Dr. Wajahat slides

1. Pharmacodynamics
(Action of drugs on the body)

2. What drugs can do?
• Drugs alter (activate or inhibit) normal
function of tissues or organs but cannot
confer any new function on them
• Drugs provide quantitative & not
qualitative change
• Cell’s ultimate response depends upon
the unique specialization of a particular
cell

3. How drugs act?
• Receptor medicated mechanisms
• Non-receptor mediated mechanisms
–Physical & chemical action,
–Enzymes – ACEI
–Antibody production -- vaccines
• Antimetabolite action --- Drug act as
nonfunctional analogue of a naturally
occurring metabolite

4. What are receptors?
• Receptors are Protein molecules whose
function is to recognize & respond to
endogenous chemical signals
• Receptors are macromolecules, present
on either cell surface, cytoplasm or in
the nucleus where the drugs binds and
interact to produce cell changes.

5. Drug
Receptor
Protein undergoes
an alteration in
conformation
which produces or
which induces
changes in the
system
5

6. •Drug + Receptor ↔
drug-receptor complex →
Effector molecule →
biological effects

7. • Ligand (hormones, drugs) --- Receptor
• Effector molecule - (translate the drug receptor interaction into a change in cellular activity)
– Adenylyl cyclase
– Tyrosine kinase effector -- part of insulin receptor
– Na+-K+ channel -- effector part of the nicotinic Ach
receptor
• Effector substrate – membrane lipid, ATP
• 2nd messenger ---- cAMP, cGMP, DAG, IP3,
Ca++
• Cell response (biological effect)

8. Receptor site / Ligand binding domain
/Recognition site
Effector domain which undergo
a conformational change
( three dimensional shape)
-- changes in the quaternary structure
or relative alignment of subunits of the receptors

10. Action-effect sequence
• Drug action --- combination with receptor site
–Conformational change (activator - agonist)
–Prevention of conformational change
(inhibitor - antagonist)
• Drug effect --- (Intrinsic activity) --
change in biological function, through a series
of intermediate steps (transducer)

11. Ri Ra
Receptors exist in at least two states,
inactive (R) and active (R*), that are in
reversible equilibrium with one another,
usually favoring the inactive state.

12. Agonists
The magnitude of biological effect is
directly related to the fraction of R*.
(partial agonists)
Antagonist
Inverse agonist

13. Major receptor families
• Intracellular receptors -- For lipid-soluble agents
–Receptors regulating gene expression
(transcription factors or nucleus receptors)
• Plasma membrane receptor proteins
–Ligand gated ion channels (ionotropic
receptors)
–G-protein couples receptors (metabotropic
receptors)
–Enzyme receptors

15. Pharmacological reactions elicited are
slower in onset but longer in duration
Intracelluar receptors

16. Intracellular receptors
(Cytoplasmic or Nuclear)
• Lipid soluble chemical messenger
• All steroid hormones
–Glucocorticoids,
Mineralocorticoids, Androgens,
Estrogens, Progesterones
• Thyroxine, vit D, vit A

21. Transmembrane enzyme receptors
Inner domain ---
effector mechanism
Receptor as enzymes --
Receptor tyrosine kinases
(insulin receptor)
Growth factors
epidermal growth factor (EGF),
Platelet derived growth factor (PDGF)

22. (Insulin receptor substrate)
Dimerize and phosphorylate

23. Epidermal growth factor receptor (EGF),
a representative receptor tyrosine kinase

24. Transmembrane receptor
Cytokine receptors ---
Receptor activates associated but separate cytoplasmic
tyrosine kinase ---- JAKs --- phosphorylate STATs
STATs
(signal transducers and activators of transcription )
STAT dimer (the effector) –
travel to nucleus, where they regulate transcription
Y -- tyrosine

25. Receptors for cytokines
Erythopoietin,
Growth hormone,
Inteferons
Y -- tyrosine

26. Transmembrane channels
Ligand gated ion channels
(ionotropic receptors)
Receptors with intrinsic ion channel ----
Ligand-activated (gated) ion channels
Cholinergic nicotinic receptors

27. Receptors with intrinsic ion channel
• Agonist binding opens
the channel and causes
depolarization/
hyperpolarization /
change in cytosolic ionic
composition, depending
on the ion that flows
through
• The onset and offset of
responses is the fastest

28. Receptors with intrinsic ion channel
• Nicotinic receptors for Ach --- ANS ganglia,
NM junction, & CNS ---is coupled to a Na+/K+
ion channel
– Drugs --- Nicotine, Choline esters, Ganglion
blockers, & skeletal muscle relaxants
• GABA-A receptor in CNS which is coupled to
chloride channel is modulated by
Anticonvulsants, BZP, and barbiturates

29. G protein coupled receptors
(metabotropic receptors)
Which utilize a coupling protein
Gq
Gs – (GαS)
Gi – (Gαi)
to activate a separate effector molecule
Phospholipase C & adenylyl cyclase

30. G protein coupled receptor
Seven-transmembrane (7-TM) or ‘serpentine’ receptors
The third of which is coupled to G protein effector mechanism

