Pharmacokinetics
1

 how the human body act on the drugs?
 Pharmacokinetics is the quantitative study of drug movement
in, through and out of the body. Intensity of effect is related to
concentration of the drug at the site of action, which depends
on its pharmacokinetic properties
 Pharmacokinetic properties of particular drug is important to
determine the route of administration, dose, onset of action,
peak action time, duration of action and frequency of dosing
2

Dosage Regimen
Concentration at the
site of action
Absorption
Distribution
Metabolism
Concentration in
Plasma Excretion
Pharmacokinetics
Pharmacodynamics
Effect
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4

5

6

7

 Drug molecules can cross cell membrane
by:
 Passive Diffusion
 Protein – mediated transport (carrier mediated)
 Facilitated Transport
 Active trnsport
 Primary
 Secondary
8

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Most important Mechanism for most of the Drugs
Majority of drugs diffuses across the membrane in the
direction of concentration gradient
No active role of the membrane
Proportional to lipid : water partition coefficient
Lipid soluble drugs diffuse by dissolving in the lipoidal matrix
of the membrane
Characteristics
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Not requiring energy
Having no saturation
Having no carriers
Not resisting competitive inhibition
9

Affecting factors :
• the size of molecule
• Lipid solubility
• Polarity
• degree of
ionization
• the PH of the
environment
such as: fluid of
body fluid in cell
blood, urine
10

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11

 Most of drugs are weak acids or weak
bases.
 The ionization of drugs may markedly
reduce their ability to permeate
membranes.
 The degree of ionization of drugs is
determined by the surrounding pH and their
pKa.
12

pKa = negative logarithm of acid dissociation constant
[A-] = ionized Drug
[HA] = unionized drug
13

14

 Acidic drugs re absorbed are largely unionized in
stomach and absorbed faster while basic drugs
are absorbed faster in intestines
 Ion trapping
 Acidic drugs are excreted faster in alkaline urine –
urinary alkalizers
 Basic drugs are excreted faster in acidic urine –
urinary acidifiers
15

 Passage of Drugs through aqueous pores in
membrane or through Para cellular space
 Lipid insoluble drugs can cross – if the molecular
size is small
 Majority of intestinal mucosa and RBCs have
small pores and drugs cannot cross
 But, capillaries have large paracellular space and
most drugs can filter through this
16

17

 Involve specific membrane transport proteins know as drug
transporters or carriers – specific for the substrate
 Drug molecules bind to the transporter, translocated across
the membrane, and then released on the on other side of the
membrane.
 Specific, saturable and inhibitable
 Depending on Energy requirement - Can be either Facilitated
(passive) or Active Transport
18

 Move substrate of a
single class
(uniporters) down a
concentration gradient
 No energy dependent
 Similar to entry of
glucose into muscle
(GLUT 4)
19

 Active (concentrative) transporters
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
can move solutes against a concentration gradient
energy dependent
 Primary active transporters - generate energy
themselves (e.g. ATP hydrolysis)
 Secondary transporters - utilize energy stored in
voltage and ion gradients generated by a primary
active transporter (e.g. Na+/K+-ATPase)

 Symporters (Co-transporters)
Antiporters (Exchangers)
20

• ATP-Binding Cassette Transporters (ABC) Super
family – Primary active transport
• P-glycoprotein (P-gp encoded by MDR1)
•
•
Intestinal mucosa, renal tubules and blood brain barrier etc.
Mediate only efflux of solute from cytoplasm - detoxification
 Solute Carrier (SLC) transporters – Secondary
active transport


Organic anion transporting polypeptides (OATPs)
Organic cation transporters (OCTs)
 Expressed in liver and renal tubules – metabolism and
excretion of drugs
21

 It involves the invagination of a part of the
cell membrane and trapping within the cell
of a small vesicle containing extra cellular
constituents. The vesicle contents can than
be released within the cell, or extruded from
the other side of the cell. Pinocytosis is
important for the transport of some
macromolecules (e.g. insulin through BBB).
22

1. ABSORPTION OF DRUGS
Absorption is the transfer of
a drug from its site of
administration to the blood
stream
Most of drugs are absorbed
by the way of passive transport
Intravenous administration
has no absorption
Fraction of administered
dose and rate of absorption are
important
23

Drug properties:
lipid solubility, molecular weight, and polarity etc
Blood flow to the absorption site
Total surface area available for absorption
Contact time at the absorption surface
Affinity with special tissue
Routes of Administration (important):
24

