Assoc. Prof. Ivan LambevE-mail: itlambev@mail.bg

ANTIADRENERGIC DRUGS(Sympatholytics,

Adrenolytics)

1) 1 & 2 )

BopindololEsmololOxprenololPindololPropranololSotalolTimolol

Carvedilol(antioxidant)Labetalol

& )

Beta-blockers (antagonists)

AcebutololAtenololBetaxalol BisoprololCeliprololMetoprololNebivolol

Selective Non selective Mixed

β-blockers with ISA (intrinsic symatho- mimetic activity) or partial agonists: Acebutolol, Celiprolol, Oxprenolol, Pindololβ-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-blockersHydrophilic drug: Atenolol

Lipophilic -blockers (e.g. propranolol) arewell absorbed from the gut, but undergoextensive first-pass metabolism in the liver,with considerable variability.

Hydrophilic -blockers (e.g. atenolol) areless completely absorbed from the gut andare eliminated unchanged by the kidney.The dose range to maintain effective plasmaconcentrations is narrower than for drugswhich undergo metabolism and the clinicalresponse 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-blockingactivity

-blockers

15 50

25

293

1,9

S e l e c t i v i t y

(55–65/min)

Heart Arterioles

200

100Bloodpressure

Heartcontractions

1 mg/kg i.v.epinephrine

0.5 mg/kg i.v.propranolol

1 mg/kg i.v.epinephrine

β1-effect

α-effect

VDCC ROCC

Receptor

AP

Ca2+

Ca2+

Sarcoplasmaticreticulum

Cellwall

(–)

Beta-blockers

AP – action potential, NA – noradrenalineVDCC – voltage dependant calcium channelsROCC – receptor operating calcium channels

(–)

Calciumblockers

receptor

1 tabl. daily

NebivololSelective 1-blockerReleases NO (causes vasodilation)24 h effect (EE/PE >90%); t1/2: 11 h

1 tabl. daily

F (p.o.): 90%t1/2: 11 h24 h effect

Antitachyarrhythmic effectof the beta-blockers

Reduce the rate of spontaneous depo- larization of sinus and AV nodal tissueIndiations: 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 ofreversible 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” effectof β-sympatholytics

Adverse reactions of -blockers•Blockade of1-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-receptorslowers 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-blockersDoxazosin 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 smoothmuscles of the prostate gland, and the prostatic part of the urethra.Indication: hyperplasiaof prostategland

Carvedilol (antioxidant)

Labetalol•Arterial hypertension•Chronic heart failure•Contraindication: - cor pulmonale

Mixed beta- & alpha-antagonists

Centrally acting drugs (Antihypertensive action)

2-agonistsI1-agonists

• Clonidine ( HCl) xerostomia (dry mouth) withdrawal phenomenon sedation postural hypotension

The stimulation of presynaptic 2-receptorsin CNS inhibits NA release, reduces sym-pathetic influence on the vasomotor centre; reduces peripheral arterial and venous tone.

a) 2-agonists (< t1/2: 2–3 times daily p.o.)

The site of action of α-methyldopa appearsto 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-methylnorepinephrinefrom the noradrenergic nervesactivates CNS α2-adrenoceptors whose function is to decrease sympathetic outflow.

Clonidineα-methyl-NE

(+)

The stimulation of I1-receptors:•in CNS reduces sympathetic tone and lowers blood pressure;•in kidney inreases secretion of ANP

•Moxonidine •Rilmenidine

b) I1(Inosin-1)-agonists(> t1/2: 1 time daily p.o.)

Adrenergicneuronblockers•Guanethidine•Reserpine•Numerous ARS R

auw

olfi

a se

rpen

tin

a

Adrenergic neuron blockers

These drugs use the active transportmechanisms for monoamines toaccumulate in the adrenergic nerveterminal. Inside the cell they prevent the release of NA from vesicles.