General pharmacology modified__ppt[1]

Introduction
• Definition and Scope of Pharmacology
• Pharmacology came from the Greek words “Pharmacon” meaning
drug or medicine and “logos” meaning the truth about or a rational
discussion
• It is the study of substances that interact with living systems
through chemical process, especially by binding to regulatory
molecules and activating or inhibiting normal body process
• It also includes history, source, physicochemical properties, dosage
forms, routes of administration , absorption, distribution,
mechanisms of action, biotransformation, excretion, clinical uses, and
adverse effects of drugs
2

 Since the dawn of civilization, herbal drugs and other
natural source materials have been used for the
alleviation of human suffering
 "Traditional" systems of medicine were developed by all
civilizations
 Pan Tsao is the great herbal "materia medica" of China.
Sken Ming probably wrote it in 2735 B.C.
 It contained many vegetable and mineral
preparations as well as a few animal products
 Ayurveda contains the earliest Indian records of
"traditional" medicine
It dates back to 2500 BC.
3

 Eber's Papyrus is the first written account of medical
experiences from Egypt
It contains more than 700 prescriptions
 Hippocrates (a Greek physician of 5th century B.C.)
is known as the Father of Modern Medicine, because
he organized the science of medicine on the basis
of analysis, observations and deductions
 Theophrastus (300 BC) is called the Father of
Pharmacognosy because of his accurate
observations of medicinal plants 4

 Galen, a Greek pharmacist physician (131-201 AD),
introduced the concept of polypharmacy
He wrote 200 books which included preparations of crude
vegetable drugs
His name is retained in the term "galanical" pharmacy
 Paracelsus (1493-1541 AD) criticized the Galenic
system of polypharmacy and introduced the use of
simple chemicals for treating diseases such as
mercurials in the treatment of syphilis
5

• Clinical pharmacology: It evaluates the
pharmacological action of a drug’s, preferred
route of administration and safe dosage range in
humans by clinical trials
• Molecular Pharmacology: study of the
biochemical and biophysical characteristics of
interactions between drug molecules and those
of the cell
• Drug receptor interaction 6

• Pharmacogenomics (pharmacogenetics)
o It is the study of the genetic variations that cause
differences in drug response among individuals
or population
o Future clinicians may screen every patient for a
variety of such differences before prescribing a
drug
• Biochemical Pharmacology
o It studies of how drugs act with and influence the
chemical ‘machinery’ of the organism
o Eg. signal transduction through G proteins
7

• Pharmacotherapeutics
o It is the use of drugs to diagnose, prevent, mitigate or
treat disease or to prevent pregnancy
o It deals with the proper selection and use of drugs for the
prevention and treatment of disease
• Chemotherapy
o It deals with the effect of drugs upon micro organisms,
parasites and neoplastic cells living and multiplying in
living organism
8

• Toxicology
 It is the branch of pharmacology which deals with
undesirable effects of chemicals on living systems, from
individual cells to complex ecosystems
 It is the science of poisons
 Many drugs in larger doses may act as poisons
 Poisons are substances that cause harmful, dangerous or
fatal symptoms in living substances
9

Pharmacology boundaries and Its Link with Other Biomedical
Disciplines
10

…
Definition of selected terminologies
Two basic areas of pharmacology:
• Pharmacokinetics: deals with absorption, distribution,
biotransformation and excretion of drugs (“i.e what the
body does to the drug”)
• Pharmacodynamics: the study of biochemical and
physiological effects of drugs and their mechanisms of
action (i.e, “what the drug does to the body”)
11

 It is a chemical substance of known structure, other than a
nutrient or an essential dietary ingredient
 It is chemical substance, which interacts with living
organisms and produce some pharmacological effects
 In the great majority of cases, drug interacts with a specific
molecule in a biological system that plays a regulatory-role
(receptor)
 Drugs may be synthesized within the body (e.g., hormones)
or may be chemicals not synthesized in the body, i.e.
xenobiotics
12

 It is any chemical which is used in prevention, diagnosis, treatment
and maintenance of health by altering body function
 A drug is thus any chemical which alters the function of a living
system
 They may produce a beneficial effect (a therapeutic effect) or an
undesirable (adverse/toxic effect)
MEDICINE
 a chemical preparation which usually but not necessarily contain
one or more drugs
 Mostly, Drug + additives
13

POISONS
 Are drugs or substances that have almost exclusively
harmful effects
 However, Paracelsus (1493–1541) famously stated that "the
dose makes the poison," meaning that any substance
can be harmful if taken in the wrong dosage
TOXINS
 They are usually defined as poisons of biologic origin, i.e.,
synthesized by plants or animals, in contrast to inorganic
poisons such as lead and arsenic 14

Sources of drugs
 Until the end of the 19th century, medicines
were natural organic or inorganic products,
mostly dried, but also fresh, plants or plant
parts
 These might contain substances possessing
healing (therapeutic) properties or
substances exerting a toxic effect
 Drugs are obtained mainly from plants,
animals, microbes and mineral sources
 However, a majority of them that are used
therapeutically at this time are from
synthetic or semi-synthetic products 15

Plant origin
• Any part of plant may be useful
• The pharmacologically active components in vegetable drugs are:
 alkaloids :
– Opium (Papaver somniferum): Morphine group
– Cinchona (Cinchona officinalis): Quinine etc.
– Belladonna (Atropa belladonna): Atropine group.
– Pilocarpus sp.: Pilocarpine.
– Vinca (Vinca rosea): Vincristine, vinblastine.
– Rauwolfia serpentina (root): Reserpine.
– Coca (Erythroxylum coca): Cocaine
 Glycosides :
– Digitalis (Digitalis purpurea, Digitalis lanata): Digoxin etc.
16

Animal sources
 Different animal products after purification in a suitable
dosage form for the treatment of disease are
• hormones e.g. Insulin from cows and pigs
• vitamins e.g. A and D from fish oil
• Immunoglobulins
17

Microorganisms
• The different classes of drugs obtained/ isolated from microbes are:
o Penicillin: Penicillium chrysogenum and notatum (Fungus).
o Streptomycin: Streptomyces griseus (Actino-mycetes).
o Erythromycin: Streptomyces erythreus (Actinomycetes).
o Chloramphenicol: Streptomyces venezuelae (Actinomycetes).
o Tetracyclines: Streptomyces aureofaciens and rimosus (Actinomycetes).
o Polymyxin B: Bacillus polymyxa.
o Bacitracin: Bacillus subtilis
o Nystatin: Streptomyces nouresi
o Griseofulvin: Penicillium griseofulvum.
o Streptokinase, an enzyme from gram positive cocci (S. pyogenes).
18

• Minerals:-
o Liquid paraffin, FeSO4, magnesium trisilicate, etc
• Semi synthetic and synthetic chemicals
o Also used as a source of drugs, but needs sophisticated
equipment and highly skilled personnel
o Eg. Synthetic agents: Aspirin, sulphonamides, paracetamol,
zidovudine, etc.
o Out of all the above sources, majority of the drugs currently
used in therapeutics are from synthetic source
• Genetic engineering: Human insulin, human growth hormone
etc
19

The Nature of Drugs
 To interact chemically with its receptor, a drug molecule must have the
appropriate:
– Size
– Electrical charge
– Shape
– Atomic composition
 A drug is often administered at a location distant from its intended site of
action, eg, a pill given orally to relieve a headache
 Therefore, a useful drug must have the necessary properties to be:
 Transported from its site of administration to its site of action
 Inactivated or excreted from the body at a reasonable rate so that its
actions will be of appropriate duration
20

a) The physical nature of drugs
 Drugs may be solid at room temperature (eg, aspirin,
atropine), liquid (eg, nicotine, ethanol), or gaseous
(eg, nitrous oxide,halothane)
 These factors often determine the best route of
administration
 A number of useful or dangerous drugs are inorganic
elements, eg, lithium, iron, and heavy metals
 Many organic drugs are weak acids or bases
 This factor has important implications for the way
they are handled by the body
 Because pH differences in the various compartments of the
body may alter the degree of ionization of such drugs
21

b) Drug size
 The molecular size of drugs varies from very small (lithium
ion, MW 7) to very large (eg, alteplase [t-PA], a protein of
MW 59,050)
 However, most drugs have molecular weights between
100 and 1000
 To have a good "fit" to only one type of receptor, a drug
molecule must be sufficiently unique in shape, charge,
and other properties, to prevent its binding to other
receptors 22

 To achieve such selective binding, it appears that a
molecule should in most cases be at least 100 MW units
in size
 Drugs much larger than MW 1000 do not diffuse readily
between compartments of the body
 Therefore, very large drugs (usually proteins) must often
be administered directly into the compartment where
they have their effect
 Eg. Alteplase is administered directly into the vascular
compartment by intravenous or intra-arterial infusion 23

c) Drug reactivity and drug-receptor bonds
 Drugs interact with receptors by means of chemical
forces or bonds
 Some of these bonds are : covalent, electrostatic,
hydrogen bond and hydrophobic
 Covalent bonds are very strong
In many cases not reversible under biologic conditions
It is formed between the acetyl group of aspirin and its
enzyme target in platelets, cyclooxygenase
 It is reversed only by the synthesis of new enzyme in
new platelets, a process that takes about 7 days
 Other examples of highly reactive, covalent bond-
forming drugs are the DNA-alkylating agents used in
cancer chemotherapy to disrupt cell division in the
tumor
24

 The drugs that bind through weak bonds to their
receptors are generally more selective than drugs
that bind by means of very strong bonds
 This is because weak bonds require a very
precise fit of the drug to its receptor
 Thus, if we wished to design a highly selective
short-acting drug for a particular receptor
we would avoid highly reactive molecules that
form covalent bonds and instead choose
molecules that form weaker bonds
25

d) Drug shape
 The shape of a drug molecule must be permit binding of a
drug to its receptor site
 The drug's shape is complementary to that of the
receptor site in the same way that a key is
complementary to a lock
 The phenomenon of chirality (stereoisomerism) is so
common in biology
 Because more than half of all useful drugs are chiral
molecules - they exist as enantiomeric pairs
 One of these enantiomers is much more potent than its
mirror image enantiomer, reflecting a better fit to the
receptor molecule
26

