Download The free fraction of quinidine(a) is assumed to be 0.1

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Contents:
- Introduction on Quinidine:
 Generic name
 Brand names
 Preparations
 Drug class and mechanism of action
 Prescription
 Drug-drug interactions
 Side effects
 Overdosage treatment
 Warnings and patient information
- Clinical pharmacokinetics of Quinidine:
 Therapeutic plasma concentration and plasma protein binding
 Bioavailability
 Volume of distribution
 Clearance
 Elimination half-life
 Time to sample
- Discussion of some clinical cases:
 Case 1: a patient with CHF and atrial fibrillation.
 Case 2: quinidine dose adjustment in case of haemodialysis.
 Case 3: a patient with a long history of alcohol abuse, liver
cirrhosis, and premature ventricular contractions, and CHF.
 Case 4: intramuscular dose adjustment in a hospitalized
patient.
 Case 5: intravenous infusion dose adjustment.
 Case 6: evaluating quinidine plasma concentration in a patient
taking a sustained-release quinidine formulation.
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QUINIDINE
QUINIDINE as a drug, falls into two categories:
Antiarrythmic
Antimalarial
However, since quinidine is an important, and one of the majour
antiarrythmic drugs used nowadays, its pharmacokinetic parameters should
be considered, and widely discussed in terms of cardiac arrythmias, as
would be seen further on in this presentation.


Generic name: quinidine
Brand names: QUINAGLUTE, QUINIDEX

Preparations:
Generic quinidine sulfate tablets (200, 300 mg); QUINIDEX extentabs
(300 mg); QUINAGLUTE dura-tabs (324 mg); as well as parentral IV
preparations.

Drug class and mechanism of action:
Quinidine is a sodium channel blocker with Class Ia activity.
In cardiac muscle and in Purkinje fibres, quinidine depresses the rapid
inward depolarizing sodium current, thereby slowing phase-0
depolarization and reducing the amplitude of the action potential without
affecting the resting potential. In normal Purkinje fibres, it reduces the
slope of phase-4 depolarization, shifting the threshold voltage upward
towards zero.
Therefore it is used to correct heart rhythm disturbances (arrhythmias)
and is an antiarrhythmic medication. Three actions are responsible for
quinidine's ability to stop heart rhythm disturbances and prevent their
recurrence:
1- Quinidine decreases the speed of electrical conduction in the heart
muscle.
2- It prolongs the electrical phase during which heart muscle cells
become electrically stimulated (action potential) and prolongs the
5
recovery period during which the heart muscle cells cannot be stimulated
(refractory period).
3-Quinidine also blocks the normal inhibitory effect of the vagus nerve
on the heart, causing an increase in heart rate.
Quinidine reduces the force of contraction of heart muscle cells, and
therefore may further impair the pumping efficiency of a failing heart
muscle.
It also blocks alpha-receptors in peripheral arteries which lowers blood
pressure, and can cause excessively low blood pressure when combined
with other blood vessel relaxing drugs (vasodilators).

Prescription:
Quinidine is an antiarrhythmic drug used in the treatment of abnormal
heart rhythms, such as:
1-Early (premature) atrial and ventricular beats.
2-Intermittent rapid rhythms (tachycardias) involving the atria and AV
junction as well as extra pathways (bypass tracts) between the atria and
ventricles.
3-Intermittent atrial fibrillation and flutter.
4-Sinus rhythm after conversion from atrial fibrillation or flutter to
prevent recurrence.
5-Ventricular tachycardia.

Drug-drug interactions:
Pharmacokinetics of quinidine can be altered by many drugs:
 Diltiazem significantly decreases the clearance and increases the
t1/2 of quinidine, but quinidine does not alter the kinetics of
diltiazem.

Carbonic-anhydrase inhibitors, Sodium bicarbonate, Thiazide
diuretics, i.e drugs which alkalinize the urine, reduce renal
elimination of quinidine (since quinidine is a basic drug).

Amiodarone and Cimetidine reduce the clearance of quinidine
through direct inhibition of microsomal metabolism, resulting in a
higher quinidine serum levels.
6


Nifedipine increases quinidine serum levels, which is presumed to
be due to the decrease in clearance secondary to a decrease in
cardiac output (the decrease in cardiac output is due to the
vasodilator effect of nifedipine)

Phenobarbitone and Phenytoin (anticonvulsant drugs) increase
quinidine clearance due to their liver microsomal enzyme
inductive effect, which results in an accelerated hepatic
elimination.

Verapamil significantly reduces hepatic clearance of quinidine,
resulting in higher quinidine serum levels.

Rifampin accelerates hepatic elimination of quinidine through
liver microsomal enzyme inductive effect.
Side effects:
Quinidine preparations have been used for many years, but there are
only sparse data from which the incidence of various adverse reactions
(side effects) can be estimated. The adverse reactions most frequently
reported have consistently been gastrointestinal, including:
diarrhea and nausea which can occur even at low doses. These
symptoms cause discontinuation of the drug in 1/4 to 1/3 of patients.
Other side effects include vomiting, heartburn(oesophagitis), rash, fever,
dizziness, and headache.
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.
In a reported study that was made on QUINAGLUTE®, 86 adult
outpatients with atrial fibrillation were followed for six months while
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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 shown below:
Diarrhea
Fever
Rash
Arrythmia
Abnormal
electrocardiogram
Nausea/vomiting
Dizziness
Headache
Asthenia
Cerebral ischaemia
(%)
21
5
5
3
3
Incidence
24%
6%
6%
3%
3%
3
3
3
2
2
3%
3%
3%
2%
2%
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.

Overdosage treatment:
Gastric lavage:
Adequate studies of orally-administered activated charcoal in human
overdoses of quinidine have not been reported, but there is at least one
human case report in which the elimination half-life of quinidine in the
serum was apparently shortened by repeated gastric lavage. Activated
charcoal should be avoided if an ileus is present; the conventional dose
is 1 gram/kg, administered every 2-6 hours as a slurry with 8 mL/kg of
tap water.
Accelerated renal elimination:
Although renal elimination of quinidine might theoretically be
accelerated by maneuvers to acidify the urine, such maneuvers are
potentially hazardous and of no demonstrated benefit.
8
Dialysis:
Quinidine is not usefully removed from the circulation by dialysis.
Withdrawal of some coadmministered drugs if found:
Following quinidine overdose, drugs that delay elimination of quinidine
(cimetidine, carbonic-anhydrase inhibitors, thiazide diuretics) should be
withdrawn unless absolutely required.

