Alpha blockers

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 – Receptor Antagonists /  – Blockers:

 – Receptor Antagonists /  – Blockers Dr.S.P.Dhanya Assistant Professor Dept of Pharmacology TDMC,Alappuzha

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

ADRENOCEPTOR BLOCKERS:

ADRENOCEPTOR BLOCKERS ADRENOCEPTOR ANTAGONISTS Alpha-blockers Beta-blockers Alpha 2 -selective Beta 2 -selective Alpha 1 -selective Beta 1 -selective Nonselective Nonselective Reversible Irreversible +

α -Adrenoceptor antagonists / α blockers: :

α - Adrenoceptor antagonists / α blockers: O ccupy the α a drenoceptors Prevent activation by catecholamines & related agonists.

Classification :

Classification Reversible (Competitive , short acting) Imidazoline- Phentolamine Tolazoline Ergot alkaloid s- Ergotamine,Ergotoxine Hydrogenated ergot alkaloids - Dihydroergotamine , dihydroergotoxine Irreversible (Noncompetitive, long acting) Phenoxybenzamine Dibenamine

Reversible / Competitive antagonists:

Reversible / Competitive antagonists Weak binding to the receptors. Antagonist can dissociate from receptors. Block can be surmounted with sufficiently high concentration of agonist.

Irreversible / Non-Competitive antagonists :

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.

Classification According To Receptor Selectivity:

Classification According To Receptor Selectivity A. Selective -Blockers i ) Selective  1 Blockers PRAZOSIN DOXAZOSIN ALFUZOSIN TERAZOSIN TAMSULOSIN BUNAZOSIN URAPIDIL INDORAMIN ii) Selective  2 Blockers YOHIMBINE , RAUWOLSCINE,IDAZOXAN

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B . Mixed  and β Blockers Labetalol , Carvedilol C . Other drugs with - blockade as adverse effect Chlorpromazine Haloperidol Trazodone Ketanserin

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 Y ohimbine  2 >>  1 Mixed antagonists Labetalol , carvedilol β 1 = β 2 _ >  1 >  2

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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 platelets lipocytes  cells of pancrease CNS Inhibition of transmitter release Aggregation promoted Inhibition of lipolysis Inhibition of insulin release. Inhibition of central sympathetic out flow to periphery Through Gi Inhibition of Adenylyl cyclase ↓ cAMP

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

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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: ( Vasomotor reversal 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.

Phenoxybenzamine:

Phenoxybenzamine Non selective Irreversible bond- ethyleniminium intermediate Slow and long acting Partial blockade-H, 5HT, Cholinergic Postural hypotension, tachycardia, miosis , nasal stuffiness, failure of ejaculation

Uses:

Uses Pheochromocytoma pre treatment before surgery normalize blood volume prevents marked BP rise Hypertension- Clonidine withdrawal Cheese reactio n Sec.shock * counteracts vasoconstriction shifts blood improves circulation PVD BHP Autonomic hyperreflexia in patients with spinal cord transection

Phentolamine:

Phentolamine Non selective Quick and Short acting Uses 1. Diagnostic and intraoperative management of Pheochromocytoma 2.Hypertension-clonidine withdrawal,cheese reaction 3.Extravasation of NA/DA—dermal necrosis 4.PIPE therapy

Adverse effects:

Adverse effects Hypotension Tachycardia Arrhythmia Myocardial ischemia Nasal congestion Headache Exacerbation of peptic ulcer

Tolazoline:

Tolazoline Less potent  blocking –short acting Vasodilator & stimulates heart Persistent PHT in newborn/ PGs, NO Visualizing distal peripheral vessels- arteriography

Prazosin- 1blocker:

Prazosin -  1 blocker Competitive-alpha 1 selective(1000:1) Phosphodiesterase enzyme inhibitor FIRST DOSE HYPOTENSION Fall in BP-postural hypotension HR- minimal change Cardiac preload  Selective  1 blocker Blocks central sympathetic outflow

Pharmacokinetics:

Pharmacokinetics Orally effective Highly bound to plasma proteins Metabolised in liver t1/2=2-3h,duration 7-10 hrs Thrice a day

Uses:

Uses Anti HT-start with 1mg then titrate Raynaud’s disease BHP CCF

Terazosin:

Terazosin Similar to prazosin High oral BA-90% Long plasma t1/2=12 h,duration =18h Single daily use-2-10mg OD Induction of apoptosis

Doxazosin:

Doxazosin Congener of prazosin t1/2=20h, duration=36 h-----longest Induction of apotosis BHP,Hypertension

TAMSULOSIN:

TAMSULOSIN Uroselective  1A & 1D t ½=5-10hrs No CVS side effects Dizziness and retrograde ejaculation Modified release preparations---0.4 mg/day

Other drugs:

Other drugs Alfuzosin 1-BHP TIMAZOSIN BUNAZOSIN- antiHT URAPIDIL-CNS actions- antiHT INDORAMIN- antiHT

Yohimbine:

Yohimbine Bark of Pausinystalia yohimbe Alpha 2 antagonist,also 5 HT,stimulate NE release Use Postural hypotension Diabetic neuropathy Psychogenic erectile dysfunction

Uses of  blockers:

Uses of  blockers Pheochromocytoma Hypertension Secondary shock decrease vc shift pulmnary to systemic return fluid from extravascular to vascular Peripheral diseases- prazosin,phenoxybenzamine Congestive heart failure- prazosin BHP-  1a blocker, 5-  reductase inhibitor- finasteride PIPE therapy

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