2.

Introduction to Pharmacokinetics
After the end of this chapter the students will be able to:
define different terminologies
explain passage of drugs across a biological membrane and
factors affecting the passage of drugs across a biological
membrane
compare different types of transport systems across cell
membranes
describe routes of drug administration with their respective
advantages and disadvantages
explain factors affecting drug absorption 1
Ctnd…
discuss factors that determine drug
distribution in the body
discuss types of biotransformation and
therapeutic consequences of drug metabolism
explain factors affecting drug metabolism
discuss drug excretion and steps in renal
excretion
discuss factors influencing drug excretion
discuss drug use and breast feeding
differentiate loading dose and maintenance
dose
2
 Pharmacokinetics
Divisions of Pharmacology:
Pharmacokinetics: - study of what the body
does to the drugs
Pharmacodynamics: - the study of what the
drug does to the body
Pharmacogenomics:- the study of the
relation of genetic makeup of an individual
to the drugs response.

3
Pharmacokinetics is a branch of pharmacology
dedicated to:
– the determination of the fate (time course) of
substances administered to a living organism.
• it studies “what the body does to the drugs”.

• Pharmacokinetic concepts are used during drug

development to determine the:
optimal formulation of a drug,
dose (along with effect data), and
dosing frequency.
4
Cntd…
• The four major pharmacokinetic processes are:
 Drug absorption

 Drug distribution

 Drug metabolism

 Drug excretion

5
The four basic pharmacokinetic processes
6
Ctnd…
• Pharmacokinetic processes:
– Determine the concentration of a drug at its sites
of action (pharmacokinetics of the drug).
• All phases of pharmacokinetics involve drug
movement.
• Factors that determine the passage of drugs
across membranes have profound influence
on all phases.

7
Passage of drugs across a biological membrane

• It is translocation of a drug from one side of

the biological barrier to the other.

8
Structure of biological membrane

• The outer surface of the cell is covered by a

very thin structure known as plasma
membrane.
• A common feature of all cell membranes is a
phospholipid bilayer.
• Arranged with the hydrophilic heads on the
outside and the lipophilic chains facing
inwards.
9
10
Ctnd…
• It is composed of lipid and protein molecules.
• The membrane proteins have many functions:
contributing structure to the membrane
acting as enzyme
acting as carrier for transport of substances
acting as receptors
• The plasma membrane is a semipermeable
membrane
 allowing certain substances to pass freely but preventing
others to transverse the membrane.
11
Major mechanisms of drug transfer
A. Passive transfer
– Simple passive diffusion
– filtration
B. Specialized transport
– Facilitated diffusion
– Active transport
– Endocytosis

12
1. Passive transfer
a. Simple passive diffusion
• It is the commonest means of crossing the cell
membrane.
• Drug molecules move down a concentration
gradient.
• The process requires no energy to proceed.

13
Ctnd…
• Many drugs are weak acids or weak bases.
• Can exist in either unionized or ionized form,
depending on the pH
• The unionized form of a drug is lipid-soluble and
diffuses easily by dissolution in the lipid bilayer.
• Thus the rate at which transfer occurs depends
on the pKa of the drug in question and pH of the
solution.

14
 Factors influencing the rate of diffusion

 Molecular size
 Concentration gradient
 Ionization
 Lipid solubility
 Protein binding
 Surface area

15
Molecular size and shape

• Small molecules will diffuse much more

readily than large ones and vice versa.
• Drug shape affects affinity of the drug for
carrier molecules or other binding sites such
as plasma proteins or tissue.
• Drugs of similar structure may exhibit
competition for such binding sites, which can
affect their pharmacokinetics.

16
Concentration gradient

• The rate of transfer across a membrane is

proportional to the concentration gradient
across the membrane.
• Thus increasing the plasma concentration of a
drug will increase its rate of transfer across
the membrane.

17
 Ionization

• The nonionized form of drugs is more lipid

permeable and therefore better able to diffuse
across biologic barriers.
• The lipophilic nature of the cell membrane
permits the passage of the uncharged
(unionized) fraction of any drug.
• The degree to which a drug is ionized in a
solution depends on the molecular structure of
the drug and pH.
18
Lipid solubility

• The lipid solubility of a drug reflects its ability

to pass through the cell membrane.
• The lipid-water partition coefficient is an index
of lipid solubility.
• The greater the lipid-water partition coefficient,
the greater the drug flux.
– Drugs with higher lipid-water partition coefficients
will cross biologic membranes more quickly.