Warnings and patient information:
Warnings:
1-Check with your doctor before taking quinidine if you have blood,
kidney or liver disease, asthma, an infection, psoriasis (a skin disease),
or overactive thyroid.
2-Tell your doctor or dentist that you are taking quinidine before you
have any kind of surgery.
3-Do not suddenly stop taking this medicine without checking with
your doctor.
4-Talk with your doctor before taking quinidine if you are pregnant or
breastfeeding. although serious side effects are uncommon, it has been
shown to cause mild uterine contractions, premature labour, and blood
problems in the neonate.
5-Quinidine may make you dizzy or drowsy. Be careful if you drive a
car or operate machinery.
6-Ask your doctor or pharmacist before using any other medicine,
including over-the-counter medicines, vitamins, and herbal products
7-Make sure your doctor knows if you are taking other heart medicines
such as Procan®, Lanoxin®, Cordarone®, or Inderal®, blood thinners
such as Coumadin®, acetazolamide (Diamox®), or pimozide (Orap®).
Patient information:
Before prescribing quinidine as prophylaxis against recurrence of atrial
fibrillation, the physician should inform the patient of the risks and
benefits to be expected.
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Discussion should include the facts that the goal of therapy will be a
reduction (probably not to zero) in the frequency of episodes of atrial
fibrillation; and that reduced frequency of fibrillatory episodes may be
expected, if achieved, to bring symptomatic benefit; but
that no data are available to show that reduced frequency of fibrillatory
episodes will reduce the risks of irreversible harm through stroke or
death; and in fact that such data suggest that treatment with quinidine is
likely to increase the patient's risk of death.
This is the reason why physicians prefer not to treat cardiac arrythmias,
unless they become life-threatening.
In the next section, we will discuss the pharmacokinetic
parameters of quinidine, and we shall see their importance in the
treatment of cardiac arrythmias, in patients with different clinical
status.
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Clinical pharmacokinetics of Quinidine
Quinidine is administered orally in the form of quinidine suphate,
gluconate, or polygalacturonate salts, and by slow intravenous infusions as
the gluconate salt.
Usual doses of quinidine are 200 to 300 mg orally 3 to 4 times a day.
Quinidine serum levels must be checked periodically, especially in
patients suffering from congestive heart failure (CHF), liver diseases,
nephrotic syndrome, or in case of recent stress like surgeries, since these
might alter protein binding and clearance of quinidine, and thereby,
significantly influence the interpretation of plasma quinidine
concentrations and related toxicities.
Key parameters
1 – 4mg/L
Therapeutic plasma concentration
Volume of distribution (Vd)
Normal
Chronic heart failure
Chronic liver disease
2.7L/Kg
1.8L/Kg
3.8L/Kg
Clearance (Cl)
Normal
Congestive heart failure
Chronic liver disease
0.28L/Kg/hr
0.17-0.23L/Kg/hr
decreased
Quinidine
Sulphate
Gluconate
Polygalactouronate
S-factor
0.82
0.62
0.62
Plasma protein binding
Half-life of elimination
F
0.7
0.7
0.7
80%-90%
7 hours
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Therapeutic plasma concentration:
Early quinidine assay procedures were less specific, and tended to
measure inactive metabolites of quinidine, resulting in a therapeutic range
more than the one currently used.
As assays became more specific, and utilized extraction techniques, to
eliminate many of the polar compounds of quinidine, the therapeutic range
of quinidine decreased, which is safer.
Specific quinidine assays originally utilized either reversed phase high
performance chromatography (HPLC), or thin layer chromatography
coupled with fluorecence detection procedure.
Current assays used in clinical practice are almost based upon some type
of immunoassay technique, and lead to a typical therapeutic range of
1-4mg/L.
Plasma protein binding:
Changes in plasma protein binding can alter the desired plasma
concentration of quinidine, since the free or unbound drug fraction is the
active fraction.
Quinidine is a basic drug which binds mainly to the plasma protein α1-acid
glycoprotein.
Quinidine is 80% to 90% bound to plasma protein (i.e free fractions (α)
are 0.2 to 0.1 respectively), but in most patients, (α) was found to be 0.1
The patient’s clinical status, determines the desired therapeutic plasma
concentration of quinidine:
Patients with chronic liver disease:
Plasma protein binding is reduced in these patients due to a decrease in the
concentration of α1-acid glygoprotein, secondary to liver impairment.
This would increase the free fraction of quinidine, hence, the desired
plasma concentration for these patients will be lower than usual.
Patients with nephrotic syndrome:
Studies have not been conducted in these types of patients, however it is
known that these patients show low levels of α1-acid glygoprotein in
addition to hypoalbuminaemia.
This would decrease plasma protein binding of quinidine and increases its
free fraction, hence, the desired plasma concentration levels should be
lower than usual.
12
Cases of acute stress:
α1-acid glygoprotein levels are increased in response to stress.
Factors associated with increased levels of α1-acid glycoprotein, appear
common in case of tissue damage, surgeries, wound healing, myocardial
infarction, or inflammatory responses.
Such events tend to increase the total drug concentration (the bound and
unbound fraction) in the plasma with relatively little changes in the free
drug levels.
Since altered plasma protein binding may influence plasma quinidine
concentrations, periodical testing of plasma quinidine levels must be done,
and knowledge of the medical history of the patient is very important in
order to manipulate the doses of quinidine, to be given.
Factors known to alter
α1-acid glycoprotein concentrations
Increased
Tumours
Rheumatoid arithritis
Pulmonary tuberculosis
Acute infection
Obstructive liver disease
Inflammatory bowel disease
Burns
Fractures
Trauma
Surgery
Myocardial infarction
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Decreased
Pregnancy
Oral contraceptives
Cirrhosis
Nephritis
Bioavailability:
Quinidine is approximately 70% bioavailable, regardless the chemical
form in which it is administered (F=0.7). However, a range of 47% to 96%
has been reported.
Quinidine is rapidly absorbed, therefore some physicians, prefer to
prescribe it in the sustained-release form, in order to reduce frequency of
dosing per day.
Volume of distribution (Vd):
The initial volume of distribution of quinidine is 1.0L/Kg, and the
apparent volume of distribution is 2.7L/Kg.
The distribution half life is so brief, 6-12 minutes, i.e it is instantaneous
as in a one-compartment modeling, and this makes the initial volume of
distribution and associated two-compartment modeling, of low
significance following oral administration. Two compartment modeling
need only be considered if quinidine is to be given intravenously.
This can be explained by the following:
In oral administration, the rate of absorption is relatively slow, and the
therapeutic plasma concentration is achieved at a slower rate than in the
case of intravenous administration.
Therefore the amount of drug absorbed from the oral dose, will be rapidly
distributed to the tissues (peripheral compartment), and equilibrium
between central and peripheral compartment is achieved quickly.
The α-phase (or the distribution phase) becomes short, and of no
significance in case of oral administration , thus, the two-compartment
modeling of oral quinidine becomes of no consequence too.
However, two-compartment modeling of quinidine is needed to
demonstrate pharmacokinetics of quinidine when given intravenously.
