PHARMACODYNAMICS

• In Greek
Pharmacon = Drug
Dynamics = Action/Power

It covers all the aspects relating to

“What a drug does to the body”
Mechanism of action
• Action: How and Where the
effect is produced is called as
Action.

• Effect: The type of response

producing by drug.
 Site of Drug Action

• Where:

1. Extra cellular
2. Cellular
3. Intracellular
 Types of Drug Action
EFFECT (Type of responses):-
1.Stimulation
2.Inhibition/Depression
3.Replacement
4.Irritation
5.Cytotoxic
 Mechanism of Action of Drugs
• Drug act either by receptor or by non
receptor or by targeting specific genetic
changes.
Majority of drugs acts by (HOW)

Receptor mediated Non receptor mediated

 Receptor Mediated action
• Drug produce their effect through interacting
with some chemical compartment of living
organism c/s Receptor.

• Receptors are macromolecules

• Most are proteins
• Present either on the cell surface, cytoplasm or
in the nucleus
 Ligand binding
domain

Transduction of
signal into response

Receptor Functions : Two essential functions

• 1. Recognization of specific ligand molecule
(Ligand binding domain)
• 2. Transduction of signal into response (Effector
domain)
Drug(D) +Receptor® Drug receptor complex Response

Drug receptor interaction:-

1. Selectivity:- Degree of complimentary co relation
between drug and receptor.
Ex:- Adrenaline Selectivity for α, ß Receptor

2. Affinity:- Ability of drug to get bound to the

receptor.

3. Intrinsic activity (IA) or Efficacy:- Ability of drug

to produce a pharmacological response after
making the drug receptor complex.
 Drug classification
(on the basis of affinity & efficacy)
Response No response
• Partial agonist :These drug have full affinity to
receptor but with low intrinsic activity (IA=0 to 1).
• These are only partly as effective as agonist

(Affinity is lesser when comparison to agonist)

Ex: Pindolol, Pentazocine
• Inverse agonist: These have full affinity
towards the receptor but intrinsic activity is
zero to -1 i.e., produces effect is just
opposite to that of agonist.

Ex:- ß-Carboline is inverse agonist for

Benzodiazepines receptors.
 Receptor families

Four types of receptors families

1. Ligand-gated ion channels (inotropic
receptors)
2.G-protien coupled receptor (Metabotropic
receptors)
3. Enzymatic receptors (tyrosinekinase)
4.Receptor regulating gene expression
(transcription factors/ Steroid )
 Characteristics of receptor families
Ligand G-protein Enzymatic Nuclear
gated coupled

Location Membrane Membrane Membrane Intracellular

Effector Ion channel Ion Channel Enzyme Gene

or enzyme

coupling Direct G-protein Direct Via DNA

Example Nicotinic Muscarinic Insulin Steroid ,

hormone
Signal transduction mechanism
• Ion gated receptors:- Localized on cell
membrane and coupled directly to an ion
channel. Io
n
Blocker

Agonist
Receptor
Receptor
Na+2
Permeation of
Hyper polarization or
ion is blocked
depolarization

No cellular effect
Cellular effect
• Ex: Nicotinic cholinergic receptor
 G-protein coupled receptors
• Membrane bound, which are coupled to
effector system through GTP binding
proteins called as G-proteins

Bound to inner
face of plasma
membrane (2nd
messenger)
 Varieties of G-protein
G-protein Receptor for Signaling pathway/
Effector
Gs ß adrenegic, AC— cAMP
H,5HT,Glucagon
Gi1,2,3 α2 adrenergic, Ach, AC— cAMP,
Open K+
Gq Ach Phospholipase-C,
IP3’cytoplasmic Ca+2
Go Neurotransmitters Not yet clear
in brain
 G-protein effector systems

• 1.Adenylase cyclase : cAMP system

• 2.Phospholipase –C: Inositol phosphate system

• 3. Ion channels
cAMP system
Phospholipase-C system
 Ion channel regulation
• G-protein coupled receptors can control
the functioning of ion channel by don't
involving any second messenger
• Ex:- In cardiac muscle
 Enzymatic receptors
• These receptor are directly linked tyrosine
kinase.
• Receptor binding domain present in extra
cellular site.
• Produce conformational changes in intra
cellular
Ex:- Insulin receptors
Enzymatic receptors
Extra cellular receptor
binding domain

Intra cellular
changes
 Receptor regulating gene expression
(transcription factors)
Increase RNA
polymerase activity

Unfolds the receptor and

expose normally
masked DNA binding
site
 Receptor regulation theory
• Receptors are in dynamic state.

