This interesting and useful ppt highlights different pharmacokinetic concepts with illustrations for easy understanding - an overview for revision for medical and paramedical students

23. PHARMACOLOGY

30. The young physician starts life with 20 drugs for each disease,
and the old physician ends life with one drug for 20 diseases…
Sir. William Osler
1849 - 1919

36. FOUR PROCESSES OF DRUG THERAPY

37. FOUR PROCESSES OF DRUG THERAPY
1. The pharmaceutical process
2. The pharmacokinetic process
3. The pharmacodynamic process
4. The therapeutic process

38. PHARMACEUTICAL
PROCESS

40. PHARMACOKINETIC
PROCESS

41. PHARMACODYNAMIC
PROCESS

42. THERAPEUTIC
PROCESS

43. FOUR SIMPLE QUESTIONS
1. Is the drug getting into the patient ?
2. Is the drug getting to its site of action?
3. Is the drug producing the required pharmacological effect ?
4. Is the pharmacological effect being translated into an appropriate
therapeutic effect?

44. Site of
Action
Dosage Effects
Plasma
Concen.
Pharmacokinetics Pharmacodynamics

45. DR.V.SATHYANARAYANAN M.B.B.S., M.D., ACME
PROFESSOR OF PHARMACOLOGY
SRM MCH & RC, KATTANKULATHUR
CHENNAI, INDIA
GENERAL PHRMACOLOGY -
PHARMACOKINETICS

46. PHARMACOKINETICS

47. PHARMACOKINETICS
WHAT THE BODY DOES TO THE DRUG

48. WHAT THE BODY DOES TO THE DRUG ?

49. Pharmacokinetic Process
Extravascular
Administration
Intravascular
Administration
Gut
Wall
Body
tissues
Blood
Liver
Kidney
ABSORPTION
DISTRIBUTION
METABOLISM
EXCRETION

50. PHARMACOKINETICS CONCERNED ABOUT
IS THE DRUG GETTING TO ITS SITE OF ACTION ?

51. DRUG ABSORPTION

53. OVERVIEW
1. Definition of absorption
2. Processes involved in absorption
3. Factors affecting drug absorption
4. Bioavailability
5. Bioequivalence

54. DRUG ABSORPTION
What is absorption ?
Movement of drug
from its site of administration
into the circulation

56. PROCESSES
OF DRUG
ABSORPTION
PASSIVE DIFFUSION
CARRIER MEDIATED TRANSPORT
 FACILITATED DIFFUSION
 ACTIVE TRANSPORT
FILTRATION
PINOCYTOSIS

65. The most
important
Bio transport
process for
majority of
drugs is
a. Pinocytosis
b. Filtration
c. Active transport
d. Passives diffusion

66. Passive
diffusion
depends on
A. Lipid solubility of a drug
B. Intact mucosal surface
C. Availability of carrier substance
D. Availability of energy

67. FACTORS
AFFECTING
DRUG
ABSORPTION
Lipid solubility
pH
Aqueous solubility
Concentration
Area of absorbing surface
Vascularity of absorbing surface
Route of administration
Pharmaceutical factors
Biological factors
Disease states

68. Pharmacokinetics
(how the body handles drugs)
(a,d,m,e)
most drugs are weak acids or bases:
HA H+ + A-
BH+ B + H+
only the non-ionized form
can cross cell membranes
when H increases get more
HA and BH+
even if the drug is not ionized,
it still needs to be lipid soluble
to cross cell membranes
pH=pKa + log (base)
(acid)

69. Acidic drugs are absorbed
better at
a. Acidic pH
b. Alkaline pH
c. Neutral pH
d. Un ionized state

71. BIOAVAILABILITY (F)
It is a measure of the (F) fraction / percentage of
administered dose of a drug that reaches the
systemic circulation in the unchanged form.

