Alpha Adrenergic receptor blockers 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 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

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

 PVR –  blockade + direct (non adrenergic) 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 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  hydroxylase Disulfiram Release of NA Tyramine 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  COMT Pyrogallol --- Talcapone Entacapone

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