Subject Quinidine

Quinidine sulfate 600 mg, given one hour before intravenous morphine sulfate 150 mierograms/kg, did not alter morphine-induced miosis in healthy subjects. However, the same dose of quinidine given before oral morphine sulfate 30 mg (with ondansetron as an antiemetic) increased morphine-induced miosis by 56%. This increase was considered proportionate to the increase in morphine AUC (60%) and maximum level (88%). There was no change in the elimination half-life of morphine. Similarly, in another study in healthy subjects, quinidine 800 mg, given one hour before intravenous morphine 7.5 mg did not alter the respiratory depressant nor mitotic effects of morphine, and there was no change in plasma morphine or morphine glucuronide levels. ... 

Nifedipine serum levels In a study in 10 healthy subjects quinidine sulfate 200 mg every 8 hours increased the AUC of nifedipine by 37%, and heart rates were significantly increased. Quinidine levels were unchanged. Another study found that quinidine had a modest inhibitory effect on the metabolism of nifedipine (half-life prolonged by 40%). A further study in 12 healthy subjects found that the AUC of a single 20-mg dose of nifedipine was increased 16% by quinidine 200 mg and its clearance was reduced by 17%, but these modest changes were not considered clinically relevant. ... 

In a single-dose study in 6 healthy subjects, quinidine sulfate 400 mg, given one hour before moxonidine 200 micrograms, caused a minor 11% increase in the AUC of moxonidine and decreased its clearance by 10%. These small changes are unlikely to be of any clinical relevance. ... 

In a study in 5 healthy subjects quinidine 50 mg given 1 hour before a single 50-mg dose of nortriptyline increased the nortriptyline AUC... 

Of the other cinchona bases, the dextrorotatory forms cinchonine and quinidine have been used as anti-malarial drugs in cases of idiosyncrasy to quinine, a subject to which Dawson has given much attention. Quinidine is used to eontrol auricular fibrillation, and its value for this purpose in comparison with dihydroquinidine has been investigated by several workers. Dawes has recently devised a method of testing... 

D6 Desipramine, dextromethorphan, atomoxetine Paroxetine, quinidine, fluoxetine (use of PM vs. EM subjects) None identified... 

Spectra for the diastereoisomeric pairs quinine-quinidine, cinchonine-cinchonidine alkaloids are mirror images of each other and mixtures have been determined using CD detection [57]. Spectra for the pilocarpine-isopilocarpine pair were such low quality that they could be used only for qualitative distinction. CD detection combined with UV detection was used to measure enantiomeric excesses in mixtures of L-hyoscyamine and atropine, i.e. racemic hyoscyamine. This subject is returned to in greater depth later. 

Administration of the CYP2D6 inhibitor quinidine, 200 mg/day for 2 days, to the extensive metabolizers reduced the oral clearance of venlafaxine to the level seen in poor metabolizers. Quinidine had no effect on venlafaxine clearance in subjects who were poor metabolizers before treatment. The authors suggested that poor metabolizers may be at particular risk of venlafaxine toxicity, as could subjects who take inhibitors of CYP2D6. 

After single oral doses of 4.5 mg/kg of quinidine sulphate to 10 subjects, peak plasma concentrations of 0.9 to 1.8 xg/ml (mean 1.2) were attained in about 50 minutes (T. W. Guentert et al., J. Pharmacokinet. Biopharm., 1979, 7,315-330). 

Following daily oral doses of 8 to 19 mg/kg (mean 12) to 5 subjects, steady-state serum concentrations of 0.5 to 2.5 pg/ml (mean 1.8) of quinidine, 0.38 to 0.94pg/ml (mean 0.55) of 3-hydroxyquinidine, and 0.02 to 0.12 pg/ml (mean 0.07) of quinidin-2 -one, were reported following daily oral doses of 8.6 to 13.3 mg/kg (mean 10.7) to 8 subjects with mild renal dysfunction, steady-state serum-quinidine concentrations ranged from 1.4 to 3.6 ig/ml (mean 2.3) (D. E. Drayer et al., Clin. Pharmac. Ther., 1978,24,31-39). 

FIGURE 19.3 Predicted changes in QT interval after administration of intravenous (dotted line) and oral (solid line) single doses of quinidine to healthy subjects (12). The delay in effect lAuth respect to plasma concentration causes hysteresis loops. The slope of the biophase concentration effect relationship is greater after oral doses due to active metabolites formed during quinidine absorption. (Reproduced with permission from Holford NHG, Coates PE, Guentert tW, Riegelman S, Sheiner LB. Br J Clin Pharmacol 1981 11 187-95.)... 

The membrane-stabilizing activity of beta-blockers can play a major role in toxicity. Of 208 deaths in subjects who had taken beta-blockers, 206 occurred with drugs that have membrane-stabilizing activity. This quinidine-like effect can be reversed by sodium bicarbonate, which is also used to counteract the cardiotoxic effects of cyclic antidepressants, which also have membrane-stabilizing activity. 

