General pharmacologyroute in of asmn

1. GENERAL PHARMACOLOGY

2. 2
Contents
:
A. Introduction to Pharmacology-
 Definition, historical landmarks and scope of pharmacology,
nature and source of drugs, essential drugs concept and
routes of drug administration.
 Agonists, antagonists( competitive and non competitive),
spare receptors, addiction, tolerance, dependence,
tachyphylaxis, idiosyncrasy, allergy.
B. Pharmacokinetics-
 Membrane transport, absorption, distribution, metabolism
and excretion of drugs.
 Enzyme induction, enzyme inhibition, kinetics of elimination

3. 3
1.Pharmacology:
• Science of drugs (Greek:Pharmacon--drug; logos-discourse in).
• Deals with interaction of exogenously administered
chemical molecules (drugs) with living systems.
The two main divisions of pharmacology are:
• Pharmacodynamics: knowledge about drugs, but most importantly
- What the drug does to the body.
• Pharmacokinetics (Greek: Kinesis-movement):- What the
body does to the drug.

4. 4
2. Drug (French: Drogue -a dry herb)
"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."
1. Pharmacotherapeutics:
• It 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 specific features of a patient are
a part of pharmacotherapeutics.

5. 5
1.Clinical pharmacology:
 Scientific study of drugs in man.
 Pharmacodynamic and pharmacokinetic investigation
in healthy volunteers and in patients.
 Evaluation of efficacy and safety of drugs
 Comparative trials with other forms of treatment;
 Surveillance of patterns of drug use, adverse effects etc.
2. Chemotherapy:
 Treatment of systemic infection/malignancy
 Specific drugs that have selective toxicity for the
infecting
 organism malignant cell with no/minimal effects on the
host cells

6. 6
6.Toxicology:
It 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.

7. administration etc.) 7
DRUG NOMENCLATURE
Three categories of names:
(a) Chemical name:
It describes the substance chemically, e.g.1-(lsopropylamino)-
3-(1-naphthyloxy) propan-2-ol for propranolol.
This is cumbersome and not suitable for use in prescribing.
A code name, e.g. RO 15-1788 (later named flumazenil)
may be assigned by he manufacturer for convenience and
simplicity before an approved name is coined.
a) Brand name –
Original drug which is defended by patent and may be
produced during patent term only by this pharmaceutical firm
b) Generic name–
When term of patent is discontinued the drug may be produced by
different pharmaceutical companies under new product (trade)
names but at the basis of original active substance (similar quantity,
route of

8. ESSENTIAL DRUGS (MEDICINES) CONCEPT
The WHO has defined Essential Drugs (medicines) as "those that
satisfy the priority healthcare needs of the population.
They are selected with due regard to public health relevance,
evidence on efficacy and safety, and comparative cost
effective.
Essential medicines are intended to be available within the context
of functioning health systems at all times and in adequate
amounts, in appropriate dosage forms, with assured quality and
adequate information, and at a affordable price.
For optimum utilization of resources, governments (especially
in developing countries) should concentrate on well
tested,cheaper,safe and efficacious drugs by identifying them as
Essential medicines.
8

9. 9
WHO criteria for the selection of an
essential medicine.
a) Adequate data on its efficacy and safety should be available.
b) Available in a form in which quality, including bioavailability, and stability on
storage can be assured.
c) Its choice should depend upon pattern of prevalent diseases; availability of
facilities and trained personnel; financial resources; genetic, demographic
and enviromental factors.
d) In case of two or more similar medicines, choice should be made on the basis
of their relative efficacy, safety, quality, price and availability, by comparative
pharmacokinetic properties and local facilities for manufacture and storage.
f) Most essential medicines should be single compounds.
Fixed ratio combination products should be included only when dosage of each
ingradient meets the requirements of a defined population group, and when the
combination has a proven advantage in therapeutic effect, safety, adherence or
in decreasing the emergence of drug resistance.

10. (g) Selection of essential medicines should be a continuous
process which should take into account the changing
priorities for public health action, epidemiological conditions
as well as availability of better medicines/ formulations and
progress in pharmacological knowledge.
rational use of
(a) Recently, it has been emphasized to select essential medicines
based on rationally developed treatment guidelines.
 First Model List of Essential Drugs along with their dosage
forms and strengths in 1977 by WHO which could be
adopted after suitable modifications according to local
needs.
 India produced its National Essential Drugs List in 1996 and has
revised it in 2003 with the title "National List of Essential
Medicines". This includes 354 medicines which are considered
to be adequate to meet the priority healthcare needs of the
general population of the country.
 Adoption of the essential medicines list for procurement and
supply of medicines, especially in the public sector healthcare
system, has resulted in improved aP
vre
as
ie
lant
bed
ilib
tyy:

11. 11
Orphan Drugs
• These are drugs or biological products for diagnosis/treatment/
prevention of a rare disease or condition, or a more common
disease (endemic only in resource poor countries) for which
there is no reasonable expectation that the cost of developing
and marketing it will be recovered from the sales of that drug.
• The list includes:
Sodium nitrite, fomepizole, liposomal amphotericin 8,
ancrod, rifabutin, succimer, somatropin, digoxin immune
Fab (digoxin antibody), liothyronine (T3) and many more.
• Though these drugs may be life saving for some patients,
they are
commercially difficult to obtain.
• Governments in developed countries offer tax benefits and
other incentives to pharmaceutical companies for
developing and marketing orphan drugs (e.g. Orphan Drug
Act in USA).

12. 12
Route of drug
adminsteration
Definition:
A route of administration is the path by
which a drug, fluid, poison or other
substance is brought into contact with the
body.

13. 13
Classification
Routes of administration can broadly be divided
into:
1. Topical:
Drugs are applied topically to the skin or mucous membranes,
mainly for
local action.
2. Oral:
used for systemic (non-local) effect, substance is given via the
digestive
tract.
3. Parenteral:
A drug administered parenterally is one injected via a hollow needle
into
the body at various sites and to varying depth.
4. Rectal: Drugs given through the rectum by suppositories or enema.
5. Inhalation: The lungs provide an excellent surface for absorption

14. 14
ROUTES OF DRUG ADMINISTRATION
Mostly common considerations are:
1. Physical and chemical properties of the drug
- Solid/liquid/ gas
– Solubility and stability
– PH and irritancy
1. Site of desired action - localized and aprochable
2. Rate and extent of absorption of the drug from
different routes.
3. Effect of digestive juices and first pass metabolism of
the drug.
4. Rapidity with which the response is desired
(eg.routine treatment or emergency).
5. Accuracy of dosage required (i.v. and inhalation).
6. Condition of the patient (unconscious, vomiting)
etc.

15. 15
Local
route
• These routes can only be used for localized lesions
at accessible sites and for drugs whose systemic
absorption from these sites is minimal or absent.
• Thus, high concentrationsare attained at the desired
site
without exposing the rest of the body.
• Systemic side effects or toxicity are consequently absent
or
minimal.
• The same can serve as systemic route of administration,
e.g. glyceryl trinitrate (GTN) applied on the skin as
ointment or transdermal patch.

16. A.Topical route
This refers to external application of the drug to the
surface
for localized action.
It is often more convenient as well as encouraging to the
patient.
Drugs can be efficiently delivered to the localized
lesions on skin, oropharyngeal/nasal mucosa, eyes, ear
canal, anal canal or vagina.
The dosage forms are lotion, ointment, cream,powder,
paints,
drops, spray, lozengens, suppositories or pesseries.
Nonabsorbable drugs given orally (sucralfate,
vancomycin), inhalation of drugs for action on
bronchi
(salbutamol, cromolyn sodium) and irrigating
16

17. 1- Topical route:
I Skin
A-Dermal – cream, ointment (local action)
B- Transdermal- absorption of drug through skin (i.e systemic
action)
I. stable blood levels(controlled drug delivery system)
II. No first pass metabolism
III.Drug must be potent or patch becomes too large
II Mucosal membranes
•eye drops (onto the conjunctiva)
• ear drops
• intranasal route (into the nose)
17

18. 2- Oral route:
- By swallowing.
- It is intended for systemic effects
resulting from drug absorption
through the various epithelia and
mucosa of the gastrointestinal
tract.
18

19. 19
Advantages:
1 Convenient - portable, no pain, easy to take.
2 Cheap - no need to sterilize,
compact,
multi-
dose
bottles
,
automated machines produce tablets in large quantities.
3- Variety - tablets, capsules, suspensions, mixtures .
Disadvantages:
1 Sometimes inefficient - low solubility drugs may suffer
poor
availability e.g. Griseofulvin
2First-pass effect - drugs absorbed orally are transported to
the general circulation via the liver. Thus drugs which are
extensively metabolized will be metabolized in the liver during
absorption. e.g. propranolol

20. First pass
effect:
First pass
effect
20

21. 21
1. The first pass effect is the term used for the hepatic metabolism
of a pharmacological agent when it is absorbed from the gut
and delivered to the liver via the portal circulation.
2. The greater the first pass effect, the lower the bioavailability
of the
drug(the rate and extent of the drug reaching systemic
circulation).
3. Food and G-I motility can affect drug absorption.Often patient
instructions include a direction to take with food or take on an
empty stomach.
4. Absorption is slower with food(milk and milk products) for
tetracyclines and penicillins, etc. However, for propranolol
bioavailability is higher after food, and for griseofulvin
absorption is higher after a fatty meal.
First pass effect (Cont.):

22. 22
1. Sometimes may have adverse reactions –
e.g. Antibiotics may kill normal gut flora and
allow overgrowth of fungal varieties. Thus,
antifungal agent may be included with an
antibiotic.
2. Not suitable for unconscious patient -
Patient must be able to swallow solid
dosage forms. Liquids may be given by
tube.
3.May cause irritation to gastric mucosa,
nausea and vomiting.
4.Effect too slow for emergencies.

