Cholinolytic Drugs

Dr. Mohammed Ezzi

Introduction
Divided into muscarinic and nicotinic antagonists. Antinicotinic - Ganglion blockers, NMJ blockers

Introduction - Antimuscarinic
Five subtypes of muscarinic receptors:
M1 (CNS, sympathetic postganglionic, presynaptic) M2 (myocardium, smooth muscle). M3 (glandular) M4, M5 (CNS)

Block PNS discharge. Prototype is atropine.

Chemistry
Atropine (hyocyamine), scopolamine (hyoscine) are tertiary amines (alkaloid esters of tropic acid). Occur as both d(+) and l(-) isomer (X 100 potent). Tertiary amines have both peripheral and CNS effects Quartanery amines have more peripheral effects.

Absorption
Tertiary amines are well absorbed. Scopolamine is also absorbed through the skin. 10 - 30% of quaternary amine is absorbed.

Distribution
Tertiary amines widely distributed (significant CNS levels). Scopolamine has the most CNS effects. Quaternary amines are free of CNS effects.

Metabolism and Excretion

Atropine elimination occurs in two phases:
Rapid (2 hours) Slow phase (13 hours)

50% excreted unchanged (hydrolysis, conjugation) Rapid decline of function except the eye (72 hours).

Mechanism of Action
Reversible but surmountable muscarinic blockade. Prevents release of IP3 and cAMP. Some are inverse agonist:
Atropine Trihexyphenidyl Glycopyrrolate Pirenzepine Ipratropium

Mechanism of Action
Effectiveness varies with tissues:
Most sensitive: salivary, bronchial, sweat glands. Least sensitive: gastric parietal cells

Block exogenous agonist more than endogenous Ach.

CNS Effects
Normal doses:
Minimal stimulant effects Drowsiness (scopolamine) Amnesia (scopolamine)

CNS Effects
Toxic doses:
Excitement Hallucinations Agitation Coma.

Reduce tremor of Parkinsons disease Reversing or preventing vestibular disturbances.

Eye
Unopposed sympathetic pupillary dilator activity (mydriasis). Weakened contraction of the ciliary muscle (cycloplegia with loss of accommodation) Reduced lacrimation.

CVS Effects
Heart:
Tachycardia (high dose - vagal blockade). Bradycardia (low dose - prejunctional M1 blockade). Reduce the PR interval (AVN blockade) Intraventricular conduction block (toxic doses)

CVS Effects
Vessels:
Coronary artery vasocontriction Skeletal vasculature vasoconstriction Cutaneous vasodilation (toxic doses)

4. Respiratory system Both smooth muscle and secretory glands of the airway receive vagal innervation and contain muscarinic receptors. Even in normal individuals, administration of atropine can cause some bronchodilation and reduce secretion. The effect is more significant in patients with airway disease, although the antimuscarinic drugs are not as useful as the -adrenoceptor stimulants in the treatment of asthma (see Chapter 20 ). The effectiveness of nonselective antimuscarinic drugs in treating chronic obstructive pulmonary disease (COPD) is limited because block of autoinhibitory M 2 receptors on postganglionic parasympathetic nerves can oppose the bronchodilation caused by block of M 3 receptors on airway smooth muscle. Nevertheless, antimuscarinic agents are valuable in some patients with asthma or COPD. Antimuscarinic drugs are frequently used before the administration of inhalant anesthetics to reduce the accumulation of secretions in the trachea and the possibility of laryngospasm.