Pharmacy Pharmacology - Chapter I - Part 1.pdf

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1. CHAPTER ONE
GENERAL PHARMACOLOGY
1

2. INTRODUCTION
Definition
•Pharmacology - derived from two Greek words
-Pharmakon = Drug
-Logos = Science / Study
is the study of drugs and their interactions with
living systems


2

3. Cont…
Scope of Pharmacology
•Pharmacology encompasses the study of the
physical and chemical properties of drugs as well as
their biochemical and physiologic effects
•It includes knowledge of the history, sources, and
uses of drugs as well as knowledge of drug
absorption, distribution, metabolism, and
excretion

3

4. Cont…
Branches of Pharmacology
•Pharmacology is divided into several branches
-Pharmacokinetics
-Pharmacodynamics
-Pharmacotherapeutics
-Clinical pharmacology
-Chemotherapy
-Toxicology etc.
4

the two major branches of
pharmacology

5. Cont…
•Pharmacokinetics (Greek: Kinesis = movement)
-refers to movement of the drug in / out and
alteration of the drug by the body
What the body does to the drug
-includes:
Absorption
Distribution
Metabolism / biotransformation and
Excretion of the drug
5

6. Cont…
•Pharmacodynamics (Greek: dynamis = power)
-includes physiological and biochemical effects of
drugs and their mechanism of action at organ
system / subcellular / macromolecular levels
What the drug does to the body


6

7. Cont…
•Pharmacotherapeutics
-is the application of pharmacological information
together with knowledge of the disease for its
prevention, mitigation or cure
•Selection of the most appropriate drug, dosage
and duration of treatment taking into account the
stage of disease and the specific features of a
patient are a part of pharmacotherapeutics
7

8. Cont…
•Clinical pharmacology – is the scientific study of
drugs in man
-Includes:
PD and PK investigation in healthy volunteers as
well as in patients
Evaluation of efficacy and safety of drugs and
comparative trials with other forms of treatment
Surveillance of patterns of drug use, adverse
effects, etc.
8

9. Cont…
-The aim of clinical pharmacology is to generate
data for optimum use of drugs and the practice of
'evidence based medicine'
•Chemotherapy
-is the treatment of systemic infection or
malignancy with specific drugs that have selective
toxicity for the infecting organism or malignant cell
with no or minimal effects on the host cells
9

10. Cont…
•Toxicology – is the study of poisonous
effect of drugs and other chemicals (household,
environmental pollutant, industrial, agricultural,
homicidal) with emphasis on detection, prevention
and treatment of poisonings
-It also includes the study of adverse effects of
drugs, since the same substance can be a drug or
a poison, depending on the dose
10

11. Cont…
•Pharmacy – is the art and science of
compounding and dispensing drugs or preparing
suitable dosage forms for administration of drugs
-includes:
collection,
identification,
purification,
isolation,
synthesis,
standardization and
quality control of medicinal substances
11

12. Cont…
History of Pharmacology
•In early human history, there was a natural bond b/n
religion & the use of drugs
•Priests, shamans, holy persons, witches, and
soothsayers were mediators b/n the world & the sprit
world in the use of drugs
•Originally, religion dominated its partnership with
therapeutics, and divine intervention was called upon
for every treatment
12

13. Cont…
•Use of drugs to effect cures led to a profound
change in both religious thought and structure
•Effectiveness of drugs started to diminish the
importance of the divine intervention
•Treatment of patients became the province of the
priests rather than the gods to whom the priests
served
13

14. Cont…
•Contribution of different cultures
China
-Pen Tsao (2700 B.C): contained classifications of
individual medicinal plants as well as compilations
of plant mixtures to be used for medical purposes.
-The Chinese doctrine of signatures (like used
to treat like): enables us to understand why
medicines of animal origin were of such great
importance in the Chinese pharmacopoeia.
-Materia medica: the science of drug preparation
and the medical use of drugs—began to develop
as the precursor to pharmacology.
14

15. Cont…
Egypt
-Ebers papyrus (1550 B.C.): Contains about 800
prescriptions quite similar to those written today
-Contains active substances as well as vehicles
(animal fat for ointments; and water, milk, wine,
beer, or honey for liquids) for suspending or
dissolving the active drug
-Offer a brief statement of how the preparation is to
be prepared (mixed, pounded, boiled, strained,
left overnight in the dew) and how it is to be
used (swallowed, inhaled, gargled, applied
externally, given as an enema)
15