When intravenous administration of quinidine is required, quinidine is
given in the form of slow intravenous infusion, in order allow the
quinidine concentration in the central compartment to equilibriate with the
quinidine concentration in the peripheral compartment, to prevent possible
acute toxicities due to the rapid and sudden increase in the concentration of
quinidine in the plasma, and which is associated with the distribution
phase.
14
Intravenous quinidine gluconate, in doses less than or equal to 6mg/Kg,
infused over a period of 20 to 30 minutes, are considered slow enough to
allow equilibrium to take place.
Volume of distribution is affected by the clinical status of the patient:
Patients with CHF:
Volume of distribution is decreased to about 1.8L/Kg, due to the decreased
effective blood circulation.
Patients with chronic liver disease:
Volume of distribution increases to about 3.8L/Kg, because of the
decreased protein binding of quinidine in these patients, and this would
increase the free fraction of quinidine, hence, this increase is met by an
increase in volume of distribution.
Patients with nephrotic syndrome:
Due to the decreased plasma protein binding in these patients, the volume
of distribution increases.
In general:
Increased plasma protein binding of quinidine, will result in an increase in
the free fraction of the drug, and therefore the volume of distribution
increases, while the desired plasma concentration is decreased.
Similarly, a decrease in the plasma protein binding of quinidine will result
in a decreased volume of distribution, and therefore the desired plasma
concentration is increased.
Clearance (Cl):
The average clearance of quinidine in a normal patient is 0.28L/Kg/hr
(4.7ml/Kg/min).
Most of the clearance of quinidine is due to microsomal metabolism in the
liver, and only 20% of quinidine clearance is due to renal excretion.
When the urine pH is less than 7, about 20% of administered quinidine
appears unchanged in the urine, but this fraction drops to as little as 5%
when the urine is more alkaline. The net renal clearance is about
0.06L/Kg/hr (1 mL/Kg/min) in healthy adults.
15
Clearance is also affected by the clinical status of the patient:
Patients with CHF:
Clearance of quinidine is decreased in these patients to 0.17 to
0.23L/Kg/hr (3.0 to 3.9ml/Kg/min). This can be due to the diminished
hepatic blood flow, which results in a decreased extraction ratio into the
liver tissues, hence, reduced metabolism and consequently reduced
quinidine clearance.
Patients with chronic liver disease:
Clearance is not affected in case of hepatic cirrhosis, since the increase in
the volume of distribution in these patients, leads to a proportionate
increase in t1/2:
Cl = kd * Vd
And:
kd = 0.693
t1/2
Increase in t1/2  increase in kd
The decrease in kd is compensated by the increase in volume of
distribution, and therefore clearance may appear to remain in the normal
range.
Patients with nephrotic syndrome:
These patients suffer from impaired kidney function, and this will lead to a
decrease in renal clearance, due a decrease in ke:
Renal Cl = ke * Vd
And:
kd = km + ke + kothers
So a decrease in ke, will result in a proportionate decrease in kd.
And similar to the case of liver diseased patients, the decrease in kd is met
by an increase in Vd, and clearance may appear to be normal.
16
There is some evidence that quinidine exibits dose-dependent or
capacity-limited metabolism, i.e its metabolism is a saturable process.
Though non-linear pharmacokinetics for quinidine are not as significant as
for some other drugs like phenytoin, caution should be taken when
quinidine maintenance doses are increased, to make sure that the plasma
concentration at the steady state does not increase excessively.
This is because an increase in dose would not result in a proportional
increase in plasma concentration, and steady state concentration becomes
hardly predictable.
Elimination half-life (t1/2):
Half-life of quinidine is normally about 7 hours.
Half-life time can be represented by the following formula:
t1/2 = 0.693
kd
Since:
kd = Cl
Vd
Then:
t1/2 = 0.693 (Vd)
Cl
In case of a patient suffering from congestive heart failure, the half-life
time of quinidine would not be altered, since Vd and Cl decrease by about
the same proportion.
In case of a patient suffering from chronic liver disease, the half-life time
would increase, because the metabolic capacity for quinidine is diminished
(a decrease in Cl), and the Vd is increased.
In patients that exibit a change in plasma protein binding, but no change in
the metabolism of the free fraction of quinidine, as in the case of nephrotic
syndrome patients, where there is a decrease in plasma protein binding,
both the Cl and Vd are altered proportionaly depending on the relative
magnitudes of kd and Vd according to the following equation:
Cl = kd * Vd
17
If the magnitude of kd was insignificant relative to the magnitude of Vd,
any change in Vd will result in a similar change in Cl, and in the same
direction.
Time to sample:
Constant monitoring of quinidine serum levels is needed, in order to keep
track of the effective quinidine concentration present in the blood.This is
done by periodical analysis of blood samples.
The need of knowing quinidine levels in the serum arises from the fact
that the desired therapeutic plasma concentration varies according to the
clinical status of the patient, and in addition, quinidine in concentrations
higher than the therapeutic plasma concentration, produces acute toxicity
which can be fatal in some cases.
Since the half-life time of quinidine is approximately 7 hours, and 3 to 4
half-lives are required in order to reach 90% of steady state (i.e 21 to 28
hours), the plasma concentration of quinidine in a normal patient, must be
evaluated after about 24 hours of therapy.
The best time to obtain a blood sample for the purpose of evaluating the
plasma concentration for both sustained-release and non-sustained release
formulations of quinidine, is just before the next scheduled dose (at trough
levels).
Plama trough concentrations are more reproducible and can be obtained
using the following equation:
(S)(F)(Dose)
Cpss min =
Vd
. (e-kdt)
(1 – e-kdt)
Also, taking the blood sample when trough level is reached, would help in
avoiding many problems which may be associated with delayed drug
absorption and the uncertainty of when a peak concentration will occur
following an oral dose.
When the drug is taken orally, the peak plasma concentration is reached at
tmax (time of maximum absorption), and the value of tmax in case of oral
18
administration is uncertain, since it depends on the rate of absorption
according to the following equation:
tmax = ln (ka/kd)
ka - kd
Any factor that will delay absorption, will affect tmax, and thereby affecting
the plasma concentration values obtained before reaching trough level.
If patient seemed to develop symptoms of toxicity, or is at a high risk of
developing them (due to sensitivity of the patient to the drug or due to
other complications like CHF), the plasma concentration should be
evaluated even if the time estimated for the drug concentration to reach the
steady state has not elapsed yet.
This early evaluation of the plasma concentration helps the physician to
develop and idea on how to manipulate the dose for a specific patient
according to his clinical status. The dose can be increased if the normal
dose of quinidine did not succeed in reaching the therapeutic plasma
concentration, or it can be decreased if the patient is at high risk of
developing toxicity, or if toxicity symptoms have already started to appear.
However, quinidine concentrations obtained before the passage of two
half-lives, yield very little information about the steady state concentration
that is to develop eventually.
19
Discussion of some clinical cases

