VPT 321: Veterinary Neuropharmacology (2+1) copy 1

DIRECTLY ACTING CHOLINOMIMETICS

• These drugs act directly on cholinergic receptors and produce the effects like ACh, these act on effector organs innervated by parasympathetic nerve fibres and also in those organs not innervated by parasympathetic nerve fibers , but have cholinergic receptor like skeletal muscles and blood vessels

Choine esters (cholinomimetic esters)

• These are esters of choline. ACh as such has no therapeutic value because   of lack of specificity and its rapid hydrolysis by choline esterase enzyme. However, Ach is prototype of the drugs in this group.

Mechanism of action Ach

• Acts on both muscarinic and nicotinic receptors. The quaternary nitrogen group of ACh with positive charge electrostatically binds with the anionic site    of cholinergic receptors. The intervention of quaternary nitrogen in the anionic site    of the receptor causes a conformational changes that leads to alterations in membrane permeability to one or more of variations such as K⁺, Na⁺, Ca²⁺, and /or Cl^-.  This in turn causes either hyperpolarization in some tissues (Eg: Myocardial pacemaker cells) or depolarization (eg. Smooth muscles of the GI tract).

Pharmacological effects

• Depending on the receptors through which action mediates its effects, peripheral actions  of ACh are categorized into muscarinic or nicotinic effects

Muscarinic effects

• These actions of ACh are akin to those produced by the mushroom alkaloid “muscarine”. these effects are evident in cardiovascular system smooth muscles and exocrine glands, where muscarinic receptors are present.

Cardiovascular system

• Blood vessels
  • Injected with ACh causes dilatation of all blood vessels, even though most the blood vessels do not receive cholinergic innnervation. This action mediated through M₃ subtype of muscarinic receptors located on the endothelial cells. Stimulation of these receptors results in release of NO from endothelial cells and the NO then diffuses in to the adjacent smooth muscles.

Blood pressure

• IV administration of small doses of ACh produces a rapid fall BP due to vasodilatation. Large doses, however produce an increase in BP by stimulation of nicotinic receptors in autonomic ganglia and adrenal medulla. This effect is particularly evident when muscarinic receptors are blocked by atropine prior to administration of ACh.

Heart

• Injected ACh decreases the heart rate and force of contraction. Decrease in force of contraction is mainly evident in atrial muscle as ventricles have only limited parasympathetic innervations ACh also decreases the rate of conductions in SA and AV nodes. Cardiac output decreases mainly due to decrease in the force of contraction.

Non-vascular smooth muscles

• ACh causes contraction of all non-vascular smooth muscles. ACh increases the tone and motility of stomach and intestines and relaxes the sphincters. ACh also increases secretions in the GI tract.
• Contractile effect is also observed in uterus, gall bladder and bronchi. In the urinary bladder the detrusor muscle contracts while the bladder trigone and sphincter relax leading to urination.