Sympatholytic drugs

Pharmacology of Sympatholytic drugs

1. Sympatholytic Drugs Prepared by: Sangeeta Dwivedi Asst. Professor

2. These are drugs which antagonize the receptor action of adrenaline and related drugs. They are competitive antagonists at α or β or both α and β adrenergic receptors. They differ in important ways from the “adrenergic neurone blocking agents”, which act by interfering with the release of adrenergic transmitter on nerve stimulation. α - ADRENERGIC BLOCKING DRUGS These drugs inhibit adrenergic responses mediated through the α adrenergic receptors without affecting those mediated through β receptors .

3. Sympatholytic drugs can block the sympathetic adrenergic system at three different levels. 1. Peripheral sympatholytic drugs such as alpha-adrenoceptor and beta-adrenoceptor antagonists block the influence of NA at the effector organ (heart or blood vessel) 2. Ganglionic blockers block impulse transmission at the sympathetic ganglia. 3. Centrally acting sympatholytic drugs drugs that block sympathetic activity within the brain are called centrally acting sympatholytic drugs.

4. General effects of α- receptor blockers : 1. Vasodilator: Blockade of vasoconstrictor α1 (also α2) receptors reduces peripheral resistance and causes pooling of blood in capacitance vessels → venous return and cardiac output are reduced → fall in BP. 2. Reflex tachycardia: Due to fall in arterial mean pressure 3 . Nasal stuffiness and miosis: result from blockade of α receptors in nasal blood vessels and in radial muscles of iris respectively. 4. Intestinal motility: Increased— diarrhoea may occur. 5. Renal blood flow: Decreased renal blood flow GFR Na+/H20 Reabsorption sodium retention blood volume increases. 6. Tone of smooth muscle in bladder trigone, sphincter and prostate is reduced= urine flow is improved α- receptor blockers have no effect on Adrenergic Cardiac stimulation Vasodilation Metabolic changes and Bronchodilation

5. Phenoxybenzamine It cyclizes spontaneously in the body giving rise to a highly reactive ethyleniminium intermediate which reacts with α adrenoceptors and other biomolecules by forming strong covalent bonds. The α blockade develops gradually and lasts for 3–4 days. Prazosin: It is first of the highly selective α1 blockers. It is tend to decrease LDL level and increase HDL level. It blocks sympathetically mediated vasoconstriction and produces fall in BP which is attended by only mild tachycardia; NA release is not increased due to absence of α2 blockade. Terazosin: It is chemically and pharmacologically similar to prazosin, Terazosin is more popular for use in BHP. Doxazosin: Another long acting (t½ 18 hr ) congener of prazosin with similar pharmacological profile. Yohimbine: An alkaloid from West African plant Yohimbehe . It is a relatively selective α2 blocker with short duration of action. Chlorpromazine: and some other neuroleptics have additional α adrenergic blocking activity

6. PHARMACOKINETICS PRAZOSIN: short half-life (2-3 hours); liver metabolism; excreted from bile, orally effective, higly bound to plasma proteins TERAZOSIN: 12 hours half-life; duration 18 hours; liver metabolism; kidney excretion DOXAZOSIN: 20 hours half-life; duration 36 hours; liver metabolism; kidney excretion THERAPEUTIC USE: Pheochromocytoma 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/prostate smooth muscle. Α1 adrenergic blockers (prazosin like): decrease tone of prostatic/bladder neck muscles. 3. Secondary shock: Shock due to blood or fluid loss is accompanied by reflex vasoconstriction. If volume replacement fails to reverse this, therapy with an α blocker (phenoxybenzamine i.v. ) can help by: ( i ) Counteracting vasoconstriction. (ii) Shifting blood from pulmonary to systemic circuit. (iii) Returning fluid from extravascular to the vascular compartment so that cardiac output improves. 4. Congestive heart failure (CHF): The vasodilator action of prazosin can afford symptomatic relief in CHF in the short-term, Selective alpha-1 receptor blockers:

