Addis Ababa Science and

Technology University
College of Applied Science
Department of Industrial Chemistry

Industrial Pharmacy
By
Yitayal Admassu (PhD, RPh)
Assistant Professor of Pharmaceutics and
Nanotechnology

1 AAST
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Outlin
e
 Chapter 1 Drugs
 Chapter 2. Introduction to dosage forms &
pharmaceutical Industry
 Chapter 3. Granulation,Tablets and compaction and
Tablet coating
 Chapter 4, capsules (Hard and soft GC)
 Chapter 5; Solutions, Suspension and emulsion
 Chapter 6; Sterile product
 Chapter 7. Drug stability and Kinetics
 Chapter 8 Current good manufacturing practices

2 AAST
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 Chapter 1
 Drugs & Pharmaceutical dosage
form

3 AAST
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Cont
…
 Definition of Pharmacy
 Is the clinical health science that links medical science with
chemistry and it is charged with the discovery, production,
disposal, safe and effective use, and control of medications and
drugs.
 Is the science and technique of preparing as well as dispensing
drugs and medicines.
 The scope of pharmacy practice includes more
traditional roles such as
 Compounding and dispensing medications, and it also
includes more modern services related to health care,
including clinical services, reviewing medications for safety
and efficacy, and providing drug information.

4 AAST
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Cont
…
 Pharmacists, therefore, are the
experts on drug therapy and
are the primary health
professionals who optimize
use of medication for the
benefit of the patients.
 Fields/Areas of Study in
Pharmacy
 Pharmacognosy
 Pharmaceutics
 Pharmaceuticals
Chemistry
(Pharmaceutical analysis
and medicinal
Chemistry )
5 Pharmacology and AAST
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Toxicology
Cont
…Drug:

 Any substance that brings about a change in biologic
function through its chemical action.
 A drug is an agent intended for use in diagnosis (e.g.
Barium Sulfate), prevention (e.g. Chloroquine), treatment
([Link]) or mitigation ([Link]) of disease.
 Drugs mostly interact with a specific molecule in a
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 &
 Atomic composition

6 AASTU,
Cont
…
 Source of drugs
 Mineral: liquid paraffin, Mg
Trisilicate
 Animals: Insulin, heparin, thyroid,
 Plants: M orphine
 Synthetic: Aspirin,digoxin, atropine,
castor oil, quinine
 Microorganism: Penicillin,
streptomycin
 Genetic engineering: Human
insulin

7 AAST
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Cont
…Drug nomenclature

 A drug generally has three categories
of names:
 Chemical Names:
 Is given according to the chemical constitution of a drug and
indicates the precise arrangement of atoms and atomic
groups in the molecule.
 Such names are usually too lengthy and complicated to use.
 E.g. Atenolol --- 4-[2-hydroxy-3-[(1-methyl ethyl) amino]
propoxy] benzene acetamide.
 This is cumbersome and not suitable f
 or use in prescribing

8 AAST
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Cont
… Approved, official, Non-proprietary or generic names
 Is a common name drug that allows different product with the
same ingredient to be identified as such.
 It is internationally accepted common name of the drugs
 E.g. Propranolol, omeprazole, paracetamol, atenolol etc
 Proprietary name, trade name or brand name:
 Is unique name to particular manufacturer as it is given by its
manufacture
 Serves in establishing the identity of the product in the market.
 One drug may have a multiple proprietary names.
 Example, MEDOPRAZOLE®, OLIT®, OCID®, UFONITREN®,
LOCID®, LOSEC®

9 AAST
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Cont
…Dosage form

 A drug is an agent intended for use in diagnosis (e.g. Barium
Sulfate), prevention (e.g. Chloroquine), treatment
([Link]) or mitigation ([Link]) of disease.
 But drugs are not/ seldom administered alone because:
 Bitter taste, low dose (potent), elegancy, insoluble, and etc
 Therefore drugs are used in combination with one or more
medicinal substances that serve as sweetener, colorant, diluent,
solubility enhancer and etc… which are called
 Pharmaceutical adjuvant /excipient

Drugs + Pharmaceutical excipients ---------------Dosage forms

↓ ↓
Activ Inactiv Formulatio
e e n

1 AAST
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Cont
…
 Dosage forms:
 Are the means by which drugs are delivered to the sites of
action within the body.
 The form in which the drugs are administered
 Four dosage forms are known
 Solid DF e.g. tablet, capsule and powder
 Liquid DF e.g. syrup, suspension and solution
 Gas DF e.g. aerosol,

