Sources of Drugs

chemicals

Animal Plants

DRUG

microbial
Dose
Dose is the quantity of drug given at a time so that it
results in the desired effect, without causing harm

Eg : Crocin 1000 mg Fever 1000 mg is dose

Dosage form
Drug is useful when available in a form in which it is
easily handled and given to the patients, eg.

Capsules Tablets

Syrups
 Routes of drug administration
 Enteral via gastrointestinal tract (GIT).
 Oral
 Sublingual
 Rectal
 Parenteral administration = injections.
 Topical application
 Inhalation
 Oral administration
Advantages Disadvantages
- Easy - Slow effect
-No complete absorption
- Self use
- Destruction by pH and enzymes
- Safe - GIT irritation
- Food - Drug interactions
- Convenient
-Drug-Drug interactions
- cheap - First pass effect
- No need for - (low bioavailability).
sterilization Not suitable for
❑ vomiting & unconscious patient

❑ emergency

❑ bad taste drugs

First pass Metabolism
▪ Drugs taken orally are first taken to liver (via
portal circulation) where they are metabolized
before reaching to rest of body.
▪ so the amount reaching system circulation is
less than the amount absorbed

Results ?
Low bioavailability = low serum level of active
drug that can produce action
First pass effect
 Bioavailability
 Is the fraction of unchanged drug that enters systemic
circulation after administration and becomes available to
produce an action
 I.V. provides 100% bioavailability.
 Oral usually has less than I.V.
Bioavailability
 The fraction of an administered dose of drug that reaches the
blood stream.
 What determines bioavailability?
 Physical properties of the drug (hydrophobicity, pKa, solubility)
 The drug formulation (immediate release, delayed release, etc.)
 If the drug is administered in a fed or fasted state
 Gastric emptying rate
 Circadian differences
 Interactions with other drugs
 Age
 Diet
 Gender
 Disease state
 Oral Dosage Forms (oral formulations)

 Tablets (enteric coated tablets)

 Capsules (hard and soft gelatin capsules)
 Syrup
 Suspension
 Emulsion
 Sublingual
Advantages Disadvantages
❑ Rapid effect Not for
❑ can be used in emergency - irritant drugs
❑ High bioavailability - Frequent use
❑ No first pass effect.

❑ No GIT irritation

❑ No food drug - interaction

Dosage form: friable tablet

 Rectal administration
Advantages Disadvantages
Suitable for
❑ children ❑ Irregular
❑ Vomiting or unconscious absorption &
patients bioavailability.
❑ Irritant & Bad taste drugs.

❑ less first pass metabolism

❑ Irritation of
rectal mucosa.
(50%)

Dosage form:
suppository or enema
 Parenteral administration
Intradermal (I.D.) (into skin)
Subcutaneous (S.C.) (under skin)
Intramuscular (I.M.) (into muscles)
Intravenous (I.V.) (into veins)
Intra-arterial (I.A.) (into arteries)
Intrathecal (I.T.) (cerebrospinal fluids )
Intraperitoneal (I.P.) (peritoneal cavity)
Intra - articular (Synovial fluids)
 Intravenous administration

Advantages Disadvantages
❑ Rapid action (emergency) ❑ Only for water
❑ High bioavailability
soluble drugs
❑ Infection
❑ No food-drug interaction
❑ Sterilization.
❑ No first pass metabolism
❑ Pain
❑ No gastric irritation
❑ Needs skill
Suitable for ❑ Anaphylaxis

❑ Vomiting &unconscious ❑ Expensive

❑ Irritant & Bad taste drugs. Not suitable for oily

Dosage form: solutions or poorly
Vial or ampoule soluble substance
Ampoule Vial

Single use Repeated use

Injection Special Utility Limitations
I.D. minute volume (0.1 ml) not suitable for large volumes
suitable for vaccinations
& sensitivity test

