Beta blockers or beta-adrenergic blocking agents are drugs which block norepinephrine as well as epinephrine (adrenaline) from binding to beta receptors on nerves.
These compounds binds to the receptor without the ability of activating the catalytic site since no hydrogen bond can occur at this site with these compounds and they all interact with b-adrenoceptors forming drug receptor complexes so that endogenous norepinephrine and epinephrine are hindered from accessing the receptor. This leads to a competitive antagonism which is characterized by a parallel shift of the concentration-response curve of the agonist to the right. The b-receptor blockade can be completely reversed by high concentrations of the agonist. They are widely used for the treatment of cardiovascular diseases such as arterial hypertension, coronary heart disease and supraventricular and ventricular tachyarrhythmias.
The basic conditions of binding to the beta-receptor for a beta-blocker are the presence of the amine function, which has to be a secondary amine and a nonsubstituted hydroxyle function. Modifications of the aromatic ring substitutes and of the lateral chain will influence the partial agonist activity, the affinity, and the selectivity for beta1- versus the beta2-adrenergic receptor . Beta-blocker compounds are racemates with an asymmetric carbon. The L isomers are those active beta- blockers. D isomers do not bind to the receptor.
PHARMACOLOGICAL PROPERTIES
Potency of the beta-blockade activity depends on the affinity of the compound for the beta-adrenergic receptors. It is convenient to compare and contrast the pharmacological properties of different beta-adrenoceptor antagonists in relation to those of propranolol because it is the very first beta blocker being discovered and still most widely used drug. It possess the following important pharmacological properties (1) membrane stabilizing activity, (2) high lipid solubility or the lipophillic nature and the absence of (3) ??1- selectivity, and (4) partial agonist activity.
Stereospecificity, the intrinsic sympathomimetic activity and the associated vasodilating properties are also included in main properties of beta blockers.
1.) LIPID SOLUBILITY OR LIPOPHILLIC NATURE
Propranolol is lipophilic in nature whereas sotalol is hydrophilic.
The following parameters are dependent on lipophilicity:
1) duration of b-receptor blockade, 2) metabolism or renal elimination (pharmacokinetics), 3) diffusion through biological barriers (eg, blood/brain, placenta) and 4) tissue concentration (especially during intoxication).Hydrophilic b-blockers like sotalol are advantageous in patients who suffer from central nervous side effects during therapy with lipophilic drugs.
Because of lipophilic nature, the propranolol are extensively metabolized and have a low bioavailability and shorter half-life compared with hydrophilic compounds, their ability to more easily cross cellular membranes and especially the blood-brain barrier may confer additional properties that could affect therapeutic efficacy and side- effect profiles such as depression and sleep disturbances could be favored by lipophilic properties of beta- blockers.
2.) STEREOSPECIFICITY:
Propranolol is a non-selective, lipophilic beta-blocker with two additional features: On the one hand, only the non-beta-blocking d-enantiomer inhibits the conversion of thyroxin to triiodothyronin, whereas only the l-enantiomer shows beta-blocking effects . Thus, a major part of the efficacy of Propranolol in patients suffering from hyperthyroidism resides exclusively in the non-beta-blocking d-enantiomer. This effect on thyroid hormones is well achieved with generally recommended doses of Propranolol in humans. S-enantiomer 40-100 fold more potent than the R- as a ??-adrenoceptor antagonist; similar activity with respect to their membrane stabilising properties.
On the other hand, Propranolol has been shown to exert antiarrhythmic class I effects residing equally in both the d- and l enantiomers . However, only slight antiarrhythmic class I effects can be achieved even with the highest recommended doses of Propranolol in humans.
The optical isomers of the beta blocking agent propranolol exert beta receptor blocking as well as membrane stabilizing effects. The latter is thought to be responsible for the antiarrhythmic effect of the drug. In this study we quantified the electrophysiological effects of both isomers of propranolol on the conduction and pacemaker system of the heart. The experiments were performed on isolated hearts using a special ECG recording and stimulation technique. To abolish isoproterenol’s beta adrenergic stimulatory effect on heart rate, 30-times higher concentrations of (+)propranolol were necessary than of (-)propranolol in order to be consistent. Both isomers caused a similar and marked slowing of conduction velocity through the bundle of His and ventricular myocardium. Also, heart rate, as well as atrio-ventricular conduction velocity were significantly slowed by a concentration of 10 microM of either drug, (-)propranolol being slightly more effective. Only in the presence of (-)propranolol did significant changes of atrio-ventricular and His-bundle conduction occur at a concentration of 1 microM. During programmed stimulation sinus node recovery time was more prolonged by (-)propranolol than during perfusion with (+)propranolol. The highest rate of pacing with 1:1 conduction of the sino-atrial conduction, the atrial and ventricular myocardium was significantly depressed to a comparable degree by either isomers of propranolol. These effects appear to be primarily responsible for the antiarrhythmic effects of both isomers. Because of the minor effects of (+)propranolol on sinus- and AV-node activity, as well as on beta adrenergic receptors, this isomer may have potential clinical importance in the treatment of arrhythmias.
Sotalol is a non-selective, hydrophilic beta-blocker which prolongs cardiac repolarisation independent of its antiadrenergic action, thus representing class III antiarrhythmic properties.
