Pharmacokinetics

The dynamics of drug absorption, Distribution,

Metabolism, elimination
Drugs at site of administration
Absorption

Drugs in plasma Distribution

Drugs in tissues
Metabolism

Metabolite(s) in
tissues
Elimination
Drugs &/or matabolites in
urine, feces, bile
 Metabolism
 General considerations - drug metabolism
(biotransformation) usually results in more water-
soluble, more polar metabolites, thus facilitating
their excretion by reducing renal tubular
reabsorption
 drug metabolism does not always result in
detoxification and inactivation of drugs, although
these usually occur.
 Biotransformation
1. Inactivation: most drugs and their
active metabolites are rendered inactive or
less active e.g. pentobarbitone , morphine
, chloramphenicol.
 Biotransformation
2. Active metabolite from an active drug:
many drugs have been found to be
partially converted to one or more active
metabolite , the effects observed are the
sum total of that due to the parent drug
and its active metabolites .
Biotransformation
3. Activation of a inactive drug – few
drugs are inactive as such and need
conversion in the body to one or more
active metabolites . Such a drug is
called a prodrug . The prodrug may offer
advantage over the active form in being
more stable, having better
bioavailability or other desirable
pharmacokinetics properties or less side
effect and toxicity .
 Kinetics of Metabolism
1. First order Kinetics: Rate of drug
metabolism is directly proportional to
the conc. of free drug.

2. Zero order Kinetics: Rate of drug

metabolism is not dependent on the
conc. of free drug. And rate of
metabolism remain constant over time.
 Biotransformation
Biotransformation reaction can be
classified into :
a. Nonsynthetic /.phase 1 reactions –
metabolites may be active or inactive .
b. Synthetic / conjugation / phase 2
reaction – metabolite is mostly inactive .
 Directly Some drugs directly
Enter Phase II
metabolism
Oxidation ,
reduction Conjugation
Drug Phase I Phase II
and/or products

hydrolysis
Conjugated drug
Following Phase I, the drug may Is usually inactive.
be activated, unchanged,
inactivated.

The biotransformation of drugs

 Nonsynthetic reaction
1. oxidation – this reaction involves
addition of oxygen / negatively charged
radical or removal of hydrogen / positively
charge radical . Oxidations are the most
important drug metabolizing reaction .
Various oxidation reaction are :
 Nonsynthetic reaction
Hydroxylation , oxygenation at C, N,or S
atoms ; N or O –dealkylation , oxidative
deamination , etc , it may cases the initial
insertion of oxygen atom into the drug
molecule produces short lived highly
reactive quinone / epoxide / superoxide
intermediates which then convert to more
stable compounds .
 Nonsynthetic reaction
Oxidative reaction are mostly carried by
a group of monooxygenases in the liver
, which is the final step involve a
cytochrome P-450 heamoproteins ,
NADPH , cytochrome P- 450 reductase
and O2 . There are 30 – 100 cytochrome
P 450 isoenzymes differing in their
affinity for various substrates .
Microsomal enzyme oxidation
system
 Oxidation

Oxidation is the addition of oxygen and/or

the removal of hydrogen. Most oxidation
steps occur in the endoplasmic reticulum.
Common reactions include :-
Alkyl group ----> alcohol

for example phenobarbitone

Aromatic ring ----> phenol
Reduction
Addition of a hydrogen or removal of
oxygen.

azo (-N=N-) or nitro groups (-NO2) --->

(-NH2) amines
 Nonsynthetic reaction
2. Reduction – This reaction is the
converse of oxidation and involves
cytochrome P 450 enzymes working in the
opposite direction . Drugs primarily
reduced are chloralhydrate ,
chloramphenicol , halothane .
 Nonsynthetic reaction
3. Hydrolysis – This is cleavage of drug
molecule by taking up a molecule of water
.
Ester + H2O esterase Acid + alcohol