72. Dose
Destroyed
in gut
Not
absorbed
Destroyed
by gut wall
Destroyed
by liver
to
systemic
circulation
BIOAVAILABILITY

74. BIOAVAILABILITY=AUC(ORAL)×100
----------------------------------
AUC(IV)
DETERMINING BIOAVAILABILITY

75. Bioavailability of a
drug given by I.V.
route
a. 100%
b. 75 %
c. 92 %
d. 25 %

76. FACTORS
AFFECTING
BIOAVAILABILITY
Pharmaceutical factors: Particle size
Diluting substances Tablet size
Pressure used in
tabletting machine
All factors above affect
disintegration and
dissolution  affect
absorption and
bioavailability

77. BIOLOGICAL
INEQUIVALENCE
Oral formulation of a drug from different
manufacturers or different batches from same
manufacturers may have the same amount of drug
but may not yield same blood levels.

78. SIGNIFICANCE OF BIOAVAILABILITY VARIATION
For drugs with narrow safety margin eg digoxin
For drugs need precise control eg oral hypoglycemics
Success & failure of antimicrobial drugs

79. SUMMARY
What is absorption ?
Processes of absorption
Factors affecting drug absorption
Bioavailability
Factors affecting bioavailability
Bioequivalence and bioinequivalence

80. DISTRIBUTION

81. DISTRIBUTION
If a drug  to act throughout the body  it has to be distributed to other body
compartments through blood
Concentration gradient

82. DISTRIBUTION
Most drugs distribute widely
in part dissolved in body water
in part bound to plasma protein
in part bound to tissues
Often distribution is uneven – bind to PP or tissue proteins or localized in
particular organs.

83. IMPORTANCE OF DISTRIBUTION
Site of localization of a drug Influences its action
eg. Cross BBB  Brain
The amount of protein or tissue binding  affect time it spends in the body 
determines its duration of action.

84. FACTORSAFFECTINGEXTENTOF DISTRIBUTION
Lipid solubility
Ionisation at physiological pH
Extent if binding to PP, tissue protein
Difference in regional blood flow
Movement of drug proceeds until equilibrium is achieved

85. REDISTRIBUTION
Highly lipid soluble drugs  distributed to organs of high blood flow , later to
less vascular tissues
When the blood level decreases  the drug is withdrawn into the bloodstream
from the distributed organs
If the action is in the high vascular organs  redistribution results in
termination of drug action --- eg. Thiopentone
Greater the lipid solubility, faster the redistribution

86. Volume of Distribution (Vd)
The ‘apparent’ volume of distribution:
A theoretical volume only
The volume of the compartment necessary to account for the total amount of
drug
Assuming the drug is present throughout the body in the same concentration
as it is in the plasma

87. Volume of Distribution
Vd will vary between different drugs according to:
Lipid and water solubility
High lipid solubility lets the drug cross membranes
Plasma or tissue protein binding properties
High protein binding leaves less drug circulating in the plasma

88. Volume of Distribution
Vd = X
Cp
Where
X = total amount of drug in body
Cp = plasma concentration of drug

89. Imagine the body was a bucket
Dose In Overflow into
tissues
Excretion
Blood stream
Tissues

90. A low volume of distribution
tells us that the drug is mainly
confined to blood and body
water
Very little has ‘overflowed’ into the tissues

91. A high volume of distribution
tells us that the drug is widely
distributed to the tissues
A lot has ‘overflowed’ into the tissues

92. ENTEROHEPATIC
CIRCULATION
A number of drugs undergo glucuronide
conjugation  excreted in bile reach
intestines  drugs undergo hydrolysis by
intestinal bacteria  reabsorption of parent
drug  HELPS TO SUSTAIN THE PLASMA
CONCENTRATION

93. Following drugs undergo
enterohepatic cycling EXCEPT
A. Erythromycin
B. Doxycycline
C. Oral contraceptives
D. Gentamicin

94. PLASMA PROTEIN AND TISSUE BINDING
Like many natural substances drugs too circulate around the body (Iron,
Copper, Cortisol)

