6

INTRODUCTION
Clinical Pharmacokinetics Service (CPS) is an extension from of
pharmacy service that provides vital roles in patient care and individualization
therapy. Initially this services only involved drugs with narrow therapeutic range
or/and erratic plasma concentration upon minimal dose manipulation. In
Ministry of Health, this service has evolved from only focusing in
pharmacokinetic (PK) principal only towards utilizing
pharmacokinetics/pharmacodynamics (PK/PD) model in predicting
individualized treatment response.

Clinical Pharmacokinetics Pharmacy Handbook 2nd Edition is a revised

version of the 2017 publication. It is published by Pharmaceutical Practice &
Development Division as a reference material for the purpose of training
guidance for pharmacist practising clinical pharmacokinetics in Malaysia. This
handbook covers drugs that historically associated with CPS such as
aminoglycoside, vancomycin, anti-epileptics, immunosuppressant and
toxicology cases. In second edition, there is a new addition in the pre-existing
list of drugs requiring therapeutic monitoring, which is Lithium. Therapeutic
range for some drugs was also revised according to the latest clinical updates
to suit the latest clinical practice, and within the purpose of betterment in
patient care provision.

Pharmacokinetics (PKs) described the relationship between

administered dose with the drug concentration over the course of time, and is
characterized by the systemic input and the disposition kinetic processes. The
kinetic processes are commonly referred to as the absorption, distribution,
metabolism and elimination of drug (ADME concept). Therapeutic benefit is
attained when a drug achieved a given range for efficacy, yet remain below
the toxicity threshold. Knowledge in drug PKs is therefore necessary to optimize
drug therapy and provide appropriate dose recommendation in populations
of interest [1-2]. Clinical pharmacokinetics (CP) is the application of the above

2
 INTRODUCTION
mentioned principles into the clinical practice and patient management, with
the intention to produce a safe, effective and individualized
pharmacotherapy plan. The primary goal of CP includes optimising
effectiveness and minimiz

Pharmacodynamics (PDs) refer to the relationship between the

presence of drug at the site of action with the resulting effect, which includes
the exposure time and intensity of therapeutic and adverse effects. The effect
of a drug present at the site of action is determined by the
affinity with a receptor. The binding of a drug to a receptor generate a direct
or a cascade of reaction(s) that will eventually culminate in an observable
effect. The concept of PDs is well studied with antibiotics [2]. The emergence of
resistance to many antimicrobial agents over the past 10 to 15 years has
markedly increase the interest in PDs roles in antimicrobials.

The main challenge its

variability in individual PK/PD, in which it may influence the design of the dosing
regimen. Variability factors that affect pharmacokinetics and
pharmacodynamics influence dose regimen design. The rate and degree of
absorption of medications administered through routes other than intravenous
are highly dependent on the properties of each chemical entity as well as on
the environment at the site of administration. Molecular size, solubility, degree
of lipophilicity, acid dissociation constant (pKa) and stability are among the
important factors influencing the rate and extent of drug absorption.
Environmental characteristics that can affect drug absorption include pH,
blood flow, surface area, and gastrointestinal motility. In this chapter, we will
elaborate the PK/PD changes in special population to facilitate pharmacist in
designing the best treatment regime.

3
 INTRODUCTION
DEFINITIONS OF BASIC PHARMACOKINETIC PARAMETERS

ration at the site of action,

thus it would be useful to monitor this concentration. However, the site of action
are either generally inaccessible for direct observations or the drugs are widely
distributed in the body, therefore direct measurement of drug concentration
at the sites of action is not practical. Kinetic homogeneity describes the
predictable relationship between plasma drug concentration and
concentration at the receptor site when a given drug produces its therapeutic
effects. Changes in the concentration of drug in plasma directly change the
concentration of drug in most tissues proportionally. Table 1 provides common
terms and definitions related to pharmacokinetic.

Table 1: Definitions of basic pharmacokinetic parameters

Parameter Definition

Area under the

The area under a drug concentration vs time graph
curve (AUC)

Bioavailability The fraction of an administered drug reaching the systemic

(BA) circulation.