 Semi solid e.g. cream, ointment, suppository and paste

1 AAST
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Cont
…
Cont
…
 Routes of drug administration
 The administration of a drug is a fundamental
responsibility.
 An understanding of the basic concepts of
administering drugs is critical if the health
professional is to perform this task safely and
accurately
 Factors governing choice of route of
administration:
 Physical and chemical properties of the drug (solid,
liquid, gas, solubility, stability, pH
etc)
 Site of desired action localized or general.
 Rate and extent of absorption of the drug from
different routes.
 Effect of digestive juices and first pass metabolism of
1 the drug. AAST
2  Rapidity with which the response is desired (routine
U, treatment or
emergency)
 Cont
…
Drug can be applied locally (topically), administered orally
or by injection.
 It is important to know the routes of
administration because it determines.
 1. Onset
 2. Intensity
 3. Duration
 4. Degree of localization of the drug

1 AAST
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Cont
…There are three major categories of routes of drug

administration:
• Enteral, parenteral, others
 1. Enteral
 A. Oral:- the most common route of drug administration.
 The drug may be
 A Swallowed as a whole
 Chewable
 Taken sublingually
 Some drugs are absorbed from the stomach
 E.g. Alcohol, Aspirin.
 However the duodenum is often the major site of absorption

1 AAST
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Cont
…
 Advantage:
This route is
 Safe,
 Convenient & Economical.
 Disadvantage:
 First pass metabolism by the intestine or liver limit the
efficacy of many drugs except sublingual medication
 Onset of drug action is slow.
 Irritant drugs cannot be administered.
 Not useful in vomiting and sever diarrhea.
 Gastric acid and digestive enzymes may destroy some
drugs.
1 AAST
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Cont
… Water soluble drugs are absorbed poorly.
Presence of food in the stomach delays gastric

emptying leading to poor absorption.
 Enteric coating of a drug protects it from the acidic
environment and may prevent gastric irritation.
 Remark

 When drugs are absorbed from the gastro

intestinal tract, they will have to pass via the portal vein
to the liver before reaching the general circulation.
 This may be important as many drugs we metabolized
as they pass through the liver so that only a portion of
the drug which is absorbed actually reaches it's site of
action.
1 AAST
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Cont
…

1 AAST
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Cont
…  This is called first-pass effect.
 It is the term used for the hepatic metabolism of a
pharmacological agent when it is absorbed from the gut and
delivered to the liver via the portal circulation.
 The greater the first-pass effect, the less the agent will reach the
systemic
circulation when the agent is administered orally.
 B. Sublingual/ Buccal
 Some drugs are taken as smaller
tablets which are held in the mouth
or under the tongue. E.g.
Nitroglycerine
 Allows the drug to enter systemic
circulation directly.
 Since venous drainage from the mouth is to the superior venacava, the
1
drug bypass the intestine and liver and is not inactivated by
AAST
8 metabolism . U,
 e.g. If sublingual tablets of nitroglycerine are swallowed, any active
Cont
…
 Advantages
 It bypasses first pass metabolism, the acidic stomach (if the drug
is acid labile)
 Rapid onset of action
 For example nitroglycerine is effective when retained
sublingually because it is nonionic and has very high lipid
solubility.
 If a tablet of nitroglycerin were swallowed, the accompanying
hepatic metabolism would be sufficient to prevent the appearance
of any active nitroglycerin in the systemic circulation.
 Disadvantages
 Inconvenient
 Suitable only for small doses
 Unpleasant taste of some drugs
1 AAST
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Cont
…
 C. Rectal Route
 Insertion of the drug into the rectum
 The rectal route often is useful when oral
ingestions precluded because the patient is
unconscious or when vomiting is present
 A situation particularly relevant to young
children.
 dvantage
 For irritating drug e.g. indomethacin supp
 To produce local effect ,
 For unconscious patient
 For children e.g. paracetamol supp
 Approximately 50% of the drug that is absorbed from the rectum will
bypass the liver; the potential for hepatic first-pass metabolism thus is
less than that for an
oral dose
Cont
…Disadvantage

