or T3/T4 combination products ( liotrix ) for the treatment of hypothyroidism. Pharmacokinetics: Orally easily absorbed; the bioavailability of T4 is 80%, and T3 is 95%. T4 is better tolerated than T3 preparations and has a longer half-life . Levothyroxine is dosed once daily, and steady state is achieved in 6 to 8 weeks. Drugs for hypothyroidism

125. 12 Mechanism of actions of thyroid hormones T3, via its nuclear receptor, induces new proteins generation which produce effects Sensitization of adrenergic receptors to catecholamines  tachycardia, arrhythmia, raised BP,

126. Adverse reactions Overmuch leads to thyrotoxicosis Symptoms of hyperthyroidism

127. Hyperthyroidism Intolerance to heat as the body produces lot of heat due to increased basal metabolic rate caused by excess of thyroxine Increased sweating Decreased body weight due to fat mobilization Diarrhea due to increased motility of GI tract Muscular weakness because of excess protein catabolism Nervousness, extreme fatigue, inability to sleep, mild tremor in the hand Polycythemia Tachycardia

128. Anti-thyroid Drugs Thioamides Propylthiouracil Methimazole/Carbimazole β - adrenoceptor blockers Propranolol: It is used in the management of hyperthyroid symptoms Inhibitor of hormone release Iodides of Na, k Organic iodides Radioactive iodine I 131 (Radioactive iodine)

129. Thioamides Methimazole (carbimazole) Propyl thiouracil (PTU) These 2 are the major drugs used in the treatment of thyrotoxicosis (Carbimazoles converted to methimazole in vivo). MOA: These drug inhibit thyroid hormone production by Inhibiting thyroid peroxidase which is required in intrathyroidal oxidation of Iodide. Inhibiting the iodination of tyrosine Inhibiting coupling of MIT and DIT to form thyroid hormones Propylthiouracil also inhibits peripheral conversion of T4 TO T3 by inhibiting DID -1 enzyme

130. Mechanism of action of Thioamides

131. Therapeutic uses of thioamides These drugs controls thyrotoxicosis in both graves disease and toxic nodular goiter. Clinical improvement starts after 1-2 weeks Propylthiouracil : 50-150mg TDS followed by 25-50 mg BD-TDS for maintenance Carbimazole: 5-15 mg TDS initially Maintenance dose is 2.5-10mg daily in 1-2 divided doses

132. Skin rashes- Maculopapular pruritic rash – most common Fever Hepatic abnormalities- Hepatitis & cholestatic jaundice can be fatal Nausea & GI distress An altered sense of taste or smell may occur with methimazole The most dangerous – agranulocytosis (granulocyte count < 500 cells/mm 2 ). Adverse effects of thioamides

133. Iodides salts Iodide salts inhibit organification (iodination of tyrosine) and thyroid hormone release. These salts also decrease the size & vascularity of the hyperplastic thyroid gland. Since iodide salts inhibit the release as well as the synthesis of the hormone, their onset of action occurs rapidly within 2-7 days. This effect is transient because the thyroid gland escapes from iodide block after several weeks of treatment.

134. Iodides salts Iodide salts are used in thyroid storm(severe thyrotoxicosis) & to prepare the patient for surgical resections of the hyperactive thyroid. The usual forms of this drug are lugol's solution(iodine & potassium iodide) and saturated solution of potassium iodide. Lugols solution: 5% iodine in 10% KI solution : 5- 10drops/day Iodide salts (sod/pot) 100-300 mg/day

135. Adverse effects Acute adverse effects occurs in individuals who are sensitive to iodine. Manifestations are Swelling of lips, eyelids, Angioedema of larynx Fever Joint pain Petechial hemorrhage Chronic overdose Inflammation of mucous membrane Salivation Sneezing Swelling of eyelids GI disturbance

136. Radioactive iodine Radioactive iodine is administered as sodium salt of 131 I Dissolved in water and taken orally. 131 I emits x ray as well as β particles 131 I is concentrated by thyroid, incorporated in colloid- emits radiation from within the follicles. β particles penetrates around 0.5-2 mm of tissue Thyroid follicular cells are affected within undergoes pyknosis and necrosis followed by fibrosis when a large dose is given. Lugols solution

137. Use s Diagnostic purpose  25-100 μ curies in thyroid function test Therapeutic use  3-6 milli curies in toxic nodular goiter, graves disease, thyroid Ca. Adverse effect : Hypothyroidism crosses the placenta to destroy the fetal thyroid gland & is excreted in breast milk (baby become hypothyroid)

138. Beta blockers Propranolol is used to rapidly alleviate manifestations of thyrotoxicosis that are due to sympathetic over activity e.g.: Palpitation, tremor, nervousness and sweating, In addition they reduce peripheral conversion of T4 to T3

139. β- blockers β- blockers are used in hyperthyroidism in following situations: While awaiting response to propylthiouracil or carbimazole Along with iodide for preoperative preparation before subtotal thyroidectomy Thyrotoxic crisis Propranolol 1-2mg slow I.V may be followed by 40- 80 mg oral every 6 hrly .

140. Thyroid storm Thyroid storm presents with extreme symptoms of hyperthyroidism. The treatment of thyroid storm is the same as that for hyperthyroidism, except that the drugs are given in higher doses and more frequently. β-blockers, such as metoprolol or propranolol, are effective in blunting the widespread sympathetic stimulation that occurs in hyperthyroidism.

141. References Lippincott Illustrated Reviews: Pharmacology Sixth Edition

142. Unit I D: Hypothalamus and Pituitary Drugs By: Muhammad Aurangzeb Lecturer-INS/KMU

143. Objectives By the completion of this unit learners will be able to: Discuss the clinical uses of major hypothalamus and pituitary hormones Identify commonly used drugs and hormone replacement State the major nursing consideration in the care of client receiving specific hypothalamic and pituitary hormones Calculate the drug dosage accurately for oral and parental drug/hormone used for hypothalamus and pituitary replacements

144. Pituitary gland Pituitary gland often called as “ Master gland” Its function are primarily controlled by hypothalamus. Pituitary gland consist of 2 lobe: Anterior lobe Posterior lobe

145. Pituitary Hormones Anterior pituitary hormones are produced by separate group of cells: Somatotrophs: Growth hormones Lactotrophs: Prolactin Gonadotrophs: FSH, LH Corticotrophs: ACTH Posterior lobe: Vasopressin and Oxytocin Anterior pituitary hormones are regulated by negative feedback mechanism .

146. Hypothalamic & Anterior Pituitary Hormones The hormones secreted by the hypothalamus and the pituitary are all peptides or low molecular weight proteins that act by binding to specific receptor sites on their target tissues. The hormones of the anterior pituitary are regulated by neuropeptides that are called either “releasing” or “inhibiting” factors or hormones. These are produced in the hypothalamus, and they reach the pituitary by the hypophyseal portal system Each hypothalamic regulatory hormone controls the release of a specific hormone from the anterior pituitary.

147. Clinical Uses of Major Hypothalamus & Pituitary Hormones Although a number of pituitary hormone preparations are currently used therapeutically for specific hormonal deficiencies, most of these agents have limited therapeutic applications. Hormones of the anterior and posterior pituitary are administered intramuscularly (IM), subcutaneously, or intranasally because their peptidyl nature makes them susceptible to destruction by the proteolytic enzymes of the digestive tract.

148. Pharmacologic Applications of Thyroid & Pituitary Hormones Replacement therapy Antagonists for excess production of pituitary hormones. Diagnostic tools for endocrine abnormalities.

149. Adrenocorticotropic hormone (corticotrophin) Normally, ACTH is released from the pituitary in pulses with an overriding diurnal rhythm, with the highest concentration occurring in the early morning and the lowest in the late evening. Stress stimulates its secretion, whereas cortisol acting via negative feedback suppresses its release . Mechanism of action: ACTH binds to receptors on the surface of the adrenal cortex, thereby activating G protein–coupled processes that ultimately stimulate the synthesis and release of the adrenocorticosteroids and the adrenal androgens.

150. Therapeutic uses of ACTH Limited use of ACTH due to corticosteroids Used in the diagnosis of adrenocortical insufficiency. Therapeutic corticotrophin preparations are extracts from the anterior pituitaries of domestic animals or synthetic human ACTH. Adverse effects: Short-term use of ACTH for diagnostic purposes is usually well tolerated. With longer use, toxicities are similar to those of glucocorticoids and include hypertension, peripheral edema, hypokalemia, emotional disturbances, and increased risk of infection

151. Mainly to used as a diagnostic tool for differentiating between primary adrenal insufficiency (Addison disease) and secondary adrenal insufficiency (caused by the inadequate secretion of ACTH by the pituitary).

152. Growth hormone (somatotropin) Somatotropin is released by the anterior pituitary in response to growth hormone (GH)-releasing hormone Somatotropin influences a wide variety of biochemical processes (for example, cell proliferation and bone growth are promoted). Synthetic human GH (somatropin) is produced using recombinant DNA technology. Mechanism of action: Although many physiologic effects of GH are exerted directly at its targets, others are mediated through the somatomedins—insulin-like growth factors 1 and 2 (IGF-1 and IGF-2). [Note: In acromegaly (a syndrome of excess GH due to hormone-secreting tumors), IGF-1 levels are consistently high, reflecting elevated GH.]

153. Secretion of GH is inhibited by another hypothalamic hormone, somatostatin .

154. Therapeutic uses of Somatropin GH deficiency or growth failure in children. Growth failure due to Prader-Willi syndrome, Management of AIDS wasting syndrome GH replacement in adults with confirmed GH deficiency. Pharmacokinetics Somatropin is administered by subcutaneous or IM injection. Although the half-life of GH is short (approximately 25 minutes), it induces the release of IGF-1 from the liver, which is responsible for subsequent GH-like actions. Adverse effects: Adverse effects of somatropin include pain at the injection site, edema, arthralgias, myalgias, flu-like symptoms, and an increased risk of diabetes.

155. Somatostatin (Growth hormone-inhibiting hormone) In the pituitary, somatostatin binds to receptors that suppress GH and thyroid-stimulating hormone release. Originally isolated from the hypothalamus, somatostatin is a small polypeptide that is also found in neurons throughout the body as well as in the intestine, stomach, and pancreas. Somatostatin not only inhibits the release of GH but also that of insulin, glucagon, and gastrin.

156. Somatostatin: It is growth hormone release inhibiting hormone (GHRIH). Inhibits secretion of GH, also inhibits thyroid stimulating hormone, Insulin, prolactin, glucagon. Uses: Use to prevent acute bleeding due to esophageal varices. Upper GIT bleeding from hemorrhagic gastritis, intestinal or pancreatic fistula. Hypersecretory tumor of intestinal tract. Limitation: short half life, lack of specificity, GH rebound after discontinuation.

157. Octreotide [ok-TREE- ohtide ] and lanreotide [ lan -REE-oh-tide] are synthetic analogs of somatostatin . Their half-lives are longer than that of the natural compound, and depot formulations are available, allowing for administration once every 4 weeks.

158. Octreotide A long acting analogue of somatostatin. 45 times more potent. Uses: Useful in acromegaly, some hormone secreting tumors and in bleeding esophageal varices. Treatment of AIDS associated diarrhea, Cushing syndrome and insulinoma. Adverse effect: abdominal pain, nausea, steatorrhea, gallstones.

159. Gallbladder emptying is delayed, and asymptomatic cholesterol gallstones can occur with long-term treatment

160. Lanreotide Long-acting analogue of somatostatin, Similar in actions and specificity to octreotide Indicated for pharmacotherapy of acromegaly. (peg-VIH-soe-mant) Acromegaly that is refractory to other modes of therapy may be treated with pegvisomant Acts as a GH antagonist , because in presence of Pegvisomant, GH binds to the GH receptor but does not trigger signal transduction. Approved for treatment of acromegaly due to small pituitary adenoma Pegvisomant

161. Gonadotropin-releasing hormone (GnRH): Regulates the secretion of gonadotropins—FSH and LH Secreted in a pulsatile manner. Continuous administration inhibits gonadotropin secretion, that in turn, leads to reduced production of gonadal steroid hormones (androgens and estrogens). Gonadorelin is synthetic GnRH, used in diagnostic tests in hypogonadism. Pulsatile administration is used in infertility and delayed puberty. Used in prostatic cancers, precocious puberty and some gynecological conditions like uterine fibroids and endometriosis. Ex- leuprolide, Goserelin, Nafarelin, Triptorelin,

162. In 1–2 weeks they cause desensitization and down regulation of GnRH receptors inhibition of FSH and LH secretion suppression of gonadal function. Spermatogenesis or ovulation cease and testosterone or estradiol levels fall to castration levels.

163. Cont…. Recovery occurs within 2 months of stopping treatment. Used as nasal spray or injected s.c. Reversible pharmacological oophorectomy/ orchidectomy is used in precocious puberty, prostatic carcinoma, endometriosis, premenopausal breast cancer, uterine leiomyoma, polycystic ovarian disease. Used as contraceptive for both males and females.

164. GnRH antagonists Some extensively substituted GnRH analogues act as GnRH receptor antagonists. Inhibit Gn secretion without causing initial stimulation. They block the pituitary GnRH receptors and thereby suppress the secretion of LH, FSH and delay ovulation. They are used in in vitro fertilization and are also useful in prostatic cancer and in reducing uterine fibroids and endometriosis. Ex- ganirelix and cetrorelix

165. Gonadotropins (Gns) The anterior pituitary secretes two Gns viz. FSH and LH. FSH: In the female induces follicular growth, development of ovum and secretion of estrogens. In the male supports spermatogenesis and has a trophic influence on seminiferous tubules. Ovarian and testicular atrophy occurs in the absence of FSH LH: Induces ovulation In male LH stimulates testosterone secretion.

166. these hormones are injected via the IM or subcutaneous route. Injection of hMG or FSH products over a period of 5 to 12 days causes ovarian follicular growth and maturation, and with subsequent injection of hCG , ovulation occurs

167. Uses Gonadotropin deficiency in males. Undescended testes. Amenorrhea and infertility. In vitro fertilization—to time the ovulation

168. Prolactin Physiological function: Prolactin causes growth & development of breast in pregnancy. Promotes proliferation of ductal as well as acinar cells in breast and induces synthesis of milk proteins and lactose. After parturition, prolactin induces milk secretion. Regulation of secretion: Prolactin is under predominant inhibitory control of hypothalamus through PRIH. Dopaminergic agonists (bromocriptine, cabergoline) plasma prolactin levels. Dopaminergic antagonists (chlorpromazine, haloperidol, metoclopramide) and reserpine cause hyperprolactinemia.

169. Cont…. Prolactin levels in blood are low in childhood, increase in girls at puberty and are higher in adult females. A progressive increase occurs during pregnancy, peaks at term. High prolactin secretion is maintained by suckling, falls if breast feeding is discontinued. Stress, exertion and hypoglycemia also stimulate prolactin release. Hyperprolactinaemia is responsible for the galactorrhoea– amenorrhea– infertility syndrome in women. In males it causes loss of libido and decreased fertility.

170. Prolactin inhibitors Bromocriptine: Prolactin inhibitor MOA: Decreases prolactin release from pituitary by activating dopaminergic receptors on lactotrope cells. Levodopa like actions in CNS—antiparkinsonian and behavioral effects. Side Effects Nausea and vomiting by stimulating dopaminergic receptors in the CTZ. Hypotension—due to central suppression of postural reflexes and weak peripheral α adrenergic blockade. Decreases gastrointestinal motility.

171. Uses of Bromocriptine Hyperprolactinemia due to microprolactinomas causing galactorrhoea, amenorrhea and infertility in women; gynaecomastia, impotence and sterility in men. Parkinsonism Bromocriptine is used to suppress lactation and breast engorgement after delivery (like in stillbirth) and following abortion. It is a newer D2 agonist; more potent; more D2 selective and longer acting. Lower Incidence of nausea and vomiting. It is preferred for treatment of hyperprolactinemia and acromegaly Cabergoline

172. Hormones of the Posterior Pituitary Vasopressin and oxytocin Not regulated by releasing hormones. They are synthesized in the hypothalamus, transported to the posterior pituitary, and released in response to specific physiologic signals, such as high plasma osmolarity or parturition.

173. Oxytocin Uses Used in obstetrics, to stimulate uterine contraction to induce or reinforce labor. Oxytocin causes milk ejection by contracting the myoepithelial cells around the mammary alveoli. Adverse effects: Toxicities are uncommon when used properly: hypertension, uterine rupture, water retention, and fetal death have been reported. Contraindications: Contraindicated in abnormal fetal presentation, fetal distress, and premature births.

174. Vasopressin(antidiuretic hormone) Vasopressin has both antidiuretic and vasopressor effects. In the kidney, it binds to V2 receptor to increase water permeability and reabsorption in the collecting tubules. Uses: Major use of vasopressin is to treat diabetes insipidus, also used in the management of cardiac arrest and in bleeding due to esophageal varices. Other effects of vasopressin are mediated by the V1 receptor, which is found in liver, vascular smooth muscle (where it causes constriction). Adverse effects: Major toxicities are water intoxication and hyponatremia. Headache, bronchoconstriction, and tremor can also occur.

175. Desmopressin An analogue of vasopressin , Minimal activity at the V1 receptor, making it largely free of pressor effects. Longer acting than vasopressin Preferred for the treatment of diabetes insipidus and nocturnal enuresis. Administered intranasally or orally.

176. Nursing Consideration Assess for contraindications or cautions (e.g. history of allergy, pregnancy,) to avoid adverse effects. Assess height, weight, and GH levels to determine baseline status before beginning therapy and for any potential adverse effects.  Monitor patient response to therapy (return of GH levels to normal, growth and development). Monitor for adverse effects Monitor patient compliance to drug therapy Evaluate patient understanding on drug therapy by asking patient to name the drug, its indication, and adverse effects to watch for.

177. References Karch, A. M., & Karch. (2011).  Focus on nursing pharmacology . Wolters Kluwer Health/Lippincott Williams & Wilkins. Katzung, B. G. (2017).  Basic and clinical pharmacology . McGraw-Hill Education. Lehne, R. A., Moore, L. A., Crosby, L. J., & Hamilton, D. B. (2004). Pharmacology for nursing care. Smeltzer, S. C., & Bare, B. G. (1992).  Brunner & Suddarth’s textbook of medical-surgical nursing . Philadelphia: JB Lippincott.

178. Anesthetics Drugs- A By: Muhammad Aurangzeb Lecturer-INS/KMU UNIT 2

179. Objectives By the completion of this section the learners will be able to: Define the term anesthesia and anesthetic agents Differentiate between different types of anesthesia Identify the stages of general anesthesia Describe Characteristics of general and local anesthetic agents. Identify most commonly used anesthetic agents Discuss factors considered when choosing anesthetic agents. Compare general and local anesthesia in terms of administration, client’s safety and nursing care. Discuss the rationale for using adjunctive drugs before and during surgical procedures. Describe the nursing role in related to anesthetics and adjunctive drugs. Discuss the action, indication and side effects of neuro -muscular blocking agent Calculate the drug dosage of injectable anesthetic agent

180. Anesthesia The word anesthesia is coined from two Greek words: "an" meaning "without" and "aesthesis“ meaning "sensation". Anesthesia refers to the practice of administering medications either by injection or by inhalation (breathing in) that block the feeling of pain and other sensations, or that produce a deep state of unconsciousness that eliminates all sensations, which allows medical and surgical procedures to be undertaken without causing undue distress or discomfort.

181. Anesthesia It is a pharmacologically induced and reversible state of amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes or decreased stress response, or all simultaneously. An alternative definition is a "reversible lack of awareness," including a total lack of awareness (e.g. a general anesthetic) or a lack of awareness of a part of the body such as a spinal anesthetic. The pre-existing word anesthesia was suggested by Oliver Wendell Holmes, Sr. in 1846 as a word to use to describe this state. Anesthesiology is a special branch of medicine. Nurses working in this area need to have knowledge and skill to care for the patient who is being given premedication, under anesthesia and recovering.

182. Anesthetic Agents Anesthetic drugs are the agents that produces anesthesia or bring about reversible loss of sensation . Two types a) General anesthetics b) Local anesthetics

183. Types of Anesthesia Classified into 2 major types. They are : General anesthesia. Local & regional anesthesia.

184. General anesthesia General anesthesia refers to inhibition of sensory, motor and sympathetic nerve transmission at the level of the brain, resulting in unconsciousness and lack of sensation. General anesthesia – for surgical procedure to render the patient unaware / unresponsive to the painful stimuli Drugs producing General Anesthesia – are called General Anesthetics

185. Local anesthesia Local anesthesia - reversible inhibition of impulse generation and propagation in nerves. In sensory nerves, such an effect is desired when painful procedures must be performed, e.g., surgical or dental operations Drugs producing Local Anesthesia – are called Local Anesthetics e.g. Procaine, Lidocaine and Bupivacaine etc. Local anesthesia inhibits sensory perception within a specific location on the body, such as a tooth or the urinary bladder

186. Regional Anesthesia Regional Anesthesia : Regional anesthesia renders a larger area of the body insensate by blocking transmission of nerve impulses between a part of the body and the spinal cord. Two frequently used types of regional anesthesia are spinal anesthesia and epidural anesthesia .

187. Spinal Anesthesia Spinal Anesthesia: it is achieved by injection 1.8 ml of 5% lignocaine solution into the subarachnoid space through a lumber puncture. Other drugs which can be used are cinchocaine, procaine and amethocaine. It can cause serious hypotension.

188. Epidural Anesthesia Epidural Anesthesia : It is achieved by injection 1 to 2 % of lignocaine solution in the epidural space. It blocks the nerves which traverse the epidural space. It can cause hypotension, which is less severe than with spinal analgesia. For prolonged operations, a catheter may be passed into the epidural space for intermittent administration of local anesthesia.

189. Stages of General Anesthesia Four stages of anesthesia Stage I Analgesia Stage II Excitement Stage III Surgical anesthesia Stage IV Medullary paralysis

190. Stages Cont… Stage I Analgesia Loss of pain sensation Drowsiness Amnesia and reduced awareness of pain Stage II Excitement Delirium Rise and irregularity in blood pressure and respiration Risk of laryngospasm To shorten this period a rapid acting anesthetic like propofol is administered IV before inhaled anesthetic

191. Stages Cont… Stage III: Surgical anesthesia Loss of muscle tone and reflexes Ideal stage for surgery Requires careful monitoring Stage IV: Medullary paralysis Severe depression of the respiratory and vasomotor centers Death can occur unless respiration and circulation are maintained

192. Practically what is done in OT ??? There are 3 (three) phases: – Induction, Maintenance and Recovery Induction (Induction time): It is the period of time which begins with the beginning of administration of anesthesia to the development of surgical anesthesia (Induction time). Induction is generally done with IV anesthetics like Thiopentone Sodium and Propofol Maintenance: Sustaining the state of anesthesia. Usually done with an admixture of Nitrous oxide and halogenated hydrocarbons Recovery: At the end of surgical procedure administration of anesthetic is stopped and consciousness regains (recovery time)

193. General anesthetics (Defn.) General Anesthetics are the drugs which produce reversible loss of all sensation and consciousness, or simply, a drug that brings about a reversible loss of consciousness Remember !!! These drugs are generally administered by an anesthesiologist in order to induce or maintain general anesthesia to facilitate surgery General anesthetics are – mainly inhalation or intravenous Local anesthetics are drugs which upon topical application or local injection cause reversible loss of sensory perception, especially of pain in a localized area of the body

194. What are the Drugs used as GA ? (Classification) Intravenous: Inducing agents: Thiopentone, Methohexitone sodium, propofol and etomidate Benzodiazepines (slower acting): Diazepam, Lorazepam, Midazolam Other drugs Ketamine Fentanyl • Inhalation: Gas : Nitrous Oxide Volatile liquids: • • • • • • Ether Halothane Enflurane Isoflurane Desflurane Sevoflurane

195. Local Anaesthetics Ester Linkage Amide Linkage (2 Eyes!!) PROCAINE procaine (Novocaine) tetracaine (Pontocaine) benzocaine cocaine LIDOCAINE lidocaine (Xylocaine) mepivacaine (Carbocaine) bupivacaine (Marcaine) etidocaine (Duranest) ropivacaine (Naropin)

196. Factors considered when choosing anesthetic agents Choice of anesthetic drugs are made to provide safe and efficient anesthesia based on the nature of the surgical or diagnostic procedures and patient’s physiologic, pathologic and pharmacologic state

197. Patients Factors in selection of Anesthesia 2 factors are important Status of organ system Cardiovascular system Respiratory system Liver and kidney Nervous system Pregnancy Concomitant use of drugs Multiple adjunct agents Non-anesthetic drugs

198. Status of the Organ System Cardiovascular system: Anesthetic agents suppress cardiovascular functions. Ischemic injury to tissues may follow reduced perfusion pressure if a hypotensive episode occurs during anesthesia, treatment with vasoactive substances may be necessary Some anesthetics like halothane sensitize the heart to arrhythmogenic effects of sympathomimetics

199. Respiratory system Asthma may complicate control of inhalation anesthetic Inhaled anesthetics depress the respiratory system IV anesthetics and opioids suppress respiration These effects may influence the ability to provide adequate ventilation and oxygenation Status of the Organ System

200. Status of the Organ System Liver and kidneys Affect distribution and clearance of anesthetics, and might be affected by anesthetic toxic effects Their physiology must be considered Nervous system Presence of neurologic disorders like epilepsy, myasthenia gravis, problems in cerebral circulation Pregnancy Effects of anesthetic agents on the fetus Nitric oxide causes aplastic anemia in the unborn child Benzodiazepines might cause oral clefts in the fetus

201. Concomitant use of drugs Multiple adjunct agents Multiple agents are administered before anesthesia, these agents facilitate induction of anesthesia and lower the needed dose of anesthetics They may enhance adverse effects of anesthesia like hypoventilation Concomitant use of additional non-anesthetic drugs Example: Opioid abusers may be intolerant to opioids

202. Other Conditions to be Considered before Anesthesia Some specific conditions increase the risk to the patient undergoing general anesthetic: Obstructive sleep apnea Seizures Existing heart, kidney or lung conditions High blood pressure Alcoholism Smoking History of reactions to anesthesia Medications that can increase bleeding - aspirin, for example Drug allergies Diabetes Obstructive sleep apnea - a condition where individuals stop breathing while asleep

203. Rationale for using adjunctive drugs before and during surgical procedures. For patients undergoing surgical and other medical procedures anesthesia provides these benefits: Sedation and reduction of anxiety Lack of awareness and amnesia Skeletal muscle relaxation Suppression of undesirable reflexes Analgesia Because no single agent can provide all those benefits, several drugs are used in combination to produce optimal anesthesia

204. Adjunctive drugs or pre-anesthetic medications Serve to calm the patient, relieve the pain and protect against undesirable effects of anesthetics or the surgical procedure Antacids (neutralize stomach acidity) H2 blockers like famotidine (Reduce gastric acidity) Anticholinergics like atropine and glycopyrrolate (Prevent bradycardia and secretion of fluids) Antiemetics like ondansetron (Prevent aspiration of stomach contents and postsurgical nausea and vomiting and) Antihistamine (Prevent allergic reactions) Benzodiazepines like diazepam (Relieve anxiety) Opioids like fentanyl (Provide analgesia) Neuromuscular blockers (Facilitate intubation and relaxation)

205. Skeletal Muscle Relaxants It facilitate intubation of the trachea and suppress muscle tone to the degree required for surgery Following neuromuscular blockers or skeletal muscle relaxant are commonly used Pancuronium Atracurium (acuron) Succinylcholine

206. Characteristics of general and local anesthetic agents

207.  Potent general anesthetics are delivered via inhalation or IV injection Inhaled general anesthetics Intravenous general anesthetics  Local anesthetics

208. Desflurane Halothane Isoflurane Sevoflurane Nitrous oxide

209. Used for maintenance of anesthesia after administration of an IV agent The depth of anesthesia can be altered rapidly by changing inhaled concentration of the drug Narrow therapeutic index ( from 2 -4 ) The difference between the dose causing no effect, surgical anesthesia and severe cardiac and respiratory depression is small No antagonists exist

210. Potency of inhaled anesthetic is defined as the minimum alveolar concentration (MAC) MAC: the concentration of anesthetic gas needed to eliminate movement among 50% of patients Expressed as the percentage of gas in a mixture required to achieve the effect The smaller MAC is the more potent the drug Nitrous oxide alone cannot produce complete anesthesia

211. The more the blood solubility, the more the anesthetic dissolves in the blood and the longer the induction and recovery time needed and slower changes in the depth of anesthesia occur as we change the concentration of inhaled drug Halothane> isoflurane> sevoflurane>nitrous oxide >desflurane

212. Cardiac output affects the removal of anesthetic to peripheral tissues (not the site of action) The higher the cardiac output, the more the anesthetic is removed, the slower the induction time

213.  Mechanism of action No specific receptor has been identified as the locus of general anesthetic action Anesthetics increase the sensitivity of GABA receptors to the neurotransmitter GABA prolonging the inhibitory chloride ion current after GABA release, reducing the postsynaptic neurons excitability Anesthetics increase the activity of the inhibitory glycine receptors in the spinal motor neuron Anesthetics block excitatory postsynaptic nicotinic currents The mechanism by which the anesthetics perform these modulatory roles is not understood

214. Potent anesthetic, weak analgesic. Administered with nitrous oxide, opioids or local anesthetics Being replaced by other agents due to its adverse effects

215.  Adverse effects Cardiac effects: Vagomimetic effects, bradycardia, can cause cardiac arrhythmias Malignant hyperthermia: Rare and life threatening condition Uncontrolled increase in skeletal muscle oxidative metabolism, which overwhelms the body’s capacity to supply oxygen, remove carbon dioxide, and regulate body temperature If untreated would cause circulatory collapse and death Treatment: Dantrolene administration Dantrolene sodium is a postsynaptic muscle relaxant that lessens excitation-contraction coupling in muscle cells. It achieves this by inhibiting Ca²⁺ ions release from sarcoplasmic reticulum stores by antagonizing ryanodine receptors.