 For example, the (S)(+) enantiomer of methacholine, a
parasympathomimetic drug, is over 250 times more
potent than the (R)(-) enantiomer
 Ketamine is an intravenous anesthetic
The (+) enantiomer is a more potent anesthetic and is less toxic
than the (-) enantiomer
Unfortunately, the drug is still used as the racemic mixture
 Enzymes are usually stereoselective, one drug enantiomer
is often more susceptible than the other to drug-
metabolizing enzymes
 As a result, the duration of action of one enantiomer may
be quite different from that of the other
27

e) Rational drug design
 Rational design of drugs implies the ability to predict the
appropriate molecular structure of a drug on the basis of
information about its biologic receptor
 Until recently, no receptor was known in sufficient detail
to permit such drug design
 Instead, drugs were developed through random testing of
chemicals or modification of drugs already known to have
some effect
 Computer programs are now available that can iteratively
optimize drug structures to fit known receptors
 As more becomes known about receptor structure,
rational drug design will become more common
28

• Each drug has many names
• There are three common names for drugs on the market:
 Chemical name
 Generic name
 Brand name
 Chemical name
 It is given based on the structure of the drug
 It is used primarily by researchers
 A drug's chemical name is long and usually difficult to pronounce and
remember
 It indicates the chemical entity present in the drug, only one
chemical name for a drug
 It indicates atomic and molecular structure of a drug
 It is given as a chemical formula or accompanied by a diagram of its
structure
 e.g. Acetyl salicylic acid(C6H4OHCOOCH5) 29

• Chemical names are not given in any of the standard manuals,
such as the
 Physicians' Desk Reference
 official books like United States Pharmacopeia (USP), or
available software
Generic Name
 It is drug’s official name
 It is the common name throughout its lifetime all
over world:
regardless of who made it, how it was made, where it
was devised
 Nonproprietary name of a compound used
medicinally
30

 It is commonly used by health care professionals
 It is usually created when a new drug is ready to be
marketed
– The U.S. adopted name (USAN) council is responsible for
creating and assigning a functional generic name to the
drug
– Before approval by council:
 The generic name must be screened to ensure that it
does not look or sound too similar to any other
generic or brand name
It must also be considered appropriate for the specific
drug
 After approving the generic name, the council submits the
name to WHO, which has final approval 31

– After being approved by WHO, the drug is
assigned an international nonproprietary name
i.e. generic name
– The most important criterion considered when
issuing a generic name is the usefulness of that
name to health care providers
– The name should be:
short
easy to pronounce
Euphonic (having a pleasant sound)
E.g. Aspirin is the generic name of ASA
32

Brand name
 Also known as trademarks and proprietary names
 The FDA must approve the name
 The USAN council is also actively involved in selection
of brand name
 Specific generic drug may have many different trade
names
 Name by manufacturer company, several name for
single drug may occur, have letter ®, expensive
 The difference between generic product and brand
product is only the additives but not active ingredient
E.g. trade names of aspirin include Ascriptin, Bayer
Aspirin, Bufferin, Easprin and Zorprin
33

Pharmacokinetics
– It deals with the quantitative, time-dependent
changes of both the plasma drug concentration
and the total amount of drug in the body,
following the drug's administration by various
routes
– The absorption, distribution, metabolism
(biotransformation), and elimination of drugs are
the processes of pharmacokinetics
34

• Applications of pharmacokinetics studies include:
o Bioavailability measurements
o Effects of physiological and pathological
conditions on drug disposition and absorption
o Dosage adjustment of drugs in disease states, if
and when necessary
o Correlation of pharmacological responses with
administered doses
o Evaluation of drug interactions
o Clinical prediction: using pharmacokinetic
parameters to individualize the drug dosing
regimen and thus provide the most effective
drug therapy’’
35

ROUTES OF DRUG ADMINISTRATION
1. Enteral Routes
i. Oral Route
• This is the most commonly used route for drug
administration
• It is also the safest, most convenient and
economical
• But, there are some limitations of this route:
Drug action is slow, thus not suitable for
emergencies
Incapability to absorb some drugs, due to their
physical characteristics i.e. polarity of the drug 36

 Unpalatable and other irritant drugs cannot be
administered
 Cannot be used for unconscious and uncooperative
patient
 May not be useful in the presence of vomiting and
diarrhea
 Drugs, which can be destroyed by digestive juices (i.e.
insulin, penicillin G) or in liver (i.e. testosterone,
nitroglycerine) cannot be administered orally
 The absorption of certain drugs is negligible e.g.
streptomycin
 High first pass effect
37

ii. Sublingual Administration
• The highly lipid soluble and nonirritating drugs (i.e.
nitroglycerine, isoprenaline, ethyltestosterone) in the form
of tablets or pellet is placed under the tongue
• They rapidly dissolve in saliva and are absorbed quickly in the
general circulation due to the presence of the extensive
network of blood vessels facilitates rapid drug absorption
The advantages of this route are:
– Rapid onset of action
– The degradation and metabolism of the drugs in the stomach
and liver is avoided (No first pass effect)
39

iii. Rectal administration
• Used for drugs that produce
– Local effect e.g. anti inflammatory drugs
– Systemic effect -important in administering diazepam to
children who are in status epilepticus
• Absorption following rectal administration is
often unreliable
• Usually useful in patients who are vomiting or
are unable to take medication by mouth
40

2. Parenteral Routes
• (par = beyond, enteral = intestinal)
• The administration of drugs by injection directly into the tissue fluid
or blood without having to cross the intestinal mucosa
The advantages of parenteral routes are:
Rapid onset of action of drug
Can be employed in unconscious/ uncooperative patients.
Drugs, which are modified by alimentary juices and liver, can
be given by this route
Drugs, which are not absorbed in small intestine or irritate the
stomach, can be administered by this route
41

• Disadvantages are:
Less safe, more expensive
Inconvenient (painful) for the patient
Self medication is difficult
Chances of local injury at the site of injection
microbial contamination, and nerve damage
42

• The important parentral routes are:
i. Subcutaneous
The non-irritant substances can be injected by this route.
The rate of absorption of drug is constant and slow to provide a
sustained effect
The site of injection is usually the outer surface of the arm, or front of
the thigh
Self medication (e.g. insulin) is possible because deep penetration is
not needed.
Other drugs which are administered subcutaneously are adrenaline,
morphine and certain hormonal preparations
Absorption is limited by blood flow, affected if circulatory problems
exist.
Concurrent administration of vasoconstrictor will slow
absorption
43

• Advantage
– Suitable for some poorly soluble suspensions and
for instillation of slow-release implants
• Disadvantage
– Not suitable for large volumes
– Possible severe pain, necrosis, and tissue
sloughing may occur
44

ii. Intramuscular
• The soluble substances, mild irritants and
suspensions can be injected by this route in the
large skeletal muscles (deltoid, triceps, gluteus
maximus, rectus femoris etc)
• These muscles are less richly supplied with
sensory nerves and are more vascular, so
irritant solutions can be injected
• Small volumes (up to 2 ml) are injected into the
deltoid muscle, and small or large volumes (up to
10 ml) are injected into the gluteal mass 45

• Advantages
 Rate of absorption is uniform
 Onset of action is faster than oral
 Suitable for administering drugs for
unconscious patient
46

Intravenous
The drug is injected as a bolus or infused
slowly directly into a vein to produce rapid
action
It is also useful for certain irritant and
hypertonic solutions
Drugs in an oily vehicle or those which
precipitate blood constituents or
hemolyze erythrocytes should not be
given by this route
47

This route is usually reserved for
 Emergencies when a rapid action is required
 Infusion of large amounts of fluids to overcome
dehydration or to supply nutrition to
patients who cannot take food/fluids orally
But, at the same time, it is the most
dangerous route of administration
So, intravenous injection must usually be
performed slowly and with constant
monitoring of the patient
48

iii. Intradermal
 This route is employed for vaccination e.g. BCG vaccine
and for testing the sensitivity e.g. penicillin injection
iv. Intra-arterial
 This route is useful in diagnostic studies, by which
arterial blood sample may be withdrawn for blood gas
studies
 Certain cytotoxic compounds are administered by intra-
arterial perfusion in localized malignancies
 Eg. such as in the treatment of liver tumors and head/neck
cancers
 Intra-arterial injection requires great care and should be
reserved for experts
49

v. Intrathecal or Intraspinal
– For local and rapid effect of drugs on the meninges or
cerebrospinal axis, drugs are injected directly into
the spinal subarachnoid space
– This is also used:
 To produce spinal anaesthesia
For introduction of a radio-opaque contrast medium into
the subarachnoid space for visualizing the spinal cord
vi. Intra-cardiac
• In sudden cardiac arrest and other cardiac
emergencies, the adrenaline is directly injected
into the heart by a long needle in the left fourth
inter-costal space close to the sternum 50

vii. Intraperitoneal
– This route is a common laboratory procedure, but it is
seldom employed
– clinically in infants for giving fluids like glucose/
saline, as the peritoneum offers a large surface for
absorption
viii. Intra-articular
– Certain drugs (i.e. glucocorticoids) can be administered
directly into a joint space for the treatment of local
condition i.e. rheumatoid arthritis
51

3. Inhalation Route
 Drugs may be administered as aerosols and
gases (volatile substances)
 It is absorbed through the pulmonary epithelium
and mucous membranes of the respiratory tract
 Access to the circulation is rapid by this route
because the lung's surface area is large
 The principles governing absorption and excretion
of anesthetic and other therapeutic gases
52

Advantages
 avoidance of hepatic first-pass loss
 Localize the action of the drug at the desired site
of action
 Rapid onset of action due to rapid access to
circulation
 Particularly effective and convenient for patients
with respiratory complaints. E.g. asthma
Disadvantages
 Needs special apparatus
 Drugs may be irritants to the mucus membrane53

Topical /Local Route
 The absorption through skin is a passive process.
 This is due in large part to the relatively close-packed cellular
arrangement and decreased amount of lipid in these cells
 The diffusion rate of a drug through the skin is largely determined by the
compound’s lipid–water partition coefficient and the hydration state
of skin
 Thus, even highly lipid-soluble compounds will be absorbed much more
slowly through the skin than from other sites
 Drugs are applied to the mucous membranes of the conjuctiva,
nasopharynx, vagina, colon, urethra & urinary bladder primarly for
their local effects
 E.g. dusting powder, paste, lotion, drops, ointment 54

Pharmaceutical Dosage Forms
55
 Dosage forms are different preparations of a drug which
help to facilitate drug administration & delivery
 An ideal dosage form should:
Deliver the right amount of the drug to the right site
Minimize drug exposure to unwanted sites
Associated with minimal discomfort or inconvenience
Be economical & need lesser expertise knowledge
But there is no such ideal dosage form