Similarly amides and polypeptides are

hydrolysed by amidases and peptidases .
Hydrolysis
Addition of water with breakdown of
molecule. In blood plasma (esterases) and
liver
Esters ---> alcohol and acid

for example aspirin to salicylic acid

 Nonsynthetic reaction
Hydrolysis occurs in liver , intestines ,
plasma and other tissues . Ex- choline
esters , procaine , lidocaine .
4. Cyclization – this is formation of ring
structure from a straight chain compound ,
e.g. proguanil.
 Nonsynthetic reaction
5. Decyclization --- This is opening up of
ring structure of the cyclic drug molecule ,
e.g. barbiturate , phenytoin . This is
generally minor pathway.
 Enzyme Induction
An interesting feature of some of these
chemically dissimilar drug substrates is
their ability , on repeated administration
,to induce cytochrome P450 by
enhancing the rate of its synthesis or
reducing its rate of degradation .
 Enzyme Induction
A large number of drugs can cause an
increase over time in liver enzyme activity.

This in turn can increase the metabolic rate of

the same or other drugs. Phenobarbitone will
induce the metabolism of itself, phenytoin,
warfarin, etc. Cigarette smoking can cause
increased elimination of theophylline and
other compounds. Dosing rates may need to
be increased to maintain effective plasma
concentrations.
 Enzyme Induction
induction results in an acceleration of
metabolism and usually in a decrease in
the pharmacologic action of the inducer
and also of coadministered Drugs.
however in the case of drugs metabolically
transformed to reactive metabolites
,enzyme induction may exacerbate
metabolite –mediated tissue toxicity.
 Enzyme inhibition
Certain drugs substrate may inhibit
cytochrome P450 enzyme activity .
Imidazole-containing drugs such as
cimetidine and ketoconazole bind tightly to
the heme iron of cytochrome P450 and
effectively reduce the metabolism of
endogeneous substrate .
 Enzyme inhibition
 Alternately some drugs can inhibit the
metabolism of other drugs. Drug
metabolism being an enzymatic process
can be subjected to competitive inhibition.
For example, warfarin inhibits tolbutamide
elimination which can lead to the
accumulation of drug and may require a
downward adjustment of dose.
 Synthetic reaction
1.Glucuronide conjugation – this is the most
important synthetic reaction . Compounds with
a hydroxyl or carboxylic acid group are easily
conjugated with glucuronic acid which is
derived from glucose . Ex- chloramphenicol ,
aspirin , morphine . Not only drug but
endogenous substrate like bilirubin , steroidal
hormones and thyroxin utilized this pathway.
 Diagram of entero-hepatic
circulation
conjugated drug
biliary tract

liver
bacteria
portal vein absorption
unconjugated
drug gut
to circulation
 Synthetic reaction
2. Acetylation – Compounds having amino or
hydrazine residues are conjugated with the
help of acetyl coenzyme – A , e.g.
sulfonamides , isoniazid , hydralazine .
Multiple genes control the acetyl transferases
and rate of acetylation shows genetic
polymorphisn .
 Synthetic reaction
Methylation – The amine and phenols can be
methylated , methionine and cysteine acting as
methyl doners , e.g. adrenaline , histamine ,
nicotinic acid .

4. Sulfate Conjugation :The phenolic and steroid

compounds are sulfated by sulfokinase.
 Synthetic reaction

5. Glycine conjugation – salicylates and

other drugs having carboxylic acid group
are conjugated with glycine , but this is not
a major pathway of metabolism.
6. Glutathione conjugation:
7. Ribonucleoside / nucleotide synthesis :
 Elimination/ Excretion
Excretion is the passage out of systemically
absorbed drug.
Drugs and their metabolites are excreted in –
1. Urine
2. Faeces
3. Exhaled air
4. Saliva and sweat
5. Milk
 Elimination via the kidney
Depends on
- blood flow to kidney (normal 1500ml/min)
- glomerular filtration rate (normal 100mls/min)
- active secretion of drugs into the kidney
tubule
- passive reabsorption back into the tubule
Therefore those with a poor renal function will not
eliminate so well
- renal failure or dysfunction elderly or
neonates
 Elimination by the kidney

drug filtered some drugs actively

secreted

some drugs
reabsorbed
 Drug elimination via the
liver
Depends on
 blood flow to the liver
 activity of the enzyme in the liver

