PHARMACOKINETICS
WHAT THE BODY
DOES TO THE DRUG
XENOBIOTIC
A compound to which the body is exposed
that is foreign to the body.
 Includes drugs, industrial and
environmental chemicals

Pharmacodynamics – concentration –
effect
Graded response
Quantal response
 Pharmacokinetics – dose - concentration

Routes of drug administration
Oral
Inhalational
Sublingual
Transdermal
Rectal
Subcutaneous
Transnasal
Intramuscular
Intra-tracheal
Intravenous
Routes of Administration
PHARMACOKINETICS

ABSORPTION

DISTRIBUTION

METABOLISM

EXCRETION
ABSORPTION

Describes the rate and extent to which a
drug leaves its site of administration
Pharmacokinetics

Absorption –the process by which the
drug moves into the body from external
source
Drug Absorption






Orally
Rectually (drug embedded in a suppository,
which is placed in the rectum)
Parenterally (given in liquid form by injection with
a needle and syringe)
Inhaled –thru the lungs as gases, as vapors, or
as particulars carried in smoke or in an aerosol
Absorbed through the skin
Absorbed through mucous membranes (from
snorting or sniffing the drug, with the drug
depositing on the oral or nasal mucosa)
Drug Absorption caveats
Orally
Drug must be soluble and stable in stomach
fluid (not destroyed by gastric acids), enter
the intestine, penetrate the lining of the
stomach or intestine, and pass into the
blood stream.
Drug Absorption disadvantages
 May occasionally lead to vomiting and
stomach distress.
 How much of the drug will be absorbed
into the bloodstream cannot always be
accurately predicted because of the
genetic differences between people and
because differences in the manufacture
of the drugs.
 The acid in the stomach destroys some
drugs.
Drug Absorption caveats
Rectually
Rarely used unless patient is vomiting,
unconscious, or unable to swallow

Drug Absorption disadvantages
Rectually
Often irregular, unpredictable, and
incomplete
Many drugs irritate the membranes that line
the rectum.

Drug Absorption
Parenterally
Intravenous –directly into a vein
Intramuscular –directly into muscle
Subcutaneous –just under the skin

Drug Absorption
Parenterally
Often produces a more prompt response
than does oral administration because
absorption is faster.
Permits a more accurate dose because the
unpredictable processes of absorption are
bypassed.

Drug Absorption disadvantages
Parenterally
Leaves little time to respond to an unexpected
drug reaction or accidental overdose.

Requires the use of sterile techniques.
Once a drug is administers by injection, it
cannot be recalled.
Drugs that cannot become completely soluble
before injection, cannot be injected
intravenuously.
Drug Absorption
Inhaled
Lung tissues have a large surface area with
large blood flow, allowing for rapid
absorption of drugs.
Relatively quick route to the brain.*

*May even have a faster onset of effect than drugs administered
intravenously.
Drug Absorption
Absorbed through the skin
Provides continuous,
controlled release of a drug
from a reservoir through a semipermeable
membrane.
Potentially minimizes side effects associated
with rapid rises and falls in plasma
concentration of the drug contained in the
patch.

CHARACTERISTICS OF A
DRUG FAVORING
ABSORPTION

Low molecular size

Nonpolar
 Uncharged

High lipid solubility
MECHANISMS OF SOLUTE
TRANSPORT ACROSS
MEMBRANES
 Passive diffusion
 Facilitated
 Active
diffusion
transport
 Endocytosis
Passive Diffusion
 Concentration
gradient
 Lipid-water partition coefficient
 Area,
Thickness and Permeability
of the membrane
 Ionic, pH, charge gradient*
Ionic Transport

pH gradient
 Drug’s
(pKa)
acid dissociation constant
pKa – pH value at which one half
of the drug is present in ionic
form
pKa = pH + log (HA)
(A-)
Henderson-Hasselbalch equation

