Download Beta blockers

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The basic physiological function of adrenergic receptors is to enhance the response to
stress rapidly.
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Dichloro-isoprenaline was the first and Pronethalol was the second ever of beta blockers
synthesized from the structure of isoprenaline. These two compounds were never used
in clinical practice, DCI for its fairly low potency and Pronethalol due to its carcinogenic
properties in mice.
Their derivative, propranolol was the first therapeutically applied and successful drug in
the family of beta receptor blockers and became the prototype of the whole family.
The other compound developed by Sir Black was cimetidine, which was the first drug to
substantially improve healing of peptic ulcers and became the prototype of the drug
family blocking the type 2 receptors of histamine.
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These drugs bind to beta receptors reversibly while competing with the physiological
ligand cathecholamines.
Many compounds bind to the subtypes of beta receptors with equal affinities: nonselective antagonists. Some exhibit preferential binding to subtype 1: beta-1 selective
antagonists. For scientific experiments, there exist antagonists with selective binding to
B2 or B3 receptors. These, however, are not in clinical use.
Some B blockers can weakly increase B receptor activity => these are termed partial
agonists or blockers with some intrinsic sympathomimetic activity. Substantial SM
activity would, however, be disadvantageous for the action required from a B antagonist.
Slight SM activity may be beneficial for example for preventing profound bradycardia.
B receptors exhibit a regular baseline signaling even in the absence of any ligand. Some
B blockers not only displace other ligands but also reduce this baseline signaling => they
possess inverse agonist activity.
Several B blockers can induce vasodilation by various mechanisms, e.g., by blocking also
alpha receptors, by selectively activating B2 receptors while blocking B1, or by making
endothelial cells release NO.
Some drugs exhibit membrane-stabilizing activity, similar to local anesthetics that is
independent of their B receptor blocking properties.
Highly lipid soluble compounds (e.g., propranolol, metoprolol) are able to cross the
blood-brain-barrier and produce CNS side effects, whereas more water soluble ones are
less likely to do so.
A few newer drugs in this family may even have antioxidant action also.
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Drugs in the third generation decrease the peripheral resistance even after the first dose
by several different mechanisms.
Celiprolol is a B1 selective blocker, but it exhibits agonistic activity on B2 receptors and
induces endothelium-derived NO release.
Nebivolol also leads to NO release.
Labetalol blocks all subtypes of B receptors; however, it also blocks alpha-1 receptors.
Carvedilol is yet another non-selective B antagonist with alpha-1 blocking activity. In
addition, this compound exhibits free radical-scavanging (antioxidant) and vascular Ca2+
channel inhibitory actions, the latter of which contributes to its vasodilator effect.
Moreover, Carvedilol has antiproliferative effect, which is highly favorable feature in the
treatment of congestive heart failure because it inhibits myocardial remodeling, a severe
and ever-worsening consequence of CHF.
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The intensity of the effects of B antagonists depends on the tonic stimulation of B
receptors.
Spontaneous depolarization is also decreased at ectopic pacemaker sites =>
antiarrhythmic effect
The decreased HR means longer diastolic time between 2 contractions => beneficial in
ischemic heart disease countering angina.
Deceleration of the heart may not be obvious in resting state but it becomes evident
during physical exercise.
The elevated end-diastolic pressure increases the oxygen demand of the heart to a small
extent. However, the prolonged diastolic time leads to a more marked increase in
oxygen supply.
Initially, B antagonists were contraindicated for congestive heart failure because of their
negative inotropic effect, rather sympathomimetics were used. However, the constantly
increased sympathetic tone in these patients increases heart rate at the expense of the
ejected volume. The increased sympathetic tone leads to heart muscle remodeling with
further diminution of stroke volume, which further increases sympathetic tone and
cardiac remodeling. After the frightening realization that sympathomimetics increase the
mortality of CHF patients instead of improving their state, some physicians started the
administration of B blockers. It soon turned out that B antagonists can successfully
interrupt this vicious circle and now they play important role in the treatment of
congestive heart failure.
The ejection fraction increase develops gradually within a few months of B blocker
treatment, markedly improving the state of patients with congestive heart failure.
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Initial increase in blood pressure: the diminished cardiac output activates the so termed
pressor reflex resulting in increased peripheral resistance to maintain blood pressure. In
addition, non-selective drugs, such as propranolol, inhibit vasodilation evoked by
activation of B2 receptors, whereas the pressor response to alpha receptor activation is
not affected. That is why B antagonists were initially considered not suitable for
treatment of hypertension. The increase in peripheral resistance at the beginning of B
antagonist therapy is much less common with 3rd generation drugs because of their
inherent vasodilator effect.
With long-term use of B antagonists, however, the total peripheral resistance returns to
initial values or even decreases in patients with hypertension => antihypertensive effect
It was yet another surprising observation that B antagonists are capable of lowering
blood pressure with long term use.
The mechanisms of the antihypertensive effect is still obscure. One might speculate that
inhibition of renal B1 receptors decreases renin release, thus contributing to the
antihypertensive effect. However, pindolol proved effective in treating hypertension
without significant influence on plasma renin concentration. The delayed fall in the
peripheral resistance with persistent reduction of cardiac output appears to account for
most of the antihypertensive effect.