16. Cont…
Greeks: - The Iliad and the Odyssey:
-Battle wounds frequently were covered with
powdered plant leaves or bark; their astringent
and pain-reducing actions were derived from the
tannins they contained
-Veratrum alkaloids: smeared on arrow tips to
increase their killing power
-Plato’s description of the death of Socrates by
the juice of the hemlock fruit (potent hemlock
alkaloid, coniine)
16

17. Cont…
•Advances in chemistry and development of
physiology
-In the 18
th
, 19
th
, and early 20
th
centuries laid the
foundation how drugs work at the organ and tissue
levels
17

18. Cont…
•Development of chemistry made it possible to isolate
and synthesize chemically pure compounds that
would give reproducible biological results
-In 1806, Serturner (1783–1841): isolated
morphine from the opium poppy
-Pelletier (1788–1844) : isolated emetin from
ipecacuanha root
-Carentou (1795–1877) : isolated quinine from
cinchona bark
-Magendie (1783–1855): isolated strychnine from
nux vomica; and
-In 1856, Wohler (1800–1882) : isolated cocaine
from coca
18

19. Cont…
Basic principles distinguishing pharmacology
from other disciplines
•Principles include the study of the following:
-Relationship between drug concentration and
biological response
-Drug action over time
-Factors affecting absorption, distribution, binding,
metabolism, and elimination of chemicals
-Structure-activity relationships 19

20. Cont…
-Biological changes that result from repeated
drug use: tolerance, addiction, adverse reactions
-Altered rates of drug metabolism
-Antagonism of the effects of one drug by another
(Drug-drug interactions)
-Process of drug interaction with cellular
macromolecules (receptors) to alter
physiological function (i.e., receptor theory)
20

21. Cont…
Drug (French: Drogue = a dry herb)
•is the single active chemical entity present in a
medicine that is used for diagnosis, prevention,
treatment or cure of a disease
This disease oriented definition is not complete


21

22. Cont…
•This definition of drug is incomplete as it
-ignores the use of contraceptives which alter a
physiological system to prevent pregnancy, which is
not a disease
-fails to recognize general anaesthetics as drugs as
these are not used for any cure, diagnosis or
prevention of a disease
-does not cover vaccines or antisera which alter the
pathological state by formation of antibodies
22

23. Cont…
•WHO (in 1966) has given a more comprehensive
definition
“Drug is any substance or product that is used
or is intended to be used to modify or explore
physiological systems or pathological states for
the benefit of the recipient."
23

24. Cont…
•A medicine is a chemical preparation, which
usually, but not necessarily, contains one or more
drugs, administered with the intention of producing
a therapeutic effect
•Medicines usually contain other substances
(excipients, stabilizers, solvents, etc.) besides the
active drug, to make them more convenient to use
24

25. Cont…
•Drugs in general, can be divided into:
-Pharmacodynamic agents – are designed to
have pharmacodynamic effects in the recipient
-Chemotherapeutic agents – are designed to
inhibit or kill invading parasites or malignant cell,
but have no or minimal pharmacodynamic
effects in the recipient
25

26. Cont…
•Properties of an ideal drug
(1)Effectiveness
•An effective drug is one that elicits the responses
for which it is given
•Effectiveness is the most important property a drug
can have
•Regardless of its other virtues, if a drug is not
effective — if it doesn’t do what it is intended to do
— there is no justification for giving it
26

27. Cont…
(2)Safety
•A safe drug is defined as one that cannot produce
harmful effects—even if administered in very high
doses and for a very long time
•All drugs have the ability to cause injury,
especially with high doses and prolonged use
•The chances of producing harmful effects can be
reduced by proper drug selection and proper
dosing
27

28. Cont…
•However, the risk of harmful effects can never be
eliminated; E.g.:
-Certain anticancer drugs (e.g., cyclophosphamide,
methotrexate), at usual therapeutic doses, always
increase the risk of serious infection
-Opioid analgesics (e.g., morphine, meperidine), at
high therapeutic doses, can cause potentially fatal
respiratory depression
-Aspirin and related drugs, when taken long term in
high therapeutic doses, can cause life-threatening
gastric ulceration, perforation, and bleeding
-Clearly, drugs have both benefits and risks
Pharmakon – be translated as remedy and poison
28

