DRUGS ACTING ON MUSCARINIC RECEPTORS

PHARMACOLOGY
 Muscarinic agonists: pharmacological effects

Effector Effects
Heart Negative chronotropic effect and decreased conduction velocity
Arterioles Vasodilatation
Blood pressure falls due to a fall in total peripheral resistance
Lacrimation Increases
Respiratory Bronchoconstriction
system Increased bronchial secretions
GIT Increased peristaltic activity and motility
Increased salivation and GIT secretions
Urinary tract Increased contraction of the ureter and bladder smooth muscle
(detrusor)
Increased trigone and sphincter relaxation
(promotes micturition)
Sweat glands Increased sweat gland secretion
Eye Miosis and accommodation
Increased outflow of aqueous humour resulting in a reduction in
intraocular pressure
Other effects Tremor, ataxia

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Direct acting parasympathomimetic drugs

Act directly on muscarinic receptors

Mimic many of the physiological effects that result from stimulation of the
parasympathetic division of the autonomic nervous system
Include the following
• Choline esters - methacholine, bethanechol, carbachol – structurally similar to
acetylcholine
• Alkaloids: pilocarpine and muscarine
Clinical uses
• Bethanechol and carbachol: gut and bladder stimulation post-operatively to prevent
abdominal distension, gastric atony and urinary retention
• Carbachol: used for treatment of glaucoma when pilocarpine is ineffective (topical)
• Pilocarpine: used topically to decrease intraocular pressure in glaucoma
Have many adverse effects that are due to their pharmacological activity
Contra-indicated in peptic ulcer, bronchial asthma, cardiac disease and Parkinson’s
disease (worsen the conditions)
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Indirect acting parasympathomimetic agents
(anticholinesterases)

MOA: inhibit acetylcholinesterase (AChE) and increase acetylcholine (Ach) levels at

both muscarinic and nicotinic receptors
Effects: result from increased Ach at the neuromuscular junction (increase
contraction strength of skeletal muscle) and muscarinic receptors (similar effects to
direct acting muscarinic agonists)
Include the following
Short acting: edrophonium (2-10 mins)
Intermediate acting: neostigmine (2-4 hrs), pyridostigmine (3-6 hrs) and
physostigmine
Long acting (irreversible inhibition of AchE due to covalent bond formation): are
organophosphorus compounds and include ecothiophate and isoflurophate, nerve
gases (sarin and tabun) and insecticides (parathion and malathion)

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Anticholinesterases …. cont’d

Clinical uses
• Glaucoma: physostigmine and ecothiophate (given topically)
• To reverse effects of non-depolarizing neuromuscular junction blockers:
neostigmine
• Treatment of myasthenia gravis (MG): MG is an auto-immune disease in which
antibodies complex with nicotinic receptors at the neuromuscular junction to
cause skeletal muscle weakness and fatigue. Anticholinesterases increase Ach
levels at the neuromuscular junction to activate fully the remaining receptors. The
anticholinesterase used in the treatment of MG is pyridostigmine (given orally).
• Diagnosis of myasthenia gravis: edrophonium is used to diagnose MG or assess the
adequacy of treatment with AchE inhibitors. Small doses of edrophonium improve
muscle strength in untreated patients with MG or in treated patients in whom
AChE inhibition is inadequate. If there is no effect or if muscle weakness increases,
the dose of the AChE inhibitor is too high (excess Ach stimulation at the
neuromuscular junction results in depolarization blockade)
Adverse effects
• Result from excess cholinergic stimulation (both muscarinic and nicotinic)

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Organophosphate poisoning

• Organophosphates phosphorylate AchE forming stable covalent bonds

• Organophosphates are highly lipid soluble and hence are absorbed
from all routes including intact skin
• Organophosphate poisoning is quite common and occurs through
occupational exposure (spraying insecticides), homicide, suicide and
warfare
• Clinical features of poisoning result from muscarinic, nicotinic and
direct CNS effects: vomiting, abdominal cramps, diarrhoea, miosis,
sweating, increased salivary, tracheobronchial and gastric secretions,
bronchospasm, hypotension, muscular twitchings, weakness,
convulsions and coma. Death is due to respiratory paralysis.

