General Pharmacology

GENERAL PHARMACOLOGY
1
Outlines
 Definition, history, Scope and Branches of  Pharmacodynamics:
Pharmacology • Receptors and General Mechanisms of Drug
 Drug: Definition, Sources and Nomenclature Action
• Drug Receptor Interaction

 Pharmacokinetics:
• Drug Receptor Theories
• Absorption of Drugs
• Dose-Response Relationships
• Routs of Drug Administration
• Receptor-Effector Coupling and Spare
• Drug Distribution
Receptors
• Biotransformation
• Pharmacodynamic Drug Interactions
• Elimination of Drugs
 Adverse Drug Reactions
• Basics of Clinical Pharmacokinetics and
 Drug Toxicity (LD50 and Therapeutic Index)
Posology
 Development and Evaluation of New Drugs
 Gene Therapy
2
History of pharmacology
3
Pharmacology today
4
A) Definition of common terms in pharmacology
 Pharmacology:  Pharmacoeconomics
 Drug  Chemotherapy
 Medicine  Toxicology
 Pharmacokinetics  Pharmacy
 Pharmacodynamics  Essential drugs
 Pharmacotherapeutics  Orphan drug
 Pharmacogenomics
 Pharmacoepidemiology
5
Definition of pharmacology
 Pharmacology: drived from greek word
• Pharmakon=drug=remedy=to do good
• Logos=a study=science
• Study of chemicals (drugs) and their actions on living
organisms
• Deals about drugs: source, pharmacokinetic and
pharmacodynamic properties, side effects, therapeutic
uses, drug-drug interactions, drug-food interaction,
contraindications, etc.
6
Definition of pharmacology…
 Drug: is single active ingredient (chemical)that is used to modify or
explore physiological system or pathological states for the benefit of
the recipient.
 Example of drug use:

• Prevention of a disease: e.g. prevent initial or recurrent infection,
achieved by;
 Immunization vaccine: Bacillus Calmette-Guerin (BCG), cholera, hepatitis, influenza
 Drug/medicine
Prevention of OIs in HIV/ AIDS patients
PMTCT of HIV
Recurrent UTI
Malaria chemoprophylaxis
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 Example of drug use…
• Diagnosis of a disease;e.g. Tropicamide eye
drops→ dilate the pupil
• Treatment of a disease (might result in):
 Complete cure: e.g. anti-TB drugs
 Improved quality of life: e.g. anti-retroviral
drugs; for HIV
8
 Medicine:
 Is a drug along with other substances in proper, stable

dosage form, acceptable to the patient & fit for
administration
Excipients(
drug
additives )
Figure 1: combination of drug and excipients or additives
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 Medicine:
 Is a drug along with other substances in proper, stable

dosage form, acceptable to the patient & fit for
administration
Excipients(
drug
additives )
Figure 1: combination of drug and excipients or additives
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 Pharmacokinetics:
 Deals with drug absorption, distribution, binding, localization,
storage, biotransformation and excretion.
 ADME
 Pharmacodynamics:
 Deals with the biochemical and physiological effects of drugs and
their mechanism of action.
 Interaction between xenobiotic and host cells

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 Pharmacotherapeutics:
 Deals with the use of drugs in the prevention and treatment of disease,
adverse and toxic effect, contraindication, precautions and drug
interactions.
 Pharmacogenomics:
 Describing the use of genetic information to guide the choice of drug
therapy on an individual basis.
 E.g. G6PD deficiency vs drugs(quinin) causes hemolysis
 Slow or fast acetylation

• E.g. Isoniazid; slow acetylators tend to develop peripheral neuropathy more
12
 Pharmacoepidemiology:
 This is the study of drug effects at the population level.
• It is concerned with the variability of drug effects between

individuals in a population, and between populations.
 Pharmacoeconomics;
 This branch of health economics aims to quantify in economic
terms the cost and benefit of drugs used therapeutically
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 Chemotherapy:
Treatment of systemic infectious and malignant diseases with
specific drugs that have selective toxicity for the infecting
organism or malignant cells with no or minimal side effect on
the host cell.
 Toxicology:
Study of poisonous effect of drugs and other chemicals with
emphasis on detection, prevention and treatment of poisoning
as well as the side effects of the drug.
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 Pharmacy:
The art and science of:
• Compounding and dispensing drugs or
• Preparing suitable dosage forms for administration of drugs
in man or animal.
• It includes collection, identification, purification, isolation,
synthesis, standardization and quality control of medicinal
substances.
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 Essential drugs:
• At all satisfy the health care needs of majority of the
populations,
• Should be available:
Times
In adequate amounts and
In appropriate dosage forms and
In effective cost.
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 Orphan drug:
Drugs or biological products for diagnosis,

treatment, and prevention of a rare disease or a
condition.
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 Questions:
What is drug?
What is medicine?
What is the difference between drug & medicne?
What is clinical pharmacology?
What is Therapeutics?
Drug Vs medicine, Essential drug Vs Orphan drug?
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Sources of drugs
 Natural sources
 Semi-synthetic
 Synthetic
 Genetic engineering
19
Natural sources of drugs
 Plant:
e.g. morphine, atropine, digoxin
 Animal:
e.g. insulin and heparin…
. insulin, heparin, progesterone,omega-3 fatty acids
 Microorganism:
e.g. penicillin, streptokinase…
 Mineral:
e.g. magnesium salts, iodine, Iron…
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Semi-synthetic sources of drugs :-
 Semi-synthetic:
e.g. amoxicillin, ampicillin, heroin etc. aminoglycosides,
heroin, Coumarin glycosides, Dicoumarol, warfarin:

oral anticoagulants)
21
Synthetic sources of drugs:-
 Synthetic
E.g. Aspirin, chloramphenicol, paracetamol…
22
Genetic engineering sources of drugs:-
 Genetic engineering:
e.g. Human GH, insulin…
23
Drug names
 Drugs have different names, many have similar spelling
• Exact names and spelling are imperative
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Types of drug naming
 Chemical name
 Generic name
 Official name
 Trademark
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Chemical name of Drugs
 Exact chemical structure of a drug (describes the chemical
structure of the drug)
 It is too difficult to be used in prescription
e.g. Paracetamol
N-acetyl-para-aminophenol/Acetamide, N-( 4-hydroxyphenyl)
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Generic name of drugs
 Drugs common name
 Non proprietary name
 Internationally accepted name
 Unique through out the world

 e.g. Paracetamol
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Official name of drugs
 Name under which the drug is listed by the FDA
e.g. Ampicillin,USP
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Trademark name of drugs
 Brand or trade name
 Only the manufacture who owns the drug can use the
brand/trade name
 Proprietary name assigned by the manufacturer(s)
 One drug may have several proprietary names
 e.g. Panadol, Calpol, Alvedon… (Paracetamol)
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Table 1: Example of naming:paracetamol
Type of drug name Example
Chemical name N-acetyl-para-aminophenol
Generic name Paracetamol

Official name Paracetamol ,USP
Trade name Tylenol®, Paramol®, Panadol®,

panadrex…
30
Classification of medicines
 Knowing classifications is essential to understand the
properties of drugs.
 Medicines with similar characteristics can be categorized

in the same class
 Medication classification may indicate:

 the medicine desired effect, e.g. oral hypoglycemics
 A medication may be part of more than one class
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Medicines are classified by:
 Body system
• Which body system the affect?
 Therapeutic use or clinical indications:
• What disease or illness is being treated?
 Physiological or chemical action:
• Does the medication require a prescription or can it be

purchased OTC?
 Illegal drugs:
• Is the drug used for non-therapeutic reasons?

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Dosage Forms(DF)
 DF of a drug is the form of preparation designed for
administration to the body for the purpose of diagnosis,
prophylaxis, and treatment...
 After development of a specific chemical entity for its

pharmacological effects, it is formulated in a form that is
suitable for administration and even efficacy and for the
stability of the drug itself.
 There are different dosage form designs intended for the

various routes of administration.
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DF…
In addition to the active or therapeutic
ingredient(s),pharmaceutical dosage forms contain a
number of inert materials.
• The latter are known as additives or excipients.
An excipient is a pharmacologically inactive substance
formulated alongside the active pharmaceutical
ingredient of a medication.
Although excipients are the non-active ingredients, they
are essential in the successful production of acceptable
dosage forms such as tablets.
34
DF…
 Use of Excipients
• Important to satisfactory processing and compression
characteristics to the formulation.
 This includes: diluents, binders, glidants and
lubricants.
• Give additional desirable physical characteristics to
the finished tablet.
 This includes: disintegrants, colours, and in the case
of chewable tablets, flavors and sweetening agents.
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DF…
 There are different dosage form designs intended for
the various routes of administration.
 Preparation of drugs designed for administration

• Solid Dosage Forms
• Semisolid Dosage Forms
• Liquid Dosage Forms
• Inhalational Dosage Forms
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Solid Dosage Forms(SDF)
 Tablets: Enteric coated, non-enteric coated, uncoated…
 Capsules: solid/liquid drugs enclosed in a hard or soft

soluble gelatin shell
 Suppositories: into rectum. Vagina, urethra
 Lozenges, Pastilles, Granules, powder and Dental

