Pharmacology of Alpha-Receptor Antagonist Drugs

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Pharmacology of Alpha-Receptor Antagonist Drugs

• Cardiovascular Effects
• a -receptor antagonist drugs lower peripheral
  vascular resistance and blood pressure.
• These drugs can prevent the pressor effects of
  usual doses of a agonists.

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• a -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 a 2-presynaptic receptors in the
  heart leads to augmented release of NE from
  peripheral sympathetic nerves, which will
  stimulate ß1 receptors in the heart leading to
  tachycardia and increased contractility of the
  heart.
• Nonselective (a 1 a 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 a receptors,
  causing irreversible blockade of long duration
  (1448 hours or longer). It is somewhat selective
  for a 1 receptors but also blocks a 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 a 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.

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• Phentolamine
• Potent competitive antagonist at a 1 and a 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.
• Phentolamine's principal adverse effects are
  related to cardiac stimulation, which may cause
  severe tachycardia, arrhythmias, and myocardial
  ischemia.
• Phentolamine has been used in the treatment of
  pheochromocytoma.

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• Prazosin
• Highly selective for a 1 receptors and typically
  1000-fold less potent at a 2 receptors.
• This may partially explain the relative absence
  of tachycardia seen with prazosin compared with
  phentolamine phenoxybenzamine.
• Relaxes both arterial and venous vascular smooth
  muscle, as well as smooth muscle in the prostate.

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• Terazosin
• Reversible a 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 912 hours.
• Doxazosin
• Efficacious in the treatment of hypertension and
  BPH.
• Differs from prazosin and terazosin in having a
  longer half-life of about 22 hours.

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• Tamsulosin
• Competitive a 1 antagonist with a structure quite
  different from that of most other a 1-receptor
  blockers.
• High bioavailability and a half-life of 915
  hours.
• Higher affinity for a 1A and a 1D receptors than
  for the a 1B subtype.
• Has relatively greater potency in inhibiting
  contraction in prostate smooth muscle versus
  vascular smooth muscle compared with other a
  1-selective antagonists. a 1A subtype may be the
  most important a subtype mediating prostate
  smooth muscle contraction.
• It is used to treat BPH.
• Compared with other antagonists, tamsulosin has
  less effect on standing blood pressure in
  patients.

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• Drugs with Alpha- Adrenoceptor Antagonistic
  Activity
• Labetalol
• Has both a 1-selective and ß-antagonistic
  effects
• Chlorpromazine and Haloperidol
• Are potent dopamine receptor antagonists but are
  also antagonists at a receptors.
• Useful antipsychotic drugs.
• Their antagonism of a receptors probably
  contributes to some of their adverse effects,
  particularly hypotension.
• Ergot derivatives
• Ergotamine
• Dihydroergotamine
• Cause reversible a -receptor blockade,

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• Yohimbine
• An indole alkaloid, a 2-selective antagonist.
• Sometimes used in the treatment of orthostatic
  hypotension because it promotes norepinephrine
  release through blockade of presynaptic a 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 a 2-adrenoceptor agonist such as
  clonidine.

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• Clinical Pharmacology of the Alpha-ReceptorBlocki
  ng Drugs
• 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.

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• Beta-receptor antagonists are required after a
  -receptor blockade to reverse the cardiac effects
  of excessive catecholamines.
• Beta antagonists should not be used prior to
  establishing effective a -receptor blockade,
  since unopposed ß -receptor blockade could
  theoretically cause blood pressure elevation from
  increased vasoconstriction.
• Metyrosine (a -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 a -adrenoceptor antagonist drugs have limited
  application in the management of hypertensive
  emergencies.
• Labetalol has been used in Hypertensive
  Emergencies
• In theory, a -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
• a 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(First-Dose Phenomenon). They may cause
  dizziness.

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• Peripheral Vascular Disease
• Alpha-receptorblocking 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.
• a 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 a 1-receptor antagonists.