19
Protein binding

• Only the unbound fraction of drug in plasma is

free to cross the cell membrane.

20
Surface area

• The larger the absorbing surface, the greater

the drug flux.

21
b. Filtration

• Filtration means that water and dissolved

materials are forced through a membrane
from an area of higher pressure to an area of
lower pressure.
• Water soluble drugs of relatively low
molecular weight can diffuse through
membranes.
• Is means of transport of glucose, amino acids, and
other nutrients into the cells.
22
2. Specialized transport

a. Facilitated diffusion
b. Active transport
c. Endocytosis

23
a. Facilitated diffusion
• is facilitated by a carrier protein
• it is a saturable process
• it is selective
• it requires no energy
– can not move against a concentration gradient

24
b. Active transport

• Is similar to carrier mediated diffusion

• Differs in that it requires metabolic energy
and it transports molecules against
concentration gradient.

25
c. Endocytosis

• Molecules are engulfed by the cell membrane

and released in the cytoplasm.
• The process is usually used for molecules that
are too large.

26
 Differences amongst different transport systems

Characteris Simple Facilitated Active

tics diffusion transport
Incidence commonest less least
common common
Process slow quick very quick
Movement along along against
concentratio concentrati concentrati
n gradient on gradient on gradient
Carrier not needed needed needed
Energy not required not required required

27
Routes of drug administration

• are path ways (routes) through which a drug is

administered into the body.

28
Factors to be considered in selecting the route of drug
administration

• Drug related factors (nature of the drug)

• Patient related factors (patient condition)
• The desired response
Quick response (for sever problems)
Delayed (slow) response (for mild problems)
• The desired effect
Local effect
Systemic effect (usually oral or intravenous routes
are used)
29
a. Oral route (PO)

• Drug is swallowed with adequate water

(pure water) through the mouth.
• It is the most common route of drug
administration.
• It is the simplest, safest and most
economical route of administration for
systemic effect.

30
Advantages

Administration is:
• easy
• convenient
• inexpensive

31
Disadvantages
• The onset of drug action is relatively slow.
• High variability of absorption
• Drugs can be destroyed (inactivated)
• Requires compliance
• Not suitable for vomiting or unconscious
patients and uncooperative patients
• Local irritation

32
b. Parentral routes

• Drug is administered using a syringe and a

needle (by injection).
• Intravenous (IV)
• Intramuscular (IM)
• Subcutaneous (SC)

33
Intravenous (IV) route

• Drug is administered through veins.

Advantages
 Absorption is instantaneous and complete;
rapid onset
 Precise control over levels
 Used for irritating drugs

34
Disadvantages

 high cost
 cannot self-administered
 cannot reverse injection
 could cause fluid overload;
 increased risk of infection, embolism and
chance of error
 pain during injection

35
Intramuscular (IM) route
 Drug is injected through muscle layers.
Advantages
 Only barrier is capillary wall.
 used for poorly soluble drugs; for depot
preparations to decrease number of injections

Disadvantages
 Inconvenience; discomfort with administration
36
Subcutaneous (SC) route
• Drug is injected under the skin in the
subcutaneous tissue
• Almost identical to IM for advantages and
disadvantages

37
c. Rectal route

→ Application or insertion of a drug into the

rectum
→ Used for both local and systemic effect

38
Advantages
→ Suitable for vomiting patients, unconscious
patients and uncooperative patients for the
oral route
→ Useful for drugs that are irritant to the GIT
→ Reduces first pass effect

Disadvantage
• Less convenient than the oral route
39
d. Vaginal route

• Drugs are applied (inserted) into the vagina.

• Used for local or systemic effect.
• Usually used for the treatment of local ailments
• Some drugs are absorbed well; can be used for
systemic application

40
Problems associated with vaginal route of drug
administration

 Inconstant hormonal influence in the

epithelium (may be thick or thin)
 Gender specificity
 Problem of personal hygiene
 Influence of sexual inter course
• Male semen is alkaline and may increase the pH of
the vagina and hence affecting drug absorption.

41
e. Topical routes (skin, eye, nose, ear)

• For local (mostly) and systemic effect.

42
f. Buccal and sublingual routes

• Buccal cavity: between the teeth and pouch

• Sublingual: under the tongue in the mouth

Advantages
• Have relatively rapid onset of action.
• Suitable for drugs irritant to the GIT or
drugs that can be destroyed in the GIT and
liver.
43
 g. Inhalations
• Drug is inhaled through the mouth or nose for
local effect in respiratory tract or for systemic
effect.
• It is used usually for local effect.
Advantages
• Very rapid onset of action
• Minimum firs-pass effect

Disadvantages
• not all dosage forms in aerosol, gaseous forms
44
Comparing oral administration with parenteral
administration

• Oral route is preferred to parenteral except for

certain situations:
• emergency conditions
• drugs destroyed by gastric acidity
• when drug levels are to be tightly controlled
• when severe irritation would occur
• for depot preparations
• when patients cannot take oral drugs.