23. 23
3- Buccal/Sublingual
route:
• Some drugs are taken as smaller tablets which
are held in the mouth (buccal tablet) or under
the tongue (sublingual tablet).
• Buccal tablets are often harder tablets [4 hour
disintegration time], designed to dissolve
slowly.
• E.g Nitroglycerin, as a softer sublingual tablet
[2 min disintegration time], may be used for
the rapid relief of angina.

24. 24
Advantages
1 Avoid hepatic first pass - The liver is by-passed
thus there is no loss of drug by first pass effect
for buccal administration. Bioavailability is
higher.
2 Rapid absorption - Because of the good blood
supply to the area, absorption is usually quite
rapid.
3 Drug stability - pH in mouth relatively neutral
(Except.
stomach - acidic). Thus a drug may be more stable.
3- Buccal/Sublingual route (Cont.)

25. 25
Disadvantages
1 Holding the dose in the
mouth is inconvenient.
2 Small doses only can be
accommodated easily.
3- Buccal/Sublingual route (Cont.)

26. 4- Parenteral
route:
26

27. 27
A- Intravascular (IV, IA):
- placing a drug directly into blood stream.
-May be - Intravenous (into a vein) or - intraarterial (into an
artery).
Advantages
1 precise, accurate and immediate onset of action,
100%
bioavailability.
Disadvantages
2 risk of embolism.
3 high concentrations attained rapidly leading to greater risk of
adverse effects.
4- Parenteral route (Cont.)

28. 28
4- Parenteral route
(Cont)
B-Intramuscular :(into the skeletal muscle).
Advantages
1- suitable for injection of drug in aqueous solution
(rapid action) and drug in suspension or emulsion
(sustained release).
Disadvantages
1- Pain at injection sites for certain drugs.

29. 29
C- Subcutaneous (under the skin), e.g. insulin.
D- Intradermal, (into the skin itself) is used for skin testing
some
allergens.
E- Intrathecal (into the spinal canal) is most commonly used
for spinal anesthesia .
F- Intraperitoneal, (infusion or injection into the peritoneum)
e.g. peritoneal dialysis in case of renal insuffeciency.
4- Parenteral route (Cont)

30. 5-Rectal
route:
Most commonly by suppository or enema.
Advantages
1 By-pass liver - Some of the veins draining the rectum lead
directly to the general circulation, thus by-passing the
liver. Reduced first-pass effect.
2Useful- This route may be most useful for patients
unable to take drugs orally (unconscious patients) or with
younger children.
- if patient is nauseous or vomiting
30

31. 31
Disadvantages :
1 Erratic absorption - Absorption is often
incomplete and erratic.
2 Not well accepted.
5- Rectal route (Cont.)

32. 6- Inhalation
route:
- Used for gaseous and volatile agents and aerosols.
- Solids and liquids are excluded if larger than 20 micron.
- Smaller than 0.5 micron , they aren't retained.
Advantages
A- Large surface area
B- thin membranes separate alveoli from circulation
C- high blood flow
- As result of that a rapid onset of action due to rapid access
to circulation.
32

33. 33
Disadvantages
1 Most addictive route of administration because it hits the
brain so quickly.
2 Difficulties in regulating the exact amount of dosage.
3 Sometimes patient having difficulties in giving themselves a
drug by inhaler.
6- Inhalation route (Cont.)

34. Comparisons:
Presented by: Prof.Mirza
Anwar
34

35. Comparisons:
Presented by: Prof.Mirza
Anwar
35

36. Pharmacokinetic
s
Pharmacokinetics refers to what the
body does to a drug & phar-
macodynamics describes what the
drug does to the body.
• Four pharmacokinetic properties determine
the onset, intensity,and the duration of drug
action
• Absorption:
• Distribution:
• Metabolism:
• Elimination:
Using knowledge of pharmacokinetic
parameters, clinicians can design
optimal drug regimens, including the
route of administration, the dose,the
frequency, and the duration of 36
treatment.

37. Drug
absorption:
37

38. 38
B.Factors influencing
absorption:
1.Effect of pH on drug absorption:
2. Blood flow to the absorption site:
3. Total surface area available for
absorption:
4. Contact time at the absorption surface:
5. Expression of P-glycoprotein:

39. 1.Effect of pH on drug absorption:
5. Expression of P-
glycoprotein:
39

40. Bioavailabilit
y
• Bioavailability is the rate and extent
to which an administered drug
reaches the systemic circulation.
• For example, if 100 mg of a drug
is administered orally and 70 mg
is absorbed unchanged, the bio-
availability is 0.7 or 70%.
• Determining bioavailability is
important for calculating drug
dosages for nonintravenous routes
of administration.
Determination of bioavailability:
40

41. 2.Factors that influence
bioavailability:
a.First-pass
hepatic
metabolism:
b.Solubility of the
drug:
c.Chemical
instability:
d.Nature of the
drug
formulation:
41