Cones
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Tablet
 Is a SDF, compressed medication in to various shapes, (round,
oblong, cylindrical).
 It containing unit dose(API) of one or more medicament
with/without without suitable diluent, binder, disintegrant,
lubricant, coloring agent, sweetening agent, flavoring agent, etc..
 Most commonly used DF and most of are designed for oral
administration
 Most tablets are uncoated but a few are coated tablets:
Film coated tablets: covered with thin layer of polymeric substance that
protects the drug from atmospheric conditions and masks unpleasant
taste and odor of the drug
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Types of tablets
Uncoated,
Enteric coated; e.g, sugar/film coated
Non-enteric coated
Chewable tablets
Dispersible/effervescent
…
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Types of tablets…
 Enteric coated tablets:
• Compressed tablet for administration by swallowing
• Designed to by-pass the stomach and get disintegrated in the
intestine only.
Because of coated with materials resistant to acidic pH (like
cellulose acetate phthalate) of the gastric fluid but get
disintegrated in the alkaline pH of the intestine.
Used to protects the medicament from distraction by acidity
gastric juice and to prevent gastric irritation by the drug.
 Film coated tablets:
• The compressed tablets having a film coating of some polymer
substance, such as hydroxy propyl methyl cell…
• Used to protects the medicament from distraction by
atmospheric effects. 40
Types of tablets…
 Sugar coated tablets:
• The compressed tablets containing a sugar coating.
• To mask the bitter and unpleasant odor and the taste
of the medicament.
• The sugar coating makes the tablet elegant and it also
safeguard the drug from atmospheric effects.
 Modified release tablets: coated or uncoated,
prepared by special procedures that modify the rate of
release of the drug at a predetermined rate.
– Prolongs the duration of action
– Reduces the frequency of administration
• More patient compliance
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Types of tablets…
Chewable tablets:
• Tablets to be broken and chewed in between the teeth
before ingestion.
• The main applications for this dosage form are:
 To children and adults who have difficulty in swallowing
conventional tablets
 Anti-acid formulations in which the size of the tablet is
normally large and the neutralization efficacy of the
tablet is related to particle size within the stomach.
• These tablets should have very acceptable taste and flavor.
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Types of tablets…
 Buccal tablets:
• These tablets are to be placed in the side of the cheek
(buccal pouch) where they dissolve or erode slowly
and are absorbed directly in the buccal cavity without
passing into the alimentary canal.
 Sublingual tablets:
• These tablets are to be placed under the tongue where
they dissolve or disintegrate quickly and are absorbed
directly without passing into GIT
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Types of tablets…
 Lozenges
• These tablets are designed to exert a local effect in the
mouth or throat.
• These tablets are commonly used to treat sore throat
to control coughing in common cold.
• They may contain local anaesthetics, antiseptics,
antibacterial agents, and antitussives.
• In addition, contain a sweetening agent, flavoring
agent (e.g. peppermint, clove oil) and a substance
which produces a cooling effect (e.g. mentha)
44
Types of tablets…
 Dental cones
• Tablets designed to be inserted in the empty sockets
after tooth extraction.
• To prevent the multiplication of bacteria in the socket
following such extraction by using slow-releasing
antibacterial compounds or to reduce bleeding by
containing the astringent.
45
Types of tablets…
 Implantation tablets:
• These tablets are placed under the skin or inserted
subcutaneously and are slowly absorbed.
• The implants must be sterile and should be packed
individually in sterile condition. e.g. Contraceptives
 Vaginal tablets:
• These tablets dissolve slowly in the vaginal cavity.
• E.g. antimicrobial agents.
46
Types of tablets…
 Effervescent tablets
• Tablets are added to aqueous solutions where they will
rapidly disintegrate and produce either a drug
suspension or an aqueous solution.
 Hypodermic tablets
• Soft, readily soluble tablets and originally were used
for the preparation of solutions to be injected.
• These tablets are dissolved in sterile water or water
for injection and administered by parenteral route.
• These tablets are not preferred now-a-days because
the resulting solution is not always sterile.
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Advantages of tablet dosage form over other oral drug
delivery systems:
 From patients stand point:
• They are easy to handle
• They are easy to swallow
• They are attractive in appearance
• Unpleasant taste can be masked by sugar coating
• They do not require any measurement of dose.
• Some of the tablets are divided into halves and quarters by
drawing lines during manufacturing to facilitate breakage
whenever a fractional dose is required.
• Disadvantages:
– Slow absorption
– Slower onset of action
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Hard gelatin Soft gelatin
Capsules capsule capsule
Are SDF; unit doses, as solid, semisolid or liquid form of the

drug is/are enclosed in a hard or soft soluble gelatin shell to
mask its bad taste and odor as well as to enhance the
stability.
They are intended for internal use (orally administered).
 Spansules (sustained release capsules): contain the drug in
the form of granules having different coatings that dissolve
at different time intervals and provide uniform release of
drug over a prolonged period.
 Overcome problem of taste of drugs and to some extent
stability.
 More expensive than tablets
49
SDF cont’d…
 Semisolid Dosage Forms
• Ointments: 20% water and 50% hydrocarbons
Application on skin or mucous membranes
• Creams: mixtures of oil and water.
emulsions for external use as protective or

emollients to soften and sooth the skin.
• Pastes: heavy consistency (~ 50% of solid )
50
SDF cont’d…
Suppositories
• Are solid dosage forms with various sizes and shape
for administration into body cavities (rectum, vagina,
and urethra)
• Rectal suppositories are conical or bullet shaped,
vaginal suppositories spherical (oval), and urethral
suppositories pencil shaped.
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Liquid Dosage Forms(LDF)
 Syrups: a thick sweet liquid containing dissolved drugs
 Solution: - the active ingredient is soluble in the

solvent (Injections, elixir, tinctures, drops, gargles,
enemas)
 Suspension: the active ingredient is insoluble
52
LDF cont’d…
Solutions
 It can be for internal or external use.
 The active ingredient is soluble in the solvent
(Injections, elixir, tinctures, drops, gargles, enemas)
 Injectables and ere/eye solutions as well as
suspension are sterile, and packed in vial /ampoules.
Ampoules
vial
53
LDF cont’d…
 Syrups: a thick sweet liquid containing dissolved drugs
• A clear solution/ suspension of sugar containing
coloring, flavoring, and therapeutically active
substances.
• It is given to the patient by the spoon (table
spoon=15 ml, tea spoon=5 ml)
• Drug concentration is expressed as(mg/ml).
• Every suspension should have a label “shake well
before use”
54
LDF cont’d…
 Suspensions include:
• Emulsions:
Preparations consisting of two non-miscible liquids,
with an emulsifying agent.
They may be used for both internal and external use.
• Mixtures:
 Preparation of any solid material suspended in a liquid,
and intended for internal use.
• Lotion:
An aqueous suspension to be applied without friction,
for soothing, cleansing or antiseptic action on the skin.
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LDF cont’d…
• Advantages of liquid preparations
– Rapid absorption
– Prompt onset of action
• Disadvantage
– Dosage form is relatively bulky
– Greater chance of chemical incompatibility
– Disagreeable odor and taste can not be masked
completely
– Less stable
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Inhalational Dosage Forms
 Aerosol:
• Drug is dissolved or suspended in propellant and
packed in a pressurized dispenser.
 Gas :
•like oxygen, nitrous oxide and carbon dioxide
 Volatile liquids: e.g. halothane, ether
 Gaseous dosage forms: vapour and even dry powder
Inhaler
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Classification of Routs of Drug Administration
 Systemic(for systemic action)
• Enteral (via GIT)
• Parenteral (injections)
 Percutaneous (for local action)
• Topical application
• Deeper tissues
58
Classification of Routs of Drug Administration…
• Oral
• Sublingual
• Rectal
• Parenteral (injections)
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cont’d…
• Drugs administered directly into the GI tract
E.g. Orally, Sublingual, Rectal
60
cont’d…
 Oral Route
• Administration through mouth, mostly for systemic effect
• It is the most common method of drug administration
61
cont’d…
 Oral Route
Advantages
Safe, more convenient and economical
Often painless, self - administration
Both solid and liquid dosage forms can be administered
Untoward effect, if any, appears slowly
Reverse of dose management is easily done (how?)
62
cont’d…
 Oral Route; Disadvantages
 Action slower (not for emergencies), (why?)
 Unpalatable and irritant drugs difficult to administer
 Not suitable for unconscious /uncooperative and vomiting pts
 Certain drugs are not absorbed sufficiently
 Some drugs are destroyed by digestive enzyme or inactived by liver
enzymes
 Drug-food interactions may lead to formation of

unabsorbable complexes
 Presence of food in stomach delays gastric emptying and
delays the onset of action
63
cont’d…
 Sublingual / Buccal Route
Sublingual: the dosage form is placed under the tongue and
rapidly absorbed by sublingual mucosa
Buccal: the dosage form is placed between gums and inner

lining of the cheek and absorbed by buccal mucosa
64
cont’d…
 Sublingual / Buccal Route
• Non polar /lipid soluble/ drugs are rapidly absorbed
• No first pass metabolism
• Rapid effect (in emergency)
• Not useful for irritant and bad tasting drugs
• Examples - nitroglycerin, some steroids, nicotine (chewing