• The affinity of the response to drugs is not fixed.

It alters according to situation.

• Receptor down regulation:

Prolonged use of agonist

Receptor number and sensitivity

Drug effect

Ex: Chronic use of salbutamol down regulates ß2 adrenergic receptors.

• Receptor up regulation:
Prolonged use of antagonist

Receptor number and sensitivity

Drug effect

• Ex:- propranolol is stopped after prolong

use, produce withdrawal symptoms. Rise
BP, induce of angina.
Agonist: Both the high affinity as well as
intrinsic activity (IA=1)
These drug trigger the maximal biological response or
mimic effect of the endogenous substance.
Ex:- Methacholine is a cholinomimetic drug which
mimics the effect of Ach on cholinergic receptors.
 Types of agonism
• Summation :- Two drugs eliciting same
response, but with different mechanism and their
combined effect is equal to their summation.
(1+1=2)

Aspirin Codiene

PG Opiods receptor

Analgesic+ Analgesic+

++
 Types of agonism
• Additive: combined effect of two drugs acting by
same mechanism
Aspirin

PG PG

Analgesic+ Analgesic+

++
• Synergism (Supra additive):- (1+1=3)

The combined effect of two drug effect is

higher than either individual effect.
Ex:-
1.Sulfamethaxazole+ Trimethoprim
2. Levodopa + Carbidopa.
 Types of antagonism
Antagonism: Effect of two drugs is less than sum
of the effects of the individual drugs.
1. Chemical antagonism
Ex: -heparin(-ve) protamine +ve, Chelating agents
1. Physiological /Functional antagonism
2. Pharmacokinetic antagonism
3. Pharmacological antagonism
I. Competitive ( Reversible)
II. Non competitive (Irreversible)
 Pharmacokinetic antagonism
• One drug affects the absorption,
metabolism or excretion of other drug and
reduce their effect.

Ex:-Warfarin in presence of phenobarbitone,

warfarin metabolism is increased, it effect
is reduced.
 Pharmacological antagonism
• Pharmacodynamic antagonism between two
drugs acting at same receptors.
• Two important mechanism according to which
these antagonists

»1.Reversible(Competitive)
»2.Irreversible(Non)
 Reversible antagonism
(Competitive antagonism)
• These inhibition is commonly observed
with antagonists that bind reversibly to the
same receptor site as that of an agonist.

• These type inhibition can be overcome

increasing the concentration of agonist

• Ex:- Atropine is a competitive antagonist of

Ach.
 Irreversible Antagonism
• It occurs when the antagonist dissociates
very slow or not at all from the receptors
result that no change when the agonist
applied.
• Antagonist effect cannot be overcome
even after increasing the concentration of
agonist
 Non receptor mediated action

• All drugs action are not mediated by receptors.

Some of drugs may act through chemical action
or physical action or other modes.

»Chemical action
»Physical action (Astringents, sucralfate)
»False incorporation (PABA)
»Being protoplasmic action (antiseptics)
»Formation of antibody (Vaccines)
»Targeting specific genetic changes.
 Dose
• It is the required amount of drug in weight,
volumes, moles or IU to provide a desired effect.

• In clinical it is called as Therapeutic dose

• In experimental purpose it is called as effective

dose.

• The therapeutic dose varies from person to

person
Single dose:
1.Piperazine (4-5g) is sufficient to eradicate round
worm.
2.Single IM dose of 250mg of ceftriaxone to treat
gonorrhoea.

Daily dose:
It is the quantity of a drug to be administered in
24hr, all at once or equally divided dose.
1.10mg of cetrizine (all at once) is sufficient to
relive allergic reactions.
2.Erythromycin is 1g per day to be given in 4
equally divided dose (i.e., 250mg every 6 hr)
• Total dose: It is the maximum quantity of the
drug that is needed the complete course of the
therapy.
Ex:- procaine penicillin early syphilis is 6 million unit 
given as 0.6 million units per day for 10days.

