VPT 321: Veterinary Neuropharmacology (2+1)

MECHANISM OF ACTION

Competitive blockers

• Have affinity for the nicotinic (N_M) cholinergic receptors at the muscle end-plate but have no intrinsic activity.
• Most of competitive blockers have one or more quartenary N⁺ atoms which provide necessary affinity to the same site.
• Competitive blockers have a thick bulky molecules hence temed as pachycurare.
• Ach released from motor nerve endings is not able to combine with its receptors to generate end-plate potential (EPP). d-tubocurarine thus reduces frequency of channel opening but not its duration or the conductance of a channel once opened.
• When the magnitude of EPP falls below a critical level it is unable to trigger propogated muscle action potential and muscle fails to contract in response to nerve impulse.
• At very high concentrations curare like drugs directly block sodium channels to produce noncompetitive neuro muscular blockade.
• Decamethonim and succinylcholine have affinity as well as submaximal intrinsic activity at the N_M cholinoceptors.
• They depolarize musle end-plate by opening sodium channels and initially produce twitching and fasciculation because focal muscle stimulation is transient.
• Long lasting depolarization produce repetitive excitation of fibre.
• Depolarizing drugs do not dissociate rapidly from the receptor, induce partial prolonged depolarization, inactivation of sodium channels, action potential drops to 50 mV, Ach released from motor nerve endings is unable to generate propogated MAP, flaccid paralysis occurs.
• The depolarizing agents produce dual mechanism neuromuscular blockade which is divided as Phase I which is rapid in onset,results from persistent depolarization of EPP and has classical feature of depolarization blockade.The depolarization decline shortly afterwards and repolarization occurs even in the presence of drug at the receptor and Phase II supervenes.
• Phase II is slow in onset and results from desentization of the receptors to Ach.

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