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ANTIADRENERGIC DRUGS

(Sympatholytics,
Adrenolytics)
Dr. dr. Mgs. Irsan Saleh, M.Biomed
Dept of Pharmacology
FK Unsri

Beta-blockers (antagonists)
Selective

Non selective

1)

1 & 2 )

& )

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
-blockers with ISA (intrinsic symathomimetic activity) or partial agonists:
Acebutolol, Celiprolol, Oxprenolol, Pindolol
-blockers with membranostabilizing
activity: Acebutolol, Carvedilol,
Oxprenolol, Propranolol

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 1receptors which reduces renin secretion.
Blockade of presynaptic 2-adrenoceptors
which inhibits exocytose of NA.
Carvedilol and labetalol also block
-receptors and produce vasodilation.

Selectivity
-blockers
Atenolol
Bisoprolol
Metoprolol

1/ 2-blocking
activity
15
50

Nebivolol

25
293

Propranolol

1,9

(5565/min)

Heart

Arterioles

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 -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.

Postsynaptic 1-blockers
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
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-1-blockers:


block alpha-1-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)

2-agonists
I1-agonists

a) 2-agonists (< t1/2: 23 times daily p.o.)


The stimulation of presynaptic 2-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 -methyldopa appears


to be in the brain rather than in the periphery.
Systemically administered -methyldopa rapidly
enters the brain, where it accumulates in
noradrenergic nerves and converts to
-methylnorepinephrine.
Released -methylnorepinephrine

from the noradrenergic nerves


activates CNS 2-adrenoceptors whose function
is to decrease sympathetic outow.

Clonidine
-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

Rauwolfia serpentina

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.