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SYMPATHOLYTIC AGENTS..2. Alpha Adrenergic receptor blockers. ALPHA BLOCKERS Several agents Chemically heterogeneous and with different specificities According to nature of action : Two Groups, Competitive & Irreversible According to selectivity : Three Groups,
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SYMPATHOLYTIC AGENTS..2 Alpha Adrenergic receptor blockers
ALPHA BLOCKERS • Several agents • Chemically heterogeneous and with different specificities • According to nature of action : Two Groups, Competitive & Irreversible • According to selectivity : Three Groups, • 1 > 2; 1 = 2; 2 > 1
Classification - RECEPTOR antagonist 1- SELECTIVE competetive 1 > 2 2- SELECTIVE competetive 2 > 1 NON-SELECTIVE Competetive 1 = 2 NON-SELECTIVE Irreversible 1 = 2 Prazosin Yohimbine Phentolamine Phenoxy- Terazosin Idazoxan Tolazoline benzamine Doxazosin Mianserin Dibenamine Tamsulosin
Pharmacological actions • Major actions on Blood pressure • Other effects based on - role of receptors in different tissues - selectivity of the agent (2 vs1)
CVS Vasodilatation – arteriolar and venous BP PVR Magnitude dependent on symp. activity at that time More in erect that in supine position – postural hypotension More marked if hypovolaemia is present Baroreflex activation – reflex tachycardia – tends to oppose the fall by HR and CO
Reflex tachycardia more marked with non selective agents – WHY? • Compensatory salt and water retention with long term use • Prevent pressor response to usual doses of agonists • Convert pressor response of Adrenaline to depressor – Dale’s reversal • Vascular 2 receptors also vasoconstrictor but activated by circulating and not synaptic NA --no marked effects of 2 blockers • 2 blockers can NA release (presynaptic action) – CV effects
OTHER EFFECTS • ↓contraction of trigone and sphincter in bladder - urine flow • insulin secretion from islet cells (2 blockers) • Miosis • Nasal stuffiness • adrenergic sweating
α1 – blockers : Clinical uses Reduce blood pressure Hypertensive emergencies Long term treatment Phaeochromocytoma Vasodilatation Peripheral vascular insufficiency To reverse vasoconstrictor excess Improve urine flow Benign prostatic hyperplasia
α1 – blockers : Adverse effects • Postural hypotension • ( less with α1 selective - venodilatation is less) • Reflex tachycardia ( less with α1 selective) • Salt and water retention • Nasal stuffiness • Miosis • Failure of ejaculation
Specific Agents Ergot alkaloids (ergotamine): Partial agonist & blocking property Also affect other receptors (eg. 5-HT, ) Therapeutic effects (migraine, uterus) not related to blockade. Uses: Migraine (acute attack) Uterotonic – (methylergonovine) in PPH
Phenoxybenzamine: 1>2 ; Irreversible : Covalent binding with receptor Long duration of action (14 - 48 hrs) Also blocks 5-HT, ACh & H1 receptors -- ? significance Inhibits neuronal & extra-neuronal uptake of NA Absorbed from GIT, low bioavailability
Phenoxybenzamine Clinical use: Phaeochromocytoma Control of BP Prior to surgery Adverse effects: Postural hypotension, Tachycardia, Nasal stuffiness, ejaculation
Phentolamine : 1 = 2 PVR – blockade + direct (non adrenergic) HR – Reflex + 2 presynaptic on cardiac symp. terminals Poorly absorbed orally Clinical use: Phaeochromocytoma Local vasoconstrictor excess Adverse effects: Cardiac stimulation : - tachycardia, arrhythmia, angina GIT Stimulation : - diarrhoea; gastric acid secretion
Tolazoline: Similar to phentolamine Slightly less potent Better absorption from GIT Rapidly excreted in urine Limited clinical application: peripheral vasospastic disease