29. Cont…
(3)Selectivity
•A selective drug is defined as one that elicits only
the response for which it is given
•There is no such thing as a wholly selective drug
because all drugs cause side effects
•Examples include
-drowsiness caused by many antihistamines
-peripheral edema caused by calcium channel blockers
-sexual dysfunction caused by certain antidepressants
29

30. Cont…
(4)Additional properties of an ideal drug
-Reversible Action
-Predictability
-Ease of administration
-Freedom from drug interactions
-Low cost
-Chemical Stability
-Possession of a simple Generic Name
30

31. Cont…
No Drug Is Ideal
•From the preceding criteria for ideal drugs, we can see
that available medications are not ideal
-All drugs have the potential to produce side effects
-Drug responses may be difficult to predict and may be
altered by drug interactions
-Drugs may be expensive, unstable, and hard to administer
•Because medications are not ideal, all members of the
healthcare team must exercise care to promote
therapeutic effects and minimize drug-induced harm
31

32. Cont…
•Sources of drugs
(1)Plants
•Many plants contain biologically active substances
and are the oldest source of drugs
•Clues about medicinal plants were obtained from
traditional systems of medicine prevalent in various
parts of the world;
-E.g. use of opium, belladonna, ephedra, cinchona,
curare, foxglove, sarpagandha, qinghaosu has been
learnt from Egyptian, Greek, Aztec, Ayurvedic,
Chinese and other systems of medicine
32

33. Cont…
(2)Animals
•animal part have been used as cures since early
times
•it was exploration of activity of organ extracts in the
late 19
th
and early 20
th
century that led to
introduction of animal products into medicine,
-E.g. adrenaline, thyroxine, insulin, etc.
-Antisera and few vaccines are also produced from
animals
33

34. Cont…
(3)Microbes
•Most antibiotics are obtained from fungi,
actinomycetes and bacteria;
e.g. penicillin, gentamicin, tetracycline, erythromycin,
polymyxin B, actinomycin D (anticancer)
•Some enzymes, e.g. diastase from a fungus and
streptokinase from streptococci have a microbial
source
•Vaccines are produced by the use of microbes
34

35. Cont…
(4)Minerals
•Few minerals, e.g. iron salts, calcium salts, lithium
carbonate, magnesium or aluminum hydroxide,
iodine are used as medicinal substances
35

36. Cont…
(5)Synthetic
•Synthetic chemistry made its debut in the 19
th

century, and is now the largest source of medicines
•Synthetic drugs have the advantage of purity
and uniformity of the product
•They can be manufactured in any quantity as per
need, in contrast to drugs from natural sources
whose availability may be limited
36

37. Cont…
•Not only diverse congeners of naturally obtained
drugs (e.g. atropine substitutes) have been
introduced to achieve greater selectivity of action or
even novel type of activity, but many entirely
synthetic families of drugs (e.g. benzodiazepines)
have been produced
•Many drugs are being synthesized to target specific
biomolecules, e.g. ACE inhibitors
37

38. Cont…
(6)Biotechnology
•Several drugs, especially peptides and proteins are
now produced by recombinant DNA technology,
e.g. human growth hormone, human insulin,
altaplase, interferon, etc.
• Monoclonal antibodies, regulator peptides,
erythropoietin and other growth factors are the newer
drugs of biotechnological origin
38

39. Cont…
•Drug Nomenclature
•Drugs have three types of names:
(1)a chemical name,
(2)a generic or nonproprietary name, and
(3)a brand or proprietary name
39

40. Cont…
(1)Chemical name
•constitutes a description of a drug using the
nomenclature of chemistry
•given according to the chemical constitution of a
drug
•can be long, complex, hard to remember and difficult
to use in a prescription

E.g, N-acetyl-para-aminophenol
40

41. Cont…
(2)Generic Name (Non-proprietary name)
•is assigned by the United States Adopted Names
Council or by British Approved Name Council
•Each drug has only one generic name
•less complex than chemical names
•used uniformly all over the world by an international
agreement through the WHO
•E.g. Acetaminophen
41

42. Cont…
(3)Brand name (Proprietary or Trade name)
•the name under which a drug is marketed
•created by drug companies with the intention that
they be easy to recall and pronounce
designed to be catchy, short, easy to remember
and often suggestive
•must be approved by the FDA
42

