Cholinergic Drugs

·        Classification of cholinergics.

·        Physiological effects mediated by cholinergics.

·        Mechanism of action.

Classification of Cholinergics

1.       Cholinergics act on acetylcholine receptors at all sites in the body where acetylcholine is the transmitter of nerve impulse; they stimulate and later paralyze.

2.    Sites of action:

a.       Parasympathetic nervous system: ganglia and all post-ganglionic endings.

b.       Sympathetic nervous system: ganglia and a minority of post-ganglionic endings, e.g. sweat glands.

c.       Neuromuscular junction.

d.       Central nervous system.

e.    Non-innervated sites: blood vessels, chiefly arterioles.

3.       Direct-acting:

a.       Choline esters (carbachol, bethanechol) which act on all sites like acetylcholine.

b.       Muscarinic effects are more prominent than nicotinic.

c.       Alkaloids (pilocarpine, muscarine) which act selectively on end-organs of post-ganglionic, cholinergic neurons.

4.       Indirect-acting:

a.       Cholinesterase inhibitors: physostigmine, neostigmine, pyridostigmine.

b.       Inactivates acetylcholinesterase, allowing acetylcholine to persist and produce intensified effects.

5.       Nicotinic and Muscarinic effects:

a.       Nicotinic: cholinergic actions at autonomic ganglia and neuromuscular junction.

b.       Muscarinic: actions at post-ganglionic endings and those non-innervated receptors on blood vessels.

c.       Large doses of muscarinics can cause depolarization block of autonomic ganglia.

d.       Division does not apply to CNS actions.

Physiological effects of cholinergics

Choline esters

1.    The choline esters are compounds which can mediate actions similar to those produced by acetylcholine.

2.    They are relatively more selective at muscarinic receptor sites since higher concentrations are generally required to produce nicotinic effects.

3.       Mode of muscarinic actions:

a.    The choline esters produce their effects by acting directly on muscarinic receptors.

b.    In general excitatory actions are associated with depolarization of cellular membranes whereas inhibitory actions are associated with hyperpolarization.

4.       Molecular basis:

a.       Stimulation of muscarinic receptors result in the transduction of signals across the cell membrane via coupling of the receptors to G proteins.

b.    M1 and M3 receptors activate Gq which stimulates phospholipase C activity with consequent release of intraccellular calcium and stimulation of protein kinase C activity.

c.    M2 receptors couple primarily to Gi leading to inhibition of adenylate cyclase activity and Gk leading to activation of potassium channels and hyperpolarization of the cell.

d.    The fall in blood pressure is due to generalized vasodilation mediated through muscarinic receptors present in the endothelium which when activated stimulates the formation of NO synthase thereby increasing the synthesis of NO in the smooth muscle.

5.       Pharmacokinetics:

a.    They are poorly lipid soluble and are poorly distributed into the CNS.

b.    the compounds differ in their susceptibility to hydrolysis by cholinesterase but are generally longer-acting than acetylcholine itself.

6.       Therapeutic uses:

a.    In ophthalmology as a miotic and in the treatment of glaucoma to reduce raised intraocular pressure: pilocarpine.

b.       Bethanechol is used as a smooth muscle stimulant in post-operative intestinal paralysis and in non-obstructive urinary retention.

7.       Pilocarpine:

a.    Acts directly on end-organs innervated by post-ganglionic nerves.

b.    Also stimulates and then depresses the CNS.

c.       Chief clinical use to lower intraocular pressure in chronic simple glaucoma, as an adjunct to a topical beta-blocker.

d.    Oral pilocarpine is available for the treatment of xerostomia (dry mouth) in Sjogren’s syndrome, or following irradiation of head and neck tumors.

e.       Commonest adverse effect is sweating.

8.       Contraindications:

a.       Asthma.

b.       Peptic ulcer.

c.       Hyperthyroidism.

d.       Coronary insufficiency.