Download Quinidine

Quinidine
 It
is used for atrial fibrillation & other
arrhythmias. It is given orally as sulfate,
gluconate or polygalacturonate salts &
in slow IV infusion as gluconate salt.
The usual dose is 200-300mg orally 34times.
 So they are used as anti-arrhythmic &
as anti-malarial drugs.
Generic name
 Quinidine.
Brand names
 It
is found in markets under those
names Quinaglute, Quinidex
Preparations
 They
are found as sulfate salt tablets of
200, 300 & 300SR.
 As IV preparation.
Mechanism of action
It is a sodium channel blocker, it depolarize &
reduce the amplitude of the action potential
without affecting the resting potential.
 Quinidine has the ability to stop heart rhythm
& prevent recurrence & this is by decreasing
the speed of conduction, prolonging the
electrical phase (action potential) & recovery
period & blocks vagus nerve causing an
increase in heart rate.
 It also blocks α-receptor in arteries, which
cause hypotension.

Drug-Drug interactions
Diltiazem:
 This decreases clearance & increase t1/2 of
quinidine.
 Carbonic anhydrase inhibitors:
 Any drug that alkalinize urine will reduce
renal elimination of quinidine
 Amiodarone & cimetidine:
 This reduces quinidine clearance through
inhibiting microsomal metabolism

Nifedipine:
 It increase quinidine blood level due to
decrease in secondary clearance to a decrease
in cardiac output (vasodilatation effect of
nifedipine)
 Phenobarbitone & phenytoin:
 They increase quinidine clearance due to their
microsomal enzyme stimulation.
 Verapamil:
 Reduces hepatic clearance of quinidine

 Rifampin:
 Increase
hepatic elimination of
quinidine through liver microsomal
enzyme stimulator.
Side effects
 It
commonly causes diarrhea & nausea,
which can occur even at low doses
 Other S.E are vomiting, heartburn,
rash, fever, headache, tinnitus, blurred
vision & other cinchonism S.E.
Pharmacokinetics Property
We are going now to discuss the
pharmacokinetics parameters of quinidine
plus different clinical cases
Therapeutic plasma
concentration
The specific quinidine assays originally
utilized either by high performance LC or
TLC coupled with a florescence detection
procedure but the current assays used in
clinical practice are almost always based
upon some type of immunoassay technique
so this is specific & lead to a therapeutic
range of 1-4mg/L.
 It is bounded to α1-acid glycoprotein & it is
known that Quinidine free fraction is ≈ 0.1 for
most patients.


This free fraction will be increased in case of
some diseases as chronic liver disease & this
is due to decrease in the concentration of α1acid glycoprotein & it is also known in
nephrotic
patients
&
in
case
of
hypoalbuminemia & this will result in lower
therapeutic plasma concentrations. This
plasma protein binding is increased following
acute stress.
Factors known to alert α1-acid
glycoprotein concentrations
 Table
Bioavailability
 It
is ≈ 70% bioavailable & it is rapidly
absorbed & has half-life of seven hours
so some prefer to use SR quinidine. For
all quinidine salts the bioavailability is
equal to 0.7
Volume of distribution
The initial Vd is 1 L/Kg & the apparent Vd is ≈
2.7 L/Kg so when IV administration is required
it should be slow infusion so that to
equilibrate between central Vd & tissue Vd
for ex. IV dose of quinidine gluconate ≤6mg/Kg
infused over 20-30mins.
 In some disease Vd of quinidine decreases as
in CHF ≈ 1.8L/Kg & others will increase Vd as
in chronic liver disease ≈ 3.8L/Kg & this is due
to decrease in plasma protein binding of
quinidine. A Vd as large as 9.7L/Kg has been
reported in one patient.

Factors associated with α1-acid glycoprotein
will decrease volume of distribution & visversa.
 The loading dose of quinidine will remain
unchanged from that of patient with normal
plasma protein binding & this due to that
change in apparent Vd is due to change in
protein binding so if quinidine plasma
concentration is lower, the Vd will be larger.

Clearance
The average clearance is 4.7ml/Kg/min or
0.28ml/Kg/hr, most clearance is due to
metabolism & only 20% is due to excretion.
 Clearance is decreased in patients with CHF
due to hepatic blood flow diminished.
 Clearance value for patients with liver disease
is calculated from the increased free drug
concentration & this reveal impaired
metabolic capacity but not calculated from
total plasma concentration because it may
appear normal.

Co-administration of quinidine with
nifedipine will increase quinidine conc. due
to decrease in clearance to a decrease in
cardiac output.
 Amiodarone & cimetidine reduce Cl through
direct inhibition of microsomal metabolism
while phenytoin & Phenobarbital increase
quinidine Cl due to enzyme induction.

