Parasympathomimetics or Cholinergic Agents

The Parasympathetic Nervous System, which uses Acetylcholine almost exclusively to send its messages, is said to be almost entirely Cholinergic or Parasypathomimetic. Neuromuscular Junctions, preganglionic neurons of the sympathetic nervous system, the basal forebrain, and brain stem complexes are also Cholinergic.

Parasympathomimetics or cholinergic agents are the drug which produces actions similar to that of parasympathetic stimulation.

These agents may be classified in the following –

1. Esters of Choline – Acetylcholine, Methacholine, Carbachol, Bethanechol

2. Cholinomimetic Alkaloids – Pilocarpine, Arecholine, Muscarine

3. Anticholinesterases  

A. Reversible – Pyridostigmine

B. Irreversible – Tetraethylpyro phosphate (TEEPP), Parathion, Malathion, Octamethylpyrophosphoramide (OMPA)

 

All the cholinergic drugs produce their actions through two types of receptors –

A. Muscarinic Receptor

B. Nicotinic Receptors

Accordingly the actions produce are called Muscarinic and Nicotinic actions.

Muscarinic actions of cholinergic drugs are same as found from the alkaloid muscarine. Muscarinic actions of cholinergic drugs are found in gland cells, smooth muscle and heart because the organs contain muscarinic receptors.

Nicotinic actions of cholinergic drugs are observed in autonomic ganglion and in skeletal muscle. As the nicotinic-receptors are found in this site.

 

Ester of Acetylcholine: 

Acetylcholine (ACH) is an ester of choline with acetic acid.

Mechanism of action: Acetylcholine acts on the two sub types of Cholinergic Receptors –

A. Muscarinic Actions: The action produce as a result acetylcholine release from the post ganglionic parasympathetic nerve endings or the actions resulting from exogenously administrated ACH or the receptors of organ like secretary glands, smooth muscle and the heart.

There are five subtypes of Muscarinic Receptors – M1, M2, M3, M4 and M5. Muscarinic Receptors (M& M3) activate GS protein that is responsible for the stimulation of phospholipase. This leads to the hydrolysis of phosphatidylinositol polyphosphate to form inositol 1 – 4 – 5 triphosphate and diacylglycerol. The former causes releases of intracellular calcium from endoplasmic reticulum while the latter activates proteinkinase ‘C’.

The M2 receptor interact with a distinct group of G protein, with resultant inhibition of adenylyl cyclase and regulation of specific channels e.g. Activation of K+ channels particularly in the heart and modulation of the activity of calcium channels in certain cell types. These effects account for the negative chronotropic (periodical movement) and inotropic (affect in the force of muscular contraction) effects of acetylcholine.

B. Nicotinic Actions: The action of ACH at the nicotinic receptors are termed nicotinic action. Nicotinic receptors are ligand – gated ion channels, and their activation always cases a rapid increase in the cell permeability to Na+ and K+ ion with resultant depolarization and excitation.

 

Pharmacological action:

1. Heart: The effect of acetylcholine on heart is similar to that produced by stimulation of vagus. It hyperpolarizes the SA nodal cells and decreasesthe rate of the diastolic depolarization. As a result, rate of impulse generation is reduced show bradycardia or event cardiac arrest may occur. Ventricular contractility is also decrease but the affect is not marked.

2. Blood vessel:Acetylcholine dilates a variety of blood vessels (like those of skin, mucus membrane and coronary arteries) and produces a fall in blood pressure.

3. Smooth muscles: Acetylcholine produces contraction of smooth muscles like those of G.I tract, bronchi, urinary bladder and ureters. Asthmaticsare highly sensitive –dyspnoea, precipitation of an attack of bronchial asthma.

4. Glands: Secretion from all parasympathetically innervated glands is increased the – sweating, salivation, lacrimation, tracheobronchial & gastric secretion of milk and bile is not affected.

5. Eye:Contraction of circular muscle of irisproduces miosis. Contraction of ciliary muscle produces spasm of accommodation, increase outflow facility, reduction in intraoculartension (especially in glaucomatous patients).

6. Autonomic ganglia (Nicotinic action):Both sympathetic and parasympathetic ganglia are stimulated. This effect is manifested at higher dosage. High dose of ACH given after atropine causes tachycardia and rise in blood pressure.

7. Skeletal muscle (Nicotinic action):Iontophoretic application of ACH to muscle endplate causes contraction of the fiber, intra-arterialinjections of high dose can cause twitching and fasciculation, but I.V injection is generally without any effect (due to rapid hydrolysis of ACH).

Acetylcholine is inactivated in the G.I tract. So, it is administered by I.V injection.

Adverse Effect: It produces nausea, vomiting, dyspnoea (difficulty in breathing) and fainting (temporary loss of consciousness). The serious side effects include hypotension, bronchial spasm and occasionally cardiac arrhythmias or cardiac arrest.

Uses: Acetylcholine cannot be used for any therapeutic purpose because of its non-selective action.

 

CARBACHOL

Carbachol is more potent than Methacholine and Bethanechol. Carbachol is resistant to both true and pseudocholinesterase and is batter absorbed from the G.I tract.

Pharmacological action: Unlike ACH, Carbachol has a relatively selective Muscarinic effect on smooth muscle of the G.I tract and urinary bladder. It also stimulates autonomic ganglia and skeletal muscle and has a more sustained miotic effect on topical application.

Adverse effect: Flushing of the face, sweating, salivation, lacrimation, defecation, micturition and sometime produce hypotension and syncope.

Dose: 0.25 – 0.50mg by s.c. for ophthalmic.

Use:3% eye drop.

Therapeutic Use of Choline Esters:

Gastro intestinal urinary tract: Carbachol and bethanechol have often been employed for the treatment of post-operative paralytic ileus and abdominal distension following surgery and toxic sates, for relief of gastric atony and increase of urinary retention. The drug is also useful in selected cases of congenitalmegacolon. Bethanechol is administered in the dose of 15 – 30mg, 3 – 4 times a day.

Glaucoma: One drop of 0.75 – 3% solution of Carbachol is instilled in the eye every 10 minutes to reduce theintraocular tension in wide angle glaucoma.

Contraindications: Hypersensitivity, hyperthyroidism, bronchial asthma, peptic ulcer (as this agent increase gastric secretion), myocardial infarction.

 

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