27 - cholinergic antagoinsts .pptx

cholinergic antagoinsts

1. Cholinergic Antagonists 1

2. Antimuscarinic agents ( muscarinic blockers) Ganglionic blockers Neuromuscular blockers 2

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4. Antimuscarinic Agents 4

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9. Antimuscarinic Agents These agents block muscarinic receptors , causing inhibition of all muscarinic functions These drugs block the few exceptional sympathetic neurons that are cholinergic, such as those innervating sweat glands Are beneficial in a variety of clinical situations Do not block nicotinic receptors.... means ??? No nictinic receptor adverse effect A number of antihistaminic and antidepressant drugs also have antimuscarinic activity 9

10. Atropine A tertiary amine belladonna alkaloid Atropa belladonna, or deadly nightshade, and in Datura stramonium Has a high affinity for muscarinic receptors, where it binds competitively , preventing acetylcholine from binding to those sites Atropine acts both centrally and peripherally. Its general actions last about 4 hours except when placed topically in the eye, where the action may last for days 10

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13. Atropine actions Tissues most sensitive to atropine are the salivary, bronchial, and sweat glands Secretion of acid by the gastric parietal cells is the least sensitive 13

14. Eye Atropine blocks all cholinergic activity on the eye, resulting in Persistent mydriasis (dilation of the pupil) Unresponsiveness to light, and cycloplegia (inability to focus for near vision) In closed angle glaucoma it may rise pressure dangerously GI Reduce activity of GI...is used as antispasmodic Acid secretion is not significantly reduced so? 14

15. Atropine Urinary system reduce hypermotility states of the urinary bladder Occasionally used in enuresis (involuntary voiding of urine) among children Cardiovascular Divergent effect At low dose ... decreased cardiac rate ( bradycardia ) Higher dose .....cardiac rate increases modestly Arterial BP is unaffected Block vasodilation Secretions Atropine blocks the salivary glands , producing a drying effect on the oral mucous membranes ( xerostomia ) 15

16. CNS Minimal stimulant effects on the central nervous system A slower, longer-lasting sedative effect on the brain Toxic dose Cause excitement , agitation, hallucinations, and coma 16

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18. Atropine Therapeutic uses Ophthalmic Permits the measurement of refractive errors without interference by the accommodative capacity of the eye...... Antispasmodic Atropine is used as an antispasmodic agent to relax the GI tract and bladder 18

19. Atropine .. Therapeutic uses… Antidote for cholinergic agonists Atropine is used for the treatment of overdoses of cholinesterase inhibitor insecticides and some types of mushroom poisoning Antisecretory The drug is sometimes used as an antisecretory agent to block secretions in the upper and lower respiratory tracts prior to surgery 19

20. Atropine Pharmacokinetics Atropine is readily absorbed, partially metabolized by the liver, and eliminated primarily in the urine. It has a half-life of about 4 hours. Adverse effects Depending on the dose, atropine may cause dry mouth, blurred vision, sandy eyes, tachycardia, and constipation In older patients ..... it may exacerbate an attack of glaucoma, may induce urinary retention CNS.... restlessness, confusion, hallucinations, and delirium, which may progress to depression, collapse of the circulatory and respiratory systems, and death 20

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22. Scoplamine Similar effect with atropine... but scoplamine is has greater action on the CNS and longer duration of action Actions: Scopolamine is one of the most effective anti motion sickness drugs available Also has the unusual effect of blocking short-term memory In contrast to atropine, scopolamine produces sedation, but at higher doses it can produce excitement instead. Scopolamine may produce euphoria and is subject to abuse 22

23. Scoplamine Therapeutic uses Limited to prevention of motion sickness (for which it is particularly effective) and to blocking short-term memory 23

24. Ipratropium and tiotropium A quaternary derivative of atropine useful in treating asthma in patients who are unable to take adrenergic agonists also beneficial in the management of chronic obstructive pulmonary disease It is inhaled for these conditions Because of positive charge, it does not enter the systemic circulation or the CNS , isolating its effects to the pulmonary system 24

25. Tropicamide and cyclopentolate These agents are used as ophthalmic solutions for similar conditions as atropine ( mydriasis and cycloplegia ) Their duration of action is shorter than that of atropine; tropicamide produces mydriasis for 6 hours and cyclopentolate for 24 hours 25