43. Cont…
•a single drug may have a large number of brand
names
because any drug can be marketed in different
formulations and by multiple companies
•E.gs of brand names for paracetamol
-Acephen, Cetafen, Feverall, RapiMed, Silapap,
Triaminic, Tylenol, etc. from different
manufacturers
-
43

44. Cont…
44

45. Cont…
•Why do we use drug name?
-For written and verbal communication about
medicines and
-To put on labels to identify medications in container
•Which name to Use, Generic or Brand?
-Drug name recognition would be enhanced through
universal use of generic names
There are many arguments for using the
nonproprietary name in prescribing: uniformity,
convenience, economy and better comprehension

45

46. Cont…
BRANCHES OF PHARMACOLOGY
•The two major branches (basic principles) of
pharmacology are:
I.Pharmacokinetics and
II.Pharmacodynamics

46

47. I.PHARMACOKINETICS
•The term pharmacokinetics is derived from two
Greek words:
-Pharmakon = drug or poison and
-kinesis = motion/movement
•PK is the quantitative study of drug movement
throughout the body
Movement of drug in, through and out of the body
•PK is also concerned about what happens to the
drug as it makes this journey
Concerned about “What the body does to the drug”

47

48. Cont…
•The characteristics of a drug that predict its
movement and availability at sites of action are its:
-molecular size and structural features,
-degree of ionization,
-relative lipid solubility of its ionized and non-
ionized forms, and
-binding to serum and tissue proteins
48

49. Cont…
•There are four basic pharmacokinetic processes:
(1)Absorption
(2)Distribution
(3)Metabolism (biotransformation) and
(4)Excretion
ADME


49

50. Cont…
The four basic pharmacokinetic processes
•Dotted lines represent membranes that must be crossed as drugs
move throughout the body
50

51. Cont…
Schematic representation of drug
absorption, distribution, metabolism,
and elimination
51

52. Cont…
•Absorption is the movement of a drug from its site
of administration into the blood
•Distribution is drug movement from the blood to the
interstitial space of tissues and from there into cells
•Metabolism (biotransformation) is enzymatically
mediated alteration of drug structure
•Excretion is the movement of drugs and their
metabolites out of the body
The combination of metabolism plus excretion is
called elimination
Metabolism + Excretion = Elimination
52

53. Cont…
•The intensity of response is related to concentration
of the drug at its site of action, which in turn is
dependent on its pharmacokinetic properties (ADME)
•Pharmacokinetic considerations determine
-the route(s) of administration
-dose
-latency of onset
-time of peak action
-duration of action and
-frequency of administration of a drug
53

54. Cont…
Passage of Drugs Across Membranes
•All four phases of pharmacokinetics (ADME) involve
drug movement
•To move throughout the body, drugs must cross
membranes
•Drugs must cross membranes to
-enter the blood from their site of administration
-leave the vascular system and reach their sites of
action
-undergo metabolism and excretion
54

55. Cont…
•This movement or translocation of drug from one
side of the biological barrier to the other is called
biotransport and
•the mechanisms underlying the transfer of a drug
across the biological barriers are called the transport
mechanisms
55

56. Cont…
•Biologic membrane
-Biologic membranes are composed of layers of
individual cells
-The cells composing most membranes are very
close to one another
-drugs must usually pass through cells, rather than
between them, to cross the membrane
-the ability of a drug to cross a biologic membrane
is determined by its ability to pass through single
cells
56

57. Cont…
•The major barrier to passage through a cell is the
cytoplasmic membrane (the membrane that
surrounds every cell)

57
Structure of cell
membrane

58. Cont…
•The membrane structure consists of a double layer
of molecules known as phospholipids
•Phospholipids are simply lipids (fats) that contain an
atom of phosphate
are depicted as having a round head (the phosphate-
containing component) and two tails (long-chain
hydrocarbons)
•The large objects embedded in the membrane
represent protein molecules, which serve a variety of
functions
58

59. Cont…
•Transport mechanisms
(1)Passive diffusion (Non-ionic or simple diffusion)
•It is a transfer process in which the drug molecules
pass through a biological barrier in the direction of
their concentration gradient (higher to lower) without
requiring any expenditure of energy by the biological
system
•This is the most important mechanism for majority of
drugs
59

60. Cont…
•It is slow, commonest process of drug transport
•Passage of lipid soluble, uncharged drugs through
membrane
•Across concentration gradient
•Carrier and energy independent
60