56
 Four types of dosage forms exist
Solid dosage forms
Semisolid dosage forms
Liquid dosage forms
Gaseous dosage forms

57
• are those drug preparations which exist as solids
• exist in different forms/preparations
1. Tablets
• are most common forms of solid dosage forms
• Written as tab or tabs on prescriptions
• Several kinds of tablets are available
Scored tablets
Enteric coated tablets
Sustained release tablets
Caplets-oval medicinal tablet

Solid dosage forms………..
58
2. Lozenges
– are sweet tablets containing sugar, water & flavoring agents
– are to be chewed/held in the mouth not swallowed
3. Pellets/beads
– Prepared as sheets or beads for sustained release of drugs
E.g. Norplant
4. Powders (internal use)
– Are solid preparations which need to be reconstituted
before use
E.g. penicillin injection
5. Suppositories & Pessaries
– used for local effects, or for children, vomiting &
unconscious patients

59
6. Capsules
 Written as cap or caps
 Prepared in two forms
Soft capsules
 are made of soft gelatin
 Contain liquid inside & are sealed
 E.g. Vitamin A & E capsules
Hard capsules:
 are made of hard gelatin
 Contain two separable pieces or cups
 Contain powder or granules inside
E.g. Amoxicillin, tetracycline capsules

Semi-solid dosage forms
60
 are dosage forms that are too soft to be solid and too hard to be liquid
 are mainly used for topical administration
It includes:
Creams
 are semisolid emulsions of oil & water
 water is the main ingredient
E.g. hydrocortisone cream
Ointments
 are semisolid preparations
 Oil is the main ingredient
E.g. tetracycline ointment
Pastes

61
 Are found in liquid states
 Can be either clear solutions, suspensions or emulsions
 Solutions
• are clear mixtures/fluids
• They don’t need to be shaken/mixed even after
long period of storage
• They are of different forms
Elixirs
–are clear solutions which contain alcohol &
water as solvent
–also contain flavoring agents
–are mainly used for pediatric use

62
 Syrups
• are also clear solutions which contain water, sugar &
flavoring agent
• don’t contain alcohol
E.g. multivitamin syrup
 Tinctures
• are clear solutions which contain both water & alcohol as
solvent
• But, unlike elixirs, they are used for external use and
don’t contain flavoring agent
E.g. iodine tincture
 Miscellaneous solutions
• Includes injectable clear solutions, large volume
preparations E.g. gentamicin injection, glucose
preparations

63
 Suspensions
 are not clear liquids
 Contain fine, undissolved drug particles suspended in a
liquid
 Shaking is necessary before use since the solid particles
sediment upon storage
E.g. antacid suspensions
 Emulsions
 Contain oil and water with emulsifying

Gaseous dosage forms
64
 Contain medical gases & aerosols
Medical gases:
 are preparations for intrapulmonary administration
 are inhaled through breathing apparatus
 The active ingredient is found as gas or volatile liquid
E.g. inhalational anesthetics
Aerosols:
 are another gaseous dosage forms
 Contain an active drug suspended in a gaseous vehicle
 are dispersions of solid particles or liquid droplets in a
gaseous vehicle

• Most drugs after administered to the body they undergo
two major processes:
• Pharmacokinetics process: - process that involve
absorption, distribution, metabolism, and excretion
– What the body does to the drug
• Pharmacodynamics process:- process that involve
receptor – drug interaction which determines types
and selectivity of the drug effect and quantitative
determination of drug effect
– What the drug does to the body
65

 To produce its characteristic effects, a drug must be presented in
appropriate concentration at its site of action
 In a few situations, it is possible to apply a drug directly to its
target tissue
 eg, by topical application of an anti-inflammatory agent to inflamed skin
or mucous membrane
 Most often, a drug is administered into one body compartment, e.g,
the gut, and must move to its site of action in another
compartment
 e.g, the brain in the case of an antiseizure medication
67

 This requires that the drug should be absorbed
into the blood from its site of administration and
distributed to its site of action
 Finally, after bringing about its effect, a drug
should be eliminated at a reasonable rate by
metabolic inactivation
68

Passage of drugs across a biological-membrane
• All the pharmacokinetic processes involve the penetration
of drug across cell membranes
• The characteristics of a drug that predict its movement and
availability at sites of action are
 its molecular size and shape
 degree of ionization
 relative lipid solubility
 its binding to serum and tissue proteins
69

Structure of biological membrane
• Cell membranes are bilayer of amphipathic lipids
• Its hydrocarbon chains oriented inward to form a continuous hydrophobic
phase and their hydrophilic heads oriented outwards
• Intrinsic and extrinsic membrane proteins embedded in the bilayer serve
as
o Contributing structure to the membrane
o Acting as enzymes
o Acting as carrier
o Acting as a receptor
• Intrinsic proteins, which extend through the full thickness of the
membranes, surround fine aqueous pores
70

• Passage of drugs through cell membranes follows one or
a combination of the following major mechanisms.
Passive diffusion
Carrier mediated transport
Facilitated diffusion
Active transport
Endocytosis
Exocytosis
71

Fig. Mechanisms involved in the passage of drug across the biological
membrane
72

 Also called non-ionic diffusion, is the major (more than 90%)
mechanism for absorption of drugs
 The driving force for this process is the concentration gradient or
electrochemical gradient
 Defined as the difference in the drug concentration on either side of the
membrane
 It is energy independent and non-saturable process
 Drugs move down a concentration gradient
 Greater the area and lesser the thickness of the membrane, faster
the diffusion
 Greater the membrane/water partition coefficient of drug, faster
the absorption 73

Fick’s first law of diffusion
• Passive diffusion is best expressed by this law,
which states that drug molecules diffuse from a
region of higher concentration to one of lower
concentration until equilibrium is attained
• The rate of diffusion is directly proportional to
the concentration gradient across the
membranes
• Flux (molecules per unit time)= (C1–C2) x Area x Permeability Coefficient
Thickness
74

Where
– C1 is the higher concentration,
– C2 is the lower concentration,
– area is the area across which diffusion is
occurring,
– permeability coefficient is a measure of the
mobility of the drug molecules in the medium of
the diffusion path,
– Thickness is the thickness (length) of the
diffusion path
75

Aqueous Diffusion /filtration
• Requirements:
– Size of the drug should be less than size of pore (channel)
which is filled with water
– unbound to plasma protein
– has to be water soluble
 E.g. Na +, glucose, caffeine
• The capillaries of the brain, the testes, and some other tissues
are characterized by the absence of pores that permit
aqueous diffusion
 They may also contain high concentrations of drug export
pumps (MDR pumps)
76

Lipid Diffusion
 It is the most important limiting factor for drug permeation
 Determined by the lipid: aqueous partition coefficient of a drug
 As the lipid:aqueous partition coefficient increases, the diffusion rate
increases
 In the case of weak acids and weak bases, the ability to move from aqueous to
lipid or vice versa varies with the pH of the medium
 The ratio of lipid-soluble form to water-soluble form for a weak acid or
weak base is expressed by the Henderson-Hasselbalch equation
 The Henderson-Hasselbalch equation relates the ratio of protonated to
unprotonated weak acid or weak base to the molecule's pKa and the pH of the
medium as follows:
77

 Most of the uncharged form of weak base or
weak acid drugs are lipophilic
Therefore, more of a weak acid will be in the lipid-
soluble form at acidic pH, whereas more of a basic
drug will be in the lipid-soluble form at alkaline pH
 Trapping of weakly acidic and basic drugs in
body compartment depends on the PH of the
fluid
78

Fig: Trapping of a weak base in the urine when the urine is more acidic than the blood
79

 Important implications of Henderson–Hasselbalch
equation relation ship are:
1. Enhancing the urinary excretion of weak electrolytes
2. Ion trapping / pH partition
Manipulation of pH of urine can help in enhancing
urinary excretion of drugs in case of over dosage
Weak acids are excreted faster in alkaline urine
Weak bases are excreted faster in acidic urine
– Alkalinization of urine with Sodium bicarbonate can
promote excretion of weakly acidic drugs i.e Aspirin over
dosage.
– Acidification with Ammonium chloride can promote
excretion of weakly basic drugs i.e amphetamines and
opiates over dosage
82

– Forced alkaline diuresis was once extensively
used in drug overdosage, as with salicylates or
phenobarbital
However, it has little or no place in current therapy
– It is a potentially hazardous procedure
 Because it requires the infusion of relatively large
amounts of fluid and the use of loop diuretics or
mannitol
– In addition, pulmonary and cerebral edema are
possible complications, particularly in the elderly
83

Ion Trapping (pH partition )
– It means that weak acids tend to accumulate in
the compartments of relatively high pH whereas
weak basis do the reverse
– So drugs can be trapped due to pH difference in:
Stomach, intestinal contents
breast milk, prostatic/ vaginal secretions
– Increasing plasma pH causes weakly acidic drugs
to be extracted from the CNS into plasma
84

Carrier mediated transport
• Special carrier molecules exist for many
substances that are important for cell function
and too large or too insoluble in lipid to
diffuse passively through membranes
– eg, peptides, amino acids, and glucose
• Unlike passive diffusion, carrier mediated
transports are selective, saturable, and
inhibitable
• Many cells also contain less selective membrane
carriers that are specialized for expelling
foreign molecules
85

• One large family of such transporters
binds adenosine triphosphate (ATP) is
called the ABC (ATP-binding cassette)
family
Includes the P-glycoprotein or multidrug-
resistance type 1 (MDR1) transporter
found in the brain, testes, and other
tissues, and in some drug-resistant
neoplastic cells
The multidrug resistance-associated
protein (MRP) transporters play important
roles in the excretion of some drugs or their
metabolites into urine and bile 86

• Carrier mediated transport is of two types:
A. Active transport:
 It is characterized by
o It is movement of drugs against concentration gradient with the
help of carriers along with the expenditure of energy
o direct requirement for energy
o saturability
o selectivity
o Competitive inhibition by cotransported compounds
o Na/K+ ATPase is an active transport mechanism
E.g. alpha methyl dopa, levodopa, 5- fluoro – uracil, 5 –
bromouracil
87

B. Facilitated diffusion:
 Movement of drugs is along concentration
gradient but in a much faster rate than simple
diffusion
 No energy input is required
 The driving force for facilitated transport is the
concentration gradient
 E.g: TTCs, Pyrimidine 88