26. Pirenzepine and a more potent analog , telenzepine Reduce gastric acid secretion with fewer adverse effects than atropine and other less selective agents 26

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28. Summery of clinical use CENTRAL NERVOUS SYSTEM DISORDERS Parkinson's Disease Motion Sickness OPHTHALMOLOGIC DISORDERS Accurate measurement of refractive error in uncooperative patients Ophthalmoscopic examination of the retina is greatly facilitated by mydriasis RESPIRATORY DISORDERS Preoperative medication Asthma ,COPD CARDIOVASCULAR DISORDERS Management of vasovagal attack Hyperactive carotid sinus reflexes May experience faintness or even syncope as a result of vagal discharge in response to pressure on the neck, eg , from a tight collar Idiopathic dilated cardiomyopathy 28

29. Summery ... GI Rarely for PUD Travellers diarrhoea , hypermotility Usually combined with an opioid antidiarrheal drug: atropine + diphenoxylate ( e.g Lomotile ) GU Provide symptomatic relief in the treatment of urinary urgency caused by minor inflammatory bladder disorders 29

30. Summery .. GU.. Oxybutynin (M 3 selective ) and Trospium (non selective ), Darifenacin and solifenacin (greater selectivity for M 3 ) Is used to relieve bladder spasm after urologic surgery Help in reducing involuntary voiding in patients with neurologic disease Tolterodine ,( M3-selective ) is available for use in adults with urinary incontinence Propiverine newer antimuscarnic used to reduce incontinence in institutionalized elderly patients 30

31. Summery .... CHOLINERGIC POISONING To reverse the muscarinic effects A tertiary (not quaternary) amine drug must be used (preferably atropine) So that both the central and peripheral Sx are reversed 31

32. Antimuscarinics :contraindication Contraindications in this case are relative not absolute In patients with glaucoma(closed angle ) In elderly ( caution should be there) but Avoid if with prostatic hyperplasia Pts with peptic ulcer....especially the non selective ones Because they delay gastric emptying and increase symptoms in patients with gastric ulcer 32

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34. Ganglionic stimulating/blocking drugs 34

35. Ganglionic stimulating drugs Nicotine The ultimate response of any one system represents the summation of stimulatory and inhibitory effects of nicotine E,g nicotine Increases HR Excitation of sympathetic or paralysis of parasympathetic cardiac ganglia Decreases HR Paralysis of sympathetic or stimulation of parasympathetic cardiac ganglia Effect on chemoreceptors on carotid and aortic bodies plus the brain plus cardiovascular reflex Nicotine elicits a discharge of epinephrine from the adrenal medulla, which accelerates heart rate and raises blood pressure 35

36. Nicotine.. Peripheral nervous system Initially of transient stimulation and subsequently of a more persistent depression of all autonomic ganglia On adrenal medulla ..small doses evoke and large doses prevent catecholamine release NMJ….stimulant effect is largely obscured by the rapidly developing paralysis 36

37. Nicotine …. Stimulate a number of sensory receptors Mechanoreceptors that respond to stretch or pressure of the skin, mesentery, tongue, lung, and stomach Chemoreceptors of the carotid body Thermal receptors of the skin and tongue; and Pain receptors 37

38. Nicotine .. CNS Nicotine markedly stimulates the CNS Low doses produce weak analgesia; with higher doses, tremors leading to convulsions at toxic doses are evident The excitation of respiration is a prominent action of nicotine Stimulation of the CNS with large doses is followed by depression, and death results from failure of respiration owing to both central paralysis and peripheral blockade of muscles of respiration Induces vomiting by both central and peripheral actions 38

39. Nicotine .. GI tract Increased tone and motor activity of the bowel Nausea, vomiting, and occasionally diarrhea are observed following systemic absorption of nicotine in an individual who has not been exposed to nicotine previously Endocrine gland Initial stimulation of salivary and bronchial secretion then inhibition 39

40. Nicotine.. Pharmacokinetics Nicotine is readily absorbed from the respiratory tract, buccal membranes, and skin Severe poisoning has resulted from percutaneous absorption. Relatively strong base ….. so????…. Nicotine in chewing tobacco, because it is absorbed more slowly than inhaled nicotine, has a longer duration of effect The average cigarette contains 6 to 11 mg nicotine and delivers about 1 to 3 mg nicotine systemically to the smoker 40