 Inconvenience of administration
 Slow absorption of drugs
 Irregular and incomplete absorption
 Many drugs can cause irritation of the rectal mucosa.
 [Link] Routes
 Drug may be administered locally in the vagina in the
form of pessaries.
 E.g. Antifungal vaginal pessaries

2 AAST
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Cont
…
 Parentral Route - ( Para - beside & enteron –
intestine)
 This route is employed in case of drugs which are poorly
absorbed from the gastrointestinal tract or destroyed in GIT.
 It is also the route of choice when rapid absorption of drug is
essential in emergency.
 Also useful in uncooperative or unconscious patient
 Examples of parental route of administration
 Intro-muscular (IM) –
 Injection is given deep into the skeletal muscles (deltoid,
gluteous)
 Intravenous (IV)
 It could be either bolus or infusion

2 AAST
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Cont
…
 Subcutaneous (SC) –
 Drug is injected into subcutaneous tissue and only non-
irritant drugs can be given. Also important for implantation
of solid pellets.
 The less commonly used parenteral route of drug
administration
 Intra-peritoneal –
 Injection of the drug into peritoneum (space
between stomach and lung or heart)
 Intra-pleural –
 Injection of the drug into pleural cavity (membrane
surrounding the lung)
 Intra-arterial (I.A) - Drug injected into arteries
 Intra-techal Route - Way of administering a drug
through a sub-arachinoid space. (it is space
surrounding by brain )
Cont
…Advantages of parentral routes of administration over

oral route
 More rapid response
 More accurate dosage
 Useful in vomiting and unconsciousness
 Disadvantages
 Because of rapid onset, little time to combat
adverse drug reactions and accidental overdoses
 Sterile dosage forms
 Aseptic procedures
 May be painful
 Relatively expensive
 Patients can not usually administer to themselves
2 AAST
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Cont
…
 Other-topical
 Drugs are applied topically into the skin for local action
 [Link]-inflammatory, anti-fungal
 Drugs also applied topically to the mucous membrane (e.g.
eye, ear, & nose)
 Topical application can also used for systemic effect e.g.
Nassal drop
 Inhalation
 The drug prime particle will learn capillary area of the alveoli
of the lungs,
 Which provide an excellent absorbing surface for volatile
drugs, gases.
 Very efficient way of administering drug.

2 AAST
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Cont
…Pharmacokinetics

 Deals with the absorption,
distribution, metabolism and
excretion of drugs in the body.
 All pharmacokinetic processes
involve transport of the drug
across biological membranes.
 It deals with the fundamental
processes that determine the
concentration of a drug at any
moment and in any region of the
body that are translocation of drug
molecules (absorption, distribution
and excretion ) and chemical
transformation (metabolism).

2 AAST
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Cont
…Mechanisms of
  The transfer of molecules is
transport across cell directly proportional to the
magnitude of the concentration
membranes gradient across the membrane,
1. Passive diffusion the lipid-water partition
 A. Simple passive coefficient of the drug and the
diffusion membrane surface area exposed
 The drug molecule usually to the drug
penetrates by diffusion
along a concentration
gradient by virtue of its
solubility in the lipid
bilayer.
 There is no requirement
of energy and is the
most common
2 mechanism of AAST
7 transport. U,
Cont
…B. Facilitated diffusion

 This is a carrier mediated transport system
characterized by selectivity, competitiveness,
saturability, and concentration gradient.
 The rate of transport is at first related to the
concentration gradient but as the gradient increased the
rate reaches a limiting or maximal rate.
 2. Active transport
 Passage facilitated by an energy-dependent membrane
carrier mechanism such that transport can occur against
a concentration gradient.
 It exhibits structural selectivity, saturability, competition
between structural analogues and genetic variants.

28 AASTU,
Cont
…
 3. Endocytosis
 This involves passage into cell
within membrane invagination
and important mechanism for
particulates and high molecule
weight compounds, such as
proteins.
 I. Absorption of drugs
 Absorption is the transfer of a drug
from its site of administration to the
blood stream.
 The rate and extent of absorption
depends on the route of administration.
 In case of intravenous or intraarterial
administration, the drug bypasses
absorption process and it enters in to
2 the circulation directly AAST
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Cont
…
 Factors affecting drug absorption
 Physico-chemical properties of drug
 Nature of dosage form
 Physiological factors
 Pharmacogenetic factors
 Disease states
 A. Physicochemical properties of drug:-
 1. Physical state:-Liquids are absorbed better than solids
 2. 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
in to the cell more rapidly than the water soluble drugs.