Case 1:
a) A 70 Kg male patient with CHF and atrial fibrillation, to be given
quinidine sulphate 300mg orally every 6hrs.
Should the plasma concentration sample be obtained within 24 hours of
starting the therapy?
The answer is no.
This is because a patient with CHF would have the same quinidine halflife time as in a normal patient (7 hours), since there is a proportional
decrease in the Vd and Cl.
The sample can be obtained normally 21 to 35 hours after starting the
therapy.
b) What plasma concentration would be expected in this patient, if
quinidine is assayed by a specific immunoassay?
Is the prescribed quinidine sulphate regimen of 300mg every 6hrs likely to
maintain his plasma quinidine concentration within the therapeutic range?
As said before, plasma trough concentrations are more reproducible,
therefore the plasma sample should be obtained directly before the next
dose of quinidine.
Plasma trough concentration can be obtained using the following equation:
(S)(F)(Dose)
Cpss min =
Vd
. (e-kdt)
(1 – e-kdt)
in this case:
S = 0.82
F = 0.7
Cl = 0.17L/Kg/hr in a CHF patient
Therefore,
Cl = 70Kg * 0.17L/Kg/hr
= 11.9L/hr
20
Vd = 1.8L/Kg in a CHF patient
Therefore,
Vd = 70Kg * 1.8L/Kg
= 126L
Dose = 300mg
t = 6hrs
kd can be calculated from the following formula:
kd = Cl
Vd
= 11.9L/hr = 0.094 = 0.1 hr-1
126L
assuming these above values were correct for this patient, we can find the
plasma trough concentration by substituting these values in the formula
mentioned before:
Cpss min =
=
(S)(F)(Dose)
Vd
. (e-kdt)
(1 – e-kdt)
(0.82)(0.7)(300mg)
126L
. (e-(0.1hr-)(6hr))
(1- e-(0.1hr-)(6hr))
= 1.67mg/L
This plasma trough concentration of 1.67mg/L is within the therapeutic
range of 1-4mg/L.
The peak plasma concentration can be also calculated to ensure that it does
not exceed the therapeutic range:
(S)(F)(Dose)
Cpss max =
Vd
-kdt
(1 – e
21
)
(0.82)(0.7)(300mg)
=
126L
(1 - e-(0.1hr-)(6hr))
= 3.04mg/L
The previously calculated values, demonstrate that the prescribed regimen
for this patient, should produce a plasma concentration of quinidine within
the therapeutic range.
c) The measured trough concentration of quinidine for this patient, 28
hours after the regimen was initiated, was 1.5mg/L. Although this
measured plasma concentration approximated the calculated value and is
within the therapeutic range,the patient was not responding satisfactorily.
The dose of quinidine was increased to 400mg every 6 hours, and a second
trough concentration obtained 15 days later was 3.0mg/L (i.e became
double). If possible errors in the sampling time or in the laboratory assay
technique are ignored, what are the possible explanations for this
disproportionate rise in the quinidine plasma level?
There are many possible explanations for this:
1) The assumed average values for volume of distribution and clearance,
that are based upon laboratory assays performed on several patients,
may not be applicable to this patient.
The true half-life of quinidine in this patient may be longer than the
assumed 7 hours, and since the quinidine plasma concentration was
based upon a plasma sample obtained 28 hours after starting the first
regimen (i.e 300 mg every 6 hours), this plasma concentration of
1.5mg/L may not have represented a steady state concentration if the
half life of quinidine in this patient was more than 7 hours.
2) Since this patient is suffering from CHF, it is possible that his clinical
status has changed. His CHF may have worsened, resulting in a further
decrease in quinidine clearance.
3) If this patient have experienced an injury or a surgery of some kind
recently, the α1-acid glycoprotein levels could have increased, resulting
in more quinidine plasma protein binding, so volume of distribution
decreased, and consequently, clearance was decreased.
22
4) Quinidine may display some dose-dependent or capacity-limited
metabolism.
In case of linear pharmacokinetics, doubling of the dose, will result in
doubling of plasma concentration.
Here, the plasma concentration was doubled without any doubling in
the dose. This is because the linear metabolic process (1st order) of
quinidine at a low dose (300mg), had changed into a non-linear
metabolic process (zero order), due to the increase in the plasma
concentration following the increased quinidine dose (400mg), and this
means elimination became independant of the plasma concentration.
The increase in plasma concentration was not met by an equivilant
increase in clearance, and that is why it remained high.