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Organophosphorus poisoning …. cont’d

Treatment
• Supportive therapy – maintain blood pressure, patent airway,
mechanical ventilation, control convulsions etc
• The drug of choice is atropine (muscarinic receptor antagonist) –
reverses the muscarinic effects of the organophosphates
• Cholinesterase reactivators (oximes) – pralidoxime, obidoxime and
diacetylmonoxime: oximes combine with cholinesterase-
organophosphate complex, release the binding and set free AchE –
thus they reactivate the enzyme. To be effective, they should be given
within minutes after poisoning. The organophosphate-cholinesterase
bond becomes more stable soon after binding after which the
enzyme cannot be released (the process is referred to as “ageing”)

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Muscarinic receptor antagonists

• Muscarinic receptor antagonists are competitive

antagonists of Ach at all muscarinic receptors
• The prototype is atropine
• Different tissues respond differently to muscarinic
antagonists: salivary, sweat and bronchial glands are the
most sensitive and can be blocked by low doses of
atropine. Parietal cells in the stomach are the most
resistant and the block of gastric acid secretion requires
high doses of atropine.
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 Muscarinic receptor antagonists: pharmacological effects

Effector Effects
Heart Increased heart rate
Lacrimation Decreases
Respiratory system Bronchodilatation
Decreased tracheobronchial secretions
GIT Reduced peristaltic activity and motility, resulting in prolonged gastric
emptying and intestinal transit
Decreased salivation (dry mouth)
Decreased gastric secretions
Relaxation of biliary tract smooth muscles
Urinary tract Relaxation of the ureter and bladder smooth muscle
Sphincter constriction
Sweat glands Decreased sweat sweating (dry skin)
Eye Paralysis of the ciliary muscle and loss of accommodation (cycloplegia)
Pupillary dilatation (mydriasis)
Increased intraocular pressure (may precipitate glaucoma in some patients)
CNS In high doses, atropine stimulates the CNS resulting in restlessness, headache,
excitement, hallucinations and delirium. Hyoscine produces sedation and
drowsiness.

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Muscarinic receptor antagonists …. cont’d

Clinical uses
• For eye examination (testing errors of refraction and fundoscopic examination): homatropine,
cyclopentolate and tropicamide (given topically)
• Anterior uveitis and iritis - used alternatively with miotics to break adhesions between the iris and
the lens: topical homatropine
• To provide rest to the iris in iritis, iridocyclitis, keratitis and after partial iridectomy: topical
homatropine, cyclopentolate and tropicamide
• Bradycardia: atropine (parenteral)
• To reduce urinary urgency and relieve bladder spasm in inflammatory bladder disorders:
dicyclomine, oxybutinin, tolterodine, and trospium
• Prevention of motion sickness: hyoscine (a.k.a scopolamine)
• Bronchial asthma: ipratropium and tiotropium (by inhalation)
• Peptic ulcer disease: pirenzipine
• To suppress bronchiolar secretions during general and spinal anaesthesia: glycopyrrolate, atropine
and hyoscine
• Parkinson’s disease and parkinsonism: benztropine, trihexyphenidyl and benzhexol (centrally acting
anti-muscarinics)
• Cholinergic excess (e.g. in organophosphate poisoning): atropine
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Muscarinic receptor antagonists …. cont’d

Adverse effects
• The adverse effects are extensions of pharmacological
activity: mydriasis, cycloplegia, blurred vision, dry eyes,
tachycardia, dry mouth, elevated body temperature, dry
skin, urinary retention, agitation, hallucinations and delirium
Contraindications
• Glaucoma, GI and urinary obstruction (e.g. prostate
hypertrophy)
Treatment of muscarinic receptor antagonist overdose
• Physostigmine is used
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