61. Cont…
•Passive diffusion depends on:
-Lipid solubility of the drug (lipid : water partition
coefficient)
-Concentration gradient of the drug across the
membrane
-State of ionization (depends on the pH of the
medium)
-Membrane surface area exposed to the drug
-Size and shape of the drug molecule 61

62. Cont…
(2)Specialized transport mechanisms
(A)Carrier mediated transport mechanisms
(i)Facilitated Diffusion
•It is a carrier mediated transfer process to which there
is no need of energy
•Drugs are transported along the concentration
gradient
•It is a quick process than passive transport
•It shows saturability and selectivity

62

63. Cont…
•Saturability – when binding sites of the carrier is
completely occupied
•Selectivity – selection of drugs with specific
chemical structure by the carrier

63

64. Cont…
(ii)Active Transport
•Transport of a drug molecule utilizing carriers under
expenditure of energy (ATP)
•Transports against concentration gradient
•It is very quick process
•It shows selectivity and saturability


64

65. Cont…
65

66. Cont…
(B)Endocytosis
•Is engulfment of large molecules by the cell
membrane and release them intra- cellular
•Pinocytosis (fluid phase endocytosis)
•Phagocytosis (adsorptive phase endocytosis)

66

67. Cont…
Routes of Drug Administration
•a route of drug administration is the way/means by
which a drug or other substance is delivered into or
applied on the body
•Classification of routes of drug administration
-Routes can be broadly divided into those for
(A)Local action – drug acts near the site of
administration
(B)Systemic action – drug gets into the systemic
circulation and distributed throughout the whole body
67

68. Cont…

68

69. Cont…
(A)Local Routes
•Include:
(i)Topical route – application on the skin and
mucous membranes
(ii)Intra-articular route - injection directly into the
joint space (e.g. hydrocortisone) and
(iii)Intrathecal route – injection into the
subarachnoid space (e.g. amphotericin B)
69

70. Cont…
(i)Topical routes - refer to external application of the
drug to the surface for localized action
(a)Mucous membranes
•Drugs are applied on the mucous membranes of
the conjunctiva, nasopharynx, oropharynx, vagina
and colon usually for their local effects
•Absorption through mucous membranes occur
readily to cause systemic effects
70

71. Cont…
(b)Skin
•Rubbing the drug preparation onto the skin or can
be dusted or sprayed over the surface of the skin
•Safe and convenient
•Absorption is proportional to the surface area and
lipid solubility of the drug
•Conditions that increase cutaneous blood flow
enhance absorption
71

72. Cont…
-Difficulty in ascertaining the amount of the drug
absorbed
-Systemic absorption from skin is sometimes a
reason of toxicity

72

73. Cont…
(c)Eye
Ophthalmic preparations are meant for their local
action
Systemic absorption that results from drainage
through the nasolacrimal canal is usually
undesirable
Very little is lost through drainage; hence, systemic
side effects are minimized
73

74. Cont…
(B)Systemic routes
•may be divided into:
(i)Enteral routes – administration through the
alimentary tract (oral, sublingual, and rectal
route)
(ii)Parenteral routes – administration through other
sites, non alimentary (injections, inhalation)
74

75. Cont…
(i)Enteral routes
(a)Oral route
•Swallowing a drug through mouth
•Advantages:
-Most commonly used method as it is safe,
convenient and painless procedure
-It is economical as sterilization of drug is not
essential
75

76. Cont…
•Disadvantages:
-Slow onset of action (why?)
-Not suitable for Unpalatable drugs
-Not suitable for uncooperative /unconscious/
vomiting patients, unable to swallow
-Not suitable for Irritant drugs and drugs which are
poorly absorbed, metabolized extensively in the
gut by gut flora and liver (first-pass metabolism)
76

77. Cont…
-Not suitable for acid sensitive drugs (e.g.
penicillin G preparations) and for drugs which
may be inactivated by gastric enzymes (e.g.
insulin).
-Drug-food interactions may lead to formation of
unabsorbable complexes
-Presence of food in stomach delays gastric
emptying and delays the onset of action

77

78. Cont…
(b)Rectal route
•Administration through rectum
•Advantages:
-useful for patients having nausea and vomiting,
-First-pass degradation is relatively less , as a
major portion of the drug is absorbed from
external haemorrhoidal veins and
-Useful for gastric irritant drugs also
78