Clearance (CL) The volume of blood cleared of drug per unit of time.

The amount of time required for the concentration of the

Half-life (t1/2) drug to decrease by 50%. The half-life is the net effect of all
processes leading to removal of the drug.

The rate a drug is eliminated from the body per unit of time.
Elimination rate
The elimination rate constant is inversely proportional to drug
constant (Ke)
half-life.

Extraction ratio The percentage of medication removed from the blood as it

passes through the eliminating organ. The extraction ratio

4
 INTRODUCTION
depends not only on the blood flow rate but also on the free
fraction of drug and the intrinsic ability of the organ to
eliminate the drug.

First-pass effect The process of hepatic metabolism of drugs absorbed from

the GI tract as they pass through the liver. First-pass
metabolism reduces the amount of drug reaching the
systemic circulation, thus reducing bioavailability. First-pass
effect only applies to enterally administered medications.

Plasma protein The process by which a drug binds to proteins in the plasma.

binding In general, only free or unbound drugs are available to exert

this pharmacologic action or to be distributed, metabolized,
or eliminated.

Steady state A condition when the rate of drug administration is equal to

drug elimination. Steady state generally reached after four to
five half-lives of a drug. Steady state is a desirable time to
evaluate the pharmacologic effect of a drug or to measure
serum concentrations. Steady state can also be used to
estimate how long it may take for a drug to clear from the
body.

Volume of This is not a physiologic volume but, rather, a theoretical

distribution volume that relates the plasma concentration to the

administered dose. Medications that are hydrophilic and
remain in the central (vascular) compartment, and without
high affinity for plasma protein binding, tend to have a lower
volume of distribution, with a value that is closer to the
intravascular volume. Drugs that are highly lipophilic and
distribute to peripheral tissues, or are highly plasma protein
bound, tend to have a very large volume of distribution.

Adapted from Smith BS, Yogaratnam D, Lavasseur-Franklin KE, Forni A & Fong J. 2012. Introduction to drug
pharmacokinetics in the critically ill patient. CHEST. 141(5):1327-1336

5
 INTRODUCTION

REFERENCES

1. Patel K & Kirkpatrick C.M. 2017. Basic Pharmacokinetic Principles. In: Udy A, Roberts J &
Lipman J. Antibiotic Pharmacokinetic/Pharmacodynamic Considerations in the Critically
Ill. Adis, Singapore.
2. Hesham S.A. Venkata V.P.K, Landersdorfer C.B, Bulitta J.B & Duffull S.B. 2009. The time
course of drug effects. Pharmaceutical Statistics. 8(3):176-185.
3. Craig W.A. 2003. Basic pharmacodynamics of antibacterials with clinical application to the
use of b-lactams, glycopeptides, and linezolid. Infectious Disease Clinics of North America.
17:479-501.
4. Smith BS, Yogaratnam D, Lavasseur-Franklin KE, Forni A & Fong J. 2012. Introduction to drug
pharmacokinetics in the critically ill patient. CHEST. 141(5):1327-1336

6
 INTRODUCTION

PHARMACOKINETIC CHANGES IN SPECIFIC POPULATION

Pharmacokinetics is typically dependent on a variety of physiological

variables (e.g. age, ethnicity, or pregnancy) or pathological conditions (e.g.
renal impairment, hepatic impairment, cardiac dysfunction, obesity and
others). Nevertheless, the knowledge on the influences of physiological and
disease changes on pharmacokinetics parameters can provide pharmacist
an insight to predict/optimize drug response while minimizing its toxicity.
Careful dose adjustment with routine monitoring of adverse events is necessary
in the population with altered PK. In this chapter, we will try to elaborate
pharmacokinetic changes in critically ill patients, pediatrics and geriatrics
patient with aim to assist pharmacist in interpreting TDM result and optimized
patient care generally. These changes are tabulated in table 5.

a) PHARMACOKINETIC CHANGES IN CRITICALLY ILL PATIENTS

In critically ill patients, the major pathophysiological changes that occur

may cause alterations in pharmacokinetic of drugs. During critical condition,
the balance between the environment at site of administration and the
physical properties of drug can significantly different or can significantly differ
from normal population. These abnormalities in with the addition to the
alterations in distribution, metabolism, and elimination will lead to sub-optimal
drug concentration at site of action. These changes are tabulated in table 2.