45
 1. Drug absorption
• It is the movement of drugs from the site of
administration into the blood.
 The rate determines how soon its effects will
begin.
 The amount determines the intensity of a drug
effects.

46
Factors affecting drug absorption

• Rate of dissolution
• Surface area of absorption
• Blood flow
• Lipid solubility

47
 Bioavailability (F)
• Bioavailability is the amount of drug which
enters the plasma
• The amount of the unchanged drug that
reaches the systemic circulation after
administration through a certain route of
admin.
• For an IV infusion, all the drug administered
appears in the plasma.

48
Ctnd…

49
Formulation factors affecting oral absorption
• The role of the drug formulation in the delivery of drug
to the site of action should not be ignored.
• With any drug it is possible to alter its bioavailability
considerably by formulation modification.
• With some drugs an even larger variation between a
good formulation and a bad formulation has been
observed.

50
Ctnd…

• The bioavailability of a drug may be expected to

decrease in the order solution > suspension >
capsule > tablet > coated tablet.
• This order may not always be followed but it is a
useful guide.

51
Example: Sustained release dosage forms

• Enteric coated tablets which are coated with a

material which will dissolve in the intestine
but remain intact in the stomach.

• Polymeric acid compounds have been used for

this purpose with some success.

52
Benefits

• for short half-life drugs, sustained release can

be a means for less frequent dosing and thus
better compliance

• reduce variations in plasma/blood levels for

more consistent result

53
Problems
• More complicated formulation may be more
erratic in result.
• A sustained release product may contain a
larger dose.
• A failure of the controlled release mechanism
may result in release of a large toxic dose.
• More expensive technology

54
2. Drug distribution

• Is drug movement from the blood to the interstitial

space of tissues and from there into cells.
• Once a drug enters into systemic circulation it has to
be distributed into interstitial and intracellular fluids.
• The drug can be moved from the plasma to the
tissue until the equilibrium is established.

55
Ctnd…

• The distribution of any given drug is determined

by three major factors:
1. Blood flow to tissues
2. Exiting the Vascular System
3. Entering Cells

56
 1. Blood flow to tissues
• The drug is easily distributed in highly perfused
organs like liver, heart, kidney etc in large
quantities.
• in small quantities in low perfused organs like
muscle, fat, peripheral organs etc.

57
2. Exiting the Vascular System

a. Typical capillary beds

b. The blood brain barrier
c. Placental barrier
d. Plasma protein binding

58
a. Typical capillary beds

• movement from the blood stream into the interstitial

space is unimpeded.
– Fore example, the distribution of drugs through the
capillary bed of renal tubules is highly extensive due
to pores in the epithelial cells.
• This results in more widespread distribution of drugs
out the capillary bed.

59
b. The blood brain barrier
• a separation of circulating blood and
cerebrospinal fluid (CSF) in the central nervous
system (CNS).
• It occurs along all capillaries.
• Consists of tight junctions around the
capillaries that do not exist in normal
circulation.

60
Ctnd…

• Endothelial cells restrict the diffusion of microscopic

objects (e.g. bacteria) and large or hydrophilic
molecules into the CSF.
• But allow the diffusion of small hydrophobic
molecules (O2, hormones, CO2).
• Cells of the barrier actively transport metabolic
products such as glucose across the barrier with
specific proteins.

61
62
c. Placental barrier

• Allows non-ionized drugs with high lipid/water

partition coefficient by a process of simple
diffusion to the foetus.
• alcohol
• morphine

63
d. Plasma protein binding

• Drugs distribute through various body fluid

compartments such as plasma, interstitial fluid
compartment and trans-cellular compartment.
• usually reversible.
albumin for acidic drugs
alpha glycoprotein for basic drugs
• The less bound a drug is, the more efficiently
it can traverse cell membranes or diffuse.

64
65
Ctnd…
• Free drug leave plasma to site of action.
• Protein binding acts as a temporary store of a
drug.
• Protein binding reduces diffusion of drug into
the cell and there by delays its metabolic
degradation.