79. Cont…
•Disadvantages:
-Chances of rectal inflammation,
-Absorption is unreliable,
-Inconvenient and embarrassing to the patient

79

80. Cont…
(c)Sublingual route
•The drug is placed beneath the tongue
•Advantages
-Quick onset of action
-After absorption, the drug passes directly into the
systemic circulation, bypassing the portal
circulation, thus avoiding first pass degradation
-The drug can be spitted out if side effects are
observed 80

81. Cont…
•Disadvantages
-Distasteful, irritant drugs cannot be given;
-drugs of higher molecular weights are not well
absorbed by this route
81

82. Cont…
(ii)Parenteral routes
(a)Intravenous route
•Injection of drugs through lumen of the veins
•Advantages
-Suitable during emergency conditions; rapid
onset of action
-Large volume of the drug can be administered
-Too irritant drugs are to be administered
(insensitivity and rapid dilution)
-Consciousness and cooperation is not
necessary
-Bioavailability is 100% 82

83. Cont…
•Disadvantages:
-Difficulty of administration, painful
-Once administered, it can not be taken out
-More chance of thrombophlebitis, air embolism,
hemolysis
-Needs strict sterility (possible spread of disease)
-Velocity reaction due to rapid injection e.g. theophyline
-Sever anaphylactoid or hypersensitivity reactions in
allergic patients
-Not economic for the patient (expensive)
-Not suitable for suspensions, oily and alcoholic
solutions
-No local action

83

84. Cont…
(b)Intramuscular route
•Drug is injected in one of the large skeletal
muscles: deltoid, triceps, gluteus maximus, rectus
femoris etc.
•Advantages:
-Absorption is more predictable, less variable and
rapid compared to oral and subcutaneous route
-Both soluble & insoluble drugs (suspension, oily
preparations) can be administered
-Depot injections can also be given by this route
84

85. Cont…
•Disadvantages:
-Perfect aseptic conditions are needed,
-Chances of abscess at the site of injection,
-Chances of nerve damage leading to paresis of
muscle supplied by it
-Large volumes cannot be administered
85

86. Cont…
(c)Subcutaneous route
•Injection into the subcutaneous tissue under the
skin
•Is richly supplied by nerves (unsuitable for irritant
drug administration) & less vascularized (slow
absorption)
•Self injection is simple
•Oily solution or aqueous suspensions can be
injected for prolonged action
86

87. Cont…
(d)Intradermal route
•Injection into the epidermis of the skin
•is given at an angle of 10–15° to skin (epidermis)
and a bleb must be formed
•BCG vaccination and drug testing for allergy is
done by this route
87

88. Cont…

88

89. Cont…
(d)Inhalational route (Non-injectable routes)
•Inspiration through nose or mouth
•Suitable for aerosol, gas and volatile liquid drugs
•Rapid absorption due to large surface area, rich
blood supply, rapid circulation
•Advantage: Rapid absorption, avoidance of hepatic
first pass effect, used for both local and systemic
application
•Disadvantage: Poor ability to regulate the dose and
irritation of the pulmonary mucosa
89

90. Cont…
•Factors governing choice of route of
administration
-Most drugs can be administered by a variety
of routes
-The choice of appropriate route in a given situation
depends both on:
drug and
patient related factors


90

91. Cont…
(1)Physical and chemical properties of the drug
(solid/liquid/gas; solubility, stability, pH, irritancy)
(2)Site of desired action – localized and
approachable or generalized and not approachable
(3)Rate and extent of absorption of the drug from
different routes
(4)Effect of digestive juices and first pass
metabolism on the drug
(5)Rapidity with which the response is desired
(routine treatment or emergency)
(6)Accuracy of dosage required (I.V. and inhalational
can provide fine tuning)
(7)Available dosage forms in the market
91

92. Cont…
(8)Condition of the patient (unconscious, vomiting,
presence of contraindication for certain routes)
(9)Economic condition of the patient
(10)Personal factors (for example some patients do
not prefer injections or suppositories)
92

93. Cont…
•Pharmacokinetic Processes
(1)Drug Absorption
•Absorption is movement of the drug from its site of
administration into the circulation (blood)
•To be absorbed, except IV, the drug has to cross
biological membranes
•The rate of absorption determines how soon
effects will begin
•The amount of absorption helps determine how
intense effects will be
93

