The document discusses various aspects of pharmacodynamics, which is the study of how drugs act on the body. It describes different mechanisms of drug action including stimulation, depression, irritation, replacement, cytotoxic action, physical action, chemical action, action through enzymes, and action through receptors. It also discusses concepts like dose-response relationship, drug potency and efficacy, therapeutic index, drug combination effects like synergism and antagonism, and factors that can modify drug action.

1. Pharmacodynamics
Study of drug :
 How drug exert its effects on body.
 Action- effect sequence and dose effect relationship.
 Modification of drug action by another drug or by other factors.
The action of a drug on the body, including receptor interactions, dose-response phenomena, and
mechanisms of therapeutic and toxic action.
What drugs do to the body.

2. Principles of drug action:
Stimulation:
Selective enhancement of the level activity of targeted cell by the drugs.
e.g. Adrenalin---------------------- Heart
Pilocarpine -----------------------salivary gland secretion
Digitoxin ---------------------------tone of heart muscles
Depression:
Selective attenuation/weakening of specialized cell activity.
e.g. Quinidine depress cardiac activity,
Barbiturate depress CNS
Certain drug causes both stimulation and depression.
e.g. Ach stimulate intestinal SM but depress SA node in heart.

3. Irritation:
Non-selective, often noxious/toxic effect and applied to less specialized tissues like, epithelium
tissue, connective tissue.
Mild irritation - therapeutic benefit: Mild bitter tonic, counter irritant
Strong irritation – cause necrosis, inflammation, and tissue damage.
Replacement:
Uses of natural metabolites or hormones in case of deficiency. e.g. Insulin, levodopa, Vit-therapy,
Iron, Immunoglobulin etc.
Cytotoxic action:
Selective cytotoxic activity for the invading parasites and cancer cell without affecting the host
cells.
Antibiotics, anticancer drugs.

4. 1. Physical action:
Mass of the drug--------bulk laxatives (bran), protective ( dimithacone)
Adsorptive properties----------------- charcoal, keolin
Radioactivity----------------------------131I
Mechanisms of action:
2. Chemical Action:
Antacid (AlOH3)-----neutralize gastric HCl.
Acidifying agent ( NH4Cl) and Alkalinizing agent (NaHCO3)----
reacts with buffer in plasma and alter urine pH
Oxidizing agents (KMnO4)----germicidal
Chelating agent (Cal. disod. Edetate)----sequester toxic metals.

5. 3. Through Enzymes:
Enzymes catalyst all biological reaction thus enzymes are very good target of drug action.
Stimulation or Inhibition.
Stimulation:
Since enzyme activity in the biological system is optimally set thus stimulation of
enzymes by drug is unusual.
Adrenalin------------------------ Adenylyl cyclase
Penicillin------------------------ Penicillinase
Inhibition:
Common mode of drug action.
A. Nonspecific inhibition
B. Specific inhibition
1. Competitive 2. Noncompetitive

6. Nonspecific inhibition:
Denatures the proteins ( 3o structure)
e.g. strong acids, heavy metal salts, alkali, alcohols, formaldehyde , phenols etc .
Specific inhibition:
Inhibits a particular enzymes, excludes others, either competitive or noncompetitive manners.
Competitive inhibition:
Drugs competitive with normal substrate for the same site and same isoenzymes.
Equilibrium type, in which if the substrate concentration sufficiently increase that can displace the drugs.
e.g. Physostigmine, neostigmine Vs Ach for Cholinestesterase
Sulfonamides Vs PABA for folate synthase
Allopurinol Vs hypoxanthin for Xanthine oxidase

7. Non- equilibrium type Inhibition, Can occur with the drugs which react with same catalytic site of the
enzyme but either form strong covalent bond or have such a higher affinity that normal substrate can not
able to displace the inhibitors.
e.g. organophosphates --- bind to the esteretic site of cholinesterase's.
Methotrexate have affinity at least 50000 time higher than DHFA for DHF reductase.
Non-competitive inhibition:
The inhibitor react with the adjacent site, not with catalytic site of the same
enzymes but alter the enzyme in such way that enzymes loses it catalytic activity.
e.g.
Acetazolamide------------------------------Carbonic anhydrase
Aspirin , Indomethacin---------------------Cyclo-oxygenase
Disulfirum----------------------------------Aldehyde dehydrogenase
Digoxin--------------------------------------Na+ K+ ATPase

8. 4. Through Receptors:
A macromolecular component of a cell, usually a protein, with which a drug interacts
to produce a response
Binding sites are situated on the surface or inside the effector cell. Specific ligands
combine with them and initiate the characteristic response.
Ligand: Molecule which attaches selectively to particular receptors or sites.
Agonist: Activates receptor to produce an effect.
Antagonist: Prevents the action of an agonist but does not have any effect of its own.
Inverse agonist: Actives a receptor to produce an opposite action to that of an agonist.
Partial agonist: Produce submaximal effect but antagonizes the action of a full agonist.

