Pharmacological effects of Antimuscarinics

Central Nervous System: In normal doses, atropine produces little CNS effect. In toxic doses, CNS excitation results in restlessness, hallucinations, and disorientation. At very high doses, atropine can lead to CNS depression which causes circulatory and respiratory collapse. By contrast, scopolamine at normal therapeutic doses causes CNS depression, including drowsiness, fatigue and amnesia. Scopolamine may exhibit more CNS activity than atropine because scopolamine crosses the blood brain barrier more readily.

Eye:

Muscarinic receptor antagonists block parasympathetic responses of the ciliary muscle and iris sphincter muscle, resulting in paralysis of accommodation (cycloplegia) and mydriasis (pupillary dilation). Mydriasis results in photophobia, whereas cycloplegia fixes the lens for far vision only (near objects appear blurred). Systemic atropine at usual doses does not produce significant ophthalmic effect. By contrast, systemic scopolamine results in both mydriasis and cycloplegia. Note that sympathomimetic-induced mydriasis occurs without loss of accommodation. Atropine-like drugs can increase intraocular pressure, sometimes dangerously, in patients with narrow-angle glaucoma. An increase in intraocular pressure is not typical in wide-angle glaucoma.

Cardiovascular System:

The dominant effect of atropine or other antimuscarinic drug administration is an increase in heart rate.This effect is mediated by M₂-receptor blockade thereby blunting cardiac vagal tone.

• * K+ channel activation has a hyperpolarizing effect. The increase in membrane-potential (more negative) moves the membrane-potential away from threshold. The consequence of this effect is to take longer for diastolic depolarization (phase 4) to reach threshold in SA nodal pacemaker cells. Accordingly, muscarinic receptor activation decreases rate and muscarinic receptor blockade increases rate.

• Atropine by blocking parasympathetic tone may facilitate AV nodal conduction. In some clinical conditions, atropine may reduce heart block. Excessive vagal tone in digitalis toxicity can be diminished with atropine.

• Severe bradycardia and AV blockade associated with myocardial infarction may be reduced by atropine.

• Respiratory Tract:

• Parasympathetic activity produces bronchoconstriction. Activation of nicotinic and M₁-muscarinic receptors in parasympathetic ganglia which lie in the airway wall then activate postganglionic fibers. These postganglionic fibers release acetylcholine which activate M₃ muscarinic receptors which produce bronchiolar smooth muscle contraction. M₂ receptors may also be present.

• Muscarinic antagonists attenuate pulmonary smooth muscle constriction, often resulting in bronchodilation. The magnitude of the effect depends on the basal parasympathetic tone. Ipratropium has been prominent in treating respiratory disease.

• Atropine and other antimuscarinic inhibit mouth, bronchial, and pharyngeal secretion which reduce reflex laryngospasm during general anesthesia. Also, atropine or other antimuscarinics are given during general anesthesia to blunt increases in vagal tone due to mechanical effects on viscera during abdominal surgeries.

• Ipratropium, along with sympathomimetics, are useful in management of asthma, because of the following advantages over atropine:

• Ipratropium does not inhibit mucociliary clearance (atropine does)

• Ipratropium has no significant CNS effects.

• Inhaled ipratropium (a quaternary, charge molecule) has limited or no systemic effects.

• Gastrointestinal Tract

• Vagal effects on the gut are mediated not only by acetylcholine but also by actions on intramural serotonergic and dopaminergic neurons. Atropine can block Ach effects while having no effect on non-cholinergic modulation of GI motility. Vagal input affects gastrin release and may be blocked by atropine; however, gastric acid release is more effectively prevented by M₁ specific antimuscarinic drugs (pirenzapine) and H₂-selective histamine receptor blockers.

Category: Pharmacology Notes