Loading dose:- It is the large dose of drug to be

given initially to provide the effective plasma
concentration rapidly. The drugs having high Vd
of distribution.
Chloroquine in Malaria – 600 mg Stat
300mg after 8 hours
300 mg after 2 days.
Maintenance dose:- Loading dose normally
followed by maintenance dose.
• Needed to maintain the steady state
plasma concentration attained after giving
the loading dose.
Therapeutic index:
• Margin of safety
• Depend upon factor of dose producing
desirable effect  dose eliciting toxic
effect.

LD 50
Therapeutic index
ED 50

• TI should be more than one

 Therapeutic window:
Optimal therapeutic range of plasma
concentrations at which most o the patients
experience the desired effect.
Therapeutic range Therapeutic window
optimal

optimal
Sub

Toxic
• Cyclosporine – 100-400ng/ml
• Carbamazapine- 4-10µg/ml
• Digoxin- 0.8-2ng/ml
• Lithium- 0.8-1.4 mEq/L
• Phenotoin – 10-20µg/ml
• Qunindine- 2-6µg/ml
• Tolerance: Increased amount of drug
required to produce initial pharmacological
response.
• Usually seen with alcohol, morphine,
barbiturates, CNS active drugs

• Reverse tolerance:- Same amount drug

produces inc pharmacological response.
• Cocaine, amphetamine  rats- inc. motor
activity
 Types of tolerances
• Innate tolerance: Genetically lack of
sensitivity to a drug.
Ex:
• Rabbits tolerate to atropine large doses
• Chinese Castor oil
• Negros  Mydriatic action of sympathomimetics
• Eskimos high fatty diets
• Acquired tolerances:
• Occurs due to repeated use of drug
– Pharmacokinetic tolerances
– Pharmacodynamic tolerance
– Acute tolerance

Pharmacokinetic tolerances:- Repetitive

administration causes decrease their
absorption or inc. its own metabolism
Ex: Alcohol  dec. absorption
Barbiturates Inc. own metabolism
• Pharmacodynamic tolerance

• Down regulation of receptors

• Impairment in signal transduction

• Ex: Morphine, caffeine, nicotine.

• Acute tolerance: Tachyphylaxis Acute

development of tolerance after a rapid and
repeated administration of a drug in shorter
intervals
• Ex; Ephedrine, tyramine
• Ex: Monday disease.
• Nitroglycerine – Monday , Tuesday
workers get headache, after they get
tolerances.
• After holiday (Sunday) they get again
headache .
• Cross tolerances: Cross tolerance among
drugs belonging to same category.
• MORPHINHEROIN NARCOTIC
FACTORS MODIFYING THE
EFFECTS OF DRUGS
 Individuals differ both in the degree and the
character of the response that a drug may elicit

 Variation in response to the same dose of a drug

between different patients and even in the same
patient on different occasions.
 One or more of the following categories of
differences among individuals are responsible for
the variations in drug response:
 Individuals differ in pharmacokinetic handling of drugs

 Variation in number or state of receptors, coupling

proteins or other components of response

 Variation in neurogenic/ hormonal tone or

concentrations of specific constituents
 These factors modify drug action either:
a) Quantitatively
 The plasma concentration and / or the drug action is
increased or decreased

b) Qualitatively
 The type of response is altered, eg: drug allergy and
idiosyncrasy
 The various factors are:

1. Body weight/size:
 It influences the concentration of drug attained at the
site of action

 The average adult dose refers to individuals of

medium built
• For exceptionally obese or lean individuals and for children
dose may be calculated on body weight basis

BW (kg)
Individualdose x Average adult dose
70

BSA (m2)
Individualdose x Average adult dose
1.7

 BSA=BW(Kg)0.425 x Height(cm)0.725 x 0.007184

 2. Age:

Infants and Children:

 The dose of drug for children often calculated from the adult
dose

Age
Child dose x adult dose.........(Young's formula)
Age 12
Age
Child dose x adult dose.........(Dilling' s formula)
20
 However, infants and children are have important
physiological differences