9. Drug Action Through Receptors
Receptors contain a binding site (hollow or cleft on the receptor surface) that is
recognized by the ligand.
Binding of the ligand involves intermolecular bonds.
Binding results in an lock and key phenomenon or an induced fit of the receptor
protein.
Ligand does not enter the cell. It departs the receptor unchanged and is not
permanently bound.

10. Drug Action Through Receptors
Lock and Key’ Hypothesis: “ The drug molecule must fit into the receptor AND produce
its action like a key fits into the lock AND opens it also”
 Every ‘lock’ has its own ‘key’
 If the ‘key’ is not precise, the ‘lock’ does not open
 The ‘drug’ is the key that has to fit the target specifically and productively
Induced-Fit Hypothesis: The binding of the ligand to the receptor must cause a change in
the shape of the receptor that results in the proper alignment of the catalytic groups on its
surface.
 At least two steps - e.g., step 1 is initial binding of drug with receptor and step 2 is a
change in structure of the receptor (and/or drug) so that the initial drug or a new ligand
perfectly fits with the receptor.
 Receptor is flexible - can wrap around the drug.

11. Drug Action Through Receptors
Cell
Membrane
Cell
Receptor
Messenger
message
Induced fit
Cell
Receptor
Messenger
Message
Cell
Messenger
Receptor
Induced Fit Hypothesis
Lock and Key Hypothesis

12. Receptor occupation theory:
Proposed by Clark (1937)
Drug action based on occupation of receptors by specific drug.
Interaction between drug (D) and receptor (R) governed by law of mass action and
effect (E) is the direct function of the drug receptor complex (DR).
D+ R  DR E
Accordingly
1. Intensity of response ∞ fraction of receptors occupied.
2. All or none action, no partial activation.
3. Drug and receptor have a rigid ‘ lock and key relationship’

13. Deviation of the theory:
By Ariens and Stephenson in 1950s - Ariens and Stephenson Hypothesis
• All receptors need not to be occupied for a maximal effect.
Histamine can produce maximum effect when most of the receptors are occupied by competitive
antagonists.
• Different drugs have different capacities to induce a response, they must occupy different
fraction of the receptor to induce equal response. So sub maximal activation of a receptor is
possible. In that case, all or none law is not applicable.
•A drug could induce change in the receptor to make it more or less favorable to combine with
the drug.
D + R --------- DR ~~> S  E
S is the quantity denoting strength of stimulus.

14. Hypothesis of Paton – Rate Theory
“Effectiveness of a drug does not depend on the actual occupation of the receptor but by
obtaining proper stimulus.”
-Response is proportional to the rate of Drug-Receptor Complex formation
-Duration of receptor occupation determines if a drug is an agonist, partial agonist, or antagonist
This is also known as the Rate Theory.
Types of Receptor
 G- Protein Coupled Receptors
 Ligand Gated Ion Channels
 Kinase Linked Receptors
 Nuclear Receptors

15. Nature of Receptors
1. Receptors are regulatory macromolecules, mostly proteins,
though nucleic acids may also serve as receptors [hundreds of
receptor proteins have been isolated, purified, cloned and their
primary amino acid (AA) sequence has been worked out].
2. The cell surface receptors with their effector proteins are
considered to be floating in a sea of membrane lipids.
3. All types of receptors have a well defined common structural
motif, while the individual receptors differ in the details of amino
acid sequencing, length of intra/extracellular loops, etc.
4. Drugs act upon physiological receptors which mediate responses
to transmitters, hormones, autacoids and other endogenous
signal molecules; examples are cholinergic, adrenergic,
histaminergic, steroid, leukotriene, insulin and other receptors.

