pharmacology

1. Pharmacodynami
cs

2. if absorbedif absorbed
Pro-drugPro-drug oror DrugDrug
given. any routegiven. any route
conc. in
systemic circulation
Drug at
Tissues
Drug at
Site of Action
Pharmacological Effects
Therapeutic vs. Toxic Effects
Distribution
Metabolism
or Excretion
Elimination
This isThis is
PharmacodynamicsPharmacodynamics
This isThis is
PharmacokoneticsPharmacokonetics

3. The word ‘dynamis’ means
power / activity
So this branch deals with the study
of
“ What the drug does to the body ”

4. So
Pharmacodynamic
deals with
physiological / biochemical changes
produced by the drugs

5. their
mechanism of action
at macromolecular level,
and
their uses

6. RememberRemember
PhysiologicalPhysiological
andand
Biochemical changesBiochemical changes
by the drugs areby the drugs are
thethe Pharmacological EffectsPharmacological Effects ….….
Therapeutic / Toxic effectsTherapeutic / Toxic effects
Drugs cannot bring about qualitativeDrugs cannot bring about qualitative
changeschanges

7.  StimulationStimulation
 DepressionDepression
 ReplacementReplacement
 Anti-infective and cytotoxic actionAnti-infective and cytotoxic action
 Modification of immune systemModification of immune system

8. 1. Where a drug acts ?
Site of Action
may be a receptor

9. • a macromolecular component of the
organism, protein in nature, to which
the drugs binds and initiates the
drug’s effect
• They have difinite life span after
which these are degraded by the cells
and new receptors are synthesized.
• Drug-receptor interaction --------lock &lock &
keykey relationshiprelationship

10. 1. Recognition and binding of the ligandRecognition and binding of the ligand
2. Propagation of the message2. Propagation of the message
To perform these functions it has twoTo perform these functions it has two
sites(domains)sites(domains)
i. A ligand binding domain----a site to bind thei. A ligand binding domain----a site to bind the
drug moleculedrug molecule
ii. An effector domain-------which undergoes aii. An effector domain-------which undergoes a
change to propogate the message.change to propogate the message.

11. For endogenous substances like:
• Cholinergic receptors for ACh,
• Adrenergic where Epinephrine &
Norepinephrine act,
• Dopaminergic receptors for
Dopamine,

12. • Serotonergic where 5-HT
(serotonin) acts,
• Histaminergic receptors where
Histamine acts,

13. Similarly
• GABA,
• Adenosine,
• Imidazoline receptors, or
• Structural proteins, like tubulins
etc.

14. • Cholinesterases,
• MAOs / COMT,
• ACE,
• Cyclooxygenase,
• Na+
K+
ATPase,
• Xanthine oxidase, etc.

15. opening / blocking of various
channels, like:
• Na+
channels,
• K+
channels,
• Ca+
channels,
• Cl -
channels, etc.

16. 2.How a drug acts ? i.e.,
Mechanism of Action –
• how a drug modifies the
biochemical / physiological cellular
functions
• whether the sites are activated or
inhibited, and how

17.  ReceptorsReceptors
 Enzymes and pumpsEnzymes and pumps
 Ion channelsIon channels
 Chemical interactionChemical interaction
 Physical actionPhysical action
 Altering metabolic processessAltering metabolic processess

18. 3. What are the drug effects ?
Pharmacological Effects

19. A drug
may act as
agonist / partial agonist or antagonist
according to its molecular structure

20. Any chemical substanceAny chemical substance
(endogenous or exogenous) that(endogenous or exogenous) that
binds with the receptor is ligandbinds with the receptor is ligand
e.g. neurotransmitter, hormonese.g. neurotransmitter, hormones
or drugs etcor drugs etc

21.  The drug that activate its receptor
upon binding i.e. it has affinity
and intrinsic activity

22.  A drug is called an antagonist
when binding to a receptor is not
associated with a response.
 Thus a receptor has affinity and but no
intrinsic activity

23. SIGNALING MECHANISMS &
DRUG ACTION

24. Receptor families
1-1- Intracellular receptorsIntracellular receptors
2- Transmembrane Receptors2- Transmembrane Receptors
a)a) Ligand gated ChannelsLigand gated Channels
b)b) G-Proteins linkedG-Proteins linked
c)c) Tyrosine KinaseTyrosine Kinase
d)d) Cytokine ReceptorsCytokine Receptors

25. Five Basic Mechanisms
of Transmembrane
Signaling

26. Tyrosine /Tyrosine /
Serine Kinase orSerine Kinase or
Gunylyl CyclaseGunylyl Cyclase
CytokineCytokine
GeneGene
Transcription.Transcription.
IonIon
ChannelChannel
G Protein.G Protein.
IntracellularIntracellular
1. receptors1. receptors
Transmembrane ReceptorsTransmembrane Receptors
22. Tyrosine 3. Cytokine. Tyrosine 3. Cytokine 4.4. Ligand-Gated 5. G-ProteinsLigand-Gated 5. G-Proteins
KinaseKinase ReceptorsReceptors Channels linkedChannels linked

27. 1: Intracellular Receptors
A lipid-soluble
ligand that
crosses the
membrane and
acts on an
intracellular
receptor.