Liver enzymes will chemically alter the drug

to form ‘metabolites’ which are:
 inactivate or
 equally or more active than the parent drug
 Drug elimination and the liver

Metabolites are eventually eliminated via the

kidney as they become more water soluble
Factors which may reduce elimination via the
liver
 elderly have poorer blood flow
 neonates have a low liver enzyme activity
 some drugs reduce liver enzyme activity
 any extensive liver damage
 Diagram of first pass effect
(excretion)
biliary tract
metabolised drug

liver

portal vein
gut
to circulation unmetabolised
drug
 Diagram of entero-hepatic
circulation and elimination of drug
conjugated drug
biliary tract

liver
bacteria
portal vein absorption
unconjugated
drug gut
to circulation
 Clearance
Drug clearance principles are similar to the
creatinine clearance which is defined as the
rate of elimination of creatinine in the urine
relative to its serum concentration. At the
simplest level, clearance of a drug is the
factor that predicts the rate of elimination is
relation to the drug concentration:
CL= Rate of elimination / C
The systemic clearance, CL, is a measure
of the efficiency with which a drug is
irreversibly removed from the body
Elimination of drug from the body may involve
process occurring in the Kidney, the lung, liver
and other organs.
Dividing the rate of elimination at each organ by
the concentration of drug presented to its yields
the respective clearance at that organs. Added
together, these separate clearance equal total
systemic clearance:
CL renal = Rate of elimination kidney / C ----(i)

CL liver = Rate of elimination liver / C -----(ii)

CL other = Rate of elimination other / C ---(iii)

CL systemic =CL renal + CL liver + CL other ---(iv)

 Half Life
Half life (t1/2) is the time required to change the
amount of drug in the body by one half during
elimination or during a constant infusion. In the
simplest case --- and the most useful in designing
drug dosage regimens--- the body may be
considered as a single compartment of a size equal
to the volume of distribution (Vd). While the organ of
elimination can only clear drug from the blood or
plasma in direct contact with the organ, this blood or
plasma is in equilibrium with the total volume of
distribution.
Thus , the time course of drug in the body
will depend on both the volume of
distribution and the clearance.

t1/2 = 0.7 * V d / CL
 LOADING DOSE
When the time to reach steady state is
appreciable, as it is for drugs with long
half-lives, it may be desirable to administer
a loading dose that promptly raises the
concentration of drug in plasma to the
target concentration.
This is a single or few quickly repeated
doses given in the beginning to attain
target concentration rapidly.
 LOADING DOSE
In theory, only the amount of the loading
dose need be computed--- not the rate of
its administration--- and, to a first
approximation, this is so.
 The volume of distribution is the
proportionality factor that relates the
total amount of drug in the body to the
concentration in the plasma (Cp) ; if a
loading dose is to achieve the target
concentration,

Loading dose= Amount of the body

immediately following the loading dose
=Vd * TC /F
 For the theophylline example, the
loading dose will be 350 mg (35 L *10
mg/L) for a 70 kg person. For most
drugs, the loading dose can be given as
a single dose by the chosen route of
administration.
 Maintenance Dose
 In most clinical situations, drugs are
administered in such a way as to maintain a
steady state of drug in the body, ie, just enough
drug is given in each dose to replace the drug
eliminated since the preceding dose. Thus
calculation of the appropriate maintenance dose
is a primary goal.
 This dose is one that is to be repeated at
specified intervals after the attainment of target
Cpss so as to maintain the same by balancing
the elimination
 Maintenance Dose
 Clearance is the most important
pharmacokinetic term to be considered in
defining a rational steady state drug dosage
regimen.
 At steady state (SS), the dosing rate
(rate in) must equal the rate of
elimination (rate out). Substitution of the
target concentration (TC) for
concentration (C) predicts the
maintenance dosing rate:

Dosing rate ss = Rate of elimination ss

= CL*TC
 Thus, if the desired target concentration is
known, the clearance in that patient will
determine the dosing rate. If the drug is
given by a route that has a bioavailability
less then 100%, then the dosing rate
predicted by above equation must be
modified. For oral dosing
Dosing rate oral = Dosing rate / F oral
 If intermittent doses are given, The
maintenance dose is calculated from

maintenance dose=Dosing rate* Dosing interval

 Tissue storage
Brain--- Chlorpromazine,
acetazolamide, isoniazid.
Retina --- Chloroquine .
Iris--- Ephedrine, atropine .
 Tissue storage
Bone and teeth– Tetracyclines, heavy metals
.
Adipose tissue--- Thiopentone, ether,
minocycline , phenoxybenzamine,
DDTdissolve in neutral fat due to high lipid
solubility , remain stored due to pore blood
supply of fat .
 Biotransformation
Biotransformation mean chemical alter
action of the drug in the body . It is
needed to render non polar components
polar so that they are not reabsorbed in
the renal tubules and are excreted .
Most hydrophilic drugs , e.g.
streptomycin, neostigmine ,
decamethonium , etc are not
biotransformed and are excreted
unchanged .
 Biotransformation
Mechanism which metabolize drugs have
developed to protect the body from
ingested toxins . The primary site for drug
metabolism is liver , others are – kidney
intestine , lungs and plasma .
Biotransformation of drugs may lead to the
following :
1.
 Unique characteristics of the
oral route
 Influences of gastric emptying, mucosal
surface area, and drug inactivation important
for oral route
 Small intestine usually most important
because of large surface area (folds of
Kerckring, villi, microvilli)
 Clinical advantages
 Safest route
 Cheapest route
 Best patient acceptance
 Disadvantages
 Delayed effect
 Patient cooperation required
 Unique problems with GI toxicity
 Absorption of drugs (2)
 From oral, sublingual, or rectal mucosa:
passive diffusion.
 May bypass first-pass inactivation
 From the lungs: passive diffusion
 rapid absorption, dependent on particle size (6 µm
cutoff)
 Absorption of drugs (3)
 From injection sites: subcutaneous tissues,
muscle or fat, absorbed by diffusion and
affected by blood flow
 From miscellaneous sites: skin, spinal canal,
tooth pulp
 Intravenous, intraarterial injection avoids
absorption
 Bioavailability
 Clinical pharmacology of differential
absorption
 Related terms
 biologic equivalence
 chemical equivalence
 therapeutic equivalence
 Distribution
 Absorbed drugs leave capillary wall quickly
and freely (via filtration and diffusion) to enter
interstitial fluid; blood flow being important in
the regional distribution of drugs
 Binding to plasma proteins (mostly to albumin and,
for basic drugs, a1-acid glycoprotein)
 major distribution site
 highest drug concentrations usually found in blood; serve
as drug depots, thus prolonging half-life of drugs
 pharmacologic effects and toxic manifestations affected
by hypoalbuminemia and copresence of other drugs also
bound effectively to albumin
 Central nervous system: permeable to lipid-
soluble drugs only; limited permeability to
water-soluble drugs when inflamed
 Placental transfer: limited by blood flow, not
by a "barrier"
 Fat tissue: depot for thiopental and
chlorinated hydrocarbon insecticides (e.g.,
DDT)
 Sites for metabolism and excretion: liver,
kidney, intestine, lungs
 Redistribution: especially important for IV
injection of lipophilic drugs
Redistribution of thiopental
after intravenous injection
 Drug clearance
Drug clearance principles are similare to the
clearance concepts of the renal physiology in which
creatinine clearance is defined as the rate of
elimination of creatinine of the urine relative to its
serum concentration. At the simplest level clearance
of a drug is the factor that predicts the rate of
elimination in relation to the drug concentration.
Rate of elimination
CL=
Concentration
 Clerance
Elimination pof drug from the body may
involve processes occur the kidney, the
lung, the liver, and other organs.
Rate of elimination Kidney
CL=
Concentration
 Half life:
 Half life t1/2 is the time required to change
the amount of drug in the body by one half
during elimination.
 Distribution of drugs
 Does not generally target the site of action
 Is diluted in the blood stream and carried
to all parts of the body
 Tissue concentration depends on
 physico-chemical properties
e.g. lipid solubility, crossing blood/brain barrier
 blood flow
 Volume of distribution
Definition
Reflection of the amount left in the blood
stream after all the drug has been absorbed
 if drug is ‘held’ in the blood stream it will have
a small volume of distribution
 if very little drug remains in blood steam has a
large volume of distribution
 Penetration into brain and
CSF
The capillary endothelial cells in brain have
tight junction and lack large intercellular pores
. Further , an investment of neural tissues
covers the capillaries . Together they
constitute the so called blood – brain barrier .
A similar blood – CSF barrier is located in the
choroid plexus: capillaries are lined by
choroidal epithelium having tight junction .
 Penetration into brain and
CSF
Both these barriers are lipoidal and limits
the entry of non – lipid soluble drugs , e.g.
Streptomycin, neostigmine etc. only lipid
soluble drugs , therefore , are able to
penetrate and have action on the central
nervous system .
 Volume of distribution-
advanced
Formula for volume of distribution

