L 4: Cholinergic antagonists
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Transcript of L 4: Cholinergic antagonists
CHOLINERGIC ANTAGONISTS“ANTICHOLINERGIC DRUGS”
(PARASYMPATHOLYTICS)
PHARMACOLOGY I/ ANS, LECTURE 4 DR. HIWA K. SAAED, HD, MSC. PHD
PHARMACOLOGY & TOXICOLOGY
April 10, 20232
Drugs that block cholinergic receptors (M and/or N).
The actions of sympathetic stimulation are left unopposed.
Cholinergic antagonists
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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
Sites of action of cholinergic antagonists
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Muscarinic antagonists:
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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
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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 ParkinsonismIpratropium, Tiotropium: Rx of Asthma
*Imipramine a TCA with strong antimuscarinic actions, has long been used to reduce incontinence in elderly
Muscarinic antagonists:
Atropine (hyoscyamine) Mechanism of action:
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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
Pharmacologic actions of atropine
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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
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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
Atropine effects in order of increasing dose
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Decreased secretions (Salivary, bronchiolar, sweat)
Mydriasis and cycloplegiaHyperthermia (vasodilation)TachycardiaSedationUrinary retention and
constipationBehavioral excitation and
hallucinations
Therapeutic uses of atropine
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BradycardiaMydriasis 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.
Pharmacokinetics
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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
Adverse effects
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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
Scopolamine
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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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2. Neuromuscular blocking agents
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NM blockers
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I. Nondepolarizing blocking agents (antagonists)
1. Tubocurarine (prototype)2. Pancuronium: longer duration of action3. Atracurium4. VecuroniumII. Depolarizing blocking agents (agonists):5. Succinylcholine3-6 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 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.
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I. Nondepolarizing NM blockers
I. Nondepolarizing NM blockers
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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
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Fingers, orbit (small muscles)
limbs Trunk neck
IntercostalsDiaphragm
Recovery in Reverse
II. Depolarizing NM junction blockers
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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.
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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
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.
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Adverse effects of NM blockers:
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1. Bronchoconstriction caused by histamine release
2. Decreased tone and motility in GI tract3. Depolarizing agents can cause increased K+
efflux in patients with burns, trauma, or denervation and lead to hyperkalemia
4. Hypotension5. Arrhythmias6. 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???
Classification of BlockersAgent Pharmacological
PropertiesOnset 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 30-40Plasma 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 1-2Renal and liver
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3. Ganglionic blockers
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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.
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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
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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
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Therapeutic useBecause they lack the selectivity, the ganglionic
blockers very rarely used clinically. In the past, these drugs were used in
hypertensive emergencies.
3. Ganglionic blockers