7
 INTRODUCTION
Table 2: Pharmacokinetic changes in critically ill patients

Parameter Change Effect Example

During shock, blood
Absorption Perfusion Significant reduction in
flow is directed to vital
abnormalities the concentration of
organ reduced
Intestinal enoxaparin given
blood flow to GI
atrophy subcutaneously [1].
systems. This
Delayed gastric AUC and Tmax of
deprivation reduces
emptying paracetamol given
the systemic
Increased orally were significantly
absorption of drugs
gastric pH due reduced in critically ill
from GI, intramuscular
to stress ulcer patients [2].
and subcutaneous
prophylaxis Reduced the AUC of
tissues.
Interaction with weak base drug such
Reduce in the rate of
enteral feeds as ketoconazole,
absorption, Tmax, Cmax
intraconazole,
and onset of the drug
atazanavir, and
effect.
dipyridamole [1-2].
Reduction in AUC of
Plasma concentrations
drugs that are weak
of phenytoin have
bases.
been reported to
Reduction in AUC of
reduce significantly
selected drugs.
during enteral feedings
[3].

Increase Vd for Oedema and

Distribution Increase in
hydrophilic drugs such substantial fluid
total body
-lactam antibiotics, administration will
water (TBW)
which may lead to increase Vd of
and third
reduced Cmax and hydrophilic drugs [1,4].
space fluid
prolonged half-life and The Vd of gentamicin
volumes.
time above MIC if has been reported to
clearance is be as large as 0.63L/kg
unchanged. in critically ill patients
Possible reduction in [1].

efficacy for
concentration

8
 INTRODUCTION
dependent hydrophilic The Vd of
antibiotics. meropenem,
imipenem, piperacillin,
cefepime, and
ceftazidime was higher
in ICU patients as
compared to healthy
volunteers [5].
Increase in free fraction Binding ratio of
Decrease in
of drugs that are highly phenytoin is significantly
plasma
bind to albumin such as correlated with albumin
albumin and
phenytoin. levels [2,14].
-
Reduce in free fraction Notable 99% increase in
acid
of drugs that are highly clearance of
glycoprotein
bound to AAG such as ceftriaxone was
(AAG) as a
lidocaine and tricyclic observed with the
result of the
antidepressants. increment in Vd by 32%
systemic
in patient with
inflammatory
hypoalbuminaemia,
response and
leading to failure to
other reasons.
attain the
pharmacodynamics
target [6].

Increased or reduced
Alterations in
the Vd and distribution
plasma pH
of drugs dependent on
their pKa.

Impair distribution of The interstitial

Septic shock
unbound fraction of concentration of
Acute
hydrophilic drugs such piperacillin was
neurological
as antibiotics in S/C reported to be 5 to 10-
injury
tissues and/or skeletal fold lower than plasma
associated
muscle. concentration [2].
with
Increased Penetration of
inflammation
accumulation of free morphine-3-and 6-
drugs in the CNS, glucoronide into CSF

9
 INTRODUCTION
possibly as a result of increased in proportion
down-regulation of BBB to degree of elevation
efflux transporters (P- of the pro-inflammatory
gp/MDR1 or MRPs). cytokine IL-6 in CSF [7].

Hepatic impairment
Metabolism Hepatic
may lead to
dysfunction
accumulation of
hepatic metabolized
drugs.
Reduce hepatic During sepsis and septic
Reduced
clearance of high shock, cardiac output
hepatic or
extraction drugs. can be increase or
splanchnic
decrease, resulting in
blood flow as
alterations in hepatic
a result of
blood flow that leads to
shock.
reduction of hepatic
clearance of high
extraction drugs such as
metoprolol, midazolam,
propranolol, and
verapamil [7,14].
Reduce/increase in In severe burn injury, the
Hepatic
metabolism of a drug. activity of the CYP450
enzyme
enzymes system can
activity
become significantly
diminished (phase I
metabolism).
Cholestasis, which
delays the biliary
excretion of drugs, has
been found to impair
CYP450 function. The
inflammatory response
associated with trauma,
surgery, and
haemorrhagic shock

10
 INTRODUCTION
has been demonstrated
to have a variable
effect on CYP450. Data
suggest that there is a
reduction in CYP3A4,
2C19 and 2EI activity
while there is an
increase in 2C9 activity
[14].