66
Cntd….
• For highly protein-bound drugs, a small
change in plasma protein binding can lead to
a large change in the proportion of free drug
in the plasma and may lead to toxicity.
– For a drug that is 99% bound to plasma protein,
only 1% is free in the plasma.
– Reduction of plasma protein binding to 98%
results in a doubling of free drug and drug effect.

67
Cntd…
• Changes in plasma protein binding can occur
as a result of:
– Disease
– Competition between drugs for the same binding
site
– Saturation of binding sites

68
3. Entering Cells

• The same factors that determine passage

across any other membrane

69
 Tissue Binding
• drugs may also bind to components of tissues.
• It results in sequestration of drug in the tissue.
• Tissue bindings sites:
– Increase the apparent volume of distribution.
– Represent potential sites for drug interactions.
– Result in sequestration of drug in the tissue.
– May release the drug back into the circulation as the
plasma concentration falls.
– Thus tissue binding may represent a reservoir of drug
that can extend the duration of action of the drug.

70
 Volume of Distribution
• represents the theoretical volume (liters)
(apparent volume of distribution) into which a
drug is dissolved to produce the plasma
concentration.
Vd = amount of drug in body

Cp

71
3. Drug Metabolism (Biotransformation)

• Drugs after bringing pharmacological effects, they

should be eliminated from the body unchanged or
by changing to some easily excretable molecules
by a process called Drug Metabolism .
• It is Enzyme mediated alteration of drug structure.
• Liver is the major organ for biotransformation of
drugs. The others being the kidney, gut and lungs.

72
Cntd…
• Many drugs are lipophilic molecules that
resist excretion via the kidney or gut because
they can readily diffuse back into the
circulation.
• Biotransformation is an essential step in
eliminating these drugs by converting them to
more polar water-soluble compounds.

73
Enzymes responsible for metabolism of drugs

a. Microsomal enzymes
b. Non-microsomal enzymes

74
a. Microsomal enzymes

• Present in the smooth endoplasmic reticulum

of the liver, kidney and GIT.
 Glucuronyl transferase,
 Dehydrogenase ,
 Hydroxylase and
 Cytochrome P450

75
b. Non-microsomal enzymes
• Present in the cytoplasm, mitochondria of
different organs.
esterases
amidase
hydrolase

76
Types of biotransformation

• Classified as phase-I and phase–II

• In phase-I reaction the drug is converted to
more polar metabolite.
• Some metabolites may not be excreted and
further metabolized by phase–II reactions.

77
Phase I
1. Oxidation:
– Microsomal oxidation involves :-

the introduction of an oxygen (O2), OR the

removal of a hydrogen atom (H+),
dealkylation or demethylation of drug
molecule .

78
Cntd…
2. Reduction
– The reduction reaction will take place by the
enzyme reductase which catalyze the reduction of
azo (-N=N-) and nitro (-NO2) compounds.
3. Hydrolysis
– Metabolism of esters and amines (by esterases
and amidases); are found in plasma and liver.
– Is splitting of drug molecule after adding water

79
Phase II:
 Addition of polar groups to drugs that increase the
water solubility -to facilitate excretion.
a. Glucuronidation: addition glucuronide to the drug
molecule.
b. Sulfate conjugation
 Sulfotransferase transfers sulfate group
c. Acetylation
 acetyl transferase is responsible, for conjugation of
Acetic acid to drugs.
d. Glycine conjugation and
e. Methylation reactions
80
Therapeutic consequences of drug metabolism
• Promotion of renal excretion,
• Reduction of therapeutic action,
• Activation of a prodrug,
• Enhancement of therapeutic action
• Alteration of toxicity

81
82
83
Factors affecting drug metabolism

• Age
• Sex
• Chemical properties of the drug
• First pass effect
• Diet
• Genetics
• Dosage

84
Ctnd…

 Competition between drugs

 Pathologic conditions
 Liver, cardiovascular diseases
 Pulmonary dysfunction
 Hypo/hyperthyroidism

85
4. Excretion of drugs

• Removal of drugs from the body

• The major processes of excretion include:
 renal excretion,
 hepatobiliary excretion and
 pulmonary excretion

86
Ctnd…
• The minor routes of excretion are:
 saliva
 sweat
 tears
 breast milk
 vaginal fluid
 nails and hair

87
Renal drug excretion

• Renal excretion is the net result of three

processes:
1. Glomerular filtration
2. Passive reabsorption
3. Active tubular secretion

88
 1. Glomerular filtration

• Depends on:
• the concentration of drug in the plasma,
• molecular size, shape and charge of drug
• Only the drug which is not bound with the
plasma proteins can pass through glomerulus.
• All the drugs which have low molecular weight
can pass through glomerulus.

