Endoocrine Pharamacology for public health.pptx

endocrine pharmacology

1. ENDOCRINE PHARMACOLOGY For Second Year PHO Students By: Ebabu Jember(Bpharm,Mph,Msc candidate)

2. Introduction The function of the body is regulated by two major control systems: The nervous system The hormonal or endocrine system In general, the hormonal system is concerned principally With control of the different metabolic functions of the body Controlling the rates of chemical reactions in the cells or the transport of substances through cell membranes or other aspects of cellular metabolism,such as growth and secretion

3. Introduction Endocrine system is a system of glands, each of which secretes a type of hormone directly into the bloodstream. Influence the function of target cells at another location in the body Mainly controlled by the pituitary and hypothalamus. Hormones reach all parts of the body , but only target cells are equipped to respond Hormones are secreted in small amounts and often in bursts (pulsatile secretion)

4. Introduction--- Hormones include: Anterior pituitary hormones : growth hormone, Adrenocorticotropin, thyroid–stimulating hormone, follicle–stimulating hormone, luteinizing hormone, prolactin and melanocyte-stimulating hormone Posterior pituitary hormones : antidiuretic hormone (vasopressin) and oxytocin

5. Adrenocortical hormones : cortisol and aldosterone Thyroid hormones : thyroxine, tri-iodo-thyronine and calcitonin Pancreatic hormones : insulin and glucagons --

6. Ovarian hormones : estrogen and progesterone Testicular hormones : testosterone/androgen Parathyroid hormones : parathormone Placental hormones : chorionic gonadotropin, estrogen, progesterone and human placental lactogen  

7. Introduction… In clinical practice, hormones and hormone-like drugs , are mainly used for: Replacement therapy E.g. insulin in diabetes mellitus 2. Diagnosis Testing the functional integration of an endocrine system E.g. corticotrophin in diagnosis of adrenocortical dysfunction 3. Treatment of non-endocrine diseases e.g. corticosteroids –inflammatory condition (Rheumatic arthritis)

8. Thyroid and Antithyroid Drugs The thyroid gland has diverse and important effects on many aspects of metabolic homeostasis. Thyroid gland secrets 3 hormones: Traiodothyronine, or T 4 Triiodothyronine or T 3 calcitonin

9. Thyroid and cont … T 4 and T 3 : iodine-containing amino acid derivatives and are unique in that they have no discrete target tissue . Every tissue in the body is affected in some way, and almost all cells appear to require constant optimal amounts for normal operation. Calcitonin: .Regulate bone mineralization Two types of thyroid hormone related disorders: - Hypothyroidism(under secretion) -Hyperthyroidism(over secretion)

10. Treatment of Hypothyroidism The only effective treatment of hypothyroidism, unless it is due to iodine deficiency (treated with iodide) is to administer the thyroid hormones themselves: Thyroxin (levothyroxine, T 4 ) standard replacement therapy Triiodothyronine (liothyronine, T 3 ) three to four times more potent than T4 reserved for the rare condition of myxedema coma when its more rapid action is required for emergency treatment

11. Levothyroxine Sodium(T4) Is the sodium salt of the naturally occurring T 4 . Drug of choice for maintenance of plasma T4 and T3 in replacement therapy. Absorbed intact from the GIT, and its long half-life allows for convenient once-daily administration. The TSH-suppressive effects of exogenous T 4 also prove useful in removing the stimulatory effects of TSH on the thyroid gland in the management of simple goiter and chronic thyroiditis.

12. Liothyronine Sodium(T3) Is the sodium salt of the naturally occurring levorotatory isomer of T 3 . Short plasma half-life and duration of action not used for maintenance replacement therapy. The use of T 3 alone is recommended only in special situations, such as, initial therapy of myxedema and myxedema coma and short-term suppression of TSH in patients undergoing surgery for thyroid cancer.

13. Adverse Effects of Treatment With Thyroid Hormone The most common adverse effects are the result of a drug overdose; Symptoms of hyperthyroidism, Include: cardiac palpitation and arrhythmias, tachycardia, weight loss, tremor, headache, insomnia, and heat intolerance.