S.C. 0.1 ml – 1 ml not suitable for large volumes

suitable for poorly soluble
suspensions and for
instillation of slow-release
implants e.g. insulin zinc
preparation
I.M. larger volume 3-5 ml Suitable not suitable for irritant drugs
for moderate volumes, for oily Abscess- necrosis may happen
solutions or poorly soluble
substances

I.V. suitable for large volumes and not suitable for oily solutions
for irritating substances or poorly soluble substances
Must inject solutions slowly as
a rule
 Topical application
➢ Drugs are applied to skin, ear, eye, nose, vagina,
respiratory tract
➢ Usually used to provide local action.
➢ No first pass metabolism.
➢ Used for lipid soluble drugs
 Inhalation
Advantages Disadvantages

❑ mucous membrane of respiratory Not suitable for

system irritant drugs
❑ rapid absorption (large surface
area)
❑ provide local action in
Only for some
❑ limited systemic effect
drugs as
❑ less side effects.
inhalation
anesthetics &
❑ no first pass effect
bronchodilators

Dosage form: aerosol, nebulizer

Pharmacology
Is the science that deals with the study of drugs.

Pharmacodynamics Pharmacokinetics

Drug Drug
Pharmacokinetics
 DRUG ADMINISTERED
ABSORPTION

PLASMA

DISTRIBUTION

DISTRIBUTED IN THE TISSUES

PLASMA

METABOLISM

DRUG & METABOLITES IN PLASMA

ELIMINATION

DRUG & METABOLITES IN URINE,

FEACES,BILE
 Absorption

The transfer of the drug from its site of

administration to the blood stream.

Rate of absorption determines the frequency of

dosing, onset of desired & undesired effect
Distribution
Distribution is the process by which the drug reversibly
leaves the blood stream and enters the tissues
 Plasma Protein Binding Capacity
BLOOD
DRUG-PROTEIN
FLOW

DRUG

PLASMA
PROTEIN

RECEPTOR

CELL

EXTRACELLULAR FLUID
Blood Brain Barrier

➢ Semi-permeable,
➢Protects the brain from "foreign substances"
Metabolism
Metabolism is the process of chemical change that
acts on all substances entering the body, including
drugs.
IMPLICATIONS FOR DRUG METABOLISM
 IMPLICATIONS FOR DRUG METABOLISM

1. Termination of drug action

2. Activation of prodrug
3. Bioactivation and toxication
4. Carcinogenesis
5. Tetratogenesis
Termination of Drug Action

atropine tropic acid and tropine

propranolol → hydroxypropranolol
(active) (active)
Termination of Drug Action

Conversion of drug to active metabolite to inactive metabolite

Activation of Prodrug

L-dopa Dopamine
Inactive Terfenadine is Converted to its Active Metabolite
Fexofenadine
activation of prodrug
terfenadine

fexofenadine
Some Xenobiotics Are Metabolized to Carcinogenic Agents
carcinogenesis

• 3,4 Benzopyrene
• Aflatoxin
• N-Acetylaminoflluorene

Metabolites of these agents interact with DNA

 Small Amounts of Acetaminophen is Converted to the
Reactive Metabolite N-Acetylbenzoquinoneimine

bioactivation

Bioactivation of acetaminophen; under certain conditions, the electrophile N-

acetylbenzoquinoneimine reacts with tissue macromolecules, causing liver necrosis.
Thalidomide is a Teratogen
teratogensis

– THALIDOMIDE: Fetal malformations in humans,

monkeys, and rats occur due to metabolism of the parent compound
to a teratogen. This occurs very early in gestation.
FACTORS AFFECTING DRUG METABOLISM
Factors Affecting Drug Metabolism

 Age
 Diet
 Genetic Variation
 State of Health
 Gender
 Degree of Protein Binding
 Species Variation
 Substrate Competition
 Enzyme Induction
 Route of Drug Administration
Factors Affecting Drug Metabolism

 Route of drug administration

 Oral versus systemic administration
Many Drugs Undergo First Pass Metabolism
Upon Oral Administration

