Adrenoceptor blockade

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). 

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). 

FIGURE 9.21 Changes in heart rate (ordinates) for agonist-induced changes in cardiac inotropy (changes in rate of ventricular pressure) in anesthetized cats. Responses shown to isoproterenol (filled circles) and dobutamine (open circles), (a) Response in normal cats shows inotropic selectivity (less tachycardia for given changes in inotropy) for dobutamine over isoproterenol, (b) The inotropic selectivity of dobutamine is reduced by previous a-adrenoceptor blockade by phentolamine. From [61],... 

In high concentrations it blocks calcium channels and, thus, exerts prominent negative inotropic effects. Its adverse effects include proarrhythmic effects, worsening of heart failure and (due to (3-adrenoceptor blockade) bradycardia and bronchospasm. 

Class II drugs are classical (3-adrenoceptor antagonists such as propranolol, atenolol, metoprolol or the short-acting substance esmolol. These drugs reduce sinus rate, exert negative inotropic effects and slow atrioventricular conduction. Automaticity, membrane responsiveness and effective refractory period of Purkinje fibres are also reduced. The typical extracardiac side effects are due to (3-adrenoceptor blockade in other organs and include bronchospasm, hypoglycemia, increase in peripheral vascular resistance, depressions, nausea and impotence. 

Aplysin has marked effects in mammalian tissue and produces hypotension, bradycardia, neuromuscular paralysis, and contracture of intestinal smooth muscle (85). Aplysiatoxin causes an elevation in blood pressure resistant to adrenoceptor blockade (86). 

There are various neurologic disorders which can be treated with jS-blockers like migraine, certain forms of tremor and alcohol withdrawal syndrome. Somatic manifestations of anxiety respond well to /3-adrenoceptor blockade. jS-Blockers with a selectivity for the jSi-subtype might be useful to avoid extracardial side effects. 

Blockade of /32-adrenoceptors by non-selective /3-blockers causes side-effects such as bronchoconstriction, vasoconstriction and hypoglycaemia. /32-Adrenoceptor blockade is sometimes used in the treatment of migraine or particular forms of tremor. 

Congestive heart failure treatment may be improved by cautiously adding a /3-blocker to conventional management with ACE-inhibitors and diuretics. Bisoprolol and carvedilol are the preferable /3-blockers, since their beneficial effect has been convincngly demonstrated in appropriate clinical trials. Bisoprolol is a highly selective /8i-blocker. Carvedilol has additional properties to its /8-receptor blocking activity, such as a weak vasodilator component and anti-oxidant activity. The beneficial effect is very likely to be caused by /8i-adrenoceptor blockade. 

Sotalol, as the racemate (a 1 1 mixture of the d- and 1-enantiomers), has a well-documented class Ill-antiarrhythmic activity, without showing the various side-effects of amiodarone. The -adrenoceptor blockade by this agent, however, limits its use in patients with heart failure. Dofetilide is an example of a newer, rather pure class in-antiarrhythmic, virtually devoid of other pharmacological properties. 

Circulating plasma norepinephrine levels correlate inversely with survival in CHE that is, higher levels of norepinephrine are associated with a decrease in survival. It appears that norepinephrine levels are more than just markers of disease severity norepinephrine is actually directly toxic to cardiac myocytes, at least in culture. The addition of either an a- or p-blocker confers partial protection from norepinephrine damage. Combined a- and (3-blockade confers additive protection. These data from animal studies may be relevant to human heart failure, since they suggest that both a- and (3- adrenoceptor blockade may be beneficial in the man-... 

Postmyocardial infarct patients show increased smwival if treated with a (5-adrenoceptor antagonist. The beneficial effect may be related to the decrease in heart rate and the antiischemic benefits of (5-adrenoceptor blockade. 

The toxicity associated with propranolol is for the most part related to its primary pharmacological action, inhibition of the cardiac (3-adrenoceptors. This topic is discussed in detail in Chapter 11. In addition, propranolol exerts direct cardiac depressant effects that become manifest when the drug is administered rapidly by the IV route. Glucagon immediately reverses all cardiac depressant effects of propranolol, and its use is associated with a minimum of side effects. The inotropic agents amrinone (Inocor) and milrinone (Primacor) provide alternative means of augmenting cardiac contractile function in the presence of -adrenoceptor blockade (see Chapter 15). Propranolol may also stimulate bron-chospasm in patients with asthma. 

Pacemaker activity in the sinoatrial node is decreased because of 3-adrenoceptor blockade and a removal of sympathoadrenal influences on spontaneous diastolic depolarization. Sotalol increases the refractory period of atrial muscle. 

Side effects of sotalol include those attributed to both P-adrenoceptor blockade and proarrhythmic effects. This arrhythmia is a serious threat, as it may lead to ventricular fibrillation. Adverse effects attributable to its p-blocker activity include fatigue, dyspnea, chest pain, headache, nausea, and vomiting. 