Enhance excretion of 63% of patient receiving

Excretion Augmented
circulating vancomycin was found
renal
metabolites, toxins, to have vancomycin
clearance
waste products, and concentration below
(ARC)
drug compared to 10mg/L [8].
baseline as Levetiracetam
consequence of clearance was higher
glomerular hyper- compared to healthy
filtration. volunteers [9].
The impairment will Accumulation of
Acute kidney
lead to accumulation allopurinol active
injury (AKI)
of active metabolites metabolites (oxypurinol)
that can give toxic increase the risk of
effects. immune-mediated
hypersensitivity [10].
Accumulation of
morphine active
metabolites caused
CNS depression and
respiratory depression
[10].

11
 INTRODUCTION
CCVH, CVVHD, Significant amount of
Renal
CVVHDF, intermittent vancomycin is cleared
replacement
or SLED may cause during CRRT. Standard
therapy (RRT)
removal of drug dosing interval failed to
molecules/metabolites, attain the targeted
especially those with AUC/MIC [11-12].
high hydrophilicity. A relevant PK variability
was observed in
critically ill patients
receiving meropenem
[13].

REFERENCES

1. Boucher, B.A; Wood, G.C; Swanson, J.M. 2006. Pharmacokinetic changes in critical illness.
Critical Care Clinics. 22. 255-271.
2. Roberts D.J & Hall, R.I. 2013. Drug absoption, distribution, metabolism and excretion
considerations in critically ill adults. Expert Opinion in Drug Metabolism and Toxicology.
9(9):1067-1084.
3. Au-Yeung SC & Ensom MH. 2000. Phenytoin and enteral feedings: does evidence support
an interaction? Annals Pharmacotherapy. 34(7-8):830-832.
4. Blot S.I, Pea, F. & Lipman J. 2014. The effect of pathophysiology on pharmacokinetics in the
critically ill patient concepts appraised by the example of antimicrobial agents.
Advanced Drug Delivery Reviews. 77:3-11.
5. Goncalves-Pereira J & Povoa P. 2011. Antibiotics in critically ill patients: a systematic review
of the pharmacokinetics of beta-lactams. Critical Care. 15(5):R206.
6. Ulldemolins M, Roberts JA, Rello J, Paterson DL & Lipman J. 2011. The effects of
hypoalbuminaemia on optimizing antibacterial dosing in critically ill patients. Clinical
Pharmacokinetics. 50(2):99-110.
7. Roberts D.J, Goralski KB, Renton KW, Julien LC, Webber AM, Volmer DA and Hall RI. 2009
Effect of acute inflammatory brain injury on accumulation of morphine and morphine 3-
and 6- glucuronide in the human brain. Critical Care Medicine. 37(10):2767-2774.
8. Chu Y, Luo Y, Qu L, Zhao C, & Jiang M. 2016. Application of vancomycin in patients with
varying renal function, especially those with augmented renal clearance. Pharmaceutical
Biology. 54: 2802-2806.