 Higher proportion of water

 Lower plasma protein levels

 More available drug

 Immature liver/kidneys
 Liver often metabolizes more slowly

 Kidneys may excrete more slowly

Elders:
 In elderly, renal function progressively declines (intact
nephron loss) and drug doses have to be reduced

 Chronic disease states

 Decreased plasma protein binding

 Slower metabolism

 Slower excretion

 Dietary deficiencies

 Use of multiple medications

 Lack of compliance
3. Sex:

 Females have smaller body size, and so require

doses of drugs on the lower side of the dose
range

 They should not be given uterine stimulants

during menstruation, quinine during pregnancy
and sedatives during lactation
4. Pregnancy:

 Profound physiological changes which may affect

drug responses:
 GI motility reduced –delayed absorption of orally
administered drugs

 Plasma and ECF volume expands

 Albumin level falls

 Renal blood flow increases markedly

 Hepatic microsomal enzyme induction

5. Food:

 Delays gastric emptying, delays absorption (ampicillin)

 Calcium in milk –interferes with absorption of

tetracyclines and iron by chelation

 Protein malnutrition
 Loss of BW

 Reduced hepatic metabolizing capacity

 Hypoproteinemia
6. Species and race:

 Rabbits resistant to atropine

 Rat & mice are resistant to digitalis

 In humans: blacks require higher Mongols require

lower concentrations of atropine and ephedrine to
dilate their pupil
7. Route of drug administration:

 I.V route dose smaller than oral route

 Magnesium sulfate:
 Orally –purgative

 Parenterally –sedative

 Locally –reduces inflammation

8. Biorhythm: (Chronopharmacolgy)

 Hypnotics –taken at night

 Corticosteroid –taken at a single morning dose

9. Psychological state:

 Efficacy of drugs can be effected by patients

beliefs, attitudes and expectations

 Particularly applicable to centrally acting drugs

 In some patients inert drugs (placebo) may

produce beneficial effects equivalent to the
drug, and may induce sleep in insomnia
10. Presence of diseases/pathological states:

 Drug may aggravate underlying pathology

 Hepatic disease may slow drug metabolism

 Renal disease may slow drug elimination

 Acid/base abnormalities may change drug absorption

or elimination

 Severe shock with vasoconstriction delays absorption

of drugs from s.c. or i.m

 Drug metabolism in:

 Hyperthyroidism –enhanced

 Hypothyroidism -diminished
11. Cumulation:

 Any drug will cumulate in the body if rate of

administration is more than the rate of elimination
 Eg: digitalis, heavy metals etc.
12. Genetic factors:

 Lack of specific enzymes

 Lower metabolic rate

 Acetylation

 Plasma cholinesterase (Atypical pseudo cholinesterase)

 G-6PD

 Glucuronide conjugation
13. Tolerance:
 It means requirement of a higher dose of the drug
to produce an effect, which is ordinarily produced
by normal therapeutic dose of the drug
 Drug tolerance may be:
 Natural
 Acquired
 Cross tolerance
 Tachyphylaxis (ephedrine, tyramine, nicotine)
 Drug resistance
14. Other drugs:

 By interactions in many ways

 Drug classification
(on the basis of affinity & efficacy)

Agonist: Both the high affinity as well as

intrinsic activity (IA=1)
These drug trigger the maximal biological response or
mimic effect of the endogenous substance.
Ex:- Methacholine is a cholinomimetic drug which
mimics the effect of Ach on cholinergic receptors.
• Antagonist:- Which have only the affinity
no intrinsic activity (IA=0). IA=0 so no
pharmacological activity.

• Rather these drug bind to the receptor

and produce receptor blockade.

• Atropine blocks the effects of Ach on the

cholinergic muscarinic receptors.
 cAMP system
Some drugs, hormones or neurotransmitters
produce their effect by increasing or
decreasing the activity of adenylate cyclase
and thus raising or lower cAMP with in the
cell.
 Stimulation

• Some of drug act by increasing the activity

of specialized cells.

Ex: Catecholamines stimulate the heart and

Heart rate, Force of contraction
 Inhibition

• Some drug act by decreasing the activity of

specialized cells.

