This document provides an overview of pharmacodynamics, which is the study of how drugs act on the body. It discusses several key concepts: 1. Most drugs act by binding to receptors on or within cells. This can open or close ion channels, activate second messengers, or physically inhibit cellular functions. 2. Drugs can bind to different types of receptors like G-protein coupled receptors or tyrosine kinase receptors, activating various signal transduction pathways. 3. Affinity refers to how strongly a drug binds to its receptor, while efficacy refers to its ability to produce an effect after binding. Potency is the amount needed to produce a half-maximal effect. 4. Therapeutic

1. Demystified
Pharmacodynamics
Dr Lokendra Sharma
Professor Pharmacology
SMS Medical College
Jaipur

2. Objectives
Students-Led objective Tutorials
• What is Pharmacodynamics ?
• Principal of drug action ?
• Principal Target ?
• Functions of Receptor ?
• What is Drug Receptors ?
• Affinity?

3. Pharmacodynamics ?
• Pharmacon:Drug
Dynamics: action or activity
• Study of the biochemical and physiologic processes
underlying drug action

4. Principal of drug action ?
Principal Target ?
(Protein ,Lipid ,DNA ,*Receptor)
Functions of Receptor ?

5. Physical or chemical property; eg
• Bulk laxatives (isaghula) – physical mass
• Dimethicome, petroleum jelly –physical form,
opacity
Q*Paraamino benoic acid – absorption of UV rays
Q *Activated charcoal – adsorptive property
Q*Mannitol, Mag, sulfate – osmotic activity
• 131
I and other radioisotopes – radioactivity
• Antacids – neutralization of gastric HCI
• Pot. Permanganate – oxidizing property

6. Physical or chemical property; eg
Q*Chelating agents (EDTA, dimercaprol) –
chelation of heavy metals.
Q*Cholestyrammine – sequestration of bile
acids and cholesterol in the gut.
Q*Mesna-Scavenging of vasicotoxic reactive
metabolite of cylophosphamide.

7. PD Non receptor mediated ?
Ion Ion exchange-cholistyramine exchange CL+
* Osmosis-magnesium sulfate
Adsorption-kaolin
Protective-dusting powder
Demulcent-menthol,pectin
Astringent-tannic acid
*Chelation—EDTA,Penicillamine

8. Non receptor mediated ?
*False incorporation-sulfa drugs&
Mtx
*Protoplasmic poison-antiseptics(Phenol ,
formaldehyde)
Antibodies-vaccine
Placebo (I please)-starch,lactose
Genetic changes

9. PRINCIPLE S OF
ACTION
MODE EXAMPLE
STIMULATION Selective Enhancement of level
of activity of specialised cells
Excessive stimulation is often
followed by depression of that
function
Adr st imulates Heart
Pilocarpine stimulates
salivary glands
Picrotoxin – CNS
stimulant
convulsions coma
death
DEPRESSION Selective Diminution of activity
of specialised cells Certain
drugs – stimulate one cell type
and depress others
Barbiturates depress
CNS
Quinidine depresses
Heart
Ach – stimulates
smoothmuscle but
depresses SA node

10. PRINCIPLE S OF
ACTION
MODE EXAMPLE
IRRITATION Non-selective often noxious
effect – applied to less
specialised cells (epithelium,
connective tissue) -stimulate
associated function
Bitters – salivary and
gastric
Counterirritants
increase secretion
blood flow to a site
REPLACEMENT Use of natural metabolites,
hormones or their congeners
in deficiency states
Levodopa in
parkinsonism
CYTOTOXIC ACTION Selective cytotoxic action for
invading parasites or cancer
cells – for attenuating them
without affecting the host
cells
Penicillin,
chloroquine

11. Manny Drugs inhibit enzymes
Patient
(ACE inhibitors)
Microbes
(sulfas, penicillins)
Cancer cells
(5-FU, 6-MP)

12. Drugs bind to:
 Proteins
(in patient, or microbes)
 Genome
(cyclophosphamide)
 Microtubules
(vincristine)

13. .
 Most drugs act (bind) on
receptors(Macromolecule ) ?
 In or on cells
 Form tight bonds with the ligand
 Exacting requirements (size,
shape, stereospecificity)
 Agonists (salbutamol),
or Antagonists (propranolol)

14. Drug Actions
(How and where it is produced)
Most drugs bind to cellular receptors
 Initiate biochemical reactions
 PE = the alteration of an intrinsic
physiologic process and
 not the creation of a new process

15. What is Drug Receptors ?
•Proteins or glycoproteins
(Macromolecule)
–Present on cell surface,
on an organelle within the
cell, or in the cytoplasm

16. Functions of Receptors
1. To propagate regulatory Signals from outside
to inside the cell.
2. To amplify the signals
3. To integrate various intracellular and
extracellular signals
4. To adopt short term and long term changes.

