PHARMACODYNAMICS

Specific Learning Objectives

At the end of this session you will be able to
define the following :
PHARMACODYNAMICS
1. Ligand
2. Drug
3. Receptor
4. Affinity
5. Intrinsic activity
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PHARMACODYNAMICS
6. Pure Agonist
7.Pure Antagonist
8. Mixed/ Partial agonist-antagonist
9. Inverse agonist
10. Spare receptors
11. Silent receptors
12. Efficacy
13. Potency
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PHARMACODYNAMICS
PHARMACODYNAMICS: Deals with what the
drug does to the body.
At the molecular level: mechanism of action
Biological effects: pharmacological actions
Adverse effects

PHARMACODYNAMICS
Ligand: (to bind): A molecule that binds to a
specific receptor.
Drug: WHO definition
any substance or product that is
used or intended to be used
to modify or explore
physiological systems or pathological states
for the benefit of the recipient
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PHARMACODYNAMICS
Receptor: Part of a cell to which a ligand/drug
binds and initiates a response.
It could be on or in the cell
Regulatory protein macromolecules

PHARMACODYNAMICS
Affinity: Ability of a drug to bind to a receptor
Intrinsic activity: Ability of a drug to elicit a
response after binding to a receptor
ligand ch.swf
Pure Agonist= Affinity+ Intrinsic activity.
E.g. Acetyl choline (ACh)
Pure Antagonist= Affinity without intrinsic
activity. E.g. Atropine
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Mixed/ Partial agonist-antagonist: Binds to the
receptor and produces an effect less than that of a
pure agonist. E.g. Pindolol at receptors
It could also be an agonist at one receptor subtype
and antagonist at another receptor subtype.
E.g. Buprenorphine at opioid receptors

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Inverse agonist: Binds to the receptor and
produces effects opposite to that of the agonist.
E.g. -carbolines at the benzodiazepine receptor.
Spare receptors: Excess receptors. Pure agonists
can elicit maximum response by binding to a small
portion (<1%) of the available receptorsneurotransmitter conservation
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Silent receptors: Misnomer. Plasma proteins
Orphan receptors: No endogenous ligand
identified as yet. E.g. Sulfonylurea receptors

PHARMACODYNAMICS
Four major targets of drug action are proteins:
1. Enzymes
2. Ion channels
3. Transporters
4. Receptors

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PHARMACODYNAMICS
Enzymes as targets of drug action
Enzyme induction: Drugs increase enzyme
activity by stimulating synthesis of more enzyme.
Mostly hepatic CYP-450 isozyme families
Clinical consequences of enzyme induction
E.g. Rifampicin-pill failure
Tolerance- Pharmacokinetic-E.g. Carbamazepine
Also known as pharmacokinetic antagonism
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Enzyme inhibition as mechanism of drug action
Competitive inhibition: Examples
1. ACh Esterase: Physostigmine
.
.

MBBS ACh esterase.swf

MBBS AChE inhib.swf

2. Dopa decarboxylase: Carbidopa

3. Angiotensin Converting Enzyme: Captopril
4. Bacterial folate synthase: Sulfonamides
. Non-competitive inhibition: E.g.
Organophosphates, methotrexate
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Ion channels as targets of drug action
1. Ligand gated channels :E.g. Nicotinic receptor
.

ligand ch.swf

2. G-protein regulated channel:

E.g. 1 adrenergic cardiac receptors
.

