P-Adrenoceptor

Two different types of P-adrenoceptors have been characterized and categorized as P - and P2-subtypes. The P -receptors are associated primarily with the cardiac muscle, whereas the P2-subtype is located peripherally. Selective P -blockers include practolol (121) and (122), atenolol (123) and (124), and betaxolol (125) and (126). 

Catecholamine receptors are well estabUshed to be altered by a variety of homologous and heterologous influences (104). Thus, in hyperthyroidism, there is an increased level of sympathetic activity associated with increased expression of a- and P-adrenoceptors. 

Division of the receptors in the adrenergic nervous system into two classes (a and P) was proposed in 1948 (39) when a difference in the rank order of potency of epinephrine (1, R = CH ), norephinephrine (1, R = H), and isoproterenol [7683-59-2], C H yNO, (1, R = CH(CH3)2) was noted to depend on the organ examined. Eurther subdivision into groups P2 proposed in 1967 (40). Both types of P-adrenoceptors are found throughout the... 

Because of the widespread nature of adrenoceptors, nonselective P-agonists can produce many undesirable side effects. Therefore, before adrenergic agonists could become widely used in the treatment of asthma, some selectivity in action was needed. Whereas epinephrine and ephedrine have significant agonist activity at both a and P adrenoceptors, isoproterenol is a selective agonist at the P receptor (39). However, isoproterenol does not distinguish between the P and receptors and it is not active orally. 

Propafenone. Propafenone hydrochloride, an arylketone, is stmcturaHy similar to the P-adrenoceptor blocking agents. It has been in use in the former West Germany since 1977 and was introduced in the United States in 1990. Its effects may result from a combination of weak calcium channel blocking, weak nonselective -adrenoceptor blocking, and sodium channel blocking activity. Propafenone is effective in treating supraventricular tachyarrhythmias, ventricular ectopic beats, and ventricular arrhythmias. It is the most frequendy prescribed medication for ventricular arrhythmias in Europe (32). 

Class II Antiarrhythmic Agents The p-Adrenoceptor Blocking Agents... 

P-Adrenoceptors have been subdivided into P - and P2-adrenoceptors. A third subset called nontypical P-adrenoceptors or P -adrenoceptors have been described but are stiU the subject of debate. In terms of the interactions with various subsets of P-adrenoceptors, some antagonists are nonselective in that they antagonize the effects of activation of both P - and P2-adrenoceptors, whereas others are selective for either P - or P2-adrenoceptors. P - and P2-adrenoceptors coexist in almost all organs but generally, one type predominates. The focus herein is on the clinically relevant P -adrenoceptor-mediated effects on heart and on P2-adrenoceptor-mediated effects on smooth muscles of blood vessels and bronchioles, the insulin-secreting tissue of the pancreas, and skeletal muscle glycogenolysis for side effects profile (36). 

Some P-adrenoceptor blockers have intrinsic sympathomimetic activity (ISA) or partial agonist activity (PAA). They activate P-adrenoceptors before blocking them. Theoretically, patients taking P-adrenoceptor blockers with ISA should not have cold extremities because the dmg produces minimal decreases in peripheral blood flow (smaller increases in resistance). In addition, these agents should produce minimal depression of heart rate and cardiac output, either at rest or during exercise (36). 

There have been a number of long-term trials with various P-adrenoceptor blockers in patients surviving acute MI (37—39) that demonstrated a reduction in mortaUty, sudden death, and nonfatal re-infarctions. The term cardioprotective has been used to describe this effect for the dmgs studied. The... 

Propranolol. Propranolol hydrochloride, considered the prototype of the P-adrenoceptor blocking agents, has been in use since 1964. It is a nonselective, highly Hpid-soluble P-adrenoceptor blocker having no ISA. It is a mixture of (+) and (—) enantiomers, and the (—) enantiomer is the active moiety. The local anesthetic effects of propranolol are equipotent to those of Hdocaine [137-58-6] C 4H22N20, (see Anesthetics). Therapeutic effects include termination of catecholamine-induced arrhythmias, conversion of SA nodal tachycardias (including flutter and fibrillation) and AV nodal tachyarrhythmias to normal sinus rhythm, digitahs-induced arrhythmias, and ventricular arrhythmias (1,2). The dmg also has cardioprotective properties (37,39). 