28. Examples
• Nitric Oxide,
• Macrolides,
• Steroids &
• Vitamin D
• Thyroid hormone
• Other hormones

29. Intracellular Receptors for Lipid-Soluble
Agents
• Some ligands are sufficiently lipid-
soluble to cross the plasma membrane
and act on intracellular receptors.
• These are receptors that regulate gene
transcription

31. • When ligand binds with the receptors it
stimulate the transcription of genes by
binding to specific DNA sequences near
the gene whose expression is to be
regulated.

32. The mechanism used by hormonesThe mechanism used by hormones
that act by regulating gen expressionthat act by regulating gen expression
has two therapeutically importanthas two therapeutically important
consequencesconsequences

33. 1:All of these hormones produce their
effects after a characteristic lag period
of 30 minutes to several hours—the
time required for the synthesis of new
proteins.
This means that these hormones cannot be
expected to alter a pathologic state within
minutes (eg, glucocorticoids will not
immediately relieve the symptoms of acute
bronchial asthma).

34. 2: The effects of these agents can persist for
hours or days after the agonist concentration
has been reduced to zero.
• The persistence of effect is primarily
because --- most enzymes and proteins,
remain active in cells for hours or days after
they have been synthesized.

35. 2: Transmembrane Enzyme
Receptors
A transmembrane
receptor protein
• whose intracellular
enzymatic activity is
regulated by a ligand
that binds to a site on
the protein's
extracellular domain.
TYROSINE KINASE
RECEPTORS

36. • These receptors are polypeptides consisting of
1.An extracellular hormone-binding domain
2.Cytoplasmic enzyme domain,
• which may be a protein tyrosine kinase, a
serine kinase, or a guanylyl cyclase

37. A large group of receptors with intrinsic
enzymatic activity

38. 3: Transmembrane Receptors with
separate Intracellular Enzymes
A transmembrane
receptor that
binds and
stimulates a
protein tyrosine
kinase.
CYTOKINE
RECEPTORS

39. Examples
1. Insulin
2. Epidermal growth factor
(EGF)
3. Platelet-derived growth
factor (PDGF)
4. Atrial natriuretic peptide
(ANP), and many other
trophic hormones

40. 2. Ligand-Regulated
Transmembrane Enzymes
Including Receptor
e.g.Tyrosine Kinases

41. Examples
• Growth hormone,
• Erythropoietin
• Interferon, and other
regulators of growth
and differentiation

42. 4: Receptors on Membrane Ion-
Channels
A ligand-gated
transmembrane
ion channel that
can be induced to
open or close by
the binding of a
ligand
ExamplesExamples::
Nicotinic
Receptors,
GABA Receptors,
Benzodiazepine
Receptors

43. Ligand- and Voltage-Gated Channels
• Many of the 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 are acetylcholine,
serotonin, GABA, and glutamate. All of these
agents are synaptic transmitters.

44. • For example, acetylcholine causes the
opening of the ion channel in the nicotinic
acetylcholine receptor (AChR), which allows
Na+ to flow down its concentration gradient
into cells, producing a localized excitatory
postsynaptic potential—a depolarization.

47. Receptors linked to Effectors via G -
Proteins
• A transmembrane
receptor protein
• Which stimulates a
GTP-binding signal
transducer protein (G
protein)
• This G protein in turn
modulates production
of an intracellular
second messenger.
G protein coupled receptors
(GPRC)

48. Examples
• Alpha and beta
adrenoceptors
• Glucagon receptors,
• Thyrotropin receptors,
• Dopamine and
serotonin receptors

49. GPRC
• These are a large family of cell membrane
receptors
• These are linked to the effector (enzyme/
channel,/carrier protein) through one or
more G-proteins
• These include receptors for many hormones
and neurotransmitters, for example the
muscarinic acetylcholine receptor ,adrenergic
receptors

50. Sequence of events
• In most cases, GPRC use a transmembrane
signaling system with different components.
1.The extracellular ligand binds with the cell-
surface receptor
2.The receptor in turn triggers the activation of
a G protein located on the cytoplasmic face of
the plasma membrane.

51. 3. The activated G protein then changes the
activity of an effector element, usually an
enzyme or ion channel.
4. This effector then changes the concentration
of the intracellular second messenger

52. Few recognized cytoplasmic second
messengers
• cyclic AMP
• cyclic GMP
• cyclic ADP–ribose
• Ca2+
• inositol phosphates (IP3)
• Diacylglycerol (DAG)
• nitric oxide (NO)

53. What are G proteins
• The G-protein is a membrane protein
comprising three subunits (α, β, γ), the α
subunit possessing GTPase activity.
• G proteins are signal transducers that convey
information from the receptor to one or
more effector proteins.
• When this G protein binds with agonist-
occupied receptor, the α subunit dissociates
and is then free to activate an effector (a
membrane enzyme or ion channel)

54. G ProteinG Protein
Unoccupied receptors does
not interact with Gs protein
EffectorEffector

57. RestingResting

58. Types of G protein
• There are several types of G-protein, which
interact with different receptors and control
different effectors
• Gs
• Gi
• Gq

59. • There are three major effector
pathways through which GPCRs
function.