216. Undergoes little metabolism, not toxic to the liver or kidney Does not induce cardiac arrhythmias Produces dose-dependent hypotension due to peripheral vasodilation

217. Provides very rapid onset and recovery due to its low blood solubility, the lowest of all the volatile anesthetics Popular anesthetic for outpatient surgery Irritating to the airway and can cause laryngospasm, coughing, and excessive secretions, Degradation is minimal, tissue toxicity is rare

218. Low pungency, allowing rapid induction without irritating the airway, making it suitable for inhalation induction in pediatric patients Replacing halothane for this purpose Metabolized by the liver, and compounds formed in the anesthesia circuit may be nephrotoxic

219. Non-irritating and a potent analgesic but a weak general anesthetic Nitrous oxide is frequently employed at concentrations of 30–50% in combination with oxygen for analgesia . Nitrous oxide at 80 percent (without adjunct agents) cannot produce surgical anesthesia Combined with other, more potent agents to attain pain-free anesthesia Mechanism of action is unresolved, might involve activity on GABA A and NMDA receptors Least hepatotoxic of all inhaled anesthetic sm The N-methyl-D-aspartate receptor, is a glutamate receptor and ion channel protein found in nerve cells. The NMDA receptor is one of three types of ionotropic glutamate receptors. The other receptors are the AMPA and kainate receptors.

220. Used in situations that require short duration anesthesia (outpatient surgery) Primarily used as adjuncts to inhalationals Administered first Rapidly induce unconsciousness In lower doses, they may be used to provide sedation

221. Induction After entering the blood stream, a percentage of the drug binds to the plasma proteins, and the rest remains unbound (free) The drug is carried by venous blood to the heart The majority of the CO (70%) flows to the brain, liver, and kidney Once the drug has penetrated the CNS tissue, it exerts its effects The exact mechanism of action of IV anesthetics is unknown Recovery Recovery from IV anesthetics is due to redistribution from sites in the CNS

222. Propofol Fospropofol Barbiturates Benzodiazepines Opioids Ketamine

223. I V sedative/hypnotic used in the induction or maintenance of anesthesia Widely used and has replaced thiopental as first choice for anesthesia induction and sedation, because it does not cause postanesthetic nausea and vomiting The induction of anesthesia occurs within 30–40 seconds of administration Supplementation with narcotics for analgesia is required Propofol decreases blood pressure without depressing the myocardium It also reduces intracranial pressure due to systemic vasodilation

224.  Approved only for sedation  Prodrug of propofol

225. The barbiturates are not significantly analgesic, require some type of supplementary analgesic administration during anesthesia to avoid objectionable changes in blood pressure and autonomic function Can cause apnea, coughing, chest wall spasm, laryngospasm, and bronchospasm Thiopental Potent anesthetic but a weak analgesic Ultrashort-acting barbiturate Has minor effects on the cardiovascular system, but it may contribute to severe hypotension in patients with hypovolemia or shock.

226. Used in conjunction with anesthetics to sedate the patient Midazolam Diazepam Lorazepam Facilitate amnesia while causing sedation  Enhance the inhibitory effects of various neurotransmitters, particularly GABA Minimal cardiovascular depressant effect Potential respiratory depressants  Can induce a temporary form of anterograde amnesia in which the patient retains memory of past events, but new information is not transferred into long-term memory Important treatment information should be repeated to the patient after the effects of the drug have worn off

227. Commonly used with anesthetics due to their analgesic property The choice of opioid used perioperatively is based primarily on the duration of action needed Fentanyl , remifentanil b Not good amnesics Can cause hypotension, respiratory depression, muscle rigidity and postanesthetic nausea and vomiting Opioid effects can be antagonized by naloxone

228. A short-acting nonbarbiturate anesthetic Used for short procedures Induces a dissociated state in which the patient is unconscious (but may appear to be awake) and does not feel pain This dissociative anesthesia provides sedation, amnesia, and immobility Interacts with the N-methyl-D-aspartate receptor (NDMA) Stimulates the central sympathetic outflow, which, in turn, causes stimulation of the heart with increased blood pressure and CO Beneficial in patients with hypovolemic or cardiogenic shock and in patients with asthma) Not used in hypertensive or stroke patients Causes post-operative hallucinations

229. Used to stop reflexes to facilitate tracheal intubation, and to provide muscle relaxation as needed for certain types of surgery Mechanism of action is blockade of the nicotinic acetylcholine receptors in the neuromuscular junction Include pancuronium, rocuronium, succinylcholine, and vecuronium

230. Amides (lidocaine) and esters (procaine) Cause loss of sensation and, in higher concentrations, motor activity in a limited area of the body Applied or injected to block nerve conduction of sensory impulses from the periphery to the CNS

231.  Mechanism: Local anesthesia is induced when propagation of action potentials is prevented, so that sensation cannot be transmitted from the source of stimulation to the brain Work by blocking sodium ion channels to prevent the transient increase in permeability of the nerve membrane to sodium that is required for an action potential to occur

232. Lidocaine Bupivacaine Procaine Ropivacaine Tetracaine Mepivacaine Not used in obstetric anesthesia due to its increased toxicity to the neonate

233. Local anesthetics cause vasodilation, which leads to rapid diffusion away from the site of action and results in a short duration of action Adding the vasoconstrictor epinephrine to the local anesthetic, the rate of local anesthetic diffusion and absorption is decreased This both minimizes systemic toxicity and increases the duration of action

234. They are applied directly to the skin or mucous membranes Benzocaine is the major drug in this group Lidocaine and tetracaine ca be used topically They are used to relieve or prevent pain from minor burns, irritation, itching They are also used to numb an area before an injection is given. Expected adverse effects involve skin irritation and hypersensitivity reactions

235. Comparison of general vs local anesthesia

236. General anesthesia General anesthesia is a medically induced state of unconsciousness with loss of protective reflexes, resulting from the administration of one or more general anesthetic agents. Method of administration of GA Methods of administration Inhaled anesthesia IV route

237. Essential components of GA: – – – – Cardinal Features: Loss of all sensations Sleep and Amnesia Immobility or Muscle relaxation Abolition of reflexes – somatic and autoonomic – Clinically – What an Anaesthetist wants ??? Triad of GA • • • need for unconsciousness need for analgesia need for muscle relaxation

238. Advantages of general anesthesia Reduces intra-operative patient awareness and recall. Allows proper muscle relaxation for prolonged periods of time. Facilitates complete control of the airway, breathing, and circulation. Can be used in cases of sensitivity to local anesthetic agent. Can be administered rapidly and is reversible.

239. Disadvantages of general anesthesia Requires increased complexity of care and associated costs. Requires some degree of preoperative patient preparation. Can induce physiologic fluctuations that require active intervention. Associated with malignant hyperthermia

240. Nursing role in GA Assessment: Prescription, non-prescription or any other Drug History Allergies Other risk factors – smoking, obesity, alcoholism, CVS/renal/respiratory diseases Vital signs and laboratory data Interventions: Explain preoperative and post operative recovery Postoperative requirements – early ambulation, deep breathing, coughing, leg exercises, fluid balance and urine output Monitor vital signs Response to pain medication

241. Local anesthesia Local anesthesia is the reversible loss of sensation in a defined area of the body and is achieved by the topical application or injection of agents that block the generation and/or journey of nerve impulses in tissue.

242. Methods of administration Surface anesthesia - By direct application for skin & mucous membrane Infiltration anesthesia - By S.C injection to reach fine nerve branches and sensory nerve terminals. Nerve block anesthesia - By injection close to the appropriate nerve trunks (Brachial plexus) to produce a loss of sensation peripherally. . Epidural anesthesia - The LA is injected in the epidural space, between the dura & bony spinal canal containing fat & connective tissue. - It can be performed in sacral hiatus (Caudal anesthesia) Spinal - The LA is injected in the subarachnoid space in the lumbar region

243. Advantages of Local anesthetic During local anesthesia the patient remains conscious. Patient maintains own airway. Aspiration of gastric contents unlikely. Recovery is smooth as it requires less skilled nursing care as compared to other anesthesia like general anesthesia. Postoperative analgesia. There is reduction surgical stress. Earlier discharge for outpatients. Expenses are less.

244. Disadvantages/side effects of LA Very rare allergies Bruises Temporary tingling sensation or burning in the area

245. Nursing Role in LA Assess for the mentioned cautions and contraindications (e.g. drug allergies, hepatic and renal impairment, etc.) to prevent any untoward complications. Inspect site for local anesthetic application to ensure integrity of the skin and to prevent inadvertent systemic absorption of the drug. Ensure that patients receiving spinal anesthesia or epidural anesthesia are well hydrated and remain lying down for up to 12 hours after the anesthesia to minimize headache. Provide skin care to site of administration to reduce risk of skin breakdown. Provide safety measures (e.g. adequate lighting, raised side rails, etc.) to prevent injuries.

246. References Karch , A. M., & Karch . (2011).  Focus on  nursing pharmacology . Wolters Kluwer Health/Lippincott Williams & Wilkins. [ Link ] Katzung , B. G. (2017).  Basic and clinical pharmacology . McGraw-Hill Education. Lehne , R. A., Moore, L. A., Crosby, L. J., & Hamilton, D. B. (2004). Pharmacology for nursing care. Smeltzer , S. C., & Bare, B. G. (1992).  Brunner & Suddarth’s textbook of medical-surgical nursing . Philadelphia: JB Lippincott.

247. Unit-II-B Anti-Convulsants or Anti-Epileptic or Anti-seizures Drugs By: Muhammad Aurangzeb Lecturer-INS/KMU

248. Objectives By the completion of this section the learners will be able to: Discuss the pharmacokinetics, side effects and adverse reactions, therapeutic plasma phenytoin level Identify the contraindications and drug interactions. Explain the nursing interventions, including client teaching related to the use of anticonvulsants. Calculate the drug dosage accurately for oral and parental anticonvulsants drug.

249. Anticonvulsants Drugs (ACDs) Anticonvulsants or Antiseizure agents  (also known as  antiepileptic drugs ) are drugs used to manage seizures, the most prevalent neurological disorder. 

250. Basic definitions Seizure: the clinical manifestation of an abnormal and excessive excitation and synchronization of a population of cortical neurons Epilepsy  is a collection of different syndromes, all of which is characterized by sudden discharge of excessive electrical energy from nerve cells located within the brain. Status epilepticus  is a state in which seizures rapidly recur with no recovery between seizures. It is potentially the most dangerous of seizures.  

251. Cellular Mechanisms of Seizure Generation Results from an imbalance between Excitation and inhibition of Neurons in the part of the brain Excitation (too much) Ionic—inward Na+, Ca++ currents Neurotransmitter—glutamate, aspartate Inhibition (too little) Ionic—inward CI-, outward K+ currents Neurotransmitter—GABA

252. Classification of Seizures International Classification of Seizures  categorized seizures based on symptoms and characteristics. The two main categories include: Generalized Seizures These seizures are characterized by a massive electrical activity that begins in one area of the brain and rapidly spread to both hemispheres. It is usually accompanied by loss of consciousness. It is further classified into five types:

253. Generalized Seizures Cont.… Absence seizure It is an abrupt and brief (3-5 s) period of loss of consciousness common in children (starting at age 3) but frequently disappears by puberty. This seizure does not usually involve muscle contractions. Myoclonic seizure It is characterized by short, sporadic periods of muscle contractions that last for several minutes. It is relatively rare.   Atonic seizures: Sudden loss of postural tone ; most often in children but may be seen in adults

254. Tonic-clonic seizure It involves involuntary muscle contraction (tonic) followed by relaxation appearing as an aggressive spasm (clonic), loss of consciousness, and confusion and exhaustion in the early recovery period.   Generalized Seizures Cont.…

255. Partial (Focal) Seizures Originate from one area of the brain, do not spread to other parts. It can be further classified into three: Simple Partial Seizure Occurs in a single area of brain and may involve a single muscle movement or sensory alteration.   Complex Partial Seizure Occurs by late teenage years and involves a series of reactions or emotional changes and complex sensory changes (hallucinations, mental distortion, personality changes, loss of consciousness, and loss of social inhibition). Motor changes may include involuntary urination, chewing motions, and diarrhea.

256. Partial (Focal) Seizures Secondarily Generalized Seizures Begins focally, with or without focal neurological symptoms Variable symmetry, intensity, and duration of tonic (stiffening) and clonic (jerking) phases Typical duration up to 1-2 minutes Postictal confusion, somnolence, with or without transient focal deficit

257. Anticonvulsants Drugs Drugs which decreases the frequency and/or severity of seizures Goal—maximize quality of life by minimizing seizures and adverse drug effects

258. Classification of A C Ds Classical Phenytoin Phenobarbital Primidone Carbamazepine Ethosuximide Valproate (valproic acid) Newer Lamotrigine Felbamate Topiramate Gabapentin Tiagabine Vigabatrin Oxycarbazepine Levetiracetam Fosphenytoin In general , the newer ACDs have less CNS s e dating effects than the classical ACDs

259. Mechanism Of Action Of Anticonvulsants Drugs Three main mechanisms: Enhancement of GABA action Inhibition of sodium channel function Inhibition of calcium channel function. Other mechanisms include: Inhibition of glutamate release and Block of glutamate receptors.

260. Targets for Anticonvulsants Drugs Increase inhibitory neurotransmitter system— GABA Decrease excitatory neurotransmitter system— glutamate Block voltage-gated inward positive currents— Na+ or Ca++ Increase outward positive current—K+ Many AEDs pleiotropic—act via multiple mechanisms

261. Excitatory Neurotransmitter-Glutamate and its receptors The brain’s major excitatory neurotransmitter There are three types of Glutamate receptors i.e. NMDA receptors,  AMPA receptors , and kainate receptors The  NMDA receptor  when activated by glutamate and glycine (or D-serine) allows positively charged ions to flow through the cell membrane. The  AMPA receptor  ( AMPA -R) is coupled to ion channels that modulate cell excitability by gating the flow of calcium and sodium ions into the cell In addition to NMDA and AMPA receptors, kainate (KA) receptors have been found to play roles in synaptic transmission Glutamate is a powerful excitatory neurotransmitter that is released by nerve cells in the brain.

262. Glutamate Receptors as ACDs Targets NMDA receptor sites as targets Ketamine, phencyclidine, dizocilpine block channel and have anticonvulsant properties but also dissociative and/or hallucinogenic properties; open channel blockers. Felbamate antagonizes strychnine-insensitive glycine site on NMDA complex AMPA receptor sites as targets Topiramate antagonizes AMPA site

263. Inhibitory neurotransmitter-GABA Major inhibitory neurotransmitter in the CNS Two types of receptors GABAA—post-synaptic, specific recognition sites, linked to CI- channel GABAB —presynaptic autoreceptors, mediated by K+ currents

264. GABA A Receptor

265. ACDs That Act Primarily on GABA Benzodiazepines ( diazapam , clonazapam ) Increase frequency of GABA-mediated chloride channel openings Barbiturates (phenobarbital, primidone) Prolong GABA-mediated chloride channel openings Some blockade of voltage-dependent sodium channels

266. AEDs That Act Primarily on GABA Gabapentin May modulate amino acid transport into brain May interfere with GABA re-uptake Tiagabine Interferes with GABA re-uptake Vigabatrin (not currently available in US) Elevates GABA levels by irreversibly inhibiting its main catabolic enzyme, GABA- transaminase

267. Na+ Channels as ACD Targets Neurons fire at high frequencies during seizures Action potential generation is dependent on Na+ channels Na+ channel blockers reduce high frequency firing without affecting physiological firing

268. AEDs That Act Primarily on Na+ Channels Phenytoin, Carbamazepine Block voltage-dependent sodium channels at high firing frequencies—use dependent Oxcarbazepine Blocks voltage-dependent sodium channels at high firing frequencies Also effects K+ channels Zonisamide Blocks voltage-dependent sodium channels and T-type calcium channels

269. Ca 2+ Channels as Targets Absence seizures are caused by oscillations between thalamus and cortex that are generated in thalamus by T-type (transient) Ca 2+ currents Ethosuximide is a specific blocker of T-type currents and is highly effective in treating absence seizures

270. What about K+ channels? K+ channels have important inhibitory control over neuronal firing in CNS—repolarize membrane to end action potentials K+ channel agonists would decrease hyperexcitability in brain So far, the only ACD with known actions on K+ channels is valproate (Epival) Retiagabine is a novel ACD in clinical trials that acts on a specific type of voltage-dependent K+ channel

271. Pleiotropic ACDs Felbamate Blocks voltage-dependent sodium channels at high firing frequencies May control NMDA receptor Lamotrigine Blocks voltage-dependent sodium channels at high firing frequencies May interfere with pathologic glutamate release Inhibit Ca++ channels ?

272. Pleiotropic AEDs Topiramate Blocks voltage-dependent sodium channels at high firing frequencies Increases frequency at which GABA opens Cl - channels (different site than benzodiazepines) Antagonizes glutamate action at AMPA/ kainate receptor subtype? Valproate May enhance GABA transmission in specific circuits Blocks voltage-dependent sodium channels May also augment K+ channels T-type Ca2+ currents

273. Classic AEDs

274. Phenytoin First line drug for partial seizures MOA: Inhibits Na+ channels—use dependent Prodrug fosphenytoin for IM or IV administration. Highly bound to plasma proteins. The t1/2 - 12-24 hours progressively ↑es upto 60 hr when plasma concentration rises above 10 ug/ml as metabolizing enzymes get saturated. Therapeutic plasma level is between 10 and 20 µg/ mL. Some adverse effects of phenytoin are related to specific serum levels. Nystagmus is frequently observed at levels greater than 20 µg/ mL .

275. Indications of phenytoin Generalized tonic-clonic, simple and complex partial seizures. It is ineffective in absence seizures. Dose: 100 mg BD, maximum 400 mg/day; Children 5-8 mg/kg/day, Status epilepticus: occasionally used by slow i.v. injection. Trigeminal neuralgia - second choice drug to carbamazepine.

276. Adverse effects of Phenytoin Adverse effects: CNS sedation (drowsiness, ataxia, confusion, insomnia, nystagmus, etc.), gum hyperplasia , hirsutism Interactions: carbamazepine, phenobarbital will decrease plasma levels; alcohol, diazepam, methylphenidate will increase. Valproate can displace from plasma proteins. Stimulates cytochrome P-450, so can increase metabolism of some drugs.

277. Carbamazepine First line drug for partial seizures MOA: Inhibits Na+ channels—use dependent Half-life: 6-12 hours Adverse effects: CNS sedation. Agranulocytosis and aplastic anemia in elderly patients, rare but very serious adverse. A mild, transient leukopenia (decrease in white cell count) occurs in about 10% of patients, but usually disappears in first 4 months of treatment. Can exacerbate some generalized seizures. Drug interactions: Stimulates the metabolism of other drugs by inducing microsomal enzymes, stimulates its own metabolism. This may require an increase in dose of this and other drugs patient is taking.

278. Phenobarbital Partial seizures, effective in neonates Second-line drug in adults due to more severe CNS sedation Allosteric modulator of GABAA receptor (increase open time) Absorption: rapid Half-life: 53-118 hours (long) Adverse effects: CNS sedation but may produce excitement in some patients. Skin rashes if allergic. Tolerance and physical dependence possible. Interactions: severe CNS depression when combined with alcohol or benzodiazapines . Stimulates cytochrome P-450 •

279. Primidone Partial seizures Mechanism—see phenobarbital Absorption: Individual variability in rates. Not highly bound to plasma proteins. Metabolism: Converted to phenobarbital and phenylethyl malonamide , 40% excreted unchanged. Half-life: variable, 5-15 hours. PB ~100, PEMA 16 hours Adverse effects: CNS sedative Drug interactions: enhances CNS depressants, drug metabolism, phenytoin increases conversion to PB

280. Benzodiazepines (Diazepam and clonazepam) Status epilepticus (IV) Allosteric modulator of GABAA receptors—increases frequency Absorption: Rapid onset. Diazepam—rectal formulation for treatment of SE Half-life: 20-40 hours (long) Adverse effects: CNS sedative, tolerance, dependence. Paradoxical hyperexcitability in children Drug interactions: can enhance the action of other CNS depressants

281. Valproate (Valproic Acid) Partial seizures, first-line drug for generalized seizures. Enhances GABA transmission, blocks Na+ channels, activates K+ channels Absorption: 90% bound to plasma proteins Half-life: 6-16 hours Adverse effects: CNS depressant (esp. w/ phenobarbital), anorexia, nausea, vomiting, hair loss, weight gain, elevation of liver enzymes. Hepatoxicity is rare but severe, greatest risk <2 YO. May cause birth defects. Drug interactions: May potentiate CNS depressants, displaces phenytoin from plasma proteins, inhibits metabolism of phenobarbital, phenytoin, carbamazepine (P450 inhibitor).

282. Ethosuximide Absence seizures Blocks T-type Ca++ currents in thalamus Half-life: long—40 hours Adverse effects : gastric distress—pain , nausea, vomiting. Less CNS effects that other AEDs, transient fatigue, dizziness, headache Drug interactions: administration with valproate results in inhibition of its metabolism

283. Newer Drugs

284. Oxcarbazepine Approved for add-on therapy, monotherapy in partial seizures that are refractory to other AEDs Activity-dependent blockade of Na+ channels, may also augment K+ channels Half-life: 1-2 hours, but converted to 10- hydroxycarbazepine 8-12 hours Adverse effects: similar to carbamazepine (CNS sedative) but may be less toxic. Drug interactions: less induction of liver enzymes, but can stimulate CYP3A and inhibit CYP2C19

285. Gabapentin Add-on therapy for partial seizures, evidence that it is also effective as monotherapy in newly diagnosed epilepsies (partial) MOA: May interfere with GABA uptake Absorption: Non-linear. Saturable (amino acid transport system), no protein binding. Metabolism: none, eliminated by renal excretion Half-life: 5-9 hours, administered 2-3 times daily Adverse effects: less CNS sedative effects than classic AEDs Drug interactions: none known

286. Lamotrigine Add-on therapy, monotherapy for refractory partial seizures. Also effective in Lennox Gastaut Syndrome and newly diagnosed epilepsy. Effective against generalized seizures. Use-dependent inhibition of Na+ channels, glutamate release, may inhibit Ca++ channels Half-life—24 hours Adverse effects: less CNS sedative effects than classic AEDs, dermatitis potentially life-threatening in 1-2% of pediatric patients. Drug interactions: levels increased by valproate, decreased by carbamazepine, PB, phenytoin

287. Felbamate Third-line drug for refractory partial seizures Frequency-dependent inhibition of Na+ channels, modulation of NMDA receptor Adverse effects: aplastic anemia and severe hepatitis restricts its use (black box) Drug interactions: increases plasma phenytoin and valproate, decreases carbamazapine . Stimulates CYP3A and inhibits CYP2C19

288. Levetiracetam Add-on therapy for partial seizures Binds to synaptic vesicle protein SV2A, may regulate neurotransmitter release Half-life: 6-8 hours (short) Adverse effects: CNS depresssion Drug interactions: minimal

289. Tiagabine Add-on therapy for partial seizures Interferes with GABA reuptake by depressing GABA transporter GAT-1 which removes synaptically released GABA Half-life: 5-8 hours (short) Adverse effects: CNS sedative Drug interactions: minimal Uses – add on therapy of partial seizures with or without secondary generalization.

290. Zonisamide Add-on therapy for partial and generalized seizures Blocks Na+ channels and T-type Ca++ channels Half-life: 1-3 days (long) Adverse effects: CNS sedative Drug interactions: minimal

291. Topimerate Add-on for refractory partial or generalized seizures. Effective as monotherapy for partial or generalized seizures, Lennox- Gastaut syndrome. Use-dependent blockade of Na+ channels, increases frequency of GABAA channel openings, may interfere with glutamate binding to AMPA/KA receptor Half-life: 20-30 hours (long) Adverse effects: CNS sedative Drug interactions: Stimulates CYP3A and inhibits CYP2C19, can lessen effectiveness of birth control pills

292. Vigabatrin Add-on therapy for partial seizures, monotherapy for infantile spasms. (Not available in US). Blocks GABA metabolism through actions on GABA- transaminase Half-life: 6-8 hours, but pharmacodynamic activity is prolonged and not well-coordinated with plasma half-life. Adverse effects: CNS sedative, ophthalmologic abnormalities Drug interactions: minimal

293. Treatment of Epilepsy First consideration is efficacy in stopping seizures Because many AEDs have overlapping, pleiotropic actions, the most appropriate drug can often be chosen to reduce side effects. Newer drugs tend to have less CNS depressant effects. Potential of long-term side effects, pharmokinetics, and cost are other considerations

294. Partial Onset Seizures With secondary generalization First-line drugs are carbamazepine and phenytoin (equally effective) Valproate, phenobarbital, and primidone are also usually effective Without generalization Phenytoin and carbamazepine may be slightly more effective Phenytoin and carbamazepine can be used together (but both are enzyme inducers)

295. Partial Onset Seizures—New Drugs Adjunctive (add-on) therapy where monotherapy does not completely stop seizures—newer drugs felbamate , gabapentin, lamotrigine , levetiracetam , oxcarbazepine , tiagabine , topiramate , and zonisamide Lamotrigine, oxcarbazepine , felbamate approved for monotherapy where phenytoin and carbamazepine have failed.

296. Generalized Onset Seizures Tonic-clonic, myoclonic, and absence seizures— first line drug is usually valproate Phenytoin and carbamazepine are effective on tonic-clonic seizures but not other types of generalized seizures Valproate and ethoxysuximide are equally effective in children with absence seizures, but only valproate protects against the tonic-clonic seizures that sometimes develop. Rare risk of hepatoxicity with valproate—should not be used in children under 2.

297. Generalized Onset Seizures Clonazepam, phenobarbital, or primidone can be useful against generalized seizures, but may have greater sedative effects than other AEDs Tolerance develops to clonazepam, so that it may lose its effectiveness after ~6 months Lamotrigine, topiramate , and zonisamide are effective against tonic-clonic, absence, and tonic seizures

298. Status Epilepticus More than 30 minutes of continuous seizure activity Two or more sequential seizures spanning this period without full recovery between seizures Medical emergency

299. Status Epilepticus Treatment Diazepam, lorazapam IV (fast, short acting) Followed by phenytoin, fosphenytoin, or phenobarbital (longer acting) when control is established

300. Nursing role in ACDs Assess for mentioned contraindications and cautions (e.g. drug allergy, diabetes, hepatorenal dysfunction, arrhythmias, hypotension, etc.) to prevent untoward complications. Discontinue the drug at any sign of hypersensitivity reaction Provide safety measures (e.g. adequate lighting, raised side rails, etc.) to prevent injuries. Educate client on drug therapy to promote understanding and compliance. Monitor patient response to therapy (decrease in incidence or absence of seizures). Monitor for adverse effects

301. References Lippincott's illustrated pharmacology 6th edition page 157-168 Essentials of Medical Pharmacology 7th edition by KD tripathi Karch , A. M., & Karch . (2011). Focus on  nursing pharmacology . Wolters Kluwer Health/Lippincott Williams & Wilkins. [ Link ] Katzung , B. G. (2017). Basic and clinical pharmacology. McGraw-Hill Education. Lehne , R. A., Moore, L. A., Crosby, L. J., & Hamilton, D. B. (2004). Pharmacology for nursing care. Smeltzer , S. C., & Bare, B. G. (1992). Brunner & Suddarth’s textbook of medical-surgical nursing. Philadelphia: JB Lippincott.

302. Unit-II C: Anti-Parkinson’s Drugs By: Muhammad Aurangzeb Lecturer-INS/KMU

303. Objectives By the completion of this section the learners will be able to: Describe the action of anticholinergic drugs and dopaminergic drugs in treatment of Parkinsonism. Differentiate between the types of commonly used anti-Parkinson’s drugs. Describe the side effects of anti-Parkinson drugs. Discuss the nursing interventions including clients teaching of drugs used in the treatment of Parkinson’s disease Calculate the drug dosage accurately for oral and parental anti Parkinson’s drugs

304. Parkinsonism Parkinsonism is a progressive neurological disorder of muscle movement, characterized by tremors, muscular rigidity, bradykinesia (slowness in initiating and carrying out voluntary movements), and postural and gait abnormalities.

305. Parkinson Disease It is a Extrapyramidal motor disorder occurs due to degeneration of dopaminergic neurons in the substantia nigra pars compacta (SN-PC) result in dopamine deficiency It occur in 2% elderly population Classically disease of 7th decade of life An imbalance between dopaminergic(inhibitory neuron) and excitatory cholinergic neuron Cholinergic over activity

306. Pathogenesis Degeneration of dopamine-producing neurons in the substantia nigra of the midbrain Disrupts the balance of: Dopamine (DA) – neurotransmitter for normal functioning of the extrapyramidal motor system (control of posture, support, and voluntary motion) Acetylcholine (Ach) in the basal ganglia Symptoms do not occur until 80% of the neurons in the substantia nigra are lost.