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In normal individuals, the pulmonary function is affected only to a minimal extent.
However, in patients with COPD, it may lead to life-threatening constriction of the
airways and in asthmatic patients it may precipitate attacks. ISA can attenuate the
bronchoconstrictive effect.
The diminished aqueous humor production is utilized in glaucoma patients.
Metabolism must rapidly accommodate to the challenges of stress situations and the
immediate response is provided by the increased sympathetic tone through activation of
B receptors. Blockade of B2 receptors in the liver decreases glycogen breakdown,
whereas antagonizing B3 receptors diminishes fatty acid release from adipose tissue.
Serum lipid profile changes are less common with drugs possessing ISA. Drugs of the 1st
and 2nd generations may precipitate diabetes and substantially increase the risk of
atherosclerosis.
Interestingly, 3rd generation compounds not only are free of such effects, but rather
improve these metabolic conditions.
In diabetic patients who are treated with insulin the occurrence of hypoglycemic events
is unfortunately rather common. One of the early symptoms of such event is tremor,
which can be masked by B blockers. On the other hand, B antagonists are effective
treatment for essential tremor.
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The most of the adverse effects of B antagonists are related to their pharmacologic
action, the blockade of B receptors.
Vascular B2 receptors mediate vasodilation on activation, decreasing the total peripheral
resistance. Antagonism of vascular B2 receptors could, therefore, lead to cold limbs due
to increased peripheral resistance.
Rebound effects: the most likely cause of these symptoms is the compensatory upregulation of B receptors during blockade leading to enhanced sensitivity to
catecholamines on withdrawal.
These drugs should be tapered gradually over 10-14 days before cessation.
Bronchoconstriction is because of blocking B receptors within the airways. This,
however, is significant only in patients with asthma or COPD.
B blockers interfere with the secretion of melatonin from the pineal gland, the key
hormone required for normal sleep, thereby producing sleep distubances.
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The manifestation of poisoning with B blockers depends on the pharmacological
properties of the ingested drug, particularly on its B1 selectivity, ISA, and membranestabilizing effect.
The profound bradycardia can partly be overcome by atropine antagonizing type 2
muscarinic receptors in the heart.
Pacemaker is often required to maintain heart rhythm.
Glucagon provides us with a bypass opportunity to increase intracellular cAMP
concentration. B blockers can bind to the receptors strongly making hard to break
through the blockade. Activation of myocardial glucagon receptors has positive inotropic
and chronotropic effects, thereby providing us with yet another measure to fight
bradycardia.
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The pharmakokinetics of Esmolol greatly differs from that of other B antagonists.
Its half-life is very short because this compound is a methyl ester. The ester bond is
readily hydrolyzed by esterase enzymes present in the plasma and red blood cells. The
hydrolyzed carboxylic acid derivative is an active metabolite; however, its potency as B
antagonist is approximately 500 times lower than that of the parent compound. This is
why the hydrolyzed metabolite of esmolol is considered being inactive.
The unusually rapid elimination of the molecule makes necessary that Esmolol is
administered in i.v. infusion. Its onset of action is rapid (8-10 minutes) and so is the
cessation. It is suitable only for short term treatment of arrhythmia.
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The additive effects with other antihypertensive drugs is routinely utilized in clinical
practice, as treatment of hypertension usually involves combinations of agents with
different pharmacodynamic effects.
NSAIDs counter the antihypertensive effect of B blockers because they inhibit formation
of prostanoid molecules, many of which has vasodilator effect.
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The decreased heart rate and the antiarrhythmic action can be life-saving in AMI
patients.
The blood pressure lowering effect of B antagonists develops gradually during a few
weeks of treatment.
Carvedilol is particularly suitable for treating congestive heart failure because this
compound can block cardiac muscle remodeling by 2 mechanisms: (1) it antagonizes the
effect of catecholamines and (2) it has antiproliferative effect. Moreover, Carvedilol can
exert cardioprotective effect either due to its free radical scavenging action.
Interestingly, Sotalol has antiarrhythmic effect not only because of its B antagonist
action, but also of some hitherto unidentified additional action independent of its B
blocking properties.
At present, Propranolol is the only B antagonist drug for pharmacological treatment of
portal hypertension, variceal bleeding, and essential tremor.
In pheochromocytoma patients, the administration of an alpha blocker must precede
that of Propranolol, because othervise we can evoke a severe hypertensive crisis due to
the blockade of vasodiltor B2 receptors.
Hyperthyroidism results in increased expression of B receptors in many cell types,
including heart cells. This leads straight to increased sensitivity of cells to
cathecholamines, excessive sympathetic activation, which speeds up HR and promotes
arrhythmias. Propranolol can effectively suppresses these symptoms.
Migraine: By blocking B receptors, Propranolol interferes with the trigeminovascular
nociception, thereby providing some protection against the appearance of migraine
attacks. Nevertheless, it is not suitable for treating the attack itself.
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