Alpha blockers

 – Receptor Antagonists /  – Blockers: 

 – Receptor Antagonists /  – Blockers

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Anti adrenergic drugs Adrenoceptor antagonists --- α & β blockers Drugs affecting the synthesis storage & release of NE.

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α - Adrenoceptor antagonists / α blockers: A group of drugs whose major effect is to occupy the α Adrenoceptors and prevent their activation by catecholamines & related agonists.

MOA of α blockers:: 

MOA of α blockers: These agents bind to - receptors but do not activate them & prevent the binding and activation of these receptors by the endogenous catecholamines , so the usual receptor mediated events are not triggered. They differ in their binding interactions with receptors so they may : A. Reversible / Competitive antagonists. B. Irreversible / Non-Competitive antagonists. They also differ in the selectivity of receptors

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Reversible / Competitive antagonists. Weak binding to the receptors. Antagonist can dissociate from receptors. Block can be surmounted with sufficiently high concentration of agonist. DOA : Short, it is dependent on the half life of the drug & rate of its dissociation from receptors. Phentolamine ---- 2 – 4 hrs Prazosin & others α 1 selective -blockers--- 8-24 hrs

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B. Irreversible / Non-Competitive antagonists Covalent binding to the receptors Antagonist can not dissociate from receptors. Block can not be surmounted even with very high concentration of agonist. Long DOA 14 - 48 hrs Responsiveness depends upon synthesis of new receptors. Example: Phenoxybenzamine – an agent related to nitrogen mustards forms a reactive ethyleneimonium intermediate that covalently binds to - receptors

Classification According To Reversibility of Action (Duration of Action) : 

Classification According To Reversibility of Action (Duration of Action) Reversible (Competitive Blockers, short acting) Prazosin Terazosin Doxazosin Urapidil Phentolamine Tolazoline Ergotamine --partial agonist Dihydroergotamine --partial agonist Irreversible (Noncompetitive Blockers, long acting) Phenoxybenzamine Dibenamine

Classification According To Receptor Selectivity: 

Classification According To Receptor Selectivity A. Selective -Blockers i ) Selective  1 Blockers Prazosin Doxazosin Alfuzosin Terazosin Tamsulosin Urapidil Indoramin ii) Selective  2 Blockers Yohimbine , Tolazoline

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B. Non-selective Blockers / Block both  1 &  2 Phentolamine Phenoxybenzamine Dibenamine C. Mixed  and β Blockers Labetalol , Carvedilol D. Other drugs with - blockade as adverse effect Neuroleptic drugs ( Chlorpromazine , Haloperidol) Antidepressant ( Trazodone ) ERGOT ALKALOIDS: Ergotamine --partial agonist Dihydroergotamine --partial agonist

Relative selectivity of antagonists for adrenoceptors: 

Relative selectivity of antagonists for adrenoceptors  Antagonists Receptor Affinity Prazosin , terazosin , doxazosin  1 >>>>  2 Phenoxybenzamine  1 >  2 Phentolamine  1 =  2 Tolazoline , yohimbine  2 >>  1 Mixed antagonists Labetalol , carvedilol β 1 = β 2 _ >  1 >  2

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STRUCTURE

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subtypes/locations & characteristics of Adrenoceptors Receptor Location Pharmacologic effects Result of Agonist binding α 1 subtypes α 1A α 1B α 1D Postsynaptic effector cells smooth muscles of BV specially of skin & mucosa. Radial muscle of eye GIT sphincters SM of prostate& bladder base ( α 1A ) Pilomotor SM Splenic capsule Heart Contraction Vasoconstriction Mydriasis Contraction “ “ “ ↑ force of Contraction Through Gq Stimulation of phospholipase C ↑IP 3 , DAG , ↑ intracellular Ca ++

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subtypes/locations & characteristics of Adrenoceptors Receptor Location Pharmacologic effects Result of Agonist binding α 2 subtype α 2A α 2B α 2C Presynaptic adrenergic & cholinergic nerve terminals Postsynaptic effector cells of plastelets lipocytes , B cells of pancrease Some vascular SM CNS Inhibition of transmitter release Aggregation promoted Inhibition of lipolysis Inhibition of insulin release. Contraction Multiple. In hibition of central sympathetic out flow to periphery Through Gi Inhibition of Adenylyl cyclase ↓ cAMP

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Blockade of α 1 Receptors produces Inhibition of α 1 mediated contraction of arterial & venous smooth muscles. Inhibition of contraction of other smooth muscles i.e. eye, GIT , UB & prostate. Inhibition of e jeculation in males.

