Alpha-Adrenoceptor Blocking Drugs:
The first generation of alpha-blockers were non-selective, blocking both alpha1 and alpha2 receptors.
In general, blockade of alpha-receptor reduces the sympathetic tone of blood vessels resulting in decreased TPR.
When subjects take an alpha-blocker rise from the supine to erect posture the sympathetic system is activated via baroreceptors. The normal vasoconstrictive (alpha1 effect) to maintain blood pressure is blocked by the drug, and the failure of such response results in Postural (Orthostatic) hypotension.
The sympathetic system is further activated to release more and more transmitters (Noradrenaline); this increase would normally be reduced by a negative feedback via alpha2adrenoceptors, but these receptors are blocked too (especially Beta1).
The excess released transmitter is free to act on Beta-Adrenoceptors causing an unpleasant tachycardia and increased Cardiac output. So for this reason, the non-selective alpha-blockers are not used ALONE in hypertension.
An alpha1-blocker that spares the alpha2 receptor, so that negative feedback inhibition of Noradrenaline is maintained, thus it's more useful in hypertension.
Explanation:
Alpha2 receptors activation inhibition of Noradrenaline release
So when alpha2 receptor is blocked increased Noradrenaline activation of Beta-receptors tachycardia
Thus, in cases of Hypertension, it's favored to give selective alpha1-blocker rather than using non-selective alpha-blocker that inactivates alpha2 receptors in addition to alpha1 receptors.
Examples of Alpha-Blockers:
Phentolamine, Phenoxybenzamine and Prazosin.
Phentolamine Phenoxybenzamine Prazosin
Receptor Blocking Alpha1=Alpha2
(non-selective) Alpha1 > Alpha2
(non-selective) Only alpha1
(Selective)
Reversibility Reversible Irreversible, binds covalently to alpha receptor Reversible
Administration Injection (emergency) Orally and Injection Orally and Injection
Active Metabolism It's a Prodrug that needs to undergo biotransformation to be active drug, so there's a delay of few hours before blockade develops.
Duration of Action Short Long (14-48) hours because the body needs to the synthesis new Adrenoceptors to terminate its action Intermediate
Side effects (peculiar) to the drug
Diarrhea and increased Gastric acid
Because it agonists at Muscarinic and histamine receptors. Alkylating agent causes tumor in animals only
It blocks ACh and histamine receptors. (First Dose Effect or First Syncopy) may cause brisk hypotension sufficient to cause loss of consciousness.
Thus, this drug should be given by small doses first and when the patient's retired to bed.
Selective Competitive Blockers of Alpha1 receptor include:
Prazosin, Terazosin and Doxazosin
Note: Tamsulosin is an Alpha1A selective blocker, used in treatment of BPH.
In treatment of BPH, we use alpha1 blocker in addition to 5α-reductase inhibitor
Common side effects of Alpha Blockers:
Hypotension and Postural hypotension.
Tachycardia and worsening angina (increased O2 consumption)
Nasal stuffiness and red sclera (alpha2-blocker vasodilation).
In the male, failure of ejaculation and retrograde ejaculation (Block alpha1 receptors of ejaculatory duct).
Therapeutic uses of Alpha-Blockers:
Peripheral Vascular Disease:
Individuals with Reynaud's Phenomena and other conditions involving excessive reversible vasospasm in the peripheral circulation do benefit from alpha-blocker, though Calcium channel blocker may be preferable for many patients (no pathological disease). However there's no evidence that the effects are significant when morphological changes limit flow in the vessels.
Urinary Obstruction:
Alpha-receptor blockade (especially Prazosin) was found to be helpful in BPH.
The mechanism of action involves Partial reversal of smooth muscle contraction in the enlarged prostate and in the neck of bladder, so the efficacy of several alpha1 receptor antagonists in patients with BPH was demonstrated.
Local Vasoconstrictor Excess:
They're useful to reverse the intense local vasoconstriction caused by accidental infiltration of alpha-agonist into subcutaneous tissue during I.V. administration.
Pheochromocytoma:
tumor of adrenal medulla that causes an increase in secretion of Adrenaline and Noradrenalin resulting in: Hypertension, Arrhythmia, Angina and Hyperglycemia.
In case of emergency we use Phentolamine by I.V. while in chronic cases we use Phenoxybenzamine or Prazosin.
Hypertension and Hypertensive emergencies:
Essential Hypertension:
The alpha-blockers have limited application in the management of hypertension.
If Beta-blockers or diuretics fail to control hypertension, Prazosin or other SELECTIVE alpha1-blockers may be added.
Secondary Hypertension:
The alpha Adrenoceptor antagonists are most useful when increased blood pressure reflects excess circulating concentration of catecholamines which may result from:
Pheochromocytoma
Interaction of tyramine containing food (cheese) with MAO inhibitors
Clonidine withdrawal
In these circumstances Phentolamine (non-selective) can be used to control high blood pressure.
Alpha2 Antagonists:
Yohimbine is a weak alpha2 Adrenoceptor blocking agent (i.e. it blocks negative feed receptors so that adrenergic activity is enhanced).