95. PLASMA PROTEIN BINDING
Most drugs possess physiochemical affinity for plasma proteins
Significant for few drugs like phenytoin, warfarin, tolbutamide

96. FACTORS MODIFY PROTEIN BINDING
Disease: May modify protein binding of drugs
Eg. chronic renal failure  products of metabolism compete for binding sites 
decreased protein binding of drugs
Hypoalbuminemia  dec binding  inc free drug  inc.toxicity eg phenytoin
Chronic liver disease inc bilirubin compete for pp binding  inc.free drug
 toxicity eg. Diazepam, theophylline

97. Clinically significant implications
High Protein binding  restricted to vascular compartment  dec Vd
Bound form is not available for action
Forms the temporary storage site in equilibrium with the free drug
High degree of PP binding not available for metabolism or elimination
makes the drug long acting

98. Clinically significant implications
Plasma concentration refers to bound and free drug
One drug can bind to many sites
More than one drug can bind to same site
Displacement reactions  drugs bind with higher affinity will displace that bound with lower
affinity
eg. salicylates displace tolbutamide
Indomethacin displace warfarin

99. PENETRATION INTO BRAIN AND CSF
Lipoidal  limit the entry of non-lipid soluble drugs
Efflux carriers like P-glycoprotein extrude many drugs
Inflammation of meninges  increases permeability
Enzymatic BBB  MAO, cholinesterase present in capillary walls  do not allow
catecholamines, Acetyl choline

100. PASSAGE ACROSS PLACENTA
placental membranes are lipoidal
Allow free passage of lipophilic drugs
Restrict hydrophilic drugs
P-glycoprotein limit fetal exposure to maternally administered drugs
Incomplete barrier  almost any drug taken by mother can affect the fetus &
new born

102. Spot the drug which doesnot
cross the placental barrier
a. Ethyl alcohol
b. Heparin
c. Phenytoin
d. Tetracyclines

103. TISSUE
STORAGE
Examples of some drugs and their storage sites
Digoxin  Heart
Chloroquine  Retina
Atropine  Iris
Tetracyclines  Bone and teeth
Iodine  Thyroid
Chlorpromazine  Brain
Thiopentone  Adipose tissue

104. METABOLISM

105. BIOTRANSFORMATION
What is it ?
Types
Changes
CP450
Enzyme Induction
Enzyme Inhibition
Factors Affecting it
First pass metabolism

106. CLASSIFICATION
Non synthetic / phase
I reaction -
metabolite may be
active or inactive
Synthetic /
conjugation / Phase II
reaction - metabolite
is mostly inactive

107. PHASE I (NONSYNTHETIC REACTIONS)
OXIDATION REDUCTION HYDROLYSIS
CYCLIZATION DECYCLIZATION

108. PHASE II (SYNTHETIC REACTIONS)
GLUCURONIDE
CONJUGATION
ACETYLATION METHYLATION
SULFATE
CONJUGATION
GLYCINE
CONJUGATION
GLUTATHIONE
CONJUGATION

109. Non
synthetic
reactions are
all of the
following
except
a. Glucuronide conjugation
b. Oxidation
c. Reduction
d. Hydrolysis.

110. Synthetic
reactions are
the following
except
a. Glucuronide conjugation
b. Acetylation
c. Methylation
d. Hydrolysis

111. MICROSOMAL ENZYME INDUCTION
Many drugs, insecticides increase the synthesis of microsomal enzyme protein
specially Cytochrome P450 and glucuronyl transferase increased rate of
metabolism of inducing drugs and other drugs.

