1. DRUG
THERAP
Y

2. The Life of a Drug
ABSORPTION Site of drug administration
DISTRIBUTION From blood to the site of action
METABOLISM Biotransformation of the drug
Removal of drug
EXCRETION from the body

3. Pharmacokinetics

4. Is the drug
getting
into the
patient?

5. AIM:
 Adequate drug doses must be
delivered to the target tissues
so that therapeutic yet non-
toxic levels are obtained

6. DISINTEGRATIO
N
 BREAKDOWN OF
SOLID FORM OF
DRUG INTO SMALLER
PARTS

7. DISSOLUTION
Disintegration of
smaller particles in
the GIT fluid for
absorption

8. RATE LIMITING
 Time it takes for the
drug to disintegrate &
become available for
absorption

9. BIOAVAILABILITY
 FRACTION OF ADMINISTERED
DRUG THAT REACHES THE
CIRCULATION IN A
CHEMICALLY UNCHANGED
FORM

10. BIOAVAILABILITY
 If 100 mg of a drug is
administered orally and 70
mg of the drug is absorbed
unchanged, the bioavailability
is 70%

11. ABSORPTION
 Process by which drug
molecules are transferred
from the site of administration
in the body to the circulating
fluids

12. PRINCIPAL
MECHANISMS
INVOLVED IN THE
PASSAGE OF DRUGS
ACROSS CELL
MEMBRANES

13. MECHANISMS :
 SIMPLE DIFFUSION
 AQUEOUS DIFFUSION
 SPECIFIC CARRIER
MEDIATED TRANSPORT
SYSTEM
-Active Transport
-Passive Transport

14. Cell Membranes:
 This barrier is permeable to many drug molecules but
not to others, depending on their lipid solubility
 Small pores, 8 angstroms, permit small molecules such
as alcohol and water to pass through.

15. A STEADY STATE is
achieved when the
concentration of the
non-ionized species is
the same on both
sides of the
membranes

16. SIMPLE DIFFUSION
 Lipid Diffusion
- LIKE dissolves LIKE
- Drug molecules dissolves in
the membrane to penetrate to
the other side

17. AQUEOUS DIFFUSION
 FILTRATION THROUGH
PORES
 The size of the drug molecule is
relative to the size of the pores
 H2O soluble drugs penetrate cell
membrane through this process

18. ACTIVE TRANSPORT
 Process by which a substance is
transported against a concentration
gradient
 Drug moves from LOWER- HIGHER
concentration
 Energy dependent
 Involves SPECIFIC CARRIERS
 Driven by Hydrolysis of ATP

19. PASSIVE
TRANSPORT
 FACILITATED DIFFUSION
 a passive process whereby drugs
can move across cell membranes
more rapidly than simple diffusion
 Vast majority of drugs gain access
to the body by this process

20. PASSIVE TRANSPORT
 Involves the action of a
specific but saturable carrier
system
 Can only work in the
presence of an appropriate
concentration gradient

21. FACTORS AFFECTING
ABSORPTION
 Physico-chemical Factors
 Site of Absorption/ Blood Flow at
the Site
 Drug Solubility
 Effects of Food
- Blood Flow
- Gastric Emptying

22. PHYSICO-CHEMICAL
FACTORS
 Lipid solubility
 Degree of Ionization
 Effect of pH
 Molecular Weight, Size & Shape
 Chemical Stability

23. LIPID SOLUBILITY
SIMPLE DIFFUSION
- degree of lipid solubility of
the drug determines the total
amount of drug being
transferred

24. DEGREE OF IONIZATION
 Most drugs are WEAK
ELECTROLYTES either weak
acids or weak bases
 Drugs that are weak electrolytes
dissociate in solution as both
NON-IONIZED & IONIZED
FORM

25. Most drugs are partially
ionized at physiologic
pH , and only the non-
ionized species is
soluble in lipid

26. DEGREE OF IONIZATION
 Non-Ionized - Non-Polar -Lipid Soluble
Form Molecules
 Ionized - Polar -Lipid Insoluble
Form Molecules

27. EFFECT OF pH

28. DISSOCIATION
CONSTANT
 Measure of the strength of the
interaction of a compound
with a proton
 Indication of drug molecules
to be ionized