307. Normal Parkinsonism Treatment In the basal ganglia, the dopaminergic activity is balanced by the cholinergic syst e m Parkinsonism results due to depletion of dopamine in relation to cholinergic activity Also antidopaminergic drugs e.g. Phenothiazines, Haloperidol, methyldopa etc. cause Parkinsonism Pathophysiology & Treatment Pharma c olog i cal strategy:- Restore normal dopamine Ach activity at muscarinic receptor in the striatum .

308. Treatment Objectives of antiparkinsonian pharmacotherapy The dopaminergic/cholinergic balance may be restored by two mechanisms-

309. 1. Enhancement of DA-ergic activity by drugs which may: replenish neuronal DA by supplying levodopa, which is its natural precursor; administration of DA itself is ineffective as it does not cross the BBB; act as DA agonists (bromocriptine, pergolide, etc.); prolong the action of DA through selective inhibition of its metabolism (selegiline); release DA from stores and inhibit reuptake (amantadine).

310. 2. Reduction of cholinergic activity by antimuscarinic drugs this approach is most effective against tremor and rigidity, and less effective in the treatment of bradykinesia.

311. CLASSIFICATION

312. Antiparkinsonian Drugs Dopaminergic Drugs Anticholinergic Drugs Dopamine P r ecursor Levodopa Dopamine Agonists Ergot Bromocriptine Pergoli de Lesuride (D 1 &D 2 agonist) Non-ergot Piribedil Ropinirole Premipexole Peripheral Decarboxylase Inhibitors Carbidopa Benserazide MAO-B Inhibitor Selegiline (Deprenyl) COMT Inhibitor E n tac apo n e Tolcapone Dopamine Facilitator Amantadine Anticholine r g i cs T rihexyphenid y l (Benzhexol) Procyclidine Biperiden

313. Levodopa(l-dopa) Metabolic precursor of dopamine Inactive by itself 95% of an oral dose is decarboxylated in the peripheral tissues (mainly gut and liver) and converted into DA Only about 1-2% of administered levodopa crosses to the brain Always used in combination with carbidopa/benserazide (Peripheral decarboxylase inhibitor )

314. l e vodopa Dopamine LD L D DA DA L D DA Carbidopa Carbidopa inhibit the peripheral decarboxylation of Levodopa hence more Levodopa reaches brain So advantages of the combination are: Less dose of Levodopa required and more effect of Levodopa Increased half-life of Levodopa Less side effects of Levodopa, peripherally VitB 6 interaction does not occur Levodopa is usually combined with Carbidopa

315. Pharmacokinetics Absorption:- Absorbed orally by active transport by the presence of food (especially amino acids) Administered on empty stomach Bioavailability affected by: Amino acids present in food compete for the same carrier for absorption (# should be given 30-60 min before meal) Distribution: L-dopa crosses BBB (CNS disturbance ) The plasma t 1/2 of levodopa is 1 - 2 hours

316. Metabolism Peripheral dopamine is metabolized in the liver to dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), which are then excreted in urine. Levodopa undergoes high first pass metabolism in G.I. mucosa and liver Excretion:- Urine

317. Pharmacodynam i cs On CNS: - Marked symptomatic improvement occurs in Parkinsonian patients Effect on behavior: ‘General alerting response’ On CVS:- (+inotropic action )-The peripherally formed DA can cause tachycardia acting on β adrenergic receptors DA and NA formed in brain central sympathetic flow- Postural hypotension

318. On CTZ:- m Dopaminergic receptors are present in this area and DA acts as an excitatory transmitter Peripherally formed DA gains access to the CTZ elicits nausea and vomiting Endocrine action:- DA acts on pituitary mammotropes to inhibit prolactin release  In Parkinson's Disease:- Levodopa can reduce all sign and symptoms of PD. It doesn’t stop the progression of disease USES

319. Adverse effects At the initiation of therapy: a) CNS manifestations: Euphoria, anxiety, agitation, insomnia, psychological disturbances as confusion, delusions, hallucinations, Dyskinesia (abnormal involuntary movements which is corrected by dose reduction) b) GIT manifestations:- Anorexia, nausea, and vomiting due to stimulation of D2-receptors in CTZ Tolerance may develop to this adverse effect, but if nausea and vomiting persist, antiemetics are given; e.g. domperidone (D2 antagonist which does not pass BBB) Constipation and bleeding peptic ulcer may occur.

320. Adverse effects cont.. c) CVS manifestations: Postural hypotension- central sympathetic flow Tachycardia (direct β1 stimulation) Hypertension occurs with large doses or with non-selective MAO inhibitors ( α1 stimulation). Others:- Alteration of smell, taste sensation Abnormal movements-facial tics

321. After prolong therapy:- On- off phenomenon:- After prolong therapy(3-5 year) Duration of beneficial effect shortens as therapy progress Disease control become poor Fluctuation in symptoms occur frequently - This may be due to the interaction of DOPAC with H2O2 leading to formation of toxic oxygen free radicals which destroy dopamine storage vesicles (this can be prevented by adding selective MAO-B inhibitors as seligeline)

322. On-off phenomenon:- May be due to variable levels of dopamine in CNS In on state :- Patient enjoys normal mobility In off state :- loss of beneficial effect of drugs E.g.-patient unable to raise from chair on which he had sat few min ago. Fluctuation in plasma level because of short half life Treatment:- Sustained released formulation of (L-dopa+carbidopa) COMT-inhibitors Frequent administration of levodopa

323. Non selective MAO-inhibitor-(hypertensive Vit-B6 -(  metabolism, therapeutic failure) Reserpine, phenothiazine-(block dopamine Tricyclic antidepressant- ( absorption of L e v o d o pa crisis) Levodopa L e v o d o pa effect ) Levodopa levodopa ) Contraindication:- Psychoses Narrow angle glaucoma Melanoma Interaction

324. Carbidopa Carbidopa is an inhibitor of dopa decarboxylase. Because it is unable to penetrate the blood-brain barrier, it acts to reduce the peripheral conversion of levodopa to dopamine. As a result, when carbidopa and levodopa are given concomitantly: It can decrease the dosage of levodopa. It can reduce toxic side effects of levodopa.

325. Dopamine Agonist An alternative to Levodopa These will act on striatal dopamine receptors even in advanced patients . Do not require enzymatic conversion Bromocriptine Ergot derivative Don’t require enzymatic conversion to active metabolites Longer duration of action than l-dopa Prevent motor complication Mechanism:- partial D1-Agonist Strong D2-Agonist

326. USES:- Parkinsonism- can be used alone, use as- adjuent to levodopa Serves improve control-’wearing of dose’ & ‘on off fluctuation ’ 2. Use in suppression of lactation (safer than estrogen) 3.Acromegaly and ACTH-dependent tumors Adverse effect:- hallucination,confusion,vomiting Contraindication:- Peptic ulcer,MI,mental illness

327. Ergot derivative Mechanism:- agonist at D1,D2 receptor Pharmacokinetics:- Absorption -rapidly orally Metabolism :- liver by CYP-450 system 50% BA(undergo-first pass metabolism) Excretion:- urine USES:- Idiopathic PD treatment AE:- Dyspepsia,constipation,hallucination I n teractio n : - per g o l i d e CYP1A2 inhibitor(Ciprofloxacin,Diltiazem)

328. Ropinirole Mechanism of action: Selectivity at D2 receptor and less or no activity at D1 class site. Pharmacokinetics: Rapidly absorbed ,max plasma concentration is generally reached in 1-2 hours after oral absorption Bioavailability is 50% because of first pass metabolism. Metabolized by the liver by cytochrome P450 to inactive metabolites. Less than 10%excreted unchanged in urine.

329. Therapeutic uses: For treatment of idiopathic PD for early and advanced PD alone Adverse effects: dyspepsia, constipation and hallucinations.

330. It Non-ergot derivative dopamine agonist. It binds to presynaptic& postsynaptic dopamine D2 &D3receptors, but has the highest affinity for the D3 receptor subtype. Mechanism of action :- It stimulates presynaptic and post synaptic dopamine D2 receptors. Therapeutic uses:- Used as monotherapy in early PD. As an adjunct to levodopa in patients with advanced PD. Pramipexole

331. Adverse effects:- In early PD nausea, dizziness,constipation, and hallucinations. In patients with advanced disease, the most common adverse effect is orthostatic hypotension. Drug interaction:- cimetidine, ranitidine, diltiazem, verapamil, quinidine,triamterene decrease the oral clearance of pramipexole by 20%.

332. MAO-B inhibitors Two different types of isoenzymes of MAO are found (MAO –A and MAO-B). MAO-B is responsible for most of the oxidative metabolism of dopamine in the brain. Selegiline Selective irreversible inhibitors of MAO-B Advantage:- Prolonging T1/2 of Endogenously produce dopamine Anti-parkinsonism effect of dopamine ‘ On-off’,’wearing off’ phenomena

333. Mechanism of action:- Selegiline retard the breakdown of dopamine in the CNS. Blockade of presynaptic dopamine receptors. Inhibition of dopamine reuptake from the synapse. Pharmacokinetics:- Extensively metabolized in the liver. metabolites Desmethyl-selegiline Methamphetamine Adverse effects:- postural hypotension, confusion, psychosis amphetamine

334. Interaction:- Seligiline Seligiline Seli g ili n e Tricyclic antidepressant Pethidine(excitement,rigidity) SSRI  Contraindication:- Contraindicated in patients with convulsive disorder. Newer selective MAO-B inhibitor. Advantage:- 5 time more potent than seligiline Longer acting Not metabolized to amphetamine Doesn’t produce excitatory side effects Rasagiline

335. Reversible COMT-inhibitors Only periphery action Mechanism of action:- Entacapone is a selective and reversible inhibitor of COMT . Adverse effects :- Dyskinesia, nausea, diarrhoea, abdominal pain, and urinary discoloration. It increases the side effects of levodopa. Entacapone

336. selective and reversible inhibitor of COMT Both action- Peripheral + Central action SE:- occasionally associated with hepatotoxicity

337. Amantadine:- Introduced as an antiviral agent Effective against influenza A2 virus. Mechanism of action: It acts presynaptically and postsynaptically. Presynaptically:- release of stored catecholamine from intact dopaminergic terminals Inhibits catecholamine reuptake process at the presynaptic terminal . Dopamine facilitator

338. Postsynaptically:- Activation of DA receptors directly. Anticholinergic action. NMDA receptor blocking effect. USES:- Only in milder cases as monotherapy. Supplement to levodopa for advanced cases. It serves to suppress motor fluctuations and abnormal movements. Side effect:- Insomnia, dizziness, confusion, nightmares

339. Central anti-cholinergic drugs Biperiden, Trihexyphenidyl, Triperiden They are synthetic compounds (central parasympatholytics). They benefit parkinsonism by blocking ACh receptors in the CNS, thereby partially redressing the imbalance created by decreased DA-ergic activity. They also produce modest improvement in tremor, rigidity, sialorrhoea (hypersalivation), muscular stiffness and leg cramp, but little in bradykinesia, which is the most disabling symptom of Parkinson’s disease.

340. Adverse effects of anti-cholinergic drugs Dry mouth (xerostomia), Constipation, Drowsiness urine retention, glaucoma,

341. Nursing care in Anti-Parkinson Drugs Administer drug with caution for patients exposed in hot weather or environments because patients are at increased risk for heat prostration due to decreased ability to sweat. Give drug with meals to alleviate GI irritation if present. Monitor bowel function and institute bowel program if constipation is severe. Have patient void before taking the drugs to decrease risk of urinary retention.

342. Cont… Provide safety measures (e.g. adequate lighting, raised side rails, etc.) to prevent injuries. Educate client on drug therapy to promote understanding and compliance. Monitor patient response to therapy (improvement in signs and symptoms of Parkinson’s disease). Monitor for adverse effects (e.g.CNS changes, urinary retention, GI depression, decreased sweating, etc).

343. References Karch, A. M., & Karch. (2011).  Focus on nursing pharmacology . Wolters Kluwer Health/Lippincott Williams & Wilkins. Katzung, B. G. (2017).  Basic and clinical pharmacology . McGraw-Hill Education. Lehne, R. A., Moore, L. A., Crosby, L. J., & Hamilton, D. B. (2004). Pharmacology for nursing care. Smeltzer, S. C., & Bare, B. G. (1992).  Brunner & Suddarth’s textbook of medical-surgical nursing . Philadelphia: JB Lippincott.

344. Antiepileptic Drugs- D

345. ‘EPILEPSY’ , is a group of neurological disease characterized by reccurent seizures. ‘SEIZURES’ Are episodes of abnormal electri-cal activity in the cortical neurons that cause involuntary movements, sensations, or thoughts

346. CLASSIFICATION OF SEIZURES WITH CLINICAL MANIFESTATIONS SEIZURE TYPE CLINICAL MANIFESTATION A. PARTIAL (FOCAL) SEIZURES I. SIMPLE PARTIAL SEIZURES NO IMPAIRMENT OF CONSCIOUSNESS; FOCAL MOTOR, SENSORY, AUTONOMIC OR PSYCHIC DISTURBANCES II. COMPLEX PARTIAL SEIZURES IMPAIRED CONSCIOUSNESS; DREAMY WITH OR WITHOUT AUTOMATISMS (REPETITIVE BEHAVIORS) III. PARTIAL SEIZURES, SECONDARILY GENERALIZED

347. SEIZURE TYPE CLINICAL MANIFESTATION B. GENERALIZED SEIZURES I. TONIC-CLONIC SEIZURES LOSS OF CONSCIOUSNESS, FALLING ; RIGID (GRAND MAL EPILEPSY) EXTENSION OF TRUNK & LIMBS (TONIC PHASE); RHYTHMIC CONTRACTION OF ARMS AND LEGS (CLONIC PHASE) II. ABSENCE SEIZURES IMPAIRED CONSCIOUSNESS WITH STARING (PETIT MAL EPILEPSY) SPELLS, WITH OR WITHOUT EYE BLINKS III. OTHERS, INCLUDING VARIABLE DEPENDING ON SEIZURE TYPE MYOCLONIC, ATONIC (ATYPICAL), CLONIC, TONIC C. UNCLASSIFIED EPILEPTIC INCLUDES ALL OTHER SEIZURES SEIZURES

348. Possible causes include: traumatic brain injury scarring on the brain after a brain injury (post-traumatic epilepsy)  serious illness or very high fever stroke, which is a leading cause of epilepsy in people over age 35 lack of oxygen to the brain brain tumor or cyst dementia or Alzheimer’s disease

349. MECHANISM OF ACTION OF ANTIEPILEPTIC DRUGS Antiepileptics inhibit the neuronal discharge or its spread in one or more of the following ways.

350. CLINICAL CLASSIFICATION OF ANTISEIZURE DRUGS DRUGS FOR PARTIAL EPILEPSY PHENYTOIN CARBAMEZAPINE BARBITURATES LAMOTRIGINE LEVETIRACETAM TOPIRAMATE GABAPENTINE VALPROATE

351. B. DRUGS FOR GENERALIZED EPILEPSY i. TONIC-CLONIC (GRAND MAL) PHENYTOIN CARBAMEZAPINE BARBITURATES LAMOTRIGINE LEVETIRACETAM TOPIRAMATE GABAPENTINE VALPROATE

352. ii. ABSENCE SEIZURES (PETIT MAL) ETHOSUXIMIDE Sodium VALPROATE CLONAZEPAM/DIAZEPAM LAMOTRIGINE iii. MYOCLONIC SEIZURES Sodium VALPROATE CLONAZEPAM/ DIAZEPAM/ NITRAZEPAM LEVETIRACETAM LAMOTRIGINE TOPIRAMATE

353. Other type seizure iv. STATUS EPILEPTICUS DIAZEPAM/ LORAZEPAM PHENYTOIN/ FOSPHENYTOIN PHENOBARBITONE GA vi. FEBRILE SEIZURES IN CHILDREN DIAZEPAM

354. Hydantoin (Phenytoin,Fosphenytoin) Phenytoin IT IS THE OLDEST NONSEDATIVE ANTISEIZURE DRUG MECHANISM OF ACTION IT BLOCKS VOLTAGE-SENSITIVE SODIUM CHANNELS BY PROLONGING THE INACTIVATION STATE OF THESE CHANNELS THUS INHIBITS THE REPETITIVE FIRING OF NEURONS IN A SEIZURE FOCUS

355. SODIUM CHANNEL BLOCKERS

356. PHARMACOKINETICS VARIABLE INTESTINAL ABSORPTION EXTREMELY INSOLUBLE SO CRYTALLIZES OUT IN I/M INJECTION SITES; IRRITANT TO VEINS AND TISSUES 90 % BOUND TO PLASMA ALBUMIN IT IS HYDROXYLATED TO AN INACTIVE FORM BY CYP450 ENZYMES IN THE LIVER SERUM LEVELS SHOULD BE MONITORED AT THE START OF THERAPY AND WHENEVER TOXICITY OR THERAPEUTIC FAILURE OCCURS

357. CLINICAL USES TONIC-CLONIC SEIZURE (GS) PARTIAL SEIZURES STATUS EPILEPTICUS – SLOW I/V INFUSION IN NORMAL SALINE 4. OTHER USES CARDIAC DYSRHYTHMIAS TRIGEMINAL NEURALGIA (RESISTANT PAIN)

358. Osteomalacia: softening of the bones, typically through a deficiency of vitamin D or calcium. Nystagmus  is a vision condition in which the eyes make repetitive, uncontrolled movements..

359. EFFECTS ON FETUS (FETAL HYDANTOIN SYNDROME) INCRESED PERINATAL MORTALITY CLEFT PALATE , HARE LIP, MICROCEPHALY, CONGENITAL HEART DISEASE DRUG INTERACTIONS WARFARINN ORAL CONTRACEPTIVES PHENYTOIN THEOPHYLLINES (ENZYME VITAMIN D (OSTEOMALACIA AFTER INDUCER) PROLONGED USE) Note= Fosphenytoin is a prodrugwhich is converted to phenytoin after metabolism.Given im or iv .Used in status epilepticus Less cardiotoxic as compared to phenytoin

360. Mechanism of action The sedative-hypnotic action of the barbiturates is due to their interaction with GABA receptors , and prolonging the duration of the chloride channel openings PHARMACOKINETICS = MAY BE GIVEN ORALLY, I.M. OR BY SLOW I.V. INJECTION CLINICAL USES PARTIAL AND Gernalized TONIC-CLONIC SEIZURES FIRST-CHOICE IN INFANTILE SEIZURES BARBITURATES (phenobarbitone)

361. ADVERSE EFFECTS SEDATION, ATAXIA, RESPIRATORY DEPRESSION, FOLATE DEFICIENCY, CONGENITAL ABNORMAITIES REBOUND SEIZURES MAY OCCUR ON WITHDRAWAL CONTRAINDICATION PORPHYRIA DRUG INTERACTIONS AN INDUCER OF LIVER ENZYMES SEDATIVE EFFECTS OF PHENOBARBITAL ARE ADDITIVE WITH OTHER SEDATIVE/HYPNOTIC DRUGS

362. Benzodiazepins Diazepam (valium) Lorazipam Clonazepam ( rivotril ) Midazolam ( Dormicum ) Alprozalam (ALP 0.5mg) Note = Given iv as first line drug in emergency situations like status epilepticus , Tetanus, eclamptic convulsiond etc

363. Benzodiazepines MOA: Benzodiazepines increase the frequency of cl- channel openings by GABA , because binding of a benzodiazepine to its receptor site will increase the affinity of GABA for the GABA binding site. And Increase in chloride conductance.

364. Therapeutic Uses 1.Anxiety Disorders : 2. Muscular Disorders : Diazepam is useful in the treatment of skeletal muscle spasms, (such as occur in muscle strain), and in treating spasticity of multiple sclerosis and cerebral palsy. 3. Anxiety Provoking Procedures: Benzodiazepines obliterate memory of events experienced while under their influence ( anterograde amnesia) used as Pre-anesthetic medication

365. 4. Seizures: Diazepam and lorazepam are the drugs of choice in status epilepticus. 5. Sleep Disorders: Dependence Abrupt discontinuation results in withdrawal symptoms, consisting of confusion, anxiety, agitation, restlessness, insomnia, tension, and, rarely, seizures .

366. Adverse Effects Drowsiness and confusion are the most common side effects. Ataxia occurs at high doses and precludes activities that require fine motor coordination, such as driving an automobile. Cognitive impairment (decreased long-term recall and acquisition of new knowledge) can occur. CAUTION liver disease, Alcohol and other CNS depressants enhance

367. SODIUM VALPROATE IT IS FATTY CARBOXYLIC ACID MECHANISM OF ACTION SAME AS PHENYTOIN, ALTHOUGH EFFECTS ON GABA AND CALCIUM CHANNELS MAY CAUSE SOME ADDITIONAL ACTIONS

368. (2) Reducing neuronal cell membrane permeability to voltage-dependent sodium channels: carbamazepine, lamotrigine, phenytoin, and valproate. .

369. PHARMACOKINETICS VALPROATE IS WELL ABSORBED FROM THE GUT AND IS METABOLIZED TO ACTIVE METABOLITES AND INACTIVE CONJUGATES BEFORE IT IS EXCRETED THERE IS INTER-INDIVIDUAL VARIATION IN METABOLISM CLINICAL USES USEFUL AGAINST A WIDE RANGE OF SEIZURE TYPES PARTIAL SEIZURES 2. ALL FORMS OF GENERALIZED SEIZURE

370. 3. BIPOLAR DISORDER (AS AN ALTERNATIVE DRUG) 4. MIGRAINE HEADACHES ADVERSE EFFECTS SYMPTOMATIC TOXICITY GI UPSET, WEIGHT GAIN, FINE TREMOR AND ALOPECIA IDIOSYNCRASY HEPATOTOXICITY, THROMBOCYTOPENIA TERATOGENICITY SPINA FIDA AND SKELETAL ANOMALIES

371. CONTRAINDICATIONS AND WARNINGS LIVER DISEASE WOMEN OF CHILDBEARING AGE SHOULD BE ADVISED OF THE TERATOGENIC EFFECTS DRUG INTERACTIONS IT INHIBITS THE METABOLISM OF OTHER DRUGS PHENOBARBITAL PHENYTOIN

372. ETHOSUXAMIDE IT IS A SUCCINIMIDE MECHANISM OF ACTION IT INHIBITS T-TYPE CALCIUM CHANNELS IN THALAMIC NEURONS PHARMACOKINETICS IT IS WELL ABSORBED FROM THE GUT, WIDELY DISTRIBUTED TO TISSUES AND METABOLIZED TO INACTIVE COMPOUNDS BEFORE IT IS EXCRETED IN URINE

373. THERAPEUTIC USES DRUG OF CHOICE IN GENERALIZED ABSENCE SEIZURES IN CHILDREN ADVERSE EFFECTS DIZZINESS, DROWSINESS, GASTRIC DISTRESS NAUSEA

374. Carbamazepin MOA -Like phenytoin it blocks the Na+ channels thereby reduces the neuronal excitibility Uses 1)Gernalized tonic clonic seizures 2) Trigeminal and other neuralgia(is drug of choice) 3)Bipolar disorder

375. lamotrigine Inhibiting excitory neurotransmitter glutamate : Glutamate blockers Glutamate receptors which bind glutamate, an excitatory amino acid neurotransmitter. Upon binding glutamate, the receptors facilitate the flow of both sodium and calcium ions into the cell, while potassium ions flow out of the cell, resulting in excitation. Self study Stauts eplilepticus Doses table

376. Unit II E: Anti Migraine and drugs for Trigeminal neuralgia By: Muhammad Aurangzeb Lecturer-INS/KMU

377. Objectives By the completion of this session learners will be able to: Discuss the action, contraindication and side effects of Antimigraine and Trigeminal neuralgia Drugs Identify most commonly used drugs for migraine and Trigeminal neuralgia State the major nursing care if client is using drugs for migraine and Trigeminal neuralgia. Calculate the drug dosage accurately for oral anti migraine and drugs for trigeminal neuralgia.

378. Migraine “Migraine is a familial disorder characterized by recurrent attacks of headache widely variable in intensity, frequency and duration. A pulsating headache, which comes in attacks lasting 2 - 72 hours Attacks are commonly unilateral and are usually associated with anorexia, nausea and vomiting”.

379. Simplified Diagnostic Criteria for Migraine Repeated attacks of headache lasting 2 –72 h in patients with a normal physical examination, no other reasonable cause for the headache, and: At Least 2 of the Following Features: Plus at Least 1 of the Following Features: Unilateral pain Nausea/vomiting Throbbing pain Photophobia and Phonophobia Aggravation by movement Moderate or severe intensity

380. Types of Migraine Two Types:- Migraine with aura ( classical migraine ) :-headache preceded by visual or other neurological symptoms Migraine without aura( common migraine )

381. Migraine without aura (Common Migraine) Migraine without aura, is a severe, unilateral, pulsating headache that typically lasts from 2 to 72 hours. These headaches are often aggravated by physical activity and are accompanied by nausea, vomiting, photophobia (hypersensitivity to light), and phonophobia (hypersensitivity to sound). The majority of patients with migraine do not have aura.

382. Migraine with aura (Classical Migraine) Migraine with aura, the headache is preceded by neurologic symptoms called auras, which can be visual, sensory, and/or cause speech or motor disturbances. Most commonly, these prodromal symptoms are visual (flashes, zigzag lines, and glare), occurring approximately 20 to 40 minutes before headache pain begins. In the 15% of migraine patients whose headache is preceded by an aura

383. 4 Stages of Migraine 1.Prodrome Aura Headache Postdrome

384. Prodrome Vague premonitory symptoms that begin from 12 to 36 hours before the aura and headache. Symptoms: Yawning Excitation Depression Lethargy Craving or distaste for various foods Duration: 15 to 20 min.

385. Aura Aura is a warning or signal before onset of headache. Symptoms: Flashing of lights Zigzag lines Difficulty in focusing Duration : 15-30 min.

386. Headache Headache is generally unilateral and is associated with SYMPTOMS like: Anorexia Nausea Vomiting Photophobia Phonophobia Tinnitus Duration: 4-72 hrs. 8

387. Postdrome Following headache, patient complains of - Fatigue Depression Severe exhaustion Some patients feel unusually fresh Duration: Few hours or up to 2 days. 9

388. Pathophysiology of Migraine Increased excitability of CNS (Cortical Spreading Depression) Meningeal blood vessel dilation Activation of perivascular sensory trigeminal nerves Pain impulses and inflammation due to neuropeptides Vasoactive neuropeptides contain: Substance P Calcitonin gene-related peptide (CGRP) Neurokinin A Combination of increased pain sensitivity, tissue and vessel swelling, and inflammation

389. Theories about Pathophysiology: Vascular Theory:- Intracranial/Extra-cranial blood vessel vasodilation – headache. Intracerebral blood vessel vasoconstriction – aura. Serotonin Theory:- Decreased serotonin levels linked to migraine. Specific serotonin receptors found in blood vessels of brain.

390. Hunter Area Toxicology Service

391. Classification Mi l d Less than one attack a M onth Lasting up to 8 hours Throbbing but tolerable headache Moderate One or more attacks per M onth 6-24 hours Intense throbbing headache with nausea and vomiting Severe 2-3 attacks or more every month 12-48 hours Intense throbbing headache with nausea and vomiting, vertigo, GIT instability, fatigue, photophobia

392. Antimigraine agents Antimigraine agents  are drugs used to treat migraine headaches Pharmacological treatment of migraine includes Acute (abortive) treatment Preventive (prophylaxis) treatment

393. Classification of drugs used to treat migraine headache Specific Treatment TRIPTANS Almotriptan AXERT Eletriptan RELPAX Frovatriptan FROVA Rizatriptan MAXALT Naratriptan AMERGE Sumatriptan IMITREX, ALSUMA Zolmitriptan ZOMIG ERGOTS Dihydroergotamine MIGRANAL, VARIOUS Non-specific Treatment NSAIDs Aspirin BAYER, BUFFERIN, ECOTRIN Ibuprofen ADVIL, MOTRIN Indomethacin INDOCIN Ketorolac TORADOL Naproxen ALEVE, ANAPROX, NAPROSYN Anti-emetics PROPHYLACTIC AGENTS Anticonvulsants Beta-blockers Calcium channel blockers Tricyclic antidepressants

394. Management of Migraine Mild migraine: Analgesics with or without antiemetic. Moderate migraine: NSAIDs combinations / a triptan /ergot alkaloids (+antiemetic) Severe migraine: A triptan /ergot akaloids (+antiemetic) + prophylaxis

395. Acute Treatment: Step 1 Simple oral analgesic ± anti-emetic: Soluble Aspirin 600-900mg orally STAT OR Ibuprofen 400mg (Maximum of 4 doses over 24 hours) AND/OR Paracetamol 1g orally every 4 hours (Maximum of 4 g over 24 hours) for non-incapacitating headache Efficacy of analgesia may be improved by giving a pro-kinetic anti- emetic to promote gastric emptying with: Metoclopramide 10-20mg orally Domperidone 10-20mg orally. For nausea and vomiting (if required): Prochlorperazine 5mg orally or Prochlorperazine 25mg suppository Domperidone 10mg-20mg orally. If unable to tolerate either of the above due to prominent nausea and vomiting: Metoclopramide 10- 20mg IM or IV STAT

396. Step 2 Acute Treatment: Prescription NSAID (± anti-emetic as described in step 1) Naproxen 500mg-750mg with a further 250mg- 500mg in 6 hours if required (Maximum dose=1250mg/day) OR Diclofenac 50-100mg (maximum 200mg /day). Diclofenac 100mg suppository (maximum 100mg BD ) Analgesics inhibit release of prostaglandin release due to neurogenic inflammation . Metoclopramide besides being antiemetic enhances absorption of analgesics

397. Pharmacology of specific antimigraine drugs: Triptans: Selective 5-HT 1B/1D agonists Triptan includes- Sumatriptan, naratriptan, rizatriptan, eletriptan, zolmitriptan, almotriptan & frovatriptan Therapeutic Action : Triptans  is a relatively new antimigraine agent that causes cranial vascular constriction and relief of migraine headache pain. They do this by binding to serotonin receptors. Indications: Triptans  are indicated for the treatment of acute migraine and are not used for prevention of migraines.