Endocytosis and Exocytosis
Endocytosis:
 The process by which the substance is bound at a cell-surface receptor,
engulfed by the cell membrane, and carried into the cell by pinching off of
the newly formed vesicle inside the membrane
 The substance can then be released inside the cytosol by breakdown of
the vesicle membrane
 Of two type:
 Adsorptive or pahagocytic uptake of particles that have been bound to
the membrane surface
 Fluid or pinocytotic uptake, in which the particle enters the cell as part
of the fluid phase
 Responsible for the transport of vitamin B12, complexed with a binding
protein (intrinsic factor) across the wall of the gut into the blood
89

• Exocytosis: is responsible for the secretion of many
substances from cells
– For example, many neurotransmitter substances are
released from the nerve ending by the fusion of their
vesicle
Characteristics Simple diffusion Facilitated Active transport
Incidence Commonest Less common Least common
Process Slow Quick Very Quick
Movement
Along concentration
gradient
Along concentration
gradient
Against
concentration90

 Movement of a drug from its site of administration
into the central compartment and the extent to
which this occurs
 The extent of drug absorption from GIT is limited by
the characteristics of the dosage form
 the drug's physicochemical properties,
a reverse transporter associated with P-glycoprotein
 metabolism
91

 Inhibition of P-glycoprotein and gut wall
metabolism, eg, by grapefruit juice, may
be associated with substantially
increased drug absorption
 The rate of absorption is determined by
– The site of administration and the drug
formulation
 Both the rate of absorption and the extent of
input can influence the clinical
effectiveness of a drug
92

Bioavailability (F)
 It is defined as the fraction of unchanged drug reaching the
systemic circulation following administration by any route
 The area under the blood concentration-time curve (AUC) is a
common measure of the extent of bioavailability for a drug given
by a particular route
 For an intravenous dose of the drug, bioavailability is assumed
to be equal to unity
 For a drug administered orally, bioavailability may be less than
100% for two main reasons—incomplete extent of absorption
and first-pass elimination
93

 Bioavailability of a drug administered orally is the ratio of
the AUC for oral administration compared with the AUC
for IV injection
 Bioavailability (F) =AUC after oral dose
AUC after IV dose
 AUC = area under curve – which provides information about
the amount of drug absorbed
94

Bioequivalence:
• Drug products are considered to be pharmaceutical equivalents if
they contain
 the same active ingredients
 are identical in strength or concentration, dosage form, and route of
administration
• Two pharmaceutically equivalent drug products are considered to
be bioequivalent when: the rates and extents of bioavailability
of the active ingredient in the two products are not
significantly different under suitable test conditions
95

First-pass elimination
 Following absorption across the gut wall, the portal blood delivers the
drug to the liver prior to entry into the systemic circulation
 A drug can be metabolized in the gut wall (eg, by the CYP3A4 enzyme
system)
 Even in the portal blood, but most commonly it is the liver that is
responsible for metabolism before the drug reaches the systemic
circulation
 In addition, the liver can excrete the drug into the bile
 Any of these sites can contribute to this reduction in bioavailability,
and the overall process is known as first-pass elimination
96

 The effect of first pass hepatic elimination on
bioavailability is expressed as the extraction ratio (ER):
• Where Q is hepatic blood flow and CL is clearance
• The systemic bioavailability of the drug (F) can be
predicted from the extent of absorption (f) and the
extraction ratio; F=f x (1-ER)
97

Factors affecting drug absorption and bioavailability:
A. Physico – chemical properties of drug:
 Physical state:
 Liquids are absorbed better than solids
 Crystalloids absorbed better than colloids
 Lipid or water solubility: -
 Drugs in aqueous solution mix more readily than that in oily
solution
 However, at the cell surface, the lipid soluble drugs penetrate
into the cell more rapidly than the water-soluble drugs
98

 Ionization:
Most of the drugs are organic compounds
Unlike inorganic compounds, the organic drugs are not
completely ionized in the fluid
Unionized component is predominantly lipid soluble and is
absorbed rapidly
An ionized is often water-soluble component which is
absorbed poorly
Most of the drugs are weak acids or weak bases
It may be assumed for all practical purposes, that the mucosal
lining of the GIT is impermeable to the ionized form of a
weak organic acid or a weak organic base
99

• These drugs exist in two forms
 Acidic drugs are rapidly absorbed from the stomach e.g.
salicylates and barbiturates
 Basic drugs are not absorbed until they reach to the
alkaline environment i.e. small intestine when
administered orally e.g. pethidine and ephedrine
100

B. Dosage forms
 Particle size:
 Small particle size is important for drug absorption
 Drugs given in a dispersed or emulsified state are
absorbed better e.g. vitamin D and vitamin A
 Disintegration rate and dissolution rate
 Disintegration rate: The rate of breakup of the tablet or
capsule into the drug granular
 Dissolution rate: The rate at which the drug goes into
solution
101

Formulation
 The type and amount of additives may affect the rate
of disintegration
 Usually substances like lactose, sucrose, starch and
calcium phosphate are used as inert diluents in
formulating powders or tablets
 Fillers may not be totally inert but may affect the
absorption as well as stability of the medicament
 Thus, a faulty formulation can render a useful drug
totally useless therapeutically
102

C. Physiological factors
 Gastrointestinal transit time/emptying time
 Rapid absorption occurs when the drug is given on empty
stomach
 However, certain irritant drugs like salicylates and iron
preparations are deliberately administered after food to
minimize the gastrointestinal irritation
 But, sometimes the presence of fatty food in the GI tract aids the
absorption of certain drugs e.g. griseofulvin, propranolol and
riboflavin
 Conditions that shorten intestinal transit time (diarrhea)
decrease the extent of drug absorption 103

Presence of other agents
 Vitamin C enhances the absorption of iron from the
GIT
 Calcium present in milk and in antacids forms
insoluble complexes with the tetracycline
antibiotics and reduces their absorption
Area of the absorbing surface and local
circulation:
 Drugs can be absorbed better from the small
intestine than from the stomach because of the
larger surface area of the former
 Increased vascular supply can increase the
absorption 104

Enterohepatic recirculation:
 Some drugs move in between intestines and liver before
they reach the site of action
 This increases the bioavailability E.g. Phenolphthalein,
mefloquine
105

Metabolism of drug /first pass effect:
 The presence of drug metabolizing enzyme and efflux
transporters (p-glycoprotein) on the enterocytes
reduce the bioavailability
 Rapid degradation of a drug by the liver during the first
pass (propranolol) or by the gut wall (Isoprinosine) also
affects the bioavailability
 Thus, a drug though absorbed well when given orally
may not be effective because of its extensive first pass
metabolism
106

D. Pharmacogenetic factors
 Parmacogenomics (pharmacogenetics) is the study of the
genetic variations that cause individual differences in
drug response
 Individual variations occur due to the genetically
mediated reason in drug absorption and response
E. Disease states:
 e.g. Malabsorption syndromes affect the rate and extent
of absorption
107

 It is the process by which absorbed drug or drug
directly introduced into the circulation is carried to
various interstitial and cellular fluids
 It is the delivery of drugs from systemic circulation
to tissues
 It is penetration of a drug to the sites of action
through the walls of blood vessels from the
administered site after absorption
 Distribution of drugs is random (every tissues have
equal chance)
108

• Concentration of drugs in different tissues differ due to
different factors:-
Plasma protein binding
Tissue uptake (affinity of drugs to tissue)
Physiological barriers
Tissue perfusion
109

Plasma protein binding
 Many drugs circulate in the bloodstream bound to plasma proteins
 Plasma protein bound drugs are restricted to the vascular compartment
 Bound fraction is not available for action, metabolism and excretion
 Binding of drugs to plasma proteins assists absorption
 Protein binding acts as a temporary store of a drug and tends to
prevent large fluctuations in concentration of unbound drug in the
body fluids
 Drug in systemic circulation exist as bound and unbound form
 Drugs ordinarily bind with plasma protein in reversible fashion and in
dynamic equilibrium
 D + P →[DP] → D + P
110

 As free drugs leave the systemic circulation the
bound drug dissociate
 Factors affecting drug plasma protein binding are:
Drug affinity for binding site
Number of binding site
Since drug binding is saturated process --- ↑ in site of
binding --- ↑ binding
Drug concentration
 The plasma proteins includes albumin, α1-acid
glycoprotein, globulin, etc
 Albumin is a major carrier for acidic drugs
 α1-acid glycoprotein binds basic drugs like
imipramine
111

Some factors affect the binding of drugs with albumin:
 Age
 Pregnancy
 Disease state:
Hyperalbuminemia
Hypoalbuminemia
Hyperbilirubinemia
Liver disease
 Plasma protein binding is clinically important
for those drugs which have high plasma protein
binding
Warfarin
Sulphonate
acetyl salicylic acid
phenytoin …. 112

2. Tissue uptake
 Drugs will not always be uniformly distributed to and retained by
body tissues
 Some drug will be either considerably higher or considerably lower
in particular tissues
 This is due to tissue difference in affinity to the drugs
 Adipose tissue : drugs with extreme lipid solubility (excellent lipid
water partition coefficient)
 May result :–
• decrease therapeutic activity
• Prolonged activity
• Toxicity
113

 Kidneys : contain proteins, methallothionein, that have high
affinity for metals
 Cadmium, Lead, Mercury accumulation -----toxicity
 Eye – drugs which have affinity for retinal pigment, accumulate in
the eye
 Chlorpromazine (other phenothiazine) and chloroquine---accumulate in eye
 Bone- TTC, Lead, Cisplatin
 TTC accumulation may cause dysplasia, poor bone development
 Lead accumulation result bone brittleness (displace Ca2+ )
 Slow release of toxic effect may occur from lead and cisplatin accumulation
 Teeth –TTC accumulation result yellow- brown discoloration of teeth
 Liver – Chloroquine
114

 Generally tissue accumulation of drug may
have
 Advantageous effect
 target tissue therapy e.g. Chloroquine,
iodine
 sustained release effect, e.g. fat depot
 Disadvantageous effect---mainly toxicity
115

3. Physiological Barriers
a. Blood brain barrier (BBB)
 Transfer of drug to brain is regulated by BBB
 Ionized drug, Lipid insoluble drugs, bound drug do not cross BBB
 Inflammation such as due to meningitis or encephalitis increase
the permeability of BBB so permeating the passage of ionized , lipid
soluble drugs.
 E.g.:- penicillin G and ampicillin – not cross BBB ( highly ionized) but
inflammation– they can pass BBB --used for antibiotic effect centrally
 Pgp transport system: ↓ the concentration of some drugs in CNS
 Pump back to systemic circulation
116

b. Placenta blood barrier (PBB)
• Blood vessel of mother and fetus separated by PBB
• Highly polar and ionized drugs do not cross placenta readily
• Drugs with high lipid solubility shouldn't be given to pregnant
mother
 E.g. TTC–accumulate in bone and teeth of neonate—↓development of bone and
teeth
 CAF–cause gray baby syndrome
• Drug cross PBB and cause fetal abnormalities are called
teratogenic drug
c. Testicular barrier… ????
117

