VPT 321: Veterinary Neuropharmacology (2+1) copy 1

PHARMACOLOGICAL EFFECTS OF CHOLINE ESTERS

Cardiovascular system

• In small doses when acetylcholine is administered intravenously, it produces a rapid fall of systolic and diastolic blood pressure due to decrease in peripheral resistance.
• Vascular smooth muscle relaxation and dilatation of blood vessels is noticed.
• Muscarinic receptors of blood vessels are located in the endothelium rather than the smooth muscle.
• Endothelial receptor activation releases EDRF (nitric oxide), which is also responsible for vasodilatation and decrease in peripheral resistance
• Larger doses produce prolonged muscarinic effects and therefore a pronounced decrease in peripheral resistance and blood pressure.
• Heart rate is reduced.
•  A negative chronotropic and inotropic effect.

Smooth muscles

• Gastrointestinal motility and secretions are increased. This effect is not noticed with small doses, as the duration of action is short.
• Urinary bladder and uterus are contracted.
• Bronchial smooth muscle contraction is also observed. Bronchial secretions are also increased.

CNS

• Acetylcholine is lipophobic and hence poorly  penetrate   cell membrane and blood brain barrier.
• By direct injection into the brain, excitation and convulsions are noticed.

Eye

• Contraction of the sphincter muscles of the iris causing miosis and constriction of the ciliary muscle leading to accommodation of near vision.
• Acetylcholine helps in the drainage of intraocular fluids and reduction of intraocular pressure.

Exocrine glands

• Stimulation of salivation (watery), lacrimation and generalized (sympathetic) sweating (except in horse) result due to acetylcholine action on the exocrine glands.

Adrenal medulla

• Release of norepinephrine and epinephrine .

Nicotinic effects at the neuromuscular junction

• Acetylcholine will cause contraction of skeletal muscle.
• Prolonged exposure and high doses cause tremors and fasciculations which terminate in depolarising paralysis due to inactivation of sodium channels and desensitisation of nicotinic receptors.

Nicotinic effects at autonomic ganglia

• These effects are evident only at very high doses of acetylcholine where muscarinic effects on the heart may be lethal unless a muscarinic antagonist such as atropine is present.
•  Responses reflect the sum of parasympathetic and sympathetic effects. Generally sympathetic responses predominate with gastrointestinal and urinary tract responses as exceptions.
• In general the effect is an increase in blood pressure, tachycardia and other sympathetic responses. In the presence of atropine, only the sympathetic effects are noticed.

Differences between various choline esters

Choline esters	Sustibility to ChE		Receptor specificity					Antagonisity by atropine
			Muscarinic				Nicotinic
	AChE	BChE	CVS	GIT	URINARY TRACT	EYE
Acetylcholine	+++	+++	++	++	++	+	++	+++
Bethanechol	-	-	+-	+++	+++	++	-	+++
Carbachol	-	-	+	+++	++++	++	+++	+
Methacholine	++	-	+++	++	++	+	+	+++

Methacholine

• In this drug there is substitution at the beta carbon of choline with methyl group.
• This drug is more active on the CNS than gastrointestinal system.
• Duration of action is more as it is not hydrolysed fast like acetylcholine and is not acted upon by pseudocholinesterase.
• Methacholine exhibits very few agonistic properties at nicotinic receptors.
• This drug is considered as a parasympathomimetic as its activity is less at the nicotinic receptors. Its action is potentiated by anticholinesterases.

Carbachol

• In this drug acetic moiety is substituted with carbamyl group. Both muscarinic and nicotinic receptors are activated by this drug and the pharmacological effects are similar to acetylcholine.

Bethanechol

• In this drug the acetic moiety is substitutes with carbamyl group and at the beta carbon there is substitution with methyl group. It is similar to methacholine and carbachol in pharmacological activity.
• Both carbachol and bethanechol are not acted upon by acetylcholinesterases. Their duration of action is more.
• Carbachol acts on both muscarinic and nicotinic receptors and hence is known as cholinomimetic.
• Bethanechol is only a muscarinic agonist.
• Both these drugs are active on smooth muscle of the gastrointestinal tract, bladder than the cardiovascular system.

Pharmacological effects

Cardiovascular system

• Methacholine is more active.
• Depression and slowing of the heart due to muscarinic receptor activation are noticed.
• Conduction velocity in the AV node is decreased and may lead to atrial fibrillation.
• Large doses may produce heart block. These effects can be blocked by atropine.
• Carbachol is less potent on the cardiovascular system.
• Bethanechol has no cardiovascular effects.

Gastrointestinal tract

• Carbachol and bethanechol are more active.
• Methacholine acts on the gastrointestinal tract only in large doses.
• Carbachol induces profuse salivation, increases peristaltic movements, defecation with fluid faeces.
• More pronounced effects are observed in single stomached animals than ruminants.

Other smooth muscles

• Uterine contractions are exhibited by carbachol. This effect is more evident during the later periods of gestation. It can be used after parturition to expel the uterine contents.
• Constrict bronchioles.
• Carbachol and bethanechol cause contraction of the bladder leading to frequent micturition.

Skeletal muscle

• In high doses carbachol induces fasciculation and paralysis. Bethanechol and methacholine have no nicotinic effects.

Other effects

• Carbachol, like acetylcholine stimulates adrenal medulla and releases epinephrine.