398. Role of serotonin in migraine: Various studies have implicated serotonin in the pathogenesis of migraine. Serotonin vasoconstricts the nerve endings and blood vessels and in this way affects nociceptive pain. Comings43 postulated that low serotonin levels dilate blood vessels and initiate migraine

399. Adverse Effects and Contraindications of Triptans Coronary artery vasospasm, transient myocardial ischemia, atrial and ventricular arrhythmias, MI Irritation at the site of injection. The most common side effect of sumatriptan nasal spray is a bitter taste. Contraindicated - coronary artery disease , history of stroke or transient ischemic attacks, cerebrovascular or peripheral vascular disease

400. Ergot a mine Therapeutic Action: Partial agonist at α- adrenoceptors . Partial agonist at serotonergic receptors. Constricts all peripheral arteries. Ergotamine  was the drug of choice for migraines before triptans were developed. Dose: Oral/ sublingual route is preferred,1mg is given at half hours intervals till relief is obtained or total of 6mg is given

401. Adverse Effects and Contraindications of Ergot Alkaloids Nausea and vomiting, due to a direct effect on CNS emetic center. Ergotism: repeated doses cause cumulative toxicity, Severe peripheral vasoconstriction, hypertension, gangrene of extremities, anginal pain. Contraindicated in pregnant, peripheral vascular disease, coronary artery disease, hypertension, impaired hepatic or renal function. In contrast to triptans, the contractile effect of ergotamine in the human isolated coronary artery is long- lasting and persists even after repeated washings

402. Migraine Prophylaxis to reduce Frequency Raising the threshold to migraine activation by stabilizing a more reactive nervous system Enhancing antinociception Inhibiting CSD Blocking neurogenic inflammation

403. Drugs Used For Prophylaxis of Migraine

404. Trigeminal Neuralgia Sudden, usually unilateral Brief, stabbing , electric shock like recurrent pain Pain is limited to the sensory distribution of trigeminal nerve that includes middle face (maxillary division)– being most frequently involved, lower (mandibular division) & upper (ophthalmic division)– being least frequently involved

405. TN symptoms Pain in areas supplied by CN V Usually unilateral Sharp, stabbing, electric shock like pain Lasts for few seconds to minutes This transient attack may be repeated in matter of minutes or hours

406. 1st step of treatment Pharmacotherapy (Medical management of TN) Trigeminal neuralgia is usually treated with drugs called anti- convulsants which include: Carbamazepine (drug of choice) (400 1000mg/day) Phenytoin (300mg/day) Oxycarbazepine Gabapentin (600-1200mg/day) Baclofen , lamotrigine, clonazepam

407. Non Pharmacological Measures There are some things that a patient can do to minimize the frequency and intensity of TN attacks: Apply ice packs. Cold often numbs the area and will reduce the pain Get adequate rest in normal rest cycles Manage your stress well and keep stress levels low Avoid foods that may act as nerve stimulants, such as coffee, tea, and foods that are high in sugar Maintain adequate hydration and electrolyte levels Practice healthy living principles such as diet and exercise

408. Nursing Role Assess aforementioned cautions and contraindications (e.g. drug allergy, history of myocardial infarction and CAD, hepatic-renal dysfunction, etc.) to prevent complications. Administer drug to relieve acute migraines (at first sign of headache) Monitor for complaints of extremity numbness and tingling to identify effects on vascular constriction.

409. Nursing Role Educate client on drug therapy to promote understanding and compliance. Monitor patient response to therapy (relief of acute migraine headache). Monitor for adverse effects (e.g. CV changes, arrhythmias, hypertension, etc ). Monitor patient compliance to drug therapy.

410. References Karch , A. M., & Karch . (2011).  Focus on  nursing pharmacology . Wolters Kluwer Health/Lippincott Williams & Wilkins. Katzung , B. G. (2017).  Basic and clinical pharmacology . McGraw-Hill Education. Lehne , R. A., Moore, L. A., Crosby, L. J., & Hamilton, D. B. (2004). Pharmacology for nursing care. Smeltzer , S. C., & Bare, B. G. (1992).  Brunner & Suddarth’s textbook of medical-surgical nursing . Philadelphia: JB Lippincott

411. Unit II : F Skeletal Muscle Relaxants By: Muhammad Aurangzeb Lecturer-INS/KMU

412. Objectives By the completion of this section the learners will be able to: Discuss common symptoms/disorders for which skeletal muscle relaxants are used. Describe uses and effects of skeletal muscle relaxants. Differentiate between centrally acting and peripherally acting muscle relaxants Describe non-pharmacologic interventions to relieve muscle spasm and spasticity. Apply the nursing process with clients experiencing muscle spasm or spasticity. Calculate the drug dosages accurately.

413. Skeletal Muscle Relaxants (SMRs) Drugs that act peripherally at neuromuscular junction/muscle fiber or centrally in the cerebrospinal axis to reduce muscle tone or cause paralysis A muscle relaxants is a drug that affects skeletal muscle function and decreases the muscle tone.

414. Common Symptoms/Conditions in which SMRs are used In conjunction with GA : Facilitate intubation of the trachea Facilitate mechanical ventilation Optimized surgical working conditions In Muscle spasm: a sudden involuntary contraction of one or more muscle groups and is usually an acute condition associated with muscle strain (partial tear of a muscle) or sprain Musculoskeletal Injury or Sports Injury Low Back pain or neck pain Fibromyalgia, tension headaches It may be used to improve symptoms such as muscle spasms, pain, and hyperreflexia.

415. History: From Fun hunting in Jungles to Operation theatre Curare: The arrow poison Source: Chondrodendrone tomentosum and Strychnos toxifera Derived from: "ourare“ meaning arrow poison in South American Indian Tubocurarine name: Because of packing in “hollow bamboo tubes”

416. Neuromuscular Junction (NMJ)

417. Physiology of Skeletal Muscle Contraction

418. Classification of SMRs

419. Classification: Peripherally acting SMRs Neuromuscular Junction (NMJ)Blockers : Nondepolarizing (Competitive) blockers: Long acting: d-Tubocurarine, Pancuronium, Doxacurium, Pipecuronium, Gallamine and Metocurine Intermediate acting : Vecuronium, Atracurium, Cisatracurium, Rocuronium, Rapacuronium Short acting : Mivacurium Depolarizing blockers : Succinylcholine (suxamethonium), Decamethonium Botulinum Toxin Directly acting : Dantrolene

420. Nondepolarizing (Competitive) blockers Nondepolarizing (Competitive) Blockers having no intrinsic activity (antagonist) These are of 3 types based on their activity: Long acting: d-Tubocurarine, Pancuronium, Doxacurium, Pipecuronium, Gallamine and Metocurine Intermediate acting : Vecuronium, Atracurium, Cisatracurium, Rocuronium, Rapacuronium Short acting : Mivacurium

421. Nondepolarizing (Competitive) blockers Mechanism of Action They have affinity but no intrinsic activity for Nicotinic receptors (Antagonist) They are quaternary N+ compounds that contain cationic head that act only on closed Na+ channels – No action on already opened Na+ channels The cationic head binds to the anionic ACh binding site at the α – subunit of the Nm receptor but cannot bring conformational change & Na+ channels remains closed No End Plate Potential generation in nerve endings Muscle Action Potential decreases Action can be overcome by increased ACh concentration or blocking of acetylcholinesterase

422. Nondepolarizing (Competitive) blockers Pharmacological actions: Skeletal muscles: Intravenous injection of nondepolarizing blockers rapidly produces muscle weakness followed by flaccid paralysis. Autonomic ganglia: produce some degree of ganglionic blockade Histamine release: d-TC releases histamine from mast cells. Histamine release contributes to the hypotension produced by d-TC. Flushing, bronchospasm and increased respiratory secretions are other effects.

423. Pharmacological actions (Cont.,) Ca r d io v as c u lar s y s t e m: d - T u b ocu r arine p r oduc e s significant fall in BP. This is due to Ganglionic blockade Histamine release and Reduced venous return Gastrointestinal tract: The ganglion blocking activity of competitive blockers may enhance postoperative paralytic ileus after abdominal operations. Central nervous system: All neuromuscular blockers are quaternary compounds — do not cross blood-brain barrier.

424. Nondepolarizing blockers - Individual compounds d-Tubocurarine : 1st agent to undergo clinical investigation 1-2 hr. duration of action Histamine releaser (Bronchospasm, hypotension) Blocks autonomic ganglia (Hypotension) Clinical Use: Not clinical used do to its histaminic effects. Long duration of action(60 to 120 mins) and CVS effects restricted its use

425. Nondepolarizing blockers - Individual compounds Pancuronium: It is a synthetic steroidal compound, ~5 times more potent and longer acting than d-TC. Because of longer duration of action, needing reversal, its use is now restricted to prolonged operations, especially neurosurgery. Pipecuronium: Muscle relaxant with a slow onset and long duration of action; steroidal in nature; recommended for prolonged surgeries .

426. Nondepolarizing blockers - Individual compounds Vecuronium: It is a most commonly used muscle relaxant for routine surgery and in intensive care units.. Atracurium: Four times less potent than pancuronium and shorter acting. Rocuronium: Muscle relaxant with a rapid onset and intermediate duration of action which can be used as alternative to SCh for tracheal intubation without the disadvantages of depolarizing block and cardiovascular changes.

427. Depolarizing Blockers - Succinylcholine Succinylcholine have affinity and sub-maximal intrinsic activity at Nm receptor. It acts on sodium channels, open them and causes initial twitching and fasciculation. It does not dissociate rapidly from the receptors resulting in prolonged depolarization and inactivation of Na+ channels.

428. Mechanism of Action: Succinylcholine

429. Mechanism of Action: Succinylcholine Succinylcholine acts on the Nicotinic receptors of the muscles, stimulates them and ultimately cause their relaxation. This process occur in two phases : Phase I: During Phase I (depolarizing phase), they cause muscular fasciculations while they are depolarizing the muscle fibers. Phase II: After sufficient depolarization has occurred, phase II (desensitized phase) sets and the muscle is no longer responsive to Ach released by the nerve endings.

430. Advantages of Succinylcholine Most commonly used for Tracheal intubation Rapid onset (1-2 min) Good intubation conditions – relax jaw, separated vocal chords with immobility, no diaphragmatic movements Short duration of action (5-10 minutes) Dose 1-1.5mg/kg Used as continuous infusion occasionally

431. Side effects of Succinylcholine Cardiovascular: unpredictable BP, heart rate and arrhythmias Fasciculation Muscle pain Increased intraocular pressure Increased intracranial pressure Hyperkalemia: k+ efflux from muscles, life threatening in Cardiac Heart Failure, patient with diuretics etc. Malignant hyperthermia

432. What is Malignant hyperthermia Rare genetically determined reaction to susceptible persons having abnormal RyR receptor Ca+ channel Caused by Halothane and manifests as high temperature due to persistent muscle contraction Increased intracellular Ca+ Succinylcholine accentuates this condition Treatment: Rapid external cooling – ice pack Bicarbonate infusion 100% oxygen inhalation Injection of dantrolene: Direct acting muscle relaxant

433. Indication of Neuro Muscular Junction Blockers Adjuvant to General anesthesia Assisted ventilation Convulsion and trauma from electroconvulsive therapy Status epilepticus Vocal cord

434. Directly acting relaxants - Dantrolene Different from neuromuscular blockers, no action on neuromuscular transmission Mechanism of Action : Ryanodine receptors (RyR) calcium channels – prevents depolarization – no intracellular release of Ca++ Absorbed orally, penetrate brain and produces sedation, metabolized in liver, excreted in kidney. T1/2 8-12 hrs Dose: 25-100mg - 4 times daily Uses: Upper Motor Neuron disorders – paraplegia, hemiplegia, cerebral palsy and malignant hyperthermia (drug of choice 2.5-4 mg/kg) Adverse effects – Sedation, malaise, light headedness, muscular weakness, diarrhea and hepatotoxicity

435. Centrally acting Muscle relaxants Classification: Mephenesin congeners – Mephenesin, Carisoprodol, Chlorzoxazone, Methocarbamol and Chlormezanone Benzodiazepines – Diazepam, lorazepam, Clonazepam and others GABA derivative – Baclofen Central α-2 agonist – Tizanidine, clonidine

436. MOA: Centrally acting Muscle relaxants Drugs that reduce skeletal muscle tone by selective action on cerebrospinal axis Depress the spinal and supraspinal reflexes of muscle tone Also depresses polysynaptic reflexes of ascending reticular formation – wakefulness disturbed (sedation) No effect on NM junction but reduce Upper Motor Neuron spasticity and hyperreflexia

437. Mephenesin ( Relaxyl / medicreme ) Mephenesin ( Relaxyl / medicreme ) Modulation of reflexes in spinal internuncial neuron Cannot be used systemically Irritant rather than relaxant – topical preparations Carisoprodol, Chlorzoxazone ( Mobizox ), Methocarbamol ( Robinax / Robiflam ) and Chlormezanone – similar but can be used orally

438. Benzodiazepines as muscle relaxant Very potent centrally acting muscle relaxant – supraspinal Mechanism of action is via “GABAA receptor Cl - complex” enhancement Inhibitory in nature Diazepam and Clonazepam are the most potent ones Diazepam is the prototype of BZDs

439. Baclofen- GABA B agonist Mechanism of action: GABAB agonist Hyperpolarization of neurons by increasing K+ conductance and alteration of Ca++ flux Does not affect to Cl- conductance Site of action : spinal chord – depresses polysynaptic and monosynaptic reflexes Clinical effects : decreased hyperreflexia; reduced painful spasms; reduced anxiety Dose : orally 5 mg three times daily, gradually increase to 20 mg four times daily or higher Intrathecally initially 50 mcg/day increase to 300- 800 mcg/day

440. Tizanidine/ clonidine Mechanism of action: alpha-2 receptor agonist – inhibits the release of excitatory amino acids in spinal interneurons Clinical effects: reduced tone, spasm frequency, and hyperreflexia Doses: tizanidine initial 4 mg three times daily increase to 36 mg/day; clonidine initial 0.1 mg twice daily increase to 2.4 mg/day

441. Uses of Centrally acting relaxants Acute muscle spasms Backache and neuralgias Anxiety and tension Spastic neurological disorders Tetanus Electroconvulsive therapy Orthopedic manipulations

442. Centrally acting Vs Peripherally acting Centrally acting Decrease muscle tone but no reduction in power Polysynaptic reflexes in CNS CNS depression Orally and parenterally Spastic conditions, muscle spasm Peripherally acting Cause muscle paralysis Block NM transmission No CNS effect Given IV Short term surgical procedures

443. Non-pharmacologic interventions to relieve muscle spasm and spasticity Non-pharmacologic interventions include: Physical interventions (stretching, passive movements) Transcutaneous electric nerve stimulation (TENS) Transcranial direct current stimulation ( tDCS ) Shock wave Vibratory stimulation (whole body vibration) Electromyography biofeedback Repetitive transcranial magnetic stimulation (TMS) Therapeutic ultrasound & Acupuncture Orthotics (splints, casts) Thermotherapy & Cryotherapy

444. Nursing Role Monitor patient response to therapy (improvement in muscle spasm and relief of pain; improvement in muscle spasticity). Monitor for adverse effects ( e.g.CNS changes, GI depression, urinary urgency, etc ). Discontinue drug at any sign of liver dysfunction to prevent adverse effects. Monitor patient compliance to drug therapy. Provide safety measures (e.g. adequate lighting, raised side rails, etc.) to prevent injuries. Educate client on drug therapy to promote understanding and compliance.

445. References and Sources Karch , A. M., & Karch . (2011).  Focus on  nursing pharmacology . Wolters Kluwer Health/Lippincott Williams & Wilkins. [ Link ] Katzung , B. G. (2017).  Basic and clinical pharmacology . McGraw-Hill Education. Lehne , R. A., Moore, L. A., Crosby, L. J., & Hamilton, D. B. (2004). Pharmacology for nursing care. Smeltzer , S. C., & Bare, B. G. (1992).  Brunner & Suddarth’s textbook of medical-surgical nursing . Philadelphia: JB Lippincott.

446. UNIT IV CHOLINERGIC & ANTI- CHOLINERGIC DRUGS By: Muhammad Aurangzeb Lecturer-INS/KMU

447. Objectives By the completion of this section the learners will be able to: List characteristics of Cholinergic & Anti-Cholinergic drugs in terms of effects on body tissues, indications for use, adverse effects, nursing process implications, principles of therapy and observations of client‟s responses. Discuss antidotes for cholinergic drugs & Anti-Cholinergic drugs. Describe signs and symptoms of cholinergic drugs & Anti-Cholinergic drug overdose. Describe major nursing care needs of clients receiving these classes of drugs. Discuss principles of therapy & nursing process for using Cholinergic & Anti Cholinergic drugs.

448. Neurotransmitters Sympathetic: noradrenaline (norepinephrine) Parasympathetic : acetylcholine

449. Overview Drugs affecting the autonomic nervous system (ANS) are divided into two groups according to the type of neuron involved in their mechanism of action. The cholinergic drugs, act on receptors that are activated by acetylcholine (ACh), The adrenergic drugs act on receptors stimulated by norepinephrine or epinephrine.

450. Cholinergic system The  cholinergic system  is composed of nerve cells that use the neurotransmitter acetylcholine. Acetylcholine esterase enzyme that catalyzes the breakdown of acetylcholine

451. Acetlyecholinesterases ACh is degraded to choline + Acetic acid by enzyme Acetylcholinesterase (AChE). There are two types of AChE: a. True b. Pseudo

452. Cholinergic Receptors Cholinergic receptors are of two types: • Muscarinic • Nicotinic.

453. Cholinergic Receptors Muscarinic receptors are of five subtypes, i.e. M1, M2, M3, M4 and M5 Nicotinic are of two subtypes, i.e. nicotinic neuronal (Nn) and nicotinic muscle (Nm) M1 receptors are present in → autonomic ganglia, gastric glands and central nervous system (CNS) M 2 receptors are present in → heart , smooth muscles and nerves

454. Cholinergic Receptors M3 receptors are present in → exocrine glands , smooth muscles and eye M4, M5 receptors are present in → CNS Nm receptors are present in neuromuscular junction ( NMJ) Nn receptors are present in autonomic ganglia, adrenal medulla and CNS

455. Actions of Ach Characteristics M 1 (neuronal) Location & Function Ganglia – impulse t r a ns mi ss i o n M 2 (cardiac) SA node -Decreased rate of impulse generation AV node – decreased conduction velocity Atrium, ventricle - decreased co n t r a c ti li ty M 3 (glandular) E x o c ri n e glands - secretion Visceral smooth Muscle – contraction

456. Actions of Ach Characteristics M 1 Location & Function (neuronal) Ganglia , gastric cells – impulse t r a ns mi ss i o n , HCl secretion M 2 (cardiac) SA node -Decreased rate of impulse generation AV node – decreased conduction velocity Atrium, ventricle - decreased co n t r a c ti li ty M 3 (glandular) E x o c ri n e glands - secretion Visceral smooth Muscle – contraction

457. Actions of Ach Characteristics M 1 Location & Function (neuronal) Ganglia , gastric cells – impulse t r a ns mi ss i o n, HCl secretion M 2 (cardiac) SA node -Decreased rate of impulse generation AV node – decreased conduction velocity Atrium, ventricle - decreased co n t r a c ti li ty M 3 (glandular) E x o c ri n e glands - secretion Visceral smooth Muscle – contraction

458. Actions of Ach Characteristics M 1 Location & Function (neuronal) Ganglia, gastric cells – impulse t r a ns mi ss i o n, HCl secretion M 2 (cardiac) SA node -Decreased rate of impulse generation AV node – decreased conduction velocity Atrium, ventricle - decreased co n t r a c ti li ty M 3 (glandular) Exocrine glands (salivary, sweat) -secretion Visceral smooth Muscle (bronchus, bladder, GIT) – contraction

459. Actions of Ach Characteristics N M (muscle type) N N (neuronal type) Location & Function Skeletal neuromuscular junction (NMJ) – contraction Autonomic ganglia – impulse transmission

460. Acetylcholine ACh has both muscarinic and nicotinic activity. Action on cardiovascular system: Heart: acetylcholine causes decrease in heart rate and cardiac output (negative chronotropy) and negative ionotrophy) M2 Receptors Blood vessels: acetylcholine causes vasodilation and lowering of blood pressure. acetylcholine activates M3 receptors found on endothelial cells lining the smooth muscles of blood vessels causing vasodilation Gastrointestinal (GI) tract : acetylcholine increases salivary secretion and stimulates intestinal secretions and motility

461. Actions of ACh Respiratory system : acetylcholine enhances bronchiolar secretions and cause bronchoconstriction(M3) Urinary system : acetylcholine increases the tone of the detrusor muscle, causing urination(M3) Exocrine Glands : In Sweat, sebaceous and lacrimal glands ach increase their secretion Eye: Circular muscle of iris (M 3 )- contraction- miosis Ciliary muscle (M 3 ) – contraction- eye’s focus is accommodated for near vision – Better drainage of aqueous humor – reduced intraocular pressure Lacrimal glands (M 3 ) - lacrimation

462. Acetylcholine No therapeutic use because Ultra short action: rapidly hydrolyzed by cholinesterases Widespread and nonselective activity: act on all receptors

463. Cholinergic Drugs Act at same site, i.e. ACh. Mimic actions of ACh. Therefore called ‘ Cholinomimetics ’ or ‘ Parasympathomimetics ’.

464. DIRECT ACTING Indirect acting (irreversible inhibitors of acetylcholinesterase Indirect acting (reversible inhibitors of acetylcholinesterase) Acetylcholine Echothiophate Neostigmine Pilocarpine Physostigmine Carbachol Pyridostigmine Bethanechol Galantamine Classification of cholinergic drugs(   parasympathomimetics) A  parasympathomimetic  drug or cholinomimetic drug, is a substance that stimulates the parasympathetic nervous system.

465. 1). Directly acting 1. Directly acting Methacholine , bethanechol , pilocarpine , Carbachol Act on muscarinic receptors

466. Therapeutic uses Ophthalmic use : Glaucoma To counteract the effects of mydriatics To break adhesions between the iris and lens or iris and cornea

467. Therapeutic uses Carbachol/Bethanechol resistant to metabolism by both cholinesterases, hence long duration of action. Carbachol —it has both muscarinic and nicotinic actions used in glaucoma. Bethanechol: it has only muscarinic activity. It is used in post operative urinary retention and paralytic ileus: Bethanechol has more pronounced effects on smooth muscles Pilocarpine is an example of a nonselective muscarinic agonist used in clinical practice to treat xerostomia and glaucoma. Neostigmine: it is used to improve muscle strength in patients with a certain muscle disease ( myasthenia gravis ). Belladona ( Atropine) poisoning : Physostigmine – specific antidote

468. Adverse Reactions of Cholinomimetics (Mnemonic SLUDGE’) S : S alivation L : L acrimation U : U rination D: D iarrhea G: GI / G U cramps E: E mesis/Eye (miosis).

469. 2. Indirectly acting (Anticholinesterases) Reversible : Physostigmine, neostigmine, pyridostigmine , edrophonium, Galantamine Irreversible: Echothiophate Organophosphates: Parathion, Malathion

470. Mechanism of action of Anticholinesterases Inhibit acetylcholinesterase (AChE) enzyme Ach ----------- Choline + acetate AChE _ _ Neostigmine Accumulation of Ach : enhances its Action

471. Irreversible AChE inhibitors Mainly used as insecticides and pesticides Irreversible Anti­ChE i.e . Echothiophate eye drops for glaucoma

472. Irreversible Anti- ChE (Organophosphorus Compounds) Organophosphorus, compounds. They are powerful, irreversible inhibitors of anti­ChE . Binding is covalent, Hence, binding is stable and irreversible. All OP compounds (except echothiophate ) are highly lipid soluble. Hence, can be absorbed from all routes, including intact skin. Thus, OP poisoning can also occur by spraying of agricultural pesticides/insecticides.

473. Organophosphorus Poisoning OP compounds are used as agricultural insecticides/ pesticides. Hence, poisoning is frequent. Signs/Symptoms: a. Similar to cholinergic (muscarinic, nicotinic, CNS) hyperactivity. b. For example, SLUDGE c. Sweating, increased tracheobronchial secretions, increased GI secretions, bronchospasm, hypotension, convulsions and coma. d. Respiratory paralysis can cause death. Treatment: a. Poisoning via skin: i. Remove clothing. ii. Wash skin with soap and water. b. Poisoning via oral route. i. Gastric lavage. c. Maintain BP and airway patency. d. Atropine IV 2 mg every 10 minutes. Till pupil dilates/ dryness of mouth (drug of choice).

474. Cont.. Reactivation of acetylcholinesterase Pralidoxime can reactivate inhibited AChE. However, it is unable to penetrate into the CNS and therefore is not useful in treating the CNS effects of organophosphates.

475. Adverse effects of anticholinesterases Diarrhea, urination, bronchoconstriction, lacrimation, salivation, sweating, bradycardia , fasciculation of skeletal muscle Organophosphorus poisoning: treated with an anticholinergic, atropine

476. Anticholinergics Also called antimuscarinics, parasympatholytics or cholinergic blocking drugs. They block the effects of ACh on muscarinic receptors. Drugs that block nicotinic receptors are ganglionic blockers or neuromuscular blockers.

477. Cholinergic Antagonists Those drugs which antagonize the effect of acetylcholine. Atropine Scopolamine( hyoscine ) Ipratropium bromide ( atem inahalor ) Tropicamide Glycopyrolate Propantheline Pirenzepine (M1 selective antagonist) Clidinium (M1 selective antagonist)( Librax ) Dicyclomine Oxybutynin ( Ditropan ) atropa belladona

478. Mechanism of Action Anticholinergic drugs combine reversibly with muscarinic cholinergic receptors thus preventing access of neurotransmitter acetylcholine.

479. Classification Natural alkaloids : Atropine* (prototype), Scopolamine ( Hyoscine ) Semisynthetic derivatives : Homatropine *, ipratropium bromide, tiotropium bromide Synthetic compounds : Mydriatics – Cyclopentolate*, tropicamide Antiparkinsonian – Benzhexol, Biperiden , Benztropine

480. Cont … iii) Antisecretory - antispasmodics – Dicyclomine Pirenzepine G l y c o p y r r o l a te Semisynthetic and synthetic anticholinergics - Atropine substitutes

481. Atropine Eye: Atropine blocks muscarinic activity in the eye, resulting in mydriasis (dilation of the pupil) Atropine use as antidote for organic phosphate poisoining . Gastrointestinal (GI): Atropine reduce activity of the GI tract. can be used as an antispasmodic. Secretions: Atropine blocks muscarinic receptors in the salivary glands, producing dryness of the mouth (xerostomia). The salivary glands are exquisitely sensitive to atropine. Sweat and lacrimal glands are similarly affected. Cardiovascular: Atropine produces diverse effects on the cardiovascular system, depending on the dose At low doses, atropine causes decrease in heart rate. Higher doses of atropine cause a progressive increase in heart rate by blocking the M2 receptors on the sinoatrial node.

482. Cont … Respiratory system : Bronchodilatation Decreased secretions CNS: Atropine has CNS stimulant action at high dose. High doses cause cortical excitation, restlessness, disorientation, hallucination & delirium followed by respiratory depression & coma. It suppresses tremor & rigidity of parkinsonism. Smooth muscles: All visceral smooth muscles that receive parasympathetic motor innervation are relaxed by atropine due to M3 blockade Glands: Atropine decreases sweat, salivary, bronchial & lacrimal secretions by M3 blockade Body temperature : - Rise in body temperature occur at high doses due to both inhibition of sweating as well as stimulation of temperature regulating centre in the hypothalamus

483. Cont … Genitourinary tract : Relaxation of ureter and urinary bladder – urinary retention Glands : Decreases sweat, salivary, tracheobronchial and lacrimal secretion

484. Uses of atropine Preanaesthetic medication: to decrease secretion Oraganophosphorous poisoning

485. Therapeutic uses of anticholinergics Pre-anesthetic medication : reduces excessive salivation( Sialorrhea  ) & respiratory secretions. (glycopyrrolate and scopolamine) Peptic ulcer : decreases gastric secretions ( clidinium )& provide symptomatic relief in peptic ulcer now been superseded by H2 blockers. As anti- spasmodic:intestinal & renal colic, abdominal cramps To relive urinary frequency & urgency or involuntary urination (enuresis)( Oxybutynin ,   Propantheline ) Bronchial Asthma ( ipratropium ) As mydiatric & cycloplegic . As cardiac vagolytic Organophosphates Poisoning and mushroom poisoning. Antidote for cholinergic agonists: Atropine is used for the treatment of organophosphate (insecticides, nerve gases) Treatment of excessive sweating ( hyperhidrosis )

486. Therapeutic uses Motion sickness : Scopolamine Parkinson’s disease : benzhexol, benztropine etc. Bronchial asthma : ipratropium and tiotropium bromide Preanaesthetic medication : glycopyrrolate , As mydriatic during fundoscopy and testing of refractive error – Tropicamide, cyclopentolate

487. Side effects Belladona poisoning • D ry mouth, difficulty in swallowing and talking. • D ry,flushed and hot skin. D ilated pupil • Fever, difficulty in micturition, Excitement, ataxia, delirium, hallucination. • Convulsion and coma may occur in severe poisoning. Treatment of 3Ds : Physostigmine 15- 60 micro gram / kg IV every 1- 2 hourly. cycloplegia : paralysis of the ciliary muscle of the eye.