1 Selective Agents Prazosin & Terazosin: 1 >>>> 2 Effective in management of hypertension Low affinity for 2 Relative absence of tachycardia ↓ Triglycerides & LDL, ↑ HDL (favourable) Both are extensively metabolized by liver Prazosin shows high 1st Pass effect (50%) Oral absorption - good Terazosin :Bioavailability >90%; >18 h action Uses: Hypertension and BPH Adverse effects First dose effect Postural hypotension Salt & water retention ( long term use)
Doxazosin: Similar to Prazosin but longer t ½ (22 Hr) Alfuzosin : similar to prazosin Tamsulosin Selective α1 anatgonist Has greater selectivity for α1A subtype Has greater efficacy for BPH Relatively smaller effects on blood vessels USE: BPH
Indoramin & Urapidil : Newer 1-selective agents Have some utility in hypertension
2 selective Yohimbine Hardly used clinically Idazoxan Mianserin : Used as an antidepressant; 2 – blocking action within CNS contributes to its effect. Other receptor actions also (eg. 5-HT) Labetalol : 1 +
Clinical Uses Of Blockers • Pheochromocytoma • Hypertensive emergencies • Chronic hypertension – non selective blockers are not used • Peripheral vascular diaease • – spastic (Raynauds), not morphological • Local vasoconstrictor excess • – phentolamine useful- local infiltration • Urinary obstruction – BPH • – prazosin, terazosin, tamsulosin • CHF • α2- selective antagonists do not have any recognised clinical use
Some neuroleptic agents (eg. chlorpromazine, haloperidol) used in psychiatry possess α receptor blocking activity (in addition to Dopamine receptor antagonism) which may lead to cardiovascular adverse effects with these agents.
ADRENERGIC NEURON BLOCKERS Inhibit the function of peripheral, post-ganglionic adrenergic neurons Guanethidine - Antihypertensive Guanadrel - Antihypertensive Reserpine - Antihypertensive Bretylium - Anti-arrhythmic Not used now
Guanethidine : Sympathoplegic, Taken up and concentrated by neurons Blocks NE release (LA like action on terminal) Displaces NE from granules IV : initial release – initial mimetic actions Does not cross BBB Widespread sympatholytic effects Leads to several adverse effects Chronic use causes effector supersensitivity Guanadrel: Similar to Guanethidine
Bretylium : Inhibits release of NE from terminals Also has direct anti-arrhythmic activity Reserpine : Blocks vesicular uptake of NE – depletes vesicles Displaces NE from terminal – initial mimetic actions Crosses BBB – CNS effects: Depression ,suicidal tendency Adverse effects due to non specific sympatholysis These drugs rarely used now for Hypertension
Autonomic Drugs Used for Glaucoma: Cholinomimetics Muscarinic agonists Pilocarpine AChE inhibitors Physostigmine, Increased outflow Ecothiophate Alpha agonists Non – selective Epinephrine Increased outflow Dipevefrine Selective α2 Apraclonidine Decreased aqueous Brimonidine secretion Beta Blockers Timolol, betaxolol Decreased aqueous secretion Other drugs Carbonic anhydrase inhibitors – acetazolamide – ↓ formation Prostaglandins – lanatoprost – ↑ outflow
Targets for Pharmacological Interference Tyrosine hyhroxylase MPT NA DOPA decarboxylase Methyldopa Pseudotransmitter* Dopamine hydroxylaseDisulfiram Release of NATyramine Sympathomimetic Amphetamine Release of NA Guanethidine Sympatholytic Bretylium Reuptake Cocaine, effect of NT Imipramine indirect mimetics Reuptake into granules Reserpine Release Depletion
Targets for Pharmacological Interference Presynaptic 2 Catecholamines release Presynaptic 2 Catecholamines release Presynaptic M ACh release MAO Several metabolism Extrasynaptic uptake PBZ, Steroids Effect COMTPyrogallol --- Talcapone Entacapone
Dale’s Reversal Phenomenon Mean arterial blood pressure PBZ Adr Back