12
 INTRODUCTION
9. Spencer D.D, Jacobi J, Juenke J.M, Fleck J.D, & Kays M.B. 2011. Steady-state
pharmacokinetics of intravenous levetiracetam in neurocritical care patients.
Pharmacotherapy. 31: 934-941.
10. Vilay, A.M, Churchwell M.D, & Mueller B.A. 2008. Clinical review: Drug metabolism and
nonrenal clearance in acute kidney injury. Critical Care. 12:235.
11. Janattul-Ain J, Economou C.J.P, Lipman J & Roberts J.A. 2012. Improving antibiotic dosing
in special situations in the ICU: burns, renal replacement therapy and extracorporeal
membrane oxygenation. Current Opinion in Critical Care. 18: 461-471.
12. Reardon N, Bogard K, Plumb K, Yin T, Li N, Fuller S, Bultsma P, Brand-Woods C & Peitz A. 2012.
Pharmacokinetics of vancomycin during sustained low-efficiency dialysis. Critical Care
Medicine. 40:12.
13. Braune S, Koning C, Roberts J.A, Nierhaus A, Steinmetz O, Baehr M, Kluge S and Langebrake
C. 2018. Pharmacokinetics of meropenam in septic patients on sustained low-efficiency
dialysis: a population pharmacokinetic study. Critical Care. 22:25.
14. Smith BS, Yogaratnam D, Lavasseur-Franklin KE, Forni A & Fong J. 2012. Introduction to drug
pharmacokinetics in the critically ill patient. CHEST. 141(5):1327-1336

13
 INTRODUCTION
b) PHARMACOKINETIC CHARACTERISTICS OF PEDIATRICS

In pediatrics, developmental/physiological changes in absorptive surface

can influence the rate and extent of the bioavailability of a drug. Factor
including plasma protein binding and water partitioning are continuously
fluctuating throughout the first years of life, thus affecting the distribution of
drugs. Drug metabolism and elimination vary with age and depends on the
substrate or drug. These changes are tabulated in table 3.

Table 3: Pharmacokinetic characteristics of pediatrics

Parameter Change Effect Example

Reduce the At birth, gastric pH is
Absorption Increase in gastric pH
bioavailability usually neutral, the pH
of weak acids approximately drops
drugs. to 1-3 within the first 24
Increase the hours of birth. The pH
bioavailability gradually become
of weak bases. neutral by day 10 of
life. The gastric pH will
be similar to adults by
the age of 3 years
old. Acid labile drugs
such as ampicillin,
erythromycin, and
amoxicillin are more
efficiently absorbed
when given orally.
Weak acid drugs such
as phenytoin,
paracetamol, and
phenobarbital will
have low
bioavailability [1-5].

14
 INTRODUCTION
Delay Gastric emptying
Increase/delay in
absorption of time during the
gastric emptying time
certain drugs neonatal period is
prolonged relative to
that of the adults.
Delayed and
incomplete
absorption in
neonates and small
infants have been
observed with
amoxicillin, rifampicin,
phenobarbital,
digoxin, and
sulphonamides [1,5].
Increase Immature CYP3A4 in
Developmental
bioavailability preterm infants has
changes in the activity
of CYP3A4 leads to higher
of intestinal drug
substrates bioavailability of oral
metabolism enzymes
Reduce midazolam.
and transporter.
bioavailability
of glutathione
S-transferase
(GST) substrates

Reduce Gabapentin is
Reduced in intestinal
bioavailability
drug transporters
of its substrates L-amino acid
expressions/regulations.
transporter in the GI
mucosal. This
immature transporter
had being shown to
reduce bioavailability
of gabapentin [1,5].

15
 INTRODUCTION
Increase in Topically applied
Increase in hydration of
absorption of steroid in newborn
epidermis
certain drugs and infants can result
in unpredicted
systemic absorption
that leads to toxic
effects. This is due to
better hydration of
the epidermis, greater
perfusion of the
subcutaneous layer,
and the larger ration
of total BSA to body
mass compared to
adults [5].
Increase In premature infants,
Distribution Body water : fat ratio
volume of the total body water
distribution of is around 80-90% of
hydrophilic the total body weight.
drugs The extracellular
Reduce volume water content is
of distribution of about 45% in
lipophilic drugs neonates compared
to 20% in adults. These
changes will result in
increased Vd of
hydrophilic drugs
such as gentamicin,
vancomycin, linezolid,
phenobarbitone and
propofol [1]. Higher
gentamicin doses per
kilogram body weight
must be given to
adults to achieve
comparable plasma

16
 INTRODUCTION
and tissues
concentrations [6]

Increase in free Greater free fraction

Reduce in protein
fraction of of highly protein
binding
highly protein bound drug such as
bound drugs phenytoin, valproic
acid, salicylates, and
ampicillin [1,6].

