Drugs acting on the Autonomic Nervous System.pptx

Drugs acting on the Autonomic Nervous System (ANS)

1. Drugs acting on the Autonomic Nervous System ( ANS) Haftom G. (MSc) Email: [email protected] 1

2. Drugs acting on the ANS Drugs acting on the ANS Cholinergic agonists Cholinergic antagonists Adrenergic agonists Adrenergic antagonists 2

3. Introduction to NS Nervous system : divided in to two anatomical divisions CNS ( brain & spinal cord ) PNS ( neurons located outside the CNS & enter or leave the CNS PNS divided into two Efferent division Carry signal away from CNS Afferent division Bring information from the periphery to the CNS 3

4. Introduction to NS cont’d… Efferent division falls in to two Somatic efferent system Control voluntary functions ( skeletal muscles in locomotion) Autonomic efferent system: its activities are not under direct conscious control Involved in involuntary activities and innervates smooth muscle of the visceral , cardiac muscle, vasculature and exocrine glands 4

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7. Anatomy of the ANS Efferent neurons of ANS Carries impulses from the CNS to the effecter organ Two types of efferent neurons Preganglionic neuron Cell body located with in the CNS Make a synaptic connection in ganglia with the postganglionic neuron. Postganglionic neuron Cell body originated in the ganglion & terminates on effector organ Afferent neurons - important for reflex regulation 7

8. Anatomy of the ANS cont’d… The ANS : comprises two divisions The sympathetic (thoracolumbar ) outflow and The parasympathetic ( craniosacral) outflow Neurons in both divisions originate in nuclei within the CNS and give rise to preganglionic efferent fibers that exit from the brain stem or spinal cord and terminate in motor ganglia. Note : The two divisions are defined by their anatomic origin rather than by their physiological characteristics. 8

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10. Anatomy of the ANS cont’d… 10

11. General Features of Peripheral Autonomic Neurotransmission 11

12. Functions of sympathetic & parasympathetic neurons The sympathetic division has the property of adjusting in response to stressful situation ( fight or flight response). The parasympathetic division maintains essential bodily functions (rest & relaxation ). Most organs in the body are innervated by both systems. Adrenal medulla, kidney, pilomotor muscles & sweat glands , receive innervations only from the sympathetic system. 12

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15. Drugs acting on ANS cont’d… 15

16. ANS cont’d… Neurotransmitters Communication between nerve cells & nerve cells, nerve cells & effectors organs occur through the release of specific chemical signals called neurotransmitters (from the nerve terminals) NE , E , Ach , DA , S, H and  -amino butyric acid(GABA) If transmission is mediated by acetylcholine, the neuron is termed as cholinergic If epinephrine or nor-epinephrine is the transmitter, the fiber is called adrenergic 16

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21. 21 NOTE: β 2  mediated responses are caused by the effects of circulating catecholamines ; these receptors are not typically located near sympathetic nerve endings.

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23. Five key features of neurotransmitter function provide potential targets for pharmacologic therapy: Synthesis Storage Release Termination of action of the transmitter, and Receptor effects. 23

24. Cholinergic system and drugs acting on the system 24

25. Cholinergic drugs…. Cholinergic neurons Fiber to the adrenal medulla The autonomic ganglia (both symp & para) Post ganglion fiber of parasymp . Neurons innervate voluntary muscles of somatic systems 25

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27. Steps in cholinergic neurotransmission Synthesis of acetyl choline ( ACh ) From choline and acetyl CoA which catalyzed by choline acetyl transferase Up take to storage vesicle Release of acetyl choline by exocytosis Binding to receptor Degradation of acetyl choline by cholinesterase To acetate & choline Recycling of choline 27

28. Physiological role of cholinesterase(s) Family of enzymes responsible for terminating the effects of acetylcholine   There are two basic subtypes of cholinesterases Acetylcholinesterase ( AChE )  - expressed in NMJs, neural synapses and on RBC membranes . Pseudocholinesterase  - also called “ butyrylcholinesterase ” ( BChE ) is produced by the  liver  and found in the  plasma . It metabolizes the synthetic compound butyrylcholine more quickly than acetylcholine, and is responsible for metabolizing many circulating ester-containing compounds including succinylcholine, mivacurium , ester-type local anesthetics (e.g. procaine, cocaine), and heroin. 28

29. Physiological role of cholinesterase(s) Fig: Acetylcholinesterase in the skeletal muscle endplate region 29

30. Note: Pseudocholinesterase Deficiency Pseudocholinesterase deficiency & s uccinylcholine Patients with pseudocholinesterase deficiency will exhibit a more intense and greatly prolonged neuromuscular block (e.g. from a normal duration of block of 5 minutes to as long as 8 hours). If not identified, a patient with a pseudocholinesterase deficiency who is given succinylcholine can become hypoxic and potentially die if artificial ventilation is not maintained. 30

31. Note: Pseudocholinesterase Deficiency It is estimated that 6-7% of patients in most surgical populations have an abnormal plasma cholinesterase, and ~65% of all cases of prolonged NMJ blockade after succinylcholine are due to genetic factors. Pseudocholinesterase deficiency can also increase the risk of systemic toxicity produced by ester-type local anesthetics (e.g. during dental procedures). Such patients are typically given an amide-type local anesthetic instead. 31

32. Cholinergic receptors Two families Muscarinic & nicotinic receptors I. Muscarimic receptors : Bind with muscarine ; an alkaloid that is present in certain poisonous mushrooms, but show a weak affinity for nicotine Subclasses : M1, M2, M3, M4 & M5. II. Nicotinic receptors : bind with nicotine , but show only a weak affinity for muscarine . Subclasses : N N and N M 32

33. Para. Symp . N Ach Ach M Ach Ach Ach N N N NA A Sympathetic Sympathetic Adrenal medulla Somatic 33

34. Cholinergic Drugs Parasympathomimetics / Cholinomimetic Parasympatholytics 34

35. Cholinomimetic / parasympathomimetic Produce actions similar to that of Ach Direct acting: directly interact with cholinergic receptors (cholinergic agonists) Esters of Choline : Acetylcholine, Methacholine , Carbachol , Betanechol Cholinergic alkaloids : Pilocarpine , Muscarine , Nicotine, Arecoline , Varenicline Indirect acting: increase availability of Ach ( anticholine esterases ) Reversible : Neostignine , Physostigmine , Edrophonium Irreversible : Organophosphate cpds , Echotiophate 35

36. Actions of acetylcholine Actions of Ach classified as muscarinic or nicotinic Muscarinic Heart : Bradycardia (rate & force of contraction decreased) Blood vessels (skin of face & neck) Dilation – fall in blood pressure 36

37. Actions of acetylcholine cont’d… Smooth muscles : In most organs – contraction Tone & peristalsis in GIT is increased and sphincters relaxed – abdominal cramp & evacuation of bowel Peristalsis in ureter is increased – muscle contracts & sphincter relaxes – voiding of bladder Bronchial muscles constrict – dyspnea , precipitation of an attack of bronchial asthma. 37

38. Actions of acetylcholine cont’d… Glands : Secretion is increased :- sweating, salivation, lacrymation , tracheo bronchial and gastric secretion Eye : Contraction of iris sphincter muscle – miosis (constriction of pupil) Contraction of ciliary muscle – spasm of accommodation, increased out flow aqueous humor – reduction in ocular tension 38

39. B. Nicotinic Autonomic ganglia :- both sympathetic & parasympathetic ganglia are stimulated (effect is manifested at higher doses) Skeletal muscles - Contraction CNS - Stimulation followed by depression Note : Ach therapeutically of no importance Because of multiplicity of actions & its rapid inactivation by acetyl-cholinesterase. Actions of acetylcholine 39

40. Direct Cholinergic Agonists Choline esters : Methacholine , Carbachol , Bethanechol Alkaloids: Muscarine , Pilocarpine , Arecholine Differ from Ach Have longer duration of action Effective orally & parenterally Relatively more selective in their actions 40

41. Bethanechol Acetate of Ach is replaced with carbamate and choline is methylated not hydrolyzed by acetylcholine esterase have strong muscarinic activity (has no or little nicotinic actions) It’s major actions are on the smooth musculature of the bladder and GIT 41

42. Bethanechol cont’d … Therapeutic application : Postoperative ileus….Paralytic ileus??? Post operative abdominal distention. Rx acute postoperative & postpartum nonobstructive urinary retention Neurogenic  atony of the urinary bladder with retention. Side effects : Sweating, salivation, flushing, decreased blood pressure, abdominal pain, diarrhea and bronchospasm. Antidote: atropine 42