gum) are usually given by these routes
65
cont’d…
 Rectal Route
• Unpleasant drugs can be put into rectum as suppositories (melt at body
temperature) for systemic effect
• Often useful when oral route is precluded by vomiting or when the patient is
unconscious
• Less hepatic first pass metabolism (~50%)
• Inconvenient and embarrassing route
• Suitable for children
• Absorption is slow, irregular, incomplete and often unpredictable
• Irritation of rectal mucosa
66
cont’d…
Parenteral Route
(injections)
•Drug directly
introduced into tissue
fluids or blood
without having to
cross the intestinal
mucosa
67
cont’d…
 Parenteral Route (injections)
• Routes include
Intravenous: within a vein
Intramuscular: within a muscle
Subcutaneous: beneath the skin
• Other parenteral routes
Intraarterial
Intrathecal
Intraarticular
68
cont’d…
 Advantages of parenteral route
 Action faster
 Suitable for unconscious/uncooperative/vomiting pts
 No interference of food or digestive juice
 First pass effect is bypassed
 Disadvantages of parenteral route
 Preparation is costly
 Need of assistance by others during administration
 Difficult for toxicity management
69
cont’d…
Intravenous (IV) Route
Advantage Disadvantage
 Rapid action (in emergency)  Only for water soluble drugs
 High bioavailability (100%)  Not suitable for oily solutions or

poorly soluble substance
 Can be used for irritant drugs  Risk of infection
 Large volumes can be infused  Pain at the site of injection
70
cont’d…
 Subcutaneous (SC) administration
Unsuitable for irritant drugs; otherwise, severe pain,
necrosis, and tissue sloughing may occur
Oily solution or aqueous suspensions can be injected
• Slow and constant absorption, prolonged action
 For small volume 0.1 ml-1 ml
71
cont’d…
 Intramuscular (IM) administration
Substances too irritating to be injected subcutaneously may

be given IM
Larger volume 3-5 ml may be given
 For oily solutions or poorly soluble substances (prolonged

effect)
72
cont’d…
 Pulmonary Administration
• Rapid absorption due to large surface area
• Suitable for gaseous and volatile drugs
• Solutions can be atomized and the fine droplets in air (aerosol) inhaled
• Advantage: Almost instantaneous absorption, avoid hepatic first pass

effect, local application to the pulmonary system
• Disadvantage: Poor ability to regulate the dose and irritation of the

pulmonary mucosa
73
cont’d…
 Topical application
 Application could be on mucous membranes, skin or eye
• Mucous membranes
Drugs are applied on the nasopharynx,

oropharynx, vagina and colon usually for their
local effects
Absorption through mucous membranes occur

readily to cause systemic effects
74
cont’d…
 Skin
• Absorption is proportional to the surface area and

lipid solubility of the drug
• Conditions that  cutaneous blood flow enhance

absorption
 Eye
• Ophthalmic preparations are sterile solution for

their local action,
75
cont’d…
 Deeper tissues
• Approached by using a syringe and needle,
• The drug should be in such a form that systemic

absorption is slow,
E.G. Intra-articular injection (hydrocortisone acetate in

knee joint),
 Infiltration around a nerve or intrathecal injection

(lidocaine), retrobulbar injection (hydrocortisone acetate
behind the eyeball). 76
Factors governing choice of route of administration
• Physical and chemical properties of the drug
(solid/liquid/semisolid/gaseous/lipid
solubility/stability/ PH/irritancy)
• Site of desired action (localized or generalized)
• Rate and extent of absorption from different routes
• Effect of gastric acidity, digestive juices and first pass
effect
• Rapidity with which the response is desired
• Accuracy of dosage required (I.V and inhalation can
provide fine tuning)
77
Factors governing choice of route of administration…
• Condition of the patient (unconsciousness, vomiting,
presence of contraindication for certain routes, severity
of disease, emergency condition…)
• The available dosage form in the market
• Economic condition of the patient( injections need
syringes and an assistant, some dosage forms are
expensive)
• Personal factors (e.g. preference )
78
Basic principles
 Drugs act in the human body in the following ways:
• Drugs change a physiological activity within the body
• They do no create new responses
e.g. Blood Pressure drugs
 Drug forms a chemical bond within specific sites (receptors)

within the body
• Relationship between drug and receptor is like a key
79
Basic principles…
 Agonist:
• Drugs that interact with a receptor to cause a response
 Antagonist
• Drugs that attach to a receptor but do not cause a response
 Partial agonist
• Drugs that interact with a receptor to cause a response but

prevent other responses
80
Basic principles…
Pharmacokinetics Pharmacodynamics
Beneficial
Therapeutic
Drug in the Site of effect
Dosage Effect
body fluids action Adverse
Toxicology
effect
Figure 2: Relationship between pharmacokinetics and pharmacodynamics
81
PHARMACOKINETICS(PK)
 Describes: What the body does to the drug
 Deals with drug

Absorption
Distribution
ADME
Metabolism and
Excretion
 Determines how rapidly and for how long the drug will appear
at the target organ
 All PK processes involve passage of drugs through membranes
82
PK…
 Drug Transportation 2. Specialized transport
• Drugs cross cell membranes by: • Carrier mediated transport
1. Passive diffusion • Facilitated diffusion

• Simple diffusion(Lipid • Active transport
diffusion)
 Endocytosis
• Filtration(Aqueous diffusion)
 Ion pair
83
cont’d…
 Simple diffusion(Lipid diffusion)
• Factors that affect simple diffusion:
Lipid solubility
Pka of the drug
Concentration
Surface area
pH of absorption site (media)
84
cont’d…
 Filtration(Aqueous diffusion)
• Passage of water soluble, ion and some non polar molecules
of low molecular weight through the water filled pores in

membranes
85
cont’d…
 Influence of pH on passive diffusion
 Most drugs are either weak acids or weak bases that are present, as both non-
ionized and ionized species
 pH of the absorption site, pKa and lipid solubility of the unionized drug govern
absorption
 Acidic drugs are better absorbed from acidic conditions of stomach
 Basic dugs are better absorbed from the relatively alkaline conditions of the intestine
 This is important for drug absorption and drug distribution
• Drug absorption: e.g. GIT and kidney
• Drug distribution: e.g. across milk and placenta
86
cont’d…
 Characteristics of Facilitated Diffusion:
• Occurs along concentration gradient
• Requires carriers but not energy
• Quick process than passive transport
• Saturable and selective
• Example: Uptake of glucose
87
cont’d…
 Characteristics of active transport:
• Selective and saturable
• Competitive inhibition by chemical congeners
• Requires carrier and energy
• Movement against concentration gradient
 Examples: iron absorption, uptake of levodopa by brain
88
cont’d…
 Endocytosis: engulfment of large molecules by the cell
membrane and release them intracellulary
• Pinocytosis (fluid phase endocytosis)
• Phagocytosis (adsorptive phase endocytosis)
89
cont’d…
 Ion-pair transport: highly ionized cpds form neutral ion pair
complex.
• This complex penetrates the membrane by simple diffusion
90
PK…
Drug Absorption(A)
91
A…
 The movement of a drug from its site of administration in to
systemic circulation(blood, lymph)= for distribution
• Absorption takes place through one or combination of the
transport process of passive diffusion, carrier-mediated
transport, endocytosis
92
A…
 The rate and extent of absorption depend on
• The environment where the drug is absorbed
• Chemical characteristics of the drug
• The route of administration (which influences

bioavailability)
93
Bioavailability
 The fraction of the amount of drug absorbed and reached
systemic circulation in chemically unchanged form
 For I.V.: 100% (1)
 For non I.V.: ranges from 0-100% (0 – 1)
 Bioavailability = AUC oral / AUC IV
94
Factors Affecting Drug Absorption
 Route of drug administration
 Physicochemical properties of drug
• Molecular weight of the drugs
• Solubility of the drugs (aqueous and lipid solubility)
• pH and enzymatic instability (Penicillin G & insulin)
 Dosage forms
• Solution > suspension> capsule > tablet – in order of rate and

extent of absorption
 Proper reconstitution and dilution of drugs

95
Factors Affecting Drug Absorption…
 Physiological factors
• Administration in to the correct tissue
• Blood flow through the tissue where drug administered
• Gastrointestinal motility (transit time)
• Rate of gastric emptying
• Area of the absorbing surface and local circulation
• Entero-hepatic cycling
 Drug interactions (drug-drug; food-drug)
96
Factors Affecting Drug Absorption…
 Absorption of drugs applied to the skin(topical) in influence by:
• Amount and strength of drug
• Length of contact time
• Size of the affected area
• Thickness of the skin surface
• Tissue hydration
• Skin condition :intact or non intact
97
Factors Affecting Drug Bioavailability
 First pass metabolism (presystemic metabolism)
• Metabolism of drugs before reaching the systemic circulation
 First pass through the intestinal mucosa or liver
• Examples of drugs that have extensive first-pass metabolism:

morphine, nitroglycerin, propranolol, lidocaine
 First pass can be bypassed giving drugs: sublingually,

transdermally, parenteral, rectally to some extent
98
99
Unless a drug acts topically (i.e., at its site of application), it first must enter the
bloodstream and then be distributed to its site of action
Presence of a drug in the blood, does not lead to a pharmacological
response
To be effective, the drug must leave the vascular space and enter the
intercellular or intra-cellular spaces or both
The rate at which a drug reaches its site of action depends on two rates:
absorption and distribution
Absorption is the passage of the drug from its site of administration into
the blood; distribution is the delivery of the drug to the tissues
To reach its site of action, a drug must cross a number of biological

barriers and membranes, predominantly lipid
Binding to plasma proteins, tissue storage, metabolism, and excretion:
determine the amount of drug finally available for interaction with
specific receptors
100
101
PK: Drug Distribution(D)
 Drugs are transported by circulating body fluids to the site
of action(receptors) and to the site of metabolism and
excretion
 It is a process of drug disposition , Following absorption
 Distribution of a drug is not uniform throughout the body b/c

