Download Basic Pharmacology of the Alpha

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Cardiovascular Effects
 α -receptor antagonist drugs lower peripheral vascular
resistance and blood pressure.
 These drugs can prevent the pressor effects of usual doses
of α agonists.
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α -receptor antagonism converts the pressor
response of epinephrine to a depressor response.
Epinephrine reversal is
demonstrated by tracings
showing the response to
epinephrine before
(middle) and after
(bottom) phentolamine
Top tracing is Phentolamine
.
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Alpha-receptor antagonists cause orthostatic
hypotension and reflex tachycardia.
Blockade of α 2-presynaptic receptors in the heart
leads to augmented release of NE from peripheral
sympathetic nerves, which will stimulate β1
receptors in the heart leading to tachycardia and
increased contractility of the heart.
Nonselective (α 1 = α 2,) blockers usually cause
significant tachycardia if blood pressure is lowered
below normal.
Contraction of veins is an important component of
the normal capacity to maintain blood pressure in
the upright position since it decreases venous
pooling in the periphery.
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Other Effects
 Miosis.
 Nasal congestion.
 Decreased resistance to the flow of urine. Alpha
blockers, therefore, are used therapeutically for the
treatment of urinary retention due to prostatic
hyperplasia .
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Phenoxybenzamine
Binds covalently(irreversibly) to α receptors,
causing irreversible blockade of long duration (14–
48 hours or longer). It is somewhat selective for α 1
receptors but also blocks α 2 receptors.
The drug also inhibits reuptake of released NE and
blocks histamine (H1),ACh, and serotonin
receptors.
Causes relatively little fall in blood pressure in the
supine position, it reduces blood pressure when
sympathetic tone is high, e.g. in the upright
posture.
Cardiac output may be increased because of reflex
effects and because of some blockade of
presynaptic α 2 receptors in cardiac sympathetic
nerves.
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Phenoxybenzamine is poorly absorbed after oral
administration.
The major use of phenoxybenzamine is in the
treatment of pheochromocytoma .
Adverse effects
 Orthostatic hypotension and tachycardia. Nasal
stuffiness and inhibition of ejaculation also occur.
Phentolamine
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Potent competitive antagonist at α 1 and α 2
receptors
Like phenoxybenzamine can cause orthostatic
hypotension, tachycardia, increased heart
contractility, and consequently increased cardiac
output.
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Phentolamine
Phentolamine also has minor inhibitory effects at
serotonin receptors and agonist effects at
muscarinic and H1 and H2 histamine receptors.
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Phentolamine's principal adverse effects are
related to cardiac stimulation, which may cause
severe tachycardia, arrhythmias, and myocardial
ischemia.
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Phentolamine has been used in the treatment of
pheochromocytoma.
Prazosin
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Highly selective for α 1 receptors and typically
1000-fold less potent at α 2 receptors.
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This may partially explain the relative absence of
tachycardia seen with prazosin compared with
phentolamine & phenoxybenzamine.
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Relaxes both arterial and venous vascular smooth
muscle, as well as smooth muscle in the prostate.
Terazosin
Reversible α 1-selective antagonist that is effective in
hypertension.Also approved for use in men with urinary
symptoms due to benign prostatic hyperplasia (BPH).
 Terazosin has high bioavailability but is extensively
metabolized in the liver, The half-life of terazosin is 9–12
hours.
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Doxazosin
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Efficacious in the treatment of hypertension and BPH.
Differs from prazosin and terazosin in having a longer
half-life of about 22 hours.
Tamsulosin
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Competitive α 1 antagonist with a structure quite different from that
of most other α 1-receptor blockers.
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High bioavailability and a half-life of 9–15 hours.
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Higher affinity for α 1A and α 1D receptors than for the α 1B
subtype.
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Has relatively greater potency in inhibiting contraction in prostate
smooth muscle versus vascular smooth muscle compared with other
α 1-selective antagonists. α 1A subtype may be the most important
α subtype mediating prostate smooth muscle contraction.
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It is used to treat BPH.
