Nifedipine, inhibition increases

After careful pharmacokinetic assessment of the effects of fluconazole withdrawal on 24-hour ambulatory blood pressure and nifedipine plasma concentration, the authors concluded that fluconazole can enhance the blood-pressure lowering effects of nifedipine by increasing its plasma concentrations, most likely by inhibiting CYP3A4. 

During activation of postganglionic sympathetic nerves there is an exocytotlc release of norepinephrine which is dependent upon the movement of calcium across the neural cell membrane. The effects of CEB on stimulus-secretion coupling in S3nnpathetlc nerves has been studied in several different preparations. Verapamil does not affect the neural release of norepinephrine in either Isolated cat heart or in the pithed rat. In the latter model nifedipine blunted increases in blood pressure due to activation of sympathetic nerves but did not affect cardiovascular responses to exogenous norepinephrine suggesting a prejunctional site of inhibition. 

The manufacturers note that the AUC of repeated-dose nifedipine was increased 1.4-fold by quinupristin/dalfopristin, and the maximum level was increased by 1.18-fold. This is probably because quinupristin/dalfopristin inhibits the cytochrome P450 isoenzyme CYP3A4-mediated metabolism of nifedipine. Although the clinical relevance of these increases have not been assessed, the manufacturers advise blood pressure monitoring and, if necessary, a reduction of nifedipine dosage during concurrent use. It is predicted that other calcium-charmel blockers (e.g. verapamil, diltiazem) will also have their levels raised by quinupristin/dalfopristin. ... 

Figure 3 K+ channels are the effectors in the O2 constriction of the DA. (a) A freshly isolated human DA ring, studied in hypoxia to mimic in utero conditions, constricts to 4-aminopyridine and normoxia. The L-lype Ca " channel blocker nifedipine inhibits the constriction to 4-aminopyridine suggesting that constriction occurred because of 4-aminopyridine-induced depolarization, increased opening of the L-lype Ca " chaimels, and an influx of Ca +. (From Ref. 107.) (b) Patch-clamp studies of isolated rabbit DASMC show an 02-induced inhibition of K" " current, similar to that achieved by 4-aminopyridine. (From Ref 12.)...

Grapefruit juice Coadministration of nifedipine with grapefruit juice results in up to a twofold increase in AUC and Cmax) due to inhibition of CYP3A4-related first-pass metabolism. This effect of grapefruit juice may last for at least three days. Administration of nifedipine with grapefruit juice is to be avoided... 

Coadministration of nifedipine and grapefruit juice resulted in an approximately twofold increase in nifedipine area under the curve (AUC) and Cmax with no change in half-life. The increased plasma concentrations are most likely due to the inhibition of CYP3A4-related first-pass metabolism. 

Drugs metabolized by CYP that interact with cimetidine include, but are not limited to, the following lidocaine, quinidine, midazolam, triazolam, nifedipine, verapamil, and fentanyl (4). In each instance, inhibition of CYP by cimetidine results in reduced metabolic clearance and increases in serum concentrations of the other drug, which can lead to the expected toxicity and adverse experiences characteristic of the other drug. 

Calcium antagonists (felodipine, nifedipine, Grapefruit juice Increased bioavailability inhibition of first-pass... 

Bone resorption in response to continuous mechanical deformation appears to be regulated by cells of osteoblast lineage such as preosteoblasts, osteoblasts, bone lining cells and osteocytes, and stretch-enhanced, osteoclastlike cell formation involves prostaglandins, but not PGE2 (Soma et al., 1996). Stretch-induced increases in osteopontin and osteonectin were inhibited by addition of the calcium channel antagonist nifedipine suggesting an important role for L-type calcium channels in early mechanical strain transduction pathways in osteoblasts. 

Cytochrome P450 3A4 is highly expressed in the human small intestinal mucosa, and is responsible for the metabolism of cyclosporine, midazolam, clozapine and saquinavir during passage across the intestinal mucosa. Indeed, inhibition of presystemic metabolic processes is likely to be a factor in a 34% to 103% increase in the bioavailability of nifedipine observed in individuals consuming grapefruit juice. 

Because of effects on smooth muscle, the calcium channel blockers (particularly verapamil (96) but also diltiazem) can cause constipation. This may be due to colonic motor activity inhibition (97). Gastroesophageal reflux can also occur, and the calcium channel blockers should be avoided in patients with symptoms suggestive of reflux esophagitis (98). Calcium channel blockers (verapamil, diltiazem, and nifedipine) can also be associated with an increased incidence of gastrointestinal bleeding, as reported in a prospective cohort study in 1636 older hypertensives, with a relative risk of 1.86 (95% Cl = 1.22, 2.82) compared with beta-blockers (7). However, this finding was not confirmed in other retrospective studies (13,99,100). 

The histamine H2 receptor antagonist cimetidine increases plasma concentrations of nifedipine and delays its elimination by inhibition of hepatic mono-oxygenases. Maximum plasma nifedipine concentrations and AUC can be increased by as much as 80%, and this results in a significant increase in the antihypertensive and antian-ginal effects of nifedipine and also toxicity (191,192). 

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