Intrinsic -blocking activity

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). 

Figure 17.7 Possible mechanism by which atypical neuroleptics with antimuscarinic activity produce few EPSs. Normally the inhibitory effects of DA released from nigrostriatal afferents on to striatal neuron D2 receptors is believed to balance the excitatory effect of ACh from intrinsic neurons acting on muscarinic (M2) receptors (a). Typical neuroleptics block the inhibitory effect of DA which leaves unopposed the excitatory effect of ACh (b) leading to the augmented activity of the striatal neurons and EPSs (see Fig. 15.2). An atypical neuroleptic with intrinsic antimuscarinic activity reduces this possibility by counteracting the excitatory effects of released ACh as well as the inhibitory effects of DA (c). Thus the control of striatal neurons remains balanced...

FIGURE 2-4. Flowchart listing various P-blocking agents separated by P-receptor activity and intrinsic sympathomimetic activity. 

Esmolol hydrochloride is a competitive p-adrenergic receptor antagonist it is selective for pT adrenoceptors. In contrast to pindolol, esmolol has little intrinsic sympathomimetic activity, and it differs from propranolol in that it lacks membrane stabilizing activity Of all of the p-adrenergic blocking drugs, this compound has the shortest duration of action because it is an ester, it is hydrolyzed rapidly by plasma esterases and must be used by the intravenous route Esmolol is approved only for the treatment of supraventricular arrhythmias... 

The distributive term is essentially related to the partition coefficient thus if we subtract this distributive term from the EDrQ we arrive at an estimate of the binding energy of the molecule at the receptor site. Ve refer to this binding energy as intrinsic (3-blocking activity or i.b.a. thus -... 

Thus the "ideal" anti-hypertensive 3-blocking agent should be a moderately long acting cardioselective agent showing little or no intrinsic sympathomimetic activity. 

Pharmacology Carvedilol, an antihypertensive agent, is a racemic mixture in which nonselective -adrenoreceptor blocking activity is present in the S(-) enantiomer and -adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. Carvedilol has no intrinsic sympathomimetic activity. 

Mechanism of Action An antihypertensive that possesses nonselective beta-blocking. Has moderate intrinsic sympathomimetic activity. Therapeutic Effect Reduces cardiac output, decreases blood pressure (BP), increases airway resistance, and decreases myocardial ischemia severity. 

Beta-adrenergic blocking agents, SELECTIVE, intrinsic SYMPATHOMIMETIC ACTIVITY (ISA)... 

Beta-adrenergic blocking agents, selective, intrinsic sympathomimetic activity (ISA) acebutolol hydrochloride... 

Carvedilol is a dualaction cardiovascular agent with non selective beta blocking, antagonistic vasodilating properties and is devoid of intrinsic sympathomimetic activity. 

Another cardioselective beta, blocking agent devoid of intrinsic sympathomimetic activity given once daily in the treatment of hypertension and angina pectoris. 

During the acute phase of thyrotoxicosis, B-adrenoceptor blocking agents without intrinsic sympathomimetic activity are extremely helpful. Propranolol, 20-40 mg orally every 6 hours, will control tachycardia, hypertension, and atrial fibrillation. Propranolol is gradually withdrawn as serum thyroxine levels return to normal. Diltiazem, 90-120 mg three or four times daily, can be used to control tachycardia in patients in whom blockers are contraindicated, eg, those with asthma. Other calcium channel blockers may not be as effective as diltiazem. Adequate nutrition and vitamin supplements are essential. Barbiturates accelerate T4 breakdown (by hepatic enzyme induction) and may be helpful both as sedatives and to lower T4... 

Acebutolol (Sectral). Acebutolol is described as a relatively cardioselective beta blocker that tends to bind preferentially to beta-1 receptors at low doses, but binds to both types of beta receptors as the dosage increases. This drug also exerts mild to moderate intrinsic sympathomimetic activity, which means that acebutolol not only blocks the beta receptor from... 

All the clinically available (J-blockers are competitive antagonists. Nonselective [3-blockers act at both (3 and (32 receptors, whereas car-dioselective ( -antagonists primarily block 3i receptors. These drugs also differ in intrinsic sympathomimetic activity, in central nervous system (CNS) effects, and in pharmacokinetics (Figure 7.5). Although all (3-blockers lower blood pressure in hypertension, they do not induce postural hypotension because the a-adrenoceptors remain functional therefore, normal sympathetic control of the vasculature is maintained. P-blockers are also effective in treating angina, cardiac arrhythmias,... 

Drugs that preferentially block the [ receptors have been developed to eliminate the unwanted bronchoconstrictor effect (p2) of propranolol seen among asthmatic patients. Cardioselective p-blockers, such as acebutolol [a se BYOO toe lole], atenolol [a TEN oh lole], and metoprolol [me TOE proe lole], antagonize receptors at closes 50 to 100 times less than those required to block p2 receptors. This cardioselectivity is thus most pronounced at low doses and is lost at high drug doses. [Note Acebutolol has some intrinsic agonist activity.]... 

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