Therapeutic uses: so little clinical usefulness, however there's some experimental uses in:
Autonomic insufficiency.
May improve symptoms in patients with painful diabetic neuropathies.
Improve male sexual function, used in treatment of impotence.
Reynaud's phenomenon.
Type II diabetes: it increases insulin secretion because alpha2 receptors ingibit insulin secretion.
Psychiatric depression.
Beta-Adrenoceptor Blocking Drugs:
These drugs antagonize the effect of catecholamines at beta-receptors.
All Beta-Blockers are competitive antagonists, the effect depend on the amount of sympathetic tone present e.g. exercise.
Pharmacodynamics of Beta-blockers:
CVS:
They have both negative inotropic and negative chronotropic effects (i.e. reduce both contractility and automaticity, respectively).
Slowed AV conduction with increased PR interval as a result.
Cardiac output work and O2 consumption are decreased by blockade of Beta1 receptors; these effects are useful in treatment of angina.
The Beta-blockers are effective in attenuating supraventricular cardiac arrhythmia, but generally less effective against ventricular arrhythmia.
Vascular system:
Beta-blockade opposes beta2 mediated vasodilation. This may result initially in a rise in TPR from unopposed alpha-receptor mediated effects as the sympathetic nervous system discharges in response to lower blood pressure.
With chronic use: TPR returns to pre-treatment (normal) level or a little below. This reduction in the cardiac output leads to decreased blood pressure.
Beta-blockers antagonize the release of Renin so no postural hypotension occurs since alpha1 receptor that control vascular resistance is unaffected.
Respiratory:
Blockade of beta2 receptors in bronchial smooth muscle may lead to increase in airway resistance, particularly in patients with air disease as in asthma.
Eye:
Several Beta-blockers reduce intraocular pressure especially in glaucoma.
The mechanism is by decreasing aqueous humor production.
Metabolic and Endocrine:
Reduced blood pressure leads to decrease renal perfusion, this will lead to an increase in Sodium retention and plasma volume.
Beta-antagonists inhibit sympathetic nervous system stimulation of Lipolysis.
They decrease glycogenolysis, also they decrease glycogen secretion.
Chronic use of Beta-blockers is associated with increased plasma concentration of VLDL (very low density lipoprotein) and decreased HDL (high density lipoprotein), cholesterol.
They enhance hyperkalemia of muscular exercise.
Pharmacokinetics:
First order kinetics applies to elimination from plasma but receptor block followed a zero order decline. Thus half-life of pharmacodynamic effect exceeds the elimination half-life of the substance in blood.
The first generation of alpha-blockers were non-selective, blocking both alpha1 and alpha2 receptors.
In general, blockade of alpha-receptor reduces the sympathetic tone of blood vessels resulting in decreased TPR.
When subjects take an alpha-blocker rise from the supine to erect posture the sympathetic system is activated via baroreceptors. The normal vasoconstrictive (alpha1 effect) to maintain blood pressure is blocked by the drug, and the failure of such response results in Postural (Orthostatic) hypotension.
The sympathetic system is further activated to release more and more transmitters (Noradrenaline); this increase would normally be reduced by a negative feedback via alpha2adrenoceptors, but these receptors are blocked too (especially Beta1).
The excess released transmitter is free to act on Beta-Adrenoceptors causing an unpleasant tachycardia and increased Cardiac output. So for this reason, the non-selective alpha-blockers are not used ALONE in hypertension.
An alpha1-blocker that spares the alpha2 receptor, so that negative feedback inhibition of Noradrenaline is maintained, thus it's more useful in hypertension.
Explanation:
Alpha2 receptors activation inhibition of Noradrenaline release
So when alpha2 receptor is blocked increased Noradrenaline activation of Beta-receptors tachycardia
Thus, in cases of Hypertension, it's favored to give selective alpha1-blocker rather than using non-selective alpha-blocker that inactivates alpha2 receptors in addition to alpha1 receptors.
Examples of Alpha-Blockers:
Phentolamine, Phenoxybenzamine and Prazosin.
Phentolamine Phenoxybenzamine Prazosin
Receptor Blocking Alpha1=Alpha2
(non-selective) Alpha1 > Alpha2
(non-selective) Only alpha1
(Selective)
Reversibility Reversible Irreversible, binds covalently to alpha receptor Reversible
Administration Injection (emergency) Orally and Injection Orally and Injection
Active Metabolism It's a Prodrug that needs to undergo biotransformation to be active drug, so there's a delay of few hours before blockade develops.
Duration of Action Short Long (14-48) hours because the body needs to the synthesis new Adrenoceptors to terminate its action Intermediate
Side effects (peculiar) to the drug
Diarrhea and increased Gastric acid
Because it agonists at Muscarinic and histamine receptors. Alkylating agent causes tumor in animals only
It blocks ACh and histamine receptors. (First Dose Effect or First Syncopy) may cause brisk hypotension sufficient to cause loss of consciousness.
Thus, this drug should be given by small doses first and when the patient's retired to bed.