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17 Blockade of α 2 Receptors produces inhibition of : Suppression of sympathetic outflow from CNS ( VMC ) to periphery --- ↑ vagal tone. Negative feed back control of NE release----- Inhibition of NE release Inhibition of Ach release. Inhibition of insulin release. Facilitation of platelet aggregation

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PHARMACOLOGICAL ACTIONS a. Cardiovascular effects: Vasodilatation Epinephrine reversal b. Other effects: ↑ HDL Miosis Nasal stuffiness c. Decreased resistance to urinary out flow due to: Blockade of α 1A & α 1D receptors in prostate

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Vasodilatation: 1. Due to blockade of Arteriolar  1 receptors--- dilatation ↓ PVR --- ↓ Blood Pressure 2. Due to blockade of  1 receptors in Veins of lower limbs --- dilatation---- ↓ venous tone ----- pooling of blood on standing------ Postural / orthostatic Hypotension

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Epinephrine reversal: ( Vasoreversal phenomenon of Dale) Reversal in the effect of large doses of epinephrine on blood pressure from a pressor response to a depressor response (mediated by β 2 receptors) by prior administration of α blocker.

THERAPEUTIC USES : 

THERAPEUTIC USES Phaeochromocytoma Hypertensive emergencies Chronic hypertension Urinary obstruction due to Benign Prostatic Hypertrophy (BPH) Local vasoconstrictor excess Peripheral Vascular Spastic Disease ( Raynaud’s phenomenon). Limited use of α 2 Antagonists in Erectile dysfunction

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Phaeochromocytoma : It is tumor of adrenal medulla. It secretes catecholamines – NE & Epinephrine Phenoxybenzamine an irreversible ,non-surmountable blocker it attenuates the vasoconstriction produced by catecholamines . Preoperatively to control hypertension. Intraoperatively ( Nitroprusside is preferred) Chronic treatment of inoperable or metastatic tumor. .

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Other drugs used: β blockers may be required after α -blockers to reverse the cardiac effects. Metyrosine : Competitive inhibitor of Tyrosine Hydroxylase , blocks rate limiting step in ssynthesis of catecholamines . Useful in symptomatic treatment of inoperable or metastatic tumor.

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2. Hypertensive emergencies: Labetalol Severe Hypertension due to: Hypertensive crisis in Hypertensive patients Over dosage with sympathomimetic drugs. Clonidine withdrawal

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3. Chronic hypertension: α 1 selective blockers are preferred as they produce less reflex tachycardia. Prazosin Doxazosin Terazosin

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4. Urinary obstruction due to Benign Prostatic Hypertrophy (BPH) Selective α 1A Receptor Antagonist Tamsulosin It relaxes prostatic smoothmuscles more than vascular smooth muscles. Orthostatic hypotension less common .

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5. Local vasoconstrictor excess: Phentolamine 6. Peripheral Vascular Spastic Disease ( Raynaud’s phenomenon): Phentolamine , prazosin , & phenoxybenzamine --- calcium channel blocker are preferred.

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8. Applications of α 2 Antagonists. Limited use in Erectile dysfunction: Phentolamine with papaverine , now phosphodiesterase-5 inhibitors like Sildenafil are used. Experimental in: Raynaud’s phenomenon Type II diabetes mellitus Psychiatric depression.

ADVERSE EFFECTS: 

ADVERSE EFFECTS Postural /orthostatic Hypotension--- Dizziness, headache , syncope Reflex Tachycardia– palpitations , Myocardial ischemia. Nasal Stuffiness Sedation Diarrhea Failure of Ejaculation: Due to Blockade of α 1A receptors in vas deferens Anxiety with α 2- blocker Yohimbine

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Prototype Alpha-1 Blocker : Prazosin Piperazinyl quinazoline derivative. Given orally . Extensive 1 st pass metabolism in liver. Bioavailability 50%. t ½ : 3-4 hrs Peak fall in blood pressure after 4-5 hrs & DOA: 12 hrs.

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Highly selective for α 1 receptors , 1000 fold > α 2 ---- so less reflex tachycardia as negative feed back by NE ,mediated by α 2 is not blocked. Relaxes vascular smooth muscle  ↓ PVR & ↓ blood pressure ---- useful anti-hypertensive. Relaxes vascular smooth muscle in the prostate & bladder base  useful in urinary obstruction , improves urinary flow.

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DOC in hypertension---produces less reflex tachycardia. Also useful in BPH A/E: First dose phenomenon – marked hypotension with first dose specially in patients who are volume & salt depleted.. So first dose should be small & given at bed time. Other Piperazinyl quinazoline derivatives are: Terazosin & Doxazosin : better oral bioavailability & longer DOA. Uses & A/E like Prazosin

Properties of some other α-blockers: 

Properties of some other α -blockers Phenoxybenzamine Yohimbine Tamsulosin Labetalol