Pharmacodynamics

Department of
Pharmacology
NEIGRIHMS, Shillong
 Contents
 PRINCIPLES
AND MECHANISM OF
DRUG ACTION

 TRANSDUCER MECHANISMS

 DOSE-RESPONSE RELATIONSHIP

 COMBINED DRUG EFFECTS

 What is Pharmacodynamics?
What the drug does to the body when it
enters?

Defn.: It is the study of biochemical and

physiological effects of drug and their
mechanism of action at organ level as
well as cellular level.
 PRINCIPLES OF DRUG ACTION
- Do NOT impart new functions on any system,
organ or cell
- Only alter the PACE of ongoing activity

 STIMULATION
 DEPRESSION
 IRRITATION
 REPLACEMENT
 CYTOTOXIC ACTION
PRINCIPLE OF MODE EXAMPLE
ACTION
STIMULATION Selective Enhancement of level of Pilocarpine stimulates salivary
activity of specialised cells glands
- Excessive stimulation is often followed Picrotoxin – CNS stimulant 
by depression of that function convulsions  coma  death

DEPRESSION Selective Diminution of activity of Barbiturates depress CNS

specialised cells Quinidine depresses Heart
Certain drugs – stimulate one cell type Ach – stimulates smooth
and depress others muscle but depresses SA node

IRRITATION Non-selective often noxious effect –

applied to less specialised cells Bitters – salivary and gastric
(epithelium, connective tissue) secretion
-stimulate associated function Counterirritants increase blood
flow to a site

REPLACEMENT Use of natural metabolites, hormones or Levodopa in parkinsonism

their congeners in deficiency states Iron in anaemia

CYTOTOXIC Selective cytotoxic action for invading Penicillin, chloroquine

parasites or cancer cells – for
ACTION
attenuating them without affecting the
host cells
MECHANISM
OF DRUG
ACTION
 MECHANISM OF DRUG ACTION
 MAJORITY OF DRUGS INTERACT
WITH TARGET BIOMOLECULES:
Usually a Protein
1. ENZYMES
2. ION CHANNELS
3. TRANSPORTERS
4. RECEPTORS
 1. Enzymes – drug targets
 All Biological reactions are carried out under
catalytic influence of enzymes – major drug
target
 Drugs – increases/decreases enzyme mediated
reactions
 In physiological system enzyme activities are
optimally set
 Enzyme stimulation is less common by drugs –
common by endogenous substrates
– Pyridoxine (cofactor in decarboxylase activity)
– Adrenaline stimulates hepatic glycogen phosphorylase
(hyperglycaemia)
 Enzyme inhibition – common mode of drug action
 Enzymes – contd.
 Nonspecific inhibition: Denaturation
of proteins – strong acids, heavy metals,
alkalies, alcohol, phenols etc.
 Specific Inhibition:

Competitive Noncompetitive

• equilibrium
• nonequilibrium
What is specific enzyme inhibition?
Normal
 A drug may inhibit
a particular
enzyme without
affecting others
and influence that Drug + Enzyme

particular
substrate-enzyme
reaction ultimately
to influence in the
product formation
Competitive Inhibition
 Enzyme Inhibition - Examples
 Equilibrium:
– Physostigmine Vs Acetylcholine (cholinesterase)
– Sulfonamides Vs PABA (folate synthetase)
– Moclobemide Vs Catecholamines (MAO-A)
– Captopril Vs Angiotensin 1 (ACE)

 Nonequilibrium:
– Orgnophosphorous compounds/Nerve gases (cholinesterase)

 Non-competitive:
– Acetazolamide (carbonic anhydrase), Omeprazole
(HKATPase) , Aspirin (cyclooxygenase)
Effects of enzyme inhibition:

Normal Competitive (equilibrium)

 2. Ion Channnel
 Proteins take part in transmembrane
signaling and regulates ionic
composition
 Drugs also target these channels:

– Ligand gated channels

– G-protein operated channels
– Direct action on channels
 Examples
LA acting on Na+ receptors
Na+
LA receptor

++ ++ -- -- -- --

-- -- ++ ++
++ ++

Resting Open
(Closed**) inactivated
(brief) LA have highest
affinity for the
Very slow inactivated form
repolarization in
presence of LA Refractory period
 3. Transporters
 Substrates are translocated across membrane by
binding to specific transporters (carriers) – Solute
Carrier Proteins (SLC)
 Pump the metabolites/ions I the direction of
concentration gradient or against it
 Drugs interact with these transport system
 Examples: Probenecid (penicillin and uric acid),
Furosmide (Na+K+2Cl- cotransport),
Hemicholinium (choline uptake) and Vesamicol
(active transport of Ach to vesicles)
 4. Receptors