488. Side effects of atropine : Dry mouth Blurred vision and photophobia Urinary retention Constipation Dry, hot skin Precipitation of glaucoma Decreased sweating

489. References Karch , A. M., & Karch . (2011).  Focus on nursing pharmacology . Wolters Kluwer Health/Lippincott Williams & Wilkins. [ Link ] Katzung , B. G. (2017).  Basic and clinical pharmacology . McGraw-Hill Education. Lehne , R. A., Moore, L. A., Crosby, L. J., & Hamilton, D. B. (2004). Pharmacology for nursing care. Smeltzer , S. C., & Bare, B. G. (1992).  Brunner & Suddarth’s textbook of medical-surgical nursing . Philadelphia: JB Lippincott

490. UNIT X-A Cardiac Glycosides and Antiarrhythmic Drugs By: Muhammad Aurangzeb Lecturer-INS/KMU

491. By the end of this unit learners, will be able to: Review inotropic, chronotropic and dromotropic effects of cardiovascular drugs. Describe the therapeutic effects and therapeutic uses of digoxin. Discuss digitalization. Discuss the signs and symptoms of early moderate and severe digoxin toxicity. Describe the nursing care related to digoxin toxicity. Discuss pharmacological management of arrhythmias. Discuss nursing implication in relation to antiarrhythmic drugs. Calculate the drug dosage accurately while administering oral and parenteral medication Objectives

492. What is a failing Heart ??? Inability of the heart to pump sufficient blood to meet the metabolic demands of the body Systolic - In IHD, Valvular incompetence, cardiomyopathy and myocarditis etc. Diastolic - In Hypertension, aortic stenosis, congenital heart disease and hypertrophic cardiomyopathy Reduced efficiency of the heart as a pump – reduced Cardiac Output

493. Cardioactive glycosides Drugs having the cardiac Inotropic property – increase in force of contraction and cardiac output in a failing (hypodynamic) heart – They increase the myocardial contractility and improves cardiac output without proportionate increase in Oxygen consumption - Cardiac Tonic – Do not increase the heart rate • In contrast, Sympathomimetics or the cardiac stimulants increase Heart Rate and Oxygen consumption without increase in cardiac output MYOCARDIAL EFFICIENCY !

494. The difference between Inotropic, Chronotropic and Dromotropic Basis of Comparison Inotropic Chronotropic Dromotropic Definition Medicines that alter the force or energy of heart’s muscular contraction.   Drugs or medicines that change the heart rate and rhythm. Drugs that affect the conduction of electric impulses through the heart. Categorization Positive Inotopic: Strengthens the force of cardiac contraction.     Negative Inotropic: Weakens the force of cardiac contraction.     Positive Chronotropic: Plays a role of accelerating the heart rate.   Negative Chronotropic: Slows down the heart rate. Positive Dromotropic: Speeds up conduction of electric impulse through the heart.   Negative Dromotropic: Slows down conduction of electric impulse through the heart. Examples Positive Inotropic:  Dopamine, Epinephrine, Isoproterenol, Amiodarone, digoxin etc.   Negative Inotropic: Labetol and propanolol. Positive Chronotropic: Atropine, Milrinone and Theophylline.       Negative Chronotropic: Digoxin , acetylcholine and metoprolol.   Positive Dromotropic: Phenytoin.         Negative Dromotropic: verapamil.  

495. Specific Drugs Three different digitalis compounds (cardiac glycosides) are listed in the table below. The compound most commonly used in the Pakistan is digoxin. Ouabain is used primarily as a research tool. Drug Oral bioavailability* Half-life (hours) Elimination Digoxin 75% 40 kidneys Digitoxin >90% 160 liver Ouabain 0% 20 kidneys

496. What is digoxin ? Digoxin (Lanoxin) is a cardiac glycoside, C 41 H 64 O 14 , obtained from the leaves of the foxglove, Digitalis lanata. Digoxin acts by blocking the Na + K + ATPase pump.

497. Foxglove In 1775 William Withering demonstrated that the leaves of the foxglove plant alleviated certain forms of dropsy (edema), and in 1799 John Ferriar ascribed their beneficial effects to a primary action on the heart. Initially, digitalis was used to treat dropsy, which is an old term for edema. Subsequent investigations found that digitalis was most useful for edema that was caused by a weakened heart (i.e., heart failure).

498. Mechanisms of action Digitalis compounds are potent inhibitors of cellular Na + /K + -ATPase. This ion transport system moves sodium ions out of the cell and brings potassium ions into the cell. The Na + /K + -ATPase also plays an active role in the membrane potential. This pump is electrogenic because it transports 3 sodium ions out of the cell for every 2 potassium ions that enter the cell. This can add several negative millivolts to the membrane potential depending on the activity of the pump.

499. Note this transport function is necessary for cell survival because sodium diffusion into the cell and potassium diffusion out of the cell down their concentration gradients would reduce their concentration differences (gradients) across the cell membrane over time. Loss of these ion gradients would lead to cellular depolarization and loss of the negative membrane potential that is required for normal cell function

500. Cont… By inhibiting the Na + /K + -ATPase, cardiac glycosides cause intracellular sodium concentration to increase. This then leads to an accumulation of intracellular calcium via the Na + -Ca ++  exchange system. In the heart, increased intracellular calcium causes more calcium to be released by the  sarcoplasmic reticulum , thereby making more calcium available to bind to troponin-C, which increases contractility ( inotropy ). Inhibition of the Na + /K + -ATPase in vascular smooth muscle causes depolarization, which causes smooth muscle contraction and vasoconstriction. By mechanisms that are not fully understood, digitalis compounds also increase vagal efferent activity to the heart. This  parasympathomimetic  action of digitalis reduces  sinoatrial firing rate  (decreases heart rate; negative chronotropy) and reduces  conduction velocity  of electrical impulses through the atrioventricular node (negative dromotropy).

501. Note Car diac myocytes, as well as many other cells, have a Na+-Ca++ exchanger (not an active energy-requiring pump) that is essential for maintaining sodium and calcium homeostasis. The exact mechanism by which this exchanger works is unclear.  It is known that calcium and sodium can move in either direction across the sarcolemma. Furthermore, three sodium ions are exchanged for each calcium, therefore an electrogenic potential is generated by this exchanger.  The direction of movement of these ions (either inward or outward) depends upon the membrane potential and the chemical gradient for the ions. We also know that an increase in intracellular sodium concentration competes for calcium through this exchange mechanism leading to an increase in intracellular calcium concentration.

502. Continue As intracellular sodium increases, the concentration gradient driving sodium into the cell across the exchanger is reduced, thereby reducing the activity of the exchanger, which decreases the movement of calcium out of the cell. Therefore, mechanisms that lead to an accumulation of intracellular sodium cause a subsequent accumulation of intracellular calcium because of decreased exchange pump activity.

503. Na + K + K + Na + Na + Ca 2+ Ca 2+ Na + /K + ATPase Na + /Ca 2+ Exchange Myofilaments  CONTRACTILITY Digitalis K + K + K + K + Inside cell Outside cell (blood) Na + Na + Na + Na +

504. Na + K + K + Na + Na + Ca 2+ Ca 2+ Na + /K + ATPase Na + /Ca 2+ Exchange Myofilaments  CONTRACTILITY Digitalis K + K + K + K + Inside cell Outside cell (blood) Na + Na + Na + Na + Ca 2+ Ca 2+ Ca 2+ What would happen if Ca 2+ was given? What would happen if K + was low?

505. Digoxin Properties of digoxin Increases inotropy (contractility) of the heart Decreases chronotropy (heart rate) Natriuresis (sodium loss)  minor effect Neurohormonal effects - Plasma Norepinephrine - Peripheral nervous system activity - RAAS activity - Vagal tone

506. Digoxin Properties of digoxin Giving calcium would greatly increase intracellular calcium levels when high digoxin levels are present. This can cause severe arrhythmias. Low potassium levels also potentiates the actions of digoxin since both potassium and digoxin compete for the same binding site on the Na + /K + ATPase pump. Thus if there was only a little potassium present, digoxin will be able to bind easier and inhibit the pump.

507. Pharmacokinetics The total  loading dose  of parenteral  digoxin  is 500 to 1000 micrograms (0.5 to 1.0 mg) depending on age, lean body weight and renal function. Absorption:  60–80% absorbed after oral administration of tablets; 70–85% absorbed after administration of elixir; 80% absorbed from IM sites (IM route not recommended due to pain/irritation). Distribution:  Widely distributed; crosses placenta and enters breast milk. Metabolism and Excretion:  Excreted almost entirely unchanged by the kidneys. Half-life:  36–48 hr (↑ in renal impairment).

508. Pharmacokinetics The long half-life of digitalis compounds necessitates special considerations when dosing. With a half-life of 40 hours, digoxin would require several days of constant dosing to reach steady-state, therapeutic plasma levels. Therefore, when initiating treatment, a special dosing regimen involving "loading doses" is used to rapidly increase digoxin plasma levels. This process is termed "digitalization." For digoxin, the therapeutic plasma concentration range is 0.5 - 1.5 ng/ml. It is very important that therapeutic plasma levels are not exceeded because digitalis compounds have a relatively narrow therapeutic safety window. Plasma concentrations above 2.0 ng/ml can lead to digitalis toxicity. If toxicity occurs with digoxin, it may take several days for the plasma concentrations to fall to safe levels because of the long half-life.

509. Note The re is available for digoxin toxicity an immune Fab (Digibind) that can be used to rapidly reduce plasma digoxin levels. Potassium supplementation can also reverse the toxic effects of digoxin if the toxicity is related to hypokalemia (see below).

510. Digitalization Administration of digitalis in a dosage schedule designed to produce and then maintain optimal therapeutic concentrations of its cardiotonic glycosides.

511. Cont… Digoxin has low therapeutic window and margin of safety is very low Therapeutic level of digoxin is 0.5 – 1.5 ng/ml. It is administered such a way that patient gets maximum benefits with minimal adverse effects. Previously rapid digitalization was done but obsolete now Rapid IV: Seldom used now: As extreme measure in CHF and atrial fibrillation - 0.25 mg slow IV stat followed by 0.1 mg every Hourly Slow digitalization: Digoxin 0.25 mg (or even 0.125mg) daily in the evening – full response in 5-7 days If no improvement administer 0.375 for 1 week If no, administer 0.5 mg in next week Monitor patient for blood levels, if no monitor in improvement of signs and symptoms If bradycardia, stop the drug Rapid digitalization (oral): 0.5 to 1 mg stat then 0.25 mg every 6 Hourly - Monitor for toxicity - Patient is digitalized within 24 Hours

512. Drug Interactions Many commonly used drugs interact with digitalis compounds. The Class IA antiarrhythmic,  quinidine , competes with digoxin for binding sites and depresses renal clearance of digoxin. These effects increase digoxin levels and can produce toxicity. Similar interactions occur with  calcium-channel blockers  and  nonsteroidal anti-inflammatory drugs . Other drugs that interact with digitalis compounds are  amiodarone  (Class III antiarrhythmic) and  beta-blockers .  Diuretics  can indirectly interact with digoxin because of their potential for decreasing plasma potassium levels (i.e., producing hypokalemia).  Hypokalemia  results in increased digoxin binding to the Na + /K + -ATPase (possibly through increased phosphorylation of the enzyme) and thereby enhances digoxin's therapeutic and toxic effects.  Hypercalcemia  enhances digitalis-induced increases in intracellular calcium, which can lead to calcium overload and increased susceptibility to digitalis-induced arrhythmias. 

513. Therapeutic Uses of Digitalis Compounds Heart Failure ↑ inotropy ↑ ejection fraction ↓ preload ↓ pulmonary congestion/edema Arrhythmias ↓ AV nodal conduction (parasympathomimetic effect) ↓ ventricular rate in atrial flutter and fibrillation

514. Atrial fibrillation and flutter
Atrial fibrillation and flutter lead to a rapid ventricular rate that can impair ventricular filling (due to decreased filling time) and reduce cardiac output. Furthermore, chronic ventricular tachycardia can lead to heart failure. Digitalis compounds, such as digoxin, are useful for reducing ventricular rate when it is being driven by a high atrial rate. The mechanism of this beneficial effect of digoxin is its ability to activate vagal efferent nerves to the heart (parasympathomimetic effect). Vagal activation can reduce the conduction of electrical impulses within the atrioventricular node to the point where some of the impulses will be blocked. When this occurs, fewer impulses reach the ventricles and ventricular rate falls. Digoxin also increases the effective refractory period within the atrioventricular node.

515. Digoxin Digoxin and exercise Digoxin has been shown to increase exercise performance in patients with mild to moderate heart failure Digoxin does not increase exercise capacity in normal subjects Digoxin is very dangerous in athletes (especially marathon runners) due to the increased risk of kidney failure from dehydration which results in the accumulation of digoxin (since the kidneys normally help eliminate digoxin from the blood)

516. Adverse Reactions/Side Effects CNS:  fatigue , headache, weakness. EENT:  blurred vision, yellow or green vision CV:  ARRHYTHMIAS,  bradycardia , ECG changes, AV block, SA block GI:  anorexia ,  nausea ,  vomiting , diarrhea Hemat:  thrombocytopenia Metabolic:  electrolyte imbalances with acute digoxin toxicity Note: Underline  indicate most frequent.

517. Note Drugs g-induced thrombocytopenia occurs when certain medicines destroy platelets or interfere with the body's ability to make enough of them.
There are two types of drug-induced thrombocytopenia: immune and nonimmune .
If a medicine causes your body to produce antibodies, which seek and destroy your platelets, the condition is called drug-induced immune thrombocytopenia. Heparin, a blood thinner, is the most common cause of drug-induced immune thrombocytopenia.

518. Contraindication/Precautions Contraindicated in: Hypersensitivity; Uncontrolled ventricular arrhythmias; AV block (in absence of pacemaker); Constrictive pericarditis; Known alcohol intolerance (elixir only).

519. Use Cautiously in: Hypokalemia (↑ risk of digoxin toxicity); Hypercalcemia (↑ risk of toxicity, especially with mild hypokalemia); Hypomagnesemia (↑ risk of digoxin toxicity); Diuretic use (may cause electrolyte abnormalities including hypokalemia); Myocardial infarction; Renal impairment (dose ↓ required); Obesity (base dose on ideal body weight); Geri:  Very sensitive to toxic effects; dose adjustments required for age-related ↓ in renal function and body weight; OB:  Although safety has not been established, has been used without adverse effects on the fetus; Lactation:  Similar concentrations in serum and breast milk result in subtherapeutic levels in infant, use with caution.

520. Digoxin Toxicity Much less common in modern medicine Causes: - 50% of patients are on chronic therapy - 10% took accidental large dose - 40% as suicide attempts - Rarely due to ingestion of certain plants

521. Digoxin Toxicity Normal blood digoxin level is 0.5 – 1.5 ng/ml > 2.0 ng/ml leads to digoxin toxicity; exacerbated by: - Hypokalemia (low potassium) - Hypercalcemia (high calcium) The presence of hyperkalemia (> 5.0) is a bad prognostic sign: - If K + < 5.0 - mortality 0% - If K + 5.0 – 5.5 - mortality 50% - If K + > 5.5 - mortality 100%

522. Digoxin Toxicity Any arrhythmia can occur due to digoxin toxicity! Brady or tachyarrhythmias occur. One pathognomonic rhythm is bidirectional ventricular tachycardia:

523. Signs and Symptoms Fatigue Nausea, vomiting, abdominal pain Headache Dizziness Confusion, delirium, or hallucinations Yellow vision (xanthopsia)

524. Treatment

525. Treatment – Digibind Digibind is an antibody created to attack/bind digoxin

526. Nursing care related to digoxin toxicity Monitor apical pulse for 1 full minute before administering. Withhold dose and notify health care professional if pulse rate is <60 bpm in an adult, <70 bpm in a child, or <90 bpm in an infant. Monitor BP periodically in patients receiving IV digoxin. Monitor ECG throughout IV administration and 6 hr after each dose. Notify health care professional if bradycardia or new arrhythmias occur. Teach patient to take pulse and to contact health care professional before taking medication if pulse rate is <60 or >100.

527. Cont… Observe for signs and symptoms of toxicity.  In adults and older children,  the first signs of toxicity usually include abdominal pain, anorexia, nausea, vomiting, visual disturbances, bradycardia, and other arrhythmias. If signs of toxicity occur and are not severe, discontinuation of digoxin may be all that is required. Correct electrolyte abnormalities. Administer potassium so that serum potassium is maintained between 4.0 and 5.5 mmol/L.

528. Cont… Monitor ECG for evidence of potassium toxicity (peaking of T waves). Treatment of life-threatening arrhythmias may include administration of digoxin immune Fab  (Digibind) , which binds to the digitalis glycoside molecule in the blood and is excreted by the kidneys. Review signs and symptoms of digitalis toxicity with patient and family. Advise patient to notify health care professional immediately if these or symptoms of HF occur.

529. Antiarrhythmic Drugs B By: Muhammad Aurangzeb Lecturer-INS/KMU

530. By the end of this unit learners, will be able to: Discuss pharmacological management of arrhythmias. Discuss nursing implication in relation to antiarrhythmic drugs. Calculate the drug dosage accurately while administering oral and parenteral medication Objectives

531. Arrhythmia Arrhythmia is deviation of heart from normal rhythm. Normal Rhythm 1)HR- 60-100 Should origin from SA Node Cardiac impulse should propagate through normal conduction pathway with normal velocity.

532. 100 60 Normal range 150 Simple tachyarrythmia 200 Paroxysmal TA . 500 Atrial fibrillation 350 Atrial flutter 40 Mild bradyarrhythmias 20 moderate BA Severe BA Classification of Arrhythmias

533. Arrhythmias Sinus arrythmia Atrial arrhythmia Nodal arrhythmia (junctional) Ventricular arrhytmia Supra Ventricular Tachycardia

534. Types of cardiac tissue (on the basis of impulse generation) Automatic/ pacemaker/ conducting fibers (Ca++ driven tissues) Includes SA node, AV node, bundle of his, purkinje fibers Capable of generating their own impulse Normally SA node acts as pacemaker of heart Non-automatic myocardial contractile fibers (Na+ driven tissues) Cannot generate own impulse Includes atria and ventricles

535. Electrophysiology of cardiac tissue Impulse generation and transmission Myocardial action potential Depolarization and repolarization waves as seen in ECG

536. Impulse generation and transmission

537. Myocardial action potential In automatic tissues In non-automatic tissues (See video for it) https://www.youtube.com/watch?v=9xSqezCMHnw

538. Arrhythmia Definition: Disturbances in the heart rate, rhythm, impulse generation or conduction of electrical impulses responsible for membrane depolarization These disturbances can lead to alterations in overall cardiac function that can be life threatening. Antiarrhythmic drugs: Compounds used to prevent or treat cardiac arrhythmias

539. Mechanism of arrhythmias Disturbances in impulse generation may be due to Abnormal automaticity Delayed after depolarization Disturbances of impulse conduction The impulse may recirculate in heart causing repeated activation (re-entry) Conduction blocks

540. Re-entry phenomenon

541. Phases of action potential of cardiac cells Phase rapid depolarisation (inflow of Na +) Phase 1 partial repolarisation (inward Na + current deactivated, outflow of K + ) Phase 2 plateau (slow inward calcium current) Phase 3 repolarisation (calcium current inactivates, K + outflow) Phase 4 pacemaker potential (Slow Na + inflow, slowing of K + outflow) ‘autorhythmicity’ Refractory period (phases 1-3) Phase 4 II Phase Phase 1 Phase 3 mV - 80 mV I III IV Phase 2

542. Cont … Phase 0: Fast sodium channels are responsible for initial rapid depolarization Phase 1: Early fast repolarization (K + efflux) Phase 2: Prolonged depolarization “plateau” due to slow calcium influx Phase 3: Repolarization due to closing of the calcium channels and potassium efflux Phase 4: Resting membrane potential is restored

543. Goals of Treatment The goal of treatment for patients with arrhythmias is preferably to return the heart to sinus rhythm, or failing that, at least to stabilize the rate. Treatment options are pharmacological ( eg , amiodarone, lidocaine, atenolol), ablative (destruction of the malfunctioning tissue) or electrical to correct the rhythm.

544. Drug therapy Anti-arrhythmic drug therapy is used to control the frequency and severity of arrhythmias, with the aim of maintaining sinus rhythm where possible. The drugs can be grouped according to their electrophysiological effects at a cellular level, using a system known as the Vaughan Williams classification . Alternatively, drug therapies can be divided according to their main sites of action within the heart.

545. Vaughan Williams classification All anti-arrhythmic drugs act by altering the movement of electrolytes within the electrical conduction pathways of the myocardium. The Vaughan Williams classification system groups drugs according to their ability to block the movement of one or more of these ions across the myocardial cell membrane.

546. Vaughan Williams Classification of antiarrhythmic drugs Class I: Sodium channel blockers Class II: β- Adrenergic blockers Propranolol, acebutolol, esmolol Class III: Potassium channel blockers Amiodarone, bretylium, sotalol Class IV: calcium channel blockers Verapamil, diltiazem Miscellaneous Adenosine, Digoxin Atropine Note Paroxysmal Supra Ventricular Tachycardia PSVT:

547. Class I: Sodium channel blockers Class I drugs act by blocking the fast sodium channels and therefore delay the rise in phase 0 of the action potential. Can be subdivided into: IA: Prolong repolarization, increase the duration of the action potential Quinidine, procainamide, disopyramide IB: Shorten repolarization, shorten the action potential Lignocaine, mexiletine , phenytoin IC: Little effect on repolarization, no effect on action potential duration Encainide , flecainide , propafenone

548. Class I: Sodium channel blockers IA: Prolong repolarization Quinidine, procainamide, disopyramide IB: Shorten repolarization Lignocaine, mexiletine , phenytoin IC: Little effect on repolarization Encainide , flecainide , propafenone

549. Class IA

550. Quinidine D- isomer of quinine obtained from cinchona bark MOA: blocks sodium channels ↓ automaticity , conduction velocity and prolongs repolarization ↓phase depolarization , ↑ APD & ↑ERP Uses: Atrial and ventricular arrhythmias Adverse effects: Arrhythmias and heart block , hypotension, QT prolongation GIT , thrombocytopenia, hepatitis , idiosyncratic reactions High doses – cinchonism like quinine

551. Procainamide: Derivative of procaine No vagolytic or α-blocking action unlike quinidine Better tolerated Adverse effects: Nausea, vomiting and hypersensitivity reactions Higher doses can cause hypotension, heart block and QT prolongation Disopyramide: Significant anticholinergic properties: Dry mouth, blurred vision, constipation, urinary retention

552. Class IB drugs Lignocaine, phenytoin, mexiletine Block sodium channels also shorten repolarization

553. Ligno c aine Local anesthetic Raises threshold for action potential, ↓automaticity Suppress electrical activity of arrhythmogenic tissues, normal tissues less effected High first pass metabolism so given parenterally Use: ventricular arrhythmias Adverse effects: – Drowsiness, hypotension, blurred vision, confusion and convulsions

554. Phenytoin: Antiepileptic also useful in ventricular arrhythmias (not preferred) and digitalis induced arrhythmias Mexiletine: Can be used orally causes dose related neurological adverse events like tremors and blurred vision Nausea is common Used as alternative to lignocaine in ventricular arrhythmias

555. Class I C drugs Encainide, Flecainide, Propafenone Have minimal effect on repolarization Are most potent sodium channel blockers Risk of cardiac arrest , sudden death so not used commonly May be used in severe ventricular arrhythmias

556. Class I drugs and their primary indications Class of drug Drug Primary indication Class 1A Quinidine Procainamide Disopyramide  Atrial fibrillation Ventricular arrhythmias   Class 1B Lidocaine Mexilitene Phenytoin Ventricular arrhythmias Class 1C Flecainide Propafenone  AV nodal re-entry Wolff-Parkinson White syndrome-related arrhythmias Ventricular arrhythmias (but increased risk of mortality

557. Class II drugs Suppress adrenergically mediated ectopic activity Antiarrhythmic action due to of β blockade Depress myocardial contractility, automaticity and conduction velocity Propranolol: Treatment & prevention of supraventricular arrhythmias especially associated with exercise, emotion or hyperthyroidism Esmolol: IV short acting can be used to treat arrhythmias during surgery , following MI & other emergencies

558. ↑APD & ↑RP by blocking the K + channels Class III drugs

559. Amiodarone Iodine containing long acting drug Mechanism of action: (Multiple actions) Prolongs APD by blocking K + channels blocks inactivated sodium channels β blocking action , Blocks Ca 2+ channels ↓ Conduction, ↓ectopic automaticity Pharmacokinetics: Variable absorption 35-65% Slow onset 2days to several weeks Duration of action : weeks to months Many drug interactions

560. Amiodarone Uses: Can be used for both supraventricular and ventricular tachycardia Adverse effects: Cardiac: heart block , QT prolongation, bradycardia , cardiac failure, hypotension Pulmonary: pneumonitis leading to pulmonary fibrosis Bluish discoloration of skin GIT disturbances, hepatotoxicity Blocks peripheral conversion of T4 to T3 can cause hypothyroidism or hyperthyroidism

561. Other Class III Drugs Bretylium: Adrenergic neuron blocker used in resistant ventricular arrhythmias Sotalol: Beta blocker Dofetilide : Selective K + channel blocker, less adverse events Oral use in AF to convert or maintain sinus rhythm Ibutilide : K + channel blocker used as IV infusion in AF or flutter can cause QT prolongation

562. Calcium channel blockers (Class IV) Inhibit the inward movement of calcium ↓ contractility, autom at icity , and AV conduction. Verapamil & diltiazem

563. Verapamil Uses: Terminate PSVT control ventricular rate in atrial flutter or fibrillation Drug interactions: Displaces digoxin from binding sites ↓ renal clearance of digoxin

564. Other antiarrhythmics Adenosine : Purine nucleotide having short and rapid action Mechanism of action: Acetylcholine sensitive K+ channels and causes membrane hyperpolarization through interaction with A 1 type of adenosine GPCRs on SA node IV suppresses automaticity, AV conduction and dilates coronaries Drug of choice for PSVT Adverse events: Nausea, dyspnoea , flushing, headache Atropine: Used in sinus bradycardia , AV block Digitalis: Atrial fibrillation and atrial flutter Magnesium SO 4 : digitalis induced arrhythmias

565. Classification of drug according to principal site of action  Site of action  Anti-arrhythmic drug Action  AV node Verapamil, dilatiazem, adenosine, digoxin, beta-blockers  Delay AV nodal conduction Useful for control of supra-ventricular tachycardias  Ventricles Lignocaine, mexelitine, phenytoin  Control of ventricular arrhythmias  Atria, ventricles and accessory pathways  Quinidine, disopyramide, amiodarone, flecainide, procainamide, propafenone Effective in both supra-ventricular tachycardia and ventricular arrhythmias 

566. Nursing Considerations for Antiarrhythmic drugs Assess for the mentioned contraindications to this drug (e.g. renal dysfunction, heart blocks, hypersensitivity, etc.) to prevent potential adverse effects. Conduct thorough physical assessment before beginning drug therapy to establish baseline status, and to evaluate potential adverse effects. Assess cardiac status closely (e.g. blood pressure, heart rate and rhythm, heart sounds, ec. ) to determine whether change in drug dose is imperative. Monitor laboratory test results including complete blood count, renal and liver function tests to determine the need for possible change in dose and identify toxic effects.

567. Nursing Intervention These are vital nursing interventions done in patients who are taking antiarrhythmic drugs: Titrate the dose to the smallest amount enough to manage arrhythmia to decrease the risk of drug toxicity. Monitor cardiac rhythm closely to detect potentially serious adverse effects and to evaluate drug effectiveness. Ensure maintenance of emergency drugs and equipment at bedside to promote prompt treatment in cases of severe toxicity. Educate patient on drug therapy including drug name, its indication, and adverse effects to watch out for to enhance patient understanding on drug therapy and thereby promote adherence to drug regimen.

568. References Karch , A. M., & Karch . (2011).  Focus on nursing pharmacology . Wolters Kluwer Health/Lippincott Williams & Wilkins. [ Link ] Katzung , B. G. (2017).  Basic and clinical pharmacology . McGraw-Hill Education. Lehne , R. A., Moore, L. A., Crosby, L. J., & Hamilton, D. B. (2004). Pharmacology for nursing care. Smeltzer , S. C., & Bare, B. G. (1992).  Brunner & Suddarth’s textbook of medical-surgical nursing . Philadelphia: JB Lippincott

569. Anti Anginal Drugs C By: Muhammad Aurangzeb Lecturer-INS/KMU

570. Objectives By the completion of this section the learners will be able to: Discuss the main classes of drugs that are used for treating AP. Discuss the nursing responsibility of each class of drugs. Calculate the drug dosage accurately while administering oral and parenteral medications.

