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1. Pharmacodynamics:
Mechanism of Drug Action

2. Content to Discuss
1. Pharmacodynamics
2. Binding of Drug Molecules to Cells (Receptor Mediated Response)
3. Drug Classification (Agonists,Antagonists)
4. Dose Response Relationship
5. Therapeutic Index
6. Drug Receptors and their various types
7. Targets for DrugAction
8. Signal Transduction
• Drug Receptor Complexes
• Receptor States
• Receptor Up and Down Regulation
9. Major Receptor Families

3. Pharmacodynamics
‘Pharmaco Drugs’
‘Dynamics  Power/ Action’
• “What a drug dose to the body”
• Action:
• How and Where the effect is produced
• Effect:
• Type of response produces by the drug
• Sight of DrugAction:
i. Extracellular
• Antacids neutralizing gastric acidity
• Chelating agents forming complexes with heavy metals
• MgSO4 acting as purgative by retaining fluid inside lumen of intestine

4. ii. Intracellular
• Folic acid synthesis inhibitors (folic is intracellular component essential for synthesis
of proteins)
• Trimethoprim and sulpha drugs interfere with synthesis of folic acid.
iii.Cellular
• Ach on nicotinic receptors of motor end plate, leading to contraction of skeletal
muscles.
• Effect of sympathomimetics on heart muscle and blood vessels

5. • Type of Drug Responses:
• Drugs do not impart new functions on any system, organ or cell; they only alter the
pace of ongoing activity
• Major principles of drug responses are:
i. Stimulation
• Drugs act by enhancing the level of activity of specialized cells
• e.g. Catecholamines stimulates the heart and increase heart rate and force of cardiac
contraction
• Pilocarpine stimulates salivary glands
• Excessive stimulation is often followed by depression of that function
• Picrotoxin a CNS stimulant produce convulsions followed by coma and respiratory
depression
ii. Inhibition/ Depression
• Drugs act by diminution of activity of specialized cells
• Alcohol, barbiturates and anesthetics depress CNS.
• Atropine inhibitACh action.
• Quinidine depress heart
• Certain drugs stimulate one type of cells and but depress others
• ACh stimulates intestinal smooth muscles but depress SAnode in heart

6. iii.Replacement
• When there is deficiency of endogenous substance, they can be replaced by the
drugs.
• Insulin in diabetes mellitus
• Iron in anemia
• Levodopa in parkinsonism
iv.Cytotoxic
• Treatment of infectious diseases/ cancer with drugs that are selectively toxic for
infecting organisms and cancer cells
• Selective cytotoxic action for invading parasites or cancer cells, attenuating
them without significant effect on host cells is used for cure, palliation of
infections and neoplasms
• Anticancer drugs
• Antibiotics

7. v. Irritation
• Often applied to less specialized cells (epithelium and connective tissues)
• Drugs on topical application cause mild irritation of the skin and adjacent
tissues which stimulates the associated functions
• These drugs are used as counter irritants
• Eucalyptus oil and methyl salicylates are used in sprains, joint pain and
myalgia
• Strong irritation results in inflammation, corrosion, morphological damage.
• FactorsAffecting Drug Response:
• Age
• Weight
• Gender
• Environment
• Fever
• Shock

8. • Mechanism of DrugAction:
• Drugs act either by receptor or by nonreceptor or by targeting specific genetic changes
• Majority of drugs act (HOW)
i. Receptor mediated
• Drugs produce their effect through interacting with some chemical compartment of
living organism i.e. Receptor.
• Receptors are in dynamic state.
• The affinity of the response to drugs is not fixed. It alters according to situation.
ii. Non receptor mediated
• Voltage gated Ion channels
• Enzymes
• Transporters
• Drug may act by physical properties, chemical properties, modulating body function
regulators, ion channels, enzyme binding or miscellaneous mechanism

9. Binding of Drug Molecules to Cells (Receptor Mediated Response)
Drug will not work unless it is bound
• Drug molecules can be ‘bound’ to particular constituents of cells and
tissues in order to produce an effect by interacting with some chemical
compartments of living organism c/s receptors
• Receptors:
• “Any target molecule with which the drug molecule has to combine in
order to elicit its specific effect”
• Specialized areas in cell to which drugs get bound
• They are regulatory protein macromolecules present either on cell surface or
cytoplasm or nucleus