41. Nicotine … Dosage forms A gum ( nicotine polacrilex , NICORETTE) Transdermal patch (NICODERM, HABITROL, others) A nasal spray (NICOTROL NS), and A vapor inhaler (NICOTROL INHALER) The objective To obtain a sustained plasma nicotine concentration lower than venous blood concentrations after smoking 41

42. Nicotine … Approximately 80% to 90% of nicotine is altered in the body, mainly in the liver but also in the kidney and lung….. cotinine is the major metabolite Half-life following inhalation or parenteral adm ..is 2hrs Eliminated mainly in kidney ..rate of excretion decreases when urine is alkaline Milk .. the milk of heavy smokers may contain 0.5 mg/L. 42

43. Nicotine .. Acute nicotine poisoning Fatal dose in adult 6.5–13 mg/kg Smoking tobacco usually contains 1% to 2% nicotine The gastric absorption of nicotine from tobacco taken by mouth is delayed because of slowed gastric emptying, …so vomiting caused by the central effect of the initially absorbed fraction may remove much of the tobacco remaining in the GI tract 43

44. Nicotine … Sign and symptoms of poisoning Nausea, salivation, abdominal pain, vomiting, diarrhea, cold sweat, headache, dizziness, disturbed hearing and vision, mental confusion, and marked weakness Faintness and prostration ensue; the blood pressure falls; breathing is difficult; the pulse is weak, rapid, and irregular; and collapse may be followed by terminal convulsions Death may result within a few minutes from respiratory failure 44

45. Nicotine … Therapy Vomiting may be induced, or gastric lavage should be performed Alkaline solutions should be avoided A slurry of activated charcoal is then passed through the tube and left in the stomach Respiratory assistance and treatment of shock may be necessary 45

46. Ganglionic Blockers Act on the nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia These drugs block the entire output of the autonomic nervous system at the nicotinic receptor Are nondepolarizing , competitive antagonists except nicotine 46

47. Ganglionic blockers … Effect depends on knowing which division of the autonomic nervous system exercises dominant control of various organs 47

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49. Organ system effect of ganglionic blockers Reading assignment 49

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51. Therapeutic use and toxicity The responses observed are complex and unpredictable, making it impossible to achieve selective actions Therefore, ganglionic blockade is rarely used therapeutically Mecamylamine :to reduce nicotine craving Trimethaphan:in treatment of hypertensive emergencies and dissecting aortic aneurysm Controlled hypotension 51

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53. Neuromuscular Blocking Drugs Block cholinergic transmission between motor nerve endings and the nicotinic receptors on the neuromuscular end plate of skeletal muscle These neuromuscular blockers are structural analogs of acetylcholine, and they act either as Antagonists ( nondepolarizing type ) or Agonists ( depolarizing type ) at the receptors on the end plate of the neuromuscular junction 53

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55. … Neuromuscular blockers are clinically useful during surgery for Producing complete muscle relaxation, without having to employ higher anesthetic doses to achieve comparable muscular relaxation Higher doses of anesthesia may produce respiratory paralysis and cardiac depression, increasing recovery time after surgery Agents are also useful in facilitating intubation as well 55

56. Nondepolarizing (competitive ) blockers 56

57. Nondepolarizing … Curare A generic term for various South American arrow poisons Has been used for centuries for immobilizing and paralyzing wild animals used for food 57

58. Nondepolarizing ….. Include Tubocurarine , Atracurium , Mivacurium , Pancuronium , Vecuronium , Rocuronium , and Rapacuronium Are all reversible antagonists of Ach at NMJ d- tubocurarine is the prototype drug in this group. 58

59. Nondepolarizing …. Classified Based on duration of drug action Long acting D- tubocurarine , metocurine , pancuronium , and doxacurium Intermediate acting vecuronium and atracurium , Rocuronium Short acting mivacurium 59

60. Based on chemical nature Natural alkaloids or their congeners D- tubocurarine , alcuronium The ammonio steroids Pancuronium ..newer vecuronium and rocuronium Pancuronium has No histamine release but blocks muscarinic receptors … vagal blockade and tachycardia The benzylisoquinolines Atracurium , mivacurium ( metabolized by plasma esterases ) Devoid of vagolytic and ganglionic blocking actions but show a slight propensity for histamine release Important in pts with renal failure 60

