includes various types of receptors, mechanism of action, factors modifying drug action,principles of drug action,all types of drug receptor complex interactions very useful to students and post graduates..

1. PHARMACODYNAMICS
By
Dr.K.Raj kumar,MD.
Associate professor

2. 2
What is Pharmacodynamics?
–What the drug does to the body when it
enters?
–Defn: It is the study of biochemical and
physiological effects of drug and their
mechanism of action at organ level as
well as cellular level.

3. PRINCIPLES OF DRUG ACTION
– Do NOT impart new functions on any system,
organ or cell
– Only alter the PACE of ongoing activity
– STIMULATION
– DEPRESSION
– IRRITATION
– REPLACEMENT
– CYTOTOXIC ACTION
3

4. Stimulation
 Selective enhancement of the level of activity
of specialized cells.
 Adrenaline stimulates heart.
 Pilocarpine stimulates salivary glands.
 High dose picrotoxin – convulsions, coma,
respiratory depression.

5. Depression
 Selective diminution of activity of specialized
cells.
 Barbiturates depress CNS
 Quinidine depresses heart
 Omeprazole depresses gastric acid secretion.
 Acetylcholine stimulates intestinal smooth
muscles but depresses SA node

6. Irritation
 A nonselective, often noxious effect and is
particularly applied to less specialized cells
(epithelium, connective tissue).
 Strong irritation results in inflammation,
corrosion, necrosis and morphological
damage.

7. Replacement
 Use of natural metabolites, hormones or their
congeners in deficiency states.
 Levodopa in parkinsonism
 Insulin in diabetes mellitus
 Iron in anaemia.

8. Cytotoxic action
 Selective cytotoxic action on invading
parasites or cancer cells, attenuating them
without significantly affecting the host cells.
 Utilized for cure/palliation of infections and
neoplasms.
 e.g. penicillin, chloroquine, zidovudine,
cyclophosphamide, etc.

9. Mechanism of drug action
 Only a handful of drugs act by virtue of their simple physical
or chemical property; examples are:
 Bulk laxatives (ispaghula)—physical mass
 Paraamino benzoic acid—absorption of UV rays
 Activated charcoal—adsorptive property
 Mannitol, mag. sulfate—osmotic activity
 131 I and other radioisotopes—radioactivity
 Antacids—neutralization of gastric HCl
 Pot. permanganate—oxidizing property
 Chelating agents (EDTA, dimercaprol)—chelation of heavy
metals.

10. MECHANISM OF DRUG ACTION
MAJORITY OF DRUGS INTERACT
WITH TARGET BIOMOLECULES:
–Usually a Protein
–ENZYMES
–ION CHANNELS
–TRANSPORTERS
–RECEPTORS

11. Enzymes
 Almost all biological reactions are carried out
under catalytic influence of enzymes;
 Drugs can either increase or decrease the rate
of enzymatically mediated reactions.

12. 1. Enzymes – drug targets
– All Biological reactions are carried out under
catalytic influence of enzymes – major drug target
– Drugs – increases/decreases enzyme mediated
reactions
– In physiological system enzyme activities are
optimally set
– Enzyme stimulation is less common by drugs –
common by endogenous substrates
• Pyridoxine (cofactor in decarboxylase activity)
• Adrenaline stimulates hepatic glycogen phosphorylase
(hyperglycaemia)
– Enzyme inhibition – common mode of drug
action

13. Enzyme inhibition
 Selective inhibition of a particular enzyme is a
common mode of drug action.
 Such inhibition is either competitive or
noncompetitive.

14. • Enzyme Inhibition - Examples
– Equilibrium: (competetive)
• Physostigmine Vs Acetylcholine (cholinesterase)
• Sulfonamides Vs PABA (folate synthetase)
• Moclobemide Vs Catecholamines (MAO-A)
• Captopril Vs Angiotensin 1 (ACE)
– Nonequilibrium:
• Orgnophosphorous compounds/Nerve gases
(cholinesterase)
– Non-competitive:
• Acetazolamide (carbonic anhydrase), Omeprazole
(HKATPase) , Aspirin (cyclooxygenase)

15. 3/8/2024 ThepowerpointTemplates.com 15

16. Ion Channnels
– Proteins take part in transmembrane signaling
and regulates ionic composition
– Drugs also target these channels:
• Ligand gated channels
• G-protein operated channels
• Direct action on channels
– Examples: Local anaethetics and Class I anti
arrythmics act/depress Na+ channels
– Nifedipine blocks L- type voltage sensitive ca
channels

17. Ion Channels
 Certain drugs modulate opening and closing of
the channels, e.g.:
 Nifedipine blocks L-type of voltage sensitive
Ca2+ channel.
 Ethosuximide inhibits T-type of Ca2+ channels
in thalamic neurones.

18. Ion Channels
 Ligand gated channels (e.g. nicotinic
receptor)
 G-proteins and are termed G-protein
regulated channels (e.g.cardiac β1
adrenergic receptor activated Ca2+ channel).

19. Transporters
 Several substrates are translocated across
membranes by binding to specific
transporters (carriers) which either facilitate
diffusion in the direction of the concentration
gradient or pump the metabolite/ion against
the concentration gradient using metabolic
energy.

20. Transporters
• Substrates are translocated across
membrane by binding to specific transporters
(carriers) – Solute Carrier Proteins (SLC),ATP
binding cassettes(ABC).
• Pump the metabolites/ions In the direction of
concentration gradient or against it
• Drugs interact with these transport system
• Examples: Probenecid (penicillin and uric
acid)- OAT, Furosmide (Na+K+2Cl-
cotransport),
• Fluoxetine inhibit neuronal reuptake of 5 HT
with SERT
20

21. 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 21

22. • Some Definitions
–Agonist: An agent which activates a
receptor to produce an effect similar to a
that of the physiological signal molecule.
–Both affinity and intrinsic activity(E=1)
–Response is seen
–Eg – Adrenaline,Morphine

23. 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.
Only affinity but no intrinsic activity (E=0)
No response
Eg – Propronolol, CPM
23

25. Partial agonist: An agent which activates a
receptor to produce submaximal effect but
antagonizes the action of a full agonist,
e.g. pentazocine
Have full affinity but with low intrinsic activity
and hence are only partly as effective as
agonists.
25

26. –Inverse agonist: an agent which
activates receptors to produce an effect
in the opposite direction to that of the
agonist.
– e.g. beta carbolines on bzp receptors-
anxiety, insomnia, seizures
opposite response
26

27. –Ligand: any molecule which attaches
selectively to particular receptors or
sites (only binding or affinity)
–Affinity: Ability of a substrate to bind with
receptor
–Intrinsic activity (IA): Capacity to induce
functional change in the receptor
– If explained
– Agonist: Affinity+ IA (E=1)
– