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L 4: Cholinergic antagonists

  1. 28 June 20142 Drugs that block cholinergic receptors (M and/or N). The actions of sympathetic stimulation are left unopposed. Cholinergic antagonists
  2. 28 June 20143 They are classified to two subclasses: 1. Muscarinic (M1-M5) receptor antagonists: the most useful clinically. 2. Nicotinic receptor antagonists: further subdivided to:  NMJ Blocking agents: inhibit the efferent impulses to skeletal muscle via the (NM) receptor  Ganglionic Blocking agents: inhibit the nicotinic neuronal receptor (NN) of both parasympathetic and sympathetic ganglia Cholinergic antagonists
  3. Sites of action of cholinergic antagonists 28 June 20144
  4. Muscarinic antagonists: 28 June 20145  Atropine (prototype): comes from the plant Atropa belladonna and is known as a belladonna alkaloid. Belladonna in Latin means pretty lady. Inhibit all M functions.  Scopolamine (hyoscine): Rx of motion sickness ; natural occurring alkaloid  Propantheline, Dicyclomine: Rx of peptic disease, hypermotility  Clidinium (Librax), isopropamide (stelabid), Mebeverine (Duspataline)  Homatropine:Cyclopentolate, Tropicamide: mydriasis and cycloplegia  Pirenzepine & telenzipine: Selective M1 blocker. Rx of Gastric ulcer  Oxybutinin: somewhat selective for M3 receptors
  5. 28 June 20146  Trospium: nonselective comparable in efficacy and SE with oxybutinin  Darifenacin and Solifenacin: selective M3 blocker  Tolterodine: selective M3 blocker Rx of urinary incontinence  Flavoxate: also indicated for overactive bladder  Benztropine: Rx of Parkinsonism  Ipratropium, Tiotropium: Rx of Asthma  *Imipramine a TCA with strong antimuscarinic actions, has long been used to reduce incontinence in elderly Muscarinic antagonists:
  6. Atropine (hyoscyamine) Mechanism of action: 28 June 20147 It causes reversible, nonselective blockade of muscarinic receptors. Therefore, High concentration of Ach or an equivalent muscarinic agonists can be used to counteract the effects of atropine
  7. Pharmacologic actions of atropine 28 June 20148  CNS: at toxic doses can cause - restlessness, - hallucinations, - and delusions.  CVS: At low doses, atropine reduces heart rate through central stimulation of the vagus nucleus. At high doses, atropine blocks muscarinic receptors of the heart and thus induces
  8. 28 June 20149  GIT: reduces salivary gland secretion and GI motility.  Pulmonary system: reduces bronchial secretions and stimulates bronchodilation.  Urinary system: blocks muscarinic receptors in the bladder wall, which results in bladder wall relaxation.  Eye: causes paralysis of the sphincter muscle of the iris and ciliary muscle of the lens, resulting in mydriasis and cycloplegia  Sweat glands: Suppresses sweating, especially in children. Pharmacologic actions of atropine
  9. Atropine effects in order of increasing dose 28 June 201410  Decreased secretions (Salivary, bronchiolar, sweat)  Mydriasis and cycloplegia  Hyperthermia (vasodilation)  Tachycardia  Sedation  Urinary retention and constipation  Behavioral excitation and hallucinations
  10. Therapeutic uses of atropine 28 June 201411  Bradycardia  Mydriasis and cycloplegia- beneficial when a thorough fundus examination or an accurate refraction is required. NB: atropine contraindicated in a patients who has narrow-angle glaucoma, because this may result in acute crisis due to closure of the canal of Schlemm  GIT and bladder spasms:  organophosphate poisoning.
  11. Pharmacokinetics 28 June 201412  Atropine as a tertiary amine, it is well absorbed from the GIT and conjunctival membrane.  It is excreted through both hepatic metabolism and renal function.  Atropine’s duration of action is ~ 4 hrs, except when it is placed in the eye, where it usually lasts about 14 days
  12. Adverse effects 28 June 201413  Dry mouth (dry as bone)  Inhibition of sweating especially in young children (hot as a hare)  Tachycardia and coetaneous vasodilation (red as beet)  Blurring of vision (blind as a bat)  Hallucinations and delirium (mad as a hatter) Urine retention
  13. Scopolamine 28 June 201414  Like atropine, this drug is a belladonna alkaloid.  But it has a longer duration of action and more potent CNS effect  Nonselective competitive blockade of muscarinic receptors  Therapeutic uses: Prevention of motion sickness  Adverse effects: similar to those of atropine Others: Homatropine, cyclopentolate & Tropicamide: In ophthalmology, they are given topically for mydriasis and cycloplegia. Pirenzepine: a selective M1 muscarinic inhibitor, used for treating gastric ulcers
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  15. 2. Neuromuscular blocking agents 28 June 201416
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  17. NM blockers 28 June 201418 I. Nondepolarizing blocking agents (antagonists) 1. Tubocurarine (prototype) 2. Pancuronium: longer duration of action 3. Atracurium 4. Vecuronium II. Depolarizing blocking agents (agonists): 1. Succinylcholine  3-6 minutes if given as a single dose.  Metabolized by plasma cholinesterase
  18. Mechanism of action:  At low dose: these drugs competitively block cholinergic transmission at the nicotinic receptors by preventing the binding of Ach to its receptor. Their action can be reversed with edrophonium or neostigmine ????  At high dose: block the ion channels of the end plate. This action can not be reversed by CE inhibitors. 28 June 201419 I. Nondepolarizing NM blockers
  19. I. Nondepolarizing NM blockers 28 June 201420  All NM junction blockers must be given I.V because oral absorption is poor.  Therapeutic use: They are used as adjuvant drugs for anesthesia-  they promote muscle relaxation; the muscle of the eye and face are affected first, whereas the respiratory muscles are affected last.
