Classification of Cholinergic Drugs |Animals| Pharmacology

After reading this article we will learn about the classification of cholinergic drugs.

These are the drugs which produce Ach-like actions, either directly by interact­ing with the cholinergic receptors or indirectly by increasing availability of Ach at these sites.

Classification:

On the basis of mechanism of action.

Organ Selectivity:

(i) Ach → all cholinergic organs, more preferably on GIT.

(ii) Methacholine → CVS > GIT and urinary system.

(iii) Bethanechol & carbachol → GIT and urinary bladder > CVS.

Choline Esters:

Chemistry and Structure-Activity Relationship:

(i) To be pharmacologically active, the direct acting cholinergic drugs (except some natural alkaloids) require a quaternary nitrogen atom in their structures.

(ii) Both the carbonyl group and the ether oxygen are required for proper binding of drugs with receptors. Replacement of both of these two com­ponents by methylene molecules renders their drastically reduced agonistic properties at both muscarinic and nicotinic receptors.

(iii) If only the ether oxygen of Ach is substituted by a methylene group, the muscarinic potency is markedly decreased but nicotinic properties remain unaffected.

(iv) Introduction of methyl group on the β carbon atom reduces the nicotinic properties but not muscarinic activity (e.g., methacholine).

(v) Due to the presence of methyl group on carbon atom, methacholine (acetyl -β-methyl choline) is longer acting, since it is hydrolysed by acetyl cholinesterase (AChE) enzyme at a much slower rate than Ach and is almost totally resistant to hydrolysis by butyryl cholinesterase (BuChE or pseudo cholinesterase).

(vi) Carbamyl (- OCONH₂) substituted compounds, carbachol and bethanechol are almost completely resistant to hydrolysis by both AChE and BuChE, hence are long acting drugs.

Pharmacological Actions of Choline Esters:

Depending on the receptors on which the drugs act, the actions may be classified as muscarinic or nicotinic.

Muscarinic Responses:

(i) Cardiovascular system:

(a) Vasodilation

(b) Negative ionotropic and chronotropic effect on heart.

(c) Decrease in cardiac output.

(ii) Gastrointestinal system:

(a) Increase in tone and motility

(b) Increase in secretion

(c) Relaxation of sphincters

(d) Contraction of gall bladder and ducts.

(iii) Respiratory system:

(a) Bronchoconstriction

(b) Increase in tracheobronchial secretions.

(iv) Urinary tract:

(a) contraction of detrusor muscle of bladder

(b) Relaxation of trigone and external sphincter

(c) Increase in tone and motility of ureters.

(v) Uterus:

(a) Contraction of uterine smooth muscle.

(vi) Eye:

(a) Contraction of circular muscle of iris → miosis.

(b) Contraction of ciliary muscle → spasm of accommodation, increased out­flow facility, reduction in intraocular tension (specially in glaucoma).

(vii) Male sex organs:

(a) Erection.

(viii) Skin:

(a) Sweating

Nicotinic Responses:

The dose of choline esters required to stimulate nicotinic receptors is many fold higher than muscarinic receptor stimulating dose.

The nicotinic receptor-mediated responses are as follows:

(i) Skeletal muscle:

(a) Muscular fasciculations.

(b) If drug persists for a long time → persistant depolarization → paralysis.

(ii) Autonomic ganglia:

(a) Stimulation of both sympathetic and parasympathetic ganglia at higher doses.

(iii) Adrenal medulla:

Release of epinephrine → increase in B.P.

Natural Cholinomimetic Alkaloids:

Pilocarpine is obtained from Pilocarpus microphyllus and Pilocarpus jaborandi. Muscarine is obtained from Amanita muscaria. Arecoline is obtained from Areca catechu.

Pharmacological Properties:

(i) Smooth muscle:

(a) Contraction of GIT smooth muscle → increase in tone and motility.

(b) Bronchoconstriction.

(c) Increase in tone and motility of ureters, urinary bladder, gall bladder and ducts.

(d) Eye – Miosis, spasm of accommodation, fall in intraocular pressure.

(ii) Exocrine glands:

(a) Profuse sweating (diaphoresis) in man.

(b) Increase in salivary, lacrimal, gastric, pancreatic, intestinal and bronchial secretions.

(iii) CVS:

(a) Fall in blood pressure.

(b) Slowing of heart beat.