17. The Role of the receptor
Cell
Nerve
Messenger
Signal
Receptor
Nerve
Nucleus
Cell
Response

18. Receptor & Action :
–Ion channel is opened or closed
–Second messenger is activated
• cAMP, cGMP, Ca++
, inositol phosphates,
etc.
• Initiates a series of chemical reactions
–Normal cellular function is physically
inhibited
–Cellular function is “turned on”

19. Types of receptors and their characteristics
Type 1 Membrane Ion Channel Direct Nicotinic Acetylcholine,
GABA-A
Type 2 Membrane Ion Channel/ Enzyme G Protein Muscarinic
Acetylcholine,
Adrenergic
Type 3 Membrane Enzyme(kinase) Direct/Indirect Insulin, Growth, ANP
Receptors
Type 4 Intracellular
(Cytoplasm/
Nuclear)
Gene transcription Through DNA Steroid/Thyroid
Hormones Receptor

20. Signal transduction
3. Enzyme linked
(multiple actions)
1. Ion channel linked
(speedy)
2.G protein linked
(amplifier)
4. Nuclear (gene) linked
(long lasting)

21. Type 1 Ligand gated ion channel
a,b,c

22. 1a.Ligand gated Ion
channel
receptors
cell membrane
Agonist+ receptor
Open Flow of ion
Depolarization and
Hyperpolarisation
e.g. Nicotinic Chl,
GABA, glutamate

23. 1.b Ion channel
receptors
Structure:
•Protein pores
in the plasma
membrane
•Block ion
permeation
•No cellular
effects
•e.g. L.A.
Amiloride

24. 1.c Ion channel
receptors
Modulator
•Increase/decre
ase ion
permeation
•No cellular
effects
•.e.g.
Nefedipine

25. G-Proteins Effector
Gs Adenylate cyclase, ca2+
channel
Gi Adenylate cyclase, K+ channel
Go Ca2+ channel
Gq Phospholipase C
Some example of receptor and concerned G-proteins are as follows
Receptor G-protein
Muscarinic Gi, Go, Gq
Adrenergic α1 Gq
Adrenergic α2 Gs, Gi, Go
Adrenergic β Gs, Gi
Dopamine D2 Gi, Go
Serotonin (5-HT) Gs, Gi, Gq, GK
GABAB Gi, Go

26. S.No The main signal transduction pathways controlled by G-protein coupled
receptor
1 Adenylate cyclase Cyclic AMP β, D1, H2, ACTH, TSH, FSH, LH, EP2, IP, A2, V2,
glucagon
cyclic AMP Α2, M2, D2, 5-HT1, GABAB, EP3, AT1, μ and
δ opioid, somatostatin
2 Phospholipase C IP3-
DAG Α1, M1, M3, 5-HT2, FP, EP1, EP3, TP, LT1,
LT2, AT1, B2, PAF, V1, oxytocin, CCK2
(CCKB)
3 Ion channels Ca2+
β1
Ca2+
D2, GABAB, K opioid, A1, somatostatin
K+ α2, M2, D2, 5-HT1, GABAB, A1, μ and δ
A-Adenosine; β, α-Adrenoceptors; AT-Angiotensin B-bradykinin; CCK-cholecystokinin; D –
dopamine; GABA-gamma amino butyric acid; H-Histamine; ACTH, TSH, FSH, LH-hormone;
5-HT-5hydroxytryptamine; LT1, LT2-Leukotrienes; M-Muscarinic:IP, FP, EP, EP3, TP; PAF-
Platelet activating factor; prostaglandins; V-Vasopressin

27. 2. G protein-linked receptors
Structure:
•Membrane
bound
•Hetrotrimeric
•3 subunites
•Alfa,beta,delta
•3 varient
•(Gs,Gi,Gq)
•17.varient