43. Bethanechol cont’d … Contraindications: Hypersensitivity to bethanechol chloride Hyperthyroidism Peptic ulcer Latent or active bronchial asthma Pronounced bradycardia or hypotension Vasomotor instability Coronary artery disease Epilepsy Parkinsonism Pharmacokinetics:  D oes not cross the BBB   The metabolic fate and mode of excretion of the drug have not been elucidated. Administer orally or s.c. ; do not give by i.v. injection due to the risk of hypotension & bradycardia Drug Interactions: Special care is required if this drug is given to patients receiving ganglion blocking compounds because a critical fall in blood pressure may occur. Usually , severe abdominal symptoms appear before there is such a fall in the blood pressure. 43

44. Carbachol Has both Muscarinic & Nicotinic actions Not destroyed by AchE → long DOA. Has more pronounced effect in the GI & CVS (Stimulates and then depress) b/c of ganglion stimulation activity. Can be given orally or instilled in to the eye. 44

45. Carbachol cont’d … Therapeutic use : Because of its high potency, receptor non-selectivity, and relatively long duration of action, carbachol is rarely used, Except in glaucoma 45

46. Methacholine Metabolised by AchE but at a slower rate. Intermediate duration of action b/n Ach and carbachol . Carbachol > Metacholine > Ach Acts mainly on Muscarinic receptors. Actions on CVS are more marked. 46

47. 47 Choline ester Chemical structure Susceptibility to Cholinesterase Muscarinic action Nicotinic action Acetylcholine chloride ++++ +++ +++ Methacholine chloride ++ +++ + Carbachol chloride Negligible ++ +++ Bethanechol chloride Negligible +++ None

48. Pilocarpine Muscarinic agonist: used in ophthalmology Actions : rapid miosis and accommodation for near vision Therapeutic use : Glaucoma: pilocarpine is the drug of choice in the emergency lowering of intraocular pressure (glaucoma) as a result of the increased drainage of aqueous humor. Sjogren's Syndrome :  Pilocarpine is used to stimulate salivary secretions in patients with reduced saliva production caused by autoimmune disease ( Sjogren's Syndrome) or damage to saliva glands due to radiation therapy. 48

49. Pilocarpine Contraindications: Uncontrolled asthma, Known hypersensitivity to pilocarpine, When miosis is undesirable Side Effects: The most frequent include   sweating, flushing, increased urinary frequency . Pharmacokinetics : Action lasts up to 1 day Well absorbed from most sites of administration Crosses the blood brain barrier  (its a tertiary amine) Drug Interactions: Administered with caution to patients taking beta blockers because of the possibility of cardiac conduction disturbances Available as 0.5-4% eye drops 49

50. Indirect Cholinergic Agonists OR cholinesterase inhibitors 50

51. Indirect Cholinergic Agonists They inhibit AchE , protect Ach from hydrolysis Results in accumulation of Ach in the synaptic cleft Thus provoke a response at all cholinoceptros in the body, including both Muscarinic and Nicotinic receptors of the autonomic nervous system as well as the neuromuscular junction & the brain 51

52. Subtypes of Cholinesterase Inhibitors (Anticholinesterases ): ACEIs can be divided into 3 different chemical subtypes. Quaternary alcohols:   Edrophonium Carbamates: Traditional: Neostigmine , Physostigmine , Pyridostigmine Alzheimers Dementia: Donepezil, Galantamine , Rivastigmine   Organophosphates: Therapeutic :  Echothiophate  (& several insecticides) Nerve Agents:  Tabun , Sarin, Soman , VX 52

53. Anticholinesterases cont’d… Nerve gases for chemical warfare 53

54. Physostigmine A substrate for acetylcholine esterase, reversibly inactivates the enzyme Actions :- It stimulates both Muscarinic & Nicotinic sites of the ANS & nicotinic receptor of neuromuscular junction Duration of action: 2-4 hours 54

55. Physostigmine cont’d… Therapeutic use :- Increase intestinal & bladder motility (in atony of either organ) Used as nicotinic agent for the treatment of Glaucoma [But pilocarpine is more effective] Rx of overdose of drugs which produce the anticholinergic syndrome Adverse effects:- Effect on CNS may lead to convulsions with high doses Bradycardia and fall in CO Paralysis of skeletal muscle [rare with therapeutic doses] 55

56. Physostigmine cont’d… Contraindications: It should not be used in the presence of asthma, gangrene, diabetes, cardiovascular disease, mechanical obstruction of the intestine or urogenital tract or any vagotonic state, and in patients receiving choline esters and depolarizing neuromuscular blocking agents ( decamethonium , succinyicholine ) Side Effects: nausea, vomiting, and salivation Appropriate antidote is atropine sulfate 56

