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Alpha adrenergic blockers

This document summarizes the classification, mechanisms of action, pharmacokinetics, and clinical uses of α-adrenergic receptor antagonists (α-blockers). It discusses non-selective α-blockers that block both α1 and α2 receptors like phentolamine and phenoxybenzamine, as well as selective α1-blockers like prazosin, doxazosin, tamsulosin, and selective α2-blockers like yohimbine. The major uses of α-blockers include treatment of pheochromocytoma, hypertension, peripheral vascular disease, benign prostatic hyperplasia, migraine, and congestive heart failure. Common side effects include hypotension

Health & Medicine◦
Dr. K. R. Prabhakar, Resident.
CLASSIFICATION α-Adrenoceptor Antagonists Non-selective block α1 & α2 Selective Miscellaneous •Ergot alkaloids Reversible Irreversible α1-blockers α2-blockers •Phentolamine •Phenoxyben- •Prazosin •Yohimbine zamine •Terazosin •Tolazoline •Idazoxan •Doxazosin (priscoline) •Alfuzosin & Bunazosin •Tamsulosin &Silodosin
General effects of α blockers Blood vessels  α1-blockade→reduces peripheral resistance Fall in BP Postural hypotension  α2-blockade in brain ↑se vasomotor tone.  Block pressor action of adrenaline, fall in BP due toβ2. action- “vasomotor reversal of Dale”  Actions of selective α-agonists supressed.
Heart  Reflex tachycardia due to: fall in mean arterial pressure Blockade of presynaptic α2 receptors- ↑ NA release. Nose: nasal stuffiness Eye: miosis GIT: intestinal motility ↑se Kidney: Hypotension ↓se GFR NA+ & H2O reabsorption
Urinary bladder  α1A blockade- ↓se tone of smooth muscle in trigone, sphincter & prostrate.  Improved urine flow, used in BPH. Reproductive system  Contraction of vas deferens result in ejaculation through α receptors.  Blockade results in impotence.
Irreversible non-selective α- blockers Phenoxybenzamine  Cyclizes spontaneously to highly reactive ethyleniminium intermediate.  Binds covalently to α-receptors- irreversible or nonequilibrium competitive block.  Blockade is slow onset & longer duration (3-4 days).  Also inhibits reuptake of NE.  Shifts blood from pulmonary to systemic circuit.  Shift fluid from extravascular to vascular compartmentrelaxation of postcapillary vessels.
PK  Preferred ROA- i.v.  Lipid soluble penetrates brain.  Mainly excreted through urine in 24 hrs.  Accumulates in adipose tissue on ch. Administration. Dose 20-60 mg/d oral 1mg/kg/1hr slow i.v infusion. Uses Pheochromocytoma, occasionally 2oshock, PVD.
Reversible non-selective α-blockers Tolazoline  Block is modest & short lasting.  Direct vasodilator & stimulates the heart.  Also blocks 5-HT receptors, histamine like gastric secretagouge & Ach like motor action on intestine. SE  N, V, cramps, diarrhoea, nervousness, chills  Tachycardia, Exacerbation of MI, peptic ulcer. Use  PVD  Pulmonary HT of newborn.
Phentolamine  More potent α-blocker than tolazoline.  Other actions are less marked.  Duration of action is shorter (min).  Equally blocks α1 & α2 receptors- NA release ↑sed. Uses  ∆sis & intraop.management of pheochromocytoma. 5mg i.v- B.P falls by 25(D)or35(S)mmHg.  HTN due to clonidine withdrawl, cheese reaction.  Dermal necrosis due to extravasated i.v NA/DA. Given S.C as local infiltration.
Reversible, selective α1- blockers Prazosin  Highly selective α1-blocker , α1: α2 selectivity 1000:1  Fall in BP with only mild tachycardia.  Dilates arterioles more than veins  Postural hypotension occurs as 1st dose effect, minimized by starting with low doses at bed time.  Also inhibits PDE- ↑se cAMP in smooth muscle. PK  Effective orally, BA- 60%.  Highly bound to plasma proteins (α1 acid glycoprotein).
 Metabolized in liver, 1o excreted in bile.  t1/2 – 2-3hrs, effect lasts for 6-8hrs. Uses  Primarily as antihypertensive.  LVF not controlled by diuretics & digitalis.  Raynaud’s disease  BPH  Scorpion sting
Terazosin &Doxazosin  Long acting( t1/212 & 18hr) congener of prazosin.  Used in HTN & BPH as single daily dose. Tamsulosin & Silodosin  Uroselective α1A blocker  α1A –bladder base, prostrate. α1B- blood vessels.  Don't cause significant changes in BP & HR.  t1/2- 6-9hr, MR cap(0.2-0.4 mg) can be taken OD.  Efficacious in Rx of BPH.  SE: retrograde ejaculation, dizziness,, floppy iris syd.  Silodosin weaker(4-8mg/d) but longer acting.
Bunazosin & Alfuzosin  Orally effective α1 blockers similar to prazosin.  Alfuzosin t1/2 4hrs (2.5mgTDS or 10mg SR OD).  CI in hepatic impairment, metabolized in liver.  Bunazosin slightly longer t1/2.  Primarily used in BPH.
α2-receptor blockers Yohimbine  Natural alkaloid from Pausinystalia yohimbe.  No established clinical role. Idazoxan  Has membrane stabilizing action. Ergot alkaloids  Ergotamine & Dihydroergotamine  Competitive α-receptor blockers.  Principal use is migraine.
Uses of α-Blockers Pheochromocytoma  Tumor of adrenal medullary cells-excess Cas.  Cause intermittent or persistent hypertension.  Diagnosed by- ↑se urinary VMA, normetanephrine.  phentolamine test can also be performed. Rx Phenoxybenzamine  Definitive therapy for inoperable or malig.tumors.  Preoperative- orally x 2wks, i.v during surgery as-
1. Normalizes blood volume & body H2O distribution. 2. During surgery excess release of CAs in to blood. Phentolamine drip can also be used. Hypertension  Selective α1 blocker prazosin is preferred. 2o shock  Fluid loss leads to vasoconstriction.  Should not be given without fluid replacement.
Peripheral vascular disease  Little benefit in Buerger’s disease & int.claudication.  More useful in Reynaud's disease & acrocyanosis where vasoconstriction is prominent.  Prazosin or phenoxybenzamine are useful. CHF  Short term benefit, leads to Na+ & H2O retension. Migraine  Ergotamine more effective
Benign prostrate hypertrophy  Two classes of drugs are available. 1. α1-blockers- ↓ tone of prostrate and bladder neck. 2. 5-α reductase inhibitors: finasteride & dutasteride. arrest growth/reduce size of prostrate.  α1-blockers gives faster and greater symptomatic releif than finasteride.  Effect of α1-blockers decline after several years of use, must be combined with fiasteride.  Terazosin, doxazosin, tamsulosin are preferred.
Side effects of α-blockers  Palpitation  Postural hypotension  Nasal blockade  Diarrhea  Fluid retention  Inhibition of ejaculation & impotence.
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