 Oral administration
 Drug travels from gut to portal vein to liver
 Vigorous metabolism occurs in the liver. Little drug
gets to the systemic circulation
 The wall of the small intestine also contributes to first
pass metabolism
ORGAN SITES OF DRUG METABOLISM
Organ Sites of Drug Metabolism
 Liver
 Small intestine
 Kidney
 Skin
 Lungs
 Plasma
 All organs of the body
CELLULAR SITES OF DRUG METABOLISM
Cellular Sites Of Drug Metabolism

 Cytosol
 Mitochondria
 Lysosomes
 Smooth endoplasmic reticulum (microsomes)
KINETICS OF DRUG METABOLISM
Velocity Of Metabolism Of A Drug

80
70
60
(ng/g tissue/min)
Velocity

50
40
30
20
10
0
0 10 20 30 40 50 60 70

[Drug] mM D:\summer1\Kmx1.pzm
Velocity Of Metabolism Of A Drug
80
70
60 zero order metabolism
(ng/g tissue/min)
Velocity

50
40
30
20
first order metabolism
10
0
0 5 10 15 20 25 30 35 40 45 50 55 60

[Drug] mM
Kmx2.pzm
First Order Metabolism

A drug may be given in doses that produce blood concentrations

less than the Km of the enyzme for the drug.

v = Vmax [C]
Km + [C]

When Km >>> [C],

then v = Vmax [C] , and v  [C]

Km

Metabolism of the drug is a first order process. A constant

fraction of the remaining drug is metabolized per unit time.
Most drugs are given at concentrations smaller than the Km of
the enzymes of their metabolism.
Velocity Of Metabolism Of A Drug

80
70
60 zero order metabolism
(ng/g tissue/min)
Velocity

50
40
30
20
first order metabolism
10
0
0 5 10 15 20 25 30 35 40 45 50 55 60

[Drug] mM
Kmx2.pzm
Zero Order Metabolism

A drug may be given in doses that produce blood concentrations

greater than the Km of the enyzme for the drug.

v = Vmax [C]
K m + [C]

When [C] >>> Km,

then v = Vmax [C] , and v = Vmax

[C]

Metabolism of the drug is a zero order process. A constant

amount of the remaining drug is metabolized per unit time.
Phenytoin undergoes zero order metabolism at the doses
given.
Velocity Of Metabolism Of A Drug

80
70
60 zero order metabolism
(ng/g tissue/min)
Velocity

50
40
30
20
first order metabolism
10
0
0 5 10 15 20 25 30 35 40 45 50 55 60

[Drug] mM
Kmx2.pzm
Velocity Of Metabolism Of Three Drugs
By The Same Enzyme

70
60
(ng/g tissue/min)

50
Velocity

Drug A
40
Drug B
30 Drug C
20
10
0
0 10 20 30 40 50 60 70 80 90
[Drug] mM
Elimination
Elimination is the process by which the body throws out the drug, most often
in a form different from the original form.

Sites of elimination
• Renal
• Faecal
• Breast milk
• Pulmonary
• Sweat glands
Some drugs may not get metabolized at all and are eliminated in the unchanged state.
 Cmax = Maximum drug concentration
Tmax = Time taken to reach Cmax
t1/2 = Half life (time taken for the drug
concentration in plasma to fall by
half)
C max

T max t1/2

Drug given at
this point
Drug delivery system
(Vehicle)
 Vehicle
Active (Drug
agent delivery
system)
➢Penetration :Entry of the drug into the skin
➢Permeation :Penetration of the drug from one skin layer to next
➢Absorption :Topically applied drug taken up by blood vessel and enter into
systemic circulation

Important to minimise absorption so that the

drug is restricted to the disease area
Importance of drug delivery System
(Vehicle)

▪ Direct effect on disease

▪ Ability to deliver active
agents
▪ Effects on patients
compliance
Vehicles Used
……………. …………….
 Lotion  Foam