Calculates the ratio of non-ionized to ionized
drug at each ph

pH = log [A-] + pka (Acid)
[HA]
or = log [B] + pKa (Base)
[BH+]
Ka = dissociation constant
A = molar concentration of the acidic anion
HA = molar concentration of the undissociated acid
B = molar concentration of the basic anion
HB = molar concentration of the undisscociated base
Drugs and ionisation : Theory
Many drugs are weak
acids or weak bases
• Acids =aspirin,
barbiturates
• Bases =propranolol,
opioids
The pKa of a drug is
the pH at which it is
50% ionised and 50%
unionised
• aspirin has pKa of 3.5
: at an acid pH of 3.5 it
is 50% U/I
• propranolol has a pKa
of 9.4 : at a basic pH
of 9.4 it 50% U/I
Drugs and ionisation : Theory
The more acidic the pH for an acidic
drug the more of it is unionised, and
vice versa for a basic drug
The U fraction is lipid soluble and
thus crosses cell membranes more
easily than the I fraction
Drugs and ionisation:
Which of the following statements are correct? Explain
briefly
1. Ionised drugs do not easily cross lipid
barriers such as the gut, placenta and
blood brain
2. Acidic drugs are well absorbed in the
acidic medium of the stomach, basic
drugs in the alkaline medium of the small
bowel
Characteristics of Un-ionized
and Ionized Drug Molecules
Un-ionized Ionized
Pharmacologic effect
Solubility
Cross lipid barriers
Active
Lipids
Yes
Inactive
Water
No
Yes
No
No
Yes
(gastrointestinal tract,
blood-brain barrier, placenta)
Hepatic metabolism
Renal excretion
Drugs and ionisation: Practise
Acidic drugs (such as aspirin) will be
ionised in an alkaline urine and thus
cannot be reabsorbed across the renal
tubular membrane (alkaline diuresis)
 pH trap (ion trapping) is significant for
some drugs, especially local
anaesthetics in labor

Factors Affecting
DRUG ABSORPTION
Biopharmaceutic
Factors
• - Tablet
compression
• - Coating and
Matrix
• - Excipients
Interactions
• - Food
• - Other Drugs
• - Bacteria
Physiological
Factors
Factors Affecting GI Absorption

Gastric Emptying Time

Intestinal Motility

Food

Formulation Factors
“First Pass Effect”
PK Definitions
Cmax: Maximum concentration –
may relate to some side effects
Plasma Concentration
10000
AUC: Area under the curve (filled
area) = overall drug exposure
3000
1000
Cmin: minimum or
trough concentrations:
may relate with efficacy
of HIV drugs
100
0
2
4
6
8
Time Postdose (hr)
http://www.thebody.com/content/art875.html
10
12
Drug Levels & Resistance
BIOAVAILABILITY
Quantity of drug in systemic
circulation
Quantity of drug administered
Bioavailability
BIOAVAILABILITY is the fraction of the oral
(rectal) dose reaching the systemic circulation
High bioavailability means good absorption
and limited liver metabolism
Are these two properties compatible?
Bioavailability
Oral and rectally administered drugs are
absorbed via the gut wall into the portal
circulation
The liver (and gut wall) removes drugs
by ‘first pass’ metabolism and binding so
only a proportion reaches the hepatic
veins and the systemic circulation
Bioavailability
Lipid soluble drugs such as propranolol are
well absorbed but have high ‘first pass’ and
hepatic extraction ratio (thus low oral
bioavailability) versus water soluble drugs
such as digoxin
1. How do you measure bioavailability?
2. Which pharmacokinetic parameter most
reliably reflects the amount of drug reaching
the target tissue after oral administration?
Measuring bioavailability
I.v. dose
Log
Concentration
Bioavailability =
AUC I.v.
AUC oral/
AUC i.v.
Oral dose
AUC oral
time
Bioavailability (f)
f = dose(IV) x AUC (PO)/dose(PO) x AUC
(IV)
Why do we need to know the
bioavailability of a drug?
To determine the correct route of
administration
e.g. i.v. versus i.m., oral versus rectal
To determine the correct dosage
DISTRIBUTION
Delivery of drug from systemic
circulation to tissues
Pharmacokinetics

Distribution –the drug is distributed
throughout the body (including fetus)
Distribution

The movement of drug from the blood
to and from the tissues
Drug Distribution
4 Body Membranes that Affect Drug
Distribution
1. Cell membranes
2. Walls of the capillary vessels in the
circulatory system
3. Brain-blood barrier
4. Placental barrier
Drug Distribution
1st Body Membrane that Affects Drug
Distribution
 Cell membranes
Permeable to small lipid (fatty) molecules
Drug Distribution
2nd Body Membrane that Affects Drug
Distribution
 Walls of the capillary vessels in the
circulatory system
Does not depend on lipid solubility
Only drugs that do not bind to plasma proteins
pass through capillary pores.
Drug Distribution
3rd Body Membrane that Affects Drug
Distribution
 Brain-blood barrier
The rate of passage of a drug into the
brain is determined by two factors:
(1) the size of the drug molecule and
(2) its lipid (fat) solubility.
Drug Distribution
4th Body Membrane that Affects Drug
Distribution
 Placental barrier
Oxygen and nutrients travel from the
mother’s blood to that of the fetus,
while carbon dioxide and other waste
products travel from the blood of the
fetus to the mother’s blood.
Fat-soluble substances (including all
psychoactive drugs) diffuse rapidly and
without limitation.
PATTERNS OF DRUG
DISTRIBUTION