14. Treatment of Hyperthyroidism Treatment options Surgical removal of the gland Radiation therapy I 131 (radioisotope of I) Antithyroids β Adrenergic BLOCKERS

15. Radiation therapy Radioiodine( 131 I) :- works by destruction of the gland by beta particles emitted first line treatment half-life of eight days used in one single dose Hypothyroidism will eventually develop, but is easily managed by replacement therapy with thyroxin should be avoided in children and also in pregnant patients because of potential damage to the fetus

16. Antithyroids Thioamides Propylthiouracil(PTU) MOA In the thyroid gland, they inhibit the activity of the enzyme TPO, which is required for The intra-thyroidal oxidation of I The incorporation of I into TG, and The coupling of iodotyrosyl residues to form thyroid hormones Also inhibit peripheral conversion of T4 to T3

17. Antithyroids cont… Iodine It is converted in-vivo to iodide which temporarily inhibits the release of thyroid hormones When high doses of iodine are given to Thyrotoxic patients, the symptom subsides within 1to 2 days There is inhibition of secretion of thyroid hormones and over a period of 10– 14 days, a marked reduction in vascularity of the gland, which becomes smaller and firmer Iodine solution in KI (Lugol’s iodine) is given orally  

18. β Adrenergic BLOCKERS Propranolol (and other nonselective β blockers) alleviate manifestations of thyrotoxicosis that are due to sympathetic overactivity: palpitation, tremor, nervousness, severe myopathy, sweating. They are used in hyperthyroidism in the following situations. While awaiting response to carbimazole or 131 I. Along with iodide for preoperative preparation before subtotal thyroidectomy thyroid storm (thyrotoxic crisis)- is an emergency afford dramatic symptomatic relief

19. Pancreatic Hormones and Antidiabetic Drugs The pancreas is both an Endocrine gland that produces the peptide hormones insulin, glucagon, somatostatin and pancreatic polypeptide , and Exocrine gland that produces digestive enzymes

20. Pancreatic Hormones---- Insulin It controls the metabolism of carbohydrate, fat and protein and normally determines blood glucose concentration   Glucagon It increases blood glucose level Somatostatin It has an indirect paracrine role in that it inhibits secretion of insulin and glucagon.

21. Regulation of blood glucose level

22. Actions of insulin

23. Diabetes Mellitus Diabetes Mellitus is a disease that occurs as a result of absolute or relative deficiency of insulin Or as result of cellular resistance to insulin's actions The etiologies include Obesity hereditary, damage of pancreatic tissue, diabetogenic hormones excess (GH,TH, epinephrine, cortisol), Other factors like Pregnancy

24. Types of DM Two main forms (TypeI &Type II) Both have similar signs & symptoms Major differences in etiology, prevalence, treatments & outcomes (illness severity and deaths) Gestational DM Diabetes that appears during pregnancy Then subsides rapidly after delivery cause Placental hormones High production of cortisol both antagonize the action of insulin Managed by diet & insulin therapy

25. The common signs and symptoms include Polyphagia (excess appetite) Polyuria (excessive urination) Dehydration due to glucosuria Polydipsia (excessive thirst) complications: Short term Ketoacidosis (in type I) hyperglycemic osmolal non ketotic coma (in type II), Long term (>90% of diabetic deaths) cardiovascular nephropathy, Retinopathy (blindness) neuropathy. Amputation impotence

26. Diagnosis Test type Diabetes if Fasting plasma glucose ≥126 mg/dL Casual plasma glucose ≥200 mg/dL plus Classic symptoms Oral glucose tolerance test (OGTT) 2-hr plasma glucose ≥200 . mg/dL, 75 gm of anhydrous glucose dissolved in water

27. Diagnosis--- Fasting is defined as no caloric intake for at least 8 hours. Casual is defined as any time of day without regard to meals. Classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss(for type I). OGTT, plasma glucose content is measured 2 hours after ingesting the equivalent of 75 gm of anhydrous glucose dissolved in water. not recommended or needed for routine clinical use.