of d/t tissues receive the drug from plasma at d/t rates and to
d/t extents
102
cont’d…
 Organs with the greatest blood supply(heart, liver,
kidneys and brain) receive the drug most rapidly
 Tissues with lesser blood supply (muscle, skin, fat)
receive the drug move slowly
 Once absorbed, a drugs distribution rate is determined
by
 Chemical properties
 How the drug is affected by the blood and tissues it
contacts
103
cont’d…
 Possible Modes of Drug Distribution:
• The drug may remain in the blood(refers to picture 1)
• May be restricted to the extracellular space(refers to

picture 2)
• May also extend into the intracellular space(refers to

picture 3)
• Certain drugs may also bind strongly to tissues(refers to

picture 4)
104
Cont’d…
 Volume of fluids:
• Total body fluid ~ (60% of body Wt in 70-kg ) ~42L
• Blood volume ~5.5L
• Plasma ~4L
• Interstitial fluid~10L
• Intracellular fluid ~28L
106
Cont’d…
 Apparent Volume of distribution (Vd)
• Relates the amount of drug in the body to the concentration
of drug in plasma or blood
Vd = Dose/Cp
• Drugs confined to the plasma compartment~ A drug is

either too large or extensively bind to plasma proteins:
(intravascular) e.g. Heparin
107
Cont’d…
 Apparent Volume of distribution (Vd)…
• Drugs distributed in the ECF ~ many polar compounds,
unable to penetrate cells; (plasma volume plus interstitial
space e.g. Gentamycin
• Distribution throughout the body water~ relatively lipid-

soluble, readily cross cell membranes: e.g. phenytoin &
ethanol
• Distribution beyond total body water > 42L: Extensively bind

to tissue proteins or partition to body fat: e.g. digoxin
108
Cont’d…
 The extent of distribution of drug depends on its:
• Plasma protein binding(PPB)
• Tissue uptake (affinity of drugs to tissue)
Physicochemical properties of the drug like molecular

size, pH and lipid solubility of the drug
Physiological barriers to diffusion of drugs
• Differences in regional blood flow
• Organ/tissue size and perfusion rate
109
Cont’d…
 The extent of distribution of drug depends on its…
• Binding of drugs to tissue components
• Binding of drugs to blood components
• Binding of drugs to extravascular tissue proteins
• Miscellaneous factors:
 Age  Diet
 Pregnancy  Disease states
 Obesity  Drug interactions.
110
Cont’d…
 PPB:
• Most drugs found in systemic circulation as bound
reversibly with one or more of the macromolecules in
plasma and free form
• Some drugs simply dissolve in plasma water
• Most drugs are associated with plasma components such

as:
 Albumin  Ceruloplasmin
 Globulins  Glycoproteins
 Transferrin  Lipoproteins
111
Cont’d…
 Acidic drugs bind principally to albumin
 Basic drugs frequently bind to other plasma proteins, such as:
• Lipoproteins and glycoprotein, in addition to albumin
 The extent of this binding will influence the drug’s distribution

and rate of elimination b/c only the unbound drug can:
Diffuse through capillary Produce toxic effect

and cell membrane Be metabolized
Produce pharmacological Be secreted
effect
112
Cont’d…
 Some factors affect the binding of drugs with albumin:
• Age
• Pregnancy
• Some diseases state are associated
Hyperalbuminemia . Hyperbilirubinemia
Hypoalbuminemia . Liver disease
In uremic patients the plasma protein binding of certain

acidic drugs (e.g., penicillin, sulfonamides, salicylates, and
barbiturates) is reduced
113
Cont’d…
 α1-acid glycoprotein(α1AGP):
• Binds mainly basic drugs
• Level differs in situations such as:
Stress, injury, trauma
Rheumatoid arthritis
Surgery
114
Cont’d…
 As free drug leave the systemic circulation the bound drug
dissociate
 Factors affecting plasma protein binding:
• Drug affinity for binding sites
• Number of binding sites
• Drug concentration
115
Cont’d…
 Others: include
• Lipoprotein
• Globulin
• Hormone binding factor
 PPB is clinically important for those drugs which have high

plasma protein binding and low excretion…?
• Warfarin, ASA, Phenytoin…

 Protein binding act as a temporary drug reservoir
• Prolong drug availability & duration of action
116
Cont’d…
 Selective accumulation of drugs
• Drug distribution is not always uniform, due to different
tissue affinity
• The concentrations of some drugs will be either
considerably higher or lower in particular tissues (simple
distribution assumptions)
• Kidney: contain proteins: metallothionein, that has high
affinity for metals
• Responsible for the renal accumulation of cadmium, lead, &
mercury…toxicity
117
Cont’d…
 Selective accumulation of drugs…
• Eye: Several drugs have an affinity for the retinal pigment
melanin and thus may accumulate in the eye…may cause
retinotoxicity
118
Cont’d…
• Fat: Drugs with high lipid soluble have a tendency to

accumulate in body fat
 However, blood flow to adipose tissue is low (about 3

mL/100g/minute), distribution into body fat occurs
slowly
May result:- Decrease therapeutic activity (thiopental)
o Prolonged activity (fat depot preparation)
o Toxicity
119
Cont’d…
• Lung
Most cpds that accumulate in the lung are basic amines

(e.g., antihistamines, imipramine, amphetamine,
phentermine, chlorphentermine, and chlorpro-mazine)
with large lipophilic groups and pK values greater than 8.
120
Cont’d…
• Bone:
TTC: accumulation may cause dysplasia, poor bone

development, yellow-brown discoloration of teeth
• Lead: accumulation result bone brittleness
• Liver: chloroquine
Generally tissue accumulation of drug may have:
Adv: target tissue therapy
Disadv: mainly toxicity

121
Cont’d…
 The extent or order of binding of drugs to various plasma
proteins is:
• Abumin > α1-Acid Glycoprotein > Lipoproteins > Globulins
122
Cont’d…
 Tissue uptake:
• Determined by the partitioning of drug between blood and
the specific tissue, which in turn depends on:
 Lipid solubility of drugs

 pH gradient between plasma and the tissue (ion
trapping)
 Binding of drug to plasma proteins and tissue
macromolecules
• Some tissues act as storage sites by accumulating the drug
and releasing it slowly over a period of time
123
Cont’d…
 Physiological barriers:
• Blood brain barrier (BBB): regulates transfer of drug to
CNS
 Not pass BBB  Pass BBB

Ionized drug unionized drug
Lipid insoluble lipid soluble
Bound drug unbound drug (small size
124
Cont’d…
 Physiological barriers:
• Inflammation such as meningitis increase the permeability

of BBB ( ionized)
• P-glycoprotein transport system- decrease the concentration

of some drugs in CNS
Pump back to systemic circulation
125
Cont’d…
 Placenta barrier (PB):
• Blood vessels of mother and fetus separated by PB.
Not pass PB Pass PB
 Ionized drug  Unionized drug
 Lipid insoluble  Lipid soluble
 Bound drug  Unbound drug (small size)
126
Cont’d…
 Tissue perfusion:
• Different tissues have different rate and amount of blood

flow
Highly perfused tissues: liver, brain, heart, kidney and

lung
Intermediate perfused tissues: skeletal muscles
Poorly perfused tissues: skin, bone, nail, fat tissue
127
Cont’d…
 Re-distribution
 Termination of drug effect usually is by biotransformation

and excretion, but it may also result from redistribution of
the drug from its site of action into other tissues or sites
128
• Drug
E.g. Redistribution of
thiopental after anxx
intravenous bolus
administration.
129
Cont’d…
METABOLISM (BIOTRANSFORMATION(BT))
130
Cont’d…
 METABOLISM (BIOTRANSFORMATION(BT))
• A chemical change (transformation) of drugs by body
enzymes
• To facilitate excretion of drugs by changing to more water

soluble form
Lipophilic → → hydrophilic
131
Cont’d…
 Consequence of BT:
• Activation of parent pro-drug :e.g. Prednisone 

Prednisolone
Improve bioavailability, mask unpleasant odor/taste,

alter drug solubility and/or provide site specific delivery
132
Cont’d…
• Conversion of drug to its toxic metabolite e.g. paracetamol to
N-Acetyl-P-benzoQuinone Imine
• Conversion of active drug in to other active metabolite e.g.

morphine
• Conversion of active drug in to inactive hydrophilic

metabolite
133
Cont’d…
 Metabolism of drug occur in all body parts
• Lung, GI, kidney, liver, blood…
• But mainly takes place in liver: contains large amount of

metabolizing enzymes (microsomal and non microsomal)
 Metabolism in liver involve 2 steps
• Phase I
• Phase II
134
Cont’d…
 Phase I rxn (non synthetic or functionalizing rxn):
• Adds functional groups or

• Exposes masked functional groups
• Produce more reactive metabolites and more
hydrophilic
• Include:-
» Oxidation
» Reduction
» Hydrolysis
135
Cont’d…
Extrahepatic microsomal enzymes

