Download Quinidine S

Clinical Pharmacokinetics of
Quinidine
Student’s Name: Mohammed Towfiq
S.No: 9850163
Abu Al Neaj
Directed by:
Dr. Rafiq Abou Shaaban
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Uses of quinidine:
They are used as anti-arrhythmic & as anti-malarial.
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 3-4times.
Generic name:
Quinidine
Brand name:
Quinaglute, Quinidex
Preparations:
They are found as sulfate salt tablets of 200, 300 & 300SR & as IV
preparation
Drug class & 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 Parameters
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 α 1-acid
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
Increase
Tumors
Rheumatoid arthritis
Rheumatic fever
Pulmonary tuberculosis
Acute infections
Obstructive liver disease
Inflammatory bowel disease
Burns
Fractures
Trauma
Surgery
Myocardial infarction
Decrease
Pregnancy
Oral contraceptive
Cirrhosis
Nephritis
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 & vis-versa.
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.
It is increased in patients with chronic liver disease because metabolic
capacity is diminished & Vd is increased
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.
Key parameters
Therapeutic plasma conc.
1 – 4 mg/L
Volume of distribution (Vd)
Normal
Chronic heart failure
Chronic liver disease
2.7 L/Kg
1.8 L/Kg
3.8 L/Kg
Clearance (Cl)
Normal
Congestive heart failure
Chronic liver disease
0.28 L/Kg.hr
0.17 – 0.23 L/Kg.hr
Decreased
Quinidine
Sulphate
Gluconate
Polygalacturonate
Plasma protein binding
S – factor
0.82
0.62
0.62
F
0.7
0.7
0.7
80% - 90%
Half-life of elimination
7 hours
DISCUSSION OF SOME 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?
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 were
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
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
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:
(S)(F)(Dose)
Cpss min =
Vd
. (e –kdt)
_________________
(1 – e –kdt)
= (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.
3. 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?
There are many possible explanations for this:
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?
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 were
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?
The pharmacokinetics of this patient is 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 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. 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:
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 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 quantitative 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?
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 intramuscularly 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.
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 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 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.
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) ( 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
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