Alpha receptor adrenergic antagonists

α receptor adrenergic antagonists inhibit all responses mediated through α adrenergic receptors without affecting those mediated by β adrenergic receptors.

Based on α-receptors sub-types these drug antagonize. these are further divided into-

1. Non-selective α adrenergic receptor antagonists (block both alpha1 and alpha2 adrenoceptors)
   • Haloalkylamine derivatives Eg: Phenoxybenzamine, Dibenamine
   • Imidazoline derivatives: Eg: Tolazoline, Phentolamine
   • Ergot derivatives Eg: Ergotmine, Dihydroergotamine, Dihydroergotoxine
   • Miscellaneous drugs
     • Neuroleptics- Chlorpromazine, Haloperidol
     • Benzodioxan derivatives- Piperoxane, Dibozane
     • Dibenzepine derivatives- Azapetine
2. Selective α adrenergic receptor antagonists
   • Selective α1 adrenergic receptor antagonists
     • Quinazoline derivatives- Prazosin, Terazosin, Doxazosin, Trimazosin
     • Indole derivatives- Indoramin
     • Miscellaneous drugs- Ketanserin, Urapidil
   • Selective α₂– adrenergic receptor antagonists- Yohimbine, Atipamazole

1. Non-selective α-adrenergic receptor antagonists

Non-selective α adrenergic receptor antagonists block both alpha1 and alpha2 adrenoceptors. important examples are Phenoxybenzamine, Tolazoline, Phentolamine and Ergot alkaloids.

Phenoxybenzamine

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

Pharmacological effects of Phenoxybenzamine

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 of Phenoxybenzamine

Phenoxybenzamine 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 of Phenoxybenzamine

Important side effect and adverse effects of Phenoxybenzamine include loss of vasomotor tone, hypotension, miosis, tachycardia, nasal congestion and inhibition of ejaculation. High doses may cause postural hypotension and shock.

Clinical uses of Phenoxybenzamine

Phenoxybenzamine is used in small animals for treatment of urinary retention and in treatment of hypertesion associated wit phaechromocytoma.

Tolazoline

Tolazoline 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

Phentolamine 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

1. Ergotamine group: These cause adrenergic blockade but have little effect on non vascular smooth muscles. Examples are Ergotamine, Ergosine
2. Ergotaxine group: This group of alkaloids have alpha blocking activity and in addition stimulate vascular smooth muscle and uterus. Eg: Ergocrytpine, Ergocristine, Ergocornine.
3. Ergometrine group: Have a weak adrenoceptor blocking activity, but are powerful stimulants of uterus (myometrium). Eg: Ergometrine (Ergonovine).

Pharmacological effects of Ergot alkaloids

Most important effects of Ergot alkaloids 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 of Ergot alkaloids

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 of Ergot alkaloids

Ergometrine is primarily used for contraction of the uterus post-partum.

2. Selective α-adrenergic receptor antagonists

Selective α-adrenergic receptor antagonists are-

Prazosin

Prazosin is a Quinazoline derivative and extremely potent highly selective α₁ adrenoceptor blocking drug with no action on α₂ receptors. It has 1000 times more greater affinity to α₁ receptors than for α₂ receptors.

It decreases peripheral vascular resistance and lowers blood pressure, by relaxing both arterial and venous smooth muscle. It also decreases venous return to the heart.

Unlike other non-specific α- receptor blockers, prazosin does not cause reflex tachycardia. This is because prazosin decrease cardiac pre-load and also does not cause release of nor adrenaline from sympathetic nerve endings in myocardium due to its no action on the pre junctional α₂– receptors. There are minimum changes in cardiac output, renal blood flow and glomerular filtation rate.

Clinical uses of Prazosin

Prazosin is used in treatment of systemic hypertension or pulmonary hypertension.

Yohimbine

Yohimbine (Selective α₂-adrenoceptor antagonists) is a competitive antagonist with selective action on α₂– receptors. It is an alkaloid with structural resemblance to reserpine obtained from Pausinystalia yohimbe.

Yohimbine produces a short duration competitive blockade of α2 adrenergic receptor and 5-HT receptors. By blocking central α₂ –adrenergic receptors releases nor adrenaline and increases sympathetic outflow. This results in increased heart rate and blood pressure. However, as it also blocks the peripheral post-junctional α₂ receptors. It causes vasodilatation and hypotension usually predominate. The vasodilator effect of yohimbine in male genetalia causes penile erection.

Yohimbine crosses readily the blood brain barrier and produces central nervous excitation, motor activity, ADH release, nausea and vomiting. It also antagonizes the effects of xylazine.

Clinical uses of Yohimbine

Yohimbine is used to antagonize the over dosage effects of xylazine.