D V= volume of distribution
V= D= dose (assuming all a
C absorbed)
C= concentration in blood
stream

If you know the volume of distribution it is possible to calculate

the concentration in the blood stream for a particular dose
Volume of distribution advanced
Suppose there is a drug that gives a plasma
concentration of 0.1mg/ml after giving a 1
gram bolus dose IV

V=1000mg/0.1 = 10 litres

Usually expressed as litres/kg body wt.

If this was a 50Kg person
V=0.5L/Kg
Decline in renal function with
Decline in renal function with
age
age
Change in Glomerular Filtration Rate with age

160
140
Approxiamte GFR

120
ml/min/1.73m2

100
80
60
40
20
0
0 1 10 20 30 40 S1
50 60
Age (years) 70 80
 Diagram of entero-hepatic
circulation (advanced)
conjugated drug
biliary tract

liver
bacteria
portal vein
unconjugated
drug gut
to circulation
Change in plasma concentration

Log Concentration (mg/L)

Concentration (mg/L)

Time (hours) Time (hours)

Rate of elimination proportional to amount in body
 Half Life
110
100
90
Concentration (m g/L)

80
70
60
50
40
30
20
10
0
0 1 2 3 4 5 6 7 8 9
Tim e (hours)

Half-life is the time taken for the concentration of drug in blood to fall
by a half
 Accumulation and therapeutic
window
4
Inject 1g stat drug
3.5 3.46
3.29
gives 1mg/L
Log Concentration (mg/L)

3 Toxicity 3.055

2.74

2.5 2.46
2.32 2.29

2.055 Half life = 1 hour

2 1.875
1.9875 1.99275 1.996375

1.75 1.75 1.74

Half life= 2 hours
1.5 1.5
1.32

1 1
0.875
0.9875 0.99275 0.996375

0.75 0.75

0.5 0.5
Therapeutic

0 0

0 1 2 3 4 5 6 7 8
Time (hrs)
 Section 3:
Therapeutics
Translating the pharmacological actions
of drugs into beneficial effects for
patients
Therapeutic and adverse effects
 Therapeutic or adverse effects
 the result of a drug’s pharmacological actions

 Important considerations
 how drug action may be modified
 how both therapeutic and adverse effects may
be mediated
 speed of onset and duration of action
 interactions between drugs and disease
states
 Quantitative aspects of drug
action
 Response alters as the dose changes
 defined by the shape of the dose response
curve
Response Full agonist