Toxic effects of propranolol are related to its blocking P-adrenoceptor blocking actions. They include cardiac failure, hypotension, hypoglycemia, and bronchospasm. Propranolol is lipophilic and crosses the blood—brain barrier. Complaints of fatigue, lethargy, mental depression, nightmares, hallucinations, and insomnia have been reported. GI side effects include nausea, vomiting, diarrhea, and constipation (1,2). 

Acebutolol. Acebutolol hydrochloride is a hydrophilic, cardioselective P-adrenoceptor blocker that has about 1/25 the potency of propranolol in this regard. The dmg has moderate ISA and weak membrane stabilizing activities. It is approved for the treatment of hypertension and ventricular arrhythmias, especially PVCs. Acebutolol should produce minimal depression of heart rate because of its ISA (32). 

Esmolol is iv adrninistered. Maximal P-adrenoceptor blockade occurs in 1 min. Its elimination half-life is about 9 min. EuU recovery from P-adrenoceptor blockade is within 30 min after stopping the infusion. The therapeutic plasma concentrations are 0.4—1.2 lg/mL. It is metabolized by hydrolysis in whole blood by red blood cell esterases resulting in the formation of a primary acid metabohte and free methanol. The metabohte is pharmacologically inactive. The resulting methanol levels are not toxic. Esmolol is 55% bound to plasma protein, the acid metabohte only 10%. Less than 2% of parent dmg and the acid metabohte are excreted by the kidneys. Plasma levels may be elevated and elimination half-hves prolonged in patients with renal disease (41). 

Other P"Adrenoceptor Blocking Agents. Several other p-adrenoceptor blocking agents are in development as antiarrhythmic agents. These include carteolol, flestolol, and bopindolol (see Table 1). 

Elestolol sulfate is a nonselective, ultrashort acting P-adrenoceptor blocker. It has no ISA and produces weak inhibition of the fast sodium channel. The dmg is under clinical investigation for supraventricular tachyarrhythmias, unstable angina, and acute MI. In humans, flestolol has hemodynamics and electrophysiologic effects similar to those of other P-adrenoceptor blockers. The pharmacokinetics of flestolol are similar to those of esmolol. It is 50 times more potent than esmolol and the elimination half-life is 7.2 min. Recovery from P-adrenoceptor blockade is 30—45 min after stopping iv infusions. The dmg is hydrolyzed by tissue esterases and no active metabohtes of flestolol have been identified (41). 

Bopindolol is a long-acting, nonselective P-adrenoceptor blocker. It has mild membrane stabilizing activity and ISA. In vivo, the compound is hydrolyzed to its active metabohte. Because of this prodmg feature the onset of action is slower than other available P-adrenoceptor blockers. Preliminary pharmacokinetic studies indicate that the compound is weU absorbed, is 70% bioavailable, and peak plasma levels are achieved in about 2 h. Whereas its elimination half-life is 4—8 h, P-adrenoceptor blocking action (- 40%) is stiU apparent after 48 h. The dmg is being studied in hypertension, angina, and arrhythmias (43). 

Isoproterenol. Isoproterenol hydrochloride is an nonselective P-adrenoceptor agonist that is chemically related to NE. It mimics the effects of stimulation of the sympathetic innervation to the heart which are mediated by NE. It increases heart rate by increasing automaticity of the SA and AV nodes by increasing the rate of phase 4 diastoHc depolarization. It is used in the treatment of acute heart block and supraventricular bradyarrhythmias, although use of atropine is safer for bradyarrhythmias foUowing MI (86). 