57. Notes: Anticholinergic syndrome Some drugs which produce the anticholinergic syndrome: Amitriptyline , Amoxapine , Anisotropine , Atropine , Benztropine , Biperiden , Carbinoxamine , Clidinium , Cyclobenzaprine, Desipramine , Doxepin, Homatropine , Hyoscine ( Scopolamine) , Hyoscyamine , Hyoscyamus , Imipramine , Lorazepam , Maprotiline , Mepenzolate , Nortriptyline, Propantheline , Protriptyline , Trimipramine . Some plants that produce the anticholinergic syndrome: Black Henbane, Deadly Night Shade, Devil’s Apple, Jimson Weed, Loco Seeds or Weeds, Matrimony Vine, Night Blooming Jessamine, Stinkweed. 57

58. Neostigmine More polar Does not enter the CNS It’s effect on skeletal muscle is greater than that of physostigmine It is used to stimulate the bladder and GI tract Antidotes for tubocurarine and other competitive neuromuscular blocking agents Used in symptomatic treatment of myasthenia gravis (weakening of muscle caused by antibodies to the nicotinic receptor) Duration of action 2-4 hours 58

59. Neostigmine cont’d… Adverse effect : Generalized cholinergic stimulation such as salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhea and bronchospasm Contraindications: Patients with known hypersensitivity to the drug Patients with peritonitis or mechanical obstruction of the intestinal or urinary tract 59

60. Neostigmine cont’d… Pharmacokinetics: Poorly absorbed from the gastrointestinal tract As a rule, 15 mg of neostigmine bromide given orally is equivalent to 0.5 mg of neostigmine methylsulfate given parenterally Major drug Interactions: Certain aminoglycoside antibiotics, especially neomycin, streptomycin and kanamycin, have a mild but definite non-depolarizing blocking action which may accentuate neuromuscular block. These antibiotics should be used in the myasthenic patient only where definitely indicated . 60

61. Pyridostigmine Similar to neostigmine but slower onset and longer duration of action. Used in the chronic management of myasthenia gravis (weakening of muscle caused by antibodies to the nicotinic receptor) Duration of action 3-6 hours Does not cross BBB Mainly excreted unchanged by the kidney 61

62. Edrophonium Similar to neostigmine except It is more rapidly absorbed (30 sec) Has a short duration of action of 5 to 10 minutes ( prototype short-acting agent ). Edrophonium is a quaternary amine Excess drug may provoke a cholinergic crisis [antidote=Atropine] 62

63. Edrophonium Indications: For the differential diagnosis of myasthenia gravis (the Tensilon Test)  and as an adjunct in the evaluation of treatment requirements in this disease. It may also be used for evaluating emergency treatment in myasthenic crises. YouTube video  of the Tensilon Test performed in a dog with Myasthenia Gravis To reverse the neuromuscular block produced by curare, or curare-like NMJ blocker  (e.g. tubocurarine , gallamine triethiodide or dimethyl- tubocurarine ) 63

64. Edrophonium Contraindications: Hypersensitivity, Intestinal and urinary obstructions of mechanical type Side Effects: Patients on edrophonium should be observed for bradycardia or cardiac standstill and cholinergic reactions if an overdose is given. Muscarine -like symptoms: N, V, D, sweating, increased bronchial and salivary secretions and bradycardia Obstruction of the airway by bronchial secretions 64

65. Edrophonium Pharmacokinetics: IV and IM administration Major drug Interactions: Care should be given when administering this drug to patients with symptoms of myasthenic weakness who are also on anticholinesterase drugs Since symptoms of anticholinesterase overdose (cholinergic crisis) may mimic under-dosage ( myasthenic weakness), their condition may be worsened by the use of this drug 65

66. Indirect Cholinergic Agonists (irreversible) Bind covalently to acetyl cholinesterase which is extremely stable leads to long lasting increase in Ach action at all sites where it is released Extremely toxic & used as nerve agents in military & insecticides Easily available and extensively used as agricultural and household insecticides Accidental, suicidal and homicidal poisoning 66

67. Irreversible anticholinesterases cont’d… Pharmacologic action Initially : miosis , salivation, sweating, vomiting, diarrhea and bronchial constriction, followed by involvement of nervous systems Cause persistent depolarization of muscle and plates resulting in blockade of neuromuscular transmission + weakness and paralysis Respiratory paralysis (central as well as peripheral) Death is generally due to respiratory failure 67

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69. Treatment of Organophosphate Poisoning Decontamination : Remove & dispense of contaminated clothing as quickly as possible Wash skin  with large amounts of soap and water (such as showering) Rinse the eyes  with plain water for 10 to 15 minutes if they are burning or if vision is blurred If sarin has been swallowed, do not induce vomiting or give fluids to drink 69