Mainly in the vascular system
ex. Dextran, highly bound to plasma
protein
apparent Vd = 3-5 L in adults (approx
plasma volume)
PATTERNS OF DRUG
DISTRIBUTION
Uniformly distributed throughout the body
water
ex.ethanol, sulfonamides
Vd = 30-50 L corresponding to total body
water

PATTERNS OF DRUG
DISTRIBUTION
Concentrated specifically in one or more
tissues that may or may not be the site of
action
 Vd – very large values
ex. Chloroquine – 1000x in the liver
Tetracycline – bone and developing
teeth

PATTERNS OF DRUG
DISTRIBUTION

Non-uniform distribution in the body
- highest concentrations usually in the
liver, kidney and intestine
- distribution varies with lipid solubility,
ability to pass thru membranes
Factors Affecting Drug Distribution
Affecting Rate of Distribution
Membrane Permeability
Blood Perfusion
 Affecting extent of distribution
Extent of plasma protein binding
Regional differences in pH
Lipid solubility
Available transport mechanisms
Intracellular Binding

Membrane Permeability
Capillary permeability
 Renal capillary permeability
large pores
 Brain capillaries

Blood Perfusion Rate
Greatest blood flow – brain, kidneys, liver
and muscle
 Highest perfusion rate – brain, kidneys,
liver, heart

Protein Binding
Extensive plasma protein binding – lower
Vd; stay in central blood compartment
 Slight change in the binding of highly
bound drugs – significant change in
clinical response
 Only free drug are active

Plasma protein binding of drugs
Acidic drugs (e.g. barbiturates) bind to
albumin
 Basic drugs (e.g. opioids, local
anaesthetics) bind to alpha 1 acid
glycoprotein
 The process is reversible
 Binding sites are non-selective for
similar drugs and thus one can displace
another

Plasma protein binding of drugs
The bound drug is
inactive whilst bound
and this limits systemic
distribution and
glomerular filtration
Only drugs which are
highly bound (>90%)
with small Vd are
affected by changes in
protein binding (e.g.
phenytoin and warfarin)
Drugs
Vit. C, salicylates,
sulfonamides,
barbiturates, penicillins,
tetracyclines, probenecid
Binding sites for acidic
agents
Albumin
Binding sites for basic
agents
Quinine, Streptomycin,
chloram, digitoxin,
coumarin
Globulins, 1, 2, β1, β2
Percent Unbound for Selected drugs
Drug
Caffeine
Digoxin
Gentamicin
Theophylline
Phenytoin
Diazepam
Warfarin
Phenylbutazone
dicumarol
% Unbound
90
77
50
85
13
4
0.8
5
3
Calculating the volume of distribution
Injected
dose
10 mg.
? Volume of container
Sampled
concentration
1 mg. l-1
Volume = injected dose/ sampled concentration = 10 litres
Calculating the apparent volume of
distribution
Injected
dose
10 mg.
? Volume of container
Sampled
concentration
0.1 mg. l-1
Volume = injected dose/ sampled concentration = 100 litres
Why do we need to know the volume of
distribution?
Vd is needed to calculate the loading dose of
a drug (e.g. lignocaine, aminophylline,
pethidine, propofol)
Loading dose = Vd * effective concentration
(Ceff) required
Question: What is the loading dose if Vd is 30
litres and Ceff is 10 mg.l-1
Weight consideration
Vd is proportional to body weight and
thus, the loading dose can be based
on body weight
 Varies with the very young, and very
old

Two compartment
pharmacokinetic model
K12
Dose
Peripheral
compartment
Central
compartment
K21
K elim
Central compartment
Intravascular space, highly perfused
tissues
 Rapid uptake of drug
 75% of cardiac output; 10% of body mass
 Apparent volume can be calculated

METABOLISM
Active Drug
 Active Drug

Inactive Prodrug
 Unexcretable drug

Inactive drug
Active or toxic
metabolite
Active drug
Excretable
metabolite
Pharmacokinetics

Metabolism –detoxification or breakdown
of the drug into metabolites that no longer
exert any effect
Drug Metabolism
Side effects are results that are different
from the primary, or therapeutic, effect, for
which a drug is taken.
 First-pass metabolism drug-metabolizing
enzymes in either the cells of the GI tract
or the liver can markedly reduce the
amount of drug that reaches the
bloodstream.