3 AAST
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Cont
…
 3. 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 and 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 portion of a weak organic
acid or a weak organic base.
 These drugs exist in two forms. Acidic drugs are rapidly absorbed
from the stomach. eg. Salycilates, Barbiturates
 Basic drugs are not absorbed until they reach to the alkaline
environment i.e the small intestine eg. Ephedrine, Pethidin
31 AASTU,
Cont
…
 B. Dosage forms
 3. Formulation; Usually
substances like lactose,
 1. Particle size: Small sucrose, starch and calcium
particle size is important phosphate are used as inert
for drug diluents in formulating
absorbtion .Drugs given in powders or [Link] type
a dispersed or emulsified and amount of additives may
state is absorbed affect the rate of
better .[Link] D, [Link]. Enteric
Vitamin A. coating.
 2. Disintegration time and
dissolution rate.
Disintegration time is the
rate of break up of the
tablet or capsule in to the
drug granules. Dissolution
rate is the rate at which
3 AAST
2 the drug goes in to U,
solution.
 Cont
…C. Physiological factors  2. Presence of other
 1. Gastro intestinal transit agents:
time:  Vitamine C inhances the
 Rapid absorption occurs absorption of Iron from the
GIT.
when the drug is given on
empty stomach.
 Calcium present in milk
and in antacids forms
 However certain irritant
insoluble complex with the
drugs like salycilates and Tetracyclines and reduce
Iron preparations are their absorption
deliberately administered
after food to minimize the
GI irritation.
 But sometimes the
presence of food in the GI
tract aids the absorption of
certain drugs.
3 AAST
3
 E.g. Grisofulvine, propranolol, U,
and riboflavine.
Cont
…3. Area of the absorbing
  D. Pharmacogentic factors: -
surface and local  Induvial variation occurs
circulation: due to the genetically
 Drugs can be absorbed mediated reason in drug
better from the small absorption and response.
intestine than from the  E. Disease states
stomach because of Like malabsorbion syndrome
 Large surface area of the affects the rate and extent of
small intestine. absorption
 Increased vascular supply
can increase absorption.
 4. Contact time at the
absorption surface of the
drug
 moves very quickly, as in
3 severe diarrhea it is not AAST
4 well absorbed. U,
Cont
…
 Bioavailability AUC after oral dose
 Bioavailability (F) =
 is the fraction of administered ----------------------------
drug that reaches the AUC after IV dose
systemic circulation in the  AUC = Area under the curve
unchanged form. which provides information about
 For example: if 100mg of a the amount of drug absorbed
drug is administered orally
and 70mg of this drug is
reached the systemic
circulation, the bioavailability is
70%.
 Bioavailability of a drug
injected in IV is 100%.
 Bioavailability of a drug
administered orally is the
ratio of the AUC for oral
administration compared
3 with the AUC for IV AAST
5 injection U,
Cont
…
 Bioequivalence
 Drug products are
considered to be
pharmaceutical
equivalents if they
contain the same
 Active ingredients and are
identical in strength or
 Two pharmaceutically
concentration, equivalent drug products
 Dosage form, and are considered to be
 Route of administration. bioequivalent when the rates
and extents of bioavailability of
the active ingredient in the
two products are not
significantly different under
suitable test conditions
3 AAST
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Cont
…
 2. Distribution of Drugs
 Penetration of drugs to the sites of
action through the walls of blood
vessels from the administered site
after absorption is called drug
distribution.
 Movement of drugs proceeds until
equilibrium is established between
unbound drug in plasma and tissue
fluids.
Possible Modes of Drug
Distribution:
 Following its uptake into the body,
the drug is distributed in the blood
 (1) and through it, the drug may be
restricted to the extracellular space
(plasma volume plus interstitial
space) (2)
3 or it may also extend into the AAST
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intracellular space (3). certain drugs
may bind strongly to tissue
Cont
…
W hat Is the effect of Ion Trapping on Drug
Distribution
Compartm Compartm
ent with ent with
Low pH High pH