70. Treatment of Organophosphate Poisoning Take steps to avoid secondary contamination Health care workers should wear latex gloves …(and have a large supply available) Atropine  as antidote Atropine antagonizes the muscarinic effects of the nerve agent 70

71. Treatment of Organophosphate Poisoning Pralidoxime  (2-PAM) pralidoxime should be given in cases where moderate to severe symptoms develop, and before aging occurs pralidoxime acts at both nicotinic and muscarinic sites to regenerate cholinesterase activity Pralidoxime & benzodiazepines should not be used for mild cases 71

72. Treatment of Organophosphate Poisoning Scopolamine  for severe intoxication ( off label use ) Animal experiments indicating that it can prevent nerve-agent-associated seizures It should not replace atropine (which is most effective in treating muscarinic toxicity outside the CNS). Benzodiazepines diazepam, lorazepam or midazolam to prevent convulsions when severe symptoms develop Other supportive measures : assisted ventilation if needed 72

73. Treatment of Organophosphate Poisoning 73

74. Irreversible anticholinesterases cont’d … Echothiophate MOA: Covalently binds to AchE and permanently inactivates Restoration requires synthesis of new enzymes Causes generalized cholinergic stimulation, paralysis of motor function and convulsions Therapuetic uses Open-angle glaucoma but not the first line Causes cataracts and this limits its use 74

75. Cholinergic Antagonists (Parasympatholytics) 75

76. II. Cholinergic antagonists Cholinergic antagonists, cholinergic blockers or anticholinergic drugs Bind to cholinergic receptor but do not trigger the usual receptor mediated intracellular effects These drugs are classified as: Antimuscarinic agents Ganglionic blockers Neuromuscular blocking drugs 76

77. Cholinergic antagonists cont’d… Antimuscarinic agents block the muscarinic synapses of the parasym . nerves Ganglionic blockers block the nicotinic receptors of the sympathetic and parasympathetic ganglia Neuromuscular blockers block the nicotinic receptors at neuro-muscular junctions 77

78. Antimuscarinic agents Atropine, Ipratropium, Scopolamine, Tropicamide Block M but do not block the N receptors have no action at skeletal NMJ or autonomic ganglia. Classification Natural alkaloids : atropine , hyoscine (scopolamine) Semi-synthetic derivatives : homatropine , atropine methonitrate , hyoscine butyl bromide , hyoscine hydrobromide , ipratropium bromide , tiotropium bromide Synthetic compounds : Cyclopentolate , tropicamide , pirenzepine , telenzepine , biperiden , benztropine , trihexyphenidyl , oxybutynin 78

79. Antimuscarinic agents cont’d … Pharmacological actions of antimuscarinic agnets (Atropine as prototype) Predicted from parasympathetic responses Atropine an alkaloid found in atropa belladona It blocks all subtypes of muscarnic receptors (central & peripheral) 79

80. Atropine Actions: Eye : Persistant mydriasis (dilation of the pupil ) Cycloplegia ( inability to focus for near vision) Raise in IOP GI : Antispasmodic ( reduce activity of GIT) Urinary system: Reduce hypermotilty of the urinary bladder * N H O C O M e C H C H 2 O H 80

81. Atropine actions cont’d … CVS : At low dose Decreased cardiac rate ( bradycardia ): M1 At higher dose increased cardiac rate ( tachycardia ): M2 Secretions : Block salivary glands (dry mouth ) & sweat glands 81

82. Pharmacokinetics of Atropine Relatively lipid soluble and readily crosses membrane barriers (tertiary amine) Well distributed into the CNS and other organs Eliminated partially by metabolism in the liver and partially by renal excretion. The elimination half-life is approximately 2 h DOA is 4-8 h except in the eye, where effects last for 72 h or longer . Administered i.v. , s.c. or i.m . Readily crosses the placental barrier and enters the fetal circulation 82

83. Therapeutic uses of atropine Pre-anesthetic medication : to prevent or reduce secretions of the respiratory tract To restore cardiac rate and arterial blood pressure during anesthesia   To reduce the degree of atrioventricular (A-V) heart block  when increased vagal tone is a major cause (e.g. as in cases of digoxin toxicity, or following an inferior MI). To prevent severe bradycardia and syncope due to a hyperactive carotid sinus reflex. As an antidote (with external cardiac massage) for cardiovascular collapse from the injudicious use of a choline ester (cholinergic) drug. Treatment of anticholinesterase poisoning from organophosphorus insecticides . Antispasmodic agent : to relax GIT and urinary bladder 83

