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

Non - selective α-adrenergic receptor antagonists

NON- SELECTIVE α - ADRENERGIC RECEPTOR ANTAGONIST
(Blocks both alpha1 and alpha2 adrenoceptors)

Phenoxybenzamine

It is a non competitive antagonists of both α₁ and α₂ receptors.

• Pharmacological effects
  • CVS: causes progressive decrease in peripheral resistance. It causes a fall in blood pressure following release of adrenaline during fight and flight.
  • Due to the non availability of α receptors, the released adrenaline acts only β – sub population.
• Phenoxybenzamine causes cutaneous blood flow to increase, but little effects are observed in skeletal or cerebral blood flow. The decreased peripheral resistance increased the COP and reflex tachycardia. The tachycardia is accentuated by neither enhanced release of nor adrenaline (because of pre junctional α₂ - receptor blockade) and its decreased inactivation (because of inhibition of neuronal and extraneuronal uptake by phenoxybenzamine).
• Phenoxybenzamine and other α- receptor antagonist block the α-agonistic actions of exogenously administered adrenaline or noradrenaline. In the presence of these antagonists, the pressor response of adrenaline is converted to a depressor response and this phenomenon is called “Dale’s adrenaline reversal”. This is because of action adrenaline only on β- receptors (as the α-receptors are blocked) that dilate the blood vessels. However, the action of nor adrenaline is not reversed, but is either diminished or blocked (nor adrenaline has no action of β₂ – receptors.)
• Other effects
  • Causes relaxation of nictitating membrane and blocks pupillary dilation. Urinary incontinence is observed due to relaxation of sphincter of urethra and relaxation of base of bladder. There is also failure of ejaculation in males.
  • Antagonises the hyperglycaemic effect of adrenaline, as it increases insulin secretion by pancreas (due to blockade of α-receptors in pancreas).
• Side/Adverse effects: Important side effect and adverse effects include: loss of vasomotor tone, hypotension, miosis, tachycardia, nasal congestion and inhibition of ejaculation. High doses may cause postural hypotension and shock.
• Clinical uses: Used in small animals for treatment of urinary retention and in treatment of hypertesion associated wit phaechromocytoma.

Tolazoline

• It is a weak to modest α₁ and α₂ receptor antagonist. Unlike phenoxybenzamine it is a reversible antagonist. In addition to α₁ and α₂ receptor blockade effects, it has also direct vasodilator and cardiac stimulant actions. It also blocks 5HT receptors and has histamine like gastric secretagogue effect and acetylcholine like motor action on intestine.
• Tolazoline is primarily used as an antidote to xylazine over dosage and to increase blood flow in peripheral vasospastic conditions like frost bite.

Phentolamine

• It is a close congener of tolazoline.
• It is more potent in blocking α-receptors compared to tolazoline, but other actions are less pronounced.

Ergot alkaloids

• Ergot is a fungus (Claviceps purpurea) that parasitizes rye and other grains. Ergot contains about 12 alkaloids ( six isomeric pairs) and the naturally occurring l-forms are much more active than the d- forms. These alkaloids act as partial agonists or antagonists at α- adrenergic, tryptaminergic and dopaminergic receptors. Different groups of ergot alkaloids are:
  • Ergotamine group: These cause adrenergic blockade but have little effect on non vascular smooth muscles. Eg: Ergotamine, Ergosine
  • Ergotaxine group: This group of alkaloids have alpha blocking activity and in addition stimulate vascular smooth muscle and uterus. Eg: Ergocrytpine, Ergocristine, Ergocornine.
  • Ergometrine group: Have a weak adrenoceptor blocking activity, but are powerful stimulants of uterus (myometrium). Eg: Ergometrine ( Ergonovine).
• Pharmacological effects: Most important effects are seen on cardiovascular system and uterine smooth muscle.
• Cardiovascular system: Initially cause direct peripheral vasoconstriction and pressor response that may persist for longer duration. Larger doses may cause blockade of α- receptors and can reverse the pressor response of adrenaline to depressor action. Still larger doses cause intense and persistant peripheral vasoconstriction leading to stasis of blood, thrombosis and obliterative endoarterities causing gangrene and sloughing of extremities ( ergotism).
• Other effects: Initially stimulate the central nervous system followed by depression. Stimulates the chemoreceptor trigger zone and produce vomition. It also stimulates gastrointestinal tract and uterine smooth muscles.
• Clinical uses: Ergometrine is primarily used for contraction of the uterus post-partum.
• Other drugs: Although neuroleptic drugs like chlorpromazine and haloperidol produce significant α- receptor blockade effect , these are not clinically used for α – receptor blockade  because of their many other pharmacological actions.