pharmacodynamics slide powerpoint .ppt

pharmacodynamics slide powerpoint .ppt

1. Pharmacodynamics

2. What Drug does to the Body?
It is the study of drug
effects inside the body

3. Principles (Types) of drug action
•Stimulation of Physiological
process
•Inhibition of Physiological process
•Replacement of Physiological
substances
•Cytotoxic effect

4. Mechanism of drug action
•Through Receptors ©
•Through Enzymes
•Physical Action
•Chemical Action

5. Physical Action
•Radioactivity ….
131
I
•Osmotic activity.. Mannitol

6. Chemical Action
•Antacids (Aluminum Hydroxide )
neutralizes gastric acid
•Chelating agents inactivates toxic
metals (BAL- Arsenic, Mercury)

7. Through Enzymes
•Most of the biological reactions are Enzymes
mediated
•Enzymes are important targets of drug action.
•Either by stimulating or by inhibiting, Drugs
can increase or decrease the rate of
reactions.

8. •Adrenaline stimulates
adenylyl cyclase
•Neostigmine inhibits
cholinesterase

9. Receptors
• Receptor is a binding site for a drug or
chemical agent
• It is a macromolecular component of
cell situated on cell surface or inside
the cell

11. Affinity
It is the ability of the drug to bind to
the receptor
Intrinsic activity
It is the ability of the drug to activate
and induce a conformational change
in the receptor after occupying the
receptor

12. The Receptor and Binding
PRE
POST
Synaptic cleft
Receptor

13. The Receptor and Binding
PRE
POST
Synaptic cleft
Chemicals (ligands) must bind to the receptor and remain bound
long enough for the receptor to be activated.

14. The Receptor - Specificity
PRE
POST
Synaptic cleft
Ligands bind to specific receptors. Not all ligands bind to
all receptors

15. The Receptor - Specificity
PRE
POST
Synaptic cleft
There are a number of specific ligands and a number of associated
receptors.

16. •Agonist
•Antagonist
•Partial agonist

17. Agonist
•High affinity
•High intrinsic activity
Agonist
Receptor

18. Agonist
•Agonists are the chemicals that interact
with a receptor , thereby initiate a
chemical reaction inside cell and
produces effect
•Eg : ACh is agonist at muscarinic
receptor in heart cell
•Will have both Affinity and maximal
Intrinsic activity

19. Antagonist
•High affinity
•No intrinsic activity
Agonist
Receptor

20. Antagonist
•A drug that binds to the receptor but
can not activate it . It blocks the effect
of an agonist for that receptor
• d-tubocurarine is antagonist of ACh -
Nicotinic receptors at skeletal muscle
end plate
•Has only Affinity but no Intrinsic
activity

21. Competitive Antagonist

22. Competitive Antagonist:
–Can be overcome by increasing the
dose of the agonist
–competes with other ligands for
binding to the receptor.
–Reversible
–Eg: propranolol- β receptor

23. Irreversible Antagonist
Irreversible Antagonist
•High affinity
•No intrinsic activity

24. Irreversible Antagonist:
–Cannot be overcome by increasing
the dose of the agonist
–Does not competes with other
ligands for binding to the receptor.
–Irreversible
–Eg: phenoxybenzamine - α receptor

25. • Agonist
• High affinity
• High intrinsic activity
• Antagonist:
• High affinity
• Low intrinsic activity

26. Partial agonist
•When given alone partial agonist
activates receptor to produce a effect.
But less response than a full agonist .
•When given along with the agonist
blocks the agonist action.
•Will have Affinity but sub maximal
Intrinsic activity

27. Action-Effect sequence
Drug action and Drug effect are not
synonymous

28. Drug action
• It is the initial combination of drug with the
receptor resulting in conformational changes
in cell
Drug effect
•It is the ultimate change in biological function
as a consequence of drug action

29. Transducer Mechanisms
•These are a series of intermediate steps
between drug action and drug effect
•Depending upon these transducer
mechanisms drug receptors can be
categorised into 5 types

30. •Intracellular receptors
•Enzymatic receptors
•Tyrosine kinase receptors
•Ion-Channel receptor
•G-Protein coupled Receptors

31. Transmembrane Signaling mechanisms
Nicotinic R
GABA R
Adrenergic R
Cytokine R
Tyrosine kinase
Insulin R
Steroid R
JAK-STAT

32. Ion channel (Nicotinic) receptor

34. Effector enzymes
•Adenylyl cyclase
•Phospholipase C
•Guanylyl cyclase
Second messengers
•cAMP- Cyclic adenosine mono
phosphate
•Calcium and Phosphoinositides
•cGMP- Cyclic Guanosine mono
phosphate

35. Second messenger signaling involves
phosphorylation of down stream
enzymes and proteins
↓
Response

36. Dose-Response relationship

37. • Dose Response
•Increases in response until it
reaches maximum, Later it
remains constant despite
increase in dose .. Plateau effect

38. DOSE RESPONSE CURVE

DOSE of drug
%

o
f

R
e
s
p
o
n
s
e
After this point
increase in
dose doesn’t
increase the
response

39. LOG DOSE RESPONSE CURVE
Log

40. LOG DRC DRC

42. Log DRC
•Sigmoid shape
( Normal DRC is rectangular hyperbola)
•Response is proportional to log dose
•Wider range of drug doses can be easily
displayed on graph