31. Phospholipase C
(Phosphatidylinositol 4,5- biphosphate)
Diacylglycerol
Inositol 1,4,5-triphosphate
Gq
α1
M1, M3
Angiotensin II &
several serotonin subtypes
effector

32. Adenylyl cyclase
Gs
β, D1
Glucagon, histamine (H2),
prostacyclines, some serotonin

33. Gi ---- α2, M2
D2 subtypes, several opioid & serotonin subtypes
AC --- ATP --- ↓ cAMP ---
↓Ca++ efflux and enzyme activity;
K+ efflux

35. ANS receptors
• M1, M3, α1
• Gq activation of phospholipase C
• M2, α2, D2
• Gi inhibition of adenylyl cyclase
• β1, β2, D1
• Gs activation of adenylyl cyclase

36. Cyclic GMP and Nitric Oxide signaling
• Nictric Oxide (NO) is synthesized in endothelial
cells and diffuses in smooth muscles
• Vasodilators ⬆the synthesis of NO by
endothelial cells
• NO activates gyanylyl cyclase, thus increasing
cGMP in smooth muscle
• cGMP is a 2nd messenger in vascular smooth
muscle that facilitates the dephosphorylation of
myosin light chain, preventing their interaction
with actin an thus causing vasodilation

37. Drugs acting via NO
• Nitrates
• M-receptor agonists --- bethanicol
• Endogenous compounds --- bradykinin and
histamine

38. Area of Plasma membrane receptors
occupied by the receptors
• Adrenaline and Ach produce
their maximum effect on frog’s
heart by occupying only
1/6000th of the cardiac surface
cells
• Different receptors for different
chemical messengers in a single
cell

39. •Cyclic AMP
cAMP (cyclic adenosine monophosphate )
•Ca++
• IP3 ---inositol triphosphate
• DAG --- diacylglycerol
• Cyclic GMP ( cyclic guanosine monophosphate)
– (Signal transduction pathway involved in vision)
second messengers
(intracellular mediators)

40. UHS
• A) What is a receptor? Explain the concept of
spare receptors with examples. (01,03)
• B) A) Give in tabulated form the sites,
structural features and post receptor
mechanism of muscarinic receptors – type 1, 2
and 3. (4.5)

41. Duration of drug action---
Termination of drug action results from
• Dissociation of the drug from the receptor
terminates the effect.
– Action is very much prolonged because of
covalent bond formation with the receptor.
– Action persists after drug dissociation because
some coupling molecule is still present in the
active form.
• Destruction of drug-receptor complex

42. Receptor regulation
• Receptors exist in a dynamic state
• Regulated in number, location, & sensitivity
• Changes can occur over short time (minutes)
and longer periods (days)
• Down regulation
• Up regulation

43. Up-regulation Down-regulation
• Continued/extended
use of antagonists
↓
• ↑ed number &
sensitivity of
receptors
↓
• ↑ed drug effect
• Continued/extended
use of agonists
↓
• ↓ed number &
sensitivity of
receptors
↓
• ↓ed drug effect

44. Up-regulation Down-regulation
• Sudden discontinuation
of β-blockers in angina
pectoris may precipitate
angina
• Clonidine &
CNS depressant /
opioid
withdrawal
syndromes
• Desensitization or
refractoriness
• Bronchial asthma
patients treated
continuously with
adrenergic agonists
• Patients of
Parkinsonism treated
with high doses of
levodopa

45. Mechanism of Down regulation
• ↓ in number -- Agonist bound receptors may be
internalized by endocytosis
• Reinserted (e.g. morphine receptors)
• Degraded (β-receptors, epidermal growth factor receptors)
• β arrestin --- Intracellular proteins may block the
access of a G protein to the activated receptor
molecule
• Depletion of some essential substrate required for
down stream effects
– Depletion of thiol cofactor --- tolerance to nitroglycerine ---
Repletion of missing substrate (glutathion) can reverse the
tolerance

46. Spare receptors
• Maximal efficacy (Emax ) – it is the greatest
effect an agonist can produce if the dose is
taken to very high levels
• EC50 -- The dose or concentration at which
effect is half-maximal
• Bmax -- The maximum number of receptors
bound
• Kd --- the concentration at which 50% of the
receptors are bound

47. Spare receptors
•Spare recptors are said
to exist if Emax is
obtained at less than
maximal occupation of
the receptors Bmax

48. Spare receptors
• The receptors which are left un-
occupied are referred as spare
receptors
• When spare receptors are occupied
they can be coupled to response

49. • Spare receptors present
If EC50 < Kd
• Spare receptors not present
If EC50 = Kd

50. Mechanism of spare receptors
• Actual number of the receptor may
exceed the number of effector
molecules available

51. • 4 receptors and 4 effectors
• 2 receptors stimulates 2 effectors
• Kd = EC50 ---- half-maximal response
• 40 receptors and 4 effectors
• Most of the receptors are now spare in
number
• EC50 < Kd
• EC50 ---- only 5% (2 of the 40) concentration of
agonist is able to elicit a half maximal
response --- 2 of 4 effectors activated)

52. Spare receptors examples
• β adrenoceptors in the heart
• Same maximal ionotropic response can be
elicited to catecholamines even under
conditions when 90% of the β receptors are
bound by the quasi-irreversible antagonist