4. Tissue perfusion/ blood flow
 Different tissue have different rate and amount
of blood flow
 As blood flow increases, the drug distribution to
the tissue increases
Highly perfused tissue:- heart, lung, brain,
liver, kidney
Intermediate perfused tissue:- skeletal
muscle
Poorly perfused tissue:- skin, bone, nail, fat
tissue
118

• Volume of Distribution
– It is a measure of the apparent space in the body
available to contain the drug
– Vd relates a concentration of drug measured in the
blood to the total amount of drug in the body
– It gives a rough indication of the overall distribution
of a drug in the body
– In general, the greater the Vd, the greater the
diffusibility of the drug
– The volume of distribution is not an actual volume
– Because its estimation may result in a volume
greater than the volume available in the body (~40 L
in a 70-kg adult)
119

For example, a highly lipid-soluble drug, such as
thiopental, may have a Vd considerably in excess
of the entire fluid volume of the body
 Because of their physicochemical characteristics,
different drugs can have quite different volumes
of distribution in the same person
 Ibuprofen a NSAIDs, for example, typically exhibits
a volume of distribution of 0.14 L/kg such that for
a 70-kg person, the Vd would be 10.8 L
120

 In contrast, the antiarrhythmic amiodarone has a
Vd of 60 L/kg, giving a total Vd of 4200 L for this
same 70-kg person
 This large Vd suggests that amiodarone
distributes widely throughout the body
 Since the total volume of the body does not equal
4200 L, it can clearly be seen that this is not a
“real” volume
 Because the plasma volume of a typical 70-kg man
is 3 L, blood volume is about 5.5 L, extracellular
fluid volume outside the plasma is 12 L, and the
volume of total-body water is approximately 42 L
121

 Amount of drug in body /V= C
 Vd = amount of drug in body
C
 Where C- is concentration of drugs in blood or
plasma
 For example, if 500 mg of the cardiac glycoside
digoxin were in the body of a 70-kg subject, a
plasma concentration of approximately 0.75
ng/ml would be observed
 Vd= 500mg/0.75ng/ml=667L
 Therefore, volume of distribution for digoxin of
about 667 L
122

 Having high Vd –high distribution
 Vd is greater than total body H2O if the drug is lipophilic
and binds to tissue and vice versa
 Vd have inverse relationship with PPB
 ↑PPB ----- ↓Vd
 The apparent volume of distribution reflects a balance
between binding to tissues and binding to plasma protein
 Changes in either tissue or plasma binding can change the
apparent volume of distribution determined from plasma
concentration measurements
123

• Vd indicate where the:
– Drug having high PPB and/ or large molecular weight--
--mainly found in plasma ( Vd in plasma)
• Eg Warfarin, heparin
– Drug has large molecular weight and water soluble
drug have Vd at extracellular water
• E.g. Gentamicin
– Highly water soluble drug—Vd is in total body water
• E.g. ethanol, phenytoin
– Highly lipophilic drug have Vd to adipose tissue
• E.g. thiopental, DDT
124

METABOLISM OF DRUGS (BIOTRANSFORMATION)
 Drug biotransformation is a process by which drugs are
chemically changed in the body as a result of their
interaction with cells or tissues
 The purpose of biotransformation is to facilitate
excretion of drugs by rendering lipid soluble drugs
more polar (water soluble) or by conjugating it with
highly polar molecules
126

Fig: role of biotransformation
127

 Inactivation or decreased activity of parent drug (most
drugs)
 Conversion of inactive drug (prodrug) to more active drug
eg. Levodopa, Enalapril, Omeprazole
 Active metabolite/s from an active drug - e.g. Codeine 
morphine
 Maintenance of activity – e.g. diazepam
 Conversion of drug to its toxic metabolite - eg. Acetaminophen
128

 Introduce a polar functional group such as –OH, NH2 or –SH
or expose a functional group on the parent drug such as
occurs in hydrolysis reactions  convert the parent drug
to a more polar metabolite
 A functionalization or non-synthetic reaction since it
includes addition or exposure of functional group
 Produce more reactive metabolites and more hydrophilic
 Generally result in the loss of pharmacological activity,
although there are examples of retention, enhancement
or alteration of activity
129

Prominent reactions in this category include :-
• Oxidation:-
 microsomal oxidation involves the introduction of an oxygen and /or
the removal of a hydrogen atom or hydroxylation, dealkylation or
demethylation of drug molecule
 e.g.barbiturates, acetaminophen, benzodiazepines
• Reduction:-
 The reduction reaction will take place by the enzyme reductase
 E.g.chloramphenicol, methadone
• Hydrolysis:-
 Drug metabolism by hydrolysis is restricted to esters and amides (by
esterases and amidases)
 It means splitting of drug molecule after adding water
 E.g. pethidine,lidocaine,Bupivacaine,atropine and acetylcholine, procaine,
oxytocin ,130

…
• In this oxidation-reduction process, two microsomal enzymes
play a key role.
 NADPH-cytochrome P450 reductase
 cytochrome P450(CYP P450)- is a hemoprotein comprising a
large family of related but distinct enzymes
• The relative abundance of P450s, compared with that of the
reductase in the liver, contributes to making P450 heme
reduction a rate-limiting step in hepatic drug oxidations
• Microsomal drug oxidations require P450, P450 reductase,
NADPH, and molecular oxygen.
131

Figure: Cytochrome P450 cycle in drug oxidations. RH, parent drug; ROH, oxidized metabolite; e–, electron 132

Human Liver P450 Enzymes
• CYP450 is found highly concentrated in liver endoplasmic
reticulum (microsomes)
• There are numerous P450 isoforms (CYP: 1A2, 2A6, 2B6, 2C8, 2C9,
2C18, 2C19, 2D6, 2E1, 3A4, 3A5, 4A11, and 7) in the human liver
• Of these, CYP3A4, CYP1A2, CYP2A6, CYP2C9, CYP2D6 and CYP2E1
appear to be the most important forms, accounting for approximately,
30%, 4%, 20%, 5%, 10%, and 15%, respectively, of the total human
liver P450 content
• CYP3A4 alone is responsible for the metabolism of over 50% of the
clinically prescribed drugs metabolized by the liver
• They are responsible for catalyzing the bulk of the hepatic drug and
xenobiotic metabolism 133

Enzyme Induction
• some drugs induce P450 by enhancing the rate of its
synthesis or reducing its rate of degradation
 Induction results in an acceleration of substrate metabolism and
usually it decreases its pharmacologic action
 enzyme induction may exacerbate metabolite-mediated
toxicity
 Various substrates induce P450 isoforms having different
molecular masses and exhibiting different substrate specificities
 Microsomal enzyme inducers include-Phenobarbitone,
Phenytoin, Rifampicin, Griseofulvin, Carbamazepin,
Nevirapine 134

Enzyme inhibition
• Certain drug substrates inhibit cytochrome P450 enzyme
activity
• Decrease liver enzyme function which consequently
decrease metabolism and excretion of drugs
• This leads to toxicity
• Microsomal enzyme inhibitors include- Cimetidine,
Isoniazid, Chloramphenicol, Erythromycin, ketoconazole,
sodium valproic acid, ritonavir
135

 If phase I metabolites are sufficiently polar, they may be
readily excreted
 However, many phase I products are not eliminated rapidly
and undergo a subsequent reaction in which an endogenous
substrate such as glucuronic acid, sulfuric acid,
glutathione ,acetic acid, or an amino acid combines with
the newly incorporated functional group to form a
highly polar conjugate
 Such conjugation or synthetic reactions are the hallmarks
of phase II metabolism
136

 In general, conjugates are polar molecules that are readily
excreted and often inactive
 A great variety of drugs undergo these sequential
biotransformation reactions
o However, in some instances the parent drug may already possess a
functional group that may form a conjugate directly
 Phase II reactions may precede phase I reactions
 Conjugate formation involves high-energy intermediates and
specific transfer enzymes
 Such enzymes (transferases ) may be located in microsomes or in the
cytosol
 Of these, uridine 5'-diphosphate [UDP]-glucuronosyl transferases [UGTs ]
are the most dominant enzymes
137

Glucuronidation
 The most important of the phase II reactions
 It is catalyzed by UDP-glucuronosyltransferases (UGTs)
 markedly increases the hydrophilicity, molecular weight of
the compound, and favors biliary excretion
 Endogenous reactant- UDP glucuronic acid
 Types of Substrates- Phenols, alcohols, carboxylic acids,
hydroxyl amines, sulfonamides
 Examples- morphine, acetaminophen, diazepam
138

Sulfation
 Sulfotransferase (SULTs) located in the cytosol transfers
sulfate group to the drug molecules
 Endogenous reactant- Phosphoadenosyl phosphosulfate
 Types of substrates- Phenols, alcohols, aromatic amines
 Examples- Estrone, acetaminophen, methyldopa
139

Acetylation
 The cytosolic N-acetyltransferases (NATs) are responsible
for acetylation
 Endogenous reactant- Acetyl-CoA
 Types of substrates- Amines
 Examples- Sulfonamides, isoniazid, clonazepam, dapsone
140

Glycine conjugation
 Acyl-CoA glycinetransferases are responsible for glycine
conjugation
 Endogenous reactant- Glycine
 Types of Substrates- Acyl-CoA derivatives of carboxylic
acids
 Examples- Salicylic acid, benzoic acid, nicotinic acid
141

Methylation
 Transmethylases are enzymes that catalyze
methylation
 Endogenous reactant- S-Adenosyl-methionine (SAM)
 Types of substrates- Catecholamines, phenols,
amines
 Examples- Dopamine, epinephrine, pyridine,
histamine
142

Glutathione conjugation
 Use glutathione transferase
 Glutathione protect cells from reactive electrophilic
compounds
 When insufficient glutathione is there
E.g,Paracetamol undergoes CYP2E1 metabolism
that lead to ------ N-Acetyl-P-Benzoquinone Imine
(NAPQI)(highly reactive)---- this could produce
hepatotoxicity
143