The effects of quinidine sulfate, 50 mg orally, an inhibitor of cytochrome CYP2D6, on the metabolism of dextromethorphan 50 mg have been studied in seven healthy volunteers in a randomized, double-blind, crossover, placebo-controlled study (24). Quinidine suppressed the conversion of dextromethorphan to dextrorphan in extensive metabolizers to the extent seen in poor metabolizers. The increased concentrations of dextromethorphan increased subjective and objective pain thresholds by 35 and 45 % respectively. This result suggests that debriso-quine/sparteine-type polymorphisms account for important differences in the effect of dextromethorphan and the balance between the analgesic effect of dextromethorphan and the hallucinogenic effect of dextrorphan. Concomitant use of quinidine or other inhibitors of CYP2D6 could... 

Flecainide is metabolized by CYP2D6, and is subject to poljmorphic metabohsm. In extensive metabolizers its clearance is reduced by quinine (74). Quinidine reduces the clearance of R-flecainide but not that of 5-flecainide (75). 

Fig. 2. Comparison of the concentrations of quinine, quinidine, cinchonine, and cinchonidine in the plasma of human subjects following ingestion of 10 mg. per kg. doses of these drugs.

D6 Desipramine, dextromethorphen Quinidine, paroxetine (use of PM subjects) Not identified... 

In contrast to caffeine, propafenone coadministration significantly reduced the metabolism of both enantiomers of mexiletine in EMs [132]. However, it did not have a significant effect on the pharmacokinetics of mexiletine enantiomers in PMs. In fact, after coadministration of propafenone to EMs, the plasma concentration-time profiles and pharmacokinetics of mexiletine enantiomers in these subjects were not distinguishable from those in PMs [132]. These results are in agreement with the inhibitory effects of propafenone on the CYP2D6 pathway and are similar to those obtained with quinidine, another CYP2D6 inhibitor (Table 13). 

The membrane transfer of drugs that are substrates for a particular transporter will change when that transporter is subject to another drug that induces or inhibits its activity. For example, the action of P-glycoprotein can be inhibited by quinidine, verapamil, erythromycin, clarithromycin and the statins. Inhibition of this transporter can interfere with its ability to keep loperamide out of the brain, resulting in opioid effects in the central nervous system. Similarly,... 

A placebo-controlled study in 12 healthy subjects found that quinidine 50 mg had virtually no effect on the analgesic effects of tramadol 100 mg but it inhibited its effect on pupil size. The manufacturers say that quinidine increases the tramadol AUC and maximum level by 25%, but this is within the normal pharmacokinetic variation seen with tramadol. Tramadol is partially metabolised to the active metabolite O-desmethyltramadol (which affects opioid receptors), by the cytochrome P450 isoenzyme CYP2D6, and it is this enzyme that is inhibited by quinidine. Blockade of the production of this metabolite appears to have little effect on the analgesic effect of tramadol. No special precautions seem to be needed. 

Quinidine, given as 200 mg 3 hours before and 100 mg 6 hours after a single 20-mg dose of oxycodone almost completely inhibited the formation of the metabolite, oxymorphone in 10 healthy extensive metabolisers of the cytochrome P450 isoenzyme CYP2D6. Despite this, the psychomotor and subjective effects of oxycodone were not altered (note that analgesia was not assessed). The AUC of the metabolite noroxycodone was increased about 85%, and the oxycodone AUC was slightly increased by 13%. Similar results were found in the preliminary report of another study. ... 

A study in 4 healthy subjects found that if a single 200-mg oral dose of quinidine was given with a single 50-mg oral dose of ajmaline, the AUC of ajmaline was increased 10- to 30-fold and the maximum plasma concentrations increased from 18 to 141 nanograms/mL. Another single-dose... 

Morike K, Roden D. Quinidine-enhanced p-blockade during treatment with propafenone in extensive metaboUzer human subjects. CUn Pharmacol Ther(y994) 55, 28-34. 

In a study in healthy subjects fluoxetine 20 mg daily for 10 days decreased the oral clearance of a single 400-mg dose of propafenone by 34% for both the R- and 5-enantiomers. The peak plasma levels increased by 39% for 5-propafenone and by 71% forR-propafenone. However, there were no differences in the changes to the PR and QRS intervals. Fluoxetine is an inhibitor of the cytochrome P450 isoenzyme C YP2D6, which is responsible for the metabolism of propafenone to its primary active metabolite 5-hydroxypropafenone (for more detail see mechanism under Propafenone -i- Quinidine , above). In vitro data have shown that, of the SSRIs, fluoxetine is the most potent inhibitor of propafenone 5-hydroxylation, and that paroxetine would also be expected to interact. As with... 

A patient on quinidine who took eight Afy/ow/a tablets daily (aluminium hydroxide gel 200 mg, magnesium hydroxide 200 mg and simeticone 20 mg) for a week and a little over 1 litre of fruit juice (orange and grapefruit) each day developed a threefold increase in serum quinidine levels (from 8 to 25 mg/L) and toxicity. However, note that the grapefruit juice , (p.280) may have contributed. In 6 healthy subjects, this dose oiMylanta for 3 days produced consistently alkaline urine in 4 subjects, and in 5 subjects when combined with fruit juice. ... 

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