Selective Competitive Blockers of Alpha1 receptor include:
Prazosin, Terazosin and Doxazosin
Note: Tamsulosin is an Alpha1A selective blocker, used in treatment of BPH.
In treatment of BPH, we use alpha1 blocker in addition to 5α-reductase inhibitor
Common side effects of Alpha Blockers:
Hypotension and Postural hypotension.
Tachycardia and worsening angina (increased O2 consumption)
Nasal stuffiness and red sclera (alpha2-blocker vasodilation).
In the male, failure of ejaculation and retrograde ejaculation (Block alpha1 receptors of ejaculatory duct).
Therapeutic uses of Alpha-Blockers:
Peripheral Vascular Disease:
Individuals with Reynaud's Phenomena and other conditions involving excessive reversible vasospasm in the peripheral circulation do benefit from alpha-blocker, though Calcium channel blocker may be preferable for many patients (no pathological disease). However there's no evidence that the effects are significant when morphological changes limit flow in the vessels.
Urinary Obstruction:
Alpha-receptor blockade (especially Prazosin) was found to be helpful in BPH.
The mechanism of action involves Partial reversal of smooth muscle contraction in the enlarged prostate and in the neck of bladder, so the efficacy of several alpha1 receptor antagonists in patients with BPH was demonstrated.
Local Vasoconstrictor Excess:
They're useful to reverse the intense local vasoconstriction caused by accidental infiltration of alpha-agonist into subcutaneous tissue during I.V. administration.
Pheochromocytoma:
tumor of adrenal medulla that causes an increase in secretion of Adrenaline and Noradrenalin resulting in: Hypertension, Arrhythmia, Angina and Hyperglycemia.
In case of emergency we use Phentolamine by I.V. while in chronic cases we use Phenoxybenzamine or Prazosin.
Hypertension and Hypertensive emergencies:
Essential Hypertension:
The alpha-blockers have limited application in the management of hypertension.
If Beta-blockers or diuretics fail to control hypertension, Prazosin or other SELECTIVE alpha1-blockers may be added.
Secondary Hypertension:
The alpha Adrenoceptor antagonists are most useful when increased blood pressure reflects excess circulating concentration of catecholamines which may result from:
Pheochromocytoma
Interaction of tyramine containing food (cheese) with MAO inhibitors
Clonidine withdrawal
In these circumstances Phentolamine (non-selective) can be used to control high blood pressure.
Alpha2 Antagonists:
Yohimbine is a weak alpha2 Adrenoceptor blocking agent (i.e. it blocks negative feed receptors so that adrenergic activity is enhanced).
Therapeutic uses: so little clinical usefulness, however there's some experimental uses in:
Autonomic insufficiency.
May improve symptoms in patients with painful diabetic neuropathies.
Improve male sexual function, used in treatment of impotence.
Reynaud's phenomenon.
Type II diabetes: it increases insulin secretion because alpha2 receptors ingibit insulin secretion.
Psychiatric depression.
Beta-Adrenoceptor Blocking Drugs:
These drugs antagonize the effect of catecholamines at beta-receptors.
All Beta-Blockers are competitive antagonists, the effect depend on the amount of sympathetic tone present e.g. exercise.
Pharmacodynamics of Beta-blockers:
CVS:
They have both negative inotropic and negative chronotropic effects (i.e. reduce both contractility and automaticity, respectively).
Slowed AV conduction with increased PR interval as a result.
Cardiac output work and O2 consumption are decreased by blockade of Beta1 receptors; these effects are useful in treatment of angina.
The Beta-blockers are effective in attenuating supraventricular cardiac arrhythmia, but generally less effective against ventricular arrhythmia.
Vascular system:
Beta-blockade opposes beta2 mediated vasodilation. This may result initially in a rise in TPR from unopposed alpha-receptor mediated effects as the sympathetic nervous system discharges in response to lower blood pressure.
With chronic use: TPR returns to pre-treatment (normal) level or a little below. This reduction in the cardiac output leads to decreased blood pressure.
Beta-blockers antagonize the release of Renin so no postural hypotension occurs since alpha1 receptor that control vascular resistance is unaffected.
Respiratory:
Blockade of beta2 receptors in bronchial smooth muscle may lead to increase in airway resistance, particularly in patients with air disease as in asthma.
Eye:
Several Beta-blockers reduce intraocular pressure especially in glaucoma.
The mechanism is by decreasing aqueous humor production.
Metabolic and Endocrine:
Reduced blood pressure leads to decrease renal perfusion, this will lead to an increase in Sodium retention and plasma volume.
Beta-antagonists inhibit sympathetic nervous system stimulation of Lipolysis.
They decrease glycogenolysis, also they decrease glycogen secretion.
Chronic use of Beta-blockers is associated with increased plasma concentration of VLDL (very low density lipoprotein) and decreased HDL (high density lipoprotein), cholesterol.
They enhance hyperkalemia of muscular exercise.
Pharmacokinetics:
First order kinetics applies to elimination from plasma but receptor block followed a zero order decline. Thus half-life of pharmacodynamic effect exceeds the elimination half-life of the substance in blood.
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