60. Adenylyl cyclase : cAMP pathway
Activation
• Binding of agonists to receptors linked to GS
proteins increases cAMP production.
1.Gs protein when stimulated cause stimulation
of adenylyl cyclase(AC)
2.Activation of AC results in intracellular
accumulation of second messenger cAMP
which functions mainly through cAMP-
dependent protein kinase A

61. 3. The protein kinase A phosphorylates and
alters function of many enzymes, ion channels
and transporters and structural proteins

62. Function mediated through this
pathway
• Increased contractllity
• Impulse generation(heart)
• Relaxation (smooth muscle)
• Glycogenclysis
• Lipolysis
• Modulation of junctional transmission,
• Hormone synthesis,

63. Cyclic GMP and Nitric Oxide Signaling
• cGMP is a second messenger in vascular
smooth muscle that facilitates
dephosphorylation of the myosin light chains
kinase(MLCK), preventing their interaction
with actin and thus causing vasodilation.
• Nitric oxide (NO), which can be released from
endothelial cells by vasodilators (e.g., H1 and
M3 agonists), activates guanylyl cyclase, thus
increasing cGMP.

64. Inhibition of adenylyl cyclase
• Binding of agonists to receptors linked to Gi
proteins decreases cAMP production.
• Responses opposite to the above are
produced when AC is inhibited through
inhibitory Gi-protein.
• Such receptors include adrenoreceptors (α 2),
ACh (M2,), dopamine (D2), and several opioid
and serotonin subtypes.

65. GsGi

66. PhospholipaseC: lP3-DAG pathway
Activation
• Other receptor systems are coupled via GTP-
binding proteins (Gq ), which activate
phospholipase C.
• Activation of this enzyme releases the second
messengers inositol triphosphate (IP3,) and
• Diacylglycerol (DAG) from the membrane
phospholipid phosphatidylinositol
bisphosphate(PIP2,).

67. • The IP3 induces release of Ca2+ from the
sarcoplasmic reticulum (SR), which, together
with DAG, activates protein kinase C.
• The protein kinase C serves then to
phosphorylate a set of tissue-specific
substrate enzymes, usually not
phosphorylated by protein kinase A, and
thereby affects their activity.

68. • These signaling mechanisms are invoked
following activation of receptors for
• ACh (M1 and M3)
• norepinephrine (α 1)
• angiotensin II
• and several opioid and serotonin subtypes.

69. R
A
G q PLC
GDP
GTP
+
PIP 2
DAG IP3
SRCa++
calmaduli
n
CCPK MLCK PKC OTHER EFFECTORS
+
Calcium
channel
PKC
Effec
t

70. • Cytosolic Ca2
* (third messenger) is a highly
versatile regulator acting through calmodulin
and protein kinase C

71. PhospholipaseC: lP3-DAG pathwayActircan
modulate
• Contraction
• Secretion
• Neurotransmitter
release
• Eicosanoid synthesis
• Intracellular movement
• Cell proliferation
• Metabolism

72. Channel regulation
• The activated G- proteins can also open or
close ionic channels
• For example Ca, K or Na, without the
intervention of any second messenger like
cAMP or IP3
• Thus bring about hyperpolarization/
depolarization /changes in intracellular Ca+

73. • Gs opens Ca2- channels in myocardium and
skeletal muscles,
• Gi and Go open K+ channels in heart and
smooth muscle as well as close neuronal Ca2-
channels.
• Physiological responses like changes in
inotropy, chronotropy, transmitter release,
neuronal activity and smooth muscle
relaxation follow.

74. Receptor Regulation
The number of receptors and their sensitivity
can be altered.
Repeated or continuous administration of an
agonist (or an antagonist) may lead to
changes in the responsiveness of the
receptor.

75. Up-Regulation
• Prolonged deprivation of the agonist or
constant action of the antagonist all
result in an increase on the number
and sensitivity of the receptors.
• e.g. prolonged use of beta- adrenergic
receptor antagonist Propranolol

76. Down- Regulation
Prolonged activation of the receptors by
an agonist result in an decrease in the
number and sensitivity of the
receptors.
• e.g. prolonged use of beta- adrenergic
receptor agonist salbutamol

77. Clinical importance
1-After prolonged adminstration, a receptor
antagonist should always be tapered.
Sudden withdrawl after prolonged use of
beta- adrenergic receptor antagonist
(Propranolol) in hypertension result in
rebound hypertension due to up-regulation
of beta-receptors.

78. 2- Prolonged use of beta- adrenergic receptor
agonist (salbutamol) in bronchial asthma
result in reduced therapeutic response due
to down-regulation of beta-receptors.

79. THANK YOU