Metabolic blockers

Some drugs are metabolized at particular positions in their skeleton. For example, the oral contraceptive megestrol acetate is oxidized at position 6 to give a hydroxyl group at that position. The introduction of a polar group such as this usually allows the formation of polar conjugates which can be quickly eliminated from the system. 

The introduction of a stable group such as a methyl group at position 6 (Fig 8.6) can block metabolism and so prolong the activity of the drug. 

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No studies were located that specifically address white phosphorus metabolism in humans after oral exposure. However, since orthophosphate is a stable end-product of the inorganic oxidation and hydrolysis of white phosphorus, it is appropriate to examine data on serum phosphate levels in humans following oral ingestion of white phosphorus (these data are discussed further in Section 2.2). Although orthophosphate is the stable end-product, linear and cyclic phosphorus compounds do exist that are stable for relatively long periods, and these may be metabolic blockers especially where phosphorus metabolism is on-going. 

Coronary blood flow is closely tied to oxygen needs of the heart. Changes in oxygen balance lead to very rapid changes in coronary blood flow. Although a number of mediators may contribute to these changes, the most important ones are likely to be adenosine, other nucleotides, nitric oxide, prostaglandins, CO2, and H. Adenosine, which is formed from adenosine triphosphate (ATP) and adenosine monophosphate (AMP) under conditions of ischemia and stress, is a potent vasodilator that links decreased perfusion to metabolically induced vasodilation, or reactive hyperemia. The synthesis and release of adenosine into coronary sinus venous effluent occur within seconds of coronary artery occlusion, and about 30% of the hyperemic response can be blocked by metabolic blockers of adenosine. " ... 

Considerable evidence indicates that glucose penetrates freely into the 0 cell whme it is phosphorylated and metabolized, thus its insulinogenic effect is not prevoited by inhibitors of active transport, such as phlorizin and 3-methylglucose (3-MG), but is markedly decreased by metabolic blockers, such as d-glucosamine. 

Isoflurane is a respiratory depressant (71). At concentrations which are associated with surgical levels of anesthesia, there is Htde or no depression of myocardial function. In experimental animals, isoflurane is the safest of the oral clinical agents (72). Cardiac output is maintained despite a decrease in stroke volume. This is usually because of an increase in heart rate. The decrease in blood pressure can be used to produce "deHberate hypotension" necessary for some intracranial procedures (73). This agent produces less sensitization of the human heart to epinephrine relative to the other inhaled anesthetics. Isoflurane potentiates the action of neuromuscular blockers and when used alone can produce sufficient muscle relaxation (74). Of all the inhaled agents currently in use, isoflurane is metabolized to the least extent (75). Unlike halothane, isoflurane does not appear to produce Hver injury and unlike methoxyflurane, isoflurane is not associated with renal toxicity. 

Sotalol is rapidly and almost completely (>90%) absorbed. Bioavahabhity of absorbed dmg is 89—100%. Peak plasma levels are achieved in 2—4 h. Sotalol is 50% bound to plasma proteins. Plasma half-life of the compound is about 5.2 h. No metabolites of sotalol have been identified indicating littie metabolism. The dmg is excreted mainly by the kidneys (80—90%) and about 10% is eliminated in the feces. The plasma half-life is prolonged in patients having renal failure. Kinetics of the compound are not affected by changes in liver function (1,2). Sotalol has ah the adverse effects of -adrenoceptor blockers including myocardial depression, bradycardia, transient hypotension, and proarrhythmic effects (1,2). 

Betaxolol hydrochloride is a lipophilic, cardioselective -adrenoceptor blocker having no ISA and Httie membrane-stabilizing activity. The dmg is as equieffective and equipotent as atenolol. It is well absorbed from the GI tract, but does not undergo extensive first-pass metaboHsm in the Hver. Its elimination half-Hfe is 15—20 h. It is metabolized in the Hver ( 84%) to two principal inactive metaboHtes and one minor active metaboHte. About 16% of the dmg is excreted unchanged urine. Excretion of the dmg is unchanged in patients having renal or Hver impairment (43). 