MBBS G-protein operated channel.mp4

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3. Voltage gated channel: E.g. Neuronal Na+
channels
4. Channel openers: Nicorandil opens ATPsensitive K+ channels
5. Channel blocker: Nifedipine blocks L-type
Ca2+ channels

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Transporters as targets of drug action
1. Serotonin reuptake inhibition: Fluoxetine
2. Noradrenaline reuptake inhibition: Imipramine
3. GABA reuptake inhibition: Tiagabine
4. Na+-K+2Cl- cotransporter inhibition: Frusemide

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PHARMACODYNAMICS
RECEPTOR: A macromolecule or site located on or in
the cell that recognizes a specific ligand/drug and
initiates a response.
TERMS
Affinity
Intrinsic activity
Agonist
Antagonist
Mixed/ Partial agonist-antagonist
Inverse agonist
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Drug action: Combination of drug and receptor
resulting in a conformational change (agonist) in
the receptor or prevention of change (antagonist)
in conformation.
Drug effect: Final change in biological function
brought about by transducers.
RECEPTORS have a ligand binding site and an
effector site
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Transducers amplify and integrate signals
Five types of transducer maehanisms
1. G-protein coupled receptors (GPCRs)
2. Ion channel receptors
3. Transmembrane enzyme linked receptors
4. Transmembrane JAK-STAT binding receptors
5. Nuclear receptors (regulating gene expression)

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G-protein coupled receptors (GPCRs)
GTP-activated proteins
, and subunits
Based on the subunit, G protein types are:
1. Gs: adrenergic
2. Gi: Muscarinic M2
3. Go: Muscarinic M2
4. Gq: Muscarinic M1
. One receptor can use more than one G-protein (agonist
pleotropy)
.

MBBS G-Protein Signaling.mp4

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GPCRs function via three effector pathways
1. Adenylyl cyclase: cAMP pathway- action of
cAMP is terminated by PhosphoDiEsterase
.

MBBS cAMP Signaling.mp4

2. Phospholipase C: IP3-DAG pathway

.

IP3-DAG.mp4

3. Channel regulation: through dimer

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PHARMACODYNAMICS
ION CHANNEL RECEPTORS: Ligand gated ion
channels
Agonist binding opens the channel
Selective for Na+, K+, Ca++ & ClACh nicotinic receptor
GABAA receptor
Milliseconds

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ION CHANNEL RECEPTORS
Pentameric proteins
Subunits arranged in a rosette
subunit bears agonist binding site
GABAA receptor also has allosteric binding site
for benzodiazepines:
MBBS RECEPTOR- GABA BDZ.flv

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TRANSMEMBRANE ENZYME-LINKED
RECEPTORS
Extracellular ligand binding site
Intracellular enzymatic site: protein kinase
Receptor Tyrosine Kinases (RTKs): Phosphorylate
tyrosine residues on target proteins: Seconds
E.g.Insulin receptor: Unliganded monomers on
ligand binding- dimerisation and kinase activation.
MBBS Receptor tyrosine kinases (RTK)s.mp4
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TRANSMEMBRANE JAK-STAT BINDING
RECEPTORS:
Agonist binding to receptor increases its
intracellular affinity for Janus Kinase (JAK).
Activated JAK phosphorylates Signal Transducer
and Activator of Transcription (STAT).
Phosphorylated STAT translocates to the nucleus
and regulates gene transcription: response:Minutes
E.g. Growth hormone, prolactin
MBBS JAK STAT Signaling.mp4
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RECEPTORS REGULATING GENE
EXPRESSION
Intracellular- cytoplasmic or nuclear receptors.
Agonist binds to cytosolic receptor or nuclear
receptor and regulates gene transcription
E.g. steroid hormones. HOURS
MBBS STEROIDS ANIMATION.flv

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RECEPTOR REGULATION
1. Upregulation: Denervation supersensitivity
. Clinical importance:
. E.g. Sudden stoppage of -blockers: Rebound
hypertension
2. Down regulation: Desensitization/
refractoriness: Prolonged use of agonist
resulting in decreased response.
. E.g. Levodopa in Parkinsonism
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SUMMARY
Functions of receptors
1. Propagate
2. Amplify
3. Integrate
4. Adapt

Receptors in UNDER 5 MINUTES.mp4

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DOSE-RESPONSE RELATIONSHIP
Dose-plasma concentration: Kinetics
Plasma concentration-response: Dynamics
Dose-response curve (DRC)
Response

Dose

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LOG DOSE-RESPONSE CURVE
Response