28. Drugs for the Treatment of Diabetes Mellitus Insulin Oral hypoglycemic agents

29. Insulin Used to treat both type I and Type II It is the main hormone controlling intermediary metabolism, having action on liver, muscle and fat Its overall effect is to conserve fuel by facilitating: uptake, utilization and storage of glucose, amino acids and fats after meal It reduces blood sugar Acutly

30. Administration Because insulin is a protein, it is degraded in the GIT it taken orally. It is therefore generally administered parenterally usually subcutaneously, but IV or occasionally IM in hyperglycemic emergency Goal of insulin administration ……. To mimc Basal insulin secretion Overnight Fasting Between meals Prandial Basal insulin secretion Meal time insulin secretion

31. Insulin preparation Fourtypes of insulin preparations are available based on the onset and duration of action Ultra-short-acting short acting Intermediate acting Long acting insulin preparations

32. Insulin preparation---- Ultra-short-acting insulin lispro, insulin aspart short acting -Regular insulin Intermediate acting: -Isophane Insulin suspension(NPH) -Lente insulin Long acting: -Ultra lente Protamine zinc Glargine

33. Insulin preparation---- Insulin preparations differs in Recombinant technique employed a.a sequence Stability Solubility Onset of action Duration of action

34. insulin preparations---- Type Appearance Onset (hr) Duration (hr) i. Rapid Regular soluble (Crystalline) Insulin Lispro (ultra short) Clear Clear 0.5 -0.7 0.25 5-8 2-5 ii). Intermediate Neutral protamin Hagedorn (NPH) or isophane Lente (semilente insulin) Cloudy Cloudy 1-2 1-2 18-24 18-24 iii). Slow Ultralente Protamine zinc Glargine Cloudy Cloudy Clear 4 -6 4 -6 2-5 20 -36 24 -36 18 -24

35. Insulin--- Regular insulin ( Natural insulin ): short acting, soluble, crystalline zinc insulin is usually given subcutaneously; 30-45’ before meals Slower acting (30-45’) & short duration(6-10 hrs) 2. Lispro, Aspart, & Glulisine preparations (analogues) ultrashort acting forms with onset more rapid than regular insulin and a shorter duration . These are less often associated with hypoglycemia. Lispro insulin is given 15 minutes prior to a meal.

36. NPH insulin (Neutral protamine Hagedorn insulin) is a suspension of crystalline zinc insulin combined with protamine (a polypeptide). The conjugation with protamine delays its onset of action and prolongs its duration of action. Turbid liquid (shaken before use) Injected S.C. (Only) Onset of action 1 - 2 hr Peak serum level 5 - 7 hr Duration of action 13 - 18 hr

37. NPH----- It is usually given in combination with regular insulin. Insulin mixtures 75/25 70/30 50/50 ( mix isophane with ultra-short or short acting insulin). Isophane (NPH) Ultra-short or short acting

38. Lente insulin Mixture of 30% semilente insulin (small crystals rapidly acting) 70% ultralente insulin (large crystals slow acting with prolonged duration) Injected S.C. (only) onset of action 1 - 3 hr Peak serum level 4 - 8 hr Duration of action 13 - 20 hr Note. Lente and NPH insulins have the same effect. given once or twice a day. Never given iv – turbid liquid prep n s. Thus not used in emergencies (e.g. diabetic ketoacidosis).

39. Indications of Insulin Type I diabetes mellitus, type II diabetes mellitus, DKA/diabetic coma hyperkalemia, Pregnant women with type II or gestational DM should take insulin by injection and avoid taking oral hypoglycemics

40. Insulin Dosing Commonly used regimen for type I DM Twice daily injection of an intermediate insulin (NPH/Lente) mixed with short acting insulin (Lispro/Aspart) Drawbacks : Doesn’t produce a near-normal glycemic control

41. AEs of Insulin Therapy 1. Severe Hypoglycemia (< 50 mg/dl ) - life-threatening - can result in shock and possible death . The Challenge! To balance glucose and insulin levels in the body. insufficient caloric intake: missed meal, improper meal content, delayed meal, etc .)