 Quinidine exhibits dose-dependent or capacity-
limited metabolism. The non-linear
pharmacokinetics for quinidine are not significant
as for phenytoin so some caution should be
used when quinidine maintenance doses are
increased to ensure that the final S.S conc. is not
excessive.
Elimination half-life
 The
usual half-life of quinidine is 7hrs
& it is not affected by CHF because Vd
& Cl are decreased by the same
proportion.
t1/2 = (0.693 X Vd)/Cl
 It
is increased in patients with chronic
liver disease because metabolic capacity
is diminished & Vd is increased
t1/2 = (0.693 X Vd) / Cl
Pharmacokinetics Key
parameters
 Table
Time to sample
3-4 half-lives are required to reach 90% of S.S,
Cp should be evaluated after 24hrs of therapy
& the best time to obtain a blood sample is
just before the next scheduled dose.
 If symptoms of toxicity appears on patient
blood sample should be evaluated even if we
didn’t reach the S.S & this will help in
deciding to stop the drug or to reduce the
dose.

Clinical Cases
Case-1
1
 A 70 kg male patient with CHF and a trial
fibrillation, to be given quinidine sulphate
300mg orally every 6hrs.
 Should the plasma concentration sample be
obtained within 24 hours of starting the therapy ?
Answer-1
 The answer is no.
 This is because a patient with CHF would have
the same quinidine half-life 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.
2
 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 ?
Answer-2
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)

…………(1)
in this case :
 S = 0.82
 F = 0.7
 C1 = 0.17L/Kg/hr in a CHF patient
 Therefore,
 C1 = 70 Kg* 0.17L/Kg/hr

= 11.9L/hr
 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 = 0.1hr –1

 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
 From equation 1
 Cpssmin = (0.82)(0.7)(300mg)

126L
. (e –(0.1hr-) (6hrs))

= 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)

Vd

Cpss max =_________________

(1 – e –kdt)

(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.

Cpssmax
3
2. 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 very 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 ?

Answer-3
a. 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 300mg 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.
b. 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.
c. 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.
d. 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
independent of the plasma concentration. The increase
in plasma concentration was not met by an equivalent
increase in clearance, and that is why it remained high.
CASE - 2
 What quinidine dosage adjustment is required
for patients undergoing haemodialysis ?
Answer of case-2
Quinidine is highly bound to plasma protein in case of
renal failure, and has a relatively large volume of
distribution, so significant extraction of quinidine from
the plasma during dialysis 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

0.1
 This is 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 equivalent 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 reasonable
desired quinidine concentration?
Answer-3
The pharmacokinetics of this patient are complex since
he is suffering from both CHF and liver diseases.
 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 to the new regimen of
100mg every 6 hours.
 But due to the change in pharmacokinetics parameters
induced by the CHF, this procedure would not be
effective.

 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 two fold 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. equivalent to 0.28L/Kg/hr).
 To calculate the steady state and trough concentrations,
using the 100mg dose every 6 hours :

C1 = 0.28L/Kg/Hr*60Kg

= 16.8L/Hr
 Vd = 3.6L/Kg*60Kg

= 216L
 Kd = Cl

V

= 16.8L/hr

216L

= 0.078hr –1

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-)(6hrs))

_________________

(1 – e -(0.078hrs-)(6hr))

= 0.44mg/L

and the peak plasma concentration

(S)(F)(Dose)

Cpss max =
Vd







-------------------------(1 – e –kdt)
= (0.82)(0.7)(100mg)
216L
________________
(1 – e –(0.078hr-)(6hr))
= 0.71mg/L
We can observe that the above calculation 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 that the therapeutic plasma concentrations, we
much consider the following :
 The metabolic activity of the liver in worse than
expected due to cirrhosis, and 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 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 6hrs, has been
hospitalized and is now unable to take this
medication orally. What intramuscular dose of
quinidine gluconate would be equivalent to the
old regimen?
Answer-4
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 the 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 equivalent 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 equivalent 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 Ffactor, and S-factor respectively.
CASE – 5
 How can quinidine gluconate be administered
safely to a patient, by the intravenous route?
Answer-5
 Quinidine gluconate can be administered
intravenously when the required dose, which
less than or equivalent 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 know that quinidine can block alpha adrenergic
receptors when given by the intravenous route, causing
sever hypotention, and consequently reflex
tachychardic, which would make the already present
cardiac arrhythmia 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 and administered.

It is know that quinidine can block alpha adremergic
receptors when given by the intravenous route, causing
sever hypotention, and consequently reflex
tachychardic, which would make the already present
cardiac arrhythmia 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 and 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 ?
Answer-6
The plasma concentration of quinidine fluctuates little
within the dosing intervals when using a sustainedrelease 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) ( T)

In this case :
 F = 0.7
 S = 0.82
 Dosing intervals (T) = 8 hrs
 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
Mohammed Towfiq Abu Al Neaj
9850163