Route of administration:
 Topical:
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 Depends on lipid solubility – only lipid soluble drugs are
penetrate intact skin – only few drugs are used
therapeutically
Examples – GTN, Hyoscine, Fentanyl, Nicotine,
testosterone and estradiol
Organophosphorous compounds – systemic toxicity
Abraded skin: tannic acid – hepatic necrosis
Cornea permeable to lipid soluble drugs
Mucus membranes of mouth, rectum, vagina etc, are
permeable to lipophillic drugs
25

Route of administration:
 Subcutaneous and Intramuscular:
 Drugs directly reach the vicinity of capillaries –
passes capillary endothelium and reach
circulation
 Passes through the large paracellular pores
 Faster and more predictable than oral absorption
 Exercise and heat – increase absorption
 Adrenaline – decrease absorption
26

Route of administration: Oral Route
 Physical properties – Physical state, lipid or water
solubility
 Dosage forms:
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Particle size
Disintegration time and Dissolution Rate
Formulation – Biopharmaceutics
 Physiological factors:
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Ionization, pH effect
Presence of Food
Presence of Other agents
27

 Before the drug reaches
the systemic circulation,
the drug can be
metabolized in the liver
or intestine. As a Result,
the concentration of
drug in the systemic
circulation will be
reduced.
28

Buccal cavity
Stomach
Intestine
Rectum
Portal
vein
Vena
cava
29

Vena
cava
30

 Intravenous administration has no
absorption phase
 According to the rate of absorption:
Inhalation→Sublingual→Rectal→intramusc
ular→subcutaneous→oral→transdermal
Example – Nitroglycerine:
IV effect – immediate, SL – 1 to 3 min and
per rectal – 40 to 60 minute
31

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Bioavailability refers to the rate and extent of
absorption of a drug from dosage form as
determined by its concentration-time curve in
blood or by its excretion in urine. It is a measure of
the fraction (F) of administered dose of a drug that
reaches the systemic circulation in the unchanged
form
Bioavailability of drug injected i.v. is 100%, but is
frequently lower after oral ingestion, because:
The drug may be incompletely absorbed
The absorbed drug may undergo first pass
metabolism in intestinal wall and/or liver or be
excreted in bile.
32

BIOVAILABILITY -
AUC
Plasma
concentration
(mcg/ml)
0 5 Time
(h)
1
0
1
5
AUC p.o.
F = ------------ x
100% AUC
i.v.
AUC – area
under the curve
F – bioavailability
33

MTC
MEC
34

2. DISTRIBUTION OF
DRUGS
 It is the passage of drug from the circulation to the
tissue and site of its action.
 The extent of distribution of drug depends on its
lipid solubility, ionization at physiological pH
(dependent on pKa), extent of binding to plasma
and tissue proteins and differences in regional
blood flow, disease like CHF, uremia, cirrhosis
 Movement of drug - until equilibration between
unbound drug in plasma and tissue fluids
35


 Definition: Apparent Volume of distribution is defined as
the volume that would accommodate all the drugs in the
body, if the concentration was the same as in plasma
Expressed as: in Liters
V = Dose administered IV
Plasma concentration
36

Total Body Fluid = 42 L (approx.)
37

 Chloroquin – 13000 liters, Digoxin – 420 L,
Morphine – 250 L and Propranolol – 280 L
 Streptomycin and Gentamicin – 18 L
(WHY ?)
`Vd` is an imaginary Volume of Fluid which will accommodate the entire
quantity of the drug in the body, if the concentration throughout
this imaginary volume were same as that in plasma
38

 Lipid solubility (lipid : water partition
coefficient)
 pKa of the drug
 Affinity for different tissues
 Blood flow – Brain Vs Fat
 Disease states
 Plasma protein Binding
39

 Highly lipid soluble drugs – distribute to brain, heart and kidney etc.
immediately followed by muscle and Fats
40

Blood brain barrier (BBB): includes the capillary endothelial cells (which
have tight junctions and lack large intracellular pores) and an investment of
glial tissue, over the capillaries. A similar barrier is loctated in the choroid
plexus
41

 BBB is a lipid layer and limits the entry of non-lipid soluble
drugs (amikacin, gentamicin, neostigmine etc.).
(Only lipid soluble unionized drugs penetrate and have action on
the CNS)
 Efflux carriers like P-gp (glycoprotein) present in brain capillary
endothelial cell (also in intestinal mucosal, renal tubular, hepatic
canicular, placental and testicular cells) extrude drugs that
enter brain by other processes.
(Inflammation of meninges of the brain increases permeability of
BBB)
 Dopamine (DA) does not enter brain, but its precursor
levodopa does. This is used latter in parkinsonism.
42