42. a. First-pass hepatic metabolism :
What is FPHM:
When a drug is absorbed from the GI tract, it enters the portal
circulation
before entering the systemic circulation.
If the drug is rapidly metabolized in the liver or gut wall during this
initial passage, the amount of unchanged drug entering the
systemic circulation is decreased. This is referred to as first-
pass hepatic metabolism.
First-pass metabolism by the intestine or liver limits the efficacy of
many
oral medications.
For example:
More than 90% of nitroglycerin is cleared during
first-pass metabolism. Hence, it is primarily administered
via the sublingual or transdermal route.
Drugs with high first-pass metabolism should be given in
doses sufficient to ensure that enough active drug reaches the
desired site of action. 42

43. Examples
:
a. Nitroglycerin pacth b. First pass
effect
43

44. 44
b.Solubility of the drug:
• Very hydrophilic drugs are poorly absorbed because of their
inability
to cross lipid-rich cell mem-branes.
• Paradoxically, drugs that are extremely lipophilic are
also poorly absorbed, because they are totally insoluble in
aqueous body fluids and, therefore, cannot gain access to
the surface of cells.
• For a drug to be readily absorbed, it must be largely
lipophilic, yet have some solubility in aqueous solutions.
• This is one reason why many drugs are either weak
acids or weak bases.
c.Chemical instability:
Some drugs, such as penicillin G, are unstable in the pH of
the gastric contents. Others, such as insulin, are destroyed
in the GI tract by degradative enzymes.

45. d.Nature of the drug formulation:
Drug absorption may be altered by factors unrelated to the
chemistry of the drug.
For example,
Particle
size Salt
form
Crystal
polymorphi
sm
Enteric
coatings,
Presence of excipients (such as binders and dispersing agents) 45

46. D.Bioequivalence
Two drug formulations are bioequivalent if they show
comparable bioavailability and similar times to achieve peak blood
concentrations.
Clinical effectiveness often depends on both the maximum
serum drug con-centration and the time required (after
administration) to reach peak concentration
E.Therapeutic equivalence
Two drug formulations are therapeutically equivalent if they
are pharmaceutically equivalent (that is, they have the same
dosage form, contain the same active ingredient, and use the
same route of administration) with similar clinical and safety
profiles.
Therefore, two drugs that are bioequivalent may not be
therapeutically
equivalent. 46

47. IV. DRUG DISTRIBUTION
• Drug distribution is the process by which a drug reversibly leaves
the bloodstream and enters the interstitium (extracellular fluid)
and the tissues.
• For drugs administered IV, absorption is not a factor, and the
initial phase (from immediately after administration through the
rapid fall in concentration) represents the distribution phase,
during which the drug rapidly leaves the circulation and enters the
tissues.
• The distribution of a drug from the plasma to the interstitium
depends on cardiac output and local blood flow, capillary
permeability, the tissue volume,the degree of binding of the drug
to plasma and tissue proteins, and the relative lipophilicity of the
drug.

48. 48

49. 49
Factors affecting distribution:
A. Blood flow
B. Capillary permeability
C. Binding of drugs to plasma proteins and
tissues
D. Lipophilicity
E. Volume of distribution

50. 50
A. Blood
flow
1. The rate of blood flow to the tissue capillaries varies widely.
2. For instance, blood flow to the “vessel-rich organs” (brain, liver,
and kidney) is greater than that to the skeletal muscles. Adipose
tissue, skin, and viscera have still lower rates of blood flow.
3. Propofol has short duration of hypnosis produced by an IV
bolus.
4. High blood flow, together with high lipophilicity of propofol,
permits rapid distribution into the CNS and produces anesthesia.
5. A subsequent slower distribution to skel-etal muscle and adipose
tissue lowers the plasma concentration so that the drug diffuses
out of the CNS, down the concentration gradient, and
consciousness is regained.

51. 51
B.Capillary permeability
• Capillary permeability is determined by capillary structure and by the chemical
nature of the drug.
1. LIVER AND SPLEEN:
• A significant portion of the basement membrane is exposed due to
large,discontinuous capillaries through which large plasma proteins can pass.
2. BRAIN:
The capillary structure is continuous, and there are no slit junctions.
• These closely jux-taposed cells form tight junctions that constitute the blood–
brain barrier.
• For example, a specific transporter carries levodopa into the brain. By contrast,
lipid-soluble drugs readily penetrate the CNS because they dissolve in the
endothelial cell membrane.
• Ionized or polar drugs generally fail to enter the CNS because they cannot pass
through the endothelial cells that have no slit junctions.

52. 52
C.Lipophilicity
1. The chemical nature of a drug strongly influences its ability to cross
cell membranes.
2. Lipophilic drugs readily move across most biologic membranes.
3. These drugs dissolve in the lipid membranes and penetrate
the
entire cell surface.
4. The major factor influencing the distribution of lipophilic drugs is
blood flow to the area.
5. In contrast, hydrophilic drugs do not readily penetrate
cell membranes and must pass through slit junctions.