Unionize Unionize
d Weak d Weak
Acid Acid Higher
total
concentrati
on of weak
Ionized
Ionized acid
Weak
Acid Weak
Acid
3 AAST
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Cont
…Factors Affecting Distribution

of Drugs
Physico-chemical properties of drugs
 Lipid solubility of the drug
 pKa of the drug
 Degree of plasma protein binding
Physiological factors
 Rate of blood flow
 Tissue uptake
Presence of barriers
 BBB
 Placental barrier
 Testicular barrier
3 AAST
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Cont
…3. Drug

metabolism
(Biotransformat
ion)
 As drugs are xenobiotics our
body tries to terminate the
biologic activity of some
drugs.
 Renal excretion plays a pivotal
role in terminating the biologic
activity of some drugs,
particularly those that have
small molecular volumes or
possess polar characteristics
4
such as functional groups that AAST
0 are fully ionized at physiologic U,
pH.
Cont
… The lipophilic characteristics of drugs that promote their
passage through biological membranes and subsequent
access to their site of action also serve to hinder their
excretion from the body.
 An alternative process that may lead to the
termination or alteration of biologic activity is
metabolism.
 In general, lipophilic xenobiotics are transformed to more
polar and hence more readily excretable products.
 In general, biotransformation reactions generate more
polar, less pharmacodynamically active than the parent
drug and may even be inactive metabolites that are
readily excreted from the body.
 However, in some cases, metabolites with potent
4
biological activity or toxic propertiesAAST
are generated.
1 U,
Cont
…  Biotransformation of drugs may lead to the
following
 In-activation render less active or inactive → most
drugs.
 Activation:-active metabolism is produced from
active drug.
 Diazepam→Nor diazepam.

 Activation of an inactive drug: - few drugs are inactive

as such and need conversion in the body to one or
more active metabolite.
 Such drug is called prodrug. Eg.L-dopa to Dopamine

4 AAST
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Cont
…
[Link] of drugs  The rate of excretion
 Means the influences the duration of
transportation of action of drugs.
unaltered or altered form  If the drug is excreted slowly,
of drug out of the body. the concentration of drug in
 The major routes of the body is maintained and
excretion include the effects of the drug will
renal excreation continue for longer period.
hepatobiliary
excretion and
pulmonary excretion.
 The minor routes of
excretion are saliva,
sweat, tears, breast
4
milk, vaginal fluid and AAST
3 hair. U,
Cont
…Clearance
 Eg. If blood level of drug A is
8.6mg/ml at 10 minutes and
 Is the volume of plasma 4.3mg/ml at 60 minutes, the half-
cleared off the drug by life of that drug is 50 minutes
metabolism (hepatic) and
excretion (renal) and other
[Link] clearance is
calculated by:-
 Ct =Ch+Cr+Cothers
 Ct=total clearance
 Ch=hepatic clearance
 Cr=renal clearance.
 Half-life (t1/2 ) of a drug is the
time taken for the
concentration of drug in the
plasma to decline to half of
original value or the amount of
4 AAST
4
drug in the body to be reduced U,
by 50%.
Cont
…
 Pharmacodynamics  Example: Adrenaline by
(PD) binding to α-receptor cause c
AMP increment.
 Pharmacodynamics deals  Then finally cause
with the study of the vasoconstriction.
biochemical and  cAMP increment: action
physiological effects of  Vasoconstriction: effect
drugs and their
mechanisms of action.
Action Vs Effect
 Action: is the property of a
drug to alter conditions in a
biological entities
 Effect: is the result we
observe when drugs act on
this biological entities
4 AAST
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Cont
…Drugs do have

selectivity on the
system on which
they act → there is a
minor & major
actions.
 Major action leads to
major effect
 Minor action (Side action)
leads to minor (side) effect
 [Link]
 Major action: analgesic,
antipyretic, anti-
inflammatory (by
4 blocking prostaglandin AAST
6 U,
synthesis)
 Minor action (SE):
Cont
…Mechanisms of drug
  2. Chemical action:-the drug
action acts according to simple
chemical equation.
 The fundamental mechanisms
of drug action can be  E g. Antacids
distinguished in to four
neutralizes gastric HCl.
categories.
 3. Enzyme action : - Enzymes
are
very important sites of drug
action.
 I. Physical action:-Physical  Drugs can either increase
property of the drug is or decrease the rate of
responsible for its action. enzymatically mediated
 Eg. Osmotic activity-
reactions; which can be
either stimulation or
magnesium sulphate. inhibition
4 AAST
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Cont
…4. Receptors action : -
  The biological molecules
 Most of the drugs act by include: Cimetidine +
Receptors:
interacting with a cellular Histamine receptor
component called a receptor.  Enzymes: Aspirin +
 Receptors are protein Cyclooxygenase
molecules present either on  Transporters (carriers):
the cell surface or with in the Cardiac glycosides +
cell. Na+/K+ ATPase,
 Structural proteins:
 Eg. Adrenergic receptors,
Colchicine +
cholinoceptors, insuline receptors.
tubuline (subunits of
 How do drugs act? microtubules)
 Drugs exert their effect either by
binding to biological molecules or
through non- specific physicochemical
mechanisms.

