SYMPATHOLYTIC AGENTS 2 Alpha Adrenergic receptor blockers ALPHA

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 Prazosin Terazosin Doxazosin Tamsulosin 2 - SELECTIVE competetive 2 > 1 Yohimbine Idazoxan Mianserin NON-SELECTIVE Competetive 1 = 2 Phentolamine Tolazoline NONSELECTIVE Irreversible 1 = 2 Phenoxybenzamine Dibenamine

Pharmacological actions Major actions on Blood pressure Other effects based on - role of receptors in different tissues - selectivity of the agent ( 2 vs 1)

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

α 1 – 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

α 1 – blockers : Adverse effects • Postural hypotension ( less with α 1 selective - venodilatation is less) • Reflex tachycardia ( less with α 1 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 & H 1 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 1 st 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 α 1 anatgonist Has greater selectivity for α 1 A 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 α 2 - 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 Guanadrel Reserpine Bretylium - Antihypertensive 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 ACh. E inhibitors Alpha agonists Non – selective Selective α 2 Beta Blockers Pilocarpine Physostigmine, Ecothiophate Increased outflow Epinephrine Dipevefrine Increased outflow Apraclonidine Brimonidine Decreased aqueous secretion 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 Dopamine hydroxylase Disulfiram Pseudotransmitter* Release of NA Tyramine Sympathomimetic Amphetamine Release of NA Guanethidine Bretylium Sympatholytic Reuptake Cocaine, Imipramine effect of NT indirect mimetics Reuptake into granules Depletion Reserpine Release

Targets for Pharmacological Interference Presynaptic 2 Catecholamines release Presynaptic M ACh release MAO Several metabolism Extrasynaptic uptake PBZ, Steroids Effect COMT Talcapone Entacapone Pyrogallol ---

Mean arterial blood pressure Dale’s Reversal Phenomenon PBZ Adr Back