Download Adrenergic System Adrenoceptor Blocking Drugs

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"Pharmacology
Adrenergic System
Adrenergic System
Adrenoceptor Blocking Drugs:
1) 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.
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Adrenergic System
Examples of Alpha-Blockers:
Phentolamine, Phenoxybenzamine and Prazosin.
Receptor Blocking
Reversibility
Phentolamine
Phenoxybenzamine
Prazosin
Alpha1=Alpha2
(non-selective)
Reversible
Alpha1 > Alpha2
(non-selective)
Irreversible, binds
covalently to alpha
receptor
Orally and Injection
It's a Prodrug that
needs to undergo
biotransformation to
be active drug, so
there's a delay of few
hours before blockade
develops.
Long (14-48) hours
because the body
needs to the synthesis
new Adrenoceptors to
terminate its action
Alkylating agent
causes tumor in
animals only
It blocks ACh and
histamine receptors.
Only alpha1
(Selective)
Reversible
Administration
Active Metabolism
Injection (emergency)
Duration of Action
Short
Side effects
(peculiar) to the
drug
Diarrhea and
increased Gastric acid
Because it agonists at
Muscarinic and
histamine receptors.
Orally and Injection
Intermediate
(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
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Adrenergic System
Common side effects of Alpha Blockers:
1)
2)
3)
4)
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:
1) 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.
2) 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.
3) 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.
4) 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.
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Adrenergic System
5) Hypertension and Hypertensive emergencies:
A) 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.
B) 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:
1)
2)
3)
4)
5)
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.
6) Psychiatric depression.
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Adrenergic System
2) 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:
1) 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.
2) 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.
3) 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.
4) Eye:
Several Beta-blockers reduce intraocular pressure especially in glaucoma.
The mechanism is by decreasing aqueous humor production.
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Adrenergic System
5) 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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