 Solution  Shampoo

 Gel  Cream
 Ointment
 Pharmacodynamics
• Receptor
• Receptor-Drug Complex
• Agonist
• Antagonist
• Potency
• Efficacy
• Therapeutic Window
 There are 5 main drug actions:
 Depressing
 Stimulating
 Destroying cells[cytotoxic]
 Irritation
 Replacing substances

 The desired activity of a drug is mainly due to one of the

following:
 Cellular membrane disruption
 Chemical reaction
 Interaction with enzyme proteins
 Interaction with structural proteins
 Interaction with carrier proteins
 Interaction with ion channels
 Ligand binding to receptors:
• Hormone receptors
• Neuromodulator receptors
• Neurotransmitter receptors
Receptor

A Drug Receptor is a specialized target molecule

present on the cell surface or intracellularly

Drug –Receptor ComplexFormation

RECEPTOR DRUG DRUG RECEPTOR

COMPLEX
Affinity
• Means ‘liking’. Most drugs have liking for a
receptor and bind (stick to them)

Intrinsic activity
• Perform some action on the cell (produce
effect) after binding to the receptor.
 Agonist

AFFINITY

CELL

RECEPTOR DRUG

AGONIST INTRINSIC
“ activate” the receptors when they occupy it ACTIVITY

Affinity
Intrinsic activity
 Antagonist

AFFINITY

CELL

RECEPTOR DRUG NO INTRINSIC

ACTIVITY

ANTAGONIST“ no activation” when they occupy

the receptor Affinity No intrinsic activity
 Agonist Antagonist

Drug

Drug

Receptor Receptor
Potency

➢ It is the measure of how much drug is required

to elicit a given response.

➢ Lower the dose, higher is the potency of a

drug.
 Drug Potency

1040F

DRUG A
15 mg 98.40F

RESPONSE
FEVER

1040F DRUG B
DRUG B I am more potent
5 mg 98.40F

RESPONSE
Efficacy:

Drugs’ capacity to produce its maximum

response.
 Drug Efficacy

1040F
1000F
DRUG X
MAXIMUM
RESPONSE

FEVER DRUG Y
I am more efficacious
MAXIMUM
1040F
RESPONSE

DRUG Y 98.40F
Side effect:
Effects beyond the effects that the drug is supposed to cause.
Eg. Drug meant to reduce BP results in very low BP in some
patients.

Adverse effect:
Undesirable effect caused by a drug. Eg. Allergy caused by a
drug meant to reduce BP.
 Therapeutic Index
Therapeutic index = median lethal dose
median effective dose

 Median lethal dose- LD50

Dose (mg/kg) which would be expected to kill 50% of the
test population
 Median effective dose-ED50
Dose in mg/kg which would bring about a desired
response in 50% of the test population

 Therapeutic Index > 1

 Approximate assessment of safety of a drug
 Therapeutic Index
Drug A Effect No Effect
Effective Dose 50
ED50 ( 5 mg)

Alive Dead
Drug A
Lethal Dose 50
LD50 ( 5000mg) THERAPEUTIC INDEX
Drug A = LD50/ ED50=5000/5
= 1000 ( GOOD)
Therapeutic Window
 A gap between minimum effective dose and
maximum tolerated dose.
 Larger the therapeutic window, more safer is the
drug
 Pharmacodynamics: Summary

• Effects of the drug on the body

• Most drugs attach to receptors to produce effect
• Agonists have affinity as well as intrinsic activity: while antagonists
have affinity but no intrinsic activity
• Potency is the measure of the drug required to produce a response
• Efficacy is the capacity of the drug to produce the maximum effect
• Therapeutic index is a rough measure of a drug’s balance between
efficacy and safety
• Therapeutic window is the gap between the minimum effective level of
a drug and its maximum safe concentration
Important Terms
Indication:
A suggestion or pointer as to the proper treatment of a disease.

Placebo:
A placebo is a substance which has no activity (inert substance).
A placebo is used as a dummy dose.

Acute:
Of short and sharp course

Chronic:
Of long duration; denoting a disease of slow progress and long
continuance