112. INDUCING
SUBSTANCES
Barbecued meat, Barbiturates
* D.D.T
* Phenytoin
* Chronic Alcohol
* INH
* Rifampicin
* Griseofulvin
* Tobacco smoke
Occurs within few days
Lasts for 2 – 3 weeks

113. CLINICAL
RELEVANCE
Drug interactions: Failure of contraception with
OCP, Warfarin
Disease may result: Phenytoin  Vit D
Tolerance: Alcohol, Rifampin
Increase variability in response to drugs:
Alcohol, heavy smoking
Drug Toxicity: Rifampicin with Paracetamol
Production of hepatotoxic metabolite
Precipitation of acute intermittent porphyria
May interfere with adjustment of dose (eg.)
Oral anticoagulants

114. MICROSOMAL ENZYME INHIBITION
Inhibition of metabolizing enzymes
Increase concentration of metabolized drugs
Fast time course
Effects are more selective and profound Toxicity
(eg.) Cimetidine CP450 enzyme inhibitors
Erythromycin
Quinolones
Omeprazole, ketoconazole

115. INTERACTING DRUGS
Theophylline
Warfarin
Terfenadine

116. Identify the microsomal
enzyme inducer
a. Ofloxacin
b. Rifampin
c. Clarithromycin
d. Allopurinol

117. FIRST PASS
METABOLISM
(presystemic
metabolism)
DEFINITION:
Metabolism of a drug during its passage from the site of
absorption into the systemic circulation
SITES – Intestinal wall, liver, skin, lungs
Clinical relevance: important Determinant of
“ORAL BIO AVAILABILITY”
EXAMPLES: Low – Theophylline
Intermediate – Aspirin
High – Morphine (not given orally)
- Propranolol (high oral dose)

119. If first pass metabolism is HIGH
1. Oral dose higher than sublingual or parenteral
dose
2. Oral bio availability in liver disease
3. Bio availability of competing drug
4.marked individual variation in the oral dose

120. Drug which has extensive
first pass metabolism is
a. Lorazepam
b. Sulfonamides
c. Propranolol
d. Amoxicillin

121. EXCRETION

122. OUTLINE
Types of drug elimination
Vital facts of drug elimination
Pharmacokinetic parameters
Drug dosage
Dosing schedule
Therapeutic drug monitoring
Prolongation of drug action

123. KIDNEY
filtration
secretion
(reabsorption)
LIVER
metabolism
secretion
LUNGS
exhalation
OTHERS
mother'smilk
sweat, salivaetc.
Elimination
of drugsfromthebody
M
A
J
O
R
M
I
N
O
R

124. Probenecid increases the
duration of action of
A. Erythromycin
B. Atropine
C. Penicillin
D. Ciprofloxacin

125. RENAL TUBULAR EXCRETION
DRUGS COMPETE for active transport utilizing the same carrier
Eg. PENICILLIN + PROBENACID
PROBENACID competes with PENICILLIN for secreting into tubules  penicillin
stays back not secreted  penicillin stays in blood for a long time 
increased duration of action of penicillin
Quinidine decreases the clearance of digoxin

126. Acidic drugs are excreted better at
a. Acidic pH
b. Alkaline pH
c. Neutral pH
d. Un ionized state

127. RENAL
TUBULAR
REABSORPTION
If fluid becomes more alkaline  acidic drug
ionizes  becomes less lipid soluble  decreased
reabsorption  increased elimination
Eg. Aspirin overdose : sodium bicarbonate is given
to alkalinize urine  increased elimination of
aspirin

128. Other routes:
Common route of excretion:
Definition:
Vital facts:
Process by which metabolites and
drugs are eliminated from the body
Urine
Feces, saliva,sweat,breast milk
Effect of old age: Decreased renal function
PHARMACOKINETICS: EXCRETION

129. BREAST MILK
Examples for drugs taken by the mother pose
HAZARD in suckling child:
Theophylline  asthma – irritability, disturbed
sleep (eliminated slowly)
Anticancer, Antidepressants
Antiepilepsy drugs
Antipsychotics
Beta blockers
Aspirin, hormones, some anti microbials