29. IONIZATION V.S pH
 Amount of ionization of a
drug depends on the pH at
the drug site in the tissues
& its dissociation
characteristics

30. DISSOCIATION
CONSTANT
 The pKa of a compound is
the same as the pH at
which it would be half
dissociated & half ionized

31. CLINICAL
SIGNIFICANCE:
 Knowing the pKa of a drug,
gives the patient the idea
as to the extent to which it
ionizes at any pH

32. ASA – pKa 3.5
Stomach – pH 1.0-1.5
 At the pH of 3.5, ASA is 50% ionized
 DECREASE pH below 3.5
DECREASE ionization to less
than 50% thus INCREASE the
amount of un-ionized form-
GREATER drug absorption

33. MOLECULAR WEIGHT,
SIZE AND SHAPE
 Substances with high
molecular weight are not
usually absorbed intact
except in minute quantities
 They are absorbed by
enzymatic actions

34. MOLECULAR WEIGHT,
SIZE AND SHAPE
 H2O soluble molecules small
enough can pass through the
membrane channels
 30 Angstrom -capillary membrane
 4 Angstrom -other cell membranes

35. MOLECULAR WEIGHT,
SIZE AND SHAPE
 Process of FILTRATION thru single
cell membranes may occur with
drugs of molecular weight of 200
daltons or less
 Drugs up to 60,000 daltons
molecular weights can filter thru
capillary membranes

36. CHEMICAL
STABILITY
 Unstable drugs may be
inactivated in the GIT

37. SITE OF
ABSORPTION
 Total Surface Area available for
absorption
 Intestine has a surface area about
1,000 times larger than the stomach
 Intestine surface is very rich in
microvilli
 Absorption in the intestine is much
efficient than the stomach

38. BLOOD FLOW TO THE
SITE OF
ABSORPTION
 Blood flow from the
intestine is much greater
than the stomach

39. EFFECTS OF FOOD
 Food influences the amount of
drug absorbed & the rate at
which drug is absorbed from the
GIT by affecting the:
BLOOD FLOW
GASTRIC EMPTYING

40. BLOOD FLOW
 LIQUID GLUCOSE MEAL
 DECREASES BLOOD FLOW

41. BLOOD FLOW
 MEAL RICH IN PROTEIN
 INCREASES BLOOD
FLOW

42. Increase absorption in
the presence of food:
 Griseofulvin
 Lithium Citrate
 Propoxyphene
 Propanolol

43. Decrease absorption in
the presence of food:
 Aspirin
 Penicillin
 Acetaminophen

44. GASTRIC EMPTYING
 Food that delays Gastric
Emptying also delays the
absorption of orally
administered drugs

45. DELAY GASTRIC
EMPTYING
 Low pH or High Fat
Solutes
 Hot Meals
 Solution Rich in Fats &
Carbohydrates

46. Slow gastric emptying
may also reduce the
amount of drug
absorbed because of
the degradation in the
acidic contents of the
stomach !

47. Rule of Thumb:
 If food reduces absorption of
drugs, giving the drug at least 1
hour before meals will minimize
this effect
 If food enhances drug absorption
the drug is given with meals

48. DISTRIBUTION

49. DISTRIBUTION
 Process by which the drug
becomes available to body
fluids such as plasma,
interstitial fluids &
intracellular fluids and body
tissues

50. PRIMARY PURPOSE
OF
DRUG TRANSPORT
 Allow drug to reach its
site of action at specific
tissue sites

51. Transport In Plasma
DISTRIBUTION
SITE
SITE
OF
PLASMA OF
ADMINISTRATION
ACTION

52. Receptors involved in the
Action of Commonly Used
Drugs
RECEPTOR Main Action of Natural
Agonist
ADRENOCEPTOR
 Alpha 1  Vasoconstriction
 Alpha 2  Hypotension/sedation
 Beta 1  Heart Rate
 Beta 2  Bronchodilation
Vasodilation
Uterine relaxation

53. Receptors involved in the
Action of Commonly Used
Drugs
RECEPTOR
Main Action of Natural
Agonist
CHOLINERGIC
 Muscarinic  Heart Rate
Secretion
Gut Motility
Bronchoconstriction
 Nicotinic  Contraction of Striated
Muscle

