A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Quinaglute Side Effects, and Drug Interactions - Quinidine Gluconate
Quinaglute Side Effects, and Drug Interactions - Quinidine Gluconate
SIDE EFFECTS
Quinidine preparations have been used for many years, but there
are only sparse data from which to estimate the incidence
of various adverse reactions. The adverse reactions most frequently
reported have consistently been gastrointestinal,
including diarrhea,
nausea, vomiting,
and heartburn/esophagitis.
In the reported study that was closest in character
to the predominant approved use of QUINAGLUTE®, 86 adult
outpatients with atrial
fibrillation were followed for six months while they received slow-release
quinidine bisulfate tablets, 600 mg
(approximately 400 mg of
quinidine base) twice daily. The incidences of adverse experiences
reported more than once were as shown in the table
below. The most serious quinidine-associated adverse reactions are
described above under WARNINGS.
ADVERSE EXPERIENCES REPORTED MORE THAN
O.C. IN 86 PATIENTS WITH
ATRIAL FIBRILLATION
| |
(%)
|
Incidence
|
| Diarrhea |
21
|
(24%)
|
| fever |
5
|
(6%)
|
| rash |
5
|
(6%)
|
| arrhythmia |
3
|
(3%)
|
| abnormal electrocardiogram |
3
|
(3%)
|
| nausea/vomiting |
3
|
(3%)
|
| dizziness |
3
|
(3%)
|
| headache |
3
|
(3%)
|
| asthenia |
2
|
(2%)
|
| cerebral ischemia |
2
|
(2%)
|
Vomiting and diarrhea
can occur as isolated reactions to therapeutic
levels of quinidine, but they may also be the first signs of cinchonism,
a syndrome that may
also include tinnitus,
reversible high-frequency
hearing loss, deafness, vertigo, blurred vision, diplopia,
photophobia, headache,
confusion, and delirium. Cinchonism is most often a sign
of chronic quinidine
toxicity, but it may appear in sensitive
patients after a single moderate dose.
A few cases of hepatotoxicity, including granulomatous
hepatitis, have been reported in patients receiving quinidine. All
of these have appeared during the first few weeks of therapy,
and most (not all) have remitted once quinidine was withdrawn.
Autoimmune and inflammatory
syndromes associated with quinidine therapy have included fever,
urticaria, flushing,
exfoliative rash, bronchospasm,
psoriasiform rash, pruritus
and lymphadenopathy,
hemolytic anemia,
vasculitis, thrombocytopenic purpura,
uveitis, angioedema,
agranulocytosis,
the sicca syndrome, arthralgia,
myalgia, elevation
in serum levels of skeletal-muscle
enzymes, a disorder
resembling systemic
lupus erythematosus, and
pneumonitis.
Convulsions, apprehension, and ataxia
have been reported, but it is not clear that these were not simply
the results of hypotension
and consequent cerebral hypoperfusion. There are many reports of
syncope. Acute psychotic reactions have been reported to follow
the first dose of quinidine,
but these reactions appear to be extremely rare.
Other adverse reactions occasionally reported include depression,
mydriasis, disturbed color
perception, night blindness, scotomata, optic
neuritis, visual field
loss, photosensitivity,
and abnormalities of pigmentation.
DRUG INTERACTIONS
Altered pharmacokinetics
of quinidine: diltiazem significantly decreases the clearance
and increases the t1/2 of quinidine, but quinidine does
not alter the kinetics
of diltiazem. Drugs that alkalinize the urine
(carbonic-anhydrase inhibitors, sodium
bicarbonate, thiazide diuretics) reduce
renal elimination
of quinidine.
By pharmacokinetic mechanisms that are not well understood, quinidine
levels are increased by coadministration
of amiodarone or cimetidine. Very rarely, and again
by mechanisms not understood, quinidine levels are decreased by
coadministration
of nifedipine.
Hepatic elimination
of quinidine may be accelerated by coadministration of drugs (phenobarbital,
phenytoin, rifampin) that induce production of cytochrome
P450IIIA4.
Perhaps because of competition
for the P450IIIA4 metabolic pathway, quinidine levels rise when
ketaconazole is coadministered.