4 AAST
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Cont
…
 Receptor  Site of drug action drug may
 Class of cellular act:-
macromolecules concerned  A. Extracellularly
specifically and directly with  Osmotic diuretics.
chemical signaling between and
within cells via chemical signals
 B. On the cell surface
(ligands).  eg. Digitalis,
 They bind hormones, Penicillins,
neurotransmitters, cytokines, Catecholamines.
peptides etc  C. Inside the cell
 eg. Anticancer drugs,
steroid hormones.
 A drug which is able to fit
on to a receptor is said
to have affinity for that
receptor
4 AAST
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Cont
…
 Factors governing drug  Intrinsic activity (efficacy):
action  The ability of a drug to
activate a receptor following
 Potency: binding
 is a measure of how much  It is reflected in the maximal
drug is required to elicit a efficacy (drugs with high
given response. intrinsic activity have high
 The lower the dose required maximal efficacy).
for a given response the more  Its value ranges from 0 to 1.
potent the drug is.  Antagonists have 0 efficacy.
 Affinity:
 The strength of the
attraction between a drug
and its receptor.
 The ability of a drug to bind
to its receptor
 Affinity is reflected in potency.
5 AAST
0 i.e. drugs with high affinity are U,
very potent.
Cont
…
 In view of binding, ligands
can be
 Agonists:
 have affinity and intrinsic
activity (A=1, IA=1)
 Antagonist:
 have affinity but no intrinsic
activity (A=1, IA=0)
 Partial
agonist/antagonist:
 have affinity but with
submaximal intrinsic activity
(A=1, 0<IA<1)

5 AAST
1 U,
Cont
…Drug Desensitization
 Non-receptor mediated
mechanisms include reduction of
 Effect of a drug often receptor-coupled signaling
diminishes when given components, reduction of drug
continuously or repeatedly concentration, physiological
and terms like adaptation.
desensitization, tachyphylaxis,
refractoriness, resistance, and
tolerance are given to this
phenomenon
 The mechanisms of drug
desensitization could be
receptor- mediated or non-
receptor- mediated.
 Receptor mediated
mechanisms include loss of
receptor function, reduction of
5 receptor number etc AAST
2 U,
Cont
…
 Therapeutic  D os
Index
 A parameter used to predict e
Is defined as the
drug safety. It considers the appropriate amount of a
dose required for a toxic drug required to produce
effect versus that required desired response in an
for the desired beneficial individual.
effect.  The dose of a drug differs
 In general, a larger T.I. interms of the desired
indicates a response.
clinically safer drug  There could be prophylactic
dose,
 Initial therapeutic
Loading dose or toxic
Dose:-
dose of the same drug.
is a higher dose or a series
of doses that may be
given at the onset of
therapy to achieve the
target concentration
rapidly.
5 AAST
3 U,
Cont
…Maintenance Dose:-
  Median Lethal Dose (LD50)
 The dose which is repeated at Thisis the dose which would
regular intervals to maintain a steady be expected to kill one half of
state concentration of the drug in a population of the same
plasma and thus to maintain the species or strain.
effect.
 Median Effective Dose
(ED50)-
 The dose which produces
a desired response in 50%
of the test population.