54. Receptors involved in the
Action of Commonly Used
Drugs
RECEPTOR Main Action of Natural
Agonist
HISTAMINE
 H1  Bronchoconstriction
Capillary Dilation
 H2  Increase Gastric Acid

55. Receptors involved in the
Action of Commonly Used
Drugs
 RECEPTOR  Main Action of Natural
Agonist
 DOPAMINE  CNS Neurotransmitter
 OPIOID  CNS Neurotransmitter

56. FORMS OF DRUG
INSIDE THE BODY
 FREE / UNBOUND  BOUND STATE
STATE
ACTIVE FORM INACTIVE FORM
Plasma H2O Albumins & Globulins

57. Only free drugs are
biologically active
and can cause a
pharmacologic
response

58. The patterns of
distribution in the body
determine how rapidly a
drug will elicit a desired
response, the duration of
the response, & in some
cases whether a
response will be elicited
at all

59. Drug activity is
related to its
concentration in
plasma H2O

60. BIOLOGIC HALF-LIFE
(t ½)
 Time necessary for the
body to eliminate half the
quantity of the drug present
in the circulation

61. Biologic Half-Life
 It takes several half lives
before more than 90% of the
drug is eliminated in the
system
 SHORT HALF-LIFE (4-8 Hours)
 LONG HALF-LIFE (24 Hours or longer)

62. Biologic Half-life
ASA - 650 mg t1/2 - 3 hrs.
T 1/2 Time of Dosage % LEFT
Elimination Remaining
1 3 325 50
2 6 162 25
3 9 81 12.5
4 12 40.5 6.25
5 15 20 3.1
6 18 10 1.55

63. Without tissue
storage sites , many
drugs would rapidly
be metabolized
&eliminated from the
body ,having little
time to exert any
effect

64. STORAGE DEPOT
( Non-Specific Site )
 Areas for transient storage
 It may prevent or prolong
the action of drugs
 Site of drug loss or storage

65. AFFINITY TISSUES
 May be sites of ACTION or
AREAS OF TRANSIENT
STORAGE
 Particular Sites:
FAT EYE
BONE MUSCLE
LIVER

66. AFFINITY TISSUES...
Guanethidine -binds to heart &
skeletal muscle
Quinacrine -binds to liver & skeletal
muscle
Tetracycline -binds to bone &
enamel
Thiopental -binds to adipose tissue

67. BIOTRANSFORMATIO
N

68. METABOLISM
 Parent drug is
converted by
enzymes into drug
LIVER metabolites ready
to perform its
action then
preparing it for
excretion

69. Most Important Intracellular
Site of Metabolism
 Endoplasmic Reticulum (Microsomes)
 Mitochondria
(Monoamine Oxidase)
 Lysosomes
 Cytosol
(Alcohol Dehydrogenase & Xanthine
Oxidase)

70. ROLE OF
METABOLISM
 It alters the pharmacologic
activity, usually decreasing it
but sometimes converting the
drug to a compound similar or
do have greater activity than
the original

71. ROLE OF
METABOLISM
 Results in metabolites that are
more water soluble & less lipid
soluble than the parent
compound & thus more readily
excreted in the urine or
processed further by conjugation

72. 3 DIFFERENT
PATTERNS OF
ENZYMATIC
MODIFICATION OF A
PARENT COMPOUND

73. Inactive Compound
To
Active Compound
(PRO-DRUG)
CONJUGATION 6-Mercaptupurine
6- Mercaptupurine
REACTION Ribonucleotide

74. Active Compound
2nd Active Compound
Inactive Compound
PHENACETIN ACETAMINOPHEN ACETAMINOPHEN
(Oxidation) (Conjugation Rxn) Glucoronide

75. Active Compound
To
Inactive Compound
Subsequently
PENTOBARBITAL Transformed
PENTOBARBITAL
ALCOHOL Into another
Inactive form

76. CONSIDERATIONS:
 Most drugs are somewhat
LIPOPHYLIC and could
remain in the body for
prolonged times if not
transformed into a more
H2O soluble derivatives

77. CONSIDERATIONS:
 Drug metabolism usually
decreases the activity of the
therapeutic agents, but there
are important exceptions
where active or toxic
metabolites are formed