Metoprolol. Metoprolol tartrate (Table 1), also a Class II antiarrhythmic agent, is a HpophiHc, cardioselective P -adrenoceptor blocking agent... 

Other P"Adrenoceptor Blocking Agents. Carteolol hydrochloride (Table 1) is also a Class II antiarrhythmic agent. In three separate studies in patients having angina pectoris, carteolol was considered effective as evidenced by a reduction in the frequency and severity of anginal episodes, reduction in the amount of nitroglycerin consumed, improvement of ECG parameters, or an increase in the duration of trea dmill exercise (42). 

P-Adrenoceptor Blockers. There is no satisfactory mechanism to explain the antihypertensive activity of P-adrenoceptor blockers (see Table 1) in humans particularly after chronic treatment (228,231—233). Reductions in heart rate correlate well with decreases in blood pressure and this may be an important mechanism. Other proposed mechanisms include reduction in PRA, reduction in cardiac output, and a central action. However, pindolol produces an antihypertensive effect without lowering PRA. In long-term treatment, the cardiac output is restored despite the decrease in arterial blood pressure and total peripheral resistance. Atenolol (Table 1), which does not penetrate into the brain is an efficacious antihypertensive agent. In short-term treatment, the blood flow to most organs (except the brain) is reduced and the total peripheral resistance may increase. 

Better antihypertensive effect of P-adrenoceptor blockers is found in patients having high PRA and most are not efficacious in patients having low PRA or in elderly patients. P-Adrenoceptor blockers usually lower arterial blood pressure about 10 mm Hg (1.3 kPa). Side effects include lethargy, dyspnea, nausea, dizziness, headache, impotency, cold hands and feet, vivid dreams and nightmares, bronchospasm, bradycardia, and sleep disturbances. 

P-Adrenoceptor blockers for the treatment of hypertension include (/) the cardioselective P -adrenoceptor blockers without intrinsic sympathomimetic activity (ISA), ie, atenolol (Table 3), bisoprolol (Table 3), and metoprolol (Table 1) (2) the cardioselective with ISA, ie, acebutolol (Table 1) (J) the noncardioselective without ISA, ie, propranolol (Table 1) and timolol [26839-75-8] C23H24N4O2S and (4) the noncardioselective with ISA, ie, oxprenolol [6452-71-7] C 3H23N03, and pindolol. 

FIGURE 2.4 Occupancy-response curves for P-adrenoceptor agonists in transfected CHO cells. Occupancy (abscissae) calculated from binding affinity measured by displacement of [125I]iodocyanopindolol. Response measured as increases in cyclic AMP. Drawn from [3],... 

FIGURE 2.8 Stimulus response cascade for the production of blood glucose by activation of P-adrenoceptors. Redrawn from [4]. 

FIGURE 2.18 Inotropic and lusitropic responses of guinea pig left atria to (3-adrenoceptor stimulation. Panels A to C isometric tension waveforms of cardiac contraction (ordinates are mg tension abscissae are msec), (a) Effect of 0.3 nM isoproterenol on the waveform. The wave is shortened due to an increase in the rate of diastolic relaxation, whereas no inotropic response (change in peak tension) is observed at this concentration, (b) A further shortening of waveform duration (lusitropic response) is observed with 3 nM isoproterenol. This is concomitant with positive inotropic response (increase maximal tension), (c) This trend continues with 100 nM isoproterenol, (d) Dose-response curves for ino tropy (filled circles) and lusitropy (open circles) in guinea pig atria for isoproterenol, (e) Dose-response curves for inotropy (filled circles) and lusitropy (open circles) in guinea pig atria for the P-adrenoceptor partial agonist prenalterol. Data redrawn from [6]. 

FIGURE 4.19 Correlation of the GTP shift for P-adrenoceptor agonists in turkey erythocytes (ordinates) and intrinsic activity of the agonists in functional studies (abscissae). Data redrawn from [16]. 

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