61. Nondepolarizing …. Mechanism of action At low dose Competitive blockers ..at motor end plate At high doses Nondepolarizing blockers can block the ion channels of the end plate…in a fashion w/c is non competitive This leads to further weakening of neuromuscular transmission, and it reduces the ability of acetylcholinesterase inhibitors to reverse the actions of nondepolarizing muscle relaxants 61

62. Nondepolarizing …. Not all muscles are equally sensitive to blockade by competitive blockers 1 st Small , rapidly contracting muscles of the face and eye are most susceptible and are paralyzed first, followed by the fingers 2 nd the limbs, neck, and trunk muscles are paralyzed 3 rd the intercostal muscles are affected, and lastly, the diaphragm muscles are paralyzed Recovery in the reverse order Those agents (for example, tubocurarine , mivacurium , and atracurium ), which release histamine, can produce a fall in blood pressure, flushing, and bronchoconstriction 62

63. Nondepolarizing … Effect on the autonomic ganglia and muscarinic sites Tubocurarine partial blockade probably is produced both at autonomic ganglia and at the adrenal medulla, which results in a fall in blood pressure and tachycardia. Pancuronium shows less ganglionic blockade at common clinical doses Atracurium , vecuronium , doxacurium , pipecuronium , mivacurium , and rocuronium are even more selective 63

64. Nondepolarizing … Pharmacokinetics All NM blockers are injected intravenously..slowly and poorly absorbed orally Poor membrane penetration Do not enter cell or BBB…so ??? Many of the drugs are not metabolized For example, tubocurarine , pancuronium , mivacurium , metocurine , and doxacurium are excreted in the urine unchanged vecuronium and rocuronium are deacetylated in the liver, and their clearance may be prolonged in patients with hepatic disease 64

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66. Nondepolarizing …. Therapeutic uses: As adjuvant drugs in anesthesia during surgery to relax skeletal muscle To facilitate intubation as well as during orthopedic surgery 66

67. Nondepolarizing (competitive) blockers The choice of an agent will depend on how quickly muscle relaxation is needed and on the duration of the muscle relaxation 67

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71. Nondepolarizing (competitive) blockers Adverse effects: In general, agents are safe with minimal side effect Drug interactions Cholinesterase inhibitors ( competative ) Can overcome the action ...but with increasing dosage they cause depolarizing block Neostigmine , pyridostigmine , edrophonium Sugammadex (not competitative , doesn’t increase Ach level) Can rapidly inactivate steroidal neuromuscular blocking drugs by forming an inactive complex, which is excreted in the urine 71

72. Drug interactions.. Halogenated hydrocarbon anaesthetics Potentiation …. By Nervous system depression at sites proximal to the neuromuscular junction Increased muscle blood flow Decreased sensitivity of the postjunctional membrane to depolarization isoflurane (most); sevoflurane , desflurane , enflurane , and halothane; and nitrous oxide (least) ( anesthatics ) 72

73. Drug interactions .. Aminoglycoside antibiotics E.g gentamicin or tobramycin inhibit acetylcholine release from cholinergic nerves by competing with calcium ions Calcium-channel blockers may increase the neuromuscular block of tubocurarine and other competitive blockers as well as depolarizing blockers 73

74. Drug interactions … Other drugs with significant interaction for both trimethaphan , opioid analgesics, procaine, lidocaine , quinidine , phenelzine , phenytoin , propranolol , magnesium salts, corticosteroids, digitalis glycosides, chloroquine , catecholamines , and diuretics 74

75. Toxicology Prolonged apnea, cardiovascular collapse, those resulting from histamine release, and, rarely, anaphylaxis 75

76. Depolarizing agents Mechanism of action Attach to the nicotinic receptor and acts like acetylcholine to depolarize the junction Unlike acetylcholine, which is instantly destroyed by acetylcholinesterase , the depolarizing agent persists at high concentrations in the synaptic cleft, remaining attached to the receptor for a relatively longer time and providing a constant stimulation of the receptor 76

77. Depolarizing agents Phase I The depolarizing agent first causes the opening of the sodium channel associated with the nicotinic receptors, which results in depolarization of the receptor This leads to a transient twitching of the muscle ( fasciculations ) Because excitation-contraction coupling requires end plate repolarization (" repriming ") and repetitive firing to maintain muscle tension, a flaccid paralysis results 77