10. • Receptors Functions:
• Two essential functions
• Recognition of specific ligand molecule (Ligand Binding Domain)
• Transduction of signals into responses (Effector Domain)
Ligand binding domain
Transduction of
signal into response

11. • Ligand:
• Ligand means the any substance which binds to receptors.
• Hormones
• Neurotransmitters
• Drugs
• Chemical substances
• Toxins etc.
• Receptor Types:
i. Receptors on the surface of the cell membranes
• Serpentine Receptors (7-pass receptors, GPCR)
• One Pass Receptors (Enzyme Linked Receptors)
• Ions Operated Channels (Ligand Gated Ion Channels)
ii. Receptors within the cell
• Nuclear Receptors

12. • Drug-Receptors Interaction:
• Drug + Receptor Drug Receptor Complex Response
i. Selectivity:
• Degree of complementary co-relation between drug and receptor
• Adrenaline selectivity for α and β-receptors
ii. Affinity:
• Ability of drug to get bound to receptor
iii.Intrinsic activity or Efficacy:
• Ability of drug to produce pharmacological response by making drug-
receptor complex

13. Drug Classification
• Association of Drug Molecules to Binding
Sites
• On basis ofAffinity and Efficacy:
i. Agonists
• Bind to receptor and produce biological
response
ii. Antagonists
• Bind to receptor and produce no response
• Bind to receptor decrease or oppose action
of other drug

14. Agonists
1. Full agonists
2. Partial agonists
3. Silent antagonists
4. Inverse agonists

15. Agonists
i. FullAgonist
• Drug bind to receptor and produce maximal response that mimics the response of
endogenous ligand
• Afull agonist produce complete activation of a receptor at high dose concentration
• Phenylephrine agonist of α1-adrenergic receptor

16. ii. Partial Agonist
• Efficacy/ intrinsic activity greater than zero but less than that of full agonist
• These drugs have partial affinity to receptors but have low intrinsic activity
• If all the receptors are occupied partial agonists cannot produce Emax.
• Affinity is less as compared to agonists
• e.g. pindolol, pentazocine

17. iii.Inverse Agonist
• They produce a response below the baseline responses measured in the absence of drug
• These drugs have full affinity to receptors but intrinsic activity is zero to -1.
• They decrease the number of activated receptors to below observed in the absence of
drug
• Exert opposite pharmacological effect of receptor agonist
• e.g. carboline is inverse agonist of benzodiazepines receptors

18. Antagonists
1. Competitive/ reversible
antagonists
2. Irreversible antagonists
3. Functional and
chemical antagonism

19. Antagonists
Definition:
• Drugs that decrease or oppose the action of another drug or endogenous ligand
• Antagonist have no effect if agonist is agonist is not present
• Antagonists itself have no intrinsic activity, produce no effect by themselves.
• Antagonists possess strong affinity to bind avidly to target receptors
i. Competitive antagonist
• If both agonist and antagonist bind to the same site on a receptor; said to be
“competitive”
• Competitive antagonist prevent agonist from binding to its receptor and maintain
receptor in its inactive conformational state.
• ED50 of agonist is increased in competitive antagonism.
• Trazosine an antihypertensive drug antagonize the effect of epinephrine at α1-
adrenergic receptor  decreasing the vascular smooth muscles tone and reduce blood
pressure.

20. ii. Irreversible Antagonists:
• Irreversible antagonist causes a downward shift of maximum, with no shift of the
curve on the dose unless spare receptors are present
• Their effect cannot be overcome by adding more agonist
• It cannot increase ED50 of agonist.
i. Mechanism ofAction:
a. Antagonist can bind covalently or with high affinity to active site of receptor
b. Antagonist can bind to allosteric site  produce conformational changes 
preventing activation of receptor even agonist attach to active site
iii.Functional and ChemicalAntagonism:
• Antagonist act at completely separate receptor, initiating effects that are completely
opposite to those of agonists
• Functional antagonism by epinephrine to histamine induce bronchoconstriction
• Also known as “PsychologicalAnatogonism”

21. Receptors and Their Various Types
1. Receptors:
• Enzymes
• Carrier Molecules
• Ion Channels
• Receptors
• Structural and Plasma Proteins (i.e. Colchicine binds to Tubulin)
2. Receptor Classification:
i. Cell Surface Receptors:
• Inotropic receptors (ligand gated ion channels)
• Metabotropic receptors (Serpentine receptors)
• Ligand regulated transmembrane receptors
ii. Intracellular Receptors:
• Nuclear receptors

