Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (for example, infection).
Pharmacodynamics and pharmacokinetics are the main branches of pharmacology, being itself a topic of biology interested in the study of the interactions between both endogenous and exogenous chemical substances with living organisms.
3. What is Pharmacodynamics?
What the drug does to the body when it
enters?
Defination.:
It is the study of biochemical and physiological
effects of drug and their mechanism of
action at organ level as well as cellular
level.
13. MECHANISM OF DRUG ACTION
or
Target of drug action
MAJORITY OF DRUGS INTERACT WITH
TARGET BIOMOLECULES:
Usually a Protein
1. ENZYMES
2. ION CHANNELS
3. TRANSPORTERS(carrier molecules)
4. RECEPTORS
15. Enzymes
Enzymes are biological molecules (proteins) that act
as catalysts and help complex reactions occur
everywhere in life
16.
17.
18. Nonspecific inhibition: Denaturation of
proteins e.g. strong acids, heavy metals,
alkalies, alcohol, phenols etc.
Specific Inhibition:
Competitive Noncompetitive
• equilibrium
• nonequilibrium
Enzyme inhibition – common mode of drug
action
19. specific enzyme inhibition
A drug may inhibit a
particular enzyme without
affecting others and
influence that particular
substrate-enzyme reaction
ultimately to influence in
the product formation
Normal
Drug + Enzyme
20. i) Competitive Inhibition
The drug being structurally similar competes with the
normal substrate for the catalytic binding site of the
enzyme so that the product is not formed or a
nonfunctional product is formed and a new equilibrium
is achieved in the presence of the drug.
21. (ii) Noncompetitive The inhibitor reacts
with an adjacent site and not with the
catalytic site, but alters the enzyme in such a
way that it loses its catalytic property.
24. Ion channels are pore-forming membrane
proteins whose functions include establishing
a resting membrane potential, shaping action
potentials and other electrical signals by gating the
flow of ions across the cell membrane.
25.
26. Ion channels are present in the membranes of all
cells.
Ion channels are considered to be one of the two
traditional classes of ionophoric proteins, with the
other class known as ion transporters (including
the sodium-potassium pump, sodium-calcium
exchanger, and sodium-glucose transport proteins,
amongst others)
27. 3. Transporters
This protein also functions as a transporter in the
blood–brain barrier. P-gp transports various
substrates across the cell membrane including.
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
28. 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)
29.
30. 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
31. 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
Some Definitions
32. Inverse agonist: an agent which activates receptors to
produce an effect in the opposite direction to that of the
agonist,
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)
33.
34. Affinity: Ability of a substrate to bind with
receptor
Intrinsic activity (IA): Capacity to induce
functional change in the receptor
35. D + R DR Complex
Affinity – measure of tendency 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 Binding
Affinity
36. Drug Receptor Interaction
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
DR Complex Effect (E)
37. 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
38. 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
39. 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
40. 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
41. 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)
42.
43.
44. A) 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
47. G Protein – these are proteins that bind to the
guanine nucleotide (GTP – guanosine
triphosphate, GDP – guanosine diphosphate)
Hydrolysis of GTP releases a phosphate group
which can act on other molecules – transmits
the signal
GTP > GDP + P
48.
49. G proteins have three subunits – α (alpha),
β (beta), and γ (gamma).
β and γ subunits are tightly bound together.
α binds to GTP
50. Ligand binding to the transmembrane protein causes a
conformational change and release of the α subunit
The α subunit exchanges GDP > GTP and becomes
active
The α subunit meets a target and phosphorylates it
(adds a phosphate group from GTP converting it to
GDP – this is hydrolysis of GTP)
Hydrolysis = cleavage
Phosphorylation = addition of a phosphate group
52. Now the α subunit is bound to GDP, it
becomes inactive again and re-
associates with the transmembrane
protein and the β and γ subunits
53.
54. Second Messengers
Second messengers – these are molecules
that relay signals from receptors on the cell
surface to target molecules inside the cell
Examples include IP3, Ca2+, cAMP
Allows for amplification of the signal
55. 3.6 Signal transduction pathway
a) Interaction of receptor with Gs-protein
GS-Protein - membrane bound protein of 3 subunits (a, b, g)
- aS subunit has binding site for GDP
-GDP bound non covalently
b g
a
GDP
3. G-protein-coupled receptors (7-TM receptors)
60. Physiological function likes,
mediates/modulates contraction,
secretion/transmission
release,eicosenoides synthesis,
neuronal excitability, intracellular
movements, membrane function,
metabolism, cell proliferation etc.
61. 3. Channel regulation
Activated G-proteins can open or close ion channels – Ca++,
Na+ or K+ etc.
62. These effects may be without intervention of any of
above mentioned 2nd messengers – cAMP or
IP3/DAG.
Bring about depolarization, hyperpolrization or Ca
++ changes etc.
63. Gs – Ca++ channels in myocardium and skeletal
muscles
Go and Gi – open K+ channel in heart and muscle
and close Ca+ in neurons.
64. Physiological responses like changes in
inotropy, chronotropy, transmitter
release, neuronal activity and smooth
muscle relaxation follow.
68. 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)
69. These cell surface receptors, also called ligand
gated ion channels, enclose ion selective channels
(for Na*, K*, Ca2* or Cl-) within their molecules.
70. Agonist binding opens the channel and
causes depolarization/hyperpolarization
/changes in cytosolic ionic composition,
depending on the ion that flows through.
71. The nicotinic cholinergic, GABA-A, glycine
(inhibitory), excitatory AA (kainate, NMDA or N-
methylD-aspartate, quisqualate) and 5HT3
receptors fall in this category
73. The agonist binding site and the catalytic
site lie respectively on the outer and inner
face of the plasma membrane
These two domains are interconnected
through a single transmembrane stretch of
peptide chain.
There are two major subgroups of such
receptors.
74. Enzyme Linked Receptors
2 (two) types of receptors:
1. Intrinsic enzyme linked receptors
Protein kinase or
guanyl cyclase domain
2. JAK-STAT-kinase binding receptor
75. a. Intrinsic enzyme receptors
The intracellular
Domain is either a protein kinase or guanyl
cyclase.
In most cases the protein kinase specifically
phosphorylates tyrosine residues on
substrate proteins,
e.g. insulin, epidermal growth factor (EGF),
nerve growth factor (NGF) receptors, but in
few it is a serine or threonine protein kinase.
76.
77. In the monomeric state, the kinase
remains inactive.
Agonist binding induces dimerization of
receptor molecules and activates the
kinase to autophosphorylate tyrosine
residues on each other, increasing
their affinity for binding substrate
proteins and carrying forward the
cascade of tyrosine phosphorylations.
78.
79.
80. 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
81. 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.
83. 4. Receptors regulating gene expression
(Transcription factors)
In contrast to the above 3 classes of receptors,
these are intracellular (cytoplasmic or nuclear)
soluble proteins which respond to lipid soluble
chemical messengers that penetrate the cell
The receptor protein (specific for each hormone/
regulator) is inherently capable of binding to specific
genes/ but is kept inhibited till the hormone binds
near its carboxy terminus and exposes the DNA
binding regulatory segment located in the middle of
the molecule.
84.
85. All steroidal hormones (glucocorticoids,
mineralocorticoids, androgens, estrogens,
progesterone), thyroxine, vit D and vit A function
in this manner.
Different steroidal hormones affect different
target cells and produce different effects because
each one binds to its own receptor and directs a
unique patten of symthesis of specific proteins.
86. This transduction mechanism is the slowest
in its time course of action (takes hours).
87. Functions of receptors
(a) To propagate regulatory signals from outside to
within the effector cell.
(b) To amplify the signal.
(c) To integrate various extracellular and intracellular
regulatory signals.
(d) To adapt to short term and long term changes in
maintain homeostasis.
89. Dose-Response Relationship
Dose-plasma concentration
Plasma concentration (dose)-
response relationship
E =
Emax X [D]
KD + [D]
E is observed effect of drug dose [D], Emax = maximum response,
Kd = dissociation constant of drug receptor complex
When a drug is administered systemically, the
dose-response relationship has two components:
91. 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
92. 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
Response
Drug in log conc.
1 2 3 4
93. Therapeutic index (TI)
Therapeutic Index =
Median Lethal Dose (LD50)
Median Effective dose (ED50)
Idea of margin of safety Margin of Safety
94. Therapeutic index (TI)
It is defined as the gap between therapeutic
effect DRC and adverse effect DRC (also called
margin of safety)
95. Combined Effects of Drugs
When two or more drugs are given simultaneously or
in quick succession may be either indifferent to each
other or exhibit synergism or antagonism.
The interaction may take place at pharmacokinetic
level or at pharmacodynamic level.
96. – Additive effect (1 + 1 = 2)
Aspirin+paracetamol,
amlodipine+atenolol
– Supraadditive effect (1 + 1 = 4)
Sulfamethoxazole+trimethoprim,
levodopa+carbidopa,
acetylcholine+physostigmine
Drug Synergism (Greek: Syn-together; ergon-work)
when the action of one drug is facilitated or increased by the other,
they are said to be synergistic.
In a synergistic pair, both the drugs can have action in the same
direction or given alone one may be inactive but still enhance the
action of the other when given together.
Synergism can be:
97.
98.
99.
100. Drug Antagonism:
1. Physical: Charcoal
2. Chemical: KMNO4, Chelating agents
3. Physiological antagonism: Histamine and
adrenaline in bronchial asthma, Glucagons
and Insulin
4. Receptor antagonism