43. Characteristics of DRC (Log DRC)
•Position of DRC - Potency
•Height of DRC - Efficacy
•Slope of DRC
–Steep DRC
–Flat DRC

44. Doses
%

o
f

B
P

R
e
d
u
c
t
i
o
n
100%
50%
0%
10mg
20mg30mg 40mg50mg
75%
25%
200mg
A
B

45. ED
50
•Dose of a drug that required to
produce 50% of maximal effect
Potency

46. Doses of Propranolol
%

o
f

B
P

R
e
d
u
c
t
i
o
n
100%
50%
0%
10mg
20mg30mg 40mg50mg
75%
25%
200mg
ED
50
ED
50

47. Doses
%

o
f

B
P

R
e
d
u
c
t
i
o
n
100%
50%
0%
10mg
20mg30mg 40mg50mg
75%
25%
200mg
Potency of Drug G > Drug R > Drug B
G R B

48. Drug Doses
%

o
f

R
e
s
p
o
n
s
e
Efficacy

49. Potency
 
•Dose of a drug that
required to produce
50% of maximal
effect (ED
50)
•Relative
Positions
 of the DRC 
on
 x-axis
•More left the DRC,
more potent the drug
Efficacy
 
•Maximum effect of the
drug
•Height of the curve
 
on
 x-axis indicates the
efficacy of the drug
•Taller the DRC ,more
efficacious the drug

50. •Drug B is less potent
but equally efficacious as
drug A
•Drug C is less potent
and less efficacious than
drug A
•Drug C is equally potent
and less efficacious than
drug B
•Drug D is more potent
than A,B ,C and less
efficacious than A and B

51. Drug Dose
F
a
l
l

i
n

B
P
Hydralazine.. steep
Thiazides.. Flat

52. SLOPE
STEEP DRC
•Moderate increase in
dose leads to more
increase in response
•Dose needs
individualization for
different patients
•Unwanted and
Uncommon
FLAT DRC
•Moderate increase in
dose leads to little
increase in response
•Dose needs no
individualization for
different patients
•Desired and Common

53. Quantal Dose-response curve
a graph of fraction of a population that shows a
specified response to increasing doses of drug
Threshold Dose
# of
Subjects
0
10
20
30
40
50
1 3 5 7 9111315
ED
50

54. LD
50
:Median lethal dose
The dose at which lethality is observed in 50% of
subjects.
TD
50:Median toxic dose
The dose at which a particular toxic effect is
produced in 50% subjects

55. Therapeutic range
E
F
F
E
C
T
Toxic effect
Th
erap
eu
tic effect
300mg 3000mg300-3000mg
M
in
im
u
m
th
e
ra
p
e
u
tic
e
ffe
c
t
M
a
x
im
u
m
to
le
ra
b
le
a
d
v
e
rs
e
e
ffe
c
t

56. log Dose
%

o
f

r
e
c
e
p
t
o
r
s

b
o
u
n
d 100%
50%
0%
0.5
5
50
500
K
d
B
max

57. Spare receptors
If maximal response is obtained with less than full
occupation of receptors
If EC50 is less than Kd – spare receptors are present
Inert binding sites
Components of endogenous molecule that bind a drug
but does not initiate events leading to drug effects
Eg: plasma albumin, acid glycoprotein

58. Therapeutic index
In animal experiments TI can be measured
TI = Median lethal Dose
Median Effective dose
= LD50
ED50

59. Combined effect of drugs
•When 2 or more drugs are given
together they exhibit either Synergism
or Antagonism

60. Synergism
1.Additive
2.Supraadditive (potentiation )

61. Synergism
•Additive
•Effect of drugs A + B= Effect of Drug A + Effect
of Drug B
•Drug effect will simply add up
•Eg: Paracetamol + Ibuprofen

62. Synergism
•Supraadditive (potentiation)
•The effect of the combination is greater
than the individual effects of the
components
•Eg: Acetylcholine + Neostigmine
–Levodopa + carbidopa

63. Antagonism
When one drug decreases the effect of
other drug
•Physical antagonism
•Chemical antagonism
•Physiological antagonism
•Receptor mediated antagonism

64. Physical antagonism
•Activated Charcoal used in
poisoning, which adsorbs the
poison material, later get
excreted

65. Chemical antagonism
•Chelating agents used in metal
poisoning…forms insoluble complexes
with metals which can be excreted
•Antacids

66. Physiological antagonism
•Also called as functional antagonism
•Two drugs act on different receptors
and produce opposite effects on same
physiological system
•Eg: Use of adrenaline in anphylaxis
Adrenaline and Histamine actions on
BP and Bronchial smooth muscle

67. Receptor mediated antagonism
•Competitive
•Irreversible

68. COMPETITIVE
•Antagonist binds with
same receptor
•Effect can be overcome
by adding more agonist
•Parallel rightward shift
of DRC
•Apparently reduces
potency of agonist
•Eg: Acetyl Choline and
Atropine
NONCOMPETITIVE
•Antagonists bind to same
receptors irreversibly with
strong covalent bonds
•Effect cannot be overcome
by adding more agonist
•Downward shift of DRC
•Apparently reduces efficacy
of agonist
•Eg: Phenoxybenzamine & NE