Factors affecting drug biotransformation
 The dose and frequency of administration required to
achieve effective therapeutic blood and tissue levels
vary in different patients because of differences in
genetic factors and nongenetic variables
Genetic factors/polymorphism
 Genetic factors that influence enzyme levels account for
individual variation of drug metabolism
 Contribute to individual variations in drug metabolism
 E.g. acetylation of isoniazid-slow acetylators (of
isoniazid and similar amines) appears to be caused
by the synthesis of less of the enzyme
144

 Diet and environmental factors
 Grapefruit juice is known to inhibit the CYP3A4
metabolism of co-administered drug substrates e.g.
diazepam, nifedipine
 Cigarette smokers metabolize some drugs more rapidly
than nonsmokers because of enzyme induction
 Industrial workers exposed to some pesticides
metabolize certain drugs more rapidly than non exposed
individuals
145

Age and Sex
 As compared to young adults, pediatrics and geriatrics are
more susceptibe to the pharmacologic or toxic activity of
drugs due to reduced activity of metabolic enzymes or
reduced availability of essential endogenous cofactors
CAF not given for infants … why?
 Sex-dependent differences in drug metabolism also exist in
humans for ethanol, propranolol, some benzodiazepines,
estrogens, and salicylates
146

Diseases
 Can affect drug metabolism
oE.g. diseases that affect liver like cirrhosis
oCardiac disease, by limiting blood flow to the liver, may
impair disposition of those drugs whose metabolism is
blood flow-limited. e.g. Amitriptyline, Morphine
oPulmonary disease may also affect drug metabolism e.g.
procainamide and procaine
147

 Co administration of drugs/drug-drug interaction
• Enzyme-inducing drugs
 The metabolism of other drugs that are co administered with these
drugs may be enhanced
 Some enhances its own metabolism which result in a pharmacokinetic
type of tolerance
• Enzyme-inhibitor drugs
 These drugs may inhibit the metabolism of some other drugs and
thereby potentiate their pharmacologic action
 may lead to toxic effects from drugs with narrow therapeutic indices
 E.g. cimetidine inhibit the metabolism of Chlordiazepoxide,
diazepam, warfarin….. 148

 Excretion of drugs means the transportation of unaltered or
altered form of drug out of the body
 Excretory organs, the lung excluded, eliminate polar compounds
more efficiently than substances with high lipid solubility
 The kidney is the most important organ for excreting drugs and
their metabolites
 The major processes of excretion include renal excretion,
hepatobiliary excretion and pulmonary excretion
 The minor routes of excretion are saliva, sweat, tears, breast milk,
vaginal fluid, nails and hair
149

• Kidney is the principal organ for most drug removal
especially for water soluble and non volatile drug
• The amount of drug or its metabolites ultimately
present in urine is the cumulative effect of:
Glomerular filtration
Tubular secretion
Tubular reabsorption
150

Glomerular filtration
 Glomerular capillary wall permits a high degree of fluid filtration
while restricting the passage of compounds having relatively
large molecular weights
 All unbound drugs will be filtered as long as their molecular
size, charge, and shape are not excessively large
 It depends on
 the concentration of drug in the plasma
 Molecular size, shape, charge and protein binding
 Factors that affect the glomerular filtration rate (GFR) also can
influence the rate of drug clearance
151

Tubular secretion
 The cells of the proximal convoluted tubule actively
transport drugs from the plasma into the lumen of the
tubule
 Drug molecules are transferred to tubular lumen by two
independent and relatively non-selective carrier
systems
 One secretes organic anions and the other secretes
organic cations
152

…
 Since it uses carrier, it is saturable and competitive (inhibited
by drugs which use the same transport mechanism)
 This has clinical importance:
o Prolonging duration of action---by ↓tubular secretion
o Eg ; penicillin G (highly ionized) is excreted active tubular
secretion with short duration of action; to prolong its action,
Probencid is coadministered
 Compounds normally eliminated by tubular secretion will be
excreted more slowly in the very young and in the older
adult; consider dose
 Examples of drugs that are actively transported
o Acetazolaminde, benzyl penicillin, dopamine, pethidine,
thiazides, histamine 153

Passive Tubular reasbsorption
 The reabsorption of drug from the lumen of the distal convoluted
tubules into plasma
 The reabsorption of water result increased concentration of drug in
luminal fluid
 So, the concentration gradient thus facilitate movement of drug out of
tubular lumen
 Drugs should be in their non-ionized form to undergo passive
reabsorption
 Generally reabsorption of drug mainly is taken place by passive
diffusion, however there is active reabsorption also
154

…
Passive tubular reabsorption depends on
 Lipid solubility
 Ionization of the drug at the existing urinary pH
– When the urine is acidic, the degree of ionization of basic drug
increase and their reabsorption decreases
– Conversely, when the urine is more alkaline, the degree of
ionization of acidic drug increases and the reabsorption
decreases
– Effect of PH on urinary drug elimination have important medical
application
– Toxicity management by facilitating excretion
• For weak acid drug toxicity—alkalinizing the urine by bicarbonate
administration
• For weak base drug toxicity ---acidification of the urine by ammonium
administration 155

BILIARY EXCRETION
 Mainly for conjugated drugs
 After excretion of drug through bile into intestine,
certain amount of drug is reabsorbed into portal
vein leading to an enterohepatic cycling which
can prolong the action of drug
e.g. chloramphenicol, bile acids, vitamins D3 and
B12, folic acid, and estrogens
156

 The administration of one drug may influence
the rate of biliary excretion of administered
drug by altering:
• Hepatic blood flow
• Rate of biotransformation
• Transport in to bile
• Rate of bile formation
157

PULMONARY EXCRETION
 Any volatile material, irrespective of its route of
administration, has the potential for pulmonary excretion
 E.g. many inhalation anaesthetics and alcohols
 The rate of drug excretion depends on
 rate of respiration
 pulmonary blood flow
 the volume of air exchange
 the solubility of drug in blood compared to that of air/gas
• E.g. NO is less soluble in blood and hence easily
removed unlike alcohol
158

SWEAT AND SALIVA
 Has only minor importance for most drugs
 Excretion mainly depends on the diffusion of the un-ionized lipid-
soluble form of the drug across the epithelial cells of the glands
 Drugs or their metabolites that are excreted into sweat may be at least
partially responsible for the dermatitis and other skin reactions
 Excretion of a drug into saliva accounts for the drug taste after given
intravenously
 A number of drugs are excreted into the sweat either by simple
diffusion or active secretion e.g. rifampicin, metalloids like arsenic
and other heavy metals.
159

MAMMARY EXCRETION
 The ultimate concentration of the individual compound in
milk will depend on many factors
 Since milk is more acidic (pH 6.5) than plasma, basic
compounds may be somewhat more concentrated in this
fluid
 A highly lipid-soluble drug should accumulate in milk
fat
 Low-molecular weight un-ionized water-soluble drugs
will diffuse passively across the mammary epithelium
and transfer into milk 160

Drug concentration–time profiles
 The time course of a drug in the body is frequently
represented as a concentration–time profile in
which the concentrations of a drug in the body
are measured analytically
 Some pharmacokinetic parameters, such as Cmax,
Tmax, area under the curve, and half-life, can be
estimated from concentration–time profiles 161

 The same drug in a formulation that permits
a faster rate of absorption would have a
shorter Tmax and generally a higher Cmax
than the formulation with slower absorptive
properties
 Likewise, all other things being equal, a drug
with a slower elimination rate will generally
exhibit a longer Tmax and higher Cmax
162

 Drugs are used for the treatment of diseases but
the modes of administration of drugs are
different
 For example atenolol is administered once daily
where as paracetamol needs 3-4 times
administration daily
 Morphine is more effective if administered via an
IM route, and insulin via a SC route
 The mode of administration is designed on the
basis of absorption, distribution, metabolism and
excretion (ADME) of drugs
Order of kinetics
163

– Drugs usually follow two processes for their
phamacokinetic behaviour in the body
– These are:
 First order
 zero order process
• First order:
– This is the most common process for many drugs
– The rate at which ADME occur are proportional
to the concentration of drugs
– i.e. a constant fraction of drug in the body will
disappear in each equal interval of time
164

• Zero order kinetic
 It is independent of the amount of drug present at the
particular sites of drug absorption or elimination
 Few drugs follow this process e.g. ethanol, phenytoin
 Here constant amount of the drug is eliminated in each
equal interval of time
 On repeated administration of drug after certain stage it
goes on accumulating in the body and leads to toxic
reactions 165

• Half-life (t1/2)
• It is a measure of the rate of removal of drug from the body
• The half-life (t1/2) is the time it takes for the plasma
concentration or the amount of drug in the body to be reduced
by 50%
• It has two phases i.e half-life of distribution and half-life of
elimination
• A half-life value can be readily determined for most drugs by
administering a dose of the drug to a subject, taking blood
samples at various time intervals and then assaying the samples
• For example if a blood level of drug A is 8.6 mg/ml at 10
minutes and 4.3 mg/ml at 60 minutes, so the half – life of that
drug is 50 minutes
166

Clearance
 Defined as the volume of blood from which drug can
be completely removed per unit of time
 Describe the efficiency of irreversible elimination of
drug from the body
 Can involve both metabolism of drug to a
metabolite and excretion of drug from the body
 Total (systemic) clearance is the clearance of drug by
all routes
Ct=Ch+Cr+Cother Ct-total clearance,
Cr-renal clearance
Ch –hepatic clearance
 Total (systemic)clearance (Cl) can be calculated by
Cl =Vd. Ke or Cl=
167

The Target Concentration Approach to Designing a
Rational Dosage Regimen
 A rational dosage regimen is based on the assumption that there
is a target concentration that will produce the desired
therapeutic effect
 By considering the pharmacokinetic factors that determine
the dose-concentration relationship, it is possible to
individualize the dose regimen to achieve the target
concentration
168

Loading Dose
 When the time to reach steady state is appreciable, as it is
for drugs with long half-lives;
 it may be desirable to administer a loading dose that promptly
raises the concentration of drug in plasma to the target
concentration
 To prevent toxicity, rate of drug administration should
be slow
 The volume of distribution is the proportionality factor that
relates the total amount of drug in the body to the
concentration in the plasma (Cp); if a loading dose is to
achieve the target concentration:
169

