Assoc. Prof. Ivan Lambev ANTIADRENERGIC DRUGS (Sympatholytics, Adrenolytics)

 1 )  1 &  2 ) Bopindolol Esmolol Oxprenolol Pindolol Propranolol Sotalol Timolol Carvedilol (antioxidant) Labetalol  &  )  Beta-blockers (antagonists) Acebutolol Atenolol Betaxalol Bisoprolol Celiprolol Metoprolol Nebivolol Selective Non selective Mixed

β-blockers with ISA (intrinsic symatho- mimetic activity) or partial agonists: Acebutolol, Celiprolol, Oxprenolol, Pindolol β-blockers with membranostabilizing activity : Acebutolol, Carvedilol, Oxprenolol, Propranolol First pass effect (hepatic metabolism, p.o. bioavailability – 22%): Oxprenolol, Pindolol, Propranolol Lipophilic drugs : more of beta-blockers Hydrophilic drug : Atenolol

Lipophilic  -blockers (e.g. propranolol) are well absorbed from the gut, but undergo extensive first-pass metabolism in the liver, with considerable variability. Hydrophilic  -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  1 -Adrenoceptor Antagonists Metoprolol Acebutolol Atenolol

Main effects of beta-blockers Antihypertensive effect Antitachyarrhythmic effect Antianginal (antistenocardic) effect “Anxiolytic” effect

Antihypertensive effect Blockade of  1 -adrenoceptors in the heart and reduction of the heart rate and myocardial contractility. Blockade of renal juxtaglomerular  1 - receptors which reduces renin secretion. Blockade of presynaptic  2 -adrenoceptors which inhibits exocytose of NA. Carvedilol and labetalol also block  -receptors and produce vasodilation.

Atenolol Bisoprolol Metoprolol Nebivolol Propranolol  1 /  2 -blocking activity  -blockers ,9 S e l e c t i v i t y (55–65/min)

HeartArterioles

β 1 -effect α-effect

VDCC ROCC Receptor AP Ca 2+ Sarcoplasmatic reticulum Cell wall (–) Beta-blockers AP – action potential, NA – noradrenaline VDCC – voltage dependant calcium channels ROCC – receptor operating calcium channels (–) Calcium blockers receptor

1 tabl. daily Nebivolol Selective  1 -blocker Releases NO (causes vasodilation) 24 h effect (EE/PE >90%); t 1/2 : 11 h

1 tabl. daily F (p.o.): 90% t 1/2 : 11 h 24 h effect

Antitachyarrhythmic effect of the beta-blockers  Reduce the rate of spontaneous depo- larization of sinus and AV nodal tissue  Indiations: SV and ventri- cular tachyarrhythmias. ( cAMP) - atenolol, pindolol, propranolol - only antiarrhytmic action: esmolol and sotalol

Atrial flutter with a 4:1 conduction ratio. Esmolol

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. Antianginal (antistenocardic) effect

“Anxiolytic” effect of β-sympatholytics

Adverse reactions of  -blockers Blockade of  1 -receptors may cause bradycardia, AV block, heart failure. Blockade of  2 -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:  -blockers should be stopped gradually.

Blockade of postsynaptic  1 -receptors lowers blood pressure by: Lowering tone in arteriolar resistance vessels. Dilating venous capacitance vessels, which reduces venous return and cardiac output. Selective  1 -adrenoceptor antagonists spare the presynaptic  2 -adrenoceptors and do not produce reflex tachycardia.  Postsynaptic  1 -blockers

Postsynaptic  1 -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

Alfuzosin (Xatral SR ® ), Doxazosin, Tamsulosin (Omnic ® ) 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

Carvedilol (antioxidant) Labetalol Arterial hypertension Chronic heart failure Contraindication: - cor pulmonale  Mixed beta- & alpha-antagonists

 Centrally acting drugs (Antihypertensive action)  2 -agonists I 1 -agonists

Clonidine ( HCl)  xerostomia (dry mouth)  withdrawal phenomenon  sedation  postural hypotension The stimulation of presynaptic  2 -receptors in CNS inhibits NA release, reduces sym- pathetic influence on the vasomotor centre; reduces peripheral arterial and venous tone. a)  2 -agonists (< t 1/2 : 2–3 times daily p.o.)

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 α 2 -adrenoceptors whose function is to decrease sympathetic outflow.

Clonidine α -methyl-NE (+)

The stimulation of I 1 -receptors: in CNS reduces sympathetic tone and lowers blood pressure; in kidney inreases secretion of ANP Moxonidine Rilmenidine b) I 1 (Inosin-1)-agonists (> t 1/2 : 1 time daily p.o.)

 Adrenergic neuron blockers Guanethidine Reserpine Numerous ARS R a u w o l f i a s e r p e n t i n a

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.