 Drugs usually do not bind directly with enzymes,

channels, transporters or structural proteins, but
act through specific macromolecules –
RECEPTORS
 Definition: It is defined as a macromolecule or
binding site located on cell surface or inside the
effector cell that serves to recognize the signal
molecule/drug and initiate the response to it, but
itself has no other function, e.g. G-protein
coupled receptor
 Some Definitions
 Agonist: An agent which activates a receptor to produce an
effect similar to a that of the physiological signal molecule,
e.g. Muscarine and Nicotine)
 Antagonist: an agent which prevents the action of an agonist
on a receptor or the subsequent response, but does not have
an effect of its own, e.g. atropine and muscarine
 Inverse agonist: an agent which activates receptors to
produce an effect in the opposite direction to that of the
agonist, e.g. DMCM
 Partial agonist: An agent which activates a receptor to
produce submaximal effect but antagonizes the action of a
full agonist, e.g. pentazocine
 Ligand: any molecule which attaches selectively to particular
receptors or sites (only binding or affinity)
 Some Definitions – contd.
 Affinity: Ability of a substrate to bind with
receptor
 Intrinsic activity (IA): Capacity to induce
functional change in the receptor
If explained in terms of affinity and IA:
 Agonist: Affinity + IA (1)

 Antagonist: Affinity + IA (0)

 Partial agonist: Affinity + IA (0-1)

 Inverse agonist: Affinity + IA (0 to -1)

 Drug-receptor binding and
agonism
Drug- Receptor: D Full agonist
Ri DRa

D
Ri DRa Partial agonist

D
Ri DRa Neutral

D Inverse agonist

DRi DRa
Two State Receptor Model
 Drug - Receptor Binding

D+R DR Complex
Affinity
Affinity – measure of propensity of a
drug to bind receptor; the
attractiveness of drug and receptor
– Covalent bonds are stable and
essentially irreversible
– Electrostatic bonds may be strong or
weak, but are usually reversible
 Drug Receptor Interaction

DR Complex Effect (E)

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
 Receptors – contd.
 Two essential functions:
– Recognition of specific ligand molecule
– Transduction of signal into response
 Two Domains:
– Ligand binding domain
– Effectors Domain – undergoes functional
conformational change
 Receptors – contd.
 Cell surface receptors remain floated in cell membrane
lipids
 Functions are determined by the interaction of lipophillic or
hydrophillic domains of the peptide chain with the drug
molecule
 Non-polar hydrophobic portion of the amino acid remain
buried in membrane while polar hydrophilic remain on cell
surface
 Hydrophilic drugs cannot cross the membrane and has to
bind with the polar hydrophilic portion of the peptide chain
 Binding of polar drugs in ligand binding domain induces
conformational changes (alter distribution of charges and
transmitted to coupling domain to be transmitted to
effector domain
 Receptors – contd.
 Drugs act on Physiological receptors
and mediate responses of
transmitters, hormones, autacoids
and others – cholinergic, adrenergic
or histaminergic etc.
 Drugs may act on true drug
receptors - Benzodiazepine receptors
 The Transducer mechanism
 Most transmembrane signaling is accomplished
by a small number of different molecular
mechanisms (transducer mechanisms)
 Large number of receptors share these handful
of transducer mechanisms to generate an
integrated response
 Mainly 4 (four) major categories:
1. GPCR
2. Receptors with intrinsic ion channel
3. Enzyme linked receptors
4. Transcription factors (receptors for gene
expression)
 G-protein Coupled Receptors
 Large family of cell membrane receptors
linked to the effector
enzyme/channel/carrier proteins through
one or more GTP activated proteins (G-
proteins)
 All receptors has common pattern of
structural organization
 The molecule has 7 α-helical membrane
spanning hydrophobic amino acid
segments – 3 extra and 3 intracellular
loops
GPCR
GPCR – contd.
 G-proteins and Effectors
 Large number can be distinguished
by their α-subunits
G protein Effector pathway Substrates

Gs Adenylyl cyclase Beta-receptors, H2,

D1
Gi Adenylyl cyclase Muscarinic M2
D2, alpha-2
Gq Phospholipase C Alph-1, H1, M1, M3

Go Ca++ channel K+ channel in heart,

sm
 GPCR - 3 Major Pathways

1. Adenylyl cyclase:cAMP pathway

2. Phospholipase C: IP3-DAG
pathway
3. Channel regulation
1. Adenylyl cyclase: cAMP pathway

Other
Functional
proteins

PKa Phospholambin
Troponin
Increased
Interaction with Faster relaxation
Ca++
Cardiac
contractility
2. Phospholipase C:IP3-DAG
pathway

PKc
 3. Channel regulation
 Activated G-proteins can open or close ion
channels – Ca++, Na+ or K+ etc.
 These effects may be without intervention
of any of above mentioned 2nd messengers
– cAMP or IP/DAG
 Bring about depolarization, hyperpolrization
or Ca ++ changes etc.
 Gs – Ca++ channels in myocardium and
skeletal muscles
 Go and Gi – open K+ channel in heart and
muscle and close Ca+ in neurones
Intrinsic Ion Channel Receptors
Intrinsic Ion Channel Receptors
 Most useful drugs in clinical medicine act
by mimicking or blocking the actions of
endogenous ligands that regulate the flow
of ions through plasma membrane
channels
 The natural ligands include acetylcholine,
serotonin, aminobutyric acid (GABA), and
the excitatory amino acids (eg, glycine,
aspartate, and glutamate)
 Enzyme Linked Receptors
 2 (two) types of receptors:

1. Intrinsic enzyme linked receptors

 Protein kinase or guanyl cyclase domain

1. JAK-STAT-kinase binding receptor

 Enzyme linked receptors

 Extracellular hormone-binding domain and

a cytoplasmic enzyme domain (mainly
protein tyrosine kinase or serine kinase)
 Upon binding the receptor converts from
its inactive monomeric state to an active
dimeric state
 Cytoplasmic domains become
phosphorylated on specific tyrosine
residues
 Enzymatic activities are activated,
catalyzing phosphorylation of substrate
proteins
Enzyme linked receptors – contd.
 Enzyme linked receptors – contd.
 Activated receptors catalyze
phosphorylation of tyrosine residues on
different target signaling proteins, thereby
allowing a single type of activated receptor
to modulate a number of biochemical
processes
 Examples:
– Insulin - uptake of glucose and amino acids
and regulate metabolism of glycogen and
triglycerides
– Trastuzumab, antagonist of a such type
receptor – used in breast cancer
JAK-STAT-kinase binding receptor

 Mechanism closely resembles that of

receptor tyrosine kinases
 Only difference - protein tyrosine kinase
activity is not intrinsic to the receptor
molecule
 Uses Janus-kinase (JAK) family
 Also uses STAT (signal transducers and
activators of transcription)
 Examples – cytokines, growth hormones,
interferones etc.
JAK-STAT-kinase Receptors
 Receptors regulating gene
expression
 Lipid soluble biological signals cross the
plasma membrane and act on intracellular
receptors – NO acts by stimulating cGMP
 Receptors for corticosteroids,
mineralocorticoids, thyroid hormones, sex
hormones and Vit. D etc. stimulate the
transcription of genes in the nucleus by
binding with specific DNA sequence –
called - “Responsive elements”
 Receptors regulating gene
expression – Clinical implication
 Hormones produce their effects after
a characteristic lag period of 30
minutes to several hours—the time
required for the synthesis of new
proteins – gene active hormonal
drugs take time to be active
(Bronchial asthma)
 Beneficial or toxic effects persists
even after withdrawal
Receptors regulating gene
expression
Summary of Transducers
 Receptor Regulation
 Up regulation of receptors:
– In tonically active systems, prolonged
deprivation 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.
– Unmasking of receptors or proliferation or
accentuation of signal amplification
 Receptor Regulation
 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)
 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

Ach
homologous
Hetero
logous

Hist
Mechanism of desensitization

ßARK (beta-adrenergic receptor kinase)

Beta-arrestin
 Dose-Response Relationship
 Dose-plasma concentration
 Plasma concentration (dose)-
response relationship
Emax X [D]
E=
Kd + [D]

E is observed effect of drug dose [D], Emax = maximum response,

Kd = dissociation constant of drug receptor complex
 Dose-Response Curve

100% 100%
% response

% response
50%
50%

Log dose
dose
 Dose-Response Curve
 Advantages:

– 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
 Potency and efficacy
 Potency: It is the amount of drug required to
produce a certain response
 Efficacy: Maximal response that can be elicited by
a drug

1 2 3 4
Response

Drug in log conc.

 Therapeutic index (TI)

Median Lethal Dose (LD50)

 Therapeutic Index =
Median Effective dose (ED50)

Idea of margin of safety Margin of Safety

 Therapeutic index (TI)
 It is defined as the gap between therapeutic
effect DRC and adverse effect DRC (also called
margin of safety)
 Combined Effects of Drugs
 Drug Synergism
– Additive effect (1 + 1 = 2)
 Aspirin+paracetamol, amlodipine+atenolol
– Supraadditive effect (1 + 1 = 4)
 Sulfamethoxazole+trimethoprim,
levodopa+carbidopa, acetylcholine+physostigmine
 Drug Abntagonism:
1. Physical: Charcoal
2. Chemical: KMNO4, Chelating agents
3. Physiological antagonism: Histamine and
adrenaline in bronchial asthma, Glucagons
and Insulin
4. Receptor antagonism
 …. Contd.
 Receptor antagonism:
1. Competitive antagonism (equilibrium)
2. Competitive (non equilibrium)
3. Non-competitive antagonism
Drug antagonism DRC
 Drug antagonism DRC – non-
competitive antagonism

Agonist

Agonist
+ CA (NE)
Response

Shift to the right

and lowered response

Drug in log conc.

 Spare Receptor
 When only a fraction of the total
population of receptors in a cell, are
needed to produce maximal effect,
then the cell is said to have spare
receptors
 Example - Beta-adrenergic blocking
 Drug Action by Physical/Chemical
properties
 Color – Tincture Card co.
 Physical mass - Ispaghula
 Smell - Volatile Oils
 Taste - Bitters
 Osmotic action – Mannitol, Magsulf
 Adsorption - Charcoal
 Soothing-demulcent – Soothing agents like calamine
 Electrical charge – Electrical charge
 Radioactivity - Iodine and others
 Radio-opacity – Barium sulfate
 Chemical properties – Chelating agents (EDTA,
dimercaprol)
 Summary
 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.
 Concept of spare receptors
Thank you