(oxidation, conjugation)
Hepatic microsomal enzymes

(oxidation, conjugation)
136
Cont’d…
 Enzyme Induction
• Enzyme inducer is a type of drug that increases the
metabolic activity of an enzyme mostly by increasing the
expression of the gene coding for the enzyme
Example. CYP450 enzymes (Most common CYP 3A4/5, CYP
2D6, CYP 2C8/9, CYP 1A2)
137
Cont’d…
 Increases metabolism of other drugs (and sometimes their own
metabolism )
• Outcomes: ↓conc. of parent drug, ↑conc. of metabolite and

either ↓sed activity or ↑se toxicity
Example: phenytoin, carbamazepine, refampine, alcohol
(chronic), barbiturates, st john's wort (PCRABS)
Rifampin (CYP3A4 inducer)  metabolism of oral
contraceptives rendering them inactive
138
Cont’d…
 Enzyme Inhibition
• Decrease liver enzyme function by competitive inhibition---
decrease metabolism---decrease excretion
• Outcome: increase the conc. of parent drug, extend

pharmacological activity, and potential toxicity
• Could be competitive (common) or noncompetitive
139
Cont’d…
• Enzyme Inhibition…
• Examples: grape fruit, protease inhibitors, Azole antifungals,
cimetidine, Macrolides(except azithromycin), Amiodarone,
nondihydropyridine calcium channel blockers (verapamil and
diltiazem), (GPACMAN)
• Warfarin + Metronidazole leads to warfarin toxicitey
• NB. These two are site drug-drug interactions
140
Cont’d…
 Phase II rxn (synthetic or conjugation rxn):-
• Involves conjugation with endogenous molecules (covalent

bond) of more polar molecule to:
• Increase water solubility
• Increase bulkiness of the drug
• Increase excretion
• Drug + endogenous polar cpd
• Saturable
141
Cont’d…
 Glucuronide conjugation
• Using glucuronosyl transferase enzyme
E.g. chloramphenicol, morphine
chloramphenicol not given for infants, why?
142
cont’d…
 Acetylation rxn:
• Involve N-acetyl transferase
E.g. INH, hydralazine
• Acetylation of INH show genetic polymorphism
Fast acetylator-rapid excretion
Slow acetylator-slow excretion
143
Cont’d…
 Sulphate conjugation:
• Use of sulfotransferase enzyme
E.g. steroids
 Methyl conjugation:
• Use methyl transferase
E.g. catecholamine, histamine
144
Cont’d…
 Glutathione conjugation:
• Use glutathione transferase
• Glutathione protect cells from reactive electrophonic cpds
E.g. Paracetamole toxicity detoxification
But at high conc. of paracetamole, since glutathione level

are limited, more toxic metabolite formed----
hepatotoxicity
145
14
6
Cont’d…
 Biotransformation…
• drug → less polar molecule → more polar molecule →

excreted
147
Cont’d…
148
Cont’d…
 Factors affecting BT:
• Physiology
• Genetic make up
e.g. N-acetyl transferase Vs Isoniazid(anti Tb)
• Drug-Drug and Drug-Diet interaction:
E.g. grape fruit juice (inhibit cyp3A4)
• Age
149
Cont’d…
 Factors affecting BT:…
• Sex
e.g. alcohol Vs alcohol dehydrogenase
• Disease state
e.g. liver damage
• Smoking
• Environment
150
Cont’d…
 ELIMINATION (DRUG ELIMINATION)
• Is process of drug removal from systemically absorbed to the

external environment in metabolite or unchanged
• Main routes of excretion:

 Renal excretion (principal organ for most drug removal
especially for water soluble and non volatile drug)
 Hepatobiliary and fecal excretion (eneterohepatic)
 Pulmonary excretion (volatile/gaseous anesthetics)
151
Cont’d…
• Minor Routes of Excretion

 Saliva, sweat, milk, tear, hair
152
Cont’d…
•Renal excretion: Involves 3

steps
1. Glomerular Filtration:
 Influenced by: Molecular

size, shape, and protein
binding
Only unbound drug can be filtered
 Renal blood flow

153
Cont’d…
2. Active tubular secretion needs energy and carrier:
• Important in drug excretion b/c anions and cations are often strongly
bound to PP and therefore not readily available for excretion by filtration
• However, since protein binding is reversible, they are excreted by active

secretory system.
• Uses carrier- saturable and competitive:-Have importance
 Prolonging duration of action---by decreases tubular secretion
E.g. penicillin G– short duration of action—co-administering

probenicid--- compute for the same carrier…Increases penicillins
concentration in lumen
154
Cont’d…
 Passive tubular reabsorption
• Passive diffusion of only unionized, lipophilic drugs
• Ionized drugs are poorly reabsorbed thus excretion is high
155
Cont’d…
 Generally the rate of urinary drug excretion will depend on:
• Vd
• Degree of PPB
• GFR
• Tubular fluid pH
• Extent of back diffusion of unionized form (passive re-

absorption)
• Extent of active tubular secretion of cpd
• Possibly, extent of active tubular re-absorption

156
Cont’d…
 Biliary excretion (Liver):
• Mainly conjugated drugs
• Enterohepatic circulation is common
Highly conjugated drugs excreted in the bile → then to

GIT → GI flora and enzymes hydrolyze → reabsorbed
Prolong duration of action of the drug
157
Cont’d…
 Excretion in Milk
• Concentration of drugs in milk depends on many factors:
Amount of drug in the maternal blood
Lipid solubility of the drug
Drug’s degree of ionization
• Milk is more acidic (pH 6.5) than plasma, hence basic drugs
are more concentrated in this fluid
158
Cont’d…
 The administration of one drug may influence the rate of biliary
excretion of the co-administered drug: it may be altering
 Hepatic blood flow  Rate of bile formation

 Rate of biotransformation  Intestinal flora
• Pulmonary excretion(lung):
 For volatile and gaseous drugs
E.g. ethanol and NO
159
Cont’d…
 Plasma Half-Life (t1/2): time required for a plasma conc. of a
drug to ↓se by 50%.
 Steady state concentration: determined by t1/2
– The rate of administration equals to rate of elimination
160
Cont’d…
 Loading Dose: one or a series of doses that may be given at the
onset of therapy
For the aim of achieving the target concentration rapidly

(Steady state)
 Maintenance Dose: a dose administered to maintain the target

concentration of a drug.
The dose is equivalent to the excreted amount
161
Cont’d…
• Measured by three ways:
1. Plasma t1/2: the time in which the plasma conc. Is reduced

by half
2. Biological effect t1/2: the time in which the pharmacological

effect of the drug or its active metabolite is reduced by half.
162
Cont’d…
• Measured by three ways:…
3. Elimination t1/2: the time in which the total amount of the

drug in the body after equilibration in plasma and other
compartment (fat, muscles, etc.) is reduced to half.
 t1/2 = 0.693/ke
 t1/2 = 0.693 Vd/CL
 CL = ke VD =where ke = Vd/CL
163
Cont’d…
 ELIMINATION ORDER
• Elimination follows either First order kinetics or Zero

order kinetics
1. First order kinetics:
A. Constant fraction of the drug is eliminated per unit of time
B. Most common
C. Increase in dose, increases elimination
D. Increase in dose, t1/2 remains unaltered
164
Cont’d…
2. Zero order kinetics:
A. Constant amount of the drug is eliminated per unit of time
B. Rare: ethanol & high dose of phenytoin, aspirin, dicoumarol
C. Increase in dose, no increase in elimination
D. Increase in dose, t1/2 is increased & chance of toxicity is

present
165
Age of Patients
• Most drugs are developed & tested in young to middle-
aged adults; data on their use in children and the
elderly are sparse
• At the extremes of age, individuals differ in PK/PD
• These differences may require substantial alteration in
the dose to produce the desired clinical effect
Children
• Drug disposition in childhood does not vary linearly
with either body weight or body surface area
• No reliable formula for converting adults doses to doses
that are safe and effective in children
Children are not small adults!
166
Age of Patients
• Drug-metabolizing enzymes can be very immature in both
premature and full-term babies.
• Renal elimination is reduced in the neonatal period.
• Neonates at term have markedly reduced GFRs.
• As a result, neonatal dosing regimens must be reduced to
avoid toxic drug accumulation.
• PD in children may also differ from adults.
Antihistamines and barbiturates?
The enhanced sensitivity to the sedating effects of
Propofol?
Tetracyclines?
Glucocorticoids?
167
ADRs Unique to Pediatric patients
168
169
As adults age, gradual changes in PK alter distribution depending on drug’s lipid
solubility & protein binding
RF declines at rate about 50% of that in young adults.

PD changes are also impt:
Hypotension from psychotropic medications
Hemorrhage from anticoagulants 170
Gender
• Until recently, women were excluded from drug studies.
• Since then many studies have revealed men and women
do show differences in PK (and response).
• These differences appear to be related to hormonal
fluctuations and variation in body composition.
• Known differences:
 Alcohol is metabolized more slowly in women
 Nevirapine – induced Hepatotoxicity more sever in women
 Women’re more sensitive to cardiotoxic effects of
Terfenadine.
171
*Sensitivity to Teratogen depends on developmental stage
172
e.g.: Thalidomide
Was a prescription drug sold during the late 1950’s
early 1960’s, used to alleviate morning sickness.
Critical period for exposure is during organogenesis
Specificity of malformations is linked to time of
exposure:
35-37 days- no ears
39-41 days- no arms
41-43 days- no uterus
45-47 days- no tibia
47-49 days triphalangeal thumbs
173
FDA Pregnancy Categories
174
…
• Drugs get through breast milk and can effect infant
• Concentration of drugs differ in milk.
• Lipid soluble drugs are in higher concentration
• Generally most drugs are in too low a concentration to
be harmful to infant - However consider:
Volume of milk consumed
Age of the infant
Liposolubility of the drug
Some drugs have known risk, hence are
contraindicated: Nicotine, Amphetamines, Lithium,
Marijuana, Anticancer Drugs, ..
175
Why you study PK?????
• ?
176
PHARMACODYNAMICS
177
PHARMACODYNAMICS
 Study of biochemical and physiological effects of drugs and
molecular mechanisms of action
Describes what the drug does to the body