78. Depolarizing agents Phase II Continued binding of the depolarizing agent renders the receptor incapable of transmitting further impulses. With time, continuous depolarization gives way to gradual repolarization as the sodium channel closes or is blocked But the repolarized channel is resistance to depolarization 78

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81. Depolarizing agents Actions The respiratory muscles are paralyzed last Succinylcholine Initially produces short-lasting muscle fasciculations , followed ,within a few minutes, by paralysis Does not produce a ganglionic block except at high doses, But it does have weak histamine-releasing action 81

82. Depolarizing agents Therapeutic uses : succinylcholine is useful when rapid endotracheal intubation is required during the induction of anesthesia (a rapid action is essential if aspiration of gastric contents is to be avoided during intubation ) Because of its rapid onset and short duration of action It is also employed during electroconvulsive shock treatment 82

83. Depolarizing agents Pharmacokinetics Succinylcholine is injected intravenously. Its brief duration of action (several minutes) results from redistribution and rapid hydrolysis by plasma cholinesterase It therefore is usually given by continuous infusion 83

84. Depolarizing agents Adverse effect Malignant Hyperthermia : Mostly when a depolarizing agent is used with anesthetic .. Halogenated hydrocarbon anesthetic with succynlchoine Uncontrolled release of Ca from sarcoplasmic reticulum is the initiating step Susceptibility is related to an autosomal dominant trait(defect in ryanodine receptor,L -type calcium channel), is associated with certain congenital myopathies such as central core disease… 84

85. Depolarizing agents Malignant hyperthermia Clinical feature includes Contracture Rigidity, and Heat production from skeletal muscle resulting in severe hyperthermia, accelerated muscle metabolism, metabolic acidosis, and tachycardia 85

86. Depolarizing agents Malignant hyperthermia Treatment Administration of dantrolene (IV), which blocks release of Ca2+ from the sarcoplasmic reticulum of muscle cells, thus reducing heat production and relaxing muscle tone Rapid cooling, inhalation of 100% oxygen, and control of acidosis should be considered 86

87. .... Apnea : Administration of succinylcholine to a patient who is genetically deficient in plasma cholinesterase or has an atypical form of the enzyme can lead to prolonged apnea due to paralysis of the diaphragm Hyperkalemia : Succinylcholine increases potassium release from intracellular stores. This may be particularly dangerous in burn patients or patients with massive tissue damage in which postassium is been rapidly lost from within cells In patients with congestive heart failure who are receiving digoxin or diuretics 87

88. … Other adverse effects Increased intraocular pressure Increased intragastric pressure Muscle pain 88

89. Common adverse effect to both Respiratory paralysis Treatment Should be by positive-pressure artificial respiration with oxygen and maintenance of a patent airway until recovery of normal respiration is ensured With the competitive blocking agents, this may be hastened by the administration of neostigmine methylsulfate (0.5 to 2 mg intravenously) or edrophonium (10 mg intravenously, repeated as required) 89

90. … To reverse other toxic effect Neostigmine to reverse skeletal muscle blocking action but may aggravate hypotention,and may induce bronchospasm Atropine to reverse muscarinic stimulation Antihistamines 90

91. …. Contraindication/caution In patients with Non traumatic rhabdomyolysis Ocular lacerations, Spinal cord injuries with paraplegia or quadriplegia, or muscular dystrophies 91

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93. Summery of clinical use of Neuromuscular Blocking Drugs Surgical relaxation Tracheal intubation Control of ventilation In critially ill patients who have ventilatory failure from various causes ( eg , severe bronchospasm , pneumonia,chronic obstructive airway disease) Treatment of convulsions 93

94. Others Many drugs and toxins block neuromuscular transmission by other mechanisms Interference with the synthesis or release of ACh Include Vasamicol,hemicholinim,Botulinium toxin But most of these agents are not employed clinically except botulinium toxin 94

95. Reading assignment Botulinium Toxin 95

96. … Botulinium Toxin Administered locally into muscles of the orbit in the management of ocular blepharospasm ( abnormal contraction of the eye lid muscles )and strabismus ( Abnormal alignment of one or both eyes ) Has been used to control other muscle spasms and to facilitate facial muscle relaxation Injected into the lower esophageal sphincter to treat achalasia Other spasms : hemifacial spasms, adductor spasmodic dysphonia , oromandibular dystonia , cervical dystonia 96

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98. … Non muscular use of Botulinium toxin Hyperhidrosis of the palms and axillae Chronic migraine 98