Transcript Adrenolytics

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.