P-blocker response

Liggett, S.B., et al. A polymorphism within a conserved Pi-adrenergic receptor motif alters cardiac function and P-blocker response in human heart failure. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 11288-11293. 

The ocular hypotensive lipids in typical ophthalmology practice are considered first-line alternatives to topical P-blockers because of their superior efficacy and safety profiles. Many clinicians may choose to use the ocular hypotensive lipids as first-line agents, especially in patients that have an initial requirement to lower IOP by more than 25%, or in patients that have relative or absolute contraindications to topical P-blockers. However, latanoprost is currently the only ocular hypotensive lipid drug that has a Food and Drug Administration (FDA) indication for first-line therapy. Bimatoprost and travoprost are indicated by the FDA for patients who are intolerant of other IOP-lowering therapy or insufficiently responsive to another IOP-lowering medication.10,38... 

In multidrug therapy, it is necessary to consider which agents rationally complement each other. A p-blocker (bradycardia, cardiodepression due to sympathetic blockade) can be effectively combined with nifedipine (reflex tachycardia), but obviously not with verapamil (bradycardia, cardiodepression). Monotherapy with ACE inhibitors (p. 124) produces an adequate reduction of blood pressure in 50% of patients the response rate is increased to 90% by combination with a (thiazide) diuretic. When vasodilators such as dihydralazine or minoxidil (p. 118) are given, p-blockers would serve to prevent reflex tachycardia, and diuretics to counteract fluid retention. 

A. Both sets of responses to isoproterenol are mediated by p-adrenoceptors, and all the choices are p-antagonists. However, drug X is more effective in antagonizing cardiac responses to isoproterenol than it is the bronchiolar responses. Drug X is therefore a cardioselective p-blocker, that is, selective for Pi over P2 receptors. Metoprolol is the only pi-selective antagonist among the choices. 

Eor many years the prevailing view was that p-blockers are contraindicated in CHE. The physiological rationale for not using 3-blockers in heart failure was certainly well founded. Heart failure patients have a decrease in cardiac output. Since cardiac output is a function of stroke volume times heart rate (CO = SV xHR), an increased heart rate would be necessary to maintain an adequate cardiac output in the presence of the relatively fixed decrease in stroke volume observed in CHE. A rapid increase in heart rate does play an important role in the physiological response to acute hemorrhage. Thus, a decrease in heart rate, along with a depression in contractility produced by p-blockers, would be expected to precipitate catastrophic decompensation and this certainly can happen in the acute setting. 

Propranolol and other p-blockers also have been shown to produce an increase in oxygen supply to the subendocardium of ischemic areas. The mechanism responsible for this effect is most hkely related to the... 

Verapamil has been shown to block the P-glycoprotein responsible for the transport of many foreign drugs out of cancer (and other) cells (see Chapter 1) other calcium channel blockers appear to have a similar effect. This action is not stereospecific. Verapamil has been shown to partially reverse the resistance of cancer cells to many chemotherapeutic drugs in vitro. Some clinical results suggest similar effects in patients (see Chapter 54). Animal research suggests possible future roles of calcium blockers in the treatment of osteoporosis, fertility disorders and male contraception, immune modulation, and even schistosomiasis. 

Timolol is a noncardioselective P-blocker without intrinsic sympathomimetic activity (ISA). Antagonism of the P2-adrenoceptor at the ciliary body is primarily responsible for the ocular hypotensive efficacy of timolol. 

Within hours of starting treatment with a P-blocker, blood pressure starts to fall. The mechanism(s) remain uncertain, and the consistency of antihypertensive response in many different types of hypertension may reflect a contribution from a variety of mechanisms. P-blockers are most effective in patients who respond also to ACE inhibitors blockade of renin secretion is likely therefore to be the main cause of blood pressure reduction. An additional contributor may be the 2-3-fold increase in natriuretic peptide secretion caused by P-blockade. 

Pharmacokinetics. For long-term use, any of the oral preparations of P-blocker is suitable. In emergencies, esmolol may be given i.v. (see Table 24.1). Esmolol has a t) of 9 min, which justifies adininistration by infusion with rapid alterations in dose, possibly titrated against response. 

Klug S, Thiel R, Schwabe R, Merker HJ, Neubert D. Toxicity of p-blockers in a rat whole embryo culture concentration-response relationships and tissue concentrations. Arch Toxicol 1994 68 375-384. 

Fig. 5. Physiological consequences of prArg389 and prGly389 expression in hearts of transgenic mice (A,B) results from workperforming preparations in hearts from 3- and 6-month-old mice (C) acute response to the P-blocker propranolol. (From ref. 8, with permission from Nature Publishing Group.)...

Response to P-blocker (heart failure) (-) Arg389, Gly49... 

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