78. 2 GENERAL TYPES
OF CHEMICAL
REACTION
NON-SYNTHETIC
SYNTHETIC

79. PHASE 1
METABOLISM
 OXIDATION
 REDUCTION
 HYDROLYSIS

80. PHASE 1
METABOLISM
 Conversion of lipophilic
molecules into more polar
molecules by introducing or
unmasking a polar functional
group
 -OH, -COOH, -NH2

81. PHASE 1
METABOLISM
 May increase, decrease or
leave unaltered the drug’s
pharmacologic activity

82. PHASE 2 METABOLISM
 CONJUGATION REACTION
 ENDOGENOUS SUBSTRATE
Glucoronic Acid
Sulfuric Acid
Acetic Acid
Amino Acid

83. CYTOCHROME P-450
( Microsomal Mixed Function
Oxidase)
 It absorbs light at 450 nm when
exposed to Carbon Monoxide
(Spectro-photometric Peak )
 Most important enzymes in the
liver
 INHIBITS MIXED FUNCTION
OXIDASE ACTIVITY

84. Liver P450 systems
 Liver enzymes inactivate some drug
molecules
 First pass effect (induces enzyme activity)

85. PHASE 2 METABOLISM
 results to a more polar &
H2O soluble compound
that are more often
therapeutically inactive

86. EXCRETION

87. ORGAN FOR
EXCRETION
Other Route:
 LUNGS
KIDNEY  SKIN
 BILE
 SALIVA
 FECES
 BREAST MILK

88. I . KIDNEY
Most important route

89.  3 PROCESSES
IMPLICATED
IN RENAL
SECRETION
 Glomerular
filtration
 Active
secretion
 Passive
reabsorption GF = glomerulus filtering. TR =
tubular reabsorption. TS = tubular
secretion.

90. 1.
GLOMERULAR
FILTRATION
Drug enters the
kidney through the
Renal Arteries

91. •Free drug flows thru
the capillary slits into
the Bowman’s space
as part of the
Glomerular Filtrate

92. •DRUG NOT TRANSFERED
INTO THE GLOMERULAR
FILTRATE LEAVES THE
GLOMERULI THRU THE
EFFERENT ARTERIOLES W/C
DIVIDE TO FORM
CAPILLARY PLEXUS
SURROUNDING THE
NEPHRITIC LUMEN IN THE
PROXIMAL TUBULES

93. •Lipid solubility & pH
do not influence the
passage of drug into
the glomerular
filtrate

94. 2.
Tubular
Reabsorption /
Active Secretion in
the Proximal Tubule

95. •Highly ionized acids &
bases are actively
secreted by tubular
cells & clearance can
approach RPF of 600
ml/min

96. GFR = 125 ml /
min
20% of the
RENAL Plasma
Flow
RPF = 600 ml /
min

97. Neonates & elderly
have low GFR & LOW
Renal Blood Flow

98. 3.
Tubular Secretion /
Passive Re-
absorption in the
Distal Tubule

99. •As the drug moves toward the
distal convoluted tubule, its
concentration increases &
exceeds that of the
perivascular space.
The drug if uncharged, may
diffuse out of the nephritic
lumen back into the systemic
circulation.

100. •Manipulating the pH of
urine to increase the
ionized form of the drug in
the lumen may be used to
minimize the amount of
back diffusion & increase
the clearance of an
undesirable drug .

101. Alkalinization of
Urine
Na
BICARBONATE
Acidification of
Urine
NH4Cl

102. •When tubular urinary pH
is more alkaline than
plasma , weak acids are
excreted more rapidly

103. •When tubular urinary pH
is more acidic than
plasma, weak acids are
excreted more slowly

104. II . ENTERO-HEPATIC
CYCLE

105. Biliary
Excretion

106. 1.
Active secretion of a
conjugated drug into
the bile

107. 2.
Unconjugated drug
liberated in the small
intestine by hydrolysis &
free drug reabsorbed into
plasma

108. 3.
Some drug escapes
reabsorption &
appears in feces

109. III . LUNGS

110. Blood / Air Partition
Coefficient
 LARGE VALUE
- slow excretion .
Rate of pulmonary circulation limiting
 SMALL VALUE
- more rapid excretion.
Rate of pulmonary ventilation limiting

111. IV . SKIN

112. Excretion via
sweat & may result
in direct irritation
or allergic
reactions

113. END OF TOPIC