BIOTRANSFORMATION
Phase I
 Phase II

PHASE I
Modify the chemical structure of a drug
OXIDATION
REDUCTION
HYDROLYSIS
Oxidative Reactions
N- dealkylation – Imipramine, erythromycin
 O-dealkylation – Indomethacin,Codeine
 Aromatic hydroxylation – Phenytoin,
phenobarbital
 N- Oxidation – chlorpheniramine, Dapsone
 S- oxidation - Cimetidine, Omeprazole
 Deamination – Amphetamine, Diazepam

Liver Microsomal System
Oxidative Reactions: Cytochrome P450 mediated
Examples
• Formation of an inactive polar metabolite
• Phenobarbital
• Formation of an active metabolite
• By Design: Purine & pyrimidine chemotherapy
prodrugs
• Inadvertent: terfenadine – fexofenadine
• Formation of a toxic metabolite
• Acetaminophen – NAPQI (N-acetyl-p-benzoquinone imine
HYDROLYSIS
Ester Hydrolysis – Procaine, aspirin,
Succinylcholine
 Amide Hydrolysis – Lidocaine,
Indomethacin
 Epoxide Hydrolysis - Carbamazepine

REDUCTION

Nitro reduction – Chloramphenicol

Dehalogenation – Halothane

Carbonyl Reduction – Methadone,
Naloxone
PHASE II
Conjugate a drug to large polar molecules to :
Inactivate a drug
Enhance drug’s solubility
Enhance excretion rate
CONJUGATION REACTIONS
Glucoronidation – Acetaminophen,
Morphine, Oxazepam
 Sulfation – Acetaminophen, Steroids
 Acetylation – Sulfonamides, INH,
Clonazepam

Metabolism
Induction – drugs can cause an increase
in liver enzyme activity thus increasing
metabolic rates of some drugs
ex. Phenobarbitone – induce metabolism
of itself, phenytoin, warfarin
 Inhibition – inhibit metabolism of other
drugs

Drug A inhibits the
production of
enzymes to
metabolize Drug B
Induction
Inhibition
Liver
This reduces
the amount of
Drug B and
may lead to
loss of Drug
B’s
effectiveness
Drug A induces the
body to produce more
of an enzyme to
metabolized Drug B
This increases the amount of
Drug B in the body and could
lead to an overdose or toxic
effects
Hepatic clearance and
ratio
extraction
Clearance = Flow X Extraction ratio
IF hepatic blood flow = 1500 ml.min-1
and extraction ratio = 50%
Clearance = 750 ml. min-1
Hepatic clearance and extraction ratio

Extraction ratio = Ci - Co/ Ci
 Ci
may be calculated by determining the
percentage of a drug absorbed, and thus
reaching the liver
 Co may be calculated from the bioavailability

Effect on clearance when hepatic blood
flow falls (e.g. hepatic disease, decreased
cardiac output and hypovolaemia)
Hepatic microsomal enzymes are capable of
being induced and inhibited
Drugs causing
induction include
• barbiturates
(i.e.phenobarbitone)
• rifampicin
• nicotine and
aminophylline
Drugs causing
inhibition include
•
•
•
•
cimetidine
erythromycin
metronidazole
disulphiram and
ethyl alcohol
Effects of hepatic blood flow and
enzyme induction/inhibition
Metabolism of high
clearance (ER) drugs (e.g.
opioids) is more dependent
on hepatic blood flow and
less dependent of enzyme
induction and inhibition
Effects of hepatic blood flow and
enzyme induction/inhibition
Metabolism of low to moderate
clearance (ER) drug ( e.g.
aminophylline) is more
dependent on enzyme
induction and inhibition and
less dependent of hepatic
blood flow
Drug metabolism:
Zero and first order kinetics
Zero order
kinetics:
First order
kinetics:
• a fixed
amount of the
drug is
metabolised
in unit time
(e.g. alcohol)
• a fixed
fraction of the
drug is
metabolised
in unit time
Drug metabolism:
Zero and first order kinetics
Most drugs are metabolised by a first order process
Amount metabolised is proportional to the
concentration of the drug
Newborn hepatic metabolism of some drugs such as
phenytoin becomes saturable at therapeutic
concentrations
The rate constant in first order kinetics and
relationship to the half life
The rate constant is the fractional change
in concentration in unit time
 It is expressed as the elimination rate
constant k, in units of h-1
 Thus, if 10% of the drug is removed per
hour, then the rate constant is 0.1h-1
 T1/2 = natural logarithm of 2 (0.693)/k
 Thus, k of 0.1 = T1/2 of 6.93 hours

