ALTERED

PHARMACOKINETICS IN
CARDIOVASCULAR DISEASES
By Vijay

Introduction
Cardiac

failure is often associated with disturbances in

Cardiac output

ANS activity

Systemic venous pressures

Cardiac failure potentially affects absorption and disposition

characteristics of drugs, which may necessitate adjustment in dosage
regimen for optimum therapy.

Drug therapy in patients with cardiac failure may be complicated by

disease related variability in absorption and disposition kinetics.

Introduction

The pharmacokinetics of a specific drug are assessed by the volume

of distribution, bioavailability, clearance and elimination half-life.
Any one or more of these parameters may be altered by physiological
changes such as ageing, or disease states such as congestive heart
failure

Congestive

heart failure is associated with hypo perfusion to various

organs including the sites of drug clearance, i.e. the liver and kidneys.
It also leads to organ congestion as seen in the liver and gut.
The

main changes in drug pharmacokinetics seen in congestive heart

failure are a reduction in the volume of distribution and impairment of

clearance.

 The

changes in pharmacokinetics assume importance only in the case of drugs

with a narrow therapeutic ratio (e.g. digoxin) and some of the

antiarrhythmics such as lignocaine (lidocaine), procainamide and
disopyramide.
Reduction

of loading and maintenance doses

Pharmacokinetic

changes are of less importance in the case of drugs with

immediate clinical response, e.g. diuretics and intravenous vasodilators such

as nitrates and phosphodiesterase inhibitors.
Not

all adverse reactions to drugs that may occur in heart failure are the result

of alterations in pharmacokinetics; rather, some may be due to important drug

interactions. An interaction may occur directly e.g. reduction of renal
clearance of digoxin by captopril and quinidine; or indirectly, e.g. through
diuretic-induced hypokalaemia, which exacerbate arrhythmias associated with
digoxin and antiarrhythmics such as quinidine and procainamide.

Mechanisms of cardiacfailure induced

pharmacokinetic changes
Drug absorption:
i.
ii.

Intramuscular administration:
Oral administration:

under simplifying conditions , passive absorption by diffusion may

be described by the equation
n =
CD

1
K.FD

1+R
.a1.VB

CD = Luminal concentration of the substance

K= permeability coefficient of the epithelium
FD = mucosal surface area
R= Relative amount of drug trapped in counter current mechanism
= villus blood flow as a fraction of total intestinal blood flow
a1= concentration ratio of whole blood : plasma water

The denominator of the equation can be viewed as the resistance of

the system
1
K.FD
The term represents the diffusion resistance of the epithelium and
depends on the permeability and area of the absorbing surface.
The term
1+R
.a1.VB
Represents the resistance of the draining system

 The

relative magnitude of the mucosal and blood flow resistance

factors determines the effect of changes in blood flow on
absorption of a particular drug. For drugs that are readily diffusible
due to lipophilicity or small molecular size , the term
1
K.FD

becomes insignificant and absorption depends primarily on blood

flow.

Drug Distribution : Drug distribution depends on route of

administration , protein binding, blood flow, diffusion rate into
organs and extent of partitioning into the tissues.

In order to consider the effects of circulatory factors on distribution,

perfusion models have been developed .

LUNG
Venou
sIV

BRAIN
RET

Arterial

RET: Rapidly equilibrating

tissues
SET: Slowly equilibrating
tissues

MUSCL
E
ADIPOS
E

SET
LIVER
GUT
Metabolism
[Rate directly proportional
HBF]
The model represents the series of mass balance equations in
which the drug is taken up into the tissues according to the
partition coefficients and blood flow to that tissue, drug is
eliminated from the system by a clearing organ.

Drug

Elimination:

Both hepatic blood flow and metabolism can be affected in cardiac failure.

Blood flow to the liver is reduced and appears to change in proportion to cardiac index.

Cardiac disease might influence the metabolic capacity of the liver either by:

a.

Hepatocellular damage resulting from hepatic congestion or hypoperfusion

b.

Hypoxemia with impaired microsomal drug oxidation.

. Tokola

et al. reported decreased drug metabolizing enzyme activity in liver biopsy

samples obtained from patients with chronic cardiac insufficiency. They pointed out
that concomitant use of enzyme inducing drugs might return enzyme activity to control
levels in age matched patients in cardiac failure.
. Cardiac

failure may affect renal clearance by:

a.

Decreasing GFR secondary to hypoperfusion

b.

Increasing tubular reabsorption owing to redistribution of intrarenal blood flow.

Pharmacokinetics of specific drugs

during cardiac failure

Lignocaine:

Primarily eliminated by hepatic metabolism

Two active and potentially toxic metabolites(monoethylglycinexylidide and

glycinexylidide) are formed which are eliminated by both metabolic and
renal routes.

Cardiac failure has been shown to influence both clearance and volume of
distribution of lignocaine.

Halkin et al. (1975)a measured blood levels of MEGX in 31 patients

receiving prolonged lignocaine infusion for treatment of arrhythmias.
MEGX concentrations were significantly high in the presence of cardiac
failure.

One patient exhibited neurological symptoms of toxicity with therapeutic

lignocaine level, but with markedly elevated MGEX level.

GX is a minor metabolite, but half life ( about 10 hrs ) much higher than
the lignocaine and MEGX.

Cont.

Digoxin: with respect to absorption, Doherty et al. (1961) reported 1

patient with cardiac failure who required larger maintenance doses of
digoxin and who had evidence of grossly impaired absorption of digoxin
when administered in solution.

Oliver et al. (1974) studied post absorptive blood levels after ingestion of
digoxin tablets in 3 patients during and after treatment of CHF. In 2 of
these patients, peak drug levels were lower and occurred later during
moderate to severe cardiac failure compared with after recovery.

These studies suggest delayed absorption

Dobbs et al. (1976) examined the value of several clinical variables in

predicting doses required to achieve a target blood level of digoxin. Their
data suggest that predictors including creatinine clearance, tend to
overestimate the doses required in the presence of severe cardiac failure,
because total clearance is reduced in these patients beyond that which can
be accounted for on the basis of reduced creatinine clearance.

Theophylline: Theophylline is predominantly metabolized by the liver.

Piafsky et al. (1974) studied 3 patients with cardiac failure and pulmonary
oedema in whom total body clearance was reduced and terminal half life of
the drug was increased 2-fold compared with 5 control subjects. The
volume of distribution appeared to be unaltered.

A summary of reported effects of cardiac

failure on drug pharmacokinetics
Drug

Effect

Dose modification

Lignocaine

volume of distribution
metabolic clearance
Variable effect on half life

Use smaller bolus or loading

dose, reduce rate of
administration, monitor plasma
levels.

Procainamide

Erratic oral absorption in acute

MI
Vd and clearance

Administer IV at least for 1st

24hr acute phase of myocardial
infarction, use smaller loading
dose, reduction of maintenance
dose possibly needed , monitor
plasma levels of procainamide
and metabolite(NAPA)

Digoxin

Total Clarence, impaired or

delayed oral absorption

Adjust dose according to

creatinine clearence and
monitor plasma levels

Hydrochlorothiazide

Half life

Monitor by usual therapeutic

end point

Cont..
Theophylline

metabolic clearance

Reduce rate of administration

Interpatient variability exceeds

kinetic changes

Always monitor plasma levels

Furosemide

No change in volume of
distribution, clearance,
bioavailability

Monitor by usual therapeutic

end point

Metolazone

Increased half life

Increased volume of
distribution
Unaltered clearance
? Decreased absorption

As above

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