Reduce Developmental
Metabolism Reduce in phase I and
hepatic change in CYP450
phase II liver
clearance iso-enzymes varies
metabolism
between ages. These
developmental
changes will
influence the
metabolism of drugs
that used this
pathway. The
delayed ontogenesis
of CYP1A2 is
responsible for slow
metabolism of
theophylline (50%) in
neonates compared
to adults [1].
Metabolism
clearance of
morphine by UGT2B7
is low in neonates
and reaches adult
levels between 2 and
6 months [6].

17
 INTRODUCTION
Reduce renal The renal excretion of
Excretion Reduce in glomerular
clearance unchanged drug is
filtration rate
generally lower in
newborns owing to
immaturity of renal
function [6]. However
there is some
exception for certain
drugs.

Reduced renal Renal tubular

Reduce in renal tubular
clearance secretion capacity
absorption and
increases over the
secretion
first months of life and
reach adult level at
approximately seven
months of age. The
renal tubular
secretion plays an
important role in
excretion of digoxin
in children and
adolescents
compared to adult.
The inhibition of renal
tubular secretion by
amiodarone may
cause a steeper
increase in serum
digoxin
concentration in
children [1,6].

18
 INTRODUCTION
Table 4: Isoenzyme activity in pediatric population compared to adult
with example [5].
Pediatrics
Isoenzyme Drug class Examples
population activity
Antidepressant Duloxetine
CYP1A2 Reduce until 2 years
Bronchodilator Theophylline
Warfarin
Anticoagulant
Reduce until 1-2 Phenytoin
CYP2C9 Antidepressant
years Diclofenac, Ibuprofen,
NSAIDs
Naproxen
Antidepressant Citalopram, Sertraline
CYP2C19 Reduce until 10 years Benzodiazepine Diazepam
PPIs Pantoprazole
Analgesic Codeine, Tramadol
Antidepressant Amitriptylline, Fluoxetine,
Venlafaxine
CYP2D6 Reduce until 12 years
Antihistamine Diphenhydramine
Antipsychotic Risperidone
Beta-blocker Labetalol, Metoprolol
Analgesic Fentanyl
Antiepileptic Carbamazepine
Antifungal Itraconazole,
Ketoconazole
CYP3A4 Reduce until 2 years
Antihistamine Loratadine
Antiretroviral Indinavir,Lopinavir,
Ritonavir, Saquinavir
Benzodiazepines Alprazolam, Midazolam
MAO A Increase until 2 years - -
MAO B Equivalent to adult - -
N-Metyltransferases Equivalent to adult - -
Analgesic Morphine
Reduce until 7-10
UGTs Antiepileptic Lamotrigine
years
Benzodiazepine Clonazepam, Lorazepam
Reduce until 1-4 Antihypertensive Hydralazine
NAT2
years Antiinfective Isoniazid

19
 INTRODUCTION
Figure 1: Developmental profile of major hepatic cytochrome P450s [5]

REFERENCES

1. Fernandez E, Perez R, Hernandez A, Tejada P, Arteta M & Ramos J.T. 2011. Factor and
mechanism for pharmacokinetic differences between paediatric population and
adults. Pharmaceutics. 3:53-72.
2. Bartelink I.H, Rademaker C.M, Schobben A.F, vab den Anker J.N. 2006. Guidelines on
paediatric dosing on the basis of developmental physiology and pharmacokinetic
considerations. Clinical Pharmacokinetic. 45:1077-1097.
3. Strolin B.M, Whomsley R, & Baltes E.L. 2005. Differences in absorption, distribution,
metabolism and excretion of xenobiotics between the pediatric and adult population.
Expert Opinion in Drug Metabolism and Toxicology. 1:447-471.
4. Strolin B.M & Baltes E.L. 2003. Drug metabolism and disposition in children. Fundamental
in Clinical Pharmacology. 14: 281-299.
5. Lu H & Rosenbaum S. 2014. Developmental pharmacokinetics in pediatric populations.
Journal of Pediatric Pharmacology Ther. 19(4):262-276.
6. Batchelor HK & Marriott JF. 2015. Paediatric pharmacokinetics: key considerations.
British Journal of Clinical Pharmacology. 79(3):395-404

20
 INTRODUCTION
c) PHARMACOKINETICS CHANGES IN GERIATRICS

In geriatrics, age-related physiological changes will affect body systems

and can alter pharmacokinetic processes in different ways. Subsequently the
effects of drugs might be modified.