Clearance
First order kinetics states that a fixed
fraction of the drug is metabolised in unit
time
 Or … the amount metabolised is
proportional to the concentration
 Or … amount metabolised = K *
concentration
 K is the ‘clearance’ and has the unit of flow
(e.g. mls.min-1 or litres.hr-1)

Why do we need to know the drug
clearance?

For effective drug therapy you need to
be able to maintain the effective
concentration (Ceff) that produces the
desired effect

Thus, we need to calculate the
maintenance dose
Why do we need to know the drug
clearance?
Maintenance dose = clearance *
effective concentration (Ceff)
e.g. if clearance is 3 l.hr-1 and Ceff is 10
mg.l-1
 Maintenance dose = 30 mg.hr-1
 We can thus predict the effect of
changes in clearance and Ceff on
maintenance dose
CLEARANCE
CLP =___rate of elimination (mg/min)______
plasma concentration of drug (mg/ml)
The elimination
half life
Half life is the time taken
for the concentration (in the
plasma) to fall by one half
HALF LIFE AND PERCENT OF DRUG
REMOVED (wash out)
Number of
Half-lives
0
1
2
3
4
5
Percent of Drug
Remaining
100
50
25
12.5
6.25
3.125
Percent of Drug
Removed
0
50
75
87.5
93.75
96.875
Half life and onset of action using
maintenance dose and no loading dose
(wash in)
Number of
Half-times
0
1
2
3
4
5
Percent of final
steady state concentration
0
50
75
87.5
93.75
96.875
The context sensitive half life
Definition:
The time for the plasma
concentration to fall by half
following steady state infusion and
constant blood levels.
Usually after several hours infusion.
FACTORS AFFECTING
DRUG METABOLISM

Genetic variation

Environmental determinants

Disease Factors

Age

Sex

Cultural
Metabolism

Genetic –people have different amounts
of enzymes that metabolize drugs
Metabolism

Physiological –if more than one drug is
present in the body, the drugs may
interact with one another either in a
therapeutically beneficial way or in a way
that can adversely affect the patient.
Metabolism

Environmental –current mood, stress,
and past experience with drug can affect
metabolism (and toxicity)
ROLE OF CYP ENZYMES IN
HEPATIC DRUG METABOLISM
RELATIVE HEPATIC CONTENT
OF CYP ENZYMES
CYP2D6
2%
% DRUGS METABOLIZED
BY CYP ENZYMES
CYP2E1
7%
CYP 2C19
11%
CYP 2C9
14%
CYP2D6
23%
CYP 2C
17%
OTHER
36%
CYP 1A2
12%
CYP 3A4-5
26%
CYP 1A2
14%
CYP 3A4-5
33%
CYP2E1
5%
Participation of the CYP Enzymes in
Metabolism of Some Clinically Important Drugs
CYP Enzyme Examples of substrates
1A1
Caffeine, Testosterone, R-Warfarin
1A2
Acetaminophen, Caffeine, Phenacetin, R-Warfarin
2A6
17-Estradiol, Testosterone
2B6
Cyclophosphamide, Erythromycin, Testosterone
2C-family
Acetaminophen, Tolbutamide (2C9); Hexobarbital, SWarfarin (2C9,19); Phenytoin, Testosterone, R- Warfarin,
Zidovudine (2C8,9,19);
2E1
Acetaminophen, Caffeine, Chlorzoxazone, Halothane
2D6
Acetaminophen, Codeine, Debrisoquine
3A4
Acetaminophen, Caffeine, Carbamazepine, Codeine,
Cortisol, Erythromycin, Cyclophosphamide, S- and RWarfarin, Phenytoin, Testosterone, Halothane, Zidovudine
Adapted from: S. Rendic Drug Metab Rev 34: 83-448, 2002
Factors Influencing Activity and
Level of CYP Enzymes
Nutrition
1A1;1A2; 1B1, 2A6, 2B6,
2C8,9,19; 2D6, 3A4,5
Smoking
1A1;1A2, 2E1
Alcohol
2E1
1A1,1A2; 2A6; 2B6; 2C;
2D6; 3A3, 3A4,5
1A1,1A2; 2A6; 1B; 2E1;
Environment
3A3, 3A4,5
Genetic
1A; 2A6; 2C9,19; 2D6;
Polymorphism 2E1
Drugs
Adapted from: S. Rendic Drug Metab Rev 34: 83-448, 2002
Pharmacokinetics