84. Therapeutic uses of atropine Anti-dote for the “rapid” type of mushroom poisoning  due to the presence of the muscarine that is found in certain fungi such as  Amanita muscaria May improve the tremor & rigidity of Parkinsonism As an eye-drop medication to cause prolonged relaxation of over-contracted eye muscles due to chronic eye inflammation. Effect lasts for more than a week (7-10 days of mydriasis, & ~2 weeks of cycloplegia ) Shorter acting antimuscarinics : homatropine , cyclopentolate or tropicamide are typically used to produce mydriasis during routine eye exams 84

85. Atropine A dverse Effects Dry mouth blurred vision: cycloplegia tachycardia, and Constipation Photophobia Anhidrosis : may occur and produce heat intolerance Marked excitement and convulsions may occur with toxic doses (in comparison, scopolamine has greater CNS effects) 85

86. Atropine A dverse Effects Blind as a bat, Mad as a hatter, Dry as a bone, Red as a beet, Hot as hell, Full as a Flask 86

87. Contraindications of atropine Atropine generally is contraindicated in patients with  glaucoma , pyloric stenosis or prostatic hypertrophy, except in doses ordinarily used for pre-anesthetic medication. Atropine Sulfate Injection should be used with caution in all individuals over 40 years of age 87

88. Hyoscine (scopolamine) An alkaloid obtained from hyoscyamys niger Produces peripheral effects similar to those of atropine Has greater action on the CNS producing  drowsiness  and  amnesia  in sensitive individuals Longer duration of action in comparison to atropine. 88

89. Hyoscine (scopolamine) cont’d… Therapeutic use : Anti-motion sickness agent, antispasmodic, to block short-term memory. Much more effective prophylactically than for treating motion sickness once it occurs. The amnesic action of scopolamine makes it an important adjunct drug in anesthetic procedures To produce mydriasis & cycloplegia  in diagnostic procedures Reduction of the  tremor of Parkinson's disease 89

90. Hyoscine (scopolamine) cont’d… Contraindications: Patients with angle-closure (narrow angle) glaucoma, or history of hypersensitivity to scopolamine. Side Effects: Therapeutic doses can cause  drowsiness & amnesia , dry mouth, transient impairment of eye accommodation, including blurred vision and dilation of the pupils. Toxic doses can cause excitement, agitation, hallucinations & coma (more likely than with atropine). 90

91. Hyoscine (scopolamine) cont’d… Major drug Interactions: Scopolamine should be used with care in patients taking other drugs that are capable of causing CNS effects such as sedatives, tranquilizers, or alcohol. Special attention should be paid to potential interactions with drugs having anticholinergic properties; e.g., other belladonna alkaloids, antihistamines (including meclizine), tricyclic antidepressants, and muscle relaxants. 91

92. Ipratropium Inhaled ipratropium , a quaternary derivative of atropine useful in treating asthma in patients who are unable to take adrenergic agonists. Also beneficial in the management of COPD including chronic bronchitis and emphysema . Because of its positive charge : Does not enter the systemic circulation or the CNS Thus, only to the pulmonary system. 92

93. Ipratropium Contraindications: patients with a history of hypersensitivity to soya lecithin or related food products such as soybean and peanut. Side Effects: Tachycardia, palpitations, eye pain, urinary retention, UTI and urticaria . Cases of precipitation or worsening of narrow-angle glaucoma and acute eye pain have been reported. Pharmacokinetics: Given as  an inhaled medication . 93

94. Glycopyrrolate A quaternary analog of atropine : does not cross the Blood-Brain-Barrier . Pharmacokinetics: Given parenterally . Side Effects: Similar to atropine (w/o CNS component ) 94

95. Glycopyrrolate Indications : Pre-op medication  to reduce salivary & respiratory secretions , as well as the volume and acidity of gastric secretions, and to block cardiac vagal reflexes during intubation & induction of general anesthesia. Used along in combination with neostigmine  to reverse the effects of non-depolarizing skeletal muscle relaxants at the conclusion of surgery . As an adjunctive drug for treatment of  peptic ulcer  when rapid anticholinergic effect is desired, or when oral medication is not tolerated . 95

96. Propantheline : anticholinergic used for peptic ulcer and gastritis It reduce gastric secretion Action lasts 6-8 hours Probanthine 15 mg tab available Clidinium : Used in combination with benzodiazepines for peptic ulcer disease . Librax ® is available (clidinium bromide + cholorodiazepoxide ) (2.5 mg + 5 mg) 96