• Mainly concerns on interaction of the drug with the
receptors
178
PHARMACODYNAMICS
• Receptors are functional macromolecular components of the
organism that recognize & respond to endogenous and
xenobiotics
• Drugs potentially are capable of modifying the physiological
function of the body but do not create new effects
179
Cont’d…
 Drug Action
No drug has a single action
When a drug is absorbed and distributed, the desired action

(expected response) usually occurs
All drugs can affect more than one body system, therefore
potentially causing side effects and adverse drug reactions
180
Cont’d…
 Drug Action
Side effects: unintended reactions to a drug given in a normal
dose
Drug reaction: unintended effect on the body from using a
legal drug, illegal drug or 2 or more drug
Each drug has parameters: therapeutic action to expect, side
effects to expect, adverse drug reactions to report and
probable drug interactions
Dosages are adjusted and monitored for the nest therapeutic
effect
181
Cont’d…
 Mechanisms of Drug Action
Physical action
E.g. Adsorption (activated charcoal), osmotic activity

(mannitol), cholestyramine resin
Chemical action
E.g. Neutralization by Antacids,
182
Cont’d…
 Mechanisms of Drug Action…
Through protein targets
• Drugs alter rate of enzyme catalyzed reactions

• Actions could be
 Stimulation/ complete agonist/partial agonist
 Inhibition/ complete antagonist/partial antagonist
183
Cont’d…
Stimulation: increased substrate affinity to enzyme
Inhibition: is a common mode of drug action
• Competitive:
drug binds to catalytic site (mostly non-covalently);
reversed by increasing concentration of substrate.
• Noncompetitive:
drug binds to a site adjacent to catalytic site and as a
result the catalytic property of the enzyme is lost.
184
Cont’d…
 Receptors:
 In pharmacology denote to a class of macromolecules
 Concerned specifically and directly in chemical signaling

between and within cells.
• The most common way by which most drugs generally act
185
Cont’d…
 Receptors Regulation: up regulation and down regulation
 Receptors are dynamically regulated in number, location, and

interaction with other molecules.
 Changes can occur over short times (minutes) and

longer periods (days)
 Frequent or continuous exposure to agonists often

results in short term diminution of the receptor
response, sometimes called tachyphylaxis.
186
Cont’d…
 Receptors Regulation:
– Long-term reductions in receptor number

(downregulation) may occur in response to continuous
exposure to agonists.
– The opposite change (upregulation) occurs when
receptor activation is blocked for prolonged periods
(usually several days) by pharmacologic antagonists or
by denervation.
187
Cont’d…
 Terms in drug receptor interaction
• Affinity (A)- the ability of the drug to bind to the receptor
• Intrinsic activity (IA)- the ability of the drug to produce a

response by itself
• Efficacy-ability of the drug to produce maximum effect

(measures effectiveness of the drug)
• Potency- the dose required to produce a given effect
188
Agonist
• Agonist- drug which have affinity and intrinsic activity (A=1,
IA=1)
• Antagonist- drug having affinity but no intrinsic activity

(A=1, IA=0)
• Partial agonist- drug having affinity but less intrinsic activity

(A=1, 0<IA<1)
• Inverse agonist- has affinity and intrinsic activity (A=1, -

1<IA<0
189
Chemistry of drug-receptor interaction
 The force that attracts the drug to its receptor must be strong
and long lasting to permit the initiation of the sequence of
events that ends with biological response.
 Covalent bond
• Form stable and strong bond
• Forms irreversible, long lasting complex
190
Cont’d…
• Ionic bond
 Less strong than covalent bond
 Common b/n ionizing drug and receptor having ionizable gp

at physiological pH
• Hydrogen bond
 Form stable but reversible complex
 Role-establish selectivity and specificity of D-R interaction
191
Cont’d…
• Vander waals force
 Quite weak force(reading assignment)
 Role in determining D-R specificity
192
Drug
Receptor
Theories
193
Drug Receptor Theories
1. Occupancy theory
2. Rate theory
194
1. Occupancy theory
 This theory suggests that the response to drug depends on:
The proportion of receptors occupied by the drug (not all
receptors need necessarily to be occupied by an active agonist
in order to give a maximal response)
For full agonists there often was a large receptor reserve,
certain number of receptors still remain free (spare
receptors)
195
1. Occupancy theory …
The drugs affinity to the receptors (the ability of the drug to
combine/bind the receptor)
The drug’s intrinsic activity (the ability of the drug to activate
the receptor)
 N.B. drugs exert an all or none action on each receptor, either a
receptor is fully activated or not at all, there is no partial
activation
196
Cont’d…
2. Rate theory
 The effect of the drug depends on the rate of combination of
the drug with the receptors
• Agonist + receptors → A-R →response
• Agonist combines rapidly with the receptor and the complex

dissociates rapidly to free the receptor for further
combination with other agonist
197
Cont’d…
2. Rate theory…
• On the other hand, an antagonist (a)- receptor complex

dissociates slowly. a + R→ a-R→ no response
• Describes the phenomenon of tachyphylaxis (gradual

decrease in the response by the same dose)
A +R→A-R (dissociate slowly)→↓response
198
Signal transduction
 process by which stimulus produced as a result of ligand
receptor binding is relayed into the cell.
 Based on molecular structure and on the linkage between the

receptor occupation and the ensuing response, receptors are
classified into:
I. Ligand-gated ion channels
II. G-protein-coupled receptors (GPCR)
III. Kinase-linked receptors
IV. Nuclear receptors

199
Cont’d…
I. Ligand-gated ion channels
Ionotropic receptors involved
mainly in fast synaptic
transmission
Ligand binding and channel

opening occur on a millisecond
time scale.
Examples: nicotinic cholinoceptor,

gamma-aminobutyric acid type A The nicotinic acetylcholine
receptor
(GABAA) receptors
200
Cont’d…
II. G-Protein-Coupled Receptors
Metabotropic receptors
Comprise seven membrane-spanning segments. One of the

intracellular loops interacts with G-protein .
G-protein (could be stimulatory Gs or inhibitory Gi): is a

membrane protein comprising three subunits (αβγ), the α-
subunit possessing GTPase activity.
201
Cont’d…
II. G-Protein-Coupled Receptors…
When the G-protein binds to a ligand-occupied receptor, the

α-subunit dissociates and is free to activate an effector.
Effector activation is terminated by hydrolysis of the bound

GTP
Is largest receptor family and includes the muscarinic

acetylcholine receptor, adrenoceptors and neuropeptide
receptors.
202
Cont’d…
203
Cont’d…
 The main targets for G-proteins, through which GPCRs

control different aspects of cell function
• Adenylate cyclase: the enzyme responsible for cAMP
formation
• Phospholipase C: the enzyme responsible for inositol
triphosphate (IP3) and diacylglycerol (DAG) formation
• Ion channels: particularly calcium and potassium
channels
204
Cont’d…
• The adenylate cyclase/cAMP system
• cAMP is synthesised within cells from ATP by the action of a

membrane-bound enzyme, adenylate cyclase
• It is produced continuously and inactivated by hydrolysis to

5'-AMP through the action of phosphodiesterases
205
Cont’d…
 The adenylate cyclase/cAMP system…
• cAMP regulates the activity of protein kinases which in turn

regulate many aspects of cellular function
e.g.:- enzymes involved in energy metabolism, cell division and

cell differentiation, ion transport, ion channels, and the
contractile proteins in smooth muscle.
206
Cont’d…
 The adenylate cyclase/cAMP system…
Drug
outside
GPCR plasma
membrane
  cytosol

AC
GDP GTP
GTP GDP ATP cAMP + PP i
207
Cont’d…
 The Phospholipase C/Inositol Phosphate System
• PIP2 (Phosphatidylinositol 4,5-bisphosphate) is the

substrate for a membrane-bound enzyme, PLCβ, which splits
it into diacylglycerol (DAG) and inositol 1,4,5-trisphosphate
(IP3).
208
Cont’d…
 The Phospholipase C/Inositol Phosphate System …
• IP3 binds to the IP3 receptor on ligand-gated calcium

channel present on the membrane of the endoplasmic
reticulum and cause release of Ca2+ to the cytosol.
• The main effect of DAG is to activate a membrane-bound

protein kinase, protein kinase C (PKC), which catalyses the
phosphorylation of a variety of intracellular proteins
209
Cont’d…
 The Phospholipase C/Inositol Phosphate System …
210
-Cellular effects linked to
activation of PKC
Stimulation of cell growth
Regulation of ion channels
Changes in the cytoskeleton
Increases in cellular pH
Effects on secretion of proteins
11/29/2023 211
Cont’d…
 Ion Channels as Targets for G-proteins
• GPCRs can control ion channel function directly by

mechanisms that do not involve second messengers such as
cAMP or IP3
• These actions are produced by direct interaction between the

G-protein subunit and the channel, without the involvement of
second messengers.
212
Cont’d…
 Ion Channels as Targets for G-proteins…
• Voltage-dependent Ca(2+) channels and the G-protein-

activated K(+) channels
• The G-protein beta gamma subunits (G beta gamma) are the

active regulators
213
Cont’d…
III.Kinase-linked receptors
 Responds to protein mediators
 Comprise an extracellular ligand-binding domain linked to an

enzymatic intracellular domain by a single transmembrane
helix
 Activation involves dimerisation of receptors, followed by

autophosphorylation of tyrosine residues
214
Cont’d…
III.Kinase-linked receptors…
 The phosphotyrosine residues act as acceptors for a variety of

intracellular proteins, thereby allowing control of many cell
functions.
 The enzymatic activity could be protein kinase or guanylate

cyclase.
 Includes receptors for insulin and various cytokines and

growth factors (protein kinase), atrial natriuretic factor
(guanylate cyclase)
215
Cont’d…
III.Kinase-linked receptors…
Growth Hormone Kinase-linked receptors

