Alpha blockers
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Alpha blockers their classification, therapeutic uses and adverse effects
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Alpha blockers
- 1. Alpha Blockers Dr Naser Ashraf Tadvi Associate Professor Department of Pharmacology Ayaan Institute of Medical Sciences
- 2. Objectives • Classify alpha blockers according to the selectivity of receptor subtype • Describe the mechanism of action and pharmacological actions of alpha blockers • Discuss the clinical uses and important adverse effects • Briefly describe individual alpha blockers
- 3. Alpha receptors 2-receptor1-receptor Postsynaptic • Blood vessels, smooth muscles, • Bladder sphincter, radial muscle of iris. • Liver & skeletal muscle Presynaptic Post synaptic Inhibit release of NE in synapse Gi Gq Gq Blood vessels Contraction
- 4. Adrenoceptor Blockers (Antagonists) (peripheral) D-blockers-blockers -blockers 1 -blockers 2-blockers 1 -blockers 2 -blockers 3 -blockers Peripheral D- blockers are not clinically significant 1A 1D 1B
- 5. blockers Non-selective Selective Irreversible Reversible 1 selective 2 selective Ergot alkaloids Imidazolines Miscellaneous Classification of blockers
- 6. Irreversible (Non-equilibrium) type – -Haloalkylamines • Phenoxybenzamine. Ergot alkaloids – Ergotamine, ergotoxine – Dihydroergotamine (DHE), – Dihydroergotoxine • Imidazolines (1 = 2) – Tolazoline, – Phentolamine • Miscellaneous – Chlorpromazine, – Ketanserin Reversible (Equilibrium type) • Urapidil • Indoramine • Yohimbine • Idazoxan Selective (1-selective) • Prazosin, • Terazosin, • Doxazosin • Alfuzosin • Tamsulosin • Bunazosin Selective (2-selective) Non-selective
- 7. Blockers Pharmaclogical actions Nasal Stuffiness Miosis Relaxation of smooth muscles GFR Intestine motility Salt & Water Retention BP Vasodilatation
- 8. Reversible non selective α blockers • Similar affinities for α-1 and α-2 • Cardiovascular effects – Vasodilation & reflex tachycardia – Postural hypotension • Other effects – Nasal stuffiness – Miosis – Improved urinary flow rates – Failure of ejaculation & impotence – Nausea, vomiting and diarrhea Phentolamine and tolazoline
- 9. Usual increase in BP 2 effect Adrenaline 1 + 1 effect Adrenaline causes fall in BP !!! 2 effect (DHE) -blockers 2 effect Adrenaline Adrenaline Sir Henry Dale (1906) Dales Vasomotor reversal phenomenon
- 10. • Diagnosis & intraoperative management of phaeochromocytoma • Hypertensive crisis – Control hypertension in clonidine withdrawal – Cheese reaction • Peripheral vascular disease (Raynaud`s syndrome & frost bite) • Extravasation of Noradrenaline / dopamine • Erectile dysfunction Reversible non selective α blockers Therapeutic Uses of Phentolamine Tolazoline: less potent, better absorbed from GIT
- 11. Irreversible non selective α blockers • Slow onset & long duration of action 3-4 days • Inhibits NE reuptake & also blocks muscarinic, histamine and 5-HT receptors • CVS effects – Similar to phentolamine: ↓BP, tachycardia etc – Na+ & fluid retention – CVS effects are not reversed by Catecholamine • Other effects: – Similar to phentolamine – Sedation, Fatigue Phenoxybenzamine Pharmacological actions
- 12. Therapeutic Uses of Phenoxybenzamine • Phaeochromocytoma – Intraoperatively – Treatment of inoperable cases (with metyrosine) • To treat peripheral vascular disease like Raynaud`s syndrome and frost bite
- 13. Reversible, Selective 1 receptor blockers • Prazosin, • Terazosin, Doxazosin • Bunazosin, Alfuzosin • Tamsulosin, silodosin (1A-1D) • Indoramine, Urapidil
- 14. Prazosin • Cardiovascular effects – Vasodilatation Hypotension – Inhibits cyclic phosphodiestase enzyme ↑cAMP in vascular smooth muscle – Less tachycardia than non-selective blockers • Does not block pre-synaptic 2 autoreceptor • Decrease cardiac pre-load • Suppresses sympathetic outflow from CNS
- 15. Pharmacological Effects • Lipid Profile – Rise in HDL level – Lowers LDL and triglyceride level • Genito-urinary System – Relaxes smooth muscles in bladder neck, prostate capsule and prostatic urethra improve in urine flow in benign prostatic hypertrophy. Prazosin
- 16. Therapeutic Uses of prazosin 1.Hypertension Advantage: Favorable lipid profile Disadvantage: First dose effect (1 mg at bed time – titrated upwards) 2.Benign prostatic hyperplasia: symptomatic treatment Disadvantage – Twice daily dose – Postural hypotension 3.Raynaud’s Disease
- 17. Adverse Effects of prazosin • Postural hypotension at initial dose (First dose effect) – syncopal attack • Impotence • Nasal congestion • GI Tract upset • Sodium and Water retention
- 18. Terazosin and doxazosin • Selective alpha 1 blockers with longer duration of action • Terazosin t ½ = 12 hrs, doxazosin =18 hrs • Well absorbed orally • Use: – Benign prostatic hyperplasia • Preferred due to once daily dosing • Apoptosis promoting effect on prostrate • Faster action than finasteride