28. 2. G-protein coupled receptors
(GPCR)
• Metabotropic or 7-transmembrane-spanning (heptahelical)
receptors
• Large family of cell membrane receptors linked to the
effector
enzymes or channel or carrier proteins through one or more
GTP activated proteins (G-proteins)
• The molecule has 7 α-helical membrane spanning
hydrophobic
amino acid segments – 3 extra and 3 intracellular loops

29. 2 a. G protein-linked receptors
Structure:
•Membran
e bound
•Hetrotrim
eric
•3
subunites
•Alfa,beta,
delta
•3 varient
•(Gs,Gi,Gq
)
•17.varient

30. 2.b G protein-linked receptors
Structure:
•Single
polypeptide
chain threaded
back and forth
resulting in 7
transmembrane
å helices
•There’s a G
protein
attached to the
cytoplasmic
side of the
membrane
(functions as a
switch).

33. G- PROTEIN COUPLED RECEPTOR

34. PHOSPHOLIPASE PATHWAY

35. IP3- DAG PATHWAY

36. 3. Tyrosine-kinase receptors
Structure:
•Receptors exist as individual polypeptides
•Each has an extracellular signal-binding
site
•An intracellular tail with a number of
tyrosines and a single å helix spanning the
membrane

37. .
Receptor directly link
Tyrosine kinase (insulin)
Guanylate cyclase
(atrial natriuretic
peptide)

39. 5.JAK-STAT PATHWAY

40. 5.JAK-STAT-kinase Binding
Receptor
Only difference - protein tyrosine kinase activity is not intrinsic to the
receptor molecule
• Dimerization =activates intracellular domain=affinity to bind Free
cytosolic protein kinase JAK (Janus kinase)
JAK phosphorylates tyrosine residues = binds to STAT (Signal transducer
and activation of transcription)
=Activated JAK phosphorylates STAT tyrosine residues
=Phosphorylated STAT dimerize,=dissociate from receptor and
= moves to nucleus

41. Affinity
–Strength /capacity of binding
between a drug and receptor
–Number of occupied receptors is a
function of a balance between
bound and free drug
–eg key enter in hole

42. Dissociation constant (KD)
–Measure of a drug’s affinity for
a given receptor
–The concentration of drug
required in solution to achieve
50% occupancy of its receptors

43. Agonist
–Drugs which alter the physiology
of a cell by binding to plasma
membrane or intracellular
receptors
eg Methacholine act like
acetylcholine

44. Response
Dose
Full agonist
Partial agonist
Q.Agonist Dose Response Curves

45. Q.Partial agonist (full affinity & low IA)
• A drug which does not produce
maximal effect
even when all of the receptors
are occupied
–eg Pentazocine act on mu receptor

46. Inverse agonist(Negative antagonism)
* full affinity but IA is 0 to
minus 1
* e.g. betacarboline on
benzodiazipine receptor

47. Competitive and noncompetitive?

48. Mechanism of drug action:
receptor Pharmacology
Enzyme Endogenous substrate Competitive inhibitor
Cholinesterase Acetylcholine Physostigmine, Neostigmine
Monoamine-oxidase A
(MAO-A)
Catecholamines Moclobemide
Dopa Decarboxylase Levodopa Carbidopa, Benserazide
Xanthine oxidase Hypoxanthine Allopurinol
Angiotensin converting
enzyme (ACE)
Angiotensin-1 Captopril
5 α-Reductase Testosterone Finasteride
Aromatase Testosterone,
Androstenedione
Letrozole, Anastrozole
Bacterial folate
synthase
Para-amino benzoic acid
(PABA)
Sulfadiazine

49. Antagonists
Inhibit or block responses caused by agonists
– Eg Atropine block the effect ACh
Competitive antagonist
– Competes with an agonist for receptors
Q*High doses of an agonist can generally overcome
antagonist

50. Noncompetitive antagonist
–Binds to a site other than the agonist-
binding domain
–Induces a conformation change in the
receptor
– such that the agonist no longer
“recognizes” the agonist binding site.

