Systemic Effects and Organ Impacts
When administered into the body, muscarinic receptor (M-receptor) stimulation dominates, reproducing the clinical picture of massive parasympathetic nervous system activation.
Key systemic changes include:
- Cardiovascular system: Decreased heart rate (bradycardia), vasodilation, and a marked reduction in blood pressure.
- Smooth muscle: Sharp increase in tone, manifesting as enhanced gastrointestinal motility, bronchospasm, and elevated tone of the urinary bladder, gallbladder, and uterus.
- Exocrine glands: Generalized hypersecretion, primarily involving bronchial, digestive, and sweat glands.
The Dosing Paradox: Hemodynamic Impact
The cardiovascular effects of acetylcholine depend directly on the dose administered. Its direct chronotropic effect on heart rate can be modified by reflex mechanisms of the sympathetic nervous system.
- Low doses (20–50 mcg/min, IV): The primary effect is a drop in blood pressure caused by vasodilation. This hypotension triggers a compensatory response—reflex tachycardia.
- High doses: Direct excitation of cardiac M-receptors predominates, leading to bradycardia and depressed atrioventricular (AV) conduction. The direct negative chronotropic and inotropic effect overrides any reflex mechanisms, even in the presence of persistent hypotension.
Hidden Nicotinic Action
Acetylcholine is also capable of stimulating nicotinic receptors (N-receptors); however, this effect is unmasked only when M-receptors are blocked (e.g., following administration of the M-anticholinergic drug atropine).
Under these conditions, opposing effects appear: tachycardia, vasoconstriction, and elevated blood pressure (pressor effect). The mechanism involves:
- Stimulation of sympathetic ganglia.
- Stimulation of chromaffin cells in the adrenal medulla, leading to a massive release of adrenaline.
- Stimulation of carotid bodies.
When extremely high doses are administered, initial stimulation gives way to persistent depolarization of the postsynaptic membrane, leading to complete blockade of neurotransmission in cholinergic synapses.
Pharmacokinetics and Clinical Limitations
The acetylcholine molecule is a quaternary ammonium compound. It crosses the blood-brain barrier extremely poorly and has virtually no central nervous system effects. Once in synapses or the bloodstream, the neurotransmitter is rapidly hydrolyzed by acetylcholinesterase and plasma cholinesterase, resulting in a duration of action of only a few minutes.
Lack of selectivity and short duration strictly limit the clinical utility of lyophilized acetylcholine chloride. It is primarily used in experimental pharmacology. In clinical practice, it is rarely used:
- Therapeutics: Subcutaneously or intramuscularly as a vasodilator for peripheral vascular spasms (intermittent claudication) and retinal artery spasms.
- Eye surgery: Topically in combinations to achieve miosis during surgical procedures.
Synthetic Analogue: Carbachol
For clinical applications, the synthetic analogue carbachol (carbacholine) was developed. Its spectrum of pharmacological action mirrors that of acetylcholine.
Its major advantage is resistance to degradation by acetylcholinesterase, extending its duration of action to 1–1.5 hours. Carbachol is used as eye drops for glaucoma treatment and is administered parenterally for urinary bladder atony.