 Only lipid soluble drugs can penetrate –
limitation of hydrophillic drugs
 Placental P-gp serves as limiting factor
 But, REMEMBER, its an incomplete
barrier – some influx transporters operate
 Thalidomide
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44


 Plasma protein binding (PPB): Most drugs possess
physicochemical affinity for plasma proteins. Acidic
drugs bind to plasma albumin and basic drugs to
α1-glycoprotein
Extent of binding depends on the individual compound.
Increasing concentration of drug can progressively
saturate the binding sites
The clinical significant implications of PPB are:
a) Highly PPB drugs are largely restricted to the vascular
compartment and tend to have lower Vd.
b) The PPB fraction is not available for action.
c) There is an equilibration between PPB fraction of drug
and free molecules of drug.
45

d) The drugs with high physicochemical affinity for plasma
proteins (e.g. aspirin, sulfonamides, chloramphenicol) can
replace the other drugs(e.g, warfarin) or endogenous
compounds (bilirubin) with lower affinity.
e) High degree of protein binding makes the drug long acting,
because bound fraction is not available for metabolism,
unless it is actively excreted by liver or kidney tubules.
f) Generally expressed plasma concentrations of the drug refer
to bound as well as free drug.
g) In hypoalbuminemia, binding may be reduced and high
concentration of free drug may be attained (e.g. phenytoin).
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47

Drugs may also accumulate in specific organs or get bound to
specific tissue constituents, e.g.:
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Heart and skeletal muscles – digoxin (to muscle proteins)
Liver – chloroquine, tetracyclines, digoxin
Kidney – digoxin, chloroquine
Thyroid gland – iodine
Brain – chlorpromazine, isoniazid, acetazolamide
Retina – chloroquine (to nucleoproteins)
Iris – ephedrine, atropine (to melanin)
Bones and teeth – tetracyclines, heavy metals (to
mucopolysaccharide of connective tissue)
Adipose tissues – thiopental, ether, minocycline, DDT
48

3.
BIOTRANSFORMATION
Metabolism of Drugs
49


 NON-POLAR LIPID SOLUBLE
POLAR LIPID INSOLUBLE
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50

1. Active drug and its metabolite to inactive metabolites –
most drugs (ibuprofen, paracetamol, chlormphenicol
etc.)
2. Active drug to active product (phenacetin –
acetminophen or paracetamol, morphine to Morphine-6-
glucoronide, digitoxin to digoxin etc.)
3. Inactive drug to active/enhanced activity (prodrug) –
levodopa - carbidopa, prednisone – prednisolone
and enlpril – enlprilat)
4. No toxic or less toxic drug to toxic metabolites (Isoniazid
to Acetyl isoniazid)
51

2 (two) Phases of
Biotransformation:
•Phase I or Non-synthetic –
metabolite may be active or
inactive
•Phase II or Synthetic –
metabolites are inactive
(Morphine – M-6 glucoronide is
exception)
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53

 Most important drug metabolizing reaction –
addition of oxygen or (–ve) charged radical or
removal of hydrogen or (+ve) charged radical
 Various oxidation reactions are – oxygenation or
hydroxylation of C-, N- or S-atoms; N or 0-
dealkylation
 Examples – Barbiturates, phenothiazines,
paracetamol and steroids
54

• Involve – cytochrome P-450 monooxygenases (CYP), NADPH and
Oxygen
• More than 100 cytochrome P-450 isoenzymes are identified and
grouped into more than 20 families – 1, 2 and 3 …
• Sub-families are identified as A, B, and C etc.
• In human - only 3 isoenzyme families important – CYP1, CYP2 and
CYP3
• CYP 3A4/5 carry out biotransformation of largest number (30–50%) of
drugs. In addition to liver, this isoforms are expressed in intestine
(responsible for first pass metabolism at this site) and kidney too
Inhibition of CYP 3A4 by erythromycin, clarithromycin,
ketoconzole, itraconazole, verapamil, diltiazem and a constituent
of grape fruit juice is responsible for unwanted interaction with
terfenadine and astemizole
• Rifampicin, phenytoin, carbmazepine, phenobarbital are
inducers of the CYP 3A4
55