42. Hypoglycemic signs and symptoms Tachycardia Shakiness Dizziness Sweating Hunger Headache Pale skin Sudden moodiness or behavior changes Confusion or difficulty paying attention Diabetics are usually really good at recognizing hypoglycemic symptoms

43. AE---- 2. Hypokalemia: Insulin draws K + into the cell with glucose. 3. Insulin resistance (when the patient needs more than 200 units/day) (IgG anti-insulin antibodies, infection, expired insulin(rare)). 4. Lipodystrophy at injection site - Make 1 inch apart among injection sites(Site rotation) 5. Weight gain

44. Oral Hypoglycemic Agents Are useful in the treatment of patients who have NIDDM but cannot be managed by diet alone. The patient most likely to respond well to oral hypoglycemic agents is one who develops diabetes after age 40 and has had diabetes less than 5 years. Patient with long-standing disease may require a combination of a hypoglycemic drug and insulin

45. Oral hypoglycemic agents----

46. Sulfonylureas ----- Pharmacokinetics Metabolized by the liver and are excreted by the liver or kidney Contraindicated in patients with hepatic or renal insufficiency (Because their accumulation in such patients results in hypoglycemia) The sulfonylureas traverse the placenta and secreted in breast milk , can deplete insulin from the fetal pancreas and the infant . Therefore the NIDDM pregnant women should be treated with insulin alone. Also contraindicated in breast feeding

47. . Sulfonylureas Side Effects Hypoglycemia Stimulate appetite => weight gain Cardiovascular deaths (Because they non-selectively block K + channels found in the heart or blood vessels) Contraindications Sulphonyl Ureas are contraindicated in Obesic diabetic patients Patients with hepatic or renal insufficiency Obesic pregnant women Alcoholic patients (because Sulphonyl Ureas inhibit alcohol metabolism)

48. B. Biguanides Examples include :-Metformin, Phenformin, Butformin Mechanisms of action They decrease glucose production by liver They increase glucose uptake by skeletal muscles They lower plasma lipids (LDL)

49. Biguanides --- Advantage of Biguanides over Sulphonyl Ureas: suppress appetite (therefore they can be safely be given for Obesic diabetic patients) Does not cause hypoglycemia -because it does not stimulate insulin release They can be safely used in pregnant women Side effects GI disturbance Rarely, potentially fatal lactic acidosis Long-term use may interfere with B 12 absorption Contraindications Renal and hepatic insufficiency

50. C. Glucosidase inhibitor Drugs :- Acarbose, Miglitol MOA: Inhibition of α (Acarbose ) and Beta(Migiltol)- glucosidases enzymes (Intestinal enzymes that digest bigger sugars) → decrease digestion and absorption of sugars → ↓postprandial glucos Uses Mono Tx for type II Adjunctive Tx with other OHGA (SU, Metformin, etc) Side Effects Flatulence Diarrhea Abdominal cramping

51. D. Meglitinides Example: Repaglinide The meglitinides are a new class of insulin secretagogues MOA: Modulate β cell insulin release by regulating potassium efflux through the potassium channels. Are helpful in patients with a known allergy to sulfa drugs SE: Hypoglycemia is the common SE with meglitinides

52. Treatment algorism for type II a stepwise approach is often used Step 1. Implement lifestyle changes : caloric and carbohydrate restriction, exercise, and weight loss. Step 2. Initiate therapy with just one oral hypoglycemic drug Drug selection is based on the patient's body composition and degree of hyperglycemia For lean patients, try a sulfonylurea. Why? For obese patients, try metformin. Why?

53. Answers for Why Because lean patients are usually insulin deficient, and sulfonylureas stimulate insulin release. Because in obese patients, insulin's target cells tend to be insulin resistant. Metformin can reduce insulin resistance, and has the added benefit of suppressing appetite, which can help the patient lose weight.