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Compared with other antagonists, tamsulosin has less effect on
standing blood pressure in patients.
Drugs with Alpha- Adrenoceptor Antagonistic Activity
Labetalol
 Has both α 1-selective and β-antagonistic effects
Chlorpromazine and Haloperidol
 Are potent dopamine receptor antagonists but are also
antagonists at α receptors.
 Useful antipsychotic drugs.
 Their antagonism of α receptors probably contributes to
some of their adverse effects, particularly hypotension.
Ergot derivatives
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Ergotamine
Dihydroergotamine
 Cause reversible α -receptor blockade,
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Yohimbine
An indole alkaloid, α 2-selective antagonist.
Sometimes used in the treatment of orthostatic
hypotension because it promotes norepinephrine
release through blockade of presynaptic α 2
receptors.
It was once widely used to improve male erectile
dysfunction but has been superseded by
phosphodiesterase-5 inhibitors like sildenafil
Yohimbine can reverse the antihypertensive effects
of an α 2-adrenoceptor agonist such as clonidine.
Clinical Pharmacology of the Alpha-Receptor–
Blocking Drugs
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Pheochromocytoma is a tumor of the adrenal medulla or
sympathetic ganglion cells. Patients have many
symptoms and signs of catecholamine excess, including
intermittent or sustained hypertension, headaches,
palpitations, and increased sweating.
 Phenoxybenzamine is given orally in the preoperative period to
control hypertension.
 It is also very useful in the chronic treatment of inoperable or
metastatic pheochromocytoma.
Beta-receptor antagonists are required after α -receptor
blockade to reverse the cardiac effects of excessive
catecholamines.
Beta antagonists should not be used prior to establishing
effective α -receptor blockade, since unopposed β receptor blockade could theoretically cause blood
pressure elevation from increased vasoconstriction.
Metyrosine (α -methyltyrosine), a competitive inhibitor of
tyrosine hydroxylase, is especially useful in symptomatic
patients with inoperable or metastatic
pheochromocytoma.
Because it has access to the central nervous system,
metyrosine can cause extrapyramidal effects due to
reduced dopamine levels
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Hypertensive Emergencies:
 The
α -adrenoceptor antagonist drugs have limited
application in the management of hypertensive
emergencies.
 Labetalol has been used in Hypertensive Emergencies
 In theory,
α -adrenoceptor antagonists are most useful
when increased blood pressure reflects excess circulating
concentrations of agonists, eg, in pheochromocytoma,
overdosage of sympathomimetic drugs, or clonidine
withdrawal.
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Chronic Hypertension
 α 1-selective antagonists are efficacious drugs in the
treatment of mild to moderate systemic hypertension.
 They are generally well tolerated, but they are not
usually recommended as monotherapy for
hypertension because other classes of
antihypertensives are more effective in preventing
heart failure.
 Their major adverse effect is orthostatic hypotension,
which may be severe after the first few doses(FirstDose Phenomenon). They may cause dizziness.
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Peripheral Vascular Disease:
 Alpha-receptor–blocking drugs do not seem to be effective in the
treatment of peripheral vascular occlusive disease characterized
by morphologic changes that limit flow in the vessels.
 Occasionally, individuals with Raynaud's phenomenon and other
conditions involving excessive reversible vasospasm in the
peripheral circulation do benefit from prazosin or
phenoxybenzamine, although calcium channel blockers may be
preferable for most patients.
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Urinary Obstruction:
 Benign prostatic hyperplasia is common in elderly men.
 α 1A-receptor antagonists have improved efficacy and safety in
treating this disease.
 The mechanism of action in improving urine flow involves partial
reversal of smooth muscle contraction in the enlarged prostate
and in the bladder base.
 Prazosin, doxazosin, and terazosin are all efficacious in patients
with BPH, but they also lower the blood pressure.
 Tamsulosin is efficacious in BPH and has relatively minor effects
on blood pressure at a low dose. This drug may be preferred in
patients who have experienced orthostatic hypotension with
other α 1-receptor antagonists.