Therapeutic uses of Direct Acting Cholinomimetics:

(a) Intestinal colic and impaction-

(i) Carbachol- Horse → 1-2 mg, s.c. inj, 30-60 min intervals

Foals → 0.25 – 0.5 mg, s.c. inj, 30- 60 min intervals.

(b) Ruminal atony and impaction-

(i) Carbachol- Cattle → 1-2 mg, s.c. inj, 30-60 min intervals.

[Before treatment with carbachol in above two cases, oral demulcent and saline purgative administration is desirable]

(c) At the middle of farrowing – carbachol

Sow -2mg, s.c. inj.

(d) Urinary bladder atony – bethanechol

Cat -1 mg, s.c. inj., twice daily.

(e) Glaucoma-Pilocarpine (0.5-4%), with or without physostigmine (0.5-1%).

All animals – 1-2 drops on infected eye, or subconjunctival injection.

(f) Teniasis in dogs-Arecholine hydrobromide 1 mg/kg, orally after fasting.

(g) For cataract extraction of eye-

(i) Acetylcholine -1%

(ii) Carbachol-0.01%

Anticholinesterase Agents:

These are indirectly acting parasympathomimetic agents. They inhibit acetyl cholinesterase (AChE) enzyme resulting in accumulation of Ach at cholinergic effector sites. So, their effects are due to accumulation and function of Ach.

These drugs may be classified into two groups:

(i) Reversible Inhibitors:

They bind to the active sites of the enzyme reversibly to act as an alternate substrate for AChE. They do not allow the main substrate, Ach, to bind to the enzyme resulting in inhibition of hydrolysis of Ach. In compare to physostigmine or neostigmine (long acting), the binding with edrophonium is easily reversible (short acting).

(ii) Irreversible Inhibitors:

The organophosphorous compounds bind to esteretic site of the enzyme by a covalent bond resulting in the formation of an irreversible or very highly stable complex. Unless regenerated by drugs, the inhibited enzyme can not hydrolyse Ach, which is accumulated at its effector sites and produces persistant cholinergic responses.

Regeneration of Inhibited AChE:

The enzyme re-activators or oximes (2 PAM or pralidoxime, obidoxime, diacetyl monoxime, etc.) remove organophosphorous com­pounds (after binding with them) from the active sites of AChE. The free regenerated enzyme is now able to hydrolyse Ach.

Physostigmine (eserine):

(i) It is an alkaloid obtained from Physostigma venenosum.

(ii) It is well absorbed from GIT, mucous membrane and s.c. tissues.

(iii) It induces miosis.

(iv) Large doses may cause fasciculation, and then paralysis of skeletal muscles.

Neostigmine:

(i) It is a synthetic compound, stable for longer time than physostigmine.

(ii) It is well absorbed orally. It does not penetrate BBB.

(iii) It stimulates the actions of Ach.

(iv) In addition to the anticholinesterase activity, neostigmine also has a direct action on nicotinic receptors of skeletal muscle.

(v) It reverses the neuromuscular blockade produced by curare and its deriva­tives. The mechanism of this action involves cholinesterase inhibition, re­lease of increased amount of Ach from nerve endings, and a direct action on skeletal muscle nicotinic receptors.

(vi) It is the drug of choice in the treatment of myasthenia gravis.

Edrophonium:

(i) It is more rapidly absorbed and has a shorter duration of action than neostigmine. It is administered parenterally.

(ii) Its actions are similar to those of neostigmine, except that at high dose it stimulates neuromuscular junction without affecting muscarinic effector organs.

Clinical uses of Anticholinesterase Agents:

(i) Myasthenia gravis – (muscular weakness of nervous origin).

(a) For treatment-Physostigmine or neostigmine.

(b) For diagnosis- edrophonium.

Dogs -Neostigmine- 60 mg, orally, twice daily.

(ii) Glaucoma- to reduce intraocular pressure.

Physostigmine → 0.5-1%, with or without pilocarpine 2-4%, initially every 10 min, then at longer intervals.

(iii) To antagonize curare-like drugs- Edrophonium and Pyridostigmine are more commonly used than others.

(iv) Ruminal impaction- Physostigmine

Cattle → 30-45 mg, s.c. inj.

(v) To control ectoparasites – Carbaryl (sevin, Notix), Coumafos (Asuntol), Propoxur (Baygon), trichlorfon (Neguvon), etc.

(vi) In snake bite – Specially in cobra bite (venom has curare like neurotoxin). Neostigmine + atropine is given to prevent respiratory paralysis.