Medical Pharmacology Chapter 6:  Autonomic Pharmacology: Cholinergic Drugs

Antimuscarinic Effects on Organ Systems

• Central Nervous System Effects of Antimuscarinic Agents

  • 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 also may produce euphoria, a basis for some abuse potential.

  • Scopolamine may exhibit more CNS activity than atropine because scopolamine crosses the blood brain barrier more readily.

  • Antimuscarinics are used clinically as preanesthetic medication to reduce vagal effects secondary to visceral manipulation during surgery.

  • Antimuscarinics with L-DOPA are used in Parkinson's disease.

  • Extrapyramidal effects induced by some antipsychotic drugs may be treated with antimuscarinic agents.

  • Scopolamine (transdermal) is effective in preventing motion sickness.

• Autonomic Ganglia and Autonomic Nerve Terminals

  • The primary cholinergic receptor class at autonomic ganglia is nicotinic; however, muscarinic M₁-cholinergic receptors are also present.

  • Muscarinic M₁-ganglionic cholinergic receptor activation produce a slow EPSP that may have a modulatory role.Muscarinic receptors are also located at adrenergic and cholinergic presynaptic sites where their activation reduces transmitter release.

    •  Blockade of these presynaptic receptors increase transmitter release.

• Opthalmological

  • 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.

  • Increases 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.

• Reflex slowing of the heart is blocked.

  •  Reflex slowing can occur due to carotid sinus stimulation, pressure on the eyeballs, peritoneal stimulation (as may occur during surgery).

• 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.

• Atropine has limited effects on circulation because most vascular beds lack prominent cholinergic innervation.

  • Cholinergic sympathetic vasodilatory nerves to skeletal muscle vessels are not affected presumably because their activity does not contribute prominent to vessel tone.

• 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.

Adapted from Table 6-2: Lefkowitz, R.J, Hoffman, B.B and Taylor, P. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics, (Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, p119.

• Muscarinic antagonists attenuate pulmonary smooth muscle constriction, often resulting in bronchodilation.

  • The magnitude of the effect depends on the basal parasympathetic tone.

  • Ipratropium (Atrovent) has been prominent in treating respiratory disease.

• Muscarinic antagonists attenuate pulmonary smooth muscle constriction, often resulting in brochodilation.

  • The magnitude of the effect depends on the basal parasympathetic tone. Ipratropium (Atrovent) 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.

    • Antimuscarinics, especially ipratropium, along with sympathomimetics, are useful in management of asthma. Ipratropium (Atrovent) has an advantage in asthma compared to atropine because:

      • 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.

      • Ipratropium is more effective that beta-adrenergic agonists in COPD (cholinergic tone may be the only component that may be reduced).

• 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.

Brown, J.H and Taylor, P. Muscarinic Receptor Agonists and Antagonists In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.149-159.

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