cholinergics & anticholinergics

Introduction Drugs affecting the autonomic nervous system (ANS) are divided into two groups according to the type of neuron involved in their mechanism of action. The cholinergic drugs act on receptors that are activated by acetylcholine (ACh), whereas the adrenergic drugs act on receptors stimulated by norepinephrine or epinephrine. Cholinergic and adrenergic drugs both act by either stimulating or blocking receptors of the ANS. Acetylcholine is a widespread chemotransmitter in the body, mediating a broad range of physiological effects. The two classes of receptor for acetylcholine are defined on the basis of their preferential activation by the alkaloids nicotine and muscarine.

 Cholinergic drugs (acetylcholine receptor agonists) mimic acetylcholine at all sites, although the balance of nicotinic and muscarinic effects is variable. Cholinergic drugs mimic the activity of the parasympathetic nervous system (PNS). They also are called parasympathomimetic drugs. An understanding of the PNS is useful in understanding the cholinergic drugs. Acetylcholine antagonists that block the nicotine-like effects (neuromuscular blockers and autonomic ganglion blockers) are described elsewhere. Acetylcholine antagonists that block the muscarine-like effects, e.g. atropine, are often imprecisely called anticholinergics. The more specific term 'antimuscarinic' is preferred here.

Cholinergic drugs: Classification Sites of action Pharmacology Choline esters Alkaloids with cholinergic effects Anticholinesterases; organophosphate poisoning Disorders of neuromuscular transmission: myasthenia gravis

Drugs that oppose acetylcholine action: Antimuscarinic drugs

 CHOLINERGIC DRUGS (CHOLINOMIMETICS) These drugs act on postsynaptic acetylcholine receptors (cholinoceptors) at all sites in the body where acetylcholine is the effective n.transmitter. They initially stimulate and usually later block transmission. In addition, like acetylcholine, they act on the non-innervated receptors that relax peripheral blood vessels.

 Uses of cholinergic drugs 1-For myasthenia gravis, both to diagnose (edrophonium) and to treat symptoms (neostigmine, pyridostigmine, distigmine). 2-To lower intraocular pressure in chronic simple glaucoma (pilocarpine). 3-To bronchodilate patients with airflow obstruction (ipratropium, oxitropium). 4-To improve cognitive function in Alzheimer's disease (rivastigmine, donepezil).

CLASSIFICATION 1- Direct-acting (receptor agonists) A- Choline esters (bethanechol, carbachol), which act at all sites, like acetylcholine, but are resistant to degradation by acetylcholinesterases (AChE; see Fig.). Muscarinic effects much more prominent than nicotinic. B- Alkaloids (pilocarpine, muscarine) act selectively on end-organs of postganglionic, cholinergic neurones. Effects are exclusively muscarinic.

 2- Indirect-acting Cholinesterase inhibitors, or anticholinesterases (physostigmine, neostigmine, pyridostigmine, distigmine, galantamine, rivastigmine, donepezil), block acetylcholinesterase (AChE), the enzyme that destroys acetylcholine, allowing endogenous acetylcholine to persist and produce intensified effects.

Summary of cholinergic agonists

SITES OF ACTION: Autonomic nervous system . Neuromuscular junction . Central nervous system (CNS). Non-innervated sites: blood vessels, chiefly arterioles

Cartoon showing the different origins for acetylcholine (ACh) activating nicotinic (N) versus muscarinic (M) cholinergic receptors

 PHARMACOLOGY Autonomic nervous system There are two distinct classes of receptor for acetylcholine, defined on the basis of their preferential activation by the alkaloids nicotine (from tobacco) and muscarine (from a toxic mushroom, Amanita muscaria). Noted that the actions of acetylcholine and substances acting like it at autonomic ganglia and the neuromuscular junction mimic the stimulant effects of nicotine (hence nicotinic). In contrast, the actions at postganglionic cholinergic endings (parasympathetic endings plus the cholinergic sympathetic nerves to the sweat glands) and non-innervated receptors on blood vessels resembled the alkaloid, muscarine (hence muscarinic).

 Parasympathetic division Stimulation of cholinoceptors in autonomic ganglia and at postganglionic endings affects chiefly the following organs: Eye: Miosis and spasm of the ciliary muscle occur so that the eye is accommodated for near vision. Intraocular pressure falls so its use in the treatment of glaucoma.(figure)

 Exocrine glands: there is increased secretion most noticeably from salivary, lachrymal, bronchial and sweat glands. The last are cholinergic, but anatomically part of the sympathetic system; some sweat glands, e.g. axillary, may be adrenergic. Heart: bradycardia occurs with atrioventricular block, and eventually cardiac arrest. Bronchi: there is bronchoconstriction and mucosal hypersecretion that may be clinically serious in asthmatic subjects, in whom cholinergic drugs should be avoided if possible. Gut: motor activity is increased and may cause colicky pain. Exocrine secretion is also increased. Tone in sphincters falls which may cause defaecation (anal sphincter) or acid reflux/regurgitation (oesophageal sphincter). Urinary bladder and ureters contract and the drugs promote micturition

 Sympathetic division Only the ganglia are stimulated and cholinergic nerves to the adrenal medulla. These effects are overshadowed by effects on the parasympathetic system and are usually seen only if atropine has been given to block the latter, when tachycardia, vasoconstriction and hypertension occur. Neuromuscular (voluntary) junction The neuromuscular junction has cholinergic nerve endings and so is activated when anticholinesterases allow acetylcholine to persist, causing muscle fasciculation. Prolonged activation leads to a secondary depolarizing neuromuscular block.

 Central nervous system There is usually stimulation followed by depression but considerable

variation between drugs is observed, possibly due to differences in CNS penetration. In overdose, mental excitement occurs, with confusion and restlessness, insomnia (with nightmares during sleep), tremors and dysarthria, and sometimes even convulsions and coma. Nicotinic receptor activation in the CNS is also thought to be important for cognitive processing, which appears to be impaired in schizophrenic subjects.

Blood vessels
There is stimulation of cholinergic vasodilator nerve endings in addition to the more important dilating action on arterioles and capillaries mediated through noninnervated muscarinic receptors. Activation of these receptors stimulates nitric oxide production from the vascular endothelium that relaxes the underlying smooth muscle.

CHOLINE ESTERS Acetylcholine

As acetylecholine has such importance in the body it is not surprising that attempts have been made to use it therapeutically. Acetylecholine was first injected intravenously as a therapeutic convulsant in 1939, in the reasonable expectation that the fits would be less liable to cause fractures than those following therapeutic leptazol convulsions. Recovery rates of up to 80% were claimed in various psychotic conditions. Enthusiasm began to wane(decrease), however, when it was shown that the fits were due to anoxia resulting from cardiac arrest and not to pharmacological effects on the brain.

 Other choline esters : Carbachol Is not destroyed by cholinesterase; its actions are most pronounced on the bladder and gastrointestinal tract, so that the drug was used to stimulate these organs, e.g. after surgery. These uses are now virtually obsolete, e.g. catheterisation is preferred for bladder atony. It is occasionally applied topically (3% solution) to the eye as a miotic. Bethanechol Resembles carbachol in its actions but is some 10-fold less potent (it differs by a single -methyl group) and has no significant nicotinic effects at clinical doses.