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Digvijaya
Lecturer
School of Medical & Allied Sciences
GD Goenka UNiversity
What is Pharmacodynamics?
What drugs do to the body when they enter?
• STIMULATION
• DEPRESSION
• IRRITATION
• REPLACEMENT
• CYTOTOXIC ACTION
MECHANIS
M 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
4. Receptors
D
Ri Partial agonist
DRa
D Neutral
Ri DRa
D Inverse agonist
DRi DRa
Nature of
Receptors
Other
Functional
proteins
PKA Phospholambin
Troponin
Increased
Interaction with Faster relaxation
Ca++
Cardiac
contractility
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
2. Phospholipase C:IP3-DAG pathway
PKc
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
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 2ndmessengers – 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
G-proteins and Effectors
• Large number can be distinguished by their α-
subunits
G protein Effectors pathway
Substrates
Gs Adenylyl cyclase - PKA Beta-receptors, H2,
D1
Gi Adenylyl cyclase - PKA Muscarinic M2
D2, alpha-2
Gq Phospholipase C - IP3 Alpha-1, H1, M1,
M3
Go Ca++ channel - open K+ channel in
or close heart, sm
Transducer 2 ….
Heart1.ex
e
Animation of GPCR - 2
Heart2.ex
e
Receptors with Intrinsic Ion
Channel
Transducer 3 ….
Ach
Heterologous
Homologous R+ Transducer
Hist
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.
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
Dose-Response Relationship
• Drug administered – 2 components of dose- response
– Dose-plasma concentration
– Plasma concentration (dose)-response relationship
• E is expressed as
E max
Emax X [D]
Kd + [D]
100% - 100% -
% response
% response
50% - 50% -
1 2 3 4
Thiazide
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)
Therapeutic index (TI)
• In experimental animals
Vs
Agonist
Agonist
+ CA (NE)
Response