53. D.Volume of distribution
The apparent volume of distribution, Vd , is defined as the
fluid volume that is required to contain the entire drug in the
body at the same concentration measured in the plasma.
Vd = Amount of drug in to the body
(C0)
Plasma concentration at time zero (C0).
Although Vd has no physiologic or physical basis, it can be
useful to compare the distribution of a drug with the volumes
of the water compartments in the body.
53

54. 54
1. Distribution into the water compartments
in the body:
• Once a drug enters the body, it has the potential to distribute
into any one of the three functionally distinct compartments of
body water or to become sequestered in a cellular site.
a. Plasma compartment:
If a drug has a high molecular weight or is extensively
protein bound, it is too large to pass through the slit junctions
of the capillaries and, thus, is effectively trapped within the
plasma (vascular) compartment.
As a result, it has a low Vd that approximates the plasma
volume or about 4 L in a 70-kg individual. Heparin shows this
type of distribution.

55. b. Extracellular fluid:
• Drug with low molecular weight but is hydrophilic, it can pass
through the endothelial slit junctions of the capillaries into the
interstitial fluid.
• Hydrophilic drugs cannot move across the lipid membranes of cells
to enter the intracellular fluid.
• Therefore, these drugs distribute into a volume that is the sum of the
plasma volume and the interstitial fluid, which together constitute
the extracellular fluid (about 20% of body weight or 14 L in a 70-kg
individual).
• Example:Aminoglycoside antibiotics
c. Total body water:
Drug with LMW and is lipophilic, it can move into the interstitium
through the slit junctions and also pass through the cell membranes
into the intracellular fluid.
These drugs distributePirnesteontead bvy:oPlruofm.MeirzaoAfnwaabr out 60%
of body we5ig6 ht or about 42 L in a 70-kg individB
ua
aig
l.

56. 56
2.Apparent volume of distribution:
1. A drug rarely associates exclusively with only one of the
water compartments of the body.
2. Instead, the vast majority of drugs distribute into
several compartments, often avidly binding cellular
components, such as lipids (abundant in adipocytes and
cell membranes), proteins (abundant in plasma and cells), and
nucleic acids (abundant in cell nuclei).
3. Therefore, the volume into which drugs distribute is
called the
apparent volume of distribution (Vd ).
4. Vd is a useful pharmacokinetic parameter for calculating
the loading dose of a drug.

57. 3.Determination of Vd :
• The fact that drug clearance is usually
a first-order process allows calculation
of Vd . First order means that a
constant fraction of the drug is
eliminated per unit of time.
• This process can be most easily
analyzed by plotting the log of the
plasma drug concentration (Cp ) versus
time.
• The concentration of drug in the
plasma can be extrapolated back to
time zero (the time of IV bolus) on the
Y axis to determine C0 , which is the
concentration of drug that would have
been achieved if the distribution phase
had occurred instantly.
This allows calculation of Vd
as Vd= Dose/Co 57

58. V. DRUG CLEARANCE
THROUGH
METABOLISM
Once a drug enters the body, the process of elimination
begins. The three major routes of elimination are hepatic
metabolism, biliary elimination,and urinary elimination.
Together, these elimination processes decrease the plasma
concentration exponentially.
That is, a constant fraction of the drug present is eliminated in
a given unit of time.
Most drugs are eliminated according to first-order kinetics,
although some,such as aspirin in high doses, are eliminated
according to zero-order or nonlinear kinetics.
Metabolism leads to production of products with
increased polarity, which allows the drug to be eliminated.
58

59. • Clearance(CL) estimates the amount
of drug cleared from the body per
unit of time.
• Total
CL
reflecting
is a composite
estimate all
mechanisms
of drug
elimination and is calculated as
follows:
CL = 0 . 693 × Vd / t 1/2
59

60. 60
Kinetics of
metabolism:
1.First-order kinetics:
The metabolic transformation of drugs is catalyzed by
enzymes,
and most of the reactions obey Michaelis-Menten kinetics.
V max [ C ]
v = Rate of drug metabolism
=
------------------------
K m + [ C ]
In most clinical situations, the concentration of the drug,
[C], is much less than the Michaelis constant, K m , and the
Michaelis-
Menten equation reduces to
v = Rate of drug metabolism = V max [ C ]
K m
This means that a constant fraction of drug is metabolized
per
unit of time (that is, with each half-life,the concentration
decreases by 50%). First-order kinetics is also referred to as
linear

61. 61
2.Zero-order kinetics:
• With a few drugs, such as aspirin, ethanol,and phenytoin, the
doses are very large. Therefore, [C] is much
greater than Km , and the velocity equation becomes
V max [ C ]
v = Rate of drug metabolism = [ C ] = V max
• The enzyme is saturated by a high free drug concentration,
and the rate of metabolism remains constant over time. This is
called zero-order kinetics (also called nonlinear kinetics).
• A constant amount of drug is metabolized per unit of time.
The rate of elimination is constant and does not depend on
the drug concentration.

