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L3 ans pharmacology 2017 2018

  1. Cholinergic antagonists “Anticholinergic drugs, Parasympatholytics” Lecture 3 Dr. Hiwa K. Saaed College of Pharmacy/University of Sulaimani 2017-2018 1
  2. Cholinergic antagonists Drugs that block cholinergic receptors (M or N), and prevent the effects of Ach and other cholinergic agonists. The actions of sympathetic stimulation are left unopposed. They are classified to two subclasses: 1. Muscarinic (M1-M5) receptor antagonists: the most useful clinically. atropine, cyclopentolate, Ipratropium, scopolamine, tropicamide. 2. Nicotinic receptor antagonists: further subdivided into 2 groups: i. NMJ Blocking agents: inhibit the efferent impulses to skeletal muscle via the (NM) receptor: Atracurium, Cisatracurium, Doxacurium, Metocurine, mivacurium, Pancuronium, Rocuronium, Scuccinylcholine, Tubocurarine, Vecuronium. ii. Ganglionic Blocking agents: inhibit the nicotinic neuronal receptor (NN) of both parasympathetic and sympathetic ganglia: Mecamylamine, Nicotine.
  3. Sites of action of cholinergic antagonists 12 May 2018 3
  4. Muscarinic antagonists: Atropine (prototype): is a tertiary amine belladonna alkaloid with a high affinity for muscarinic receptors. acts both centrally and peripherally. The greatest inhibitory effects are on bronchial tissue and the secretion of sweat and saliva. Scopolamine (hyoscine): 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 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 12 May 2018 4
  5. Muscarinic antagonists: Darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, and trospium chloride: selective M3 blocker Rx of urinary incontinence Flavoxate: also indicated for overactive bladder Benztropine and trihexyphenidyl: Rx of Parkinsonism Ipratropium, Tiotropium: Rx of Asthma *Imipramine a TCA with strong antimuscarinic actions, has long been used to reduce incontinence in elderly 12 May 2018 5
  6. Atropine (hyoscyamine) Mechanism of action: Reversible, nonselective blockade of muscarinic receptors. Pharmacokinetics • 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 May 2018 6
  7. Pharmacologic actions of atropine 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 tachycardia. 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. 12 May 2018 7
  8. Atropine effects in order of increasing dose • Decreased secretions (Salivary, bronchiolar, sweat) • Mydriasis and cycloplegia • Hyperthermia (vasodilation) • Tachycardia • Sedation • Urinary retention and constipation • Behavioral excitation • and hallucinations 12 May 2018 8
  9. Therapeutic uses of Muscarinic Blockers 12 May 20189 • 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.
  10. Adverse effects of atropine • Dry mouth (dry as bone) • Inhibition of sweating especially in young children (hot as a hare) • Tachycardia and cuetaneous vasodilation (red as beet) • Blurring of vision (blind as a bat) • Hallucinations and delirium (mad as a hatter) 12 May 2018 10
  11. Neuromuscular blocking agents I. Nondepolarizing blocking agents (antagonists) Tubocurarine (prototype), Pancuronium: longer duration of action, Atracurium and Vecuronium II. Depolarizing blocking agents (agonists): Succinylcholine: 3-6 minutes if given as a single dose, Metabolized by plasma cholinesterase Mechanism of action: At low dose: these drugs competitively block cholinergic transmission at the nicotinic (Nm) 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. 12 May 2018 11
  12. I. Nondepolarizing NM blockers • 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. Sequence of Paralysis 12 May 2018 12 Fingers, orbit (small muscles) limbs Trunk neck Intercostals Diaphragm Recovery in Reverse
  13. II. Depolarizing NM junction blockers 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. 12 May 2018 13 Therapeutic Use As an adjuvant to GA to facilitate rapid intubation. Orthopedic procedures for alignment of fractures. In electroshock treatment of psychiatric disorders.
  14. Drug Interaction Cholinesterase inhibitors: can overcome the action of nondepolarizing NM blockers Halogenated hydrocarbon anesthetics: Drugs such as halothane sensitize the NM junction to the effects of NM blockers. Aminoglycoside antibiotics: inhibit Ach release from cholinergic nerves by competing with calcium ions. (Synergistic) Calcium-channel blockers: These agents may increase the Nm block of tubocurarine and other competitive blockers as well as depolarizing blockers. 12 May 2018 14
  15. Adverse effects of NM blockers: • Bronchoconstriction caused by histamine release • Decreased tone and motility in GI tract • Depolarizing agent can cause increased K+ efflux in patients with burns, trauma, or denervation and lead to hyperkalemia • Hypotension • Arrhythmias • Apnea due to respiratory paralysis (check for psudocholinesterase genetic polymorphism) • 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??? 12 May 2018 15
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  18. Ganglionic blockers 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. 12 May 2018 18
  19. Ganglionic blockers 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) • 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) Therapeutic use: Because they lack the selectivity, the ganglionic blockers very rarely used clinically. In the past, these drugs were used in hypertensive emergencies. 12 May 2018 19