Sympatholytics1 - Dr. Monira Selim - PDF

By Dr: Monira Selim  ILOS/ OBJECTIVES: By the end of this lecture the student will be able to: ▪ List sympathetic depressents &Classify alpha adrenoreceptor blockers. ▪ Recognize pharmacokinetics, dynamics, uses and adverse effects of alpha adrenoreceptor blockers. ...

By Dr: Monira Selim  ILOS/ OBJECTIVES: By the end of this lecture the student will be able to: ▪ List sympathetic depressents &Classify alpha adrenoreceptor blockers. ▪ Recognize pharmacokinetics, dynamics, uses and adverse effects of alpha adrenoreceptor blockers.  SYMPATHETIC DEPRESSANTS These are drugs, which depress adrenergic nerve function 1-Adrenergic Receptor Blockers: α- blockers , B- blockers 2- Adrenergic Neurone Depressants: 1.Drugs interfere with the synthesis of noradrenaline: e.g. α-methyl dopa. 2.Drugs deplete noradrenaline stores e.g. Reserpine 3. Drugs inhibit release of NA : (Adrenergic neurone blockers) e.g. Guanethidine. 3- Ganglion Blockers: Trimethaphan 4- central sympathetic depressants: Centrally Acting Alpha-2 Agonists: e.g. Clonidine. V.M.C. Depressants: reserpine  Alpha adrenoceptor blockers These drugs inhibit adrenergic responses mediated through the alpha adrenergic receptors without affecting those mediated through beta receptors.  Non selective α blockers Phenoxybenzamine Phentolamine & Tolazoline Dynamics block both post-synaptic α1→VD - Alpha blocker (very powerful): & pre-synaptic α2-receptors →↑release of 1- binds covalently with α-receptors → Irreversible non noradrenaline with discomfortable competitive block. tachycardia. 2-Delayed onset as it is prodrug. 3-Long duration, till resynthesis of new receptors. 4- inhibits neuronal uptake I and tissue uptake II of NA. Uses: - Anticholinergic , antihihistaminic, antiserotonine 1-Pre-operative control of Uses: pheochromocytoma as it is rapid and short Pheochromocytoma: to control hypertension and as pre- acting α blocker. operative. 2-Diagnosis of sustained Peripheral vascular diseases. Benign hypertrophy of prostate (BPH) pheochromocytoma → severe hypotension Adverse effects: more than average in pheochromocytoma 1-Nasal congestion, postural hypotension, and this test known as Regitine test. tachycardia, failure of ejaculation (α1 block) 3-peripheral vascular disease (tolazoline) 2-Dry mouth, retention of urine (Anticholinergic)  Prazosin Kinetics Absorption: absorbed orally. Metabolism: Extensively metabolized in the liver. Excretion: in urine. Dynamics Selective α1 blocker → vasodilatation…(block all α1subtypes (A,B,D) Inhibition of phosphodiesterase enzyme →↑both cA.M.P. & cG.M.P. It produces vasodilatation of both Artery & vein (mixed dilator). Arteriodilatation →↓peripheral resistance and after load. Veinodilatation →↓venous return and preload. ↓ Both systolic & diastolic blood pressure. No discomfortable tachycardia due to:  Selective α1- block with no block of presynaptic α2 → no release of endogenous NA.  Tachycardia of cAMP is antagonized by bradycardia of cGMP.  Prazosin uses ❖Hypertension. ❖Heart failure ❖Peripheral vascular diseases. ❖Benign hypertrophy of prostate (BHP). Adverse effects: 1. Dizziness, headache, and drowsiness. 2. Syncope and first dose hypotension occurs within 2 hours of the initial dose and more in salt depleted patients (avoided by starting treatment by small dose and at bed time) 3. Salt and water retention (any dr. produce hypotension→reflex sympathetic st+ → ↑Renin in kidney → ↑Aldosterone → salt & water retension) N.B. Benign hypertrophy of prostate (BHP): The urinary obstruction caused by BHP has a static component due to increased size of prostate and a dynamic component due to increased tone of bladder neck muscle. Two classes of drugs are available: α1 Adrenergic blockers (prazosin like): ↓tone of bladder neck 5-α Reductase inhibitor (finasteride): ↓size of prostate other selective α1 blocker used in treatment of BHP: Eg. Terazocin (no 1st dose syncope + Apoptosis in prostate) Alfuzosin & Tamsulosin (uroselective α blocher…not antihypertensive) NB: α1-A Dominant role urethral contraction & contraction of small arteries.  Selective alpha-2 blockers Yohimbine Selective 2 blocker Increase release of antidiuretic hormone. May be used in impotence as it improve erection in males (aphrodisiac) What are other drugs used in erectile dysfunction? Sildenafil orally: inhibit 5-phosphodiestrase enzyme →↑ cGMP which produces VD and erection. Tadalafil similar to sildenafil but longer in duration. Intracavernous phentolamine with papaverine. Yohimbine. Intracavernous PGE-1 (Aloprastadil). Apomorphine orally.  Ergot alkaloids Semi-synthetic natural Methyl ergometrine Ergotamine, Dihydroergotamine Ergometrine Methysergide Ergotoxin Bromocryptine. Claviceps purpurea  Antagonist Partial Agonist Agonist Direct action ## receptor action  Dynamics Ergot Direct 5 HT2 α1- D2 Uterus C.N.S Uses V.C. Receptor blocker agonist (Oxytocic Alkaloids (V.D.) effect) Acute migraine ++ _ (+) _ (+) _ + + headache during Ergotamine Power Partial Partial aura phase Ergotamine+ Ful agonist agonist Caffeine(Caffergot tablets?? Prevent post + _ _ _ +++ _ partum Ergometrine Weak (More hemorrhage. Help involution of powerful uterus Senile cerebral _ _ +++ _ _ + insufficiency. Ergotoxine Peripheral vascular diseases  Suppress lactation (↓prolactin) _ _ _ +++ _ _ Bromocryptine Prolactin secretory adenomas and acromegaly. Infertility due to hyperprolactinemia Treatment of Parkinsonism. _ +++ _ _ _ _ Prophylaxis of migraine. Power Treatment of carcinoid syndrome. Methysergide ful anta- gonism N.B.: Dihydroergotamine: Similar to ergotamine but less toxic, more potent as α blocker and no partial agonist on α receptors and used in treatment of acute migraine attack. Methyl ergometrine (methergine): Semi synthetic derivative of ergometrine. More powerful oxytocic with no α blocking effect. Ergot toxicity or ergotism → ▪ Cold extremities ,Tingling, numbness gangrene, ▪ Hypertension, angina ▪ Nausea & vomiting ▪ Uterine stimulation and Abortion. MCQ QUESTIONS : 1- Which one of the following is a selective α1 blocker? a. Prazocin b. Yohimbine c. Tolazoline d. Phentolamine 2- WHICH ONE OF THE FOLLOWING IS A NON-SELECTIVE Α- BLOCKER? a. Prazocin b. Yohimbine c. Phenoxybenzamine d. Terazosin 3- WHICH ONE OF THE FOLLOWING IS TRUE REGARDING PHENOXYBENZAMINE? a. Rapid onset b. Selective α1 blocker c. Long duration d. Selective α2 blocker RESOURCES & REFERENCES 1- USMLE step-1 lecture notes pharmacology(Kaplan) 2- Lippincott illustrated review 6th edition