94. Cont…
•Factors affecting drug absorption
-The rate at which a drug undergoes absorption is
influenced by
the physical and chemical properties of the
drug itself and
physiologic and anatomic factors at the
absorption site
-
94

95. Cont…
(i)Rate of dissolution
-Before a drug can be absorbed, it must first be
dissolved
-For solid dosage forms, absorption first requires
dissolution of the tablet/capsule – liberating the drug
-The rate of dissolution determines the rate of
absorption
Drugs in formulations that allow rapid dissolution
(liquid forms) have a faster onset than drugs
formulated for slow dissolution (solid forms)
95

96. Cont…
(ii)Surface area
-The surface area available for absorption is a major
determinant of the rate of absorption
The larger the SA, the faster absorption will be
-Orally administered drugs are usually absorbed from
the small intestine rather than from the stomach
the small intestine, because of its lining of microvilli,
has an extremely large surface area, whereas the
surface area of the stomach is relatively small
96

97. Cont…
(iii)Blood flow to the absorption site
-Drugs are absorbed most rapidly from sites where
blood flow is high
Because blood containing a newly absorbed drug
will be replaced rapidly by drug-free blood, thereby
maintaining a large gradient between the
concentration of drug outside the blood and the
concentration of drug in the blood
The greater the concentration gradient, the more
rapid absorption will be
97

98. Cont…
(iv)Lipid solubility
-Highly lipid-soluble drugs are absorbed more
rapidly than drugs whose lipid solubility is low
Because lipid-soluble drugs can readily cross the
membranes that separate them from the blood,
whereas drugs of low lipid solubility cannot
98

99. Cont…
(v)pH partitioning
-Absorption will be enhanced when the difference
between the pH of plasma and the pH at the site of
administration is such that drug molecules will
have a greater tendency to be ionized in the
plasma
99

100. Cont…
•Most drugs are weak electrolytes, either weak
acids (i.e., which form salts with bases) or weak
bases (i.e., which form salts with acids)
•The rate of absorption (passive diffusion) of any
weak acid or a weak base depends on its degree of
ionization which in turn depends upon the pH of the
surrounding medium

100

101. Cont…
•A relationship exists between
–its dissociation constant (pKa of the drug),
–the pH of the environment (in which it is placed)
and
–the extent of its ionization
•This relationship is expressed by Henderson
Hasselbalch equation given below:
101

102. Cont…

102

103. Cont…
•The implications of Henderson-Hasselbalch
equations are as follows:
–Very weak acids (pK
a  8) are essentially unionized
at all pH values and therefore their absorption is
rapid and independent of GI pH
–Acids with in the pK
a range 2.5 to 7.5 are better
absorbed from acidic conditions of stomach (where
pH  pK
a) where they largely exist in unionized form
–Stronger acids with pK
a  2.5 are ionized in the
entire pH range of GIT and remain poorly absorbed 103

104. Cont…
-Very weak bases (pK
a  5) are essentially unionized
at all pH values and therefore have a rapid
absorption which is independent of pH
-Bases in the pK
a range of 5 to 11 are better
absorbed from the relatively alkaline conditions of
the intestine where they largely exist in unionized
form
-Stronger bases with pK
a  11 are ionized in the
entire pH range of the GIT and therefore are poorly
absorbed
104

105. 105

106. 106

107. Cont…
•Important consequences of pH partition:
-Free-base trapping of some antimalarial drugs (e.g.
chloroquine, in the acidic environment in the food
vacuole of the malaria parasite contributes to the
disruption of the haemoglobin digestion pathway that
underlies their toxic effect on the parasite
-Urinary acidification accelerates excretion of weak
bases and retards that of weak acids
-Urinary alkalinization has the opposite effects: it
reduces excretion of weak bases and increases
excretion of weak acids - in treating aspirin overdose:
bicarbonate and acetazolamide each increase urine
pH
107

108. Cont…
–Increasing plasma pH (e.g. by administration of
sodium bicarbonate) causes weakly acidic drugs to be
extracted from the CNS into the plasma
–Conversely, reducing plasma pH (e.g. by
administration of a carbonic anhydrase inhibitor such
as acetazolamide, causes weakly acidic drugs to
become concentrated in the CNS, potentially
increasing their neurotoxicity
108

