Cholinergic drugs

Drugs that produce actions similar to acetylcholine (ACh) either by interacting with cholinergic receptors or by increasing availability of ACh at the receptor sites are called Cholinergic drugs.

The term cholinomimetic indicates an acetylcholine like effect at all cholinergic sites in the body including parasympathetic nerves, somatic nerves, CNS and autonomic ganglia. On the other hand the term parasympathomimetic denotes the action of ACh in the organs innervated by parasympathetic nervous system (smooth muscle, heart and glands) .

However, both the terms are used interchangeably and majority of drugs produce action at muscarinic receptor at much lower concentration than that needed to produce nicotinic effects.

Classification of cholinergic drugs

A. Directly acting drugs

Directly acting drugs act directly either on muscarinic or nicotinic receptors

1. Choline esters: Acetylcholine, Methacholine, Carbachol, Bethanechol
2. Alkaloids: Muscarine, Pilocarpine, Arecoline

B. Indirectly acting drugs

Indirectly acting drugs act by inhibiting acetylcholinesterase and thereby increasing the concentration of Ach-

1. Reversible inhibitors of cholinesterase: Physostigmine, Neostigmine, Edrophonium
2. Irreversible inhibitors of cholinesterase: Organophosphorus compounds like  Di-isopropyl flurophosphate, Tetra ethylpyrophosphate, Parathion, Malathion, Sarin

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.

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

Choline esters cause 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 depolarizing paralysis due to inactivation of sodium channels and desensitization of nicotinic receptors.

Nicotinic effects at autonomic ganglia

Nicotinic effects at autonomic ganglia 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.

Some choline esters drugs

Methacholine

Methacholine drug is more active on the CNS than gastrointestinal system. Duration of action is more as it is not hydrolyzed 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

Carbachol 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

Bethanechol 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. Both these drugs are active on smooth muscle of the gastrointestinal tract, bladder than the cardiovascular system.

Carbachol acts on both muscarinic and nicotinic receptors and hence is known as cholinomimetic. Bethanechol is only a muscarinic agonist.

Therapeutic uses of choline esters

1. Glaucoma – Carbachol and methacholine are used as eye drops to decrease intra ocular pressure. Methacholine is administered with a cholinesterase inhibitor like neostigmine.
2. Gut hypomotility and urinary retention – In post operative and post partum cases to increase the gut motility and urinary bladder contraction these drugs are useful.
3. Atrial tachycardia – Bethanechol is systemically administered to inhibit atrial pace maker activity.
4. Diagnosis of atropine poisoning – Methacholine is given subcutaneously to test for the loss of flush/sweating or miotic response when atropine poisoning is suspected.
5. Colic and impaction of intestinal tract – While using carbachol for this purpose care should be taken to rule out obstruction, as use of carbachol in obstruction may lead to rupture. Repeated small doses can be given to horses in colic. In ruminal atony and impaction it can be given, however higher doses may inhibit rumenoreticlular activity.

Cholinomimetic alkaloids

Cholinomimetic alkaloids stimulate the muscarinic receptors of cells innervated by post ganglionic cholinergic nerves. They are also effective in chronically denervated tissue and are not dependent upon endogenous acetylcholine. Pilocarpine, muscarine and arecoline are naturally occuring parasympathomimetic alkaloids with minimal nicotinic effects.

Pilocarpine

• Pilocarpine is obtained from Pilocarpus jaborandi and Pilocarpus microphyllus.
• It is a potent parasympathomimetic.
• It produces all the muscarinic responses of acetylcholine.
  • Increases secretion of exocrine glands – salivary, sweat, mucous, gastric, pancreatic secretions.
  • Causes contraction of the gastrointestinal tract smooth muscles and increases peristalsis.
    • Pupillary constriction is the most important effect observed.

Arecoline

• Arecoline is obtained from Areca catechu.
• It has some nicotinic agonistic activity.
• It has been used as an anthelmintic to paralyze tapeworms.
• Acts on the muscarinic receptors of effector cells of glands, smooth muscle and myocardium. It is more potent than pilocarpine.
• Depresses the heart rate and blood pressure and causes dyspnoea.
•  Secretions of the glands of the digestive tract are increased and peristalsis is also increased

Muscarine

• Muscarine is obtained from the mushroom Amanita muscaria.
• It is a potent parasympathomimetic.
• It is not used clinically. If taken accidentally, the toxic effects include severe colic, diarrhoea, exocrine secretions, miosis, dyspnoea, hypotension and bradycardia.
• The antidote of choice is atropine.
• Oxotremorine is a synthetic agent.

Anticholinesterase drugs drugs will be discussed in next article.