Coadministration of propranolol usually does not affect
quinidine pharmacokinetics, but in some studies the b-blocker
appeared to cause increases
in the peak serum levels
of quinidine, decreases in quinidine's volume
of distribution, and decreases in total quinidine clearance. The
effects (if any) of coadministration
of other b-blockers on quinidine
pharmacokinetics
have not been adequately studied.
Hepatic clearance
of quinidine is significantly reduced during coadministration of
verapamil, with corresponding
increases in serum levels
and half-life.
Altered pharmacokinetics
of other drugs: Quinidine slows
the elimination of digoxin and simultaneously reduces digoxin's
apparent volume of
distribution. As a result,
serum digoxin
levels may be as much as doubled. When quinidine and digoxin
are coadministered, digoxin
doses usually need to be reduced. Serum levels of digitoxin
are also raised when
quinidine is coadministered, although the effect
appears to be smaller.
By a mechanism that
is not understood, quinidine potentiates the anticoagulatory action
of warfarin, and the anticoagulant
dosage may need
to be reduced.
Cytochrome P450IID6 is an enzyme
critical to the metabolism
of many drugs, notably including mexiletine, some phenothiazines,
and most polycyclic antidepressants. Constitutional deficiency
of cytochrome P450IID6 is found in less than 1% of Orientals, in
about 2% of American blacks, and in about 8% of American whites.
Testing with debrisoquine is sometimes used to distinguish the P450IID6-deficient
"poor metabolizers" from the majority-phenotype "extensive
metabolizers".
When drugs whose metabolism
is P450IID6-dependent are given to p.o.
metabolizers, the serum
levels achieved are higher, sometimes much higher, than the serum
levels achieved when identical
doses are given to extensive metabolizers. To obtain similar clinical
benefit without toxicity,
doses given to poor metabolizers may need
to be greatly reduced. In
the case of prodrugs whose
actions are actually mediated by P450IID6-produced metabolites (for
example, codeine and hydrocodone, whose analgesic
and antitussive effects appear to be mediated by morphine
and hydromorphone, respectively), it may not be possible to achieve
the desired clinical
benefits in poor metabolizers.
Quinidine is not metabolized by cytochrome
P450IID6, but therapeutic
serum levels of quinidine inhibit the action
of cytochrome P450IID6,
effectively converting extensive metabolizers into p.o.
metabolizers. Caution must be exercised whenever quinidine is prescribed
together with drugs metabolized by cytochrome
P450IID6.
Perhaps by competing for pathways of renal
clearance, coadministration
of quinidine causes an increase in serum
levels of procainamide.
Serum levels of haloperidol are increased when quinidine
is coadministered.
Presumably because both drugs are metabolized by cytochrome
P450IIIA4, coadministration of quinidine causes variable
slowing of the metabolism of nifedipine. Interactions with
other dihydropyridine calcium
channel blockers have not been reported, but these agents (including
felodipine, nicardipine, and nimodipine) are all dependent
upon P450IIIA4 for metabolism,
so similar interactions with quinidine should be anticipated.
Altered pharmacodynamics
of other drugs: Quinidine's anticholinergic, vasodilating,
and negative inotropic
actions may be additive
to those of other drugs with these effects, and antagonistic to
those of drugs with cholinergic, vasoconstricting, and positive
inotropic effects.
For example, when quinidine and verapamil are coadministered
in doses that are each well tolerated as monotherapy, hypotension
attributable to additive peripheral a-blockade is sometimes reported.
Quinidine potentiates the actions of depolarizing (succinylcholine,
decamethonium) and nondepolarizing (d-tubocurarine, pancuronium)
neuromuscular blocking agents. These phenomena are not well
understood, but they are observed in animal
models as well as in humans. In
addition, in vitro addition of quinidine to the serum
of pregnant women reduces
the activity of pseudocholinesterase,
an enzyme that is essential
to the metabolism
of succinylcholine.
Non-interactions of quinidine with other drugs: Quinidine
has no clinically significant
effect on the pharmacokinetics
of diltiazem, flecainide, mephenytoin, metoprolol, propafenone,
propranolol, quinine, timolol, or tocainide.
Conversely, the pharmacokinetics
of quinidine are not significantly affected by caffeine, ciprofloxacin,
digoxin, diltiazem, felodipine, omeprazole, or quinine.
Quinidine's pharmacokinetics
are also unaffected by cigarette smoking.
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