130. ENTEROHEPATIC CIRCULATION
A number of drugs undergo glucuronide conjugation  excreted in bile
reach intestines  drugs undergo hydrolysis by intestinal bacteria 
reabsorption of parent drug  HELPS TO SUSTAIN THE PLASMA
CONCENTRATION

131. Hofmann elimination of drug occurs with
a. Pancuronium
b. Corticosteroids
c. Morphine
d. Atracurium

132. KINETICS OF ELIMINATION

133. Elimination
• Zero order: constant rate of elimination irrespective of plasma
concentration.
• First order: rate of elimination proportional to plasma
concentration. Constant Fraction of drug eliminated per unit time.
Rate of elimination ∝ Amount
Rate of elimination = K x Amount

134. Zero order kinetics is exhibited by
A. Phenobarbitone
B. Ampicillin
C. Doxycycline
D. Ethyl alcohol

135. PHARMACOKINETICS HELPS TO
OPTIMIZE DRUG THERAPY
 DOSE
 DOSAGE REGIMEN
 DOSAGE FORM

136. • Dose: The quantity of drug administered
at one time
• 500mg of Paracetamol
• Dosage: The amount of the drug that
should be given over time
• 500 mg Paracetamol TID for 3 days
DOSE Vs DOSAGE

137.  Can be studied by measuring
 The concentrations of the Drug and metabolites
 In blood and/or urine
 Over periods of time
 after dosing
The pharmacokinetic process

138. PHARMACOKINETIC PARAMETERS
BIOAVAILABILITY VOLUME OF
DISTRIBUTION
CLEARANCE HALF-LIFE PROTEIN
BINDING

139. PK PARAMETERS
 Bioavailability  quantifies absorption
 Volume of distribution  quantifies distribution
 Clearance  quantifies elimination
 Half-life  secondary PK parameter

140. PRINCIPLE
Elimination of drugs from the body usually
follows first order kinetics with a
characteristic half-life (t1/2) and fractional
rate constant (Kel).

141. • Half life is the time required to reduce the plasma
concentration to 50% of its original value
• Will determine dosing requirements / how long a drug will
remain in the body
• Used in determining dosing interval
DRUG HALF-LIFE (t1/2 )

142. • 1 t1/2 - 50 % drug is eliminated
• 2 t1/2 - 50+25 (75 %) drug is eliminated
• 3 t1/2 - 50+25 +12.5 (87.5 %) drug is eliminated
• 4 t1/2 - 50+25 +12.5+6.25 (93.7 %) drug is
eliminated
Thus, nearly complete drug elimination occurs in 4-5
half lives.
DRUG HALF-LIFE (t1/2 )

143. Onrepeateddosing ofadrugwithplasmahalf-lifeof6hours undergoing
firstorder kinetics ofeliminationwill reachsteadystateconcentration after
a. 12 hours
b. 15 hours
c. 30 hours
d. 60 hours

144. 50
25
12.5
6.25
3.12
1.56
DRUG HALF-LIFE (t1/2 )

145. PRINCIPLE
The half-life of elimination of a drug (and
its residence in the body) depends on its
clearance and its volume of distribution
t1/2 is proportional to Vd
t1/2 is inversely proportional to CL
t1/2 = 0.693 x Vd/CL

146. Pharmacokinetic parameters
• Volume of distribution Vd = DOSE / C0
• Plasma clearance Cl = Kel .Vd
• plasma half-life t1/2 = 0.693 / Kel
• Bioavailability (AUC)x / (AUC)iv
Get equation of regression line; from it get Kel, C0 , and AUC

147. Knowledge of pharmacokinetic data
about a drug tells us:
 What dose to give
 How often to give it
 How to change the dose in certain
clinical conditions
 How some drug interactions occur

148. Dosing
• Dosing Interval - How often the drug
should be given
• Loading dose – Which puts the plasma
concentration in the therapeutic range
• Maintenance dose - Routine smaller doses
to maintain the steady state (Plateau)

149. Loading dose to fill up the
tissues
Dose In Overflow into
tissues
Excretion
Blood stream
Tissues

150. Uses of Volume of
Distribution
Imagine a bucket with a leak
You give a loading dose
to fill up the bucket in
the first place
After that you only need to give
enough to replace the amount
leaking out.
This is the maintenance dose.