54. DRUGS ACTING ON THE UTERUS Phsiologicaly labor, delivery, and birth require a complex interplay of hormonal action, neuronal activity, and uterine smooth muscle contraction. During the first two trimesters of pregnancy, the uterus remains in a relatively quiescent state, demonstrating little or no contraction of the myometrium. This inactivity is largely the result of the inhibitory action of high circulating levels of progesterone on the uterine musculature. At the end of pregnancy to facilitate birth,the cervix begins to soften ( cervical ripening ) ; this process may involve the actions of the peptide hormone relaxin, which is produced both in the corpus luteum and in the placenta .

55. DRUGS ACTING ON THE UTERUS--- Release of oxytocin at this stage of parturition promotes prostaglandin production, particularly of the E and F series, within the decidua; these prostaglandins are powerful myometrial stimulants and thus further enhance uterine contractions Generally two classes of drugs that act on the utrus: Utrine Stimulants ( OXYTOCICS) Utrine Relaxants( Tocolytics)

56. OXYTOCICS Drugs that cause contraction of the uterus Include: Oxytocin Prostaglandins Ergometrine Oxytocic agents have three applications: induction or augmentation of labor , control of postpartum bleeding , and induction of abortion .

57. Oxytocin ----- Actions: Stimulates the uterus and cause physiologic type of contraction Causes ejection of milk Use : Induction of labor near term - check for cervical ripening 1 st Relief of breast engorgement during lactation- Reduction in postpartum hemorrhage Note: Oxytocin is generally considered to be the drug of choice for inducing labor at term . S/Es : Rupture of the uterus in woman with uterine scar Water retention leading to water intoxication when given IV

58. Oxytocin---- Precautions and contraindications Improper use of oxytocin may result in uterine rupture and leads to death to the mother as well as the infant. Thus, in presence of fetal malpresentation, placental abnormalities, umbilical prolapse, previous uterine surgery, and fetal distress the likely hood of trauma is high.

59. Prostaglandins Misoprostol (PGE1 analogue) Carboprost (PGF2α analogue ) Dinoprostone (PGE2 analogue)

60. PGs use Induce labor at anytime during pregnancy Misoprostol to initiate ripening of the cervix prior to induction of labor (Dinoprostone, Misoprostol) = vaginally To induce abortion (Mifepristone + Misoprostol) = early in pregnancy (within 7 weeks) , in the second trimester (Carboprost, Dinoprostone) = 2 nd trimister only for controlling postpartum hemorrhage ( Carboprost ) to protect against peptic ulcers (Misoprostol)

61. Prostaglandins… A/Es : abdominal pain , nausea, vomiting, diarrhea, headache, fever ( PGE2 ), Bronchospasm (PGF2α ), Flushing (PGE2), vaginal bleeding, etc. C/Is: ectopic pregnancy, hemorrhagic disorders, use of anticoagulant drugs, glucocorticoid therapy (Mifepristone blocks GC receptor), Fetal distress .

62. Ergometrine ( Ergonovine ) It initiates strong and prolonged uterine contraction Completely absorbed after sc and iv administration. Metabolized in the liver and eliminated in the bile & urine Use : To prevent postpartum bleeding Note: . If used to induce or augment labour it causes uterine rupture and fetal hypoxia.

63. Ergometrine- ---- Side effects By constricting blood vessels it may result; increase in blood pressure, nausea, vomiting, blurred vision, and headache.. Contraindications Hypertension induction or augmentation of labour. presence of labor Pelvic inflammation For abortion purpose

64. Tocolytics Drugs that cause uterine relaxation 2-adrenergic agonist (e.g. Retodrine ) Ca2+-channel blocker (e.g. nifedipine) PG-synthase inhibitors (NSAIDs) Magnesium sulfate Clinical use Delay premature labor

65. Magnesium sulfate (MgSO 4) It is a drug of choice for suppressing preterm labor It is the most commonly used anticonvulsants in the treatment of pregnancy induced hypertention(preeclampsia) Mechanism of action: It inhibits Ach release at uterine neuromuscular junctions. Side effects Muscle weakness.