Log Dose
Rectangular parabola transformed into
Sigmoid curve
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PHARMACODYNAMICS
Advantages of log dose-response curve
1. Linear relationship between log dose and
response in 30-70% region
2. Wide range of doses can be used
3. Comparison between agonists and study of
antagonists becomes easier

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POTENCY: Amount of drug needed to elicit a
response.
Position of DRC on the dose axis: More to the
right- less potent
Relative potency: Comparing the EC50
10mg morphine=100 mg pethidine
Potency helps in choosing the dose of a drug

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EFFICACY: Ability of a drug to elicit maximal
response.
Upper limit of DRC
Fentanyl vs morphine vs aspirin for analgesia

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Therapeutic Index: Gap between the therapeutic
effect DRC and adverse effect DRC defines the
margin of safety of a drug.
LD50 : Median Lethal Dose
ED50 : Median Effective Dose
Therapeutic Index=LD50 / ED50
Done in experimental animals
Indicates margin of safety of a drug
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Higher the TI, greater the margin of safety

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PHARMACODYNAMICS
In humans: THERAPEUTIC WINDOW

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Therapeutic window:
Drugs with a narrow therapeutic window require
Therapeutic Drug Monitoring (TDM)
E.g. Lithium, digoxin, phenytoin
Other indications for TDM?

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DRUG SYNERGISM- syn:together; ergos:work
Facilitation of a pharmacological response by the
concomitant use of two or more drugs.
Types
1. Additive: 1+1=2.
. E.g. propranolol+ thiazide diuretic as
antihypertensives
2. Supraadditive: 2+2=5
. E.g. Trimethoprim+ sulfamethoxaxole
. Individually bacteriostatic. Combination: cidal
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PHARMACODYNAMICS
3. Potentiation: 1+0=2. In vitro
E.g. Isolated frog rectus contraction by ACh in the
presence of physostigmine
In vivo: Carbidoa+ levodoa
4. Time synergism: Prolongation of duration of
action of one drug by combining with another drug
E.g. Local anesthetic + adrenaline

Penicillin + probenicid
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DRUG ANTAGONISM occurs when the action
of one drug opposes the that of another ( decrease
or complete block).
Types of antagonism
1. Chemical
2. Competitive or reversible
3. Non-competitive or irreversible
4. Physiological or functional

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PHARMACODYNAMICS
1. Chemical antagonism
E.g. Antacids neutralize gastric HCl

Chelating agents bind to heavy metals

2. Competitive/ reversible/ surmountable
antagonism:
Agonist and antagonist compete for the same
binding site on receptor
Non-covalent bonding
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PHARMACODYNAMICS
Increasing dose of agonist will displace the
antagonist
Maximum response is achievable
DRC shifts to the right in a parallel manner
E.g. ACh and atropine
Propranolol and adrenaline

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Non-competitive/ irreversible/ insurmountable
antagonism.
At the same site: (Non-equilibrium): Antagonist
binds covalently to receptor- cannot be displaced
by increasing agonist concentration
At allosteric site: Antagonist binds to different
location on receptor and induces a conformational
change
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PHARMACODYNAMICS
DRC shifts to right
Non-parallel manner
Maximum response cannot be achieved by
increasing agonist concentration
E.g. Adrenaline and phenoxybenzamine on
vascular smooth muscle
Decamethonium and ACh at neuromuscular
junction
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PHARMACODYNAMICS
PHYSIOLOGICAL/ FUNCTIONAL
ANTAGONISM:
Opposing effects
Different receptors
E.g. Histamine and adrenaline
Histamine via H-receptors: Bronchoconstriction,
vasodilation, cardiac depression
Adrenaline via adrenergic receptors:
Bronchodilation, vasoconstriction & cardiac
stimulation
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Pharmacokinetic antagonism:
Microsomal enzyme inducing drug decreasing the
actions of a drug metabolized by microsomal
enzymes.
E.g.

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THANK YOU
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