51. Noncompetitive antagonist
High doses of an agonist
do not overcome
the antagonist in this situation

52. Some enzymes as target for drug action and their competitive inhibitors
Enzymes Competitive Inhibitors
Acetylcholinesterase Physostigmine, neostigmine
ACE Captopril, lisinopril
Aromatase Letrozole
Dopa decarboxylase Benserazide, carbidopa
Folate Synthetase (Bacterial) Sulphonamides (e.g. sulfadiazine)
5-α Reductase Finasteride
MAO-A Moclobemide
Xanthine oxidase Allopurinol
ACE= Angiotensin converting Enzyme
MAO = Monoamine Oxidase

53. Noncompetitive inhibitor Enzyme
Acetazolamide Carbonic anhydrase
Aspirin, indomethacin Cycloxygenase
Disulfiram Aldehyde
Dehydrogenase
Omeprazole H+
K+
ATPase
Digoxin Na+
K+
ATPase
Theophylline Phosphodiesterase
Propylthiouracil
Lovastatin HMG-CoA reductase
Sildenafil Phosphodiesterase-5

54. Irreversible Antagonist
–Bind permanently to the
receptor binding site
–therefore they can not be
overcome with agonist

55. Efficacy
Degree to which a drug is able to
produce the desired response
Efficacy (or Intrinsic Activity) – ability
of a bound drug to change the
receptor in a way that produces an
effect
some drugs possess affinity but NOT
efficacy

56. Drug (D)
Ri
DRi DRa
Ra
CONFORMATIONAL SELECTION
HOW TO EXPLAIN EFFICACY?
*Dual nature
*The relative affinity
Of the drug to either
conformation will
determine the effect
of the drug

57. Drug (D)
Ri
DRi DRa
Ra
CONFORMATIONAL SELECTION
HOW TO EXPLAIN EFFICACY?
*open/close ion
channel
*active/inactive
tyrosine kinase
*productive/nonprod
uctive G-protein

59. POTENCY

60. Potency
–Amount of drug required to
produce 50% of the maximal
response
–the drug is capable of inducing
–Used to compare compounds
within classes of drugs

61. Potency
Relative position of the dose-
effect curve along the dose axis
Has little clinical significance
for a given therapeutic effect

62. Potency
A more potent of two drugs is not
clinically superior
Low potency is a disadvantage
only if the dose is so large that it is
awkward to administer

63. Analgesia
Dose
hydromorphone
morphine
codeine
aspirin
Relative Potency

64. Effective Concentration 50% (ED50)
–Concentration of the drug
which induces a specified
clinical effect in 50% of
subjects

65. Lethal Dose 50% (LD50)TD50 - Median Toxic Dose 50
Concentration of the drug which
induces death in 50% of subjects
TD50 - Median Toxic Dose 50 - dose at
which 50 percent of the population
manifests a given toxic effect

66. Therapeutic Index
Measure of the safety of a drug
Calculation: LD50/ED50
Margin of Safety
Margin between the therapeutic
and lethal doses of a drug

67. The therapeutic index
 Therapeutic Ratio/index LD50 / ED50
 The higher the TI the better the drug.
 TI’s vary from: 1.0 (some cancer
drugs)
to: >1000 (penicillin)

68. Effect of Disease on PD
• Up regulation of receptors
• Down regulation of receptors
–Decreased number of drug receptors
• Altered endogenous production of a
substance may affect the receptors

69. UPREGULATION &
DOWNREGULATION

70. Receptor Regulation
• Sensitization or Up-regulationSensitization or Up-regulation
1. Prolonged/continuous use of receptor blocker
(antagonist)
2. Inhibition of synthesis or release of
hormone/neurotransmitter – De nervation
3.Externalization
eg Thyrotoxicosis ,B 1 receptor, tachacardia

71. Receptor Regulation
• Desensitization or Down-regulationDesensitization or Down-regulation
1. Prolonged/continuous use of agonist
2. Inhibition of degradation or uptake of agonist
3. Endocytosis or internalization
4 eg.asthama –salbutamol-B2 receptor-no longer
effective
clonidine withdraw
Homologous vs. Heterologous
Uncoupling vs. Decreased Numbers

72. Denervation supersensitivity of receptor
• New receptor are synthesis
• Prolong blocked of receptor by antagonism
E.g. tardive dyskinasia /neuroleptics/DA
receptor supersensitivity

73. Receptor related diseases
• Myasthenia gravis
• Insulin resistance diabetes
• Testicular feminization
• Familial hypercholesterolemia

74. SILENT RECEPTORS

75. Spare receptors?
Q. Allow maximal response
without total receptor
occupancy
(increase sensitivity of the
system)
Receptor reserve
All Ach receptor block by toxin
Q.Ach muscle twitch amplitude