216
Cont’d…
V. Nuclear Receptors
 Ligands include steroid hormones, thyroid hormones, vitamin

D and retinoic acid.
 Receptors are intracellular proteins, so ligands must first enter

cells.
 Receptors consist of a conserved DNA-binding domain

attached to variable ligand-binding and transcriptional control
domains.
217
Cont’d…
V. Nuclear Receptors…
 DNA-binding domain recognizes specific base sequences, thus

promoting or repressing particular genes.
 Effects are produced as a result of altered protein synthesis

and, therefore, are slow in onset.
218
Cont’d…
V. Nuclear Receptors…
219
Cont’d…
Summary…
Figure. Types of receptor- effector linkage

220
Receptor Regulation
 Sensitization or Up-regulation
I. Prolonged/continuous use of receptor blocker
II. Inhibition of synthesis or release of

hormone/neurotransmitter - Denervation
 Desensitization or Down-regulation
I. Prolonged/continuous use of agonist
II. Inhibition of degradation or uptake of agonist
221
Dose-response
relationship(DRRS)
222
Dose-response relationship(DRRS)
 The magnitude of the drug effect depends on the drug
concentration at the receptor site
 Graded dose–response curve: Determine Potency & Efficacy
I. Graded dose–response relations
II. Quantal Dose–response Relations
223
Dose-response relationship(DRRS)
I. Graded dose–response relations
 As the concentration increases, effect also increases until all

the receptors are occupied (the maximum effect) in
individuals.
 Plotting the magnitude of response against increasing doses

of a drug produces a graded dose–response curve
224
Cont’d…
 Potency is a measure of the amount of drug necessary to
produce a minumum effect of a given magnitude
• The concentration of drug producing 50% of the maximum

effect (EC50) is usually used to determine potency
225
Potency…
226
Cont’d…
 Efficacy: is the magnitude drug that produce maximum
response
• It is dependent on the number of drug–receptor complexes

formed and the intrinsic activity of the drug
227
Cont’d…
• Intrinsic Activity (IA): …
The ability of the drug to activate the receptor and cause a

cellular response
It determines the efficacy of a drug
• IA = 1; Full agonist (produce maximal effects- high

efficacy)
228
Cont’d…
• Intrinsic Activity (IA):
• 0< IA <1 Partial agonist (produce only sub-maximal effects
• IA = 0 Antagonist (No efficacy )
• IA = -1 Inverse Agonist (negative effect)
229
Cont’d…
• Intrinsic Activity (IA):…
230
Cont’d…
 Currently there are a number of well established true inverse
agonists including antipsychotics, antidepressants and other
drugs that have inverse agonist activity at serotonin, dopamine,
histamine, opioid, cannabinoid and muscarinic receptors.
231
Drug Specificity
 The chemical structure of a drug determines to the drug’s
specificity.
 A drug that interacts with a single type of receptor will exhibit

high specificity.
E.g. ranitidine, H2 R antagonist used to treat ulcers
232
Drug Specificity
 Drugs acting on widely expressed receptor will exhibit
widespread effects
• Could produce serious side effects or toxicities
• Digoxin, which inhibits the ubiquitously expressed enzyme

Na+, K+-ATPase
• Antifolate (methotrexate) inhibit dihydrofolate reductase, an

enzyme required by all cells for the synthesis of purines
• Lidocaine has local anesthetic effects when administered

locally to relieve pain, but can also have cardiac and CNS
effects if it reaches the systemic circulation. 233
 This is relationship between the dose of the drug and the
proportion of a population that responds to it
• These responses are known as quantal responses; for any

individual, effect either occurs or it does not [all or none]
• Quantal dose–response curves are useful for determining

doses to which most of the population responds
234
II. Quantal Dose–response Relations…
• The ED50 (= EC50) is the drug dose (concentration) that
causes a therapeutic response in half of the population
• TD50 is the dose of drug that causes a toxic response in 50%

of the population
• LD50 is the dose which causes the death of 50% of a group

of test animals.
235
236
Therapeutic Index
 An estimate of a drugs margin of safety
 The therapeutic index (TI) of a drug is the ratio of the dose that
produces toxicity in half the population (TD50) to the dose that
produces a clinically desired or effective response (ED50) in
half the population.
237
Clinical usefulness of the TI
 It is a measure of drug safety
 Drug trials and accumulated clinical experience usually reveal a

range of effective doses and a different (sometimes
overlapping) range of toxic doses
 The larger the therapeutic index (TI) the safer the drug (the
lower the TI, the more toxic the drug).
E.g. Penicillin has high TI (and is a safe drug) while digitalis

has much less TI (hence is a toxic drug).
238
 Drugs with low TI:-
• Digitalis (an antiarrhythmic drug, also used in heart failure)
• Gentamicin (An antibiotic; used to treat some infections)
• Lithium (used in the treatment of mania)
• Warfarin (anticoagulant used in treatment of thrombosis)
239
 An estimate of a drugs margin of safety
• A more realistic estimate of drug safety would include a comparison of the lowest
dose that produces toxicity (LD1) and the highest dose that produces maximal
therapeutic response (ED99)
• Therapeutic window: the range of plasma conc. of the drug in which therapeutic
effect is observed in most of the patients with adverse effect in a very small
percentage of patient.

240
Therapeutic drug monitoring is required:
 While initiating therapy or adjusting dose
 For the critically ill or patients with rapidly changing

physiological status
E.g. acute renal failure
 To confirm toxicity/lack of effect in a poorly controlled patient
 Where a drug interaction is suspected
 As a measure of patient compliance
241
THERAPEUTIC INDEX – AN INDEX OF SAFETY
242
THERAPEUTIC INDEX – AN INDEX OF SAFETY
243
Potency & Intrinsic Activity
 Potency
• Drug “a” is more potent than drug “b”
• Drugs “b” and “c” are of equal potency
• Configuration of curve with respect to the x-axis is indication of potency
 Intrinsic activity (IA)

• Related to the attainment of maximum response
• Drugs “a” and “b” have equal IA while “c” has less IA
• Configuration of curve with respect to the Y-axis gives indication of IA
244
Effect of Antagonists on DRC
 Selectivity
• Dose response curves can help determine how much
selectively a drug produces a specific desired effect
• DRC for the various responses are made and their EC50 are
determined.
245
Effect of Antagonists on DRC
 Selectivity…
• The horizontal gap on the graph (the difference between the
EC50 of the various effects) shows the extent of selectivity of
the drug.
• Such a comparison is also employed to define the safety
margin; the horizontal gap between the DRCs of a
therapeutic effect and adverse effect.
246
Individual Variation
 Drug response curves of same effect (response) from different
individuals is made and compared for EC50
 Sensitive individuals display smaller EC50 value indicating that
smaller dose of a drug produces higher response in this
individuals.
247
Graded -vs- Quantal Response
248
Graded DRCs
 Response obtained from the administration of graded dose to a
single animal or patient.
 With graded responses, one can obtain a complete dose–

response curve in a single animal or patient.
 The curve is continuous
249
Graded DRCs…
Death
Coma
Hypnosis
sedation
Awake
250
Quantal DRCs
 Relationship between dose and some specified quantum of
response among all individuals taking the drug
 Effect is either present or absent (all or none)
E.g. protection of convulsion by anti-epileptic agents.
 Its construction requires that data be obtained from many
individuals.
251
Quantal DRCs…
 ED50 : dose at which 50% of those treated show specific
intensity of effect
 LD50 : Dose at which 50% of those treated die (in animals)
252
Quantal DRCs…
253
Factors that Modify Drug Effect
254
 Body weight
 Age :
 Infants
 Small volume of body fluid compartment
 Incomplete development of the BBB
 Undeveloped renal system
 Undeveloped enzyme system
255
 Aged:
 Decreased liver function and liver blood flow
 Decreased renal function
 Reduced level of albumin and increased level of alpha-1 acid gp
 Reduced total body water and increase in fat level
 Polypharmacy
256
 Sex
• Females usually require smaller doses than males due to:
 Their relative small body size
 Female sex hormones are enzyme inhibitors
 Pregnancy and lactation
257
 Route of administration
• Drugs action e.g. MgSo4-orally-laxative, i.v- CNS depressant
• Onset of action
• The dose
 Time of administration
• On Empty stomach-rapid absorption
• Irritant drugs, antacids- after meal
• CNS stimulants should not be administered in the e
258
 Tolerance to drugs
 Presence of Pathological conditions that alter pharmacokinetics

parameters.
• Some drugs are effective in the presence of a disease. e.g.