62. B.Reactions of drug metabolism
The kidney cannot efficiently eliminate lipophilic drugs
that readily cross cell membranes and are reabsorbed in
the distal convoluted tubules.
Therefore, lipid-soluble agents are first metabolized into
more polar (hydrophilic) substances in the liver via two
general sets of reactions, called phase I and phase II.
62

63. 63
1.Phase I:
• Phase I reactions convert lipophilic drugs into more polar
molecules by introducing or unmasking a polar functional
group,such
as –OH or –NH 2 .
• Phase I reactions usually involve reduction, oxidation, or hydrolysis.
• Phase I metabolism may increase,decrease, or have no effect
on
pharmacologic activity.
• a.Phase I reactions utilizing the P450 system:
• Most frequently involved reactions in drug metabolism are
catalyzed by the cytochrome P450
• The P450 system is important for the metabolism of many
endogenous compounds (such as ste-roids, lipids) and for the
biotransformation of exogenous substances (xenobiotics).
• Cytochrome P450, designated as CYP,is a superfamily of
heme- containing isozymes that are located in most cells, but
primarily in the liver and GI tract.

64. 1 Nomenclature: The family name is indicated by the
Arabic number that follows CYP, and the capital letter
designates the subfamily, for example, CYP3A. A
second
number indicates the specific isozyme, as in CYP3A4.
2 Specificity:
Different P450 isoforms present.
Have the capacity to modify a large number of
structurally
diverse substrates.
An individual drug may be a substrate for more than
one isozyme.
Four isozymes are CYP3A4/5,CYP2D6, CYP2C8/9, and
CYP1A2.
Most of the CYP3A4 are found in intestinal mucosa, accounting
for first-pass metabolism of drugs such as
chlorpromazine and clonazepam.
64

65. [3] Genetic variability:
P450 enzymes exhibit considerable genetic variability among
individuals and racial groups.
Variations in P450 activity may alter drug efficacy and the
risk of adverse events.
CYP2D6, in particular, has been shown to exhibit genetic
polymorphism.
CYP2D6 mutations result in very low capacities to
metabolize
substrates.
No benefit from the opioid analgesic codeine due to lack
the
CYP2D6 enzyme that activates the drug.
Although CYP3A4 exhibits a greater than 10 fold variability
between individuals, no polymorphisms have been identified so far
for this P450 isozyme.
65

66. 66
[4] Inducers:
I. The CYP450-dependent enzymes are an important target for
pharmacokinetic drug interactions through inducing the
CYP isozymes.
II. Certain drugs (phenobarbital, rifampin, and carbamazepine)
increasing the synthesis of one or more CYP isozymes.
results in loss of pharmacological effect of drugs
which are metabolized by these CYP isozymes.
III. Rifampin significantly decreases the plasma concentrations of
HIV pro- tease inhibitors, thereby diminishing their
ability to suppress HIV replication.
IV. St. John’s wort is a widely used herbal product and is a potent
CYP3A4 inducer.
V. Many drug interactions have been reported with concomitant
use of St. John’s wort.

67. [5]
Inhibitors:
An important source of drug interactions
that lead to serious adverse
events.
Inhibition of drugs metabolism is through competition for the
same
isozyme.
Omeprazole is a potent inhibitor of three of the CYP
isozymes
responsible for warfarin metabolism.
If the two drugs are taken together, plasma concentrations of
warfarin increase, which leads to greater anticoagulant effect and
increased risk of bleeding.
More important CYP inhibitors are erythromycin,ketoconazole,
and
ritonavir, because they each inhibit several CYP isozymes.
Grapefruit juice inhibits CYP3A4 and leads to higher levels and/or
greater potential for toxic effects with drugs, such as nifedipine,
clarithromycin, and simvastatin, that are metabolized by this system.
67

68. b.Phase I reactions not involving the
P450 system:
These include
Amine oxidation (catecholamines or
histamine) Alcohol dehydrogenation
(ethanol oxidation) Esterases (metabolism
of aspirin in the liver) Hydrolysis (procaine).
68

69. 69
2.Phase II:(conjugation
reactions)
phas
e
I metabolism)
,subsequent
• Polar metabolite of drugs can be excreted by the
kidneys.
• Lipophillic metabolite (after
conjugation
reaction with an endogenous substrate, such as
glucuronic acid, sulfuric acid, acetic acid, or an amino acid,
results in polar, usually more water-soluble compounds
that are often therapeutically inactive.
• A notable exception is morphine-6-glucuronide, which is more
potent than morphine.
• Glucuronidation is the most common and the most
important conjugation reaction.
• Drugs already possessing an –OH, –NH 2 , or –COOH group
may enter phase II directly and become conjugated
• The highly polar drug conjugates are then excreted by the
kidney or in bile.