- 19. Alfuzosin • Similar to prazosin • Used for symptomatic treatment of Benign prostatic hyperplasia
- 20. Tamsulosin & sildosin • Relatively uroselective α1A / α1D blocker • lacks prostatic apoptosis promoting property • More efficacious in BPH treatment with little effect on Blood pressure • Adverse effects: – Intraoperative floppy iris during cataract surgery – Abnormal ejaculation – Selective α1A blocker – Weaker but longer acting analog of tamsulosin Tamsulosin Sildosin
- 21. Subdivision of 1 Blockers 1A 1B Location Bladder neck and urethra Blood vessels Block Relaxation of smooth muscles and opening of urethral urine flow Relaxation of smooth muscle of blood vessels vasodilatation
- 22. α2 Adrenergic receptor blocker • Natural alkaloid • Also blocks 5 HT receptors Therapeutic Use: (Off label) • Diabetic neuropathy • Treatment of postural hypertension • Male sexual dysfunction Yohimbine
- 23. Therapeutic uses of Alpha Blockers • Phaeochromocytoma • Hypertension • Benign prostatic hyperplasia • Peripheral vascular disease • Papaverine/ phentolamine induced penile erection therapy for impotence
- 24. Thank You
Notas del editor
- Sympatholytic drugs are the drugs which inhibit the action produced by stimulation of sympathetic nervous system
- Phentolamine is poorly absorbed from GIT & is administered intravenously. It has an immediate onset but shorter duration of action, venodilation predominates arteriolar dilation To prevent dermal necrosis Inj regitine 10mg/ml
- It is a hslogenated alkylamine that cyclizes rapidly in body to form highly reactive ethyleneium intermediate which reacts with alpha receptors forming strong covalent bond The alpha blockade is of non equilibrium type develops gradually even after iv inj and lasts 3 to 4 days till fresh receptors are synthesized Partial Blocks muscarinic, histamine and 5-HT receptor also but not beta 2 receptors Drug crosess the BBB and can cause CNS stimulation, nausea and vomiting on injection. But oral doses produce depression, tiredness and lethargy Same as phentolamine ↓BP, Reflex tachycardia and palpitation Postural hypotension Vasomotor reversal of Dale.. Iv – cns stimulation Oral cns depression Pharmacokinetics: oral absorption of phenoxybenzamine is erratic and incomplete, im and sc injections are very painful should not be given. Chronic administration leads rto accumulation in the tissues Trade name fenoxene 10 mg cap , biophenox 50 mg / ml inj
- Treatment of pheocromocytoma : 1mg/ kg slow iv infusion controls episodes of severe hypertension during surgical manipulation of phaechromocytoma. In cases of malignant phaechromocytoma it can be given along with metyrosine a competitive inhibitor of tyrosine hydroxylase – rate limiting enzyme in synthesis of NE and E Occasionally used in peripheral vascular disease
- It causes peripheralvasodilation and fall in arterial bp with less tachycardia because it lacks alpha 2 action so doesn’t promote NE RELEASE from sympathetic nerve terminals It decreases cardiac preload Supresses sympathetic outflow from CNS It is a potent inhibitor of Cyclic phosphodiesterase enzyme hence consequential rise in cAMP in vascular smooth muscle could possibly contribute to its vasodilating effect
- One more favourable effect is observed rise of HDL and lowered LDL
- Drug is well absorbed after oral administration and the plasma half life is 2-4 hours and effect of single dose lasts 6-8 hours , effective orally, highly bound to plasma proteins mainly alpha-1 acid glycoprotein , metabolized in liver and excreted primarily in bile Prazopress 0.5, 1 , 2 mg tabs dose 1-4 mg bd –tds
- Dilates arterioles more than the veins postural hypotension is less marked but may occur in beginning causing a dizziness and fainting epidose. This can be minimized by starting a low dose and taking it at bed time . Subsequently tolerance develops to this side effect due to hemodymanic adjustments. Other alpha blocking side effects like miosis, nasal stuffiness, inhibition of ejaculation are also milder for these reasons prazosin has replaced phenoxybenzamine and phentolamine
- Oral BA = 80-90% Dose 1-8 mg od Hytrin Doxacard However the combination works better
- Alfuzosin is short acting half life = 3-5 hours , a congener of prazosin developed specifically for symptomatic trearment of BHP Non selective for apha 1A,b, d subtypes Bunazosin has longer half life but no favourable profile than prazosin
- Alpha 1 a receptors primarily located on bladder neck and 1b on blood vessels Tamsulosin better bioavailability and less cardiac side effects
- Lipid soluble crosses BBB Actions : heart rate and BP are elevated due to increased central sympathetic outflow as well as enhanced peripheral NE release It may cause congestion in genitals and is considered as an aphrodisiac. The effect is only psychological and overcome psychological impotence in some patients