Case 2:
What quinidine dosage adjustment is required for patients undergoing
haemodialysis?
Quinidine is highly bound to plasma protein, and has a realtively large
volume of distribution, so significant extarction on quinidine from the
plasma during dialysis would not be expected.
However, to determin wether quinidine is likely to be dialysed or not, we
should follow the following procedure:
The first step in this procedure is concerned with the unbound volume of
distribution (the volume of distribution carrying the unbound drug), which
can be obtained from the following equation:
Unbound volume = Vd
of distribution
α
If the weight if the patient is 70Kg, and the apparent volume of distribution
is 2.7L/Kg, the total volume of distribution (or size of compartment
necessary to account for the total amount of the drug in the body) would be
189L (2.7L/Kg * 70Kg).
The free fraction of quinidine(a) is assumed to be 0.1
Unbound volume = Vd
of distribution
α
= 189L = 1890L
23
0.1
This means that the total apparent volume of distribution for quinidine
corresponds to an unbound volume of distribution of 1890L.
The upper limit of unbound volume of distribution for dialyzable drugs is
given as equivilant to 250L.
And since the unbound volume of distribution of quinidine was far more
than that, it means that significant amounts of quinidine are not removed
by haemodialysis, and doses do not need to be adjusted for patients
undergoing haemodialysis.