70. VI. DRUG CLEARANCE BY THE KIDNEY
Polar drugs are eliminated easily from the body.
Number of routes are available for elimination, the most
important being elimination through the kidney into the urine.
Patients with renal dysfunction may be unable to excrete
drugs
and are at risk for drug accumulation and adverse effects.
Elimination of drugs via the kidneys into urine involves
the processes
– Glomerular filtration,
– Active tubular secretion
–
Passive tubular rePraebsesnoterdpbtyi:
oPrno.f.Mirza Anwar
70

71. Summery Drug
elimation:
71

72. 1.Glomerular filtration:
Free drug (not bound to albumin) flows through the capillary
slits into the Bowman space as part of the glomerular filtrate.
The glomerular filtration rate (GFR) is normally about 125
mL/min but may diminish significantly in renal disease.
Lipid solubility and pH do not influence the passage of drugs
into the glomerular filtrate.
However, variations in GFR and protein binding of drugs do
affect this process.
72

73. 2. Proximal tubular secretion:
Drugs that were not transferred into the glomerular filtrate leave the
glomeruli through efferent arterioles,(network)
Two energy-requiring active transport systems take part in secretion of
drugs:
a. For anions (deprotonated forms of weak acids)
b. For cations (protonated forms of weak bases).
Each of these transport systems shows low specificity and can transport
many compounds.
Thus, competition between drugs for these carriers can occur within each
transport system.
73

74. 3.Distal tubular reabsorption:
As a drug moves toward the distal convoluted tubule, its concentration
increases and exceeds that of the perivascular space.
The uncharged drug may diffuse out of the nephric lumen, back into the
systemic circulation.
Manipulating the urine pH to increase the fraction of ionized drug in the
lumen may be done to minimize the amount of back diffusion and increase
the clearance of an undesirable drug.
As a general rule, weak acids can be eliminated by alkalinization of the
urine,whereas elimination of weak bases may be increased by acidification of
the urine. This process is called “ion trapping.”
For example,a patient presenting with phenobarbital (weak acid) overdose
can be given bicarbonate, which alkalinizes the urine and keeps the drug
ionized, thereby
P re s en t ed by : P r o f .M i rz a Anwar
75
Baig

75. 4.Role of drug metabolism:
chemical
are lipid soluble and, without
the
tubular
lumen
to
Most drugs
modification,
perivascular
would diffuse from
space (why) due to concentration gradient
between the drug concentration in the filtrate and perivascular
space.
To minimize this reabsorption, drugs are modified primarily in
the liver into more polar substances via phase I and
phase II reactions.
The polar or ionized conjugates are unable to back diffuse out
of the kidney lumen.
75

76. Summery Drug
elimation:
76

77. VII. CLEARANCE BY OTHER ROUTES
Drug clearance may also occur via the intestines, bile, lungs, and breast,milk
etc.
Drugs that are not absorbed after oral administration or drugs that are secreted
directly into the intestines or into bile are eliminated in the feces.
The lungs are primarily involved in the elimination of anesthetic gases (for
example, isoflurane).
Elimination of drugs in breast milk may expose the breast-feeding infant to
medications and/or metabolites being taken by the mother and is a potential
source of undesirable side effects to the infant.
Excretion of most drugs into sweat, saliva, tears,hair, and skin occurs only to a
small extent.
Total body clearance and drug half-life are important measures of drug
77

78. A.Total body clearance:
The total body (systemic) clearance, CL total , is the sum of
all clearances from the drug-metabolizing and drug-
eliminating organs.
The kidney is often the major organ of elimination. The liver
also contributes to drug clearance through metabolism and/or
excretion into the bile.
Total clearance is calculated using the following equation:
CL total = CL hepatic + CL renal + CL pulmonary + CL other
where CL hepatic + CL renal are typically the most important.
78

79. B.Clinical situations resulting in changes in drug half-life
• Adjustment in dosage is required when a patient has an abnormality.
Increase in drug half-life include in case of
1) diminished renal or hepatic blood flow
2) decreased ability to eliminate drug from plasma
3) decreased metabolism,
These patients may require a decrease in dosage or less frequent dosing
intervals.
In contrast, the half-life of a drug may be
1) decreased by increased hepatic blood flow
2)decreased protein binding, or increased metabolism.
This may necessitate higher doses or more frequent dosing intervals.
79

80. 80
FACTORS MODIFYING
DRUG ACTION

81. 81
Factors:
1. Body weight
2. Age
3. Sex
4. Species and race
5. Genetics
6. Route of administration
7. Environmental factors and time of administration
8. Psychological factor
9. Pathological states

82. 82
Introduction:
 Variation in response to the same dose of a drug between different
patients and even in the same patient on different occasions was
observed.
 Categories of differences among individuals are responsible for
the variations in drug response:
(1) Individuals differ in pharmacokinetic handling of drugs:
(2) Variations in number or state of receptors, coupling proteins or other
components of response effectuation.
(3) Variations in neurogenic/hormonal tone or concentrations of specific
constituents, e.g. atropine tachycardia depends on vagal tone,
propranolol bradycardia depends on sympathetic tone

83. 83
The factors modify drug action either:
a) Quantitatively:
The plasma concentration of the drug is increased or decreased. Most
of the factors introduce this type of change and can be dealt with by
adjustment of drug dosage.
b) Qualitatively:
The type of response is altered, e.g. drug allergy or idiosyncrasy.
This
is less common but often precludes further use of that drug in
the affected patient.