Ex: Alcohol, Barbiturates, General anesthetic

these drug depress the CNS system.
Atropine inhibits Ach action.
 Replacement

• When there is a deficiency of endogenous

substances, they can replaced by drugs.

Ex: Insulin in Diabetes mellitus

Throxine in cretinism and myxedema
 Irritation
• Certain drugs on topical application cause
irritation of the skin and adjacent tissues.

• These drugs are using for counter irritant.

Ex: Eucalyptus oil, methyl salicylates (Used

in sprains, joint pain, myalgia.
 Cytotoxic

• Treatment of infectious disease/cancer

with drugs that are selectively toxic for
infecting organism/cancer cells

Ex: Anticancer drugs

All Antibiotics
 Phospholipase-C system
Activation Hydrolysis
Agonist
Gq PLC PIP2 Hydrolysis

DAG

IP3 PKC
Water soluble
ATP ADP
release
S Product
Cam Ca+2

E Cam E*
Response

PLC= Phospholipase-C PIP2 =Phosphotiydl inositol 4,5 di phosphate

IP3 =Inositol tri phosphate DAG = Diacylglycerol
E= Ezyme PKC = Phosphokinase -C
 Extra cellular site of action

1.Antacids neutralizing gastric acidity.

2.Chelating agents forming complexes

with heavy metals.

3.MgSo4 acting as purgative by

retaining the fluid inside the lumen of
intestine.
 Cellular Site of Action

1.Ach on Nicotinic receptors of motor end

plate, leading to contraction of skeletal
muscle.

2.Effect of sympathomimetics on heart

muscle and blood vessels.
 Intracellular site of action

-Folic acid synthesis inhibitors.

Folic acid which is intracellular component
essential for synthesis of proteins.

Trimethoprim and sulfa drug interfere with

synthesis.
Gs/Gi
G protein Effector

+ or - AC

cAMP ATP

Phosphorylation

Ca+2 release
Protein kinase Active
FC of heart muscle

Lipolysis Glycogen Glycogen breakdown

synthesis to glucose
 Physical action
• Absorption: Kaolin absorbs bacterilal toxin
and thus acts as antidiarrhoeal agent.
• Protectives:- Various dusting powders.
• Antagonist:- Which have only the affinity
no intrinsic activity (IA=0). IA=0 so no
pharmacological activity.

• Rather these drug bind to the receptor

and produce receptor blockade.

• Atropine blocks the effects of Ach on the

cholinergic muscarinic receptors.
 Physical Action
• Osmosis:- MgSo4 acts as a purgative by
exerting osmatic effect within lumen of the
intestine.
• Astringents:- They precipitate the surface
proteins and protect the mucosa Ex: tannic
acid in gum patients

• Demulcent:- These drugs coat the

inflamed mucus membrane and provide
soothing effect. Ex: Menthol
 False incorporation
• Bacteria synthesis folic acid from PABA
(Para Amino Benzoic Acid), for growth
sand development.

• Sulfa drugs resemble PABA, therefore

falsely enter into the synthesis process of
PABA, cause nonfunctional production
and no utility for bacterial growth.
 Protoplasmic poison

• Germicides and antiseptics like phenol

and formaldehyde act as non specifically
as protoplasmic poison causing the death
of bacteria
Through formation of antibodies

• Vaccines produce their effect by inducing

the formation of antibodies and thus
stimulate the defense mechanism of the
body
• Ex:- Vaccines against small pox and
cholera
 Targeting specific genetic changes.

• Anti cancer drugs that specifically target

genetic changes.

• Inhibitors of specific tyrosine kinase that

that block the activity of oncogenic
kinases.
 Physiological antagonism

• Two antagonists, acting at different

sites, counter balance each other by
producing opp. effect on same
physiological system.

• Histamine –Vasodilatation
• Nor epinephrine – Vasoconstriction
 Chemical action
1.Ion Exchanges:-Anticoagulant effect of
heparin(-ve charge) antagonized by
protamine (+ve charged) protein.

2.Neutralization:- Excessive gastric acid is

neutralized by antacids.

3. Chelation:-These are trap the heavy

metals. Ex:-EDTA, BAL.