22. Targets for Drug Action
1. Enzymes as receptors
• Acetylcholinesterase
• Cyclo-oxygenase
• Angiotensin-converting Enzyme
• Monoamine Oxidase
• Phosphodiesterase Type V
• Dihydrofolate Reductase
• Thymidine kinase
2. Carrier Molecules/ Transporters
• Noradrenaline Transporter (Membrane)
• WeakAcid Carrier (Renal Tubule)
• Na+
/K+
/2Cl−
• Co-transporter (Loop Of Henle)
• Proton Pump (Gastric Mucosa)
• MDR Transporter

23. 3. Ion Channels
• Voltage-gated Na+
Channels
• Renal Tubule Na+
Channels
• Voltage-gated Ca2+
Channels
• ATP-sensitive K+
Channels
• GABA-gated Cl−
Channels
4. Receptors
• NicotinicACh receptor
• β-Adrenoceptor
• Histamine (H1 receptor)
• Opiate (μ-receptor)
• Dopamine (D2 receptor)
• Oestrogen receptor

25. Signal Transduction
i. Drug Receptor Complex:
• Cells have different types of receptors, each of which is specific for a particular ligand
and produces a unique response
Drug + Receptor ←→ Drug–receptor complex → Biologic effect
• e.g. heart have receptors that bind and respond to epinephrine or norepinephrine as
well as muscarinic receptors specific for acetylcholine.
• The magnitude of response is proportional to the number of drug-receptor complex
i. Receptor states
• Inactive (R) sates
• Active R* states (show response)
Receptor (R)←→ Receptor (R*)
• These are in reversible equilibrium with one another.
• Unoccupied receptor does not influence intracellular processes

26. Two-state receptor model

27. iii. Signal Transduction:
• Receptor with bound ligand is activated
• It has altered physical and chemical properties, which leads to interaction with cellular
molecules to cause a biologic response
• Recognition of a drug by a receptor ,triggers a biologic response called signal
transduction

28. Major Receptor Families
i. Receptor Families:
• Ligand-gated ion channels (Ionotropic Receptors)
• G protein–coupled receptors (Metabotropic Receptors)
• Enzyme–linked receptors (One Pass Receptors)
• Intracellular receptors

29. i. Ligand Gated Ion Channels:
• Ionotropic receptors
• Similar structure to ion channels incorporating a ligand binding site in
extracellular domain
• Ligand binding and channel opening occur in millisecond timescale
• Oligomeric assembling of subunits surrounding central pore
• These are receptors for fast neurotransmitters
 GABAreceptors
 Glutamate receptors
 Nicotinic acetylcholine receptors
 5-HT3 receptors

31. • Gating Mechanism in Ligand Gated Ion Channels:
 Receptors control the fastest synaptic events
 Neurotransmitter acts on the postsynaptic membrane and transiently increases
permeability to particular ions (Na+ and K+)
 Na+ influx generates action potential due to cell depolarization reaches to peak in
few milliseconds and also decays in milliseconds
 The sheer speed of this response implies that the coupling between the receptor
and the ionic channel is a direct one
 In contrast to other receptor families no intermediate biochemical steps are
involved in the transduction process.

32. Signal molecules binds as a ligand
at a specific site on the receptor
Conformational changes open the
channel allowing ions to flow into
the cell
The changes in ion concentration
within the cell triggers cellular
responses

33. • Effects due to Concentration Changes in Different Ions:
 Na+ and Ca+ Ions:
• Increase Level  Excitatory
• Decrease Level  Inhibitory
 K+ Ions:
• Increase Level  Inhibitory
• Decrease Level  Excitatory
 Cl- Ions:
• Increase Level  Inhibitory
• Decrease Level  Excitatory

34. • Importance of Ligand Gated Ion Channels:
 Generation and propagation of nerve impulse
 Synaptic transmission of neurons
 Muscle contraction
 Salt balance
 Hormones release
 Muscle relaxants, anti-arrythmatics, anesthetics  act by blocking ions channels

35. ii. G-Protein Coupled Receptors (Serpentine Receptors):
• Metabotropic receptors or 7-transmembrane (7-TM or heptahelical) receptors.
• Membrane receptors coupled to intracellular effector systems via a G-protein
• The largest family include receptors for many hormones and slow transmitters,
 Muscarinic acetylcholine receptor
 Adrenoceptors
 Chemokine receptors

36. • Molecular Structure:
 Four to five subunits (α2, β, γ, δ) form a cluster surrounding a central transmembrane
pore
 Lining is formed by the M2 helical segments of each subunit
 Receptor contains negatively charged amino acids making them cation (+ve) selective

37. • Families of G-Protein Coupled Receptors:
 Rhodopsin Family
• Amines NT
• Purines
• Cannabinoids
 Secretin/Glucagon Receptors Family
• Peptide hormones
 Metabotropic Glutamate Receptors/ Calcium Sensor Family
• GABA
• Glutamate

38. • Roll of G-Proteins:
 Membrane resident proteins  Recognize activated GPCRs Pass message to
effectors
 Occur in interaction with membrane nucleotides ; freely moving in cytoplasm
 α, β and γ subunits  trimmer in resting states
 Three subunits attached to GPCRs through fatty acid chains  Prenylation

39. • Secondary Messenger System involved in Signal Transduction:
 Adenyl cyclase / cAMP system
 cAMP -nucleotide synthesized fromATP- byAdenyl cyclase, metabolized by PDE
 Regulate enzymes of metabolism, growth and contractile muscle proteins
 NT- acts on GPCRs -Gs / Gi activated- produce effects by increase and decrease activity
ofAdenyl cyclase / cAMP.
 cAMP activates protein kinase which activates/inactivates enzymes by phosphorylation
 Cellular events
 Phospholipase C / Inositol phosphate system
 Phospholipase C: cleaves membrane phospholipids- Phosphoinositides-
 PLC beta –cleaves phosphatidylinositol (4,5)bis phosphate PIP2 into DAG and IP3
 DAG and IP3 – secondary messenger elicit cellular responses

41. 1. Adenylyl cyclase: cAMP pathway
PKA Phospholambin
Increased
Interaction with
Ca++
Faster relaxation
Troponin
Cardiac
contractility
Other
Functional
proteins

42. Adenylyl cyclase: cAMP pathway
• Main Results:
– Increased contractility of heart/impulse generation
– Relaxation of smooth muscles
– Lipolysis
– Glycogenolysis
– Inhibition of Secretions
– Modulation of junctional transmission
– Hormone synthesis
– Additionally, opens specific type of Ca++ channel – Cyclic
nucleotide gated channel (CNG) - - -heart, brain and kidney
– Responses are opposite in case of AC inhibition

43. • G-Proteins Subtypes:
G- Proteins
Gs
Signaling Pathways
Adenyl cyclase cAMP
Excitatory effects
Gi1, Gi2, Gi3
Receptor For
BetaAdrenergicAmines
Serotonin
Glucagon Histamines
Alpha2 AdrenergicAmines
Serotonin
Opioids
Adenyl cyclase cAMP
Cardiac K+ channels
Golf Olfactory epithelium Adenyl cyclase cAMP
Go
NT
Opioids
Cannabinoids
Not Clear
Gq
Serotonin
5 HT2
G , G
t1 t2
Rodopsins and color opsins in retinal rods
and cone cells
PLC
IP3
DAG
Cytoplasmic Ca
cGMP
Phosphodiestrase cGMP

44. • Action of Gs Coupled Receptors:
Ligand
Bind to
GPCR
α-subunit of Gs proteins become activated
α-subunit leaves the beta and gamma subunit
α-subunit
bind to
Adenylyl
Cyclase
Conversion ofATPto cAMP
Activation
of protein
kinaseA
Alteration of cell metabolism
Alteration of genomic expression
Alteration in electric properties of cells via activation of ion channels

45. • Action of Gi Coupled Receptors:
Ligand Bind with the
serpentine receptors
Alpha subunit of Gi
proteins become
activated
Alpha subunit leaves
the beta and gamma
subunit and bind with
the protein called
Adenylyl Cyclase
NowA.C sends signals
to the effector domain
to stop the conversion
ofATPinto cAMP
Beta and Gamma unit
binds with the ions
channels and causes the
efflux of potassium
from membrane
Beta and Gamma unit
binds with the ions
channels and causes the
efflux of potassium
from membrane

46. • Action of Gq Coupled Receptors:
Ligand Bind with the
serpentine receptors
Alpha subunit of Gq
proteins become
activated
Alpha subunit leaves
the beta and gamma
subunit and bind with
the Phospholipase C
Phospholipase C
causes the breakdown
of PIP2 and resulting
in IP3 and DAG

47. • Action of Gq Coupled Receptors:
Phospholipase
C
IP3
Binds to IP3 sensitive Ca2+
channels
Calcium activates
Calmodulin protein
Activation of enzyme CaM
Kinase
Alteration of cell
metabolism
Alteration of genomic
expression
Alteration in electric
properties of cells via
activation of ion channels
DAG
Activate an enzyme called
Protein Kinase
Alteration of cell
metabolism
Alteration of genomic
expression
Alteration in electric
properties of cells via
activation of ion channels

48. 2. Phospholipase C:IP3-DAG pathway
PKc

49. IP3-DAG pathway
• Main Results:
–Mediates /modulates contraction
–Secretion/transmitter release
–Neuronal excitability
–Intracellular movements
–Eicosanoid synthesis
–Cell Proliferation
–Responses are opposite in case of PLc
inhibition

50. • Action of Gq Coupled Receptors:

51. • Secondary Messenger System involved in Signal Transduction:
 Ion channels
 GPCR -Directly controls ions channels without secondary messengers-
 e.g. Muscarinic receptors in heart- activates K+ channels

52. iii.Enzyme Linked Receptors:
• Heterogeneous group of membrane receptors respond to protein mediators
• They comprise an extracellular ligand-binding domain linked to an intracellular
domain by a single transmembrane helix.
• The intracellular domain is enzyme in nature
i. Protein kinase activity
ii. Guanylyl cyclase activity

53. • Role of Enzyme Linked Receptors:
• Involved in growth factors -growth, proliferation, differentiation and survival-
• Mediate action of protein mediators –Growth factors, cytokines, hormones,
insulin
• Slow- require expression of new gene
• Single membrane spanning helix- extracellular ligand binding domain-
intracellular domain

54. • Types of Enzyme Linked Receptors:






 Tyrosine Kinase Receptors
Insulin receptors
 Tyrosine KinaseAssociate Receptors
 Serine/ Threonine Kinase Receptors
Phosphorylate enzymes causing the alteration in cell metabolism.
 Cytokine Receptors
 Guanylyl Cyclase Receptors
Activated GCR leads to the conversion of GTP into cGMP.
cGMP will activate the protein kinase G.
Which will further lead to the phosphorylation of enzyme and genes transcriptional factors.
 Tyrosine Phosphatases
Once it is activated it causes the dephosphorylation of the other phosphorylated proteins.

55. • Enzyme Linked Receptors Mechanism:
 Receptors for various growth factors incorporate tyrosine kinase in their
intracellular domain.
 Cytokine receptors have an intracellular domain that binds and activates cytosolic
kinases when the receptor is occupied.
 The receptors all share a common architecture, with a large extracellular ligand-
binding domain connected via a single membrane-spanning helix to the
intracellular domain.
 Signal transduction generally involves dimerization of receptors, followed by
autophosphorylation of tyrosine residues.
 The phosphotyrosine residues act as acceptors for the SH2 domains of a variety of
intracellular proteins, thereby allowing control of many cell functions.
 They are involved mainly in events controlling cell growth and differentiation, and
act indirectly by regulating gene transcription.

56. • Transduction Mechanisms of Enzyme-Linked Receptors.:
 Growth Factor Pathway:

57.  Cytokines Pathway:

58. • Protein Phosphorylation in Signal Transduction:
 Many receptor-mediated events involve protein phosphorylation, which controls
the functional and binding properties of intracellular proteins.
 Receptor-linked tyrosine kinases, cyclic nucleotide activated tyrosine kinases and
intracellular serine/ threonine kinases comprise a ‘kinase cascade’ mechanism that
leads to amplification of receptor mediated events.
 There are many kinases, with differing substrate specificities, allowing specificity
in the pathways activated by different hormones.
 Desensitization of G-protein-coupled receptors occurs as a result of
phosphorylation by specific receptor kinases, causing the receptor to become non-
functional and to be internalized.
 There is a large family of phosphatases that act to reverse the effects of kinases.

59. • Central role of Kinase Cascades in Signal Transduction:

60. iv.Intracellular Receptors:
a. Nuclear receptors
• Ligand activated transcription factors
• Present in soluble form -either in cytoplasm or nucleus- freely diffusable.
• Ligand must have lipid solubility to cross membrane
• Transduce signals by modifying gene transcription
• Play vital role in endocrine signaling and metabolic regulations
i. Steroid hormones
ii. Glucocorticoids
iii. Vit. D &A
iv. Orphan receptors (No well defined ligands)
b. Response:
• 30 minutes to days
c. Example:
• Transcription of DNAinto RNA
• Translation of RNAinto an array of proteins

61. • Receptors that Control Gene Transcription:
 Receptors are intracellular proteins ligand first enter cell
 Receptors consist of a conserved DNA binding domain attached to variable ligand
binding and transcriptional control domains
 DNAbinding domains recognize specific base sequences, thus promoting or
repressing particular genes
 Pattern of gene activation depends on both cell type and nature of ligand, so effects
are highly diverse
 Effects are produced as a result of altered protein synthesis and therefore are slow
in onset
 One type of nuclear receptor is responsible for the increased expression of drug
metabolizing enzymes induced by many therapeutic agents.

63. Receptors of gene expression - Image

64. Receptor Regulation
• Up regulation of receptors:
• In tonically active systems, prolonged use of agonist (by denervation or
antagonist) results in supersensitivity of the receptor as well as to effector
system to the agonist.
• Sudden discontinuation of Propranolol, Clonidine etc.
• 3 mechanisms - Unmasking of receptors or proliferation or
accentuation of signal amplification

65. Receptor Regulation – contd.
• Continued exposure to an agonist or intense receptor stimulation causes
desensitization or refractoriness: receptor become less sensitive to the
agonist
• Examples – beta adrenergic agonist and levodopa Causes:
1. Masking or internalization of the receptors
2. Decreased synthesis or increased destruction of the receptors (down regulation) -
Tyrosine kinase receptors

66. Desensitization
• Sometimes response to all agonists which act through different receptors
but produce the same overt effect is decreased by exposure to anyone of
these agonists – heterologous desensitization
• Homologous – when limited to the agonist which is repeatedly activated – In
GPCRs (PKA or PKC) Kinases may also phosphorylate the GPCRs
R+ Transducer
Homologous
Ach
Hist
Heterologous

67. Functions of Receptors - Summary
1. To Regulate signals from outside the cell to inside the
effector cell – signals not permeable to cell membrane
2. To amplify the signal
3. To integrate various intracellular and extracellular signals
4. To adapt to short term and long term changes and maintain
homeostasis.

68. Non-receptor mediated drug action – clinically relevant
examples
• Physical and chemical means - Antacids, chelating agents and
cholestyramine etc.
• Alkylating agents: binding with nucleic acid and render cytotoxic
activity – Mechlorethamine, cyclophosphamide etc.
• Antimetabolites: purine and pyrimidine analogues – 6 MP and 5 FU –
antineoplastic and immunosuppressant activity

69. Dose-Response Relationship
• Drug administered – 2 components of dose- response
– Dose-plasma concentration
– Plasma concentration (dose)-response relationship
• E is expressed as
Emax X [D]
Kd + [D]
E is observed effect of drug dose [D], Emax = maximum response,
KD = dissociation constant of drug receptor complex at which half
maximal response is produced
E max

70. Dose-Response Curve
dose Log dose
%
response
%
response
100% -
50% -
100% -
50% -
Emax X [D]
E =
Kd + [D]

71. Dose-Response Curve
• Advantages:
– Stimuli can be graded by Fractional change in
stimulus intensity
– A wide range of drug doses can easily be displayed on a
graph
– Potency and efficacy can be compared
– Comparison of study of agonists and antagonists become
easier

72. How we get DRC in vitro
Practically??
• Example: Frog rectus muscle and Acetylcholine
response – in millimeters
– Can compare with a drug being studied for having
skeletal muscle contracting property

73. Potency and efficacy
• Potency: It is the amount of drug required to produce a
certain response
Efficacy: Maximal response that can be elicited by the drug
•
Response
Drug in log conc.
1 2 3 4

74. Potency and efficacy - Examples
• Aspirin is less potent as well as less efficacious than
Morphine
• Pethidine is less potent analgesic than Morphine but
equally efficacious
• Diazepam is more potent but less efficacious than
phenobarbitone
• Furosemide is less potent but more efficacious than
metozolone
• Potency and efficacy are indicators only in different
clinical settings e.g. Diazepam Vs phenobarbitone
(overdose) and furosemide vs thaizide (renal failure)

75. Slope of DRC
• Slope of DRC is also important
• Steep slope – moderate increase in dose markedly increase the
response (individualization)
• Flat DRC – little increase in response occurs in wide range of
doses (standard dose can be given to most ptients)
• Example: Hydralazine and Hydrochlorothiazide DRC in Hypertension
Hydralazine
Thiazide
Fall
in
BP

76. Selectivity
• Drugs produce different effects – not single
• DRC of different effects may be different
• Example – Isoprenaline – Bronchodilatation and cardiac
stimulation – same DRC
• Salbutamol – different (selective bronchodilatation)

77. Therapeutic index (TI)
• In experimental animals
• Therapeutic Index =
Median Lethal Dose (LD50)
Median Effective dose (ED50)
Idea of margin of safety Margin of Safety

78. Therapeutic index (TI)
• It is defined as the gap between minimal therapeutic effect
DRC and maximal acceptable adverse effect DRC (also called
margin of safety)

79. Risk-benefit Ratio
• Estimated harm (ADRs, Cost, inconvenience)
Vs
• Expected advantages (relief of symptoms,
cure, reduction of complications, mortality,
improvement of lif etc)

80. Combined Effects of Drugs
• Drug Synergism:
– Additive effect (1 + 1 = 2)
• Aspirin + paracetamol, amlodipine + atenolol, nitrous oxide +
halothane
– Supra-additive effect (1 + 1 = 4)
• Sulfamethoxazole + trimethoprim, levodopa + carbidopa,
acetylcholine + physostigmine
• PABA DHFA THFA
Sulfamethoxazole Trimethoprim
Folate
synthase
Dihydrofolate
Reductase

81. Drug Antagonism
1. Physical: charcoal adsorbs alkaloids and can prevent
their absorption—used in alkaloidal poisonings
2. Chemical: KMnO4, Chelating agent used for gastric
lavage in poisoning.
3. Physiological antagonism: Histamine and adrenaline in
bronchial asthma, Glucagon and Insulin on blood sugar level.
4. Receptor antagonism:
a. Competitive antagonism (equilibrium)
b. Non-competitive
c. Non-equilibrium (competitive)

82. Receptor antagonism - curves
• Competitive:
• Antagonist is chemically similar to agonist and binds to same receptor
molecules
• Affinity (1) but IA (0), Result – no response Log
DRC shifts to the right
• But, antagonism is reversible – increase in concentration of agonist
overcomes the block
• Parallel shift of curve to the right side
• Non-competitive:
• Allosteric site binding altering receptor not to bind with agonist
• No competition between them – no change of effect even agonist conc. .is
increased
• Flattening of DRC of agonist by increasing the conc. Of antagonist

83. Receptor antagonism - curves
• Non – equilibrium:
– Antagonists Binds receptor with strong bond
– Dissociation is slow and agonists cannot displace
antagonists (receptor occupancy is unchanged)
– Irreversible antagonism developes
– DRC shifts to the right and Maximal response
lowered

84. Drug antagonism DRC

85. Drug antagonism DRC – non- competitive antagonism
Response
Agonist
Agonist
+ CA (NE)
Shift to the right
and lowered response
Drug in log conc.

86. Spare Receptor
• When only a fraction of the total population of receptors in a
system, are needed to produce maximal effect, then the
particular system is said to have spare receptors
• Example – Adrenaline (90%)

87. Competitive Vs NC antagonism
Competitive
• Binds to same receptor Resembles
chemically
• Parallel right shift of DRC in
increasing dose of agonist
• Intensity depends on the conc. of agonist
and antagonist
• Example – Ach and atropine,
Morphine and Naloxone
• Binds to other site No
resemblance
• Maximal response is suppressed
• Depends only on concentration
of antagonist
• Diazepam - Bicuculline
Non competitive

88. Summary
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Basic Principles of Pharmacodynamics
Mechanisms of drug action – Enzymes, Ion channels, Transporters and
Receptors with examples
Definitions of affinity, efficacy, agonist and antagonists etc.
Drug transducer mechanisms
GPCR and different GPCR transducing mechanisms – cAMP, Protein kinase
etc.
Up regulation and down regulation of receptors and desensitization
Principles of dose response curves and curves in relation to agonist,
competitive antagonist etc.
Therapeutic index, margin of safety and risk-benefit ratio concepts
Combined effects of drugs – synergism etc.
Dose response curve (DRC) – agonist and antagonist
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