571. Angina pectoris (AP) Angina pectoris – chest pain due to imbalance between the oxygen requirement of the heart and oxygen supplied to it via the coronary vessels.

572. Definition of terms Angina Pectoris – is the principal symptoms of patient with ischemic heart disease. Manifested by sudden, severe, pressing substernal pain that often radiates to the left shoulder and along the flexor surface of the left arm. Usually precipitated by exercise, excitement or a heavy meal.

573. Cont… Myocardial ischemia which produces a ngina results from imbalances in myocardial oxygen supply & demand relationship such as decreased oxygen supply and/or increased oxygen demand. Etiology Decrease oxygen supply Increase demand for oxygen

574. Types of angina Atherosclerotic angina (classic angina [common form]) : Attacks are predictably provoked (stable angina) by exercise, emotion, eating and subside when the increased energy demand is withdrawn. Rest, by reducing cardiac work, usually leads to complete relief of the pain within 15 min. Atherosclerotic angina constitutes about 90% of angina cases. S econdary to advanced atherosclerosis of the coronary vessels A ssociated with ST-segment depression on ECG

575. Types of angina V asospa s t i c angi n a ( r e s t angina, variant angina, or Prinzmetal’s angina [uncommon form]) : Attacks occur at rest or during sleep. Vasospastic angina is responsible for less than 10% of angina cases. A ssociated with ST-segment elevation on ECG S econdary to vasospasm of the coronary V essels Coronary artery calibre changes in classical and variant angina

576. Types of Angina Unstable angina (crescendo angina, also known as acute coronary syndrome) : It is characterized by increased frequency and severity of attacks that result from a combination of atherosclerotic plaques, platelet aggregation at fractured plaques, and vasospasm. the duration of manifestation is longer than the first two and has the manifestation of Myocardial infarction R e f ere n ce : Drug s Used in t h e T r e a t m e n t o f Ang i n a P e c t o ri s . In : T r ev o r A J , K a t z un g BG, K ru i d eri n g -Hall M. e d s. K at z un g & T r e vor's Phar m a c o l ogy : E x am i na t i o n & B oar d R e vi e w , 1 1 e N e w Y o rk, N Y : M c G r a w -Hill; 2 1 5 .

577. T r e a tme n t of Angina P ec t oris D r ug s use d in angi n a e xp l o it t w o main s t r at egie s: r educt io n o f o x y g en de m and i nc r ease o f o x y g en de li v e r y t o the m y o c a r d i um

578. Classifi c a tion of a n tianginal drugs Nitrates Short acting: Glyceryl trinitrate (GTN, Nitroglycerine) Long acting: Isosorbide dinitrate (short acting by sublingual route), Isosorbide, mononitrate, β Blockers: Propranolol, Metoprolol , Atenolol and others. Calcium channel blockers Phenyl alkylamine : Verapamil Benzothiazepine : Diltiazem Dihydropyridines: Nifedipine,, Amlodipine, Nitrendipine , Nimodipine ,

579. Classifi c a tion of a n tianginal drugs Clinical classification Used to abort or terminate attack: GTN ( angisid ), Isosorbide dinitrate (sublingually). Used for chronic prophylaxis: All other drugs.

580. Antianginal drugs I. Agents which ↓ O 2 demand & ↑ O 2 Supply A. Nitrates B. Calcium channel blockers II . Agents which ↓ O 2 demand Beta blockers

581. Nit r a t es / O r g anic Nit r a t es Preload reduction: Peripheral pooling of blood → decreased venous return (preload reduction). Afterload reduction: Nitrates also produce some arteriolar dilatation → slightly decrease total peripheral resistance or afterload on heart. Redistribution of coronary flow: In the arterial tree, nitrates preferentially relax bigger conducting ( angiographically visible) coronary arteries than arterioles or resistance vessels.

582. Nit r a t es / O r g anic Nit r a t es Mechanism of action: The organic nitrate agents are prodrugs that are sources of NO. NO activates the soluble isoform of guanyl cyclase , thereby increasing intracellular levels of cGMP . In turn, cGMP promotes the dephosphorylation of the myosin light chain and the reduction of cytosolic Ca 2+ and leads to the relaxation of smooth muscle cells in a broad range of tissues. References: Eschenhagen T. Treatment of Ischemic Heart Disease. In: Brunton LL, Hilal-Dandan R, Knollmann BC. eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e New York, NY: McGraw-Hill

583. Nitrates Coronary artery dilatation Decrease coronary bed resistance (Relieved coronary vasospasm) Increase coronary blood flow Increase oxygen supply

584. Nitrates Reduction on peripheral resistance (Secondary to dilatation of aorta) Decrease blood pressure Decrease after load Decrease workload Decrease oxygen consumption

585. Nitrates Reduced venous return (Due to dilatation of the veins) Decrease left ventricular volume Decrease preload Decrease workload Decrease oxygen consumption

586. Effects 1. Coronary artery dilatation 2. Reduction of peripheral arterial resistance – decrease after load 3. Reduce venous return – decrease preload

587. Pharmacokinetics of Nit r a t es / O r g anic Nit r a t es Organic nitrates are lipid soluble, well absorbed from buccal mucosa, intestines and skin. Ingested orally, all except isosorbide mononitrate undergo extensive and variable first pass metabolism in liver. They are rapidly denitrated by a glutathione reductase and a mitochondrial aldehyde dehydrogenase.

588. Uses of Nit r a t es / O r g anic Nit r a t es Angina pectoris: GTN produces relief within 3 min in 75% patients, the rest may require another dose or take longer (up to 9 min). Acute coronary syndromes: Nitrates are useful by decreasing preload as well as by increasing coronary flow. Myocardial infarction (MI): GTN is frequently used during evolving MI with the aim of relieving chest pain and limiting the area of necrosis by favorably altering O 2 balance in the marginal partially ischemic zone.

589. Adverse effects Nit r a t es / O r g anic Nit r a t es Headache is the most common adverse effect of nitrates. High doses of nitrates can also cause postural hypotension, facial flushing, and tachycardia. Phosphodiesterase type 5 inhibitors such as sildenafil potentiate the action of the nitrates. To prevent the dangerous hypotension that may occur, this combination is contraindicated.

590. β Blo c k e r s The β-adrenergic blockers decrease the oxygen demands of the myocardium by blocking β 1 receptors, resulting in decreased heart rate, contractility, cardiac output, and blood pressure. All β blockers are nearly equally effective in decreasing frequency and severity of attacks and in increasing exercise tolerance in classical angina, but cardioselective agents (atenolol, metoprolol ) are preferred over nonselective β 1 + β 2 blockers (e.g. propranolol).

591. Hemodynamics Effects Decrease heart rate Reduced blood pressure and cardiac contractility without appreciable decrease in cardiac output B-Blockers

592. B-Blockers Decrease heart rate & Contractility Increase duration of diastole Decrease workload Increase coronary blood flow Increase oxygen supply Decrease O 2 consumption

593. Calciu m channe l bloc k e r s Phenyl alkylamine: Verapamil Benzothiazepine: Diltiazem Dihydropyridines: Nifedipine, Felodipine , Amlodipine, Nitrendipine , Nimodipine , Lacidipine , Lercanidipine , Benidipine

594. Calciu m channe l bloc k e r s Pharmacol ogi c al actio n s : S moot h m u scl e : T h e CC B s c a us e r el a x a ti o n b y d ec r eas i ng i n t r a c ell u l a r a v ailabili t y o f Ca 2 + . T h e d i h y d r o p yri d i n e s (DHPs) e.g. amlodipine have the most marked smooth muscle relaxant and vasodilator action; verapamil is somewhat weaker followed by diltiazem .

595. Calciu m channe l bloc k e r s Pharmacological actions: Heart: calcium channel blockers protect the tissue by inhibiting the entrance of calcium into cardiac and smooth muscle cells of the coronary and systemic arterial beds and decreases smooth muscle tone and vascular resistance, afterload .

596. Ca - Channel Blockers Effects 2. Coronary artery dilatation 3. Reduction on peripheral arterial resistance – decrease after load

597. Ca Channel Blockers Coronary artery dilatation Decrease coronary bed resistance (Relieved coronary vasospasm) Increase coronary blood flow Increase oxygen supply

598. Ca channel Blockers Reduction on peripheral resistance ( Secondary to dilatation of aorta ) Decrease blood pressure Decrease after load Decrease workload Decrease oxygen consumption

599. Calciu m channe l bloc k e r s Phenyl alkylamine: Verapamil: It dilates arterioles and decreases total peripheral resistance. It slows atrioventricular (AV) conduction directly and decreases heart rate, contractility, blood pressure, and oxygen demand. It also has some α adrenergic blocking activity. Verapamil has greater negative inotropic effects than amlodipine, but it is a weaker vasodilator. Verapamil should not be given with β blockers, digoxin, cardiac depressants like quinidine and disopyramide .

600. Calciu m channe l bloc k e r s Benzothiazepine: Diltiazem: Diltiazem also slows AV conduction, decreases the rate of firing of the sinus node pacemaker, and is also a coronary artery vasodilator. Diltiazem can relieve coronary artery spasm and is particularly useful in patients with variant angina. It is somewhat less potent vasodilator than nifedipine and verapamil, and has modest direct negative inotropic action, but direct depression of SA node and A-V conduction are equivalent to verapamil.

601. Calciu m channe l bloc k e r s Dihydropyridine (DHP) calcium channel blockers: Nifedipine: Nifedipine is the prototype DHP with a rapid onset and short duration of action. It causes arteriolar dilatation and decreases total peripheral resistance. Nifedipine is usually administered as an extended-release oral formulation. It causes direct depressant action on heart in higher dose.

602. Adverse effects of CCBs Frequent side effects are palpitation, flushing, ankle edema, hypotension, headache, drowsiness and nausea. Nifedipine has paradoxically increased the frequency of angina in some patients.

603. Uses Calciu m channe l bloc k e r s Calcium channel blockers can be safely given to patients with peripheral vascular disease in whom β blockers are contraindicated. CCB are used for the treatment of angina pectoris hypertension cardiac arrhythmias

604. References Karch , A. M., & Karch . (2011).  Focus on nursing pharmacology . Wolters Kluwer Health/Lippincott Williams & Wilkins. [ Link ] Katzung , B. G. (2017).  Basic and clinical pharmacology . McGraw-Hill Education. Lehne , R. A., Moore, L. A., Crosby, L. J., & Hamilton, D. B. (2004). Pharmacology for nursing care. Smeltzer , S. C., & Bare, B. G. (1992).  Brunner & Suddarth’s textbook of medical-surgical nursing . Philadelphia: JB Lippincott

605. Anti-Hypertensive Drugs D By: Muhammad Aurangzeb Lecturer-INS/KMU

606. Objectives By the completion of this section the learners will be able to: Discuss the pharmacological management of hypertension and hypertensive crisis. Discuss the nursing responsibility related to antihypertensive drugs. Calculate the drug dosage accurately while administering oral and parenteral medications.

607. Hyper t ens i o n Most common CVS condition Persistent and sustained increased BP has damaging effect on heart, brain, kidney, eye Types Primary /essential No specific cause 95% cases Secondary hypertension Due to specific disease or drug 5% cases

608. E tiology of Hyper t ension A specific cause of hypertension established in only 5-10% of patients. Patients in whom no specific cause of hypertension are said to have essential or primary hypertension . Patients with a specific etiology are said to have secondary hypertension . Genetic factors, psychological stress, and environmental and dietary factors as contributing to the development of hypertension. The heritability of essential hypertension is estimated to be about 30%.

609. Hypertension means when the blood pressure is higher than 140/ 90 mmHg Classification of hypertension on the basis of blood pressure

610.  Baroreceptors and sympathetic nervous system Baroreceptors  are pressure sensors. They are located in the carotid sinus and in the aortic arch. Their function is to sense pressure changes. Baroreflex  or  baroreceptor reflex  is a homeostatic mechanisms that helps to maintain blood pressure at nearly constant levels. Homeostasis is a process by which biological systems tend to maintain stability while adjusting to conditions. If  homeostasis  is successful, life continues; if unsuccessful, disaster or death occur

611. Normal R egul a tion of Blood P r essu r e According to the hydraulic equation, arterial blood pressure (BP) is directly proportionate to the product of the blood flow (cardiac output, CO) and the resistance to passage of blood through precapillary arterioles (peripheral vascular resistance, PVR) BP = CO × PVR

612. Ang io t ens i n I Ang i o t ens i n II Al do s t e r one Na+ r e t e n ti on V o l um e ↑ Ar t e r i o l ar w all ↑ Bl o o d p r essu r e R en i n Ce n t r al Mechani sms H y potha lamus S ymp a th e tic Gan g lia P o s t g angli on i c ad r en e r gi c ne r v e end ings Ba r o r e c e p t o r s P h y s i o l og y o f Hyper t ens i o n

613. Physiological mechanisms involved in hypertension 1. Cardiac output and peripheral resistance : normal blood pressure is subject to balance between the cardiac output and peripheral vascular resistance . Most patients with hypertension have a normal cardiac output but a raised peripheral resistance. Peripheral resistance is determined by small arterioles, the walls of which contain smooth muscle cells. In some cases of hypertension the peripheral resistance is not raised and the elevation of the blood pressure is caused by a raised cardiac output, which is related to sympathetic overactivity.

614. 2. Renin-angiotensin system: The renin-angiotensin system is the most important of the endocrine systems affecting the blood pressure. Renin is secreted from the juxtaglomerular apparatus of the kidney in response to glomerular under-perfusion or a reduced salt intake. It is also released in response to stimulation from the sympathetic nervous system . Renin is responsible for converting renin angiotensinogen to angiotensin I, a physiologically inactive substance which is rapidly converted to angiotensin II angiotensin converting enzyme (ACE). Angiotensin II is a potent vasoconstrictor Angiotensin II stimulates the release of aldosterone from the adrenal gland

615. The renin-angiotensin system (RAS) plays an integral role in blood pressure regulation

616. A n ti h yper t ensi v e a g e n ts Diu r e tics Th iazi des : H y d r och l o r oth iazi de , Ch l ortha li don e , H igh c e ili ng : Fu r o s emi d e , K+ Spa r i ng : Sp i r on o l a c t one , Ami l or i de A C E i n h i b i t o r s C a p t opr il, En alapri l , L i s i n o pr i l , P e r i ndopr il , Rami pr i l , Fosinopril , etc. Angiotensin (AT1 receptor) blockers: Losartan, Candesartan, Irbesartan , Valsartan, Telmisartan Direct renin inhibitor: Aliskiren β Adrenergic blockers: Propranolol, Metoprolol, Atenolol, etc.

617. A n ti h yper t ensi v e a g e n ts Calcium channel blockers Verapamil, Diltiazem , Nifedipine , Felodipine , Nitrendipine , Lacidipine , Aml od i p i n e, etc. β + α Adrenergic blockers: Labetalol, Carvedilol α Adrenergic blockers: Prazosin , D o x a z o s i n , Terazosin, Phentolamine , Phenoxybenzamine Central sympatholytics : Clonidine, Methyldopa Vasodilators Hydralazine,

618. Sites of action of the major classes of antihypertensive drugs

619. Diu re tics Thiazid e diur e tics: Th iazi d e d i u r e t i c s , s u c h h y d r o c hl o r othi azi de as and chl ortha l i d on e, l ow er blo o d pressure increasing i n it i a l l y by sod iu m and water excretion. diuretics can Thiazide induce h ypo k al e m i a , and, to a lesser hyperglycemia in patients. extent, some

620. Diu re tics Loop diuretics: The loop diuretics act promptly by blocking sodium and chloride reabsorption in the kidneys, even in patients with poor renal function or those who have not responded to thiazide diuretics. Loop diuretics cause decreased renal vascular resistance and increased renal blood flow.

621. Diu re tics K+ Sparing: potassium-sparing diuretics ( spironolactone ) are competitive antagonists that either compete with aldosterone, or directly block epithelial sodium channel ( amiloride ).

622. A C E in h ibi t o r s Renin Inhibitors ACE Inhibitors Angiotensin blockers

623. A C E in h ibi t o r s The ACE inhibitors, are recommended as first-line treatment of hypertension in patients with a variety of compelling indications, including high coronary disease risk or history of diabetes, stroke, heart failure, myocardial infarction, or chronic kidney disease.

624. A C E in h ibi t o r s ACE is also responsible for the breakdown of bradykinin , a peptide that increases the production of nitric oxide and prostacyclin by the blood vessels. Both nitric oxide and prostacyclin are potent vasodilators .

625. A C E in h ibi t o r s ACE inhibitors decrease angiotensin II and increase bradykinin levels. Vasodilation is result of decreased vasoconstriction ( from diminished levels of angiotensin II ) and enhanced vasodilation ( from increased bradykinin ). By reducing circulating angiotensin II levels, ACE inhibitors also decrease the secretion of and ald o s t e r on e , r e s ul t i n g i n d e c r e a se d s od i um water retention. ACE inhibitors reduce both cardiac preload and afterload , thereby decreasing cardiac work .

626. A C E in h ibi t o r s Adverse effects of ACE inhibitors: The adverse effect profile of all ACE inhibitors is similar. Captopril is well tolerated by most patients, especially if daily dose is kept below 150 mg. Hypo t ensi o n : A n i n i t i al shar p f all i n BP especia l l y i n diu r e tic t r e at ed and CH F p a tie n ts Hy per k alaemia Cough R a shes , urt i c aria Ang ioe d ema oc c u r s

627. A C E in h ibi t o r s Ad v a n t a g e s o f A C E inh i bi t or : F r ee of p o s t u r al h y p o t en s i on , elect r o l y t e disturbances, feeling of weakness and CNS effects Safety in asthmatics, diabetics No rebound hypertension on withdrawal

628. Uses o f A C E inhibi t o r s Hypertension: The ACE inhibitors are first line drugs in all grades of hypertension , but the angiotensin receptor blockers (ARBs) have now surpassed them in popularity. Essential hypertension respond to monotherapy with ACE inhibitors and majority of the rest to their combination with diuretics or beta blockers.

629. Uses o f A C E inhibi t o r s Congestive Heart Failure (CHF): ACE inhibitors cause both arteriolar and venodilatation in CHF patients; reduce afterload as well as preload. Myocardial infarction: Long-term ACE inhibitor therapy reduces recurrent MI. Prophylaxis in high cardiovascular risk subjects: ACE inhibitors are protective in high cardiovascular risk subjects even when there is no associated hypertension or left ventricular dysfunction. ACE inhibitors may improved endothelial function.

630. Angio t ensi n a n t a g oni s ts (ARBs) Angiotensin antagonists: losartan, candesartan, valsartan, telmisartan. Their pharmacologic effects of ARBs are similar to those of ACE inhibitors. ARBs produce arteriolar and venous dilation and block aldosterone secretion, thus lowering blood pressure and decreasing salt and water retention. ARBs do not increase bradykinin levels . ARBs may be used as first-line agents for the treatment of hypertension, especially in patients with a compelling indication of diabetes, heart failure, or chronic kidney disease .

631. Di r ec t r eni n inhibi t or A selective renin inhibitor, aliskiren directly inhibits renin and, thus, acts earlier in the renin– angiotensin–aldosterone system than ACE inhibitors or ARBs. It lowers blood pressure about as effectively as ARBs, ACE inhibitors, and thiazides. Aliskiren should not be routinely combined with an ACE inhibitor or ARBs . Aliskiren can cause diarrhea, especially at higher doses, and can also cause cough and angioedema, but probably less often than ACE inhibitors. Aliskiren is contraindicated during pregnancy.

632. β-adrenergic blockers β-adrenergic blockers are mild antihypertensives and do not significantly lower BP in normotensives. In stage 1 cases of hypertensive patients (30 - 40%), β- adrenergic blockers are used alone.

633. β - ad r ene r gi c bloc k e r s Propranolol Propranolol is a first β blocker showed effective in hypertension and ischemic heart disease. Propranolol has now been largely replaced by cardioselective β blockers such as metoprolol and atenolol . hypertension. In severe hypertension, β blockers are especially useful in preventing the reflex tachycardia that often results from treatment with direct vasodilators. All β - a d r enoce pt o r - b l ock i ng a g e n ts a r e us e fu l f or l ow er i n g b l o o d p r e ss u r e i n mild to mode r at e

634. β - ad r ene r gi c bloc k e r s Metoprolol & Atenolol Metoprolol and atenolol, which are cardioselective , are the most widely used β blockers in the treatment of hypertension. Metoprolol is atenolol is inhibiting stimulation of β1 adrenoceptors. Sustained-release metoprolol is effective in reducing mortality from heart failure and is particularly useful in patients with hypertension and heart failure. Atenolol is reported to be less effective than metoprolol in preventing the complications of hypertension.

635. β - ad r ene r gi c bloc k e r s Other b e t a bloc k ers Lab e t al o l, Ca r v ed i l o l, & Neb i v o l o l h a v e bot h β - blocking and vasodilating effects. Esmolol is a β1-selective blocker that is rapidly metabolized via hydrolysis by red blood cell esterases. Esmolol is used for management of intraoperative and postoperative hypertension , and sometimes for hypertensive emergencies , particularly when hypertension is associated with tachycardia or when there is concern about toxicity such as aggravation of severe heart failure .

636. α -Ad r ene r gi c bloc k e r s Prazosin , terazosin, and doxazosin Prazosin is a prototype α 1 -adrenergic blocking agent. Terazosin and doxazosin are long-acting congeners of prazosin Alpha blockers reduce arterial pressure by dilating both resistance and capacitance vessels. Other alpha- adrenoceptor blocking agents phe n t o la m ine ( r e v e r s i b le n o nsel ecti v e α -a d r ene r gic antagonist) and phenoxybenzamine (non-selective, irreversible alpha blocker) are useful in diagnosis and treatment of pheochromocytoma .

637. Ce n t r ally a cting ad r ene r gi c drugs Clonidi ne C l on i d i ne acts c e n t r ally as an α 2 a g on i s t t o p r o d u c e inhibition of sympathetic vasomotor centers, decreasing sympathetic outflow to the periphery. This leads to reduced total peripheral resistance and decreased blood pressure. At present, it is occasionally used in combination with a diuretic. Methyldopa It is an α 2 a g on i s t th a t is c o n v er t e d to methylnorepinephrine centrally to diminish adrenergic outflow from the CNS . It is mainly used for management of hypertension in pregnancy, where it has a record of safety.

638. Vasodilators Hydralazine/ Dihydralazine and minoxidil not used as primary drugs to treat hypertension. These vasodilators act by producing relaxation of vascular smooth muscle, primarily in arteries and arterioles. This results in decreased peripheral resistance. Both agents produce reflex stimulation of the heart, resulting in the competing reflexes of increased myocardial contractility, heart rate, and oxygen consumption. Hydralazine is an accepted medication for controlling blood pressure in pregnancy induced hypertension.

639. Note K chan nel opener
Minoxidil Causes hyperpolarization of vascular smooth muscles , vasodilation and decrease BP

640. Fenoldopam Fenoldopam: Fenoldopam is an agonist of peripheral dopamine D1 receptors. It is used as a rapid-acting vasodilator to treat severe hypertension in hospitalized patients.

641. Hyp e r t en s i v e cr i s is Hypertensive urgencies DBP>120 mm Hg or higher with impending complications or progressive target organ damage such as stroke, myocardial infarction DBP needs to be reduced to 100 mm Hg in 24-48 hrs Severe epistaxis Unstable angina Hypertensive emergencies Evidence of target organ damage AMI, LVF, Encephalopathy Rapid lowering of BP within 1 hr to 150/100 mm hg

642. Drug s us e d in h yper t ens i v e cri s is S o d i u m n i t r opru s s i de Ni t r o g l y ceri ne Labe t o l ol N i f ed ip i ne Cap t opr il IV Sub l i n gual

643. Summary of WHO-ISH and British Hypertension Society (BHS) 2004, guidelines Except for stage II hypertension, start with a single most appropriate drug Follow A B C D rule (A—ACE inhibitor/ARB; B—β blocker; C—CCB, D—diuretic). While A and (in some cases) B are preferred in younger patients (<55 years), C and D are preferred in the older (> 55 years) for the step I or monotherapy. Initiate therapy at low dose; if needed increase dose moderately. If only partial response is obtained, add a drug from another complimentary class or change to low dose combination

644. Summary of WHO-ISH and British Hypertension Society (BHS) 2004, guidelines If no response, change to a drug from another class, or low dose combination from other classes In case of side effect to the initially chosen drug, either substitute with drug of another class or reduce dose Majority of stage II hypertensives are started on a 2 drug combination

645. Antihypertensive to be avoided in pregnancy D i u r e tics Ri s k o f p lace n t al w a st a g e, s ti l l bi rths A C E i nh i b i t o r s Ri s k o f f e t al dama g e, g r owth r e t a r d a t i on B e t a b l oc k er L B W , neon a t al b r ad y c a r di a, h y p og l y cemia

646. S a f e drug s in p r egnancy H y d r alaz i ne A l ph a m e t h yl dopa CCBs P r a z os in C l on i d i ne Ca r d i ose lect i v e b e t a b l oc k e r s

647. Tha n k y ou

648. Nursing Responsibilities If patient is on antihypertensive medications,  blood pressure is assessed  to  determine the effectiveness  and  detect changes  in the blood pressure. Complete history  should be obtained to assess for signs and symptoms that indicate target organ damage. Pay attention to the rate, rhythm, and character of the apical and peripheral pulses.

649. Nursing Interventions Encourage the patient to  consult a dietitian  to help develop a plan for improving nutrient intake or for weight loss. Encourage  restriction of sodium and fat Emphasize  increase intake of fruits and vegetables . Implement regular  physical activity . Advise patient to  limit alcohol  consumption and avoidance of tobacco. Assist the patient to develop and adhere to an  appropriate exercise regimen. 

650. References Karch , A. M., & Karch . (2011).  Focus on nursing pharmacology . Wolters Kluwer Health/Lippincott Williams & Wilkins. [ Link ] Katzung , B. G. (2017).  Basic and clinical pharmacology . McGraw-Hill Education. Lehne , R. A., Moore, L. A., Crosby, L. J., & Hamilton, D. B. (2004). Pharmacology for nursing care. Smeltzer , S. C., & Bare, B. G. (1992).  Brunner & Suddarth’s textbook of medical-surgical nursing . Philadelphia: JB Lippincott

651. UNIT V- E Thrombolytic Therapy By: Muhammad Aurangzeb Lecturer-INS/KMU

652. Objectives By the completion of this section the learners will be able to: Discuss the main classification of thrombolytic therapy. Discus the action of different thrombolytic therapy Discuss the nursing responsibility during thrombolytic therapy

653. Topics to be covered Anticoagulants Fibrinolytics Antiplatelets

654. Blood Components Erythrocytes Leukocytes Platelets Plasma

655. Platelets Platelets, also called thrombocytes. Their function is to stop bleeding by forming a clot.  The normal platelet count is 150,000-450,000 per microliter of blood.

656. What is coagulation of blood? Coagulation or clotting  is the process by which blood forms clots. Clot: Clot is a gel-like mass formed by platelets and fibrin in the blood. Clotting factors and anticoagulants are made in the liver. They have the ability to turn on or turn off as needed.

657. What is Thrombosis? Coagulation or clotting of the blood in a part of the circulatory system is thrombosis. The formation or presence of a blood clot in a blood vessel. The vessel may be any vein or artery as, for example, in a deep vein thrombosis  or a coronary (artery)  thrombosis . The clot itself is termed a  thrombus .

658. What is embolism? An  embolism  is the sticking of an embolus in blood vessel. The embolus may be a blood clot (thrombus), a fat globule (fat  embolism ), a bubble of air or other gas (gas  embolism ), or foreign material.

659. Important to know Prothrombin: Prothrombin is a protein produced by the liver. Prothrombin is present in blood plasma that is converted into active thrombin during coagulation. Prothrombin is converted into  thrombin  by a clotting factor known as factor X or prothrombinase. Function of Thrombin: it is an enzyme that causes the clotting of blood by converting fibrinogen to fibrin Prothrombin activator: Prothrombin activator  is a complex of coagulation factors that functions in catalyzing  prothrombin into thrombin Fibrinogen: Fibrinogen  is the major plasma coagulation factor Antithrombin : it is a small protein molecule that inactivates several enzymes of the coagulation system. (Factors IIa, IXa, Xa ). 

660. Factor I: fibrinogen
Factor II: prothrombin

661. Stages of Blood Clotting In general, blood clotting occurs in three stages: 1. Formation of prothrombin activator 2. Conversion of prothrombin into thrombin 3. Conversion of fibrinogen into fibrin.

662. Anticoagulants (Heparin, Warfarin, Rivaroxaban ) Anticoagulants are those substances which prevent coagulation of blood. Anticoagulants are of three types: 1. Anticoagulants used to prevent blood clotting inside the body, i.e. in vivo (In the living organism). Eg , warfarin 2. Anticoagulants used to prevent clotting of blood that is collected from the body, i.e. in vitro. 3. Anticoagulants used to prevent blood clotting both in vivo and in vitro. Eg heparin Anticoagulants and antiplatelet agents are medicines that reduce blood clotting in an artery, a vein or the heart. In vitro anticoagulants: those that remove calcium ions from the blood to prevent coagulation, such as  citrate ,  oxalate , fluoride, and  ethylene diamine tetra acetic acid  ( EDTA )

663. Stages of blood coagulation

664. Heparin Heparin is a naturally produced anticoagulant in the body. It is produced by mast cells and  basophils . Mechanism of Action of Heparin: It prevents blood clotting by its antithrombin activity. It directly suppresses the activity of thrombin (Combines with antithrombin III (a protease inhibitor present in circulation) and removes thrombin from circulation). Heparin is enhancing the activity of the endogenous inhibitor, antithrombin by 1000 x.

665. Mechanism of action of heparin

666. Heparin Pharmacokinetics Absorption and Distribution: Because of its polarity and large size, heparin is unable to cross membranes, including those of the GI tract. Consequently, heparin cannot be absorbed if given orally, and therefore must be given by injection (IV or subQ ). Since it cannot cross membranes, heparin does not traverse the placenta and does not enter breast milk. Metabolism and Excretion: Heparin undergoes hepatic metabolism and excreted through renal route. Under normal conditions, the half-life is short (about 1.5 hours). However, in patients with hepatic or renal disease, the half-life is increased.

667. Adverse Effects and Contraindications Hemorrhage: bruises, petechiae , hematomas Heparin-Induced Thrombocytopenia . Precautions: hemophilia, increased capillary permeability, peptic ulcer disease Contraindicated: Heparin is contraindicated for patients with thrombocytopenia activated partial thromboplastin time ( aPTT ).

668. The PTT is used to evaluate the coagulation factors XII, XI, IX, VIII, X, V, II (prothrombin), and I (fibrinogen) as well as prekallikrein (PK) and high molecular weight kininogen (HK).
A PT test evaluates the coagulation factors VII, X, V, II, and I (fibrinogen).

669. Congenital antithrombin III deficiency Congenital antithrombin III deficiency leads to increased risk of venous and arterial thrombosis, with an onset of clinical manifestations typically appearing in young adulthood. Congenital absence of protein C Protein C is a circulating anticoagulant, which inactivates Factors V and VIII. Thrombosis occurs in the absence Of this protein. Congenital absence of protein C causes thrombosis and death in infancy. Protien S also anti coagulant.

670. Heparin—Clinical Applications Prophylaxis and treatment of Venous thrombosis (DVT) Pulmonary Embolism(PE) Peripheral arterial embolism Prevention of post-op DVT/PE Treatment of DIC?? Prevention of clotting in surgery Anticoagulant in blood transfusions and dialysis Disseminated intravascular coagulation ( DIC ) is a condition in which blood clots form throughout the body blocking small blood vessels

671. Protamine Sulfate for Heparin Overdose 1 unit of heparin means the amount of heparin that will prevent 1 mL of sheep plasma from coagulating for 1 hour Antidote of heparin: Protamine sulfate Protamine sulfate is an antidote to severe heparin overdose. Protamine is a small protein that has multiple positively charged groups. These groups bond ionically with the negative groups on heparin Dosage of protamine is based on the fact that 1 mg of protamine will inactivate 100 units of heparin. Hence, for each 100 units of heparin in the body, 1 mg of protamine should be injected.

672. Factor X inhibitor Rivaroxaban 2007 Rivaroxaban is an anticoagulant  taken orally Rivaroxaban inhibits both free Factor Xa and Factor Xa bound in the prothrombinase complex Inhibition of Factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi.

673. Why new born babies are given Vitamin K? Newborns are prone to vitamin K deficiency because… 1.Vitamin K is not easily transported across the placental barrier 2.Prothrombin synthesis in the liver is an immature process in newborns, especially when premature. 3.The neonatal gut is sterile, lacking the bacteria that is necessary in Vitamin K synthesis.

674. What is Warfarin ? Warfarin is an anticoagulant used to prevent clots. Vitamin K antagonists act only in vivo and have no effect on clotting if added to blood in vitro. Role of vitamin k: The clotting factors II (prothrombin) VII, IX and X are synthesized as inactive precursors (zymogens) in the liver. Vitamin K act as a Coenzyme for activation.

675. Warfarin

676. Mechanism of action of warfarin Warfarin inhibits the vitamin K-dependent synthesis of clotting factors II, VII, IX and X. Warfarin acts as a substrate for Vit k epoxide reductase and inhibits the conversion of vitamin K epoxide to Vit . K hydroquinone Side effects of warfarin Severe bleeding, including heavier than normal menstrual bleeding. Hematuria Black or bloody stool. Blood in vomiting Blood in sputum.

677. Pharmacokinetics Warfarin is readily absorbed following oral dosing. Once in the blood, about 99% of warfarin binds to albumin. Warfarin molecules that remain free (unbound) can readily cross membranes, including those of the placenta and milk-producing glands warfarin has a long half-life (1.5 to 2 days)

678. Fibrinolytics Blood clot is defined as the mass of coagulated blood which contains RBCs, WBCs and platelets entrapped in fibrin meshwork. RBCs and WBCs are not necessary for clotting process. However, when clot is formed, these cells are trapped in it along with platelets. The trapped RBCs are responsible for the red color of the clot. Fibrinolysis: Lysis of blood clot inside the blood vessel is called fibrinolysis . It helps to remove the clot from lumen of the blood vessel.

679. Fibrin clot

680. Fibrinolysis Lysis of blood clot inside the blood vessel is called fibrinolysis. It helps to remove the clot from lumen of the blood vessel. This process requires a substance called plasmin or fibrinolysin . Plasmin is formed from inactivated plasminogen. Plasminogen is synthesized in the liver. Plasminogen is converted into plasmin by tissue plasminogen activator( tPA ). It is a protein involved in the breakdown of blood clots.

681. Formation of Plasmin Plasmin is formed from inactivated glycoprotein called plasminogen. Plasminogen is synthesized in liver Plasminogen is converted into plasmin by plasminogen activator called urokinase plasminogen activator (u-PA). It is derived from blood.

682. Tranexamic acid is an antifibrinolytic that competitively inhibits the activation of plasminogen to plasmin

683. Fibrinolytics or Thrombolytic drugs Alteplase Reteplase Anistreplase Streptokinase Urokinase

684. Mechanism of action of fibrinolytics Plasmin is produced in the blood to break down fibrin, the major constituent of blood thrombi, thereby dissolving clots once they have fulfilled their purpose of stopping bleeding. Fibrinolytics i.e. streptokinase activate plasminogen to produce plasmin. And plasmin then break down fibrin

685. Side effects Besides risk of serious internal bleeding, other possible risks include: Bruising or  bleeding  at the access site Damage to the blood vessel. Migration of the blood clot to another part of vascular system.

686. Antiplatelets (aspirin, clopidogrel , and Prasugrel ) Antiplatelets are a group of medicines that stop blood cells (called platelets) from sticking together and forming a blood clot.

687. Basic steps Prothrombin activator --> Prothrombin --> Thrombin --> Fibrinogen --> Fibrin Platelets activation: increase expression of glycoprotein IIb / IIIa  ( GPIIb / IIIa , also known as integrin ) . What increase the above? Answer: Thromboxane A2, ADP (adenosine diphosphate), and thrombin.

688. Platelet activation step's

689. Adenosine diphosphate Under normal conditions, platelets circulate in the blood freely and without interaction with one another. ADP is stored in inside platelets and is released upon platelet activation. ADP interacts with a family of ADP receptors found on platelets (P2Y12) which leads to platelet aggregation.

690. What is thromboxane A2? Thromboxane A2 is a type of thromboxane that is produced by activated platelets and has prothrombotic properties It stimulates activation of new platelets as well as increases platelet aggregation. This is achieved by increasing expression of the glycoprotein complex GPIIb/ IIIa .

691. What is thromboxane? Thromboxane  is a member of the family of lipids known as  eicosanoids (lipids) Thromboxane-A synthase, an enzyme found in platelets, converts the arachidonic acid to thromboxane-A2 which activate aggregation of platelets by increasing the expression of the glycoprotein complex GPIIb/ IIIa .

692. How do Clopidogrel and Aspirin act as antiplatelete ? Clopidogrel acts by inhibiting the ADP receptor on platelet cell membranes. The drug specifically and irreversibly inhibits the P2Y12 subtype of ADP receptor, which is important in activation of platelets and cross-linking by the protein fibrin. Aspirin in lower doses(75-150 mg) exert antiplatelet effect by prevent the synthesis of thromboxane A2 by inhibiting Thromboxane-A synthase.

693. Glycoprotein IIb / IIIa Receptor Antagonists The GP IIb / IIIa antagonists cause reversible blockade of platelet GP IIb / IIIa receptors, and thereby inhibit the final step in aggregation As a result, these drugs can prevent aggregation stimulated by all factors, including collagen, TXA 2 , ADP, thrombin, and platelet activation factor. DRUGS: Abciximab , Tirofiban ( aggrastat ),

694. Side Effects Headaches or dizziness. Nausea. Diarrhea or constipation. Indigestion (dyspepsia) Stomach ache or abdominal pain. Nose bleeds . Increased  bleeding

695. Tranexamic acid

696. Mechanism Tranexamic acid  is an antifibrinolytic that competitively inhibits the activation of plasminogen to plasmin

697. Tranexamic acid indications Tranexamic acid: it is used to treat or prevent excessive blood loss from major trauma, post partum bleeding, surgery, tooth removal, nose bleeds (epistaxis)

698. References Karch , A. M., & Karch . (2011).  Focus on nursing pharmacology . Wolters Kluwer Health/Lippincott Williams & Wilkins. [ Link ] Katzung , B. G. (2017).  Basic and clinical pharmacology . McGraw-Hill Education. Lehne , R. A., Moore, L. A., Crosby, L. J., & Hamilton, D. B. (2004). Pharmacology for nursing care. Smeltzer , S. C., & Bare, B. G. (1992).  Brunner & Suddarth’s textbook of medical-surgical nursing . Philadelphia: JB Lippincott

699. Unit: VI-A Drugs Affecting The Respiratory System By: Muhammad Aurangzeb Lecturer-INS/KMU

700. OBJECTIVES By the end of this unit learners will be able to: Define antihistamine, Decongestant, antitussive and expectorant List the drug groups that are used for the COPD and Asthma. Explain the therapeutic effects, side effect, Toxic level and nursing consideration. Calculate the drug dosage accurately while administering oral and parenteral medications .

701. Introduction

702. Common Diseases Affecting the Respiratory Tract Chronic bronchitis – condition caused by chronic respiratory irritation, inflammation, and characterized by increased secretions and infection Emphysema – disease characterized by destruction of alveoli, labored respiratory gas exchange, and shortness of breath Asthma – inflammatory disease of the respiratory passageways characterized by bronchoconstriction and shortness of breath

703. Reactive Airway Disease (Asthma) Asthma is a chronic disease of respiratory system. In asthma the bronchi of the lungs become constricted causing difficulty in breathing. In addition, there is smooth muscle spasm and excessive bronchial secretion, and inflammation.

704. Chronic Obstructive Pulmonary Disease (COPD) Chronic obstructive pulmonary disease (COPD) refers to a group of disorders that damage the lungs. These disorders make breathing increasingly difficult over time. The most common forms of COPD are chronic bronchitis and emphysema. Both are chronic illnesses that impair airflow in the lungs. Most cases of COPD are related to cigarette smoking, breathing in pollution, genetics, or a history of lung infections can increase your risk for COPD.

705. Inflammatory Mediators of the Respiratory Tract Histamine Eosinophilic chemotactic factor of anaphylaxis (ECF-A) Prostaglandins and leukotrienes Slow-reacting substance of anaphylaxis (SRS-A)

706. Antihistamines Drugs that directly compete with histamine for specific receptor sites. There are two histamine receptors such as H1 and H2. H1 antagonists are commonly referred to as antihistamines. Antihistamines have many properties antihistaminic, anticholinergic, sedative. 10-20% population has environmental allergies Histamine-mediated disorders Allergic rhinitis, anaphylaxis, angioneurotic edema, drug fevers, insect bite reactions, urticaria

707. Cont. Antihistamines: Mechanism of Action: Block action of histamine at H1 receptor sites. Compete with histamine for binding at unoccupied receptors. Cannot push histamine off the receptor if already bound. The binding of H1 blockers to the histamine receptors prevents the adverse consequences of histamine stimulation, such as vasodilation, increased GI and respiratory secretions, and increased capillary permeability. Its more effective in preventing the actions of histamine rather than reversing them. Should be given early in treatment, before all the histamine binds to the receptors. Histamine Effects Dilation and increased permeability (allowing substances to leak into tissues) stimulate salivary, gastric, lacrimal, and bronchial secretions. Mast cells release histamine and other substances, resulting in an allergic reaction.

708. Cont.. Antihistamine Effects Reduce dilations of BV, reduce increased permeability of BV, reduce salivary, gastric, lacrimal, and bronchial secretions, binds to histamine receptors, thus preventing histamine from causing a response. Causes reduce capillary permeability, wheal-and-flare formation, itching, drying effect that reduces nasal, salivary, and lacrimal gland secretions (runny nose, tearing, and itching eyes). And some antihistamines cause drowsiness. Antihistamine: Indications Management of nasal allergies, seasonal or perennial allergic rhinitis, allergic reaction, motion sickness, Parkinson's disease, sleep disorders. Also used to relieve symptoms associated with common cold, such as sneezing, runny nose, palliative treatment, not curative.

709. Antihistamines: Nursing Implications Contraindicated in the presence of acute asthma attacks and lower respiratory disease, such as pneumonia. Use with caution in increased intraocular pressure, cardiac or renal disease, hypertension, asthma, COPD, peptic ulcer disease, BPH, or pregnancy. Report excessive sedation, confusion, or hypotension. Avoid operating and driving under influence. Best tolerated when taken with food. Dry mouth = gum.

710. Antitussives agents Drugs used to stop or reduce coughing. Opioid and nonopioid. Used only for nonproductive coughs! May be used in cases where coughing is harmful. Antitussives: Mechanism of Action of Opioids Suppress the cough reflex by direct action on the cough center in the medulla. Ex.) codeine (robitussin), hydrocodone Antitussives: mechanism of action nonopioids Suppress the cough reflex by numbing the stretch receptors in the respiratory tract and preventing the cough reflex from being stimulated. Ex.) benzonatate, dextromethorphan.

711. Cont. Antitussive: adverse effects – benzonatate dizziness, headache, sedation, nausea, and others Antitussive: adverse effects – dextromethorphan dizziness, drowsiness, nausea Antitussive: adverse effects – opioids sedation, nausea, vomiting, lightheadedness, constipation

712. Antitussive: Nursing Implications Do not drive or operative heavy machinery, patients taking chewable tabs or lozenges should not drink liquids for 30-35 minutes afterward, used for nonproductive coughs, report a cough that last more than one week, persistent headache, fever, rash.

713. Expectorants Drugs that aid in the expectoration of mucus. Reduce the viscosity of secretions, disintegrate and thin secretions. Expectorants: Drug Effects By loosening and thinning sputum and bronchial secretions, the tendency to cough is indirectly diminished. Expectorants: Indications Used for the relief of productive coughs associated with common cold, bronchitis, laryngitis, pharyngitis, coughs caused by chronic paranasal sinusitis, pertussis, influenza, measles. Expectorants: Common Adverse Effects Nausea, vomiting, and gastric irritation

714. Expectorants: Nursing Implications Expectorants should be used with caution in the elderly or those with asthma or respiratory insufficiency. Patient taking expectorants should receive more fluids, if permitted, to help loosen and liquefy secretions. Report a fever, cough, or other symptoms lasting longer than a week.

715. What are Decongestants? Decongestants are medicines that relieve congestion by reducing swelling, inflammation and mucus formation within the nasal passages or the eye.  They have no other effect on symptoms such as a runny nose or sneezing. Decongestants may be taken orally to help relieve congestion that is affecting the nose, sinuses, and eyes or sprayed directly in the nose or instilled in the eye for a more local effect.

716. Cont. Decongestants: Types Adrenergic, anticholinergics, corticosteroids Decongestants: Dosage forms Oral and inhaled/topically applied to the nasal membranes Adrenergic Largest group, sympathomimetics Anticholinergics Less commonly used, parasympatholytic Corticosteroids Topical, intranasal steroids

717. Cont.… Oral Decongestants Prolonged decongestant effects, but delayed onset. Effect less potent than topical. No rebound congestion. Topical Nasal Decongestants Topical adrenergic have a prompt onset, potent, sustained use over several days, causes rebound congestion, making the condition worse Topical Nasal Decongestants: Types Adrenergic : phenylephrine; Intranasal steroid : nasalide, flonase

718. Cont. Adrenergics: mechanisms of action Constrict small blood vessels that supply upper respiratory structures. As a result these tissues shrink, and nasal secretions in the swollen mucous membranes are better able to drain. Nasal stuffiness is relieved. Nasal decongestants: Drug effects Shrink engorged nasal mucous membranes and relieve nasal stuffiness Nasal Decongestants: Indications Relief of nasal congestion associated with acute or chronic rhinitis, common cold, sinusitis, hay fever, and other allergies. Nasal Decongestants: Adverse Effects Nervousness, insomnia, palpitations, tremors, local mucosal dryness, and irritation

719. Nasal decongestants: Nursing Implications Decongestants may cause hypertension, palpitations, and CNS stimulation - avoid in patients with these conditions. Patients should avoid caffeine and caffeine-containing products.

720. Autonomic Control of the Respiratory Tract Bronchiolar smooth muscle is relaxed by beta-2 adrenergic receptor stimulation Bronchiolar smooth muscle is contracted by cholinergic receptor stimulation Respiratory secretions are increased by cholinergic stimulation Drugs that increase intracellular levels of cyclic AMP produce bronchodilation

721. Classification of Antiasthmatic Drugs

722. Classification Bronchodilators Selective beta-2 agonist: salbutamol,salmeterol,formoterol Non-selective sympathomimetics: Epinephrine,Ephedrine,isoprenaline Anticholinergics: ipratropium, titropium Methylxanthines: theophylline, Aminophylline, diprophylline Corticosteroids Oral: prednisone, Methylprednisolone Inhalation: Beclomethasone, flunisolide Mast cell stabilizer : Nedocromil, ketotifen Leukotriene modulator : zafir-leukast , montelukast Monoclonal anti- IgE antibody : omalizumab

723. Bronchodilator Drugs The parasympathetic and sympathetic nervous system and humoral factors control the tone of bronchial smooth muscle. The parasympathetic nervous system produces bronchoconstriction through acetylcholine and bronchodilation and vasodilation of pulmonary blood vessels is by noradrenaline of sympathetic nervous system. Sympathomimetics – drugs that stimulate beta-2 adrenergic receptors Xanthine derivatives – theophylline Parasympatholytic – drugs that block cholinergic receptors (anticholinergic drugs)

724. Mechanism of action of bronchodilators and methylxanthines

725. Theophylline Increases cyclic AMP levels to cause bronchodilation and inhibition of chemical mediator release from mast cells Theophylline is usually administered orally In COPD theophylline decreases secretions and stimulates respiration Overdosage produces cardiac and CNS stimulation, and may cause seizures

726. Beta Adrenergic Drugs Epinephrine and isoproterenol are nonselective beta-1 and beta-2 agonists Albuterol, terbutaline, and salmeterol are selective beta-2 agonists that do not cause excessive cardiac stimulation Selective beta-2 drugs are preferred for the control of asthma Epinephrine SC is the drug of choice to treat an acute attack of asthma

727. Anticholinergic Drugs Ipratropium bromide is the only drug currently available By blocking cholinergic receptors ipratropium produces bronchodilation and decreased respiratory secretions The drug is administered by oral inhalation

728. Corticosteroids Adrenal gland hormone derivatives used in inflammatory and allergic conditions Administered orally or parenterally in acute asthmatic and inflammatory diseases Administered by oral inhalation for the chronic control of asthma and related inflammatory conditions Inhalation limits systemic toxicity

729. Leukotriene Inhibitors Antiinflammatory drugs that interfere with the inflammatory actions of the leukotrienes Zafirukast and montelukast block leukotriene receptors Zileuton blocks the enzyme 5-lipoxygenase required for the formation of leukotrienes Drugs are indicated for the chronic treatment and control of asthma

730. Montelukast is in the leukotriene receptor antagonist family of medications. It works by blocking the action of leukotriene D4 in the lungs resulting in decreased inflammation and relaxation of smooth muscle.
Zileuton is an orally active inhibitor of 5-lipoxygenase, and thus inhibits leukotrienes formation, used for the maintenance treatment of asthma.

731. Mast cell stabilizer: Antiallergic Drugs Cromolyn and nedocromil inhibit the antigen-antibody reaction on mast cells that triggers allergic reactions Administration is by oral inhalation Drugs are used on a daily basis and are intended to prevent or decrease allergic reactions Several weeks are usually required for the full therapeutic effects

732. Mucolytics Mucolytics are intended to break apart and liquefy thick respiratory secretions to facilitate easier removal Acetylcysteine is the most widely used mucolytic and is inhaled by nebulization Administration is usually followed by postural drainage and tracheal suction

733. Antihistamines Types of Drugs in this Class: Antihistamines chlorpheniramine ( Chlor- Trimeton ), diphenhydramine ( Benadryl ), fexofenadine ( Allegra ), loratidine ( Claritin ), desloratidine ( Clarinex ) Antiallergics cromolyn sodium ( Intal )

734. Mechanism of Action Antihistamines block the physiological effects of histamine by selectively acting on receptors to prevent histamine from stimulating the receptor and inducing the common effects observed during an allergic reaction: Redness, edema, itching Allergy headache Breathing difficulty

735. Cont. The pharmacological effects of antihistamines are the result of blocking the physiological effects of histamine (histamine antagonists). occupying acetylcholine receptors to inhibit the action of acetylcholine (anticholinergic)

736. Clinical Indication of Antihistaminic Drugs Prevent or interrupt the symptoms of seasonal allergy, rhinitis, cold or flu Acute allergic reactions-urticaria, hay fever, insect bites, rhinitis and dermatitis Adjunct medication pre-, post-anesthesia To induce sedation, minimize irritability Active ingredient in cough/cold, to induce sedation, dry secretions

737. Antihistamines: Nursing Implications Contraindicated in the presence of acute asthma attacks and lower respiratory disease, such as pneumonia. Use with caution in increased intraocular pressure, cardiac or renal disease, hypertension, asthma, COPD, peptic ulcer disease, BPH, or pregnancy. Report excessive sedation, confusion, or hypotension. Avoid operating and driving under influence. Best tolerated when taken with food.

738. Antiallergic Drugs Antiallergic drugs inhibit the physiological effects of histamine by attaching to mast cell membranes and inhibiting the release of histamine. Antiallergic drugs have no effect on the histamine receptors and have the best result before large amounts of histamine have been released (prophylactic)

739. Clinical Indication of Antiallergic Drugs Prevent the symptoms of: severe bronchial asthma exercise-induced bronchospasm allergic rhinitis mastocytosis

740. Mastocytosis is a condition that occurs when mast cells accumulate in skin and/or internal organs such as the liver, spleen, bone marrow, and small intestines. The signs and symptoms vary based on which part(s) of the body are affected.

741. Cautions and Contraindications Because of their anticholinergic activity, antihistamines should be used with caution in patients with: Cardiovascular disease Hypertension Increased intraocular pressure Urinary retention Stenosing peptic ulcer A history of sensitivity to this class CNS depression Used with caution in elderly patients Not used by nursing mothers, dehydrated children

742. Drug Interactions Increase drowsiness of antihistamines CNS depressants- sedatives, tranquilizers, alcohol Elevate plasma levels of antihistamines Macrolide antibiotics- erythromycin, clarithromycin, troleandomycin Antifungal drugs

743. Drugs Used To Treat Chronic Obstructive Pulmonary Disease Inhaled bronchodilators, such as anticholinergic agents (ipratropium and tiotropium ) and beta2 adrenergic agonists are the foundation of therapy for COPD. Longer acting drugs such as salmeterol and tiotropium have the advantage of less frequent dosing and together provide synergistic effect. They improve the lung function and provide a better relief in COPD.

744. Cont … Inhaled Corticosteroids such as beclamethasone are also used for the treatment of COPD. Theophylline can be given by mouth but is of uncertain benefit. Its respiratory stimulant effect may be useful for patients who tend to retain CO 2 . Mucolytic agents are also used

745. References Pharmacology for Nurses and Allied Health Sciences,Kamalakannan P. 1 st Edition. Basic Pharmacology for Nurses, D. Clayton, J.Willihnganz,17 Edition

746. Anti-Tuberculosis Drugs VI-B Muhammad Aurangzeb Lecturer INS/KMU 913

747. Objectives At the end of this lecture students will be able to: Discuss the characteristics of anti-tubercular drugs i.e. Mechanism of action Indication Contraindication Discuss primary and secondary management of TB. Describe the rationale for multiple drug therapy in treatment of TB. Discuss appropriate nursing implication for client receiving anti-tuberculin therapy. Calculate the drug dosage accurately while administering oral and parental medications. 914

748. Introduction Robert Koch discovered Mycobacterium tuberculosis in 1885 In 2016 worldwide 10.6 million people became sick with TB and 1.7 million TB-related deaths. Over 10 million people in the US are infected and they have a lifelong risk of developing TB Without treatment, approximately 5-10% of patients with latent TB will progress to active TB disease at some point in their lifetime Isoniazid (INH) can reduce the incidence of active TB about 90% Before drugs, the treatment was rest in the open air, in specialized sanatorium 915

749. Historical Background 1944 – Para- aminosalicylic acid (PAS) 1946 – Streptomycin (SM) 1946 – Thioacetazone 1952 – Isoniazid (INH) Replaces sanatorium as major treatment. Patients can be treated as out-patient 1952 – Pyrazinamide (PZA), Combination therapy of INH and PZA cures TB 1955 - Cycloserine (CS) 916

750. 1957 - Kanamycin/ amikacin (AK) 1961 – Ethambutol (EMB) 1966 – Rifampin (RIF) Combination of rifampin and INH adopted as international regimen for treatment of TB 1966 – Ethionamide (ETA) 1967 – Capreomycin (CM) 917 Cont;

751. The Aims of anti‐TB Treatment To cure the patient of TB To prevent death from active TB or its late effects To prevent TB relapse or recurrent disease To prevent the development of drug resistance To decrease TB transmission to others. 918

752. Treatment Through more than one Drug TB disease must be treated for at least 6 months or longer. Most of the bacteria are killed during the first 8 weeks of treatment; however, there are persistent organisms that require longer treatment. If treatment is not continued for a long enough duration, the surviving bacteria may cause the patient to become ill and infectious again. 919

753. Cont; There are several options for daily and intermittent therapy, but the goal of treatment for TB disease should be to provide the safest and most effective therapy in the shortest period of time. Given adequate treatment, almost all patients will recover and be cured. Regimens for the treatment of TB disease must contain multiple drugs to which the bacteria are susceptible. 920

754. Cont; The standard of care for initiating treatment of TB disease is a four-drug regimen. Treatment with a single drug can lead to the development of a bacterial population resistant to that drug. Likewise, the addition of a single drug to a failing anti-TB regimen can lead to additional resistance. When two or more drugs to which in vitro susceptibility has been demonstrated are given together, each helps prevent the emergence of tubercle bacilli resistant to the others. 921

755. Anti -tuberculosis drugs First-line Isoniazid Rifampicin Ethambutol Pyrazinamide Second-line Clarithromycin Ciprofloxacin Capreomycin Cycloserine Kanamycin Amikasin streptomycin 922

756. Isoniazid Acts only on mycobacteria Interferes with mycolic acid synthesis (unique to mycobacterial cell wall) 924

757. Cont; Passes freely to mammalian cell wall Effective for intracellular organism Bacteriostatic – to resting organism Bactericidal – to multiplying organism 925

758. Pharmacokinetics of Isoniazid Well absorbed from GIT Fatty food & aluminum-containing antacids may reduce absorption CSF penetration: 20% of plasma concentration with non-inflamed meninges  Penetrate well into caseous material Excretion - urine 926

759. Adverse effects Hepatotoxicity Elderly, slow acetylators more prone Polyneuropathy Prevented by concurrent pyridoxine Rashes, acne Hematological – hemolytic anemia in G6PD deficiency 927

760. Rifampicin Inhibits bacterial DNA-dependent RNA polymerase Bactericidal Gram positive and negative kill intracellular organism 928

761. Well absorbed from GIT CSF penetration: 10-40% of plasma concentration with non-inflamed meninges Elimination hepatic, renal Pharmacokinetics 929

762. Rashes, hepatotoxicity, thrombocytopenia Mild elevation of liver enzymes – common Orange discoloration of urine, sweat, tears 930 Adverse effects

763. Ethambutol Inhibits arabinosyl transferases involved in cell wall biosynthesis Bacteriostatic to M. Tuberculosis Resistance develops rapidly if used alone 931

764. Well absorbed from GIT Bioavailability 80% CSF penetration poor Elimination renal 932 Pharmacokinetics

765. Optic retro-bulbar neuritis Red-green colour blindness → reduced visual acuity Dose-related Reversible May be unilateral Adverse effects 933

766. Pyrazinamide Interferes with mycobacterial fatty acid synthesis Inactivate mycobacteria at acidic PH Effective against intracellular organism in macrophages – PH is low 934

767. Well absorbed from GIT CSF penetration: equal to plasma concentration Hepatic metabolism Excretion - kidney 935 Cont;

768. GI disturbances Hepatotoxicity Hyperuricaemia – gout Arthralgia 936 Adverse effect

769. Streptomycin Aminoglycoside - Inhibits protein synthesis Bactericidal Poorly absorbed from GIT - given IM. CSF penetration: poor Renal elimination 937

770. Adverse effects Ototoxicity, vestibular toxicity, nephrotoxicity Uses very ill patients Multi- drug resistance Not responding to treatment 938 Cont;

771. Capreomycin Peptide antibiotic IM effect 8 th cranial nerve – deafness, ataxia 939

772. Cycloserine Broad spectrum antibiotic Reaches the CSF well Causes CNS side effects Use in drug resistant TB

773. Pulmonary TB Initial phase – INAH+Pyridoxine Rifampicin Ethambutol Pyrazinamide Continuation phase – INAH+Pyridoxine Rifampicin 2 Months 4 Months

774. Anti-TB therapy Multiple drugs are used to reduce the emergence of resistance Given as combination tablets Taken 30 min before the breakfast as absorption of rifampicin is influenced by food

775. Cont… A fixed dose combination (FDC) - formulation of two or more active ingredients combined in a single dosage Improve medication compliance To target a single disease like AIDS, TB and malaria.