 Dosage
 Means the amount and frequency
of administration of a drug and
duration of therapy

5 AAST
4 U,
Cont
…
 Drug Interactions  B) Pharmacokinetic drug
 It is a phenomenon which interaction-
occurs when the effects of  This is an interaction which
one drug are modified by the occurs during the process of
prior or concurrent absorption, distribution,
administration of other drugs.
metabolism or excretion of
 Drug interaction may result drugs.
in a
 [Link] +Calcium
beneficial or harmful effect.
 Drug interaction may be → decreased absorbtion
classified as:- of Tetracycline.
 Sulphonamides +
 A. Pharmaceutical
Salicylates →
drug interaction- Sulphonamide toxicity.
 Eg. Diazepam if added in infusion  Because sulphonamides will
fluid, there will be a precipitate
be displaced from their
formation.→ loss of therapeutic
binding site.
effect.
 Warfarine + Barbiturate

5 (enzyme
AAST inducer) →
5 decrease
U, anticoagulation
Cont
… Pharmacodynamic  4. Antagonism:
Interaction:  It occurs when the effect of
 1. Additive effect: -
one drug is diminished by
another drug .There are
 Combined effect of the two different modes of
drugs having the same action antagonism
is equal to the sum of their
individual effects.  Chemical antagonism
E.g Ephedrin + Aminophyillin  Chemical antagonist combines
 2. Potentiation: - with drug to produce insoluble
inactive complex.
 The effect of one
 [Link] and alkaloid form
chemical bond
drug is increased by the  Physiological (functional, variant)
other which does not have antagonism - the “antagonist” has
the same action, the opposite biological action by
E.g Amoxycillin + its action on a different receptor.
Clavuletnic acid  E.g. Insulin and glucagon
 3. Supra-aditive effect  Histamine and omeprazole
5 (synergism):- AAST
6 U,
 Combined effect of two drugs
having same action is greater
Cont
…Drug toxicity and
  Are pharmacological effects
management of drug poising produced with therapeutic
dose of the drug.
The drug that produce useful

 E.g Dryness of the mouth
therapeutic effect may also
with Atropine
produce unwanted or toxic
effects, an adverse drug
reaction is defined or any
responses to a drug that is
noxious and unintended that
occurs at doses used in man
for prohylaxis, diagnosis or
therapy.
 Adverse effects may develop
promptly or only after
prolonged
 The adverse medication
effects or
even after stop of the drug.
are
 1) Side effects: -
5 AAST
7 U,
Cont
…
 Untoward effects: -  Teratogenic effect:
 Develop with therapeutic dose  Some drugs given in the
of a drug. first three months of
 They are undesirable and if pregnancy may cause
very severe, may congenital abnormalities
necessitate the cessation of and are said to be
treatment. teratogenic
 E.g Potasium loss (hypo
kalemia) with diuretics like
Frusamide.
 Allergic Reaction
Most drugs when
(S)-isomer is teratogenic
administered at therapeutic
Antiemetic = a medication that
doses are capable if causing
helps prevent and control
allergic (hypersensitive) nausea and
reactions. These reactions vomiting
5
may be mild or severe. AAST
8 U,
Cont
…

 Birth defects caused by use of

thalidomide

5 AAST
9 U,
Cont
… The most sensitive period  NB.
of teratogenesis during  It is advisable not to use
pregnancy is 3-10 weeks of any drug during
pregnancy i.e the time of pregnancy unless
organogenesis. definitely indicated.
 Teratogenesity receives a
great attention after
thalidomide disaster in
1959-61 in West
Germany leading to large
number of cases of
phocomelia (seal limbs).
 At present, it is mandatory
to test the teratogencity of
any new drug in animals
before introduction in
6 therapy. AAST
0 U,
Cont
…
 Drug Discovery
 How are drugs
discovered and
developed?
 The ultimate aim of  Choose
pharmacological studies a
in animals is to find out disease
 Choose a drug target
a therapeutic agent
 Identify a “bioassay”
suitable for clinical
 bioassay = A test used
to
evaluation in man.
determine biological
 Drug development activity.
comprises of two steps :-
 a) Preclinical development
and
 b) Clinical development
6 AAST
1 U,
Cont
…
 Drug Design
 Identification of therapeutic area
 Intensive literature search
 Determination of the presence of unmet medical need
 The presence of plausible assay
 Identification of a lead
Lead compound:
•Natural product
- microbial fermentation broths
- plant extracts
- animal derived
•Through screening of synthetic compound libraries
•Virtual screening (in silico screening)
- requires 3D-structure of target protein (x-ray
crystal structure, homology model)
- 3D-pharmacophore of an active ligand
Cont
…