Oxidation - CYP
CYP3A4/5
56

 Some Drugs are oxidized by non-
microsomal enzymes (mitochondrial and
cytoplsmic) – Alcohol, Adrenaline,
Mercaptopurine
 Alcohol – Dehydrogenase
 Adrenaline – MAO and COMT
 Mercaptopurine – Xanthine oxidase
57

 This reaction is conversed of oxidation and
involves CYP 450 enzymes working in the
opposite direction.
 Examples - Chloramphenicol, levodopa,
halothane and warfarin
Levodopa
(DOPA)
Dopamine
DOPA-
decarboxylase
58


 This is cleavage of drug molecule by taking up of a molecule of
water. Similarly amides and polypeptides are hydrolyzed by
amidase and peptidases. Hydrolysis occurs in liver, intestines,
plasma and other tissues.
Examples - Choline esters, procaine, lidocaine, pethidine, oxytocin
Ester + H20 Acid +
Alcohol
Esterase
59

 Cyclization: is formation of ring structure
from a straight chain compound, e.g.
proguanil.
 Decyclization: is opening up of ring
structure of the cyclic molecule, e.g.
phenytoin, barbiturates
60

 Conjugation of the drug or its phase I metabolite with an endogenous
substrate - polar highly ionized organic acid to be excreted in urine or bile -
high energy requirements
Glucoronide conjugation - most important synthetic reaction
 Compounds with hydroxyl or carboxylic acid group are easily conjugated
with glucoronic acid - derived from glucose
 Examples: Chloramphenicol, aspirin, morphine, metroniazole, bilirubin,
thyroxine
 Drug glucuronides, excreted in bile, can be hydrolyzed in the gut by
bacteria, producing beta-glucoronidase - liberated drug is reabsorbed and
undergoes the same fate - enterohepatic recirculation (e.g.
chloramphenicol, phenolphthalein, oral contraceptives) and prolongs their
action
61

62

 Acetylation: Compounds having amino or
hydrazine residues are conjugated with the help
of acetyl CoA, e.g.sulfonamides, isoniazid
Genetic polymorphism (slow and fast acetylators)
 Sulfate conjugation: The phenolic compounds
and steroids are sulfated by sulfokinases, e.g.
chloramphenicol, adrenal and sex steroids
63

 Methylation: The amines and phenols can be
methylated. Methionine and cysteine act as
methyl donors.
 Examples: adrenaline, histamine, nicotinic
acid.
 Ribonucleoside/nucleotide synthesis:
activation of many purine and pyrimidine
antimetabolites used in cancer chemotherapy
64

 Factors affecting biotransformation
 Concurrent use of drugs: Induction and inhibition
 Genetic polymorphism
 Pollutant exposure from environment or industry
 Pathological status
 Age
65

 One drug can inhibit metabolism of other – if
utilizes same enzyme
 However not common because different drugs
are substrate of different CYPs
 A drug may inhibit one isoenzyme while being
substrate of other isoenzyme – quinidine
 Some enzyme inhibitors – Omeprazole,
metronidazole, isoniazide, ciprofloxacin and
sulfonamides
66

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 CYP3A – antiepileptic agents - Phenobarbitone,
Rifampicin and glucocorticoide
CYP2E1 - isoniazid, acetone, chronic use of alcohol
Other inducers – cigarette smoking, charcoal broiled
meat, industrial pollutants – CYP1A
Consequences of Induction:

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 Decreased intensity – Failure of OCPs
Increased intensity – Paracetamol poisoning (NABQI)
Tolerance – Carbmazepine
Some endogenous substrates are metabolized faster – steroids,
bilirubin
67

4. EXCRETION
68

 Excretion is a transport procedure which the
prototype drug (or parent drug) or other
metabolic products are excreted through
excretion organ or secretion organ
 Hydrophilic compounds can be easily excreted.
 Routes of drug excretion
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Kidney
Biliary excretion
Sweat and saliva
Milk
Pulmonary
69

Hepatic Excretion
Drugs can be excreted in
bile, especially when the are
conjugated with – glucuronic
Acid
• Drug is absorbed  glucuronidated or sulfatated
in the liver and secreted through the bile 
glucuronic acid/sulfate is cleaved off by bacteria
in GI tract  drug is reabsorbed (steroid
hormones, rifampicin, amoxycillin, contraceptives)
• Anthraquinone, heavy metals – directly excreted
in colon
Portal
vein
BILE
DUCT
Intesti
nes
70

RENAL EXCRETION
 Glomerular Filtration
 Tubular Reabsorption
 Tubular Secretion
71