Maintenance Dose
 In most clinical situations, drugs are administered in such a way as
to maintain a steady state of drug in the body
 ie, just enough drug is given in each dose to replace the drug
eliminated since the preceding dose
 Thus, calculation of the appropriate maintenance dose is a
primary goal
 Clearance is the most important pharmacokinetic term to be
considered in defining a rational steady state drug dosage
regimen
170

• Steady state plasma concentration:
 When a drug dose is given repeatedly over a given period,
a steady state is eventually reached
 This occurred at point where the amount of drug
absorbed is in equilibrium with that eliminated from the
body
 In contrast, the time to reach steady state is affected by
neither the dose amount nor dosing frequency
 The time to reach steady state is solely affected by the
elimination rate
 For most of the drugs that follow first order kinetics a
Steady state is achieved after 4 to 5 half lives
E.g. a drug with a half life of 6 hours will be expected to
be at steady state after more than 24 hours of
administration
 The pattern of drug accumulation, during repeated
administration of a drug at intervals equals its
elimination half-life
171

 For some drugs, the effects are difficult to
measure
 Toxicity and lack of efficacy are both potential
dangers, and/or the therapeutic window is
narrow
 This nonlinearity often occurs because the drug-
metabolizing enzymes for the drug become
saturated at typical blood concentrations, such
that despite increases in dose, drug is still
metabolized at the same rate
 In these circumstances doses must be adjusted
carefully to a desired steady- state concentration
by giving loading and maintenance doses
173

PHARMACODYNAMICS
 It studies the physiological and biochemical effects of
drugs
 It includes actions of drugs as well as their mechanism
 Mainly concerns on the interaction of the drug with
receptors
 Drugs interact with receptors to produce their
characteristic effects
 Drugs do not create effects but instead modulate intrinsic
physiological functions
174

…
What are receptors?
 Receptors are protein molecules present either on the cell
surface or within the cell
 Receptors are the macromolecular component of the cell to
which a drug bind to produce its effect
 They are mainly protein molecule whose function is to recognize
and respond to endogenous chemicals and xenobiotics
 Many drugs also are selective and act on such physiological
receptors
 They may be;
• Enzyme--- eg acetylcholinesterase ---neostigmine
• Ion channel---Ca2+ channel ----calcium channel blocker (verapamil)
• Carrier molecule –proton pump inhibitor--- omeprazole
175

Functions of the receptors:
Propagation of signal from outside to inside the cell
Amplify the signal
Adapt to short and long term changes
RECEPTOR FAMILIES
 Receptors can be divided into four families
1. Ligand gated ion channels
2. G-protein coupled receptors
3. Enzyme linked receptors
4. Intracellular receptors/Nuclear receptors
(Transcription Factors)
176

Fig:- Families of receptors 177

…
 LIGAND GATED ION CHANNELS(IONOTROPIC)
 The cell surface has a selective ion channel like Na, K ,
Ca , or Cl
 Onset of action through these types of receptors is fastest
– milliseconds
 Nicotinic cholinergic receptors, GABA-A and NMDA
receptors
G-PROTEIN COUPLED RECEPTOR
 These are cell membrane receptors which are linked to
effector mechanisms through G-proteins
 Effector mechanisms includes adenylyl cyclase,
phospholipase C, channel regulation
Onset of response in seconds
Eg : adrenergic receptors, histamine receptors
179

ENZYME LINKED RECEPTOR
 These cell membrane receptors are enzymatic in
nature
 Insulin, atrial natriuretic peptide (ANP) acts
through this receptors
– Onset of response in minutes
 INTRACELLULAR RECEPTOR
 Receptors for small sized hydrophobic drugs
like Steroids, thyroxine
 It takes days to produce its actions
180

 The effects of most drugs result from their interaction
with macromolecular components of the organism
 These interactions alter the function of the pertinent
component and initiate the biochemical and
physiological changes that are characteristics of the
response to drug
181

Non – receptor mechanism
o Drugs may act either to change the environment of the cell or to alter the rate of cell
functions, but they cannot alter the nature of cell functions
o Example
 lubrication (e.g. mineral oil)
 osmotic effect (E.g. Mannitol)
 Adsorption (e.g. activated charcoal)
 Chemical process involves the reaction of drugs with other chemicals, thereby
producing change in the constituents of body fluids
 e.g:- Alteration of pH (e.g. Antacids)
Receptor mechanism
 Most of the drugs act on by interacting with a cellular component called receptors
 Occupation of a receptor by a drug molecule may or may not result in activation of
the receptor
182

Drug –receptor interaction
 In most cases, the drug molecule interacts with a specific molecule in
the biologic system that plays a regulatory role (receptor)
 To interact chemically with its receptor, a drug molecule must have the
appropriate size, electrical charge, shape, and atomic composition
 The shape of a drug molecule must be such as to permit binding to its
receptor; in the same way that a key is complementary to a lock
 In terms of shape, the phenomenon of chirality (stereoisomerism) is so
common in biology that more than half of all useful drugs are chiral
molecules; that is, they can exist as enantiomeric pairs
183

 Interaction of receptors with ligands
involves the formation of chemical bonds :
Electrostatic
Hydrogen bond
Vanderwaals force
Covalent bond (irreversible interaction)
184

 The two models of ligand- receptor binding:
• “lock and key” Model
 states that the precise fit required of the ligand echoes the characteristics of
the “key,” whereas the opening of the “lock” reflects the activation of the
receptor
• The induced-fit model
 Suggests that the receptor is flexible(undergo conformational
change), not rigid as implied by the lock-and-key model
 In the presence of a ligand, the receptor undergoes a conformational
change to bind the ligand
 The change in conformation of the receptor caused by binding of the
agonist activates the receptor, which leads to the pharmacologic effect
185

 Modern concepts of drug-receptor interactions consider the
receptor to have at least two conformations:
 Ri (inactive)
 Ra (active )
 In the Ri conformation, the receptor is inactive/nonfunctional and
produces no effect, even when combined with a drug (D) molecule
 In the Ra conformation, the receptor can activate its effectors and
produce an effect, even in the absence of a ligand
 The effect produced in the absence of agonist (which is a small observable
effect) is referred to as ‘Constitutive Activity’
 In the absence of ligand, a receptor exists in a state of
equilibrium (Ri + Ra) between the two conformations
186

…
 The equilibrium between the Ri and Ra forms determines the
degree of constitutive activity produced by the receptor
 Thermodynamic studies/considerations indicate that, in the
absence of any ligand, the Ri form of the receptor is favored
(more stable)
 a small percentage of the receptor molecules exist in the Ra
form some of the time
 Receptor systems in humans exhibit a low level of constitutive
activity in the absence of agonist
 confirming that these receptors exist in a state of equilibrium (Ri +
Ra) with most of the receptor molecules are in the Ri form
187

 Some receptors, once activated, can directly bring
about the pharmacological effect, such as the case of
enzymes and ion channels
 Other receptors are linked through one or more
coupling molecules to a separate effector molecule
as a result, activating this particular type of receptor
will bring about the pharmacological effect
188

• Some drugs mimic the effect of a receptor agonist by
inhibiting the molecules responsible for terminating the
action of an endogenous agonist
e.g. phosphodiesterase inhibitors
acetylcholinesterase inhibitors
• Although these drugs don’t bind to the receptor, they are
able to extend/amplify the pharmacological effect of the
receptor agonist
189

…
Full Agonists
 Have a much higher affinity for binding to the Ra
conformation and are able to fully stabilize it (i.e., they
have high intrinsic efficacy)
 Binding of full agonists favors the formation of the Ra-D
complex with a much larger observed effect
 cause a shift of all of the receptor pool to the Ra-D pool when
administered at sufficiently high concentrations
 It results in full activation of the effector system and the
production of the maximal pharmacologic effect
190

Partial Agonists
 have an intermediate affinity for binding to both Ri and Ra forms (Ra-D +
Ri-D), with somewhat greater affinity for the Ra form
o They do not stabilize the Ra form as fully as full agonists, so that a
significant fraction of receptor molecules exists in the Ri-D
pool (i.e., partial agonists exhibit lower intrinsic efficacy)
o may act as either an ‘agonist’ (in the absence of a full agonist) or
as an ‘antagonist’ (in the presence of a full agonist)
 E.g. pindolol a β2 recepter partial agonist
192

…
Inverse agonists
 are drugs that bind to the receptor and stabilize it in
its inactive (nonfunctional) conformation
 reducing/eliminating any constitutive activity of the
receptor
 generates effects that are the opposite of the effects
produced by conventional agonists at the receptor
Allosteric agonists
 also known as Allosteric Activators
 are drugs that enhance the efficacy/binding affinity of the
receptor agonist by binding to allosteric sites on the receptor
molecule
193

Pharmacologic Antagonists
• have equal affinity for binding to both the Ra and Ri forms of
the receptor molecule
– Binding fixes the fractions of Ri-D and Ra-D complexes in the same
relative amounts as in the absence of any drug (i.e., binding does
not shift the Ra /Ri equilibrium)
• The same level of constitutive activity is maintained
– However, binding of the antagonist blocks the receptor site and
prevents agonists from binding
• can be either
– ‘Competitive Antagonists’ concentration dependent or
– ‘Noncompetitive Antagonists’ not concentration dependent
194

RECEPTOR THEORIES
Occupational theory
 States that the intensity of drug response is directly proportional to the
number of receptors occupied
 Maximum response is achieved if all receptors occupied
 Interaction between agonist and antagonist based on occupational
theory
Agonists: they activate the receptor and generate a signal as a direct result of
binding to it.
Have both efficacy and affinity
Their intrinsic activity is unity
Antagonists: they bind to receptors but do not activate generation of a
signal; consequently, they interfere with the ability of an agonist to activate
the receptor.
The effect of a so-called "pure" antagonist on a cell or in a patient depends
entirely on its preventing the binding of agonist molecules and blocking
their biologic actions.
Their intrinsic activity is zero 196

Partial agonist:
 are drugs not only block the access of the natural agonist to the receptor but are also
capable of activating the receptor
 They have both agonist and antagonist activity
 May act as either an ‘agonist’ (in the absence of a full agonist) or as an ‘antagonist’
(in the presence of a full agonist)
 Partial agonists have intrinsic activities greater than zero, but less than that of a
full agonist
 Even if all the receptors are occupied, partial agonists cannot produce a maximum
effect of as great a magnitude as that of a full agonist.
 A unique feature of these drugs is that, under appropriate conditions, a partial
agonist may act as an antagonist of a full agonist
Inverse agonists:- are those which stabilize the receptor in its inactive
conformation
– It activates the receptors to produce an effect opposite to that of agonist.
197