109. Cont…
•Note:
–If a drug is a weak electrolyte, it is the unionized form
which is lipid soluble and the ionized form is water
soluble
–When medium is same, drugs can cross the
membrane
Acidic drugs can cross the membranes in acidic
medium i.e. acidic drugs are lipid soluble in acidic
medium (for this acidic drugs must be mainly in the
un-ionized form in acidic medium) 109

110. Cont…
As gastric pH is acidic, therefore acidic drugs are
more likely to be absorbed from the stomach, because
these will be in unionized (lipid soluble) form here
Thus, aspirin is more likely to be absorbed in the
stomach than morphine or atropine (basic drugs)

Opposite is also true for basic drugs
110

111. Cont…
(v)Interaction with other drugs
•Examples:
-Drug that delay gastric emptying
-Formation of unabsorbable complex (TTC with
Calcium)
-Antacids and cholesteramine
-Vasoconistrictor drugs
111

112. Cont…
(vi)Route of administration of the drug
-Rate of drug absorption per route of administration:
Inhalation > IM > SC > Intestine > skin and
stomach
112

113. Cont…
(vii)Contact time at the absorption surface:
-If a drug moves through the GI tract very quickly,
as can happen with severe diarrhea, it is not well
absorbed
-Conversely, anything that delays the transport of the
drug from the stomach to the intestine delays the
rate of absorption of the drug
The presence of food in the stomach both dilutes the
drug and slows gastric emptying
A drug taken with a meal is generally absorbed more
slowly
113

114. Cont…
•First Pass Effect or Metabolism
-Drugs absorbed from all sites along the GI tract
(except the oral mucosa and the distal segment of
the rectum) first pass through the GIT wall and then
through the liver (via the portal circulation) before
they reach the general circulation
Here, some of the drug may be metabolized (first
pass metabolism or pre-systemic metabolism) and
rest of the drug reaches the systemic circulation (go
through the GIT wall and then through the liver, enter
the inferior vena cava, and reach the general
circulation)

114

115. Cont…
-First-pass effect/metabolism means the drug
degradation by enzymes in the gut wall and liver
occurring before the drug enters the systemic
circulation
-If the drug is rapidly and extensively metabolized
during this initial passage, the amount of
unchanged drug entering the systemic circulation is
decreased
-The net result is the decreased bioavailability and
diminished therapeutic response
115

116. Cont…
Vascular pathway of
drugs absorbed from
various systemic routes
of administration and
sites of first pass
metabolism
116

117. Cont…
-Examples of Drugs with high first pass metabolism
Nitrates
Hydrocortisone
Lignocaine
Propranolol
Salbutamol
Morphine
117

118. Cont…
•Bioavailability (BA)
-refers to the rate at which and the extent (amount)
to which the active concentration of an
administered drug reaches the systemic circulation
-is a measure of the fraction (F) of administered
dose of a drug that reaches the systemic circulation
in the unchanged form
-BA of drug injected I.V. is 100%

118

119. Cont…
-BA is lower after oral ingestion because:
the drug may be incompletely absorbed
the absorbed drug may undergo first pass
metabolism in the intestinal wall/liver or be excreted
in bile
-Incomplete BA after S.C. or I.M. injection is less
common, but may occur due to local binding of the
drug
119

120. Cont…
•BA can be calculated by comparing the AUC (area
under plasma concentration time curve) for I.V. route
and for that particular route
•It can also be calculated by comparing the excretion
in the urine

120

121. Cont…
•AUC tells about the extent of
absorption of the drug
•Tmax. tells about the time to
reach maximum concentration,
i.e. rate of absorption
•Cmax is the maximum
concentration of a drug that can
be obtained
121

122. Cont…
•Factors that influence bioavailability:
–First-pass metabolism
–Solubility of the drug
–Chemical instability – e.g. penicillin G, insulin
–Nature of the drug formulation – e.g., particle size, salt
form, crystal polymorphism, enteric coatings, and the
presence of excipients (such as binders and
dispersing agents) can influence the ease of
dissolution and, therefore, alter the rate of absorption
122

123. Cont…
•Bioequivalence
-Many different pharmaceutical companies can
manufacture same compound (with same dose as
well as dosage form)
-If the difference in the BA of two preparations (same
drugs, same dose, same dosage forms) is less than
20%, these are known to be bioequivalent
As the term implies, these are biologically equal i.e.
they will produce similar plasma concentrations
123