Acetylcholine

Acetylcholine is the prototype of the group parasympathomimetics. It is NOT USED AS A DRUG

Acetylcholine is rapidly hydrolyzed, if effects are to be observed, very high IV doses are to be administered, while IM and subcutaneous injections produce only local effect.

Pharmacokinetics

Acetylcholine & other choline esters have a permanently charged quaternary ammonium group in their structure, thus are polar compounds and are poor lipid soluble, resulting in decreased absorption, especially by oral route.

They are rapidly hydrolyzed. Acetylcholine is hydrolyzed more rapidly and produces effects only for 5-20 seconds. Methacholine has beta methyl group, so is more resistant to hydrolysis. It has longer duration of action. Carbachol is more resistant, so has further longer action. All are hydrolyzed in the GIT.

The tertiary natural cholinomimetic alkaloids (pilocarpine, nicotine, lobeline) are well absorbed from most sites of administration. They are lipid soluble thus cross into CNS and bring about stimulant effects on brain. Muscarine, a quaternary amine is less completely absorbed from the GIT and is toxic too.

Nicotine is easily absorbed from skin, lungs, GIT. Among naturally acting, muscarine has quaternary structure and are less absorbed from GIT, when ingested has potential toxic effects involving CNS (exception).

Most of the drugs are excreted by kidney. Acidification promotes their elimination.

True cholinesterase or Acetyl cholinesterase	Pseudocholine esterase or Butyryl cholinesterase
Rapidly acting	Slow acting
Synthesized by neurons and muscles	Synthesized by liver
Found in RBCs, synaptic cleft, nerve endings	Found in plasma, mammary glands, lymph, glial cells, satellite cells, pre and post synaptic terminals.
2 portions; active/esteratic site and anionic site

Pharmacological Actions/ Organ system effects:

a. Muscarinic Actions

b. Nicotinic Actions

Eye (M3):

Miosis (constriction of pupil).
Spasm of accommodation (ciliary muscles)

These two effects are effective in glaucoma, an increase in intra-ocular due to resistance to flow of aqueous humor which has to be drained by canal of Schema.

3. Decrease in intraocular pressure.

4. Conjunctiva hyperemia (dilatation of vessels)

5. Lacrimation due to stimulation of lacrimal glands

CVS (Heart & Blood Vessels)

a. Heart (M2)

Acetylcholine has depressant effect similar to activation of vagus nerve. It decreases total peripheral resistance and blood flow. In small doses decrease in total peripheral resistance causes reflex increase in heart rate. In high IV doses decrease total peripheral resistance occurs along with hypotension, decreased intraventricular conduction.

Mechanism:

Negative ionotropic
Negative chronotropic
Decrease in AV conduction
Little effects on ventricles because cholinergic receptors are more in atria than ventricles.

Acetylcholine has direct effect on SA node (negative ionotropic and negative chronotropic)

b. Blood Vessels (M3)

Acetylcholine has relaxant effect on the smooth muscles in blood vessels through nitric oxide. Endothelial derived relaxant factor (EDRF) is released which causes activation of guanylcyclase activity leading to increased cGMP, producing hyper polarization and smooth muscle relaxation along with vasodilatation.

Pilocarpine has different action. Instead of hypotension, it causes hypertension. Initial hypotension is followed by hypertension. M1 postganglionic receptors are activated through sympathetic ganglion system, K+ channels are closed (instead of opening), causing post-synaptic potentials. Hence hypertension is seen.

M5 receptors in brain release NO which produces vasodilatation.

If endothelium is damaged, acetylcholine directly acts on smooth muscles increasing intracellular calcium (IP3, DAG) producing vasoconstriction.

Respiratory system (M3)

Activation of tracheo-bronchial tree occurs leading to bronchoconstriction and bronchospasm. Excessive bronchial secretion also takes place. Chronic obstructive pulmonary disease may occur.

Gastro intestinal tract

Stimulation of gastric salivary secretions occur which are excessively produced. The sphincters are relaxed and increase in peristaltic movements occur, which may cause diarrhea, by

release of calcium from channels
depolarization produced through nicotinic receptors

Urinary bladder

Contraction of detrusor muscles and relaxation of sphincters and trigone occurs, which promotes voiding.

Exocrine glands

Acetylcholine causes stimulation of sweat, lacrimal, nasolacrimal and GIT secretions thus profused sweating, excessive salivation and increased lacrimation occurs.

Its effects on adrenal medulla cause increase in catechol secretion while exocrine portion of pancreas has increased secretions as well.

Central Nervous System

Both muscarinic and nicotinic receptors are stimulated. More muscarinic receptors are found in the brain, still nicotinic effects are more prominent. Alkaloid nicotine has more potent CNS effects because is lipid soluble, can cross BBB and has toxic potential. It is obtained from plant source. 40 mg nicotine or one drop of pure nicotine is found in two cigarettes and has toxic effects on CNS. But most of it gets burned in smoke. If alkaloid is ingested in high amounts, vomiting and expulsion occurs. If ingested by small children, toxicity occurs leading to tremors and fatigue. Increased doses cause convulsions, respiratory distress or even coma. Carcinoma might result as well.

Peripheral nervous system

Sympathetic limb effects are more pronounced in CVS, in rest of the systems parasympathetic, effects are more pronounced e.g. respiratory, eye, GIT, urinary and exocrine systems.

N.M Junction

N_Mreceptors are more activated. Agonists combine with nicotinic receptors having specific structure (4 subunits 2 alpha and 2 beta). Acetylcholine combines with 2 alpha subunits hence conformational change takes place, opening sodium channels (nicotinic receptors), due to which depolarization takes place. As depolarization is due to agonist, it occurs as long as the agonist binds the receptors. If binding is for prolonged duration, muscle fasciculations might result.