  20. Sequence of Paralysis 28 June 201421 Fingers, orbit (small muscles) limbs Trunk neck IntercostalsDiaphragm Recovery in Reverse
  21. II. Depolarizing NM junction blockers 28 June 201422 Succinylcholine: Mech. of action: Phase I- opens the Na channels- membrane depolarization- transient fasciculations. Flaccid paralysis will follow in a few minutes Phase II: the membrane partially repolarize. However, these receptors are now desensitized to Ach, Thus preventing the formation of further action potentials. In other words, is now acting in a manner similar to tubocurarine.
  22. 28 June 201423 1. As an adjuvant to GA to facilitate rapid intubation. 2. Orthopedic procedures for alignment of fractures. 3. In electroshock treatment of psychiatric disorders. Therapeutic Use
  23. Drug Interaction  Cholinesterase inhibitors: can overcome the action of nondepolarizing neuromuscular blockers  Halogenated hydrocarbon anesthetics: Drugs such as halothane sensitize the neuromusclular junction to the effects of neuromuscular blockers.  Aminoglycoside antibiotics: inhibit Ach release from cholinergic nerves by competing with calcium ions. (Synergistic)  Calcium-channel blockers: These agents may increase the neuromuscular block of tubocurarine and other competitive blockers as well as depolarizing blockers. 28 June 201424
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  26. Adverse effects of NM blockers: 28 June 201427 1. Bronchoconstriction caused by histamine release 2. Decreased tone and motility in GI tract 3. Depolarizing agents can cause increased K+ efflux in patients with burns, trauma, or denervation and lead to hyperkalemia 4. Hypotension 5. Arrhythmias 6. Apnea due to respiratory paralysis (check for psudocholinesterase genetic polymorphism) 7. Malignant hyperthermia (succinylcholine+halothane especially); Rx by dantroline. It blocks the release of Ca+2 from the sarcoplasmic reticulum which subsequently reduces skeletal muscle contraction. Q. Do NM junction blocking agents block autonomic ganglia as well???
  27. Classification of Blockers Agent Pharmacological Properties Onset time (min) Duration (min) Elimination Succinylcholine Ultra-short acting; Depolarizing 1-1.5 6-8 Plasma cholinesterase D-tubocurarine Long duration; Competitive 4-6 80-120 Renal and liver Atracurium Intermediate duration; Competitive 2-4 30-40 Plasma cholinesterase Mivacurium Short duration; Competitive 2-4 12-18 Plasma cholinesterase Pancuronium Long duration; Competitive 4-6 4-6 Renal and liver Rocuronium Intermediate duration; competitive 1-2 1-2 Renal and liver 28 June 201428
  28. 3. Ganglionic blockers 28 June 201429 Nicotine, Hexamethonium, Mecamylamine, Trimethaphan  Ganglionic blockers compete with Ach to bind with nicotine receptors of both Parasympathetic and Sympathetic ganglia  Ganglionic blockers divided into two groups: 1. Drugs such as nicotine, which initially stimulate the ganglia and then block them because of a persistent depolarization 2. Drugs such as hexamethonium, mecamylamine, and trimethaphan, which block ganglia without any prior stimulation.
  29. 28 June 201430 The physiologic effects of ganglionic blockers can be predicted depending on which division of the ANS exercises dominant control of the organ in question:  Heart: tachycardia results because the parasympathetic system is normally dominant on the heart.  Arterioles and veins: vasodilation, increased peripheral blood (sympathetic normally dominant) 3. Ganglionic blockers
  30. 28 June 201431  Eye: cycloplegia, mydriasis (parasympathetic normally dominant)  GIT: reduced motility; diminished gastric and pancreatic secretions (parasympathetic normally dominant)  Urinary system: urinary retention (parasympathetic normally dominant)  Sweat glands: reduced sweating (sympathetic normally dominant) 3. Ganglionic blockers
  31. 28 June 201432 Therapeutic use Because they lack the selectivity, the ganglionic blockers very rarely used clinically. In the past, these drugs were used in hypertensive emergencies. 3. Ganglionic blockers