Medical Pharmacology: Cholinergic Pharmacology

Anesthesia Pharmacology: Autonomic Pharmacology: Cholinergic Drugs

Direct vs. Indirect-Acting Cholinomimetics
- A direct-acting cholinomimetic drug produces its pharmacological effect by receptor activation.
- An indirect-acting drug inhibits acetylcholinesterase, thereby increasing endogenous acetylcholine levels, resulting in increased cholinergic response.

**Choline esters: Comparisons and Contrasts**
Choline Ester	Sensitivity to ACHE	Cardiovascular	Gastrointestinal	Urinary Bladder	Atropine Sensitive	Activity at Nicotinic Sites
Acetylcholine
Methacholine
Carbachol	No
Bethanechol (Urecholine)	No	??				No

**Potentiation by Acetylcholinesterases**
Choline Ester Agent	Sensitivity to ACHE
Acetylcholine (potentiated by AchE inhibitors)
Methacholine (potentiated by AchE inhibitors)
Carbachol (AchE inhibitors have no effect)	No
Bethanechol (Urecholine) (AchE inhibitiors have no effect)	No

Pharmacological Effects of Cholinomimetics

Cardiovascular: Four major effects

**Vasodilation**
The vascular response is due to endothelial cell nitric oxide (NO) release following agonist interactions with endothelial muscarinic receptors. Increased NO activates guanylate cyclase which increases cyclic GMP concentrations. Subsequent activation of a Ca²⁺ ion pump reduces intracellular Ca²⁺. Reduction in intracellular Ca²⁺ causes vascular smooth muscle relaxation. Ca²⁺complexes with calmodulin activating light-chain myosin kinase Increased cGMP promotes dephosphorylation of myosin light-chains. Smooth-muscle myosin must be phosphorylated in order to interact with actin and cause muscle contraction. This effect is mediated by muscarinic receptor activation and is especially prominent in the salivary gland and intestines.
Vasodilation may also occur due to ACh inhibition of N.E. release from post-ganglionic sympathetic fibers. Damaged endothelium can result in ACh causing vasoconstriction by direct action on vascular smooth muscle.

**"Autonomic Inneravation of the Heart"**

Attribution: Morton DA Autonomic Innervation of the Heart https://www.youtube.com/watch?v=Bsz95YS_0R8 The Noted Anatomist https://www.youtube.com/channel/UCe9lb3da4XAnN7v3ciTyquQ

Negative chronotropic effect (Decrease in heart rate)
- Decreases phase 4 (diastolic depolarization)
  - As a result, it takes longer for the membrane potential to reach threshold.
- Mediated by M₂ muscarinic receptors
Decreased SA nodal and AV nodal conduction velocity
- Excessive vagal tone may induce bradyarrhythmias including partial or total heart block.
  - Impulses cannot pass through the AV node to drive the ventricular rate; in this case, the idioventricular or intrinsic ventricular rate must maintain adequate cardiac output.
- Transmission through the AV node is especially dependent on Ca²⁺ currents.
  - ACh decreases calcium currents in the atrioventricular node.
Negative inotropism (decreased myocardial force of contraction (contractility)
- This effect is more prominent in atrial than ventricular tissue and occurs because of a decrease in I_Ca2+ inward current.
- In the ventricle, adrenergic tone dominates.
  - At higher levels of sympathetic tone, a reduction in contractility due to muscarinic stimulation is noted.
  - Muscarinic stimulation reduces the response to norepinephrine by opposing increases in cAMP in addition to reducing norepinephrine release from adrenergic terminals.
Effect of muscarinic receptor activation on cardiac currents
- (1) Muscarinic receptor activation causes an increase in I _{K (Ach)} in atrial muscle and in SA and AV nodal tissue.
- (2) Muscarinic receptor activation results in a decrease in slow, inward calcium (I_Ca2+) current which reduces atrial contractility and decreases AV nodal impulse conduction.
- (3) Muscarinic receptor activaiton decreases the heart pacemaker diastolic depolarizing current (I_f) thus decreasing heart rate. This effect occurs because it takes longer for the membrane potential to reach threshold since there is less depolarizing I_fcurrent.
Gastrointestinal and Urinary Tracts
- Muscarinic agonists increase intestinal peristalsis, tone, and contraction amplitude.
- Carbachol and bethanecol (not ACh or methacholine) stimulate the urinary tract by increasing ureteral peristalsis and by contraction of the urinary bladder detrusor muscle.

Brown, J.H. and Taylor, P. Muscarinic Receptor Agonists and Antagonists, In, Goodman and Gillman's The Pharmacological 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.149-150.

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