97. Drugs Acting on Autonomic GanglioNs (Ganglionic Blocker) 97

98. Drugs Acting on Autonomic Ganglios (Ganglionic Blocker ) Act on the nicotinic receptor Show no selectivity (parasympathetic or sympathetic ganglia) They block the entire output of the autonomic nervous system at the nicotinic receptor. The response observed are complex & unpredictable , making impossible to have selective actions Rarely used therapeutically today. However they often serve as tools for experimental pharmacology 98

99. Drugs Acting on Autonomic Ganglions (Ganglionic Blocker ) Pharmacological effects : Depends on the quantity and the relative proportion of the total autonomic input coming from sympathetic or parasympathetic nerve Hypotension because of the vasodilaton , resulting from the sympathetic ganglia blockade Constipation , tachycardia , blurred vision, dry mouth and urine retention , all of which are because of the parasympathetic ganglia blockade 99

100. classified as: A) Competitive blockers Quaterinary ammonium compounds Hexa methonuim Pentolinium Amines (secondary/tertiary) Mecamylamine Pempidine Monosulfonium compound Trimethaphan B) Persistent depolarizing blockers Nicotine (large dose) Anticholinesterases (large dose) 100

101. Nicotine A natural liquid alkaloid obtained from Nicotina tobacum Small doses of nicotine activate the nicotinic cholinergic receptors Large doses inhibit the receptor by exerting persistent depolarization. Effects result from its action on The adrenal medulla, The ganglia (both sympathetic & parasympathetic), The neuromuscular junction and on the CNS 101

102. Nicotine cont’d… In small doses: Rise in BP because of the release of cathecolamines from the adrenal medulla and sympathetic ganglia, leading to increase HR and vasoconstriction. Increase secretion of glands because of the parasym stimulation Contraction of skeletal muscle b/c of its action on the neuromuscular junction Excitation because of its action on the CNS 102

103. Nicotine cont’d… Higher doses : The BP falls Because of gangliomic blockade , and activity both in GlT & bladder musculature ceases It’s not used clinically because no useful purpose can be served by stimulating both sympathetic and parasympathetic ganglia concurrently 103

104. Nicotine cont’d… Mechanism of Action: Binds stereo-selectively to nicotinic-cholinergic receptors at the  autonomic ganglia , in the  adrenal medulla , at  neuromuscular junctions , and in the  brain Two types of central nervous system effects are believed to be the basis of nicotine’s positively reinforcing properties: A stimulating effect is exerted mainly in the cortex via the locus ceruleus A reward effect is exerted in the limbic system At low doses the stimulant effects predominate while at high doses the reward effects predominate The cardiovascular effects of nicotine include peripheral vasoconstriction, tachycardia, and elevated blood pressure 104

105. Nicotine cont’d… Indications: Aid to smoking cessation  for the relief of nicotine withdrawal symptoms Side Effects: Nausea Abdominal pain Vomiting, diarrhea, Diaphoresis (profuse sweating) Flushing Dizziness Disturbed hearing and vision, Confusion Weakness Palpitations Altered respiration Hypotension 105

106. Trimethaphan Is a short acting, competitive nicotinic ganglionic blocker The drug was used for emergency lowering of BP 106

107. ADE of Ganglion blockers Because ganglion blockers interrupt sympathetic control of venous tone , They cause marked venous pooling Postural hypotension is a major manifestation of this effect. Other toxicities include Dry mouth, Blurred vision, Constipation, and S evere sexual dysfunction. As a result, ganglion blockers are rarely used 107

108. Neuromuscular blocking drugs 108

109. Neuromuscular blocking drugs Block cholinergic transmission b/n motor nerve endings and the nicotinic receptors on the neuromuscular endplate of skeletal muscle. Structural analogue of Ach and act either as Antagonists (non-depolarizing type) or Agonists (depolarizing type) Useful clinically during surgery to produce complete muscle relaxation 109

110. Neuromuscular blocking drugs cont’d… 110

111. Non- depolanizing (competitive) blockers The first drug was curare , native hunters of the Amazon in south America used to paralyze animals. Tubocurarine was ultimately purified and introduce into clinical practice. 111

112. d- Tubocurarine (Prototype Nondepolarizing Neuromuscular Blocker ) Mechanism of Action: 3 mechanisms   might contribute to skeletal muscle relaxation: At low concentrations:   compete with ACH  interfere with presynaptic release of ACh   At higher concentrations:  they can also produce a more intense motor blockade by  blocking the pore  of the nicotinic receptor-channel complex . 112

