VPT 321: Veterinary Neuropharmacology (2+1)

DRUGS THAT AFFECT NORADRENALINE RELEASE

• The mechanisms by which these drugs interfere with release of noradrenaline include:
• inhibition of noradrenaline release in response to depolarization of the nerve terminal and/or
• complete depletion of noradrenaline from its storage sites.  

Guanethidine

• It is selectively inhibits release of noradrenaline from peripheral postganglionic adrenergic neurons, with no effect on adrenal medulla.
• Mechanism of action
  • Guanethidine has complex mechanism of action.
  • It has bretylium like effect-blocks nerve impulse coupled release of stored noradrenaline
  • Tyramine like effect-displaces noradrenaline from storage vesicles
  • Reserpine like effect-causes gradual depletion of noradrenaline in storage vesicles
  • Blocks uptake1 carrier transport system for noradrenaline
  • When chronically administered guanethidine acts as a “substitute neurotransmitter”, as it is stored noradrenaline storage vesicles and is released by stimuli that normally release noradrenaline.
  • Has some local anesthetic like action
  • Guanethidine in large doses caused structural damage to adrenergic neurons.
• Pharmacological effects
  • Following oral administration, guanethidine produces fall in blood pressure and bradycardia, because of decreased release of noradrenaline. However, after IV administration, it produces characteristic triphasic response in blood pressure.
  • Initially it produces decrease in blood pressure (due to decreased peripheral resistance an cardiac output, resulting from initial noradrenaline blockade).
  • The fall is then followed by increase in blood pressure (due to release of noradrealine) and then finally there is fall in blood pressure ( due to depletion of noradrenaline).
• Clinical uses: Seldom used in veterinary practice.

Bretylium

• Inhibits the release of noradrenaline, accumulates in nerve terminals and exerts a selective local anesthetic effect on sympathetic nerve terminals.
• It does not block release of catecholamines from adrenal medulla and does not affect nerve terminals other than those that release nor adrenaline.
• Bretylium also has effect on K⁺ channels in myocardium and exerts anti arrhythmic effect.