Modified Theory (Stephenson’s theory)
 It states that, without occupancy of all receptors, maximum response can be achieved, i.e. introduced
the concept of spare receptors
– The presence of spare receptors or receptor reserve provides a mechanism to drive the
mass balance equation governing interaction of drug and receptor toward the
formation of drug-receptor complexes
– Spare receptors greatly increase a tissue's sensitivity to agonist and decrease a tissue's
sensitivity to antagonists
 This theory introduces two concepts:
1. Efficacy and intrinsic activity
 Efficacy is: capacity of the drug to initiate response
 efficacy is clinically more important than potency
 Intrinsic activity: the ability of the drug to activate the receptor after binding.
 Maximal efficacy: the maximum effect the drug can bring about
2. Affinity: the strength of attraction between a drug and its receptors.
 The affinity of receptors in their potency
– High affinity →potent
– Low affinity→ less potent
198

 It is the measure of the amount of a drug needed to produce
the response
 Drugs producing the same response at lower dose are more
potent whereas those requiring large dose are less potent
 Drug potency does not necessarily mean therapeutic
superiority
 It is important not to equate greater potency of a drug with
therapeutic superiority:
 Because one might simply increase the dose of a less potent drug and thereby
obtain an identical therapeutic response
 In drug response curve, more a drug is on left side of the
graph, higher is its potency and vice a versa
199
Potency

– The difference in potency is quantified by the ratio:
ED50b = 3/0.3 = 10
ED50a
– Thus, drug a is 10 times as potent as drug b
– In contrast, drug c has less maximum effect than either drug a or
drug b
– Drug c is said to have a lower intrinsic activity than the other two
– Drugs a and b are full agonists with an intrinsic activity of 1
– Drug c is called a partial agonist and has an intrinsic activity of 0.5
because its maximum effect is half the maximum effect of a or b
201

 The potency of drug c is the same as that of drug b,
because both drugs have the same ED50 (3 µg /kg)
 The ED50 is the dose producing a response that is
one-half of the maximal response to that same
drug
202

• Two types of dose response relationship curves:
Graded dose- response relationship
Quantal dose -relationship
 Biological responses to drugs are graded
 The response continuously increases (up to the
maximal responding capacity of the given
responding system) as the administered dose
continuously increases
 When a graded dose–response relationship exists:
The response to the drug is directly related to the
number of receptors with which the drug effectively
interacts 203

 More common than the quantal dose–response
relationship
 It is the situation in which a single animal (or
patient) gives graded responses to graded doses
 With graded responses, one can obtain a
complete dose– response curve in a single animal
 A good example is the effect of the drug
levarterenol (LL-norepinephrine) on heart rate
204

Fig. Dose-response curves illustrating the graded responses of five guinea pigs (a-e)
to increasing doses of levarterenol. The responses are increases in heart rate above
the rate measured before the administration of the drug. Broken lines indicate 50% of
maximum response (horizontal) and individual ED50 values (vertical)
205

• Limitation
 Since an entire dose–response relationship is
determined from one animal:
the curve cannot tell us about the degree of biological
variation inherent in a population of such animals
 Such curves may be impossible to construct if the
pharmacologic response is an either-or (quantal)
event, such as prevention of convulsions,
arrhythmia, or death
206

B. Quantal Relationships
 It is used to indicate the relationship between dose and
some specified quantum of response among all
individuals taking that drug
 This is obtained by evaluating data obtained from a
quantal dose–response curve
 Eg. anticonvulsants can be suitably studied by use of
quantal dose–response curves
In the presence of a given dose of the drug, the animal either has
the seizure or does not; that is, it either is or is not protected
In the design of this experiment, the effect of the drug
(protection) is all or none
 In contrast to a graded response, the quantal response
must be described in a noncontinuous manner
207

 The construction of a quantal dose–response curve
requires that data be obtained from many
individuals
 It is plotted as the dose on the horizontal axis that
evaluated against the percentage of animals in the
experimental population that is protected by each
dose (vertical axis)
 Eg. Five groups of 10 rats per group were used
 The animals in any one group received a particular
dose of phenobarbital of 2, 3, 5, 7, or 10 mg/kg body
weight
 The lowest dose protected none of the 10 rats to
which it was given, whereas 10mg/kg protected 10 of
10
208

Fig. Quantal dose–response curves based on all-or-none responses.
A. Relationship between the dose of phenobarbital and the protection of groups of rats
against convulsions.
B. Relationship between the dose of phenobarbital and the drug’s lethal effects in
groups of rats. ED50, effective dose, 50%; LD50, lethal dose, 50%
209

 The quantal dose–response curve is actually a
cumulative plot of the normal frequency
distribution curve
 If one graphs the cumulative frequency versus
dose, one obtains the sigmoid-shaped curve
 The sigmoid shape is a characteristic of most
dose–response curves when the dose is plotted on
a geometric, or log, scale
210

 Both quantal- dose response and graded –dose
response curves provide information regarding
the potency and selectivity of drugs
 The graded dose-response curve indicates the
maximal efficacy of a drug
 The quantal dose-effect curve indicates the
potential variability of responsiveness among
individuals
211

• Therapeutic index
 This is an approximate assessment of the safety of a
drug
 It is the ratio of the median lethal dose and the
median effective dose
 Also called as therapeutic window of safety
 Therapeutic index (T. I) = LD50
ED50
 The larger the therapeutic index, the safer the drug is
 Penicillin has a very high therapeutic index, while a
digitalis preparation and warfarin would have a much
lower index
212

214
Fig. Quantal dose-response curve

 It is a phenomenon which occurs when the effects of one
drug are modified by the prior or concurrent
administration of another drug(s)
 Drugs can also interact with other dietary constituents
and herbal remedies
 It may be beneficial or harmful
 May be classified as
 Pharmaceutical
 Pharmacokinetic
 Pharmacodynamic
215

I. Pharmaceutical drug interactions
 Serious loss of potency can occur from
incompatibility between an infusion fluid and a
drug that is added to it
 e.g. if diazepam is added to an infusion fluid a
precipitate will form  loss of therapeutic effect
216

II. Pharmacokinetic drug interaction
 Alteration of the concentration of a drug that reaches its site of action.
 During absorption
– Interactions may result in an increase or decrease in either the relative rate of
absorption or the total amount of drug that is absorbed
– If two drugs given simultaneously, the absorption of the two drugs may be
decreased. e.g.
• Salts of divalent or trivalent metals (Ca2+,Mg2+,Al3+) decrease the absorption of
Tetracycline
– GI absorption
• It is slowed by drugs that inhibit gastric emptying (e.g. atropine or opiates)
• Accelerated by drugs that hasten gastric emptying (e.g. metoclopramide)
217

During distribution
 Certain drugs compete with other drugs for drug-binding sites on albumin
and can displace albumin-bound drugs
 There are several instances where drugs that alter protein binding
additionally reduce elimination of the displaced drug, causing clinically
important interactions
 e.g. Phenylbutazone displaces warfarin from binding sites on albumin,
resulting in increased bleeding
• Tissue-binding displacement has more potential for adverse effects than
plasma protein-binding displacement
• E.g.
– Quinidine displaces digoxin from tissue-binding sites
– Sulfonamide can be displaced by salicylates from plasma proteins and it leads to
sulfonamide toxicity.
218

During biotransformation
 Inhibition of metabolism
– Enzyme inhibition, particularly of P450 system, slows
metabolism and hence increases the action of other drugs
metabolized by the enzyme
 E.g. Cimetidine is a potent inhibitor of hepatic enzyme activity.
 Thereby potentiate the effects of some drugs like diazepam,
chlordizepoxide, morphine, phenytoin, carbamazepine,
theophylline, digitoxin and quinidine
 Grapefruit juice reduces the metabolism of Ca2+-channel blockers
 Acceleration of metabolism
– Many drugs cause enzyme induction and thereby decrease
the pharmacological activity of a range of other drugs
• E.g. Phenobarbital, rifampcin, griseofulvin,
phenytion,carbamazepine
• Smoking appears to quicken the metabolism of several drugs by
stimulating hepatic drug-metabolizing enzymes 219

During excretion
 The mechanism by which one drug can affect the
rate of renal excretion of another drugs are by
Altering protein binding and hence filtration
Inhibiting tubular secretion
Altering urine flow and/or urine pH
Inhibition of tubular secretion
 E.g. -probenecid inhibit penicillin secretion
 Probenecid also inhibit excretion of zidovudine
220

…
Alteration of urine flow and urine pH
 Changes in the urinary flow rate will affect both the process of
reabsorption and the pH, thus, influence the excretion of drugs
through the kidney
 Changes in the urine pH could be induced by sodium bicarbonate,
ammonium chloride, long term, high-dose antacid therapy,
acetazolimide, and thiazide diuretics
 Alkalinization of urine increases the rate of excretion of acidic drugs
(e.g. acetazolimide, phenobarbital, salicylates, sulfonamides)
 Likewise, acidification of urine increases urinary excretion of basic
drugs (e.g. amphetamines, quinidine, tricyclic antidepressants)
221

III. Pharmacodynamic interactions
Additive [1+1=2]:
 combined effect of the two drugs having the same
action is equal to the sum of their individual effects
– E.g. ephedrine + aminophyline
Synergistic [1+1>2]:
 combined effect of two drugs is greater than the
sum of their individual effect
– E.g. trimethoprine + sulfamethoxazole
– penicillin + amino glycosides
222

…
 Potentiation [0+1>1]:
 The effect of one drug is increased by the other inactive agent, which
does not have the same action
– E.g. Amoxicillin + clavulanic acid
Antagonism
 It is most frequently encountered in clinical practice
223

Drug antagonism
– It lacks intrinsic activities and efficacy
– The several types of antagonism can be classified as follows:
1. Chemical antagonism
2. Functional antagonism
3. Competitive antagonism
a) Equilibrium competitive
b) Non-equilibrium competitive
4. Noncompetitive antagonism
224

1. Chemical Antagonism
 Chemical antagonism involves a direct chemical
interaction between the agonist and antagonist
 Such interaction render the agonist to be
pharmacologically inactive
 A good example is the use of chelating agents to
assist in the biological inactivation and removal
from the body of toxic metals
225

2. Functional antagonism
 Functional antagonism is a term used to represent
the interaction of two agonists that act
independently of each other but happen to cause
opposite effects
 Thus, indirectly, each tends to cancel out or reduce
the effect of the other
 A classic example is acetylcholine and epinephrine
226

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