Pharmacokinetic variations in disease state.pptx

Pharmacokinetic variations in
disease state

Glossary
• Pharmacokinetics is the study of the activity
of drugs in the body over a period of time,
including the processes by which drugs are
absorbed, distributed in the body, localized in
the tissues, and excreted.
• Pharmacodynamics is the study of the
biochemical and physiologic effects of drugs.

What is disease?
‘A disease is a particular abnormal condition
that adversely affects the structure or function
of all or part of an organism and is not
immediately due to any external injury.
Diseases are often known to be medical
conditions that are associated with specific
signs and symptoms.’

Diseases affecting pharmacokinetics of drugs
1.Absorption
GI Diseases:
Conditions like
Crohn's disease or
celiac disease can
affect the integrity of
the intestinal
mucosa, altering drug
absorption.
Acidity Changes:
Diseases that affect
gastric pH, such as
gastroesophageal
reflux disease
(GERD), can influence
the solubility and
absorption of drugs.
2.Distribution
Fluid Status:
Edema in heart failure
or renal disease can
increase the volume
of distribution (Vd) for
hydrophilic drugs.
Protein Binding:
Liver disease can
reduce albumin
production, affecting
the free fraction of
drugs that are highly
protein-bound,
potentially leading to
increased drug effects.
3. Metabolism
Liver Function:
Hepatic diseases (e.g.,
cirrhosis) can impair
the metabolism of
drugs that undergo
first-pass metabolism,
resulting in higher
systemic
concentrations.
Enzyme
Induction/Inhibition:
Conditions like chronic
inflammation can
induce or inhibit
cytochrome P450
enzymes, altering drug
clearance.

4. Excretion
Renal Impairment:
Conditions such as
chronic kidney disease
significantly affect the
clearance of renally-
excreted drugs,
necessitating dosage
adjustments to avoid
toxicity.
Age and Comorbidities:
Older adults often have
altered renal function
due to age-related
decline, impacting drug
excretion.
Pharmacogenomics
Genetic Variability: Certain
diseases can also influence
genetic expression related to
drug metabolism (e.g.,
polymorphisms in metabolizing
enzymes), affecting
pharmacokinetics on an
individual basis.

Renal impairment
• There are kidney disease stages according to
your estimated glomerular filtration rate
(eGFR).
• eGFR is a calculation of how well your kidneys
filter substances. A normal eGFR is about 100.
The lowest eGFR is 0, which means there’s no
remaining kidney function.

Stages of renal impairment
• The stages of any kidney disease include:
Stage I. Your GFR is higher than 90 but below 100. At this stage, your kidneys have mild
damage but still function normally.
Stage II. Your GFR may be as low as 60 or as high as 89. You have more damage to your
kidneys than in stage I, but they still function well.
Stage III. Your GFR may be as low as 30 or as high as 59. You may have mild or severe
loss of kidney function.
Stage IV. Your GFR may be as low as 15 or as high as 29. You have severe loss of kidney
function.
Stage V. Your GFR is below 15. Your kidneys are nearing or at complete failure.

Renal impairment
• The kidneys are involved in the elimination of many drugs. The
degree of renal excretion of an unchanged drug or its metabolites
is the net result of glomerular filtration, tubular secretion, tubular
reabsorption, and to a lesser degree, metabolism in the
kidneys.2When a drug is eliminated primarily through renal
excretion, patients with renal impairment frequently have
different PK and may require a different recommended dosage
than patients with normal kidney function.
• Impaired renal function can alter some drug metabolism and
transport pathways in the liver and gut; thus, there is potential for
renal impairment to also affect drugs that are predominantly
cleared non-renally.3

Terminologies
The half-life of a drug (T½) is the time taken for the
concentration in the blood to fall to half of a previous value.
This may be a single value or one of several values depending
on the distributional characteristics of the drug in the body.
The volume of distribution of a drug (V d) is equal to the ratio
of the amount of drug in the body to its concentration in the
plasma (or blood). There may be more than one volume of
distribution depending on
• the rate of distribution within the body and therefore on such
characteristics of the drug as lipid and water solubility and
degree of binding to plasma and tissue proteins.
• It also depends on characteristics of the patient such as size,
body composition and plasma protein concentrations,

• The clearance of a drug is a measure of the
functional ability of the body to remove it
independently of other pharmacokinetic
processes. It is often defined as the volume of
plasma from which the drug is, in effect,
completely removed per unit time by the body's
Anaesthesia and Intensive Care, Vol. J 1, No. 4,
November, 1983 eliminating mechanisms

EFFECTS OF RENAL FAILURE ON DRUG KINETICS
Absorption
• There is little quantitative information available on the
influence of impaired renal function on oral or
intramuscular absorption. Most studies have
concentrated on antibiotics and have suggested that
with trimethoprim, cloxacillin and cefazolin there is no
impairment of absorption mechanisms in uraemia.
• However, hepatic drug metabolism may be impaired in
the uraemic patient and this may result in changes in
the bioavailability of drugs which are extensively
metabolised during their first pass through the liver
after oral doses.