84. Factors affecting dose response:
Fall in two categories
1. Genetic 2. Non genetic
Provide guidance for the selection of appropriate drug and
dose for an individual patient.
However, final adjustments have to be made by observing
the
response in a given patient on a given occasion.
84

85. Factors modifying drug action:
1. Body size:
It influences the concentration of the drug attained at the site of
action. The average adult dose refers to individuals of medium built.
For exceptionally obese or lean individuals and for children dose may be
calculated on body weight (BW) basis:
It has been argued that body surface area (BSA) provides a more accurate basis
for dose calculation, because total body water, extracellular fluid volume and
metabolic activity are better paralleled by BSA.
85

86. 86
2. Age:
Infants and children have important physiological differences from adults.
 The newborn has low g.f.r. and tubular transport is immature.
 The t1/2 of drugs excreted by glomerular filtration (gentamicin) and tubular
secretion (penicillin) is prolonged by 3 to 5 times.
 Glomerular filtration reaches adult rates by 5 month of age and
tubular secretion takes about 7 months to mature.
 Hepatic drug metabolizing system is inadequate in
newborns - chloramphenicol can produce gray baby syndrorne.
 Blood-brain barrier is more permeable-drugs attain higher concentration in
the CNS (accumulation of unconjugated bilirubin causes kernicterus).
 Drug absorptjon may also be altered in infants because of lower gastric
acidity and slower intestinal transit.
 Transdermal absorption,is faster because their skin is thin and more
permeable.

87. 87
 After the first year of life, drug metabolism is often faster than
in adults, e.g. theophylline, phenytoin, carbamazepine t1/2 is
shorter in children.
 Solid dosage forms and aerosol inhalations are difficult to
administer to young children.
 Children are growing and are susceptible to special adverse
effects of drugs eg: suppression of growth can occur with
corticosteroiods.
 In the elderly, renal function progressively declines (intact
nephron loss) so that is - 75% at 50 years and - 50% at 75
year'
compared to young adults. Drug doses has to be reduced

88. consideration must alsoPbreesgenivteednbyt:oPmrofe.MnisrztaruAantwioarn,
pregnancy and lactation8.9
Baig
3. Sex
a. Females have smaller body size and require doses that are on the lower
side
of the range.
b. Subjective effects of drugs may differ in females because of their mental
makeup .
c. Maintenance treatment of heart failure with digoxin is reported to be
associated with higher mortality among women than among men.
d. A number of antihypertensives ( clonidine, methyldopa, Beta-blockers,
diuretics) interfere with sexual function in males but not in females .
e. Gynaecomastia is a side effect (of ketoconazole,
metoclopramide, chlorpromazine, digitalis) that can occur only in
men.
f. Ketoconazole causes loss of libido in men but not in women.
g. Androgens are unacceptable to women and estrogens to men. In

89. 89
Drugs given during pregnancy can affect the
foetus . during pregnancy,
There are marked and progressive physiological changes
especially in the third trimester, which can alter drug disposition.
(i) Gastrointestinal motility is reduced -> delayed
absorption administered drug.
of orally
(i) Plasma and extracellular fluid volume expands-volume of drug distribution may
increase.
(ii) While plasma albumin level falls, -the unbound fraction of acidic
drugs
increases but that of basic drugs decreases.
(iii) Renal blood flow increases markedly polar drugs are eliminated faster.
(iv)Hepatic microsomal enzymes undergo induction-many drugs are metabolized
faster.
Thus, the overall effect on drug disposition is complex and often difficult to
predict.

90. 90
4. Species and race
• Rabbits are resistant to atropine.
• Rats and mice are resistant to digitalis and rat is more sensitive to curare
than cat.
• These differences are important while extrapolating results from
experimental animals to man.
• Blacks require higher and Mongols require lower concentrations of atropine
and ephedrine to dilate their pupil.
• Beta-blockers are less effective as antihypertensive in AfroCaribbeans.
• Indians tolerate thiacetazone better than whites.

91. 5. Genetics
The dose of a drug to produce the same effect may vary by 4--6 fold
among different individuals.
All key determinants of drug response, viz. transporters,
metabolizing enzymes, ion channels, receptors with their couplers
and effectors are controlled genetically.
The study of genetic basis for variability in drug response is
called 'Pharmacogenetics'.
As the genomic technology has advanced, gene libraries and huge data
bases (like 'pharmacogenetics and pharmacogenomics knowledge base',
'Human genome variation database', etc.) have been created aiming at
improving precision in drug therapy.
91

92. 92
6. Route of administration
• It governs the speed and intensity of duration of response.
• Parenteral administration is often resorted to for more rapid,
more
pronounce and more predictable drug action.
• A drug may have entirely different uses through different routes,
e.g. magnesium sulfate given orally cause: purgation, applied
on sprained joints-decreases swelling, intravenously it produces
depression and hypotension.

93. 7. Environmental factors and time of administration
Exposure to insecticides, carcinogens,tobacco smoke and consumption of
charcoil,broiled meat are well known to induce drug metabolism.
8. Psychological factor:
Efficacy of a drug can be affected by patient's beliefs, attitudes
and expectations.
This is particularly applicable to centrally acting drugs, e.g. a nervous
and anxious patient requires more general anaesthetic; Alcohol generally
impairs performance.
Punishment (which induces anxiety) is introduced, it may actually
improve
performance.
93