776. Cont… For pulmonary TB – 6 months treatment For renal, bone and CNS infection – longer treatment

777. Drug resistance Multidrug resistance (MDR) Resistant to at least isoniazid & rifampicin MDR-TB rate - 1.4% among newly diagnosed cases Extensive drug resistance (XDR) MDR strains also resistant to any fluoroquinolone & at least one injectable second-line drugs ( amikacin , capreomycin , kanamycin)

778. Primary drug resistance Those exposed to resistance organism Secondary drug resistance After initial drug sensitivity Due to non compliance Cont;

779. Treatment for 2 years HIV positive patients 12 months after negative culture Cont;

780. Directly observed therapy (DOT) -To improve the compliance Hospital stay for uncooperative people Cont;

781. Nursing Implication Obtain thorough medical history/assessment Baseline labs (liver functions, thyroid functions) Assess for contraindications (pregnancy, drugs interactions, liver/renal functions) Patient education • Compliance • Durations of therapy up to 24 months • Avoid alcohol • Personal health (nutrition, blood sugar… etc ) Monitor Side Effects 949

782. TB Drug Daily Dose Isoniazid 5 mg/kg (usual dose 300 mg) Rifampin 10 mg/kg (usual dose 600 mg) Rifabutin 5 mg/kg (usual dose 300 mg) Pyrazinamide 15 mg - 25mg/kg (usual dose 1000-2000 mg) Ethambutol 10 mg - 20mg/kg (usual dose 800-1600 mg) 950 Dosage Calculation

783. References Recommendations for Use of an Isoniazid- Rifampentine Regimen with Direct Observation to Treat Latent Mycobacterium tuberculosis infection. World Health Organization. 2008 tuberculosis facts. www.who.int/tb. CDC. Reported Tuberculosis in the United States, 2006. Atlanta, GA: U.S. Department of Health and Human Services, CDC; September 2 CDC: Tuberculosis Data and Statistics.www.cdc.org CDC. Treatment of tuberculosis. MMWR. 2003; 52:1-77. Micromedex® Healthcare Series [intranet database]. Version 2.0. Greenwood Village, Colo : Thomson Healthcare. Accessed May 2013. New Drugs against Tuberculosis: Problems, Progress, and Evaluation of Agents in Clinical Development. Journals.asm.org. antimicrobial Agents and Chemotherapy. 2009, 53(3):849. Accessed from http://aac.asm.org/content/53/3/849 . The Tuberculosis Treatment Pipeline:A breakthrough year for the treatment of XDR- TB.www.pipeline report.org 951

784. 952

785. 953

786. 954

787. Drugs used in Ophthalmic/ENT Disorders By: Muhammad Aurangzeb Lecturer-INS/KMU

788. Objectives By the completion of this section the learners will be able to: Review ocular structure that influence drug therapy Discuss different categories of drugs used in E ENT disorders Review the proper methods of instilling the EEN drops Utilize nursing process while taking care of clients using drugs related to EENT disorders. Calculate drug dosage calculations accurately.

789. Ocular Structure The eye is broadly divided into two compartments called the anterior (front of the eye) and posterior (back of the eye) segment The anterior segment of the eye consists of the cornea, conjunctiva, iris, ciliary body and the lens. The posterior segment of the eye refers to the posterior two‐thirds of the eye, including the anterior hyaloid membrane and all the structures behind it such as the vitreous, retina, choroid and optic nerve.

790. Pharmacotherapy in Ophthalmic Diseases Ocular administration of drug is primarily associated with the need to treat ophthalmic diseases. The common eye diseases are cataract, glaucoma and uveitis, with cataract (accounting for 51% blindness), infections e.g. conjunctivitis etc. Eye is the most easily accessible site for topical administration of a medication. Ideal ophthalmic drug delivery must be able to sustain the drug release and to remain in the vicinity of front of the eye for prolong period of time.

791. Pharmacotherapy in Ophthalmic Diseases Local applications do pose some disadvantages. Topically administered drugs often display limited bioavailability (< 5%) due to many physical and biochemical barriers including pre‐corneal tear film, the structure and biophysiological properties of the cornea, the limited volume that can be accommodated by the cul‐de‐sac, the lacrimal drainage system, reflex tearing and the aqueous outflow within the eye.

792. Factors Affecting Intraocular Bioavailability Inflow & outflow of lacrimal fluids. Efficient naso-lacrimal drainage. Interaction of drug with lacrimal fluid. Dilution with tears. Blinking of the eyes (increase tears formation) Corneal barriers (closely packed corneal epithelium) Blood–retinal barrier (BRB)

793. Barriers in Ocular Absorption Precorneal Constraints It include – Solution drainage Lacrimation Tear dilution Tear turnover Conjunctival absorption Corneal constraints Cornea as rate limiting barrier Anatomy of cornea Outer Epithelium (lipophilic), Middle Stroma (hydrophilic), Inner Endothelium (lipophilic)

794. Cont.… Therefore, intra vitreous (i.v.t.) injections are required to administer drugs directly to the posterior segment to achieve high doses. Although repeated administration of i.v.t. injections, poses potential complications including endophthalmitis, retinal detachment, traumatic cataract, intraocular hemorrhage and ocular infections

795. Examples of drugs used in eye diseases Anti-infectives – e.g. antibacterials, antifungals, antivirals Anti-inflammatories – e.g. corticosteroids, Antihistamines Mydriatics & cycloplegics –e.g. atropine – dilate pupil & paralyze ciliary muscle to facilitate examination of interior of the eye Antiglaucoma agents –reduce IOP e.g. beta-blockers Miotics – e.g. pilocarpine –constrict pupil & contract ciliary muscle Anesthetics – e.g. topical & surgical procedures

796. Drugs used to Treat Eye Infection Superficial bacterial, fungal, and viral infection can occur in the: Eye Eyelid and surrounding structures Cornea Conjunctiva Lacrimal duct

797. Drugs used to Treat Eye Infection Treated topically or systemically with: Antibiotic drugs for bacterial infections Antifungal for fungal infections Antiviral for viral infections

798. Drugs used to Treat Eye Infection Topical antibiotics for bacterial eye infections Disrupt the cell wall of bacteria or inhibits protein synthesis Not effective against viral infections Example are: Azithromycin Bacitracin Ciprofloxacin Erythromycin Chloramphenicol Gentamicin Ofloxacin Tobramycin

799. Drugs used to Treat Eye Infection Topical antifungal drugs for fungal eye infections Natamycin (Natacyn) Topical antiviral drugs for viral eye infections Trifluridine (viroptic ) Affective against viruses Herpes Simplex Virus, type 1 and type 2 Ganciclovir (Vitrasert) Administered as an implant that is placed with in the eyes in vitreous humor so that the drug will come in contact with retina Also use topically to cytomegalovirus retinitis

800. Drug used to Treat Eye Inflammation Inflammation of the eye may be due to: Injury Trauma Contact with chemicals Allergies Infections

801. Drug used to Treat Eye Inflammation Anti inflammatory drugs treat inflammation in the following areas of the eye: Eyelid Cornea Conjunctiva Lacrimal duct

802. Drug used to Treat Eye Inflammation Corticosteroid drugs Used topically to treat inflammation Suppress the immune system’s local response local inflammatory response Drugs that are commonly used are: Dexamethasone (Maxidex) Difluprednate (Durezol) Fluromatholone (Flarex) Loteprednol (Lotepred Forte) Prednisolone (Pred Forte) Remexolone (Vexol)

803. Drug used to Treat Eye Inflammation Corticosteroid drugs Following anti-inflammatory drugs are administered with in eye into the vitreous humor uveitis Dexamethasone (oxudex) is an implant Fluocinolone (Retisert) is an implant Triamcinolone (Trivaris) is injected as a solution Note uveitis : inflammation in the tissue of middle layer of the eye wall (uvea)

804. Drug used to Treat Eye Inflammation NSAIDS Non-steroidal anti-inflammatory drugs treat pain and inflammation after cataract or LASIK surgery on the eye. Following NSAIDs are commonly used Diclofenac Ketorolac Nepafenac Bromofenac NSAIDs has 3 types of effects Anti-inflammatory Analgesic Antipyretic (COX-2) Inhibits the cyclooxygenase pathway

805. Newer NSAIDS Nepafenac 0.1% and Bromofenac 0.09%are topical, nonsteroidal anti-inflammatory, recently introduced Nepafenac is a prodrug, converted by ocular tissue hydrolases to amfenac, which inhibits the action of prostaglandin H synthase(cyclooxygenase)

806. Mydriatics & Cycloplegics Mydriatics are the drugs which dilate the pupil and cycloplegics are agents which causes paralysis of ciliary muscles Mydriatics are of two types Adrenergic agonist Adrenaline Phenylephrine Cholinergic antagonists Tropicamide Atropine Scopolamine

807. Drugs used To Treat Allergy Symptoms Human eye has about 50 million mast cells, which contains preformed chemical mediators (histamines) Eye allergy occur from the same reason as other parts of the body Foreign substances enter the body, antibodies attach to the antigen, forming an antigen-antibody complex Antigen-antibody can be destroyed, in the process histamine released from mast cells Cause vasodilation of blood vessels Tissue become swollen, inflamed and red Irritates tissues causing pain and itching

808. Anti-histamine Drugs for Eye Allergy These drugs block histamine receptors, hence inhibits effects of histamine Following are commonly used anti-histamine drugs Alcaftadine (H1 receptors antagonist) Azelastine eye drop (Anti-histaminic effects) Emedastine eye drop (H1 receptors antagonist) Epinastine eye drop (highly selective H1 receptors antagonist) Ketotifen eye drops (anti-histamine & mast cell stabilizer) Olopatadine eye drop (H1 receptors antagonist & mast cell stabilizer)

809. Mast Cell Stabilizers for Eye Allergy Mast cell stabilizers as anti-histamine drugs, prevent the cell membrane of the mast cells in the eye from releasing histamines Commonly used drugs are: Bapotastine eye drop (non-sedating mast cell stabilizer) Cromolyn eye drop (mast cell stabilizer & also prevent release of leukotriene) Lodoxamide eye drop (mast cell stabilizer) Nedocromil eye drop(non- selective mast cell stabilizer) Pemirolast eye drop (mast cell stabilizer)

810. Decongestants Drugs for Eye Allergy Decongestant drugs constrict blood vessels in the conjunctiva to reduce redness Commonly used decongestants are Naphazoline Oxymetazoline Phenylephrine Tetrahydrozoline

811. Combination Anti-histamine & Decongestant Eye Drugs Combine an anti-histamine drug with a decongestant drug Opcon A Naphazoline plus Pheniramine Visine-A Pheniramine plus Tetrahydrozoline

812. Drugs used to Treat Dry Eye Syndrome Xerophthalmia is caused by an insufficient production of tears because of eye inflammation or because of old age Also a side effects of certain drugs Treated with OTC lubricant Drugs (artificial tears) or prescription drugs Commonly used drugs are Carboxymethylcellulose: OTC artificial tears gel Cyclosporine : decrease T cells that cause inflammation, producing more tears Hydoxypropyl cellulose : dissolving insert to stabilize tear film and keep it in place through out the day

813. Drugs used for Glaucoma Increased intraocular pressure that, if left untreated, can lead to blindness Drugs acts either by: Decreasing the amount of aqueous humor circulating in the anterior and posterior chambers of eye Decreasing intraocular pressure

814. Drugs used for Glaucoma Glaucoma drugs act either by: Constricting the pupil (miosis) to open the angle of contact between the iris and trabecular meshwork Allows aqueous humor to flow freely Beta blockers drugs used to treat glaucoma: it block beta receptors in the eye Decrease the production of aqueous humor to decrease IOP Has no effects on pupil size so does not cause blurred vision Beta blockers drugs used for glaucoma includes: Betaxolol Cartelol Levobunolol Metipranolol Timolol

815. Drugs used for Glaucoma Alpha Receptor Agonists These drugs stimulates alpha-2 receptors in the eye Decrease the production of aqueous humor Increase outflow of aqueous humor Commonly used drugs are Apraclonidine Brimonidine

816. Drugs used for Glaucoma Prostaglandin F Agonists Stimulate prostaglandins F receptors Increase the outflow of aqueous humor and decrease the IOP Examples: Bimatoprost Latanoprost Tafluprost Travoprost. Note: :Bimatoprost : hair growth (eye lashes)

817. Drugs used for Glaucoma Carbonic Anhydrase Inhibitors Inhibits enzyme carbonic anhydrase present in epithelium of ciliary body Prevents the bicarbonate and sodium influx and decreases aqueous formation Useful in short term treatment of acute glaucoma Onset of action within 1 hour and maximum effect in 4 hours Given orally Acetazolamide Dorzolamide & Brinzolamide are topical Carbonic Anhydrase Inhibitors

818. Miotic drugs for Glaucoma First drugs drug developed to treat glaucoma Have the same action as acetylcholine Causes the pupil to constrict Increases the outflow of aqueous humor Lowers the IOP Miotic drugs includes Carbachol Pilocarpine

819. Cholinesterase Inhibitors Drugs for Glaucoma This class of drugs inhibits enzyme cholinesterase that normally destroys acetylcholine Hence acetylcholine available for long period of time, and cause pupil to constrict Echothiophate iodide is example of this class.

820. Combination Drugs for Glaucoma Following is a common combination drugs Cosopt is combination of Dorzolamide 2% (carbonic anhydrase inhibitors) & Timolol 0.5% (beta-blocker drug) Brimonidine 0.2% and Timolol 0.5% Latanoprost 0.005% and Timolol 0.5% Travaprost 0.004% and Timolol 0.5% Bimatoprost 0.03% and Timolol 0.5%

821. Anesthetic Ophthalmic Drugs Used in the eye to facilitate eye examination and for short surgical procedures such as foreign body removal or suture removal Drugs in this class are Lidocaine Proparacaine Tetracaine

822. Ear Nose Throat Drugs

823. ENT Drugs ENT drugs can be divided into the following categories Decongestants Antihistamines Mast Cell Stabilizer Drugs Corticosteroids Nasal steroid preparations Antibiotics Anti-fungal/anti-yeast drugs Antitussives Expectorants Combination ENT Drugs

824. Decongestant Drugs Act as vasoconstrictors by stimulating alpha receptors in the smooth muscle around the blood vessels Reduce blood flow to edematous mucous membranes in the nose, sinuses and pharynx Alleviate nasal stuffiness and sinus congestion Allow secretions to drain Commonly prescribed for colds and allergies Can be administered topically as nasal drops or nasal sprays or orally Phenylpropanolamine & Pseudoephedrine are commonly used decongestants

825. Decongestant Drugs   Others drugs in this class are: Naphazoline Oxymetazoline Tetrahydrozoline Xylometazoline

826. Antihistamine Drugs Exert their therapeutic effect by blocking histamine (H1) receptors in the nose and throat Histamine released from mast cells in the tissues when an antibody-antigen complex is created during an allergic reaction Causes vasodilation in which the blood vessels and mucous membranes become swollen and red Irritates the tissue directly, causing pain and itching

827. Antihistamine Drugs Block the action of histamine at H1 receptors to dry up secretions Shrink edematous mucous membranes Decrease itching and redness Side effects 1 st generation antihistamines causes drowsines , s while 2 nd generation antihistamine, do not cause drowsiness because of a different chemical structure.

828. Antihistamine Drugs 1 st generation drugs are: Chlorpheniramine, Cyproheptadine, Diphenhydramine, brompheniramine, carbinoxamine, clemastine, dexchlorpheniramine, phenindamine, promethazine, and triprolidine 2 nd generation drug are: Azelastine, cetirizine, levocetirizine, loratadine, desloratadine, fexofenadine and olopatidine Azelastine (Astelin) is administered as a nasal spray. It is used to treat allergic rhinitis, which is characterized by an itchy, runny, stuffy nose. Loratadine (Claritin) is used to treat allergy symptoms in the eyes and nose

829. In Depth First-generation antihistamine drugs, such as diphenhydramine (Benadryl), are nonselective in that they bind to both central histamine (H1) receptors in the brain as well as peripheral H1 receptors in body tissues. This drug action in the brain results in drowsiness and impaired performance while driving or operating machinery.
In Depth Second-generation antihistamine drugs, such as cetirizine (Zyrtec) and loratadine (Claritan), only bind to peripheral H1 receptors in the body tissues; this blocks the action of histamine and relieves the symptoms of redness, inflammation, and itching associated with allergies – without producing drowsiness.

830. Continue In depth Hydroxyzine (Vistaril) is also a first-generation antihistamine. However, it is not used to treat allergies. Instead,its typical side effect of drowsiness and dry mouth are used as therapeutic effects when Vistaril is given as a preoperative medication to calm the patient and decrease oral secretions prior to intubation during surgery.

831. Did You Know? Antihistamines are not effective in treating bacteria or viruses that cause the common cold. Although symptoms of allergies and colds are similar, no release of histamine occurs with the common cold. Nevertheless, drug companies combine antihistamine drugs and decongestant drugs in over-the-counter cold remedies because antihistamine drugs have a drying effect on the mucous membranes that is helpful during a cold.
Figure 19-2 Figure 19-3. It is one of the newer antihistamine drugs and does not cause drowsiness. It is advertised in television commercials as helping patients be “Claritin clear,” that is, free of the fogginess or drowsiness associated with older antihistamine drugs.

832. Mast Cell Stabilizer Drugs Stabilize the cell membranes of mast cells in the tissues of the nose. Prevent them from releasing histamine during the immune response to an antigen. Prevents edema of the nasal mucous membranes and sneezing in patients with allergic rhinitis, Commonly used drug is cromolyn (Nasalcrom)

833. Corticosteroid Drugs Act by inhibiting the body’s immune system Decrease inflammation and edema of the mucous membranes Have no decongestant or antihistamine effect Are not used to treat the common cold Corticosteroid drugs are administered intranasally to treat allergic and nonallergic rhinitis Drugs in this class includes beclomethasone, budesonide (Rhinocort), flunisolide, fluticasone, mometasone, triamcinolone

834. Cont.…. Budesonide is a prescription corticosteroid drug that is sprayed into the nose to treat allergy symptoms. Mometasone (Nasonex) is  a corticosteroid drug that is given intranasally to treat allergy symptoms in the nose. Triamcinolone (Kenalog ) applied topically as a paste to treat mouth ulcers inflammation Dexamethasone applied topically as a solution in the external ear canal o decrease inflammation associated with allergies or infections

835. Antibiotics Antibiotics are prescribed for colds caused by bacterial infections, particularly streptococci that causes strep throat Antibiotic ofloxacin (Floxin Otic) applied topically as a solution to the external ear canal to treat bacterial infections, swimmer’s ear, external otitis, infections of the tympanic membrane (otitis media) Sulfonamide drugs such as sulfadiazine & sulfisoxazole are a type of anti-infective drug that inhibits the growth of bacteria and given orally to treat an infected tympanic membrane (otitis media)

836. Common cold not effective in because it is usually caused by a virus although they may be prescribed to prevent subsequent superimposed bacterial infections from developing, this practice is not recommended
Did You Know? Most people contract two or more colds per year. There are over 120 different viruses, and most colds are caused by viruses. The common cold is considered the single most expensive illness in the United States in terms of time lost from work and school. No drug is currently available to treat viral common colds; available drugs merely provide temporary relief of various symptoms until the cold has run its course

837. Anti-yeast/anti-fungal Drugs Yeasts are organisms that are closely related to fungi grow easily in the warm, moist, dark environments of the mouth especially true in patients whose immune systems are compromised by disease Candida albicans yeast infections of the mouth are also known as oral candidiasis(thrush) Topical anti-yeast drugs such as clotrimazole and nystatin are used to treat oral candidiasis in the mouth

838. Drug Alert! Topical antiyeast drugs used to treat oral candidiasis (thrush) are administered in several unique ways. (1) An infect with oral candidiasis is given an oral suspension of the drug. The entire dose is placed in an unattached nipple, and the infant sucks on the nipple until the dose is gone.
Drug Alert! The drug is not mixed with milk or formula in a bottle because the infant may not drink the entire bottle and would not get the full dose of medicine. Also, the drug should not be diluted with milk or formula because it needs to adhere to the mucous membranes of the oral cavity in order to be effective.

839. Drug Alert! (2) An adult with oral candidiasis is told to “swish and swallow” the oral suspension. The swishing action helps to coat all areas of the oral cavity, and swallowing ensures that the medication coats the pharynx and esophagus, which can also be infected.
Drug Alert! (3) Alternatively, an adult can suck on a troche that contains the antiyeast drug. A troche is an oblong tablet that dissolves in the mouth like a lozenge. Pastille is another name for a troche. Pastille is a French word that means little lump of bread.

840. Antitussive Drugs Decrease coughing by suppressing the cough center in the brain and by anesthetizing stretch receptors in the respiratory tract Main purpose is to control dry, nonproductive coughs Not prescribed to treat productive coughs because it is important for the patient to cough the sputum up Benzonatate and dextromethorphan drug commonly seen in combination drugs used to treat coughs and colds Some antitussive drugs contain codeine a narcotic drug Codeine hydrocodone are used to treat severe, nonproductive coughs

841. Expectorant Drugs Expectorant Drugs increases volume and decreases viscosity of respiratory secretions E.g. Guaifenesin is used to treat productive coughs that create amounts of sputum that must be expelled from the lungs

842. Combination ENT Drugs These combination drugs contain an antihistamine drug and a decongestant drug and antitussive drug Allegra-D (fexofenadine, pseudoephedrine) Clarinex-D (desloratadine, pseudoephedrine) Phenergan VC (promethazine, phenylephrine) Rondec (chlorpheniramine, phenylephrine) Zyrtec-D (cetirizine, pseudoephedrine) Rondec-DM chlorpheniramine (an antihistamine), phenylephrine (decongestant drug), dextromethrophan (antitussive drug)

843. Note Drugs Alert! Prescription cough syrups that contain a controlled substance are very effective in treating severe coughing, but they also contain a narcotic drug that can be addicting. These narcotic antitussive drugs include codeine (a Schedule IV drug), dihydrocodone (a Schedule III drug), hydrocodone (a schedule III drug), and hydromorphone (a Schedule II drug).
Drug Alert! Schedule drugs cause euphoria (an exaggerated sense of well-being and happiness) and slowed muscle movements. The Drug Enforcement Agency (DEA) reports that these prescription cough syrups are available to addicts whose drug of abuse is cough syrup from some online pharmacies that do not verify prescriptions sent to them.

844. Continue Drug Alert! The Website for Partnership for a Drug-Free America notes that the nonnarcotic antitussive drug dextromethorphan is also being abused by 1 out of every 10 teenagers. It causes distortions in color and sound, disorientation, hallucinations, and an out-of-body experience in addition to dizziness, nausea and vomiting, loss of motor control, and a rapid heart rate. Because it is an over-the-counter drug, it is commonly available.

845. C ontinue Combinations Prescription ENT Drugs These combination prescription drugs contain a decongestant drug (phenylephrine, pseudoephedrine) and an expectorant drug (guaifenesin) to relieve edema and nasal dripping and treat a productive cough Entex Guaifenex PSE
Figure 19-7 Prescription bottle of Guaifenex PSE. This combination prescription drug contains a decongestant and an expectorant drug to help expel sputum produced from the throat and lungs.
Combination Prescription ENT Drugs These Rx drugs contain an antibiotic ciprofloxacin neomycin polymyxin B a corticosteroid dexamethasone hydrocortisone used topically in the ear treat infections of the external ear (otitis externa) tympanic membrane (otitis media)

846. Continue Combination Prescription ENT Drugs Ciprodex (ciprofloxacin, dexamethasone) Cipro HC Otic (ciprofloxacin, hydrocortisone) Coly-Mycin S Otic (hydrocortisone, neomycin) Cortisporin Otic (hydrocortisone, neomycin, polymyxin B) Octicair (hydrocortisone, neomycin, polymyxin B) Otosporin (hydrocortisone, neomycin, polymyxin B) Pediotic (hydrocortisone, neomycin, polymyxin B)
Combination Over-the-Counter ENT Drugs Hundreds of OTC combination drugs, with common brand names Claritin-D Dimetapp Drixoral Entex Excedrin Mucinex Pediacare Polaramine Primatene Robitussin Rondec Sudafed Theraflu Triaminic Tylenol

847. Continue Combination Over-the-Counter ENT Drugs Hundreds of OTC combination drugs contain various combinations of analgesic drugs (acetaminophen, ibuprofen, naproxen) decongestant drugs (ephedrine, phenylphedrine, pseudophedrine) antihistamine drugs (brompheniramine, cetirizine, chlorpheniramine, clemastine, dexchlorpheniramine, diphenhydramine, fexofenadine, loratadine, phenyltoloxamine, triprolidine) and expectorant drugs (guaofenesin)

848. Installation of eye drops Wash your hands & do not touch the dropper opening. Look upward. Pull the lower eyelid down to make a ‘gutter. Bring the dropper as close to the gutter as possible without touching it or the eye. Apply the prescribed amount of drops in the gutter. Close the eye for about two minutes. Do not shut the eye too tight. If more than one kind of eye-drop is used wait at least five minutes before applying the next drops. Eye-drops may cause a burning feeling but this should not last for more than a few minutes. If it does last longer consult a doctor or pharmacist.

849. Installation of Eye Drops into The Eye of a Minor Let the child lie back with head straight. The child's eyes should be closed. Drip the amount of drops prescribed into the corner of the eye. Keep the head straight. Remove excess fluid.

850. Installation of Eye Ointment Wash your hands. Do not touch anything with the tip of the tube. Tilt the head backwards a little. Take the tube in one hand, and pull down the lower eyelid with the other hand, to make a gutter. Bring the tip of the tube as close to the gutter as possible. Apply the amount of ointment prescribed. Close the eye for two minutes. Remove excess ointment with a tissue. Clean the tip of the tube with another tissue.

851. Installation of Ear Drops Warm the ear-drops by keeping them in the hand or the armpit for several minutes. Do not use hot water tap, no temperature control! Tilt head sideways or lie on one side with the ear upward. Gently pull the lobe to expose the ear canal. Apply the amount of drops prescribed. Wait five minutes before turning to the other ear. Use cotton wool to close the ear canal after applying the drops ONLY if the manufacturer explicitly recommends this. Ear-drops should not burn or sting longer than a few minutes.

852. Installation of Nose Drops Blow the nose. Sit down and tilt head backward strongly or lie down with a pillow under the shoulders; keep head straight. Insert the dropper one centimeter into the nostril Apply the amount of drops prescribed and remove the dropper. Immediately afterward tilt head forward strongly (head between knees). Sit up after a few seconds, the drops will then drip into the pharynx. Repeat the procedure for the other nostril, if necessary. Rinse the dropper with boiled water.

853. Installation of Nasal Spray Blow the nose. Sit with the head slightly tiled forward. Shake the spray & insert the tip in one nostril. Close the other nostril and mouth. Spray by squeezing the vial and sniff slowly. Remove the tip from the nose and bend the head forward strongly (head between the knees). Sit up after a few seconds; the spray will drip down the pharynx. Breathe through the mouth. Repeat the procedure for the other nostril, if necessary. Rinse the tip with boiled water.

854. Nursing consideration Obtain a complete health history including allergies, drug history, and possible drug interactions Monitor the client for specific contraindications for the prescribed drug. Remove contact lenses before administering eye solutions. Blow the nose before applying nasal drugs Administer ophthalmic and ENT drugs using proper technique. Monitor for ocular and reaction to the drug such as conjunctivitis Monitor response of the dugs Encourage compliance with treatment regimen. Educate the patients regarding self use of drops and ointment

855. References Snell RS, Lemp MA; Clinical Anatomy of the Eye (2nd ed.), 1998, chapter 6. Blackwell Science Hall & Colman's Diseases of the Ear, Nose and Throat (15th ed.); Burton M, Leighton S, Robson A, Russell J. Churchill Livingstone, 2001 Karch , A. M., & Karch . (2011).  Focus on nursing pharmacology . Wolters Kluwer Health/Lippincott Williams & Wilkins. Katzung , B. G. (2017).  Basic and clinical pharmacology . McGraw-Hill Education. Lehne , R. A., Moore, L. A., Crosby, L. J., & Hamilton, D. B. (2004). Pharmacology for nursing care. Smeltzer , S. C., & Bare, B. G. (1992).  Brunner & Suddarth’s textbook of medical-surgical nursing . Philadelphia: JB Lippincott.