Case 3:
A 52-year-old, 60Kg male patient, with a long history of alcohol abuse and
liver cirrhosis, developed premature ventricular contractions (PVCs) and
CHF. Quinidine is to be administered to him. What is a reasonable starting
dose for him? What is a reasonable desired quinidine concentration?
The pharmacokinetics of this patient are complex since he is suffering
from both CHF and liver disease.
In case of liver disease:
The decreased concentrations of α1-acid glycoprotein, will decrease
quinidine plasma protein binding, and therefore would increase the free
fraction of quinidine in the blood, consequently, increasing the volume of
distribution.
In fact, the free fraction of quinidine might increase as much as two or
threefold, hence, this means the desired plasma concentration of quinidine
should be decreased to one half or one third the usual value of 1 – 4mg/L.
In case of CHF:
The volume of distribution is decreased, and clearance too.
At first glance, it would seem sensible to halve the usual quinidine dose of
200mg every 6 hours, and the maximum and minimum quinidine plasma
concentrations can be calculated according to the new regimen of 100mg
every 6 hours.
But due to the change in pharmacokinetic parameters induced by the CHF,
this procedure would not be effective.
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This is because the decreased volume of distribution due to CHF, will be
increased by the low plasma protein binding in proportion to the change in
α (free fraction) due to liver cirrhosis.
The same happens with the clearance.
The decreased clearance due to CHF and cirrhosis, will be increased by
the decreased protein binding.
The extent to which the clearance and volume of distribution in this patient
should be adjusted, can not be quantified accurately, but since the average
volume of distribution in case of CHF it is 1.8mg/L, and in case of liver
disease it is 3.8mg/L (i.e doubled), we can assume that the volume of
distribution in this patient will be equal to 3.8mg/L. The decrease in
volume of distribution because of CHF was compensated by a twofold
increase in the volume of distribution due to liver cirrhosis.
The clearance was decreased by both CHF and liver cirrhosis, but because
of the decreased protein binding of quinidine and the increase in its free
fraction, the clearance increased, therefore, we can assume that the
clearance in this patient did not change, and remained as in a normal
patient, i.e equivilant to 0.28L/Kg/hr.
To calculate the steady state and trough concentrations, using the 100mg
dose every 6 hours:
Cl = 0.28L/Kg/hr * 60Kg
= 16.8L/hr
Vd = 3.6L/Kg * 60Kg
= 216L
kd = Cl
Vd
= 16.8L/hr
216L
= 0.078hr-1
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so the plasma trough concentration is calculated as follows:
Cpss min =
(S)(F)(Dose)
Vd
. (e-kdt)
(1 – e-kdt)
(0.82)(0.7)(100mg)
=
216L
. (e-(0.078hr-)(6hr))
(1 - e-(0.078hr-)(6hr))
= 0.44mg/L
and the peak plasma concentration:
Cpss max =
(S)(F)(Dose)
Vd
(1 – e-kdt)
(0.82)(0.7)(100mg)
=
216L
(1 - e-(0.078hr-)(6hr))
= 0.71mg/L
We can observe that the above calculated values, are below the normal
range of quinidine plasma concentration (i.e 1-4mg/L).
But we have to take into consideration the increase in the free fraction of
quinidine due to the decreased plasma protein binding.
As was mentioned before, the free fraction of quinidine might increase by
two or threefold in case of liver disease due to a decrease of about 50% in
the concentration of α1-acid glycoprotein, and therefore, the expected
plasma concentrations of the trough and peak levels are 0.88mg/L and
1.42mg/L respectively.
If the subsequent plasma concentrations were higher than the therapeutic
plasma concentrations, we must consider the following:
The metabolic activity of the liver is worse than expected due to cirrhosis,
or the α1-acid glycoprotein concentration may have not decreased by 50% ,
but by more,
And since it is theoretically hard to predict the degree of quinidine plasma
protein binding, and it is hard to quantitate liver function, the clinical
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status of this patient must be carefully evaluated before introducing any
change to the dose regimen.

