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ANTIADRENERGIC DRUGS (Sympatholytics, Adrenolytics) Assoc. Prof. Ivan Lambev E-mail: [email protected] Beta-blockers (antagonists) Selective Non selective (b1) (b1 & b2 ) (b & a ) Bopindolol Esmolol Oxprenolol Pindolol Propranolol Sotalol Timolol Carvedilol (antioxidant) Labetalol Acebutolol Atenolol Betaxalol Bisoprolol Celiprolol Metoprolol Nebivolol Mixed First pass effect (hepatic metabolism, p.o. bioavailability – 22%): Oxprenolol, Pindolol, Propranolol Lipophilic drugs: more of beta-blockers Hydrophilic drug: Atenolol β-blockers with ISA (intrinsic symathomimetic activity) or partial agonists: Acebutolol, Celiprolol, Oxprenolol, Pindolol β-blockers with membranostabilizing activity: Acebutolol, Carvedilol, Oxprenolol, Propranolol Lipophilic b-blockers (e.g. propranolol) are well absorbed from the gut, but undergo extensive first-pass metabolism in the liver, with considerable variability. Hydrophilic b-blockers (e.g. atenolol) are less completely absorbed from the gut and are eliminated unchanged by the kidney. The dose range to maintain effective plasma concentrations is narrower than for drugs which undergo metabolism and the clinical response is more predictable. Selective b1-Adrenoceptor Antagonists Metoprolol Acebutolol Atenolol Main effects of beta-blockers • Antihypertensive effect • Antitachyarrhythmic effect • Antianginal (antistenocardic) effect • “Anxiolytic” effect Antihypertensive effect •Blockade of b1-adrenoceptors in the heart and reduction of the heart rate and myocardial contractility. •Blockade of renal juxtaglomerular b1receptors which reduces renin secretion. •Blockade of presynaptic b2-adrenoceptors which inhibits exocytose of NA. •Carvedilol and labetalol also block a-receptors and produce vasodilation. Selectivity b-blockers Atenolol Bisoprolol Metoprolol b1/b2-blocking activity 15 50 Nebivolol 25 293 (55–65/min) Propranolol 1,9 Heart Arterioles 0.5 mg/kg i.v. propranolol 1 mg/kg i.v. epinephrine Heart contractions 200 Blood pressure 100 β1-effect α-effect 1 mg/kg i.v. epinephrine receptor Beta-blockers (–) AP Ca2+ Cell wall Calcium blockers (–) Receptor ROCC VDCC Ca2+ Sarcoplasmatic reticulum AP – action potential, NA – noradrenaline VDCC – voltage dependant calcium channels ROCC – receptor operating calcium channels 1 tabl. daily Nebivolol Selective b1-blocker Releases NO (causes vasodilation) 24 h effect (EE/PE >90%); t1/2: 11 h 1 tabl. daily F (p.o.): 90% t1/2: 11 h 24 h effect Antitachyarrhythmic effect of the beta-blockers Reduce the rate of spontaneous depolarization of sinus and AV nodal tissue Indiations: SV and ventricular tachyarrhythmias. ( cAMP) - atenolol, pindolol, propranolol - only antiarrhytmic action: esmolol and sotalol Esmolol Atrial flutter with a 4:1 conduction ratio. Antianginal (antistenocardic) effect Angina pectoris is a symptom of reversible myocardial ischaemia and is most frequently experienced as chest pain on exertion, which is relieved by rest. Pain is the consequence of an imbalance between oxygen supply and oxygen demand in the ischaemic area of myocardium. “Anxiolytic” effect of β-sympatholytics Adverse reactions of b-blockers •Blockade of b1-receptors may cause bradycardia, AV block, heart failure. •Blockade of b2-receptors may cause bronchospasm, cold extremities, intermittent claudication (reducing peripheral blood flow) and hypoglycemia. •CNS effects: sleep disturbance, dreams and hallucinations (more common with lipophilic drugs which cross the BBB). •Fatigue is probably a result of reducing of cardiac output and reduced muscle perfusion in exercise •Most beta-blockers raise the plasma concentration of triglycerides and lower the concentration of HDL. •Sudden withdrawal syndrome: b-blockers should be stopped gradually. Postsynaptic a1-blockers Blockade of postsynaptic a1-receptors lowers blood pressure by: •Lowering tone in arteriolar resistance vessels. •Dilating venous capacitance vessels, which reduces venous return and cardiac output. •Selective a1-adrenoceptor antagonists spare the presynaptic a2-adrenoceptors and do not produce reflex tachycardia. Postsynaptic a1-blockers Doxazosin Prazosin Prazosin – indications: - Arterial hypertension - Congestive chronic heart failure •Potentially beneficial effect: an increase in HDL and a reduction in triglycerides. •Adverse reactions (ARs) - Postural hypotension due to venous pooling (this can be troublesome after the first dose) - Lethargy Selective postsynaptic alpha-1А-blockers: block alpha-1А-receptors into the smooth muscles of the prostate gland, and the prostatic part of the urethra. Indication: hyperplasia of prostate gland •Alfuzosin (Xatral SR®), Doxazosin, Tamsulosin (Omnic®) Mixed beta- & alpha-antagonists Carvedilol (antioxidant) Labetalol •Arterial hypertension •Chronic heart failure •Contraindication: - cor pulmonale Centrally acting drugs (Antihypertensive action) a2-agonists I1-agonists a) a2-agonists (< t1/2: 2–3 times daily p.o.) The stimulation of presynaptic a2-receptors in CNS inhibits NA release, reduces sympathetic influence on the vasomotor centre; reduces peripheral arterial and venous tone. • Clonidine ( HCl) - xerostomia (dry mouth) - withdrawal phenomenon - sedation - postural hypotension The site of action of α-methyldopa appears to be in the brain rather than in the periphery. Systemically administered α-methyldopa rapidly enters the brain, where it accumulates in noradrenergic nerves and converts to α-methylnorepinephrine. Released α-methylnorepinephrine from the noradrenergic nerves activates CNS α2-adrenoceptors whose function is to decrease sympathetic outflow. Clonidine α-methyl-NE (+) b) I1(Inosin-1)-agonists (> t1/2: 1 time daily p.o.) The stimulation of I1-receptors: •in CNS reduces sympathetic tone and lowers blood pressure; •in kidney inreases secretion of ANP •Moxonidine •Rilmenidine Adrenergic neuron blockers •Guanethidine •Reserpine •Numerous ARS Adrenergic neuron blockers These drugs use the active transport mechanisms for monoamines to accumulate in the adrenergic nerve terminal. Inside the cell they prevent the release of NA from vesicles.