Comparison of P2Y12 receptor inhibition by clopidogrel and prasugrel in patients undergoing percutaneous coronary intervention.

Dual antiplatelet treatment (DAPT) with aspirin and clopidogrel is vital after percutaneous coronary intervention (PCI). Clopidogrel and prasugrel act on P2Y12 platelet surface receptors. Both these P2Y12 inhibitors are pro-drugs and depend on cytochrome system of the liver for their conversion to active metabolite. There is growing concern regarding suboptimal response in platelet inhibition by clopidogrel. Verify Now system got approval by Federal Drug Administration, USA, for assessing platelet function as its result is almost comparable to gold standard Light Transmission Aggregometry (LTA). There are no data on the prevalence of clopidogrel resistance in Bangladeshi population. Prasugrel, as an antiplatelet drug, is a newer introduction in this country. This study will show light on the efficacy of these drugs on our population especially in patients who undergo PCI where DAPT is mandatory. A total 120 (60 diabetics) patients with Acute Coronary Syndrome (ACS), were alternatively given 600 mg clopidogrel loading dose (LD) followed by 75 mg maintenance dose (MD) daily or 60 mg LD of prasugrel followed by 10 mg MD daily. Five samples of blood were taken at different time intervals over a period of 2 weeks. Measurement of percent inhibition of P2Y12 was done by VerifyNow. Patients who showed less than 20% inhibition (clopidogrel resistant) at any stage were switched to prasugrel. The outcomes of clopidogrel, prasugrel and clopidogrel switched to prasugrel groups were then compared. Nearly half (46.7%) of the patients in the clopidogrel group was found resistant to the drug as opposed to none in the prasugrel group. No difference was found between diabetic and non-diabetic subjects with respect to drug resistance. Intracoronary blood samples showed high degree of platelet inhibition with prasugrel. There was a gradual decline of platelet inhibition over two weeks with prasugrel. Almost fifty percent of the population is clopidogrel resistant in our study. Prasugrel is a much more potent antiplatelet drug and should be preferred in patients undergoing PCI. Prasugrel may also show resistance over time.

Acute statin treatment in reducing risk after acute coronary syndrome: the MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) Trial.

Three-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors (statins) reduce coronary events and death in both primary and secondary prevention trials. In these trials benefit did not appear for years after randomization. It is noteworthy that these trials did not include patients with recent myocardial infarctions or unstable angina. It is well known that mortality and recurrent ischemic events rates are the highest in the early period after acute coronary syndromes. Favorable physiologic effects of statins have been described within a few weeks of exposure to the statin in a number of experimental studies. The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study was designed to bridge the gap between primary and secondary prevention trials and specifically included patients with unstable angina or non-ST elevation myocardial infarction.

The influence of dose and ethnic origins on the pharmacokinetics of nifedipine.

The pharmacokinetics of nifedipine capsules was investigated in healthy young Caucasian and South Asian subjects. Both the area under the plasma concentration-time curve (AUC) and terminal half-life of nifedipine were significantly higher in South Asians compared with Caucasian subjects after single oral doses of 10 and 20 mg. The AUC and half-life values of the nitropyridine metabolite were also higher in South Asians than in Caucasian subjects. The serum protein binding of nifedipine was similar in the two groups. The pharmacokinetics were essentially linear in both Caucasian subjects (0 to 30 mg; n = 27) and South Asians (0 to 20 mg; n = 16). There was no indication of a separate subgroup of Caucasian subjects with high AUC values equivalent to the poor metabolizers reported previously. Pharmacodynamic modeling for South Asians gave estimates comparable to those previously reported in Caucasian subjects. Patients of South Asian origin may require lower doses of nifedipine.

The influence of posture on the pharmacokinetics of orally administered nifedipine.

1. Nifedipine (20 mg as capsules) and soluble paracetamol (1 g) were co-administered to eight healthy young volunteers on three separate occasions, following which in random order they stood, lay on their left side or lay on their right side for 4 h. 2. The time to maximum plasma concentration of paracetamol was significantly lower when standing or lying on the right side compared with recumbent left, indicating more rapid gastric emptying. 3. The times to maximum plasma concentrations of nifedipine and its metabolite produced at first pass were reduced when standing or lying on the right side. These postures were associated with significantly higher peak plasma concentrations and AUC values of nifedipine but not of its nitropyridine metabolite. 4. The increase in heart rate following nifedipine administration was significantly greater when lying on the right side compared with the left. 5. The data are consistent with transient saturation of first pass metabolism of nifedipine with postures which favour rapid gastric emptying. The results demonstrate the importance of defining the precise posture in studies in which pharmacokinetic and pharmacodynamic measurements are made on drugs which are absorbed rapidly and are subject to presystemic elimination.

Ethnic differences in the pharmacokinetics of oral nifedipine.

1. The pharmacokinetics of a single oral dose of 20 mg nifedipine, given as capsules, has been compared in five South Asian volunteers with data for 27 Caucasian volunteers. 2. The area under the plasma concentration-time curve (AUC) of nifedipine was three fold higher in South Asians (989 +/- 166 ng ml-1 h) than in Caucasians (323 +/- 116 ng ml-1 h). 3. The ratio of the AUC of nifedipine to that of the nitropyridine analogue, which is formed largely as a first pass metabolite, was significantly higher in South Asians (4.6 +/- 1.9) than in Caucasians (2.3 +/- 1.1) indicating a lower first pass metabolism in South Asians. 4. The terminal half-lives of nifedipine and the nitropyridine metabolite were significantly greater in South Asians than in Caucasians. 5. Consumption of a spicy curry diet for 3 days by Caucasians did not significantly affect the pharmacokinetics of a single oral dose of nifedipine. 6. The treatment of patients of South Asian origin with nifedipine should be initiated with lower doses than would be given to Caucasians.