Adrenoceptor blockade is a rational approach to the treatment of angina pectoris, since an increase in sympathetic nervous system activity is a common feature in acute anginal attacks. Based on their ability to reduce oxygen demand, all (3-blockers tested so far have also been shown to be effective in the treatment of second-... 

Abrupt interruption of propranolol therapy in individuals with angina pectoris has been associated with reappearance of angina, acute myocardial infarction, or death due to a sudden increase in sympathetic nervous system tone to the heart. The mechanisms underlying these reactions are unknown, but they may be the result of an increase in the number of p-receptors that occur following chronic p-adrenoceptor blockade (up-regulation of receptors). When it is advisable to discontinue propranolol administration, such as before coronary bypass surgery, the dosage should be tapered over 2 to 3 days. 

Schmidt. M.E., Matochik, J.A., Goldstein, D.S., et al. Gender differences in brain metabolic and plasma catecholamine responses to alpha2-adrenoceptor blockade. 

Carvedilol and labetalol also cause B -adrenoceptor blockade. 

The drug has a half-life of 6-8 hours. It is extensively metabolized in the liver, and stereoselective metabolism of its two isomers is observed. Since metabolism of ( R)-carvedilol is influenced by polymorphisms in CYP2D6 activity and by drugs that inhibit this enzyme s activity (such as quinidine and fluoxetine, see Chapter 4), drug interactions may occur. Carvedilol also appears to attenuate oxygen free radical-initiated lipid peroxidation and to inhibit vascular smooth muscle mitogenesis independently of adrenoceptor blockade. These effects may contribute to the clinical benefits of the drug in chronic heart failure (see Chapter 13). 

Propranolol 13- Adrenoceptor blockade Direct membrane effects (sodium channel block) and prolongation of action potential duration slows SA node automaticity and AV nodal conduction velocity Atrial arrhythmias and prevention of recurrent infarction and sudden death Oral, parenteral duration 4-6 h Toxicity Asthma, AV blockade, acute heart failure Interactions With other cardiac depressants and hypotensive drugs... 

Ketanserin (Figure 16-2) blocks 5-HT2 receptors on smooth muscle and other tissues and has little or no reported antagonist activity at other 5-HT or Hi receptors. However, this drug potently blocks vascular adrenoceptors. The drug blocks 5-HT2 receptors on platelets and antagonizes platelet aggregation promoted by serotonin. The mechanism involved in ketanserin s hypotensive action probably involves Kj adrenoceptor blockade more than 5-HT2 receptor blockade. Ketanserin is available in Europe for the treatment of hypertension and vasospastic conditions but has not been approved in the USA. 

Orthostatic hypotension, impotence, failure to ejaculate -Adrenoceptor blockade... 

In one case, beta-adrenoceptor blockade masked an unexpected thyroid crisis, resulting in severe cerebral dysfunction before the diagnosis was made (184). 

Carvedi 1 ol and labetalol also cause a adrenoceptor blockade. 

Wadenberg ML, Wiker C, Svensson TH (2007) Enhanced efficacy of both typical and atypical antipsychotic drugs by adjunctive a-2 adrenoceptor blockade experimental evidence. Int J Neu-ropsychopharmacol 10 191-202... 

VanDenMeiracker, A., Manln tVeld, A., Boomsma, F., Fischberg, D., Molinoff, P., and Schalekamp, M., Hemodynamic and beta-adrenergic receptor adaptations during long-term beta-adrenoceptor blockade. Studies with acebutolol, atenolol, pindolol, and propranolol in hypertensive patients, Circulation, Vol. 80, No. 4, 1989, pp. 903-914. 

Neuroleptic drugs can reduce exercise-induced cardiac output as a result of drug-induced increases in plasma catecholamine concentrations and concurrent alpha-adrenoceptor blockade (117). Cardiomyopathy has been associated with neuroleptic drugs, including clozapine (118-120). 

Postural hypotension is particularly hazardous in susceptible patients, such as the elderly and those with depleted intravascular volume or reduced cardiovascular output. The risk of orthostatic hypotension is markedly increased after parenteral administration. The combination of alpha-adrenoceptor blockade and sedative effects may explain the increased risk of falling when taking neuroleptic drugs (SEDA-12, 52). 

Several cases of hypertension have been associated with clozapine (SEDA-22, 57), and alpha2-adrenoceptor blockade has been proposed as a possible mechanism (28). Four patients developed pseudopheochromocytoma syndrome associated with clozapine (33) all had hypertension, profuse sweating, and obesity. The authors suggested that clozapine could increase plasma noradrenaline concentrations by inhibiting prcsynaptic reuptake mediated by alpha2-adrenoceptors. 

---