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Normal GFR – 120 ml/min
Glomerular capillaries have pores larger than usual
The kidney is responsible for excreting of all water
soluble substances
All nonprotein bound drugs (lipid soluble or insoluble)
presented to the glomerulus are filtered
Glomerular filtration of drugs depends on their plasma
protein binding and renal blood flow - Protein bound
drugs are not filtered !
Renal failure and aged persons
72

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Back diffusion of Drugs (99%) – lipid soluble drugs
Depends on pH of urine, ionization etc.
Lipid insoluble ionized drugs excreted as it is – aminoglycoside
(amikacin, gentamicin, tobramycin)
Changes in urinary pH can change the excretion pattern of drugs

 Weak bases ionize more and are less reabsorbed in acidic
urine.
Weak acids ionized more and are less reabsorbed in alkaline
urine
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
Utilized clinically in salicylate and barbiturate poisoning – alkanized
urine (Drugs with pKa: 5 – 8)
Acidified urine – atropine and morphine etc.
73

 Energy dependent active transport – reduces the free
concentration of drugs – further, more drug dissociation
from plasma binding – again more secretion (protein
binding is facilitatory for excretion for some drugs)


Bidirectional transport – Blood Vs tubular fluid
Utilized clinically – penicillin Vs probenecid, probenecid
Vs uric acid (salicylate)
Quinidine decreases renal and biliary clearance of
digoxin by inhibiting efflux carrier P-gp
74

 Acidic urine
 alkaline drugs eliminated
 acid drugs reabsorbed
 Alkaline urine
- acid drugs eliminated
- alkaline drugs absorbed
75

76

 First Order Kinetics (exponential): Rate of
elimination is directly proportional to drug
concentration, CL remaining constant
 Constant fraction of drug is eliminated per unit time
 Zero Order kinetics (linear): The rate of
elimination remains constant irrespective of drug
concentration
 CL decreases with increase in concentration
 Alcohol, theophyline, tolbutmide etc.
77

Zero Order 1st Order
conc.
Time
78


CL = RoE/C
V = dose IV/C
79

1 half-life …………. 50%
2 half-lives………… 25%
3 half-lives …….…..12.5%
4 half-lives ………… 6.25%
50 + 25 + 12.5 +
6.25 = 93.75
93.75 + 3.125 +
1.56 = 98%
after 5 HL
80

Repeated dosing:
•When constant dose of
a drug is repeated before
the expiry of 4 half-life –
peak concentration is
achieved after certain
interval
•Balances between dose
administered and dose
interval
81

At steady state, elimination = input
Cpss = dose rate/CL
Dose Rate = target Cpss x CL
In oral administration
Dose rate = target Cpss x CL/F
In zero order kinetics: follow Michaelis Menten
kinetics
RoE = (Vmax) (C) / Km + C
Vmax = max. rate of drug elimination, Km = Plasma
conc. In which elimination rate is half maximal
CL = Roe/C
82

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
 Low safety margin drugs (anticonvulsants, antidepressants,
Lithium, Theophylline etc. – maintained at certain
concentration within therapeutic range
Drugs with short half-life (2-3 Hrs) – drugs are administered
at conventional intervals (6-12 Hrs) – fluctuations are
therapeutically acceptable
Long acting drugs:
 Loading dose: Single dose or repeated dose in quick
succession – to attain target conc. Quickly
 Loading dose = target Cp X V/F
 Maintenance dose: dose to be repeated at specific intervals
83

 Useful in

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 Narrow safety margin drugs – digoxin, anticonvulsants,
antiarrhythmics and aminoglycosides etc
Large individual variation – lithium and antidepressants
Renal failure cases
Poisoning cases
 Not useful in

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Response mesurable drugs – antihypertensives, diuretics etc
Drugs activated in body – levodopa
Hit and run drugs – Reseprpine, MAO inhibitors
Irreversible action drugs – Orgnophosphorous compounds
84


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Definition of Pharmacokinetics
Transport of Drugs across Biological Membrane – different
processes with example
Factors affecting absorption of drugs
Concept of Bioavailability
Distribution of Drugs – Vd and its concept
Biotransformation Mechanisms with examples
Enzyme induction and inhibition concept and important examples
Routes of excretion of drugs
Orders of Kinetics
Definition and concept of drug clearance
Definition of half life and plateau principle
85

 By prolonging absorption from the site of
action – Oral and parenteral
 By increasing plasma protein binding
 By retarding rate of metabolism
 By retarding renal excretion
86