salicylates
• Some disease can alter drug dosage. E. g. liver and kidney

disease
 Genetic factors
 Environmental
259
 Administration time
• More of a hypnotic drug is required to induce hypnosis during

day time than during night
• More dose of antihypertensive drug is required to lower

blood pressure in cold weather than in hot one.
 Nutritional state
• Starvation causes decreased protein synthesis (drug

metabolizing enzymes), hence enhanced drug effect.
260
 Drug Interaction
• If two or more drugs are given together they might interact
• Interaction occurs at two stages
 At pharmacokinetic level
At the level of absorption, distribution, biotransformation

or excretion
 At pharmacodynamic level
At the level of receptors
261
Types of Drug Interaction
 Synergism:
 Additive:
 Potentiation:
 Antagonism:
262
Types of Drug Interaction…
 Synergism:
• the combined effect of two drugs having the same action is

greater than the sum of the effect of each drug (1+1>2).
E.g. penicillin + aminoglycoside antibacterials
 Additive:
• combined effect of two drugs having the same action is equal

to the sum of effect of each drug (1+1=2).
E.g. sulbutamol + theophyline
263
 Potentiation:
• The effect of one drug is increased by the other which does

not have the same action. (1+0>1)
E.g. penicillin + probenicid
 Antagonism:
• action of one drug inhibits the action of another
264
 Types of Antagonism drug interaction:
I. Physical antagonism: charcoal adsorbs water and toxins
II. Chemical antagonism: NaHCO3 and gastric HCl
III. Physiological/functional:
Both agents act on different receptors on the same organ

and give antagonistic effect/opposite effect.
E.g. histamine and adrenaline on bronchial smooth

muscle and blood pressure.
265
 Types of Antagonism drug interaction:…
IV. Pharmacokinetic antagonism:
• Certain agents or drugs may interfere with drugs or

antagonize them at the level of absorption, distribution,
biotransformation or excretion by preventing absorption,
interfere with PPB, enhancement of biotransformation
and excretion
266
Cont’d…
 Pharmacological /receptor antagonism:
• Antagonism takes place at the receptor site which could be

of two types:
 Competitive
 Non-competitive.
267
Cont’d…
 Competitive antagonism
• Same binding site for agonist and antagonist
• Acute toxicity of the agonist/antagonist can be treated by

giving large dose of the competitive antagonist and vice
versa
 Non-competitive antagonism
• Binding site of the agonist and antagonist is different
268
Cont’d…
269
Types of Therapy
 Physiotherapy
 Psychotherapy
 Drug therapy
270
Types of Therapy…
 Physiotherapy
271
Types of Therapy…
 Psychotherapy
272
Types of Therapy…
 Drug therapy
• Chemotherapy: drugs used against microbes, parasites, cancer cells
• Pharmacotherapy: application of drugs for their action on various body

parts.
• It could be
 Symptomatic treatment
 Curative treatment
 Replacement treatment: substance essential to body administered
The type of therapy depends on the nature of disease or illness
273
Adverse Effects (Adverse Drug Reactions = ADRs)
 Noxious and unintended effects
 Occurs at normal doses used for prophylaxis, diagnosis or

therapy
I. Predictable adverse effects: dose dependent
II. Unpredictable adverse effects: dose independent
274
I. Predictable adverse effects: dose dependent
• Side effects: Observed at therapeutic dose
• Toxic effects: Effects observed at larger dose/conc
 Acute toxicity: acute administration of larger doses
 Chronic toxicity: Prolonged and repeated use of a drug
275
II. Unpredictable adverse effects: dose independent
• Hypersensitivity reactions: abnormal response due to

antigenic nature of some drugs
• Idiosyncratic reactions: unusual or exaggerated reaction to a

drug in some people
276
Toxicology: Clinical Management of Toxicities
I. Stabilization of the patient: Airway, Breathing & Circulation
(ABCs)
II. Prevention of further absorption, exposure
• Washing of the eyes and skin
• Prevention /reduction of absorption (GI decontamination)
III. Enhancement of elimination of the suspected toxin
IV. Administration of an antidote
• Substances that counteract the effect of a drug or toxin
V. Supportive care and follow-up

277
278
279
Antidote Indication
Physiostigmine Atropine
Pyridoxine Isoniazid
280
Drug development
 Steps in drug development
• Choosing new molecular targets
• Finding a lead compound
• Optimization of the effect of the lead compound (PK and PD)
• Design of pharmaceutical forms and dosage regimens
• Preclinical trial
• Clinical development
281
Drug development…
 Choosing new molecular targets: drug targets are, with few
exceptions, functional proteins (e.g. receptors, enzymes,
transport proteins).
 Finding lead compounds:
• A lead compound is one which shows some useful biological

activity
• The level of activity may not be very great and there may be
undesirable side effects
282
Drug development…
• Lead compounds can then be studied further and modified to
intensify a desired activity or to reduce undesirable side effects
• They provide a start for the drug development process
 Drugs from natural products
Morphine: Papaver somniferum,Cocaine: Erythroxylon

coca,Digitalis: Digitalis purpurea,Quinine: Cinchona bark
and Artimesinin: Artimesia annua
283
Drug development…
284
285
General pharmacology learning outcomes assessment
• What is Pharmacology
• What are the two main divisions of pharmacology
• Other than pharmacodynamics and pharmacokinetics, what are the branches of pharmacology
• What is the difference and correlation between Drug and Medicine
• What is the difference and correlation among Pharmacokinetics and Pharmacodynamics
• Describe; Pharmacotherapeutics, Pharmacogenomics, Pharmacoepidemiology,
Pharmacoeconomics, Pharmacovagilance ,Chemotherapy, Toxicology, Pharmacy, poly
pharmacy,Essential drugs, very essential drugs, non-essential drugs and Orphan drug
• Explain the role of excipients/additives in medicine
• List the Sources of Drugs
• Prescription and Non-Prescription Drugs(OTC)
• Describe the difference between compounding rugs VS manufactured drugs
• How naming drug, what are the drug name style
• What is the difference between brand and generic drug
• What are the possibilities to classify/categorized drug methods
• List all the dosage forms and compared; in terms of advantage and disadvantage
• List all the routes of drug administration and compared; in terms of advantage and disadvantage
• What are the possible factors that affecting choice of route administration as well as dosage form
286
General pharmacology learning outcomes assessment…
• How is drug transported from site of administration (explain drug
transportation system)
• List and explain the factors affecting drug absorption from
different routes of administration
• List and explain the factors affecting drug distribution
• List and explain the factors affecting drug metabolism and the
main take place
• What are the advantages and disadvantages of drug
biotransformation
• List and explain the drugs and their metabolites are excretion
system and the organs
• What is the difference between drug elimination and drug excretion
• Explain drug excretion kinetics, loading dose, maintenance dose,
drug in body half-life vs half-life at environment, drug shelf life,
287
General pharmacology learning outcomes assessment…
• Define and describe the terms

– Receptor, receptor site, receptor structure, receptor numbers
– Receptor Sensitization vs Desensitization
– Receptor Up-regulation vs Down-regulation
– Receptors vs spare receptors
– The different types of d agonist and antagonists
– The drug response curves
– Therapeutic index vs therapeutic window
– Drug and receptor theories
• List and describe detail drug-receptor interaction mechanism
• Describe detail the drug receptor types, their site of action, their effects, and their
inactivation.
• Explain the concepts of drug specificity, affinity, efficacy, potency, intrinsic
activity and selectivity of ligands and their impact on the effect(s).
• What are the Factors that Modify Drug pharmacologic/therapeutic Effect
• Explain detail drug, drug interactions, implications and disadvantages
• Describe drug adverse reactions, drug toxicity management methods
• Explain the steps in drug development
288

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General Pharmacology

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GENERAL PHARMACOLOGY

 Drug: Definition, Sources and Nomenclature Action

• Drug Receptor Interaction

 Example of drug use:

 Is a drug along with other substances in proper, stable

Figure 1: combination of drug and excipients or additives

 Is a drug along with other substances in proper, stable

Figure 1: combination of drug and excipients or additives

 Interaction between xenobiotic and host cells

 Slow or fast acetylation

• It is concerned with the variability of drug effects between

Drugs or biological products for diagnosis,

e.g. amoxicillin, ampicillin, heroin etc. aminoglycosides,

heroin, Coumarin glycosides, Dicoumarol, warfarin:

E.g. Aspirin, chloramphenicol, paracetamol…

e.g. Human GH, insulin…

• Exact names and spelling are imperative

 It is too difficult to be used in prescription

N-acetyl-para-aminophenol/Acetamide, N-( 4-hydroxyphenyl)

 Non proprietary name

 Internationally accepted name

 Unique through out the world

 Proprietary name assigned by the manufacturer(s)

 One drug may have several proprietary names

 e.g. Panadol, Calpol, Alvedon… (Paracetamol)

Generic name Paracetamol

Trade name Tylenol®, Paramol®, Panadol®,

 Medicines with similar characteristics can be categorized

 Medication classification may indicate:

• Which body system the affect?

 Therapeutic use or clinical indications:

• What disease or illness is being treated?

 Physiological or chemical action:

• Does the medication require a prescription or can it be

• Is the drug used for non-therapeutic reasons?

 After development of a specific chemical entity for its

 There are different dosage form designs intended for the

 Preparation of drugs designed for administration

• Semisolid Dosage Forms

• Liquid Dosage Forms

• Inhalational Dosage Forms

 Capsules: solid/liquid drugs enclosed in a hard or soft

 Suppositories: into rectum. Vagina, urethra

 Lozenges, Pastilles, Granules, powder and Dental

Are SDF; unit doses, as solid, semisolid or liquid form of the

Application on skin or mucous membranes

• Creams: mixtures of oil and water.

emulsions for external use as protective or

• Pastes: heavy consistency (~ 50% of solid )

 Solution: - the active ingredient is soluble in the

 Suspension: the active ingredient is insoluble

• Enteral (via GIT)

 Percutaneous (for local action)

• Enteral (via GIT)

• Drugs administered directly into the GI tract

E.g. Orally, Sublingual, Rectal

• It is the most common method of drug administration

Safe, more convenient and economical

Often painless, self - administration

Both solid and liquid dosage forms can be administered

Untoward effect, if any, appears slowly

Reverse of dose management is easily done (how?)

 Drug-food interactions may lead to formation of