6 AAST
2 U,
Cont
…
 Find a “lead
compound”
“lead compound” = structure
that has some activity against
the chosen target, but not yet
good enough to be the drug
itself.
 If not known, determine the
structure of the “lead
compound”

 Synthesize analogs of the

lead
 Identify Structure-Activity-
Relationships (SAR’s)

6 AAST
3 U,
Cont
…Identify the “pharmacophore”


pharmacophore = the
structural features directly
responsible for activity
 Optimize structure to
improve
interactions with target

 Determine toxicity and

efficacy in animal models.
 Determine
pharmacodynamics and
pharmacokinetics of the drug.
 Pharmacodynamics explores
what a drug does to the
body, whereas
6
pharmacokinetics
AAST
explores
4 what the
U, body does to the
drug
Cont
…Patent the drug

 Continue to study
drug metabolism
 Continue to test for
toxicity

 Design a
manufacturing
process
 Carry out clinical
trials
6  Market the drug
AAST
5 U,
Cont
… Choosing a Disease
 Pharmaceutical companies
are commercial
enterprises
 Pharmaceutical companies  Most research is carried out
will, therefore, tend to avoid on diseases which afflict “first
products with a small world” countries: (e.g. cancer,
market (i.e. a disease which cardiovascular diseases,
only affects a small subset depression, diabetes, flu,
of the population) migraine, obesity).
 Pharmaceutical companies
will also avoid products
that would be consumed
by individuals of lower
economic status (i.e. a
disease which only affects
6 third world countries) AAST
6 U,
Cont
…Pre-clinical development
  Clinical
 The aim of the pre-clinical development
About one in thousand new
development phase for a chemical entities reach this
potential new medicine is to stage.
explore the drug’s efficacy and  The steps included in this stage
safety before it is administered are:-
to patients.  a) Pharmaceutical study-
 In this preclinical phase, Stability, compatibility.
varying drug doses are  b) Pharmacological study-
tested on animals and/or in Chronic toxicological study in
vitro systems. animals, metabolic and
 If active compounds are found, pharmacokinetic studies.
then studies on animals are  c) Clinical Trial- is a means by
done which includes which the efficacy of drug is
pharmacodynamics, tested on human being. It is
pharmacokinetics and toxicology divided in to four phases. With
studies have to be done each phase, safety and efficacy
6 are tested
AAST progressively
7 U,
Cont
…
 Phase 1 –
 Conducted in healthy volunteers.
 Designed to test the
tolerable dose & duration of
action.
 Carried on 20-50
subjects in one center.

 P
h
a
s
e
6 AAST
8 2 U,
Cont
…  Phase
3 Full scale evaluation of

treatment comparing it with
standard treatment is done 
in this phase. Phase 4 (Phase of post
 Comprises 250-2000
marketing surveillance)-
 Reports about efficacy & toxicity are
patients in multiple centers.
received from the medical
 Information from all studies practitioners and reviewed by the
are received by the committee of review of medicines.
If “committee
the drug isofsatisfied
safety of
by the  Renewal or cancellation of the
medicines
CSM, the “product
(CSM).license is product license depends on the
issued ,then the drug is comment of the review committee
marketed.

6 AAST
9 U,
Cont
…

7 AAST
0 U,
Pre-Clinical
Process R&D
Pharmacology Chem Eng. R&D
Safety Assessment Manufacturing
Toxicology
Drug
Metabo
lism
(ADME
Pharmaceutical R&D
) Bio Process R&D
Formulation

Clinical Investigator
& patient
Regulatory Affairs
Clinical Project Planning & Management
Pharmacology Marketing
Clinical Research

Statistics & Epidemiology

Data Coordination
Research Information Systems
Information Services
Clin7i1ca AAST
U,
l
 Drug Discovery—Convergence of
Disciplines
Combinatorial
Synthet
Patent
Chemist
ic
Law
ry
Chemistry
Modelli
Novel
ng Intellectual
Property Physiolog
Informati M olecu y
Desig Structur
on n le al Biochemis
Technolo
Activit try
gy
Physiolo
y
Safet Pharmaco Physiolog
gy
- y
M etaboli y
Safety dynamics Pharmacolo
sm
A ssessm gyImmunolo
ent In Vivo Pharmacokin gy
activity etic
Properties DMPK
Pharmacology Behavi
Patholo or
Physical Enzymolo
gy Physiolo gy
Chemistry
72
gy Physiology

AASTU,