Elimination –metabolic waste products
are removed from the body
Elimination
Drugs leave the body through:
 Kidneys
 Lungs
 Bile
 Skin
Elimination
Drugs leave the body through:
 Kidneys:
1) Excrete most of the products of body
metabolism
2) Closely regulate the levels of most of the
substances found in body fluids
•
Psychoactive drugs are often reabsorbed
out of the kidneys, so the liver has to
enzymatically transform the drugs so
with minimal reabsorption they can
exit in urine.
Elimination
Drugs leave the body through:
 Bile
After most psychoactive drugs are
processed by the liver they are usually
less fat soluble, less capable of being
reabsorbed, and therefore capable of
being excreted in urine.
Elimination
Drugs leave the body through:
 Lungs
Only occurs with highly volatile or
gaseous agents
Elimination
Drugs leave the body through:
 Skin
Small amounts of a few drugs can pass
through the skin and be excreted in sweat.
Processes That Determine
Urinary Excretion of Drug
1. Glomerular filtration
2. Tubular secretion
3. Tubular reabsorption
Drug excretion: Role of the
Kidneys
Drug excretion: Role of the
Kidneys
 Glomerular
clearance
filtration (GFR)
= fraction unbound (FU) *
GFR
if TOTAL renal clearance = the above,
then the drug is principally excreted by
filtration (e.g. gentamicin) AND
clearance is proportional to GFR
Drug excretion: Role of the Kidneys

Passive tubular reabsorption
 clearance
is less than FU * GFR (due to
reabsorption)
 e.g. aspirin and amphetamine (effect of
pH of urine)

Active tubular secretion (ATS)
 clearance
is greater than FU * GFR (due
to secretion)
 e.g. penicillin (inhibited by probenecid),
digoxin (inhibited by quinidine)
Renal Factors that Affect Urinary
Drug excretion
Glomerular filtration rate
 Tubular fluid pH
 Extent of back-diffusion of unionized form
 Extent of active tubular secretion of the
compound
 Extent of tubular reabsorption

ADME - Summary
CLINICAL
PHARMACOKINETICS
CLEARANCE
CLP =___rate of elimination (mg/min)______
plasma concentration of drug (mg/ml)
Clearance

First Order Kinetic – constant fraction of
the drug in the body is eliminated

Saturation Kinetics – constant amount of
drug is eliminated per unit time
CLEARANCE:
Clinical Utility

Determines the maintenance dose (DM)
required to achieve the target plasma conc
at steady state

DM(mg/h) = Tconcn (mg/L) x Clearance (L/h)
Volume of Distribution

Actual volume in which drug molecules are
distributed within the body
Vd = D/CO
Co = D/Vd
VOLUME OF DISTRIBUTION:
Clinical Utility

Used to determine the loading dose (LD)
LD = Css
x
(mg) (mg/L)
Vd
(L)
HALF-LIFE

Time it takes for plasma concentration or
the amount of drug in the body to be
reduced by 50%
t1/2 = (0.693 x Vd) / Cl
HALF-LIFE:
Clinical Utility
 Determines
how long it takes to reach
steady state after multiple dosing
STEADY STATE
CONCENTRATION
CSS = Bioavailability x Dose
Interval x Cl
Initial Concentration
Initial concentration = Loading Dose
Vd
Dosing Rate
Dosing rate = Target conc’n x Cl / F
Oral Digoxin is to be used as maintenance
dose to gradually digitalize a 69 kg patient
with congestive heart failure.
A steady state plasma concentration of
1.5 ng/ml is selected as an appropriate
target.
Based on the patient’s renal function, the
clearance of digoxin is computed at
1.6/ml/min/kg or 110ml/min.
How should the drug be given in
this patient?
Given:
Cl – 1.6ml/min/kg
F – 70%
Target conc’n = 1.5ng/ml

Dosing rate = 1.5ng/ml x 1.6ml.min/kg/0.7