Partial agonist

Dose (log)
 Drugs that activate receptors
 possess both affinity and efficacy
 full agonists have high efficacy
 partial agonists have lower efficacy

 Efficacy or potency
 terms that are often confused
 efficacy is the capacity to produce an effect

 Drugs that are antagonists

 have affinity but not efficacy
 may be competitive or non-competitive
 Drug efficacy
 The ability of a drug to produce an effect
 refers to the maximum therapeutic effect
 adverse effects may make the maximum
unobtainable

 Classes of analgesic differ in their efficacy

 morphine is a high efficacy analgesic
 nefopam is a moderate efficacy analgesic
 morphine gives more pain relief than nefopam
irrespective of the dose of nefopam given
 Drug potency
 Amount of drug in relation to its effect
 drugs may differ in potency, but have similar efficacy

 Opioid analgesic have different potencies

 hydromorphone 1.3mg is equivalent to
morphine 10mg
 hydromorphine is more potent than morphine
 but both drugs can achieve the same max
effect
 Excretion
 Renal excretion
 involves glomerular filtration and tubular
reabsorption and secretion
 excretion increased by decreasing tubular
reabsorption, thus basic drugs are excreted
better in acidic urine, acidic drugs better in
alkaline urine
 clinical application—aspirin and barbiturate
poisonings are treated by alkalization of
patients’ urine by giving sodium bicarbonate
 Others
 Bile
 Lung
 Feces
 Saliva (pp. 24-25, Table 2-1)
 Sweat
 Milk
 Time Course of Drug Action
 General rules
 Compartment models
 Single-compartment
 Multiple-compartment

 Exceptions to general rules

 General rules
 Plasma concentration related to degree of
receptor binding, thus magnitude of drug
effect
 Disposition processes usually first order
 Elimination usually slower process than
absorption or distribution
 First-order process:
 dC/dT = k•C (constant fraction)
 Zero-order process:
 dC/dT = k (constant amount)
 Capacity limited process:
 low C, first-order; high C, zero-order
Single-compartment model

ka Vd ke

Absorption Body Elimination

C = D/Vd or Vd = D/C
Single compartment model: no
absorption, first-order
elimination
 Clearance (CL): the measurement of blood
cleared of the drug by elimination per unit
time (as in units of mL/sec). It and the
volume of distribution (Vd) create the
dependent variable T1/2. They are related by
the following formula:

T1/2 = 0.693Vd/CL
 With renal excretion

C•Cl = U•V
Where C = plasma concentration,
Cl = clearance, U = urinary
concentration, and V = urinary
volume

Cl = U•V/C
 Drug disappearance
 usually follows first-order kinetics (exponential decay),
with a constant fraction (not amount) of drug being
eliminated per unit of time
 the process is independent of the kind and amount of
drug
 half-life (T1/2), not dose, is the primary factor in
prolonging drug effects
Overriding importance of half-
life on duration of drug effect
Drug accumulation with repeated
dosing
 Multicompartment models
 combine kinetics of redistribution and
elimination
 provide best description of drugs with high
lipid solubility and drugs given intravenously
Two-compartment model
Henderson-Hasselbach
equation

pH - pKa = log base

acid

For an acidic drug: acid = HA; base = A-

For a basic drug: acid = BH+; base = B
 Theoretical absorption of
aspirin and codeine for dental
pain
 Specialized
transport
Nonspecific active transport of drugs ,
their metabolities and some
endogenous products occurs in renal
tubules and hepatic sinusoids which
have separate mechanisms for organic
acid and organic bases . Certain drugs
have been found to be actively
transported in the brain and choroid
plexus also .
 Nonsynthetic reaction
3. Hydrolysis – This is cleavage of drug
molecule by taking up a molecule of water
.
Ester + H2O esterase Acid + alcohol

Similarly amides and polypeptides are

hydrolysed by amidases and peptidases .