Muscarinic antagonist

In neurochemistry, a muscarinic receptor antagonist is an agent that reduces the activity of the muscarinic acetylcholine receptor. Acetylcholine (often abbreviated ACh) is a neurotransmitter, whose receptor is a protein found in synapses and other cell membranes. Besides responding to their primary neurochemical, neurotransmitter receptors can be sensitive to a variety of other molecules. Acetylcholine receptors are classified into two groups based on this:

• muscarinic, which respond to muscarine
• nicotinic, which respond to nicotine

Most muscarinic receptor antagonists are synthetic, but scopolamine and atropine are belladonna alkaloids, and are naturally extracted.

Effects

Scopolamine and atropine have similar effects on the peripheral nervous system, however, scopolamine has greater effects on the CNS than atropine due to its ability to cross the blood-brain barrier. At higher than therapeutic doses, atropine and scopolamine cause CNS depression characterized by amnesia, fatigue and reduction in rapid eye movement sleep. Hyoscine has anti-emetic activity, so is used for motion sickness.

Antimuscarinics are also used as anti-parkinsonian drugs. In Parkinsonism, there is imbalance between levels of acetylcholine and dopamine in the brain, involving both increased levels of acetylcholine and degeneration of dopaminergic pathways (nigrostriatal pathway). Thus, in Parkinsonism there is decreased level of dopaminergic activity. One method of balancing the neurotransmitters is through blocking central cholinergic activity using muscarinic receptor antagonists.

Atropine acts on the M2 receptors of the heart and antagonizes the activity of acetylcholine. It causes tachycardia by blocking vagal effects on the sinoatrial node. Acetylcholine hyperpolarizes the sinoatrial node which is overcome by MRA and thus increases the heart rate. If atropine is given by intramuscular or subcutaneous injection it causes initial bradycardia. This is because by i.m/s.c it acts on presynaptic M1 receptors (autoreceptors). Intake of acetylcholine in axoplasm is prevented and the presynaptic nerve releases more acetylcholine into the synapse which initially causes bradycardia.

In the atrioventricular node, the resting potential is abbreviated which facilitates conduction. This is seen as a shortened PR-interval on an electrocardiogram.

It has an opposite effect on blood pressure. Tachycardia and stimulation of the vasomotor center causes an increase in blood pressure. But due to feed back regulation of the vasomotor center, there is fall in blood pressure due to vasodilation.

Important^[1] muscarinic antagonists include atropine, hyoscine, ipratropium, tropicamide, cyclopentolate and pirenzepine.

Comparison table

Substance	Trade names	Mechanism	Clinical use	Adverse effects
Atropine (D/L-Hyoscyamine)		non-selective antagonism, CNS stimulation[1]	in anaesthesia[1][2] anticholinesterase poisoning[1] bradycardia[1] antispasmodic in gastrointestinal hypermotility[1]	urinary retention[1] xerostomia[1] blurred vision[1]
Scopolamine (L-Hyoscine)	Scopace, Transderm-Scop, Maldemar, Buscopan	non-selective antagonism, CNS depression[1]	as atropine[1] motion sickness[1]	as atropine[1] sedation[1]
Ipratropium	Atrovent and Apovent	non-selective antagonism, without any mucociliary excretion inhibition.[1]	in asthma and bronchitis[1]
Tropicamide		short acting non-selective antagonism, CNS depression[1]	produce mydriasis and cycloplegia in diagnostics[1]	may cause ocular hypertension[1]
Pirenzepine		M1 receptor-selective antagonist[1] inhibits gastric secretion[1]	in peptic ulcer (not much anymore)[1]	(fewer than non-selective ones)[1]
Diphenhydramine	Benadryl		for extrapyramidal symptoms from typical antipsychotic medications antihistamine sleep aid
Dimenhydrinate	Dramamine		motion sickness
Dicyclomine
Flavoxate
Oxybutynin	Ditropan		overactive bladder urge incontinence
Tiotropium	Spiriva		Chronic obstructive pulmonary disease
Cyclopentolate		short acting non-selective antagonism, CNS depression[1]	produce mydriasis and cycloplegia in diagnostics[1]	may cause ocular hypertension[1]
Atropine methonitrate		non-selective antagonism, blocks transmission in ganglia.[1] Lacks CNS effects[3]	antispasmodic in gastrointestinal hypermotility[1]
Trihexyphenidyl/Benzhexol	Artane	Targets the M1 Muscarinic receptor	Parkinson's disease	Drug at relative dose has 83% activity of atropine, thus has the same side-effects
Tolterodine	Detrusitol, Detrol
Solifenacin	Vesicare	Competitive muscarinic acetylcholine receptor antagonist	overactive bladder (OAB) Urgency (urge incontinence)
Darifenacin	Enablex	Selective for M3 receptors [3]	Urinary incontinence [3]	Few side effects[3]
Benzatropine	Cogentin	Reduces the effects of the relative central cholinergic excess that occurs as a result of dopamine deficiency.	Parkinson's disease
Mebeverine	Colofac, Duspatal, Duspatalin	A muscolotropic spasmolytic with a strong and selective action on the smooth muscle spasm of the gastrointestinal tract, particularly of the colon.	Irritable bowel syndrome in its primary form (e.g. Abdominal Pain, Bloating, Constipation, and Diarrhea). Irritable bowel syndrome associated with organic lesions of the gastrointestinal tract. (e.g. diverticulosis & diverticulitis, etc.).	skin rashes
Procyclidine		Antimuscarinic	Drug-induced parkinsonism, akathisia and acute dystonia; Parkinson disease; and Idiopathic or secondary dystonia	Overdose produces confusion, agitation and sleeplessness that can last up to or more than 24 hours. Pupils become dilated and unreactive to light. Tachycardia (fast heart beat), as well as auditory and visual hallucinations

See also

• Muscarinic agonist
• Parasympatholytic
• Anticholinergic

References

1. ^ ^{a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab} Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4.  Page 147
2. ^ Mirakhur, RK (August 1991). "Preanaesthetic medication: a survey of current usage". Journal of the Royal Society of Medicine 84 (8): 481–483. PMC 1293378. PMID 1886116. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1293378. 
3. ^ ^{a b c d} Table 10-5 in: Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-06911-5. 

External links

• Effects of Muscarinic Antagonist
• Atropine (Muscarinic Receptor Antagonist), Cardiovascular Pharmacology Concepts, Richard E. Klabunde, PhD
• MeSH Muscarinic+antagonists
• MeSH list of agents 82018727