Case 4:
A patient who has been receiving 200mg of quinidine sulphate, orally
every 6 hours, has been hospitalized and is now unable to take this
medication orally. What intramuscular dose of quinidine gluconate would
be equivilant to the old regimen?
Since the chemical form of quinidine and the route of administration are
both changed, we have to take into consideration both the S-factor (which
represents the fraction of the drug base –in this case it is quinidine-), and
the F-factor (which represents the availability of the drug from a defined
route of administration).
The amount of quinidine sulphate absorbed, or amount reaching the
systemic circulation, can be calculated as follows:
Amount = (S)(F)(Dose)
= (0.82)(0.7)(200mg)
= 114.8mg
Now it is possible to calculate the equivilant dose of quinidine gluconate
taken intramuscularly:
Dose of IM = amount of quinidine sulphate absorbed orally
(S)(F) of quinidine gluconate
= 114.8mg/L
(0.62)(1)
= 185mg or equivilant to 200mg
As noticed from the above calculations, the dose to be given
intramuscularly is the same as the dose given orally.
The oral dose and intramuscular dose are comparable due to the balancing
effects of their bioavailability and chemical form (salt form), represented
by the F-factor, and S-factor respectively.
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
Case 5:
How can quinidine gluconate be administered safely to a patient, by the
intravenous route?
Quinidine gluconate can be administered intravenously when the required
dose, which less than or equivilant to 6mg/Kg, was diluted in 50 to 100ml
of IV fluid, and infused over 20 to 30 minutes. By this way, we would
allow time for quinidine to distribute itself between the central
compartment and the peripheral one, hence, preventing any possible
toxicity.
It is known that quinidine can block alpha adrenergic receptors when given
by the intravenous route, causing sevre hypotention, and consequently
reflex tachychardia, which would make the already present cardiac
arrythmia worse.
So, during IV infusion if quinidine, the patient’s blood pressure should be
monitored, and if the patient became hypotensive, quinidine infusion is
stopped immediately, and IV fluids are administered.

Case 6:
A 58-year-old, 60Kg male with CHF, has been receiving 300mg of
quinidine sulphate as a sustained-release dosage form every 8 hours.
Calculate the expected steady state trough concentration.
The plasma concentration of quinidine fluctuates little within the dosing
intervals when using a sustained-release dosage form, therefore the
minimum and maximum plasma concentrations are very near to each
other, unlike oral dosing.
So the steady state plasma concentration can be estimated by the following
equation:
Cpss ave = (S)(F)(dose)
(Cl)( Ί )
In this case:
F = 0.7
S = 0.82
Dosing intervals ( Ί ) = 8hrs
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Cl = 0.81L/Kg/hr * 60Kg
= 10.8L/hr
and the steady state plasma concentration is calculated as follows:
Cpss ave = (0.82)(0.7)(300mg)
10.8L/hr * 8hr
= 2.0mg/L
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