89
 2. Passive reabsorption

• The reabsorption of drug from the lumen of

the distal convoluted tubules into plasma
• Occurs by simple diffusion.
• When the urine is acidic, the degree of ionization of
basic drug increase and their reabsorption decreases.
• When the urine is more alkaline, the degree of
ionization of acidic drug increases and the
reabsorption decreases, thus their excretion
increases.

90
 3. Active tubular secretion

• The cells of the proximal convoluted tubule actively

transport drugs from the plasma into the lumen of the
tubule.
• Note that:
– The function of glomerular filtration and active tubular
secretion is to remove drug out of the body,
– while tubular reabsorption tends to retain the drug.

91
92
Factors affecting excretion of drugs

• Renal state
• pH of the urine
• Competition for active tubular transport
• Age of the patient

93
Drugs and Breastfeeding

• Related to a nursing mother:

Nearly all drugs pass into human milk.
Almost all medication appears in very small
amounts.
Very few drugs are contraindicated for nursing
mothers.
• The issue of which drugs are safe to take
during lactation is quite complicated.

94
Pregnancy classifications of drugs
• Class A: No risk demonstrated to the fetus in any
trimester
• Class B: No adverse effects in animals; no human
studies
• Class C: Only given after risks to the fetus are
considered; animal studies show adverse reactions
• Class D: Definite fetal risks; only given in life
threatening situations
• Class X: Absolute fetal abnormalities

95
Time Course of Drug Responses

• To achieve the therapeutic objective, we must

control the time of drug responses.
• We need to regulate time at which drug
responses start, the time when most intense,
and time when they cease.

96
Plasma Drug Levels

Clinical significance of plasma drug levels

• there is usually direct correlation between
therapeutic and toxic responses and plasma
drug levels.

• Two plasma drug levels are defined:

i. Minimum effective concentration (MEC)
ii. Toxic concentration
97
Therapeutic range

• Objective of drug dosing (between MEC and

toxic levels).

98
a. Single-Dose Time Course

99
Drug Half-Life

• Time required for amount of drug in the body

to decrease by 50%.

100
b. Drug Levels Produced with Repeated Doses

• Process by which plateau drug levels are

achieved.
• Plateau level is the steady state (elimination
equals administered dose).

101
Fig. Drug accumulation with repeated administration 102
Ctnd…

Techniques for reducing fluctuations in drug

levels:
• Continuous infusion
• Reduce dosage size while reducing dosing interval

103
Loading dose

• When plateau must be achieved quickly, a

large initial dose called loading dose can be
administered.

Maintenance doses
• The plateau can be maintained with smaller
dose called maintenance dose.

104
Drug cumulation

• The process by which blood levels of a drug

build-up, thereby increasing its therapeutic and
toxic effects.
• If drug dosage exceeds the elimination rate,
the drug will cumulate.

105
Ctnd…

• Cumulation may result from:

 poor elimination due to slow metabolism,
 binding the drug to plasma proteins or
 inhibition of excretion as occurs in patients of a
kidney disease.

106
Steady state plasma concentration
• When a drug dose is given repeatedly over a given
period, a steady state is eventually reached,

• at which point the amount of drug absorbed is in

equilibrium with that eliminated from the body.

• It is achieved after 4 to 5 half –lives for most of the

drugs which follow first order kinetics.
– For example a drug with half life of 1 hour will be expected
to be at steady state after more than 4 hours of
administration
107
• Drug accumulation by repeated administration of drug at intervals
equal to its elimination half-life.
108
Clearance
• It is the volume of plasma cleared of the drug by
metabolism (hepatic) and excretion (renal) and
other organs.
• Elimination of drug from the body may involve
processes occurring in the kidney, the lung, the
liver, and other organs.
• Dividing the rate of elimination at each organ by
the concentration of drug presented to it yields
the respective clearance at that organ.

109
 Clearance…
• Added together, these separate clearances
equal total systemic clearance.
– i.e Clearance is additive; a function of elimination
by all participating organs.
CL systemic = CLrenal + CLhepatic + CLother

• "Other" sites may include the lungs and other

sites of drug metabolism.

110
 Clearance…
• The two major sites of drug elimination are
the kidneys and the liver.
– Clearance of unchanged drug in the urine
represents renal clearance.

– Within the liver, drug elimination occurs via:

 biotransformation of parent drug to one or more
metabolites, or
excretion of unchanged drug into the bile, or
 both.

111