Table 5: Pharmacokinetics changes in geriatrics

Parameter Change Effect Example

Slightly decrease Increased
Absorption Increase in
absorption (rarely concentration of
gastric pH
clinical significant) propranolol and
Delay in gastric
Slightly increase labetalol.
emptying
absorption of drug Decreased
Reduce
that undergoes first concentration of ACE
splanchnic
past metabolism inhibitor such as
blood flow
Decrease the enalapril and
Decrease in
bioavailability of pro- perindopril that needs
absorption
drug that needs conversion to active
surface
activation in liver. metabolites[1,2,6].
Reduce in
Increased absorption
transport
of levodopa due to
protein
reduction of
dopadecarboxylase in
the gastric mucosa[6].

Increase Vd and t 1/2

Distribution Increase in Decreased
of lipophilic drugs
body fat concentration and
Increase plasma
Decrease in prolonged half-life of
concentration of
lean body lipophilic drug such as
hydrophilic drugs -
mass diazepam,
decreased/smaller
Decrease in thiopentone, and
Vd
total body lignocaine [3,6].
water Increased
concentration of water
soluble drugs digoxin,
lithium ethanol,

21
 INTRODUCTION
theophylline, and
aminoglycosides [4-6].
Increase free fraction Increased free-fraction
Decrease in
in plasma of highly of highly albumin
serum albumin
protein-bound acidic bound drug such as
drugs phenytoin and
ceftriaxone [4].
Decrease free Decreased free fraction
-
fraction of basic of basic drugs such as
acid
drugs lignocaine and
glycoprotein
propranolol [6].
First-pass metabolism Reduced clearance of
Metabolism Decrease in
can be less effective drugs with a high
hepatic blood
extraction ratio such as
flow
glyceryl nitrate,
lignocaine, pethidine,
and propranolol [6].
Phase I metabolism Reduced clearance of
Decrease in
of some drugs might drugs metabolized by
hepatic mass
be slightly impaired; phase I pathway in the
phase II metabolism liver (oxidation and
is restored reduction) [4,6].
Renal elimination of Reduced clearance of
Excretion Decrease in
drugs can be water-soluble
renal blood
impaired to a antibiotics, diuretics,
flow
variable extent digoxin, water-soluble
Decrease in
adrenoceptor blockers,
glomerular
lithium, and NSAIDS.
filtration rate
Drug with narrow
therapeutic index is
likely to cause serious
adverse events if they
accumulate only
marginally more than
intended [6].

22
 INTRODUCTION

REFERENCES

1. Tateishi T, Fujimura A, Shiga T, Ohashi K, Ebihara. 1995. Influence of ageing on the

oxidative and conjugative metabolism of propranolol. International Journal of Clinical
Pharmacology Research. 15:95-101.
2. Anantharaju A, Feller A, Chedid A. 2002. Aging liver: A review. Gerontology. 48:630-639.
3. Klotz U, Avant G.R, Hoyumpa a, Schenker S, Wilkinson,G.R. 1975. The effects of age
and liver disease on the disposition and elimination of diazepam in adult man. Journal
of Clinical Investigation. 55(2),
4. Shi S & Klotz U. 2011. Age-related changes in pharmacokinetics. Current Drug
Metabolism. 12:601-610.
5. Klotz U. 2009. Pharmacokinetics and drug metabolism in the elderly. Drug Metabolism
Review. 41(2):67-76.
6. Mangoni A.A & Jackson S.H.D 2003. Age-related changes in pharmacokinetics and
pharmacodynamics: basis principles and practical applications. British Journal of
Clinical Pharmacology. 57-1:6-14.

23