151. Concentration due to a single dose
Concentration due to
repeated doses
The time to reach steady
state is ~4 t1/2’s

152. DOSING SCHEDULE
 To specify an initial dose
 To specify a maintenance dose
 Dose calculation by body weight and surface area

153. DRUG DOSAGE
 Fixed dose – desired effect well below toxic dose eg
analgesics
 Variable dose – with crude adjustments eg antidepressants
 Variable dose – with fine adjustments eg antidiabetics,
antihypertensives
 Maximum tolerated dose – anticancer drugs, some
antimicrobials
 Minimum tolerated dose – long term corticosteroid therapy

154. THERAPEUTIC DRUG MONITORING
 As a guide to the effectiveness of drug therapy –
plasma gentamicin & other antimicrobials,
theophylline
 To reduce the risk of ADR – Lithium, aminoglycosides
 To check the patient compliance – anti epilepsy drugs
 To diagnose and to treat overdose

155. PROLONGATION OF DRUG ACTION
 Large dose
 Vasoconstriction – adrenaline along with
local anesthetic
 Slowing of metabolism
 Delayed excretion – probenecid with
penicillin
 Alteration of chemical structure – BZDines
 Modified release systems – sustained
release, depot preparations, hyaluranidase

156. SUMMARY

157. Pharmacokinetic Process
Extravascular
Administration
Intravascular
Administration
Gut
Wall
Body
tissues
Blood
Liver
Kidney
ABSORPTION
DISTRIBUTION
METABOLISM
EXCRETION

158. PHARMACOKINETICS
DETERMINE
ROUTE OF ADMINISTRATION OF THE DRUG
DOSE
LATENCY OF ONSET
TIME OF PEAK ACTION
DURATION OF ACTION
FREQUENCY OF ADMINISTRATION

159. PHARMACOKINETIC PARAMETERS
BIOAVAILABILITY
VOLUME OF
DISTRIBUTION
CLEARANCE
HALF-LIFE
PROTEIN
BINDING

160. Pharmacokinetic data about a drug tells us:
What dose to give
How often to give it
How to change the dose in certain medical
conditions
How some drug interactions occur

161. PRINCIPLE
The absorption, distribution and elimination of a drug
are qualitatively similar in all individuals. However, for
several reasons, the quantitative aspects may differ
considerably. Each person must be considered
individually and doses adjusted accordingly.

162. The good physician treats the disease;
The great physician treats the patient who has the disease !
WILLIAM OSLER
1849 - 1919

167. QUESTIONS IN PHARMACOKINETICS

168. ESSAYS
Explain the term
bioavailability. Explain
factors modifying
bioavailability.
1
Discuss drug
absorption and
factors affecting it.
2
Discuss
biotransformation
reactions with
appropriate examples
3

169. 1. Explain factors affecting bioavailability with suitable examples.
2. Explain protein binding of drugs with suitable examples. Give its
clinical importance
3. Describe redistribution of drugs with examples
4. Definition of biotransformation of drugs. Two examples for
synthetic biotransformation reactions.
5. Explain the clinical importance of plasma half life with examples.
6. Write briefly on bio-in equivalence.
7. Explain with an example how urinary pH influences drug
excretion
8. Write two drugs inducing microsomal enzymes. give one
example and its clinical relevance
SHORT NOTES (5 marks)

170. Explain briefly the following terms with examples , giving the
clinical significance of each of them
1. Enzyme induction
2. enzyme inhibition
3. Plasma half- life
4. Zero order kinetics.
5. First pass metabolism
SHORT NOTES

172. ANYWAY……