Distribution
• Most dose adjustment methods for renal impairment
assume that the volume of distribution of a drug is
essentially unaltered in patients with compromised renal
function.
• Gibaldi and Perrier were the first to examine this
assumption more closely. It was shown that a
redistribution of drug in the body may occur in renal
impairment, resulting in concentration of drug in a
central compartment at the expense of that in a tissue
compartment. E.g; The distribution volume of digoxin
has been reported to be reduced from an average of 510
liters in normal subjects to be between 230 and 380
liters in patients with renal disease.

Metabolism
• Numerous studies have been performed which show that the
free concentration of drug in plasma correlates more closely
with the concentration of drug at receptor sites, and therefore
with observed pharmacologic effect, than does the total
concentration of drug in plasma.
• Therefore, any reduction in the plasma protein binding of a drug
in an individual patient will increase free drug concentrations
leading to increased drug effect and possible toxicity. Such
protein binding changes have been found in renal failure.
• E.g; Acidic drugs are largely bound to albumen in plasma and the
decrease in binding in uraemic plasma has been attributed to
qualitative changes in the binding sites, to endogenous inhibitors
of binding, and to decreased concentrations of albumen. 1

Metabolism
• Changes of drug metabolism in uraemic patients will have
significant effects on the elimination of a drug only when
metabolism is a major route of elimination.
• Reidenberg reviewed this subject showing that the major
pathways of drug metabolism, oxidation and glucuronide
formation, appear normal in uraemia but that some of the minor
pathways are slowed.
• E.g 1; Ester hydrolysis has been studied using procaine as an
example. Significant prolongation of procaine T½ in uraemia was
shown, the cause being low levels of drug metabolising enzyme.
• E.g 2; Although hydrolysis is a relatively minor metabolic pathway,
its impairment may be of consequence for such drug esters as
clindamycin phosphate, erythromycin estolate and indanyl
carbenicillin which have to be hydrolysed in the body in order to
release the active drug form.

Elimination
• Compounds are cleared by the kidneys by
-passive filtration (glomerulus filtration) and
-active secretion (kidney tubules)
- reabsorption
Once in the tubules of the nephron, compounds may
be passively reabsorbed back into the circulation. The
first two mechanisms contribute positively, the last
negatively, to overall renal clearance. The extent to
which renal failure influences duration of action is a
function of the percentage of circulating drug cleared
through the kidney unchanged, and the
pharmacological activity of its metabolites.

Relationship of drug elimination to renal function
The relationship between the elimination half-life of some
antibiotics and creatinine clearance (CLCR) was first established
by Kunin,who described the following basic types of drugs:
• Type A (drugs eliminated almost entirely by the kidneys) T½
increases only slowly with decreasing values of CLCR until a
critical value of CLCR = 10 to 20 ml/minute is reached. Below
this point, however, T½ increases dramatically with further
decreasing values of CLCR.
• Type B (drugs eliminated almost entirely by extrarenal
mechanisms) T ½ remains practically unchanged with
decreasing values of CLCR.
• Type C (drugs that have both renal and extrarenal elimination
routes) show an intermediate behaviour.

Examples showing effect of renal impairment in drug
elimination
• It is clear that the influence of renal
impairment on drug half-life will be
a direct function of the percentage
of drug cleared through the kidney.
If the half-life of a drug which is
cleared essentially unchanged via
the kidney is plotted against the
endogenous creatinine clearance,
the resulting curve will be a
hyperbola. On the other hand, the
curve obtained from a drug which
is extensively metabolised would
be relatively flat. Examples of these
types of drugs are cefazolin
&minocycline

• In patients with renal impairment, the dosing of
renally cleared drugs has to be adjusted based on
the patient's actual GFR. In the past, this
adjustment was made using the Cockcroft-Gault
equation or by measuring creatinine
clearance. Previously, the Modification of Diet in
Renal Disease (MDRD) formula was also used.
However, the Chronic Kidney Disease-Epidemiology
Collaborative Group (CKD-EPI) creatinine-based
formula has largely replaced these older methods.

• the National Kidney Foundation (NKF) and the
American Society of Nephrology (ASN) Task
Force recommend using the CKD-EPI
creatinine-based equation.[7] This formula
uses serum creatinine, age, and constant
values. For estimated GFR, this formula has
been adopted by most major laboratories,
including national laboratories.

• The units of drug dosing are typically expressed as the amount of
drug administered per unit of time.
• Dose adjustment is typically crude for most drugs in many
circumstances, such as doubling or halving doses. In most cases,
having the means to establish when the drug dose should be
doubled or halved is crucial, whereas a 20% alteration in dose is
typically impractical and unnecessary. However, there are many
drugs for which minor changes in dose or concentration may cause
a significant effect, commonly called a narrow therapeutic index.
The therapeutic index is calculated using the following formula:
• The therapeutic index = minimum toxic dose / minimum effective
dose

Clinical Significance
• Factors and conditions that may worsen the renal injury and
thus should be either avoided or resolved include the following:
• Nephrotoxic drugs, such as nonsteroidal anti-inflammatory
drugs, aminoglycosides, and iodinated contrast
• Uncontrolled diabetes
• Systemic hypertension
• Proteinuria
• Dehydration
• Smoking
• Hyperlipidemia
• Hyperphosphatemia

Pharmacokinetic variations in disease state.pptx

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