Bevantolol hydrochloride is a moderately lipophilic, long-acting, cardioselective -adrenoceptor blocker. It has no ISA but has membrane-stabilizing activity. The dmg is in use in Europe for the treatment of hypertension and angina. It is rapidly absorbed from the GI tract. Peak plasma levels occur in 1—2 h. It is metabolized extensively in the Hver to a metaboHte that has some ISA. It is excreted by the Hver and the kidneys and excretion is delayed in patients having kidney failure. 

Poor Metabolizer Phenotype Population Pharmacokinetics Positron Emission Tomography Post-translational Modification Potassium Channels Potassium Competitive Acid Blockers PP... 

All TCAs are either secondary- or tertiary-amines of a dibenzazepine nucleus (Fig. 20.3), and they all inhibit neuronal reuptake of noradrenaline and/or 5-HT but are much less potent as dopamine reuptake blockers. A common claim is that secondary amines (e.g. desipramine) are preferential inhibitors of noradrenaline uptake whereas the tertiary derivatives (e.g. imipramine, doxepin and amitryptyline) preferentially inhibit 5-HT uptake. However, when Richelson and Pfenning (1984) actually compared the effects of a wide range of antidepressants on the synaptosomal uptake of [ H]monoamines in vitro, and compared their A s, instead of merely ranking /C50S collected from different studies, they found that tertiary- and secondary-substituted compounds were equi-potent inhibitors of [ H]noradrenaline uptake. Moreover, all the TCAs turned out to be more potent inhibitors of [ H]noradrenaline than of [ H]5-HT uptake. Tertiary amines are even less convincing inhibitors of 5-HT reuptake in vivo, because any such action is diminished by their metabolism to secondary amines (e.g. imipramine to desipramine amitriptyline to nortriptyline). Only clomipramine retains any appreciable 5-HT uptake blocking activity in vivo with (an unimpressive) five-fold selectivity for 5-HT versus noradrenaline. 

Because p-blockers decrease blood pressure and heart rate, they should be started at low doses to increase tolerability. Propranolol is hepatically metabolized, and its half-life and pharmacologic effects are prolonged in portal hypertension. A reasonable starting dose of propranolol is 10 mg two to three times daily. 

Hypertension Calcium channel blockers ACE inhibitors ARBs Diltiazem, verapamil inhibit CSA/TAC metabolism Dihydropyridines may potentiate CSA-gingival hyperplasia May exacerbate hyperkalemia monitor K+, SCr to assess for renal allograft vascular disease may be useful in posttranplant erythrocytosis (hematocrit greater than 55%)... 

For compounds not metabolized by the gut wall, liver, or affected by transporters, a direct relationship between oral absorption and bioavailability should be observed. The calculated oral absorption, using PSA as a measure for passive membrane permeability reflecting the absorption step, relates to the in vivo observed bioavailability for three classes of compounds - angiotensin-converting enzymes (ACE) inhibitors, P-blockers, and calcium antagonists - is shown below [25],... 

Fig. 19.7. Correlation between predicted oral absorption based on polar surface area (PSA) and in vivo oral bioavailability for a series of beta-blockers. The nonlinearity is related to the different levels of P-gp efflux and differences in CYP3A4 metabolism of these compounds [25],...

A similar plot was prepared using the PSA and reference curve oral absorption data for a series of p-blockers (Fig. 19.7), with predicted oral absorption data plotted against observed bioavailability. The differences in metabolic behavior were clearly apparent, as were the largely unquantified effects of P-glycoprotein (P-gp) and other possible transporters [25]. 

L The answer is d. (Hardman, p 906.) Cimetidine slows the metabolism of Ca channel blockers, which are substrates for hepatic mixed-function oxidases. Inhibition of cytochrome P450 activity is peculiar to cimetidine and is not a mechanism of action of other histamine 2 (Hz) blockers. 

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