7. β ADRENERGIC BLOCKING DRUGS These drugs inhibit adrenergic responses mediated through the β receptors. Classification of β - Blockers β - Blockers Non- selective ( β 1, β 2 ) Selective ( β 1) With alpha blocking activity Without ISA With ISA Propranolol, Sotalol, Timolol. Pindolol Labetalol, Carvedilol Metoprolol, Atenolol, Acebutolol, Bisoprolol, Esmolol, Betaxolol , Celiprolol , Nebivolol

8. Another system of classifying β blockers into 3 generations has been proposed

9. Pharmacological actions 1 . Heart: Propranolol decreases heart rate, force of contraction and cardiac output (c.o.). ( mild at resting condition). Cardiac work and oxygen consumption (Angina=ok). 2 . Blood vessels: blocks vasodilatation fall in BP (Prolonged effect) in hypotensive patient. 3. Respiratory tract: increases bronchial resistance by blocking β2 receptors (vasodilation). 4. CNS: forgetfulness, increased dreaming and nightmares have been reported with long- term use of relatively high doses. 5. Local anaesthetic : Propranolol is as potent a local anaesthetic as lidocaine, but is not clinically used for this purpose because of its irritant property. 6. Metabolism: Plasma triglyceride level and LDL/HDL ratio is increased. It also inhibits glycogenolysis in heart, skeletal muscles and in liver, due to blocking of sympathetic activity. Prolonged therapy may reduce carbohydrate tolerance by decreasing insulin release.

10. 7. Skeleton muscle: inhibits adrenergically provoked tremor. It tends to reduce exercise capacity by attenuating β2 mediated increase in blood flow to the exercising muscles, as well as by limiting glycogenolysis and lipolysis which provide fuel to working muscles. 8. Eye: i.o.t. is lowered. There is no consistent effect on pupil size or accommodation. 9. Uterus: Relaxation of uterus in response to β2 agonists is blocked. However, normal uterine activity is not significantly affected. PHARMACOKINETICS Well absorbed after oral administration, but has low bioavailability due to high first pass metabolism in liver. Bioavailability is more when taken with meals because food decreases its first pass metabolism. The metabolites are excreted in urine, mostly as glucuronides.

11. INTERACTIONS Digitalis and Verapamil: Additive depression of sinus node and A-V Conduction cardiac arrest can occur. Insulin: delays recovery from hypoglycaemia Cimetidine: inhibits propranolol metabolism. Lidocaine: retards lidocaine metabolism by reducing hepatic blood flow. Chlorpromazine: increases bioavailability of chlorpromazine by decreasing its first pass metabolism.

12. ADVERSE EFFECTS Propranolol can accentuate myocardial insufficiency and can precipitate CHF/edema by blocking sympathetic support to the heart. Bradycardia: resting HR may be reduced to 60/min or less. Worsens chronic obstructive lung disease, can precipitate life threatening attack of bronchial asthma: contraindicated in asthmatics. Carbohydrate tolerance may be impaired in prediabetics. Plasma lipid profile is altered on long term use: total triglycerides and LDL-cholesterol tend to increase while HDL-cholesterol falls. This may enhance risk of coronary artery disease. Tiredness and reduced exercise capacity: due to blunting of β2 mediated increase in blood flow to the exercising muscles as well as attenuation of glycogenolysis and lipolysis .

13. Uses 1.Hypertension: β blockers are relatively mild antihypertensives. 2. Angina pectoris: All β blockers benefit angina of effort. Taken on a regular schedule they decrease frequency of attacks and increase exercise tolerance. 3. Cardiac arrhythmias: β blockers suppress extrasystoles and tachycardias, especially those mediated adrenergically . 4. Dissecting aortic aneurysm: β blockers help by reducing cardiac contractile force and aortic pulsation. 5. Pheochromocytoma: β blockers may be used to control tachycardia and arrhythmia. (Pheochromocytoma: A hormone-secreting tumor that can occur in the adrenal glands. Pheochromocytomas usually develop in the small glands on top of the kidneys (adrenal glands).  Because of hormones secreted, symptoms include high blood pressure, sweating, rapid heartbeat and headache. 6. Glaucoma: Ocular β blockers are widely used for chronic simple glaucoma.

14. References: K. D. Tripathi 2. Goodman and Gilman 3. Katjung