Just like all other beta-blockers currently used in cardiovascular medicine, Sotalol is a racemic mixture consisting of equal amounts of d-Sotalol and l-Sotalol, with the d-enantiomer showing solely antiarrhythmic class III effects and the l-enantiomer exerting both antiarrhythmic class III and beta-blocking effects. Thus, racemic Sotalol is a combined beta-blocking and antiarrhythmic class III agent that may be useful in the treatment of both ventricular and supraventricular arrhythmias. The importance of this finding has been emphasised in the SWORD study that was terminated prematurely because d-sotalol ‘ the optically pure d-enantiomer that only exerts antiarrhythmic class III effects but no beta-blockade increased all-cause mortality compared to placebo by 65 % (p = 0.006), mainly due to arrhythmic deaths. Thus, antiarrhythmic class III properties may be useful in order to increase the antiarrhythmic efficacy of Sotalol. However, beta-blockade (effected exclusively by the l-enantiomer) appears to play a major role in the efficacy and safety of Sotalol.
Sotalol is Class III antiarrhythmic that consists of a mixture of stereoisomers, one of which (d-Sotalol) selectively blocks IKr, and the other (l-sotalol) is a non-selective beta blocker. The clinical use of sotalol has been limited by both its antiarrhythmic efficacy (a common issue for most antiarrhythmics), and its Class III-related associated side effect of Torsade de pointes (1.5-2% incidence).
The chiral beta-blocker, sotalol (STL), is marketed as a racemic mixture. Although both STL enantiomers have equal Class III antiarrhythmic activity, beta-blocking activity has been ascribed mainly to the R-enantiomer. The pharmacokinetics of STL enantiomers were studied in young (mean age 32 +/- 3 years), healthy male volunteers after oral administration of 160 mg. Subsequent plasma and urine samples were collected over 24 hours, and STL enantiomer concentrations were determined using a stereospecific high-performance liquid chromatography assay. There were no significant differences between pharmacokinetic parameters of enantiomers. The area under the time-concentration curves (mean +/- standard deviation [SD]) were 6.95 +/- 0.85 and 6.76 +/- 1.2 (mg/L)hour for S- and R-STL, respectively. Maximal plasma concentrations of S- and R-STL were 615 +/- 167 and 619 +/- 164 ng/mL, respectively, which were obtained on average, 3.13 +/- 0.60 hours after dosing. The mean residence time (mean +/- SD) was 13.2 +/- 1.2 and 12.9 +/- 1.8 hours for S- and R-STL, respectively. Respective renal clearance values for S- and R-STL were 8.98 +/- 1.5 and 9.46 +/- 2.3 L/hour, and were approximately 1.5 times greater than creatinine clearance. Renal clearance constituted approximately 76% of the oral clearance. Although stereoselective disposition of STL was absent after racemate administration, these results should not be extrapolated to patients with significantly altered physiology, or to the pharmacokinetics of S-STL after administration of pure-S-STL.
3.) MEMBRANE STABILIZING ACTION
‘ Local anesthetic action, also known as “membrane-stabilizing” action, is a prominent effect of several ?? blockers .
‘ However, the concentration in plasma is too low for the anesthetic effects to be evident.
‘ These membrane-stabilizing ??- blockers are not used topically on the eye, where local anesthesia of the cornea would be undesirable.
‘ Sotalol is a nonselective ?? -receptor antagonist that lacks local anesthetic action but has marked class III antiarrhythmic effects, reflecting potassium channel blockade (used to treat both ventricular & supraventricular arrhythmias).
SIMILARITIES OF PROPRANOLOL AND SOTALOL
4.) ??1- SELECTIVITY:
Most of the therapeutic actions of ??-blockers are due to inhibition of ??1-receptors. ??1-selective agents are better tolerated than non-selective ??-blockers as they have
fewer side effects.
One major advantage of a high ??1- selectivity is the lower incidence of air-way obstruction (??2- receptor blockade) and the bronchodilatory action of ??2- agonists even in the presence of a ??1-selective blocker. It is a further advantage of ??1-selective drugs that they show only minor effects on glucose and lipid metabolism.
However, both propranolol as well as sotalol does not show property of ??1- selectivity.
Non-selective beta blockers, for example, propranolol (Inderal), block ??1 and ??2 receptors and, therefore, affect the heart, blood vessels, and air passages.
5.) PARTIAL AGONIST ACTIVITY:
The partial agonist activity (PPA) or intrinsic sympathomimetic activity (ISA) of some ??-blockers is due to the similarity of the molecules of the agonist and antagonist. Binding
of ??-blockers with ISA to the receptor induces a weak signal transduction but at the same time antagonises the action of ??- agonists. Maximal ISA of ??-blockers needs full receptor occupation and does not reach the maximal effect of a full agonist so that ISA of ??-blockers is called partial agonist activity. ??-blockers with ISA might be useful in patients with low heart rate or with low HDL-cholesterol and/or high triglycerides. However, clinical studies have shown that ??-blockers with ISA are less effective in reducing mortality in patients with
acute myocardial infarction. In summary, the clinical significance of ISA has to be regarded as low.
Propranolol is the prototypical ?? -blocking drug. It has low and dose-dependent bioavailability.The drug has negligible effects at ?? and muscarinic receptors; however, it may block some serotonin receptors in the brain, though the clinical significance is unclear. It has no partial agonist action at ?? receptors. Propranolol is a nonselective beta-adrenergic receptor antagonist that lacks intrinsic sympathomimetic activity and thus is a pure antagonist. Antagonism of beta1 and beta2 receptors produced by propranolol is about equal
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