Medical Pharmacology Chapter 6:  Autonomic Pharmacology: Cholinergic Drugs

 
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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 

  1.  The vascular response is due to endothelial cell nitric oxide (NO) release following agonist interactions with endothelial muscarinic receptors.

  2.  Increased NO activates guanylate cyclase which increases cyclic GMP concentrations.

  3.  Subsequent activation of a Ca2+ ion pump reduces intracellular Ca2+.

  4.  Reduction in intracellular Ca2+ causes vascular smooth muscle relaxation.

  5.  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.

  6. 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.

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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