Cholinergic antagonists

Drugs or agents which block the action of acetylcholine by blocking its receptors are known as cholinoceptor antagonists or anticholinergic drugs or cholinergic blockers. Based on the receptors that are blocked, these drugs are termed as muscarinic receptor antagonists and nicotinic receptor antagonists.

Classification of Cholinergic antagonists

Muscarinic receptor antagonists block the actions of acetylcholine at the parasympathetic end organs and at the sweat glands.

Nicotinic receptor antagonists block the actions of acetylcholine at all the autonomic ganglia (both sympathetic and parasympathetic) and at the neuromuscular endplate of skeletal muscles.

• Muscarinic antagonists
  1. Alkaloids obtained from the plants belonging to the family Solanaceae have muscarinic receptor blocking effect.
  2. The important members in this group are Atropa belladonna (deadly nightshade), Datura stromonium and Hyosciamus niger.
  3. Atropine and scopolamine are the alkaloids of interest in this group.
  4. In addition to these naturally occurring compounds, synthetic agents like homatropine, tropicamide, ipratropium, benztropine etc., exhibit muscarinic receptor blocking activity.
  5. These muscarinic receptor antagonists occupy the muscarinic receptors competitively and prevent acetylcholine from binding with the cholinergic receptors.
  6. All the organs in the body are not equally affected by the muscarinic blockers. 
  7. With extremely high doses, atropine can block the nicotinic receptors
  8. Natural alkaloid- Atropine is the prototype of the family of muscarinic blockers. It is well absorbed after oral administration and parenteral administration. Most species meatabolise it readily, 50% is excreted unchanged in the urine in less than 12 hours. Duration of action is 4 to 6 hours in most species.
  9. Synthetic analogs- Scopolamine, homatropine, methscopolamine and methylatropine differ primarily in their pharmacokinetics.
  10. Scopolamine is shorter acting and has more CNS effects than atropine.
  11. Homatropine is less potent and less toxic with a faster onset and shorter duration than atropine. When applied to the eye it produces less side effects and is therefore more useful than atropine for producing mydriasis.
  12. Methscopolamine and methylatropine are quarternary amines and thus have minimal side effects but are poorly absorbed when given orally.

Cholinergic antagonists are classified in Non-selective muscarinic receptor antagonists and Selective Muscarinic Receptor Antagonists. discussed below-

Non-selective muscarinic receptor antagonists

1. Natural alkaloids. Eg: Atropine, Hyoscine (Scopolamine)
2. Semisynthetic and synthetic antimuscarinic drugs
   • Mydriatics, Eg: Homatropine, Eucatropine, Tropicamide
   • Antisecreory- antispasmodics.
     • Quaternary compounds.Eg: Propantheline, Isopropamide, Glycopyrrolate, Ipratropium.
     • Tertiary amines.Eg: Oxybutynin, Dicyclomine, Oxyphencyclimine.

1. Natural alkaloids non-selective muscarinic receptor antagonists

Pharmacological Effects of natural Non-selective muscarinic receptor antagonists

Effects produced by atropine are opposite to those produced by parasympathetic stimulation or those produced by cholinergic agonists. Due to the heterogeneity of muscarinic receptors, the pharmacological effects of atropine are dose related.

Salivary and sweat gland secretions are quite susceptible to small doses of atropine, pupil and heart are affected by modest systemic doses and high doses are required for producing GI and urinary tracts. Inhibition of GI secretions require even higher doses of atropine.

2. Semisynthetic and synthetic antimuscarinic drugs

Natural antimuscarinic alkaloids have some disadvantages like lack specificity, long duration of action and potential adverse effects. Hence they have been largely displaced by semisynthetic and synthetic antimuscarinic drugs.

Mydriatics

These drugs are tertiary amines that are instilled into the conjunctival sac to produce mydriasis and or cycloplegia. Unlike atropine and hyoscine these drugs have shorter duration of action and are devoid of systemic effects when applied in to the eye.

Homatropine

It is a semisynthetic drug that is produced from atropine. It is about 10 times less potent than atropine. Has rapid onset (30-45 min) and short duration of action.

Eucatropine

Eucatropine has rapid onset and shorter duration of action (about 1 hour) of action . It produces mydriasis without cycloplegia.

Propantheline

In the GI tract it reduces spasm and gastric secretions at doses these produces minimal side effects. In the urinary system it reduces the frequency of urination and urgency.

Clinically propantheline is used as antisecretory antispasmodic in GI disorders. Also indicated in urinary inconsistency.

Isorpropamide

• Used for its antiemetic, antidiarrrhoeal, anticholinergic effects.
• Gylopyrronium (Glycopyrrolate)
• Primarily used an adjunct to general anesthesia to reduce to reduce secretions and to treat sinus bradycardia.

Ipratropium

Ipratropium acts selectively on bronchial muscles without altering volume or consistency of respiratory secretions. Used as bronchodilator in treating chronic obstructive pulmonary disease.

Tertiary Amines

Tertiary amine antimuscarinic drugs in addition to their antimuscarinic actions also have some non- specfic direct relaxant effect on smooth muscles. In therapeutic doses, they reduce spasm of the GI tract, biliary tract, ureter and uterus.

Oxybutinin

Oxybutinin has good antispasmodic and antisecretory effects; the antispasmodoic effect is more prominent on the urinary bladder.

Dicyclomine

Dicyclomine has some direct smooth muscle relaxant effect in addition to antispasmodic action. It decreases spasm of most smooth muscles without producing atropine like effects on the heart, eyes, salivary and sweat glands. It’s a nice drug and have wide uses.

Selective Muscarinic Receptor Antagonists

Selective M₁ Muscarinic Receptor Antagonists

Pirenzepine– Inhibit gastric acid secretions at doses that do not produce other effects. It has minimal CNS effects as it cannot pass the BBB.

Telenzepine– Analogue of pirenzepine and it is more potent than pirenzepine. Used in the treatment of peptic ulcer.

 Selective M₂– Muscarinic Receptor Antagonists

Tripitamine has potential for clinical use as drug for blocking cholinergic bradycardia

Selective M₃– Muscarinic Receptor Antagonists

Darifenacin is useful in smooth muscle activity or epithelial secretions.

Read Atropine and the other muscarinic receptor antagonists?