16. Regulation of Receptors
Receptors are themselves subject to many regulatory and homeostatic controls. These controls
include regulation of
1. Synthesis and degradation of the receptor by multiple mechanisms,
2. Covalent modification,
3. Association with other regulatory proteins
4. Re-localization within the cell
Down Regulation/Desensitization: Can result from temporary inaccessibility of the receptor to
agonist or from fewer receptors synthesized and available at the cell surface (e.g., down-regulation
of receptor number).
 Decrease in response
 Caused by prolonged use of agonist
 Reduced drug effect
 When initial high response is reached, the effect diminishes within seconds/minutes even in the
continued presence of the agonist
 Reversible

17. Regulation of Receptors
Up Regulation/Super-sensitivity: Can result from higher receptors synthesis and available at the
cell surface (e.g., up-regulation of receptor number).
 Increase in response
 Caused by prolonged use of antagonist
 Increase drug effect
 Prolonged block by an antagonist causing fast up regulation of receptors
 New receptors are highly sensitive!
Functions of receptors
 Propagate regulatory signals
 Amplify signals
 Integrate extracellular and intracellular signals
 Adapt to short term and long term changes.

18. Dose-Response Relationship
DOSE = amount of drug administered to the patient
RESPONSE = effect in the body produced by the drug
Drug + Receptor ↔ Drug-Receptor Complex  Response.
i. Depends on multiple factors
ii. A drug usually has one desired effect that causes a change in a target organ or structure
iii. It will also have secondary effects because it will be absorbed by other areas of the body
iv. Main effect – the effect you want the drug to have
v. Side effects – secondary effects that may or may not be desirable or helpful
vi. Goal is to use a dose of a drug that is effective, but has minimal side effects

19. The relationship between the
concentration of drug at the
receptor site and the magnitude of
the response is called the dose-
response relationship
Dose-response curve
i. Making dosage decision
ii. Compare dosage to the percentage of
people showing different effects.

20. Potency
 Absolute amount of drug required to produce an effect
 More potent drug is the one that is required in lower amount to cause same effect.
Efficacy
 Maximal response that can be elicited by a drug.
 Agonists demonstrating high efficacy can result in a maximal effect, even when only a small fraction of the
receptors is occupied
Potency Efficacy
B<A A=B
C<A ; C=B C<A,B
D>A,B,C D<A,B; D=C
Response Drug (log conc.)
A
D
B
C

21. Therapeutic Index
 The gap between the minimum therapeutic effect of
drug and the minimum adverse effect of drug is
defined as safety margin or therapeutic index of a
drug
 The index used for judging drug's safety.
Therapeutic index = LD50 / ED50
ED50 (Median effective dose)：The dose at which 50% of
individuals (experimental animals) exhibits specified
effect.
LD50（Median lethal dose）：The dose required to
produce death in 50% of individuals.
Morphine

22. Affinity
Ability of drug to combine with the receptor.
Efficacy / intrinsic activity
Ability of a drug to activate the receptor after receptor occupation.
Agonists - both affinity and intrinsic activity/efficacy.
Competitive antagonists - have affinity but no intrinsic activity.
Partial agonists - have affinity and submaximal efficacy.
Inverse agonists - have affinity but intrinsic activity with a minus sign.
Drug action
Combination of the drug with its receptor resulting a conformational change of the receptor (in case
of agonist) or o preventing the change by the agonist ( in case of antagonist).
Drug effect
The ultimate change in the biological function due to the consequence of drug action, through a series
of intermediate steps (transduction).

23. Combination of Drugs
Combinations of two/ more drugs, simultaneously or in quick succession
1. No interference with each other’s effects
2. May oppose each other’s actions (antagonism)
3. May produce similar actions on the same organ (synergism).
Synergism
Derived from two Greek words ( Syn= together , Ergo= work, Ism)
Definition: “Drug synergy occurs when drugs can interact in ways that enhance or magnify one or
more effects, or side - effects, of those drugs.”
Positive effects:
Examples: 1) Codeine mixed with Acetaminophen or Ibuprofen to enhance the action of codeine as a
pain reliever.
2) Use of Cannabis with LSD (Lysergic acid diethylamide), where the active chemicals in cannabis
have been reported to enhance the hallucinatory experience of LSD.

24. Synergism
Negative effects:
Negative effects of synergy are a form of contraindication. For example, a combination of depressant
drugs that affect the central nervous system (CNS), such as alcohol and Valium (Diazepam), can
cause a greater reaction than simply the sum of the individual effects of each drug if they were used
separately. In this particular case, the most serious consequence of drug synergy is exaggerated
respiratory depression, which can be fatal if left untreated.
Types
1) Summation:
Definition : Combined effect of drugs which are given simultaneously is equal to the sum of
magnitude of effect produced by individual drugs.
Example: General Anesthetics

25. Synergism
Types
2) Potentiation:
Definition: Combined effect of two simultaneously given drugs is greater than the algebraic sum of
action of individual drugs.
Example: NH4Cl (Weak diuretic) potentiates the diuretic effect of Organic Mercurials.
Antagonism
Definition: Opposing action of two drugs on same biological system.
Difference between agonist and antagonist:
Agonist: Possesses both affinity and intrinsic activity.
Antagonist: Opposes the action of agonist. Possesses only affinity but no intrinsic activity.

26. Antagonism - Types
Chemical
Antagonism
Physiological
Antagonism
Pharmacological
Antagonism
Agonist-Antagonist
interaction=Agonist
loses its activity
Agonist-Antagonist act on
different receptors. Both have
opposite actions.
Antagonist prevents agonist from acting upon
its receptors.
EXAMPLES:
Antacids(NaOH ,
Al(OH)2 )
neutralize HCl
Histamine - Adrenaline
antagonism.
HISTAMINE:
*Vasodilation
*Decreases blood pressure
*Bronchoconstriction
ADRENALINE:
*Vasoconstriction
*Increases blood pressure
*Bronchodilation
Two types: 1) Competitive 2) Non-Competitive
Competitive:
1. Antagonist competes with agonist for the
same receptor site
2. Reversible phenomenon
3. Can be overcome by increasing the conc. of
agonist.
Non competitive:
1. Binds to an allosteric site other than the
agonist binding site
ii. Prevent the receptor activation by the
agonist.

27. Drug Dosage
Drug Dosage and Dose
 A dose refers to a specified amount of medication taken at one time.
 By contrast, dosage is the prescribed administration of a specific amount, number, and frequency
of doses over a specific period of time.
 The administration of a drug or agent in prescribed amounts and at prescribed intervals.
Standard Dose: The assumed average maintenance dose per day for a drug used for its main
indication in adults.
Target Level Dose: Dose of drug administered for achieving a desired plasma/serum/tissue drug
levels in patients.
Regulated Dose: Dose of drugs which, by virtue of formulation and product design, provide drug
release in a regulated form, distinct from that of the conventional dosage forms, so that dosing of
drugs can be controlled.
Titrated Dose: The continual adjustment of a dose based on patient response. Dosages are adjusted
until the desired clinical effect is achieved.

28. Factors Modifying Drug Action
Responses of a drug varies from
(1) person to person; and
(2) also same person on different occasions such as
 Individuals differ in pharmacokinetic handling of drugs
 varying plasma/target site conc.
 Metabolized drug Vs excreted unchanged drugs – Propranolol and Atenolol
 Variation in number or state of receptors, coupling proteins or other components of
response
 Variations in hormonal/neurogenic tone or concentrations – atropine, propranolol,
captopril
Categories of factors:
1. Genetic
2. Non-genetic including environmental, circumstantial and personal variables

29. Factors Modifying Drug Action
1. Body Size:
Influences the conc. of the drug attained at the site of action – obese/lean/children – Body weight
(BW) and Body Surface area (BSA)
Individual dose = BW(kg) x average adult dose;
Individual dose = BSA (m2) x average adult dose
BSA can be calculated by Dubois Formula
BSA (m2) = BW (kg) 0.425 x Height (cm) 0.725 X 0.007184
2. Age:
Young`s formula: Child dose = (Age/Age+12) x adult dose
Dilling`s formula: Child dose = (Age/20) x adult dose
3. Gender:
Females have smaller body size – required doses are lower.
Digoxin in maintenance therapy of heart failure – mortality higher in fmale.
4. Species and Race: Some strains of rabbits – resistant to atropine
5. Genetics
Determinants of drug responses – transporter, enzymes, ion channels, receptors and couplers –
controlled genetically – Individual variation of responses.
Low variants of CYP2C9 – Warfarin bleeding.

30. Factors Modifying Drug Action
6. Route of administration: Parenteral for speedy action
7. Environmental factors: Drug metabolism may get induced – exposure to insecticides, carcinogens
8. Psychological factors: Efficacy of a drug can be affected by patient`s beliefs, attitudes and
expectations – particularly CNS drugs.
Placebo: An inert substance which is given in the garb of medicine. Works by psychodynamic effects
(not pharmacodynamics) – sometimes responses equivalent to active drugs.
9. Pathological states: GIT, Liver diseases, Kidney diseases, Thyroid diseases.
10. Presence of other drugs
11. Tolerance:
Requirement of higher dose of a drug to produce a given response.
Natural: Species/individual inherently less sensitive – Rabbits to atropine and Blacks to beta –
blockers.
Acquired: Repeated use of a drug in an individual who was initially responsive become non-
responsive (tolerant) – CNS depressants.
Cross tolerance: Tolerance to pharmacologically related drugs – alcoholics to barbiturates; Morphine
and Pethidine.