113. d- Tubocurarine (Prototype Nondepolarizing Neuromuscular Blocker ) Side Effects: Allergic reactions. d- tubocurarine causes the most histamine release by a direct effect on mast cells.   Histamine release can cause bronchospasm, hypotension, salivary secretions. High doses of d- tubocurarine (& to a lesser extent other non-depolarizing blockers) can produce  ganglionic blockade , which can contribute to producing hypotension. Contraindications: Clients in whom release of histamine is hazardous. Use with caution during pregnancy and lactation and in children. 113

114. d- Tubocurarine (Prototype Nondepolarizing Neuromuscular Blocker ) Pharmacokinetics: Given by injection ( i.m ., i.v. ). Narrow margin between therapeutic dose and toxic dose. Onset, IV: 2-3 mins; IM: 15-25 min. Time to peak effect 2-5 min. Duration, IV: 80-120 min. t1/2: 1-3 hr. About 43% excreted unchanged in urine. 114

115. Depolarizing agents Succinylcholine Mechanism of action: Binds with nicotinic receptors to produce depolarization which can be observed as uncontrolled focal muscle contractions ( fasciculations ). Subsequent transmission across the NMJ is inhibited as long as succinylcholine remains at the nicotinic receptor sites. A depolarized post-junctional membrane (resulting in inactivation of Na channels) causes the postjunctional membrane to become unresponsive to ACh released by motor neurons. This is referred to as “ Phase I block ” & produces a characteristic reduction in contractile response (with no fade) during a  train of four stimuli . 115

116. Depolarizing agents Succinylcholine Mechanism of action: In less than a minute after IV administration a  flaccid paralysis  develops due to the development of a desensitized state where the membrane becomes repolarized, but insensitive to ACh (due to receptor desensitization). This is referred to as “ Phase II block ” 116

117. Depolarizing agents Succinylcholine Mechanism of action: Succinylcholine's effects at muscarinic & nicotinic receptors outside of the NMJ are responsible for numerous side effects. With a single IV dose, the period of flaccid paralysis lasts less than 10 minutes, and is terminated due to rapid hydrolysis of succinylcholine by cholinesterase in the plasma & liver. 117

118. Fig: Mechanism of action of depolarizing neuromuscular-blocking drugs. 118

119. Depolarizing agents Indications: Adjunct to general anesthesia to facilitate endotracheal intubation and relax skeletal muscle during surgery or mechanical ventilation. It has a  more rapid onset of action  as well as a  short duration of action  compared to most nondepolarizing neuromuscular blockers, making it  a drug of choice for emergency cases where rapid endotracheal intubation is necessary . 119

120. Depolarizing agents Contraindications: Genetic disorders of plasma pseudocholinesterase Family history of malignant hyperthermia Recent burns or trauma Myopathies with elevated CPK levels Acute narrow-angle glaucoma or penetrating eye injuries 120

121. Depolarizing agents Side Effects: Succinylcholine's stimulatory effect can cause  hyperkalemia . It should not be given to patients 24 to 72 hrs after  major burns or trauma  because it may cause acute hyperkalemia, hyperkalemic rhabdomyolysis & cardiac arrest. It has also produced acute hyperkalemia & cardiac arrest in otherwise healthy boys with  unrecognized muscular dystrophy , causing the FDA to issue a warning about its use in children (it should not be used in children except for emergency control of the airway ). There is an increased risk for potentially fatal  malignant hyperthermia . 121

122. Depolarizing agents Side Effects: Muscle pain due to muscle fasiculations , as well as an increased risk for regurgitation & aspiration of gastric contents caused by increases in intragastric pressure. It can cause a rapid increase in intraocular pressure due to effects on ocular blood vessels & myofibrils. It can cause cardiac arrhythmias (increase or decrease in heart rate) because of its effects on muscarinic receptors and nicotinic-ganglionic receptors . 122

123. Depolarizing agents Pharmacokinetics: Given i.v. or i.m . Metabolized by plasma pseudocholinesterase normal duration of action 4-30 min (depending on dose, route of administration & presence of normal pseudocholinesterase activity). Major drug Interactions: Aminoglycoside antibiotics  (additive skeletal muscle blockade) Cholinesterase inhibitors  (can inhibit pseudocholinesterase , and reduce metabolism of succinylcholine, which may prolong neuromuscular blockade ) 123

124. Thank you ! Any question??? Next class: Adrenergic drugs 124