76. DRUG TOLERANCE ?

77. SUMMATION ??

78. SYNERGISM ??

79. SUMMATION & SYNERGISM

80. THERAPEUTIC WINDOW ?

81. DELAYED DRUG EFFECT

82. Difference between reversible (competitive) and irreversible antagonism
Parameter Reversible (competitive) Irreversible antagonism
Receptor binding Reversible (Van der waals or
hydrogen bonds)
Irreversible (Covalent bond)
Antagonism Surmountable Insurmountable
DRC of agonist Parallet right-ward shift No such shift
Maximum response of
agonist
Can be achived Cant’t be achieved
Duration Short Long (as action returns when
new receptors are
synthesized)

83. Receptors as target for during action
Receptors Agonists Antagonists
Nicotinic Acetylcholine Nicotine D-tubocurarine
β-Adrenoceptors Isoprenaline Propranolol
Histamine H1 Histamine Mepyramine
Histamine H2 Impromidine Ranitidine
5-HT2 Serotonin (5-HT) Ketanserin
Dopamine D2 Dopamine Bromocriptine Chlorpromaz
μ-Opioid Morphine Naloxone
Oestrogen Ethinyloestradiol Tamoxifen

84. Ion channels as target for drug action
Sodium channels
Voltage gated Na+
Renal tubule Na+
Local anaesthetics,
tetrodotoxin Amiloride
Veratradine
Aldosterone
Calcium Channels
Voltage gated Ca2+
Divalent cation (Cd2+
), CCB
(infedipine)
Bay K 8644
Potassium channels
Voltage gated K2+
ATP sensitive K+
4-Aminopyridine ATP --
Sulphonylureas,
cromokalim
Chloride channels
GABA gated
Picrotoxin Benzodiazepines
Cation channels
Glutamate gated (NMDA)
Mg2+
, Ketamine, Dizocilpine Glycine

85. Some enzymes as target for drug action and their non-competitive inhibitors
Enzymes Non-Competitive Inhibitors
Aldehyde dehydrogenase Disulfiram
Carbonic anhydrase Acetazolamide
HMG-CoA reductase Atrovastatin
H+K+ATPase Lansoprazole
Monoamine oxidase Isocarboxazid
Na+K+ATPase Digoxin
Phosphodiesterase-5 Sildenafil
Thromboxane A2 Dazoxiben
Thyroid peroxidase Carbimazole

86. Carrier molecules as target for drug action
Carriers Inhibitors
Choline carrier Hemicholinium
NA uptake in vesicles Reserpine
Na+/K+ pump Cardiac glycosides (digoxin)
H+/K+ pump (proton pump) Omeprazole
NE transporter Desipramine, cocaine
5-HT transporter SSRIs (eg. fluoxetine)
DA transporter Amphetamine
GABA transporter Tigabine
Na+
K+
2CL-
cotransporter Loop diuretics (e.g. frusemide)
Na+Cl- symporter Thiazides (e.g. hydrochlorthiazide)
Organic anion transporter(OAT; for uric
acid, penicillin)
Probenecid

87. Some example of drug where effect is delayed
Drug Indication Onset of effect Reason
Iron salts (oral/i.v.) Nutritional anemia 3 weeks Time required for
haemopoiesis
Oral anticoagulants
e.g. warfarin
Venous thrpmbosis 1-3 days Time required for
utilization of already
formed clotting factors
Thyroid synthesis
inhibitors e.g.
carbimazole
Hyperthyroidism 10-15 days Time required for
utilization of already
formed hormone
Radioactive iodine
(I131
)
Hyperthyroidism
β –blockers e.g.
atenolol
Hypertension Few days/weeks
Not known
Disodium
cromoglycate
Prevention of asthma 3-4 weeks
DMARDs e.g.
sulfasalazine
Rheumatoid arthritis 2-3 months
Antidepressants e.g.
imipramine
Depression 2 weeks Possibly alteration in
receptor sensitivity
Antipsychotics eg. Schizophrenia 2 weeks

88. Competitive reversible Irreversible
1. Parallel right ward shift of agonist
DRC
2.The same maximal response can be
attained by increasing doses of agonist
(surmountable)
3.Intensity of response depends on
concentration of both agonist and
antagonist. Slope is not altered
4. Example: Ach and and atropine. NE
and phentolamine. Morphine and
1.Flattening of agonist DRC
2.Maximal response is suppressed
(unsurmoun table)
3.Response depends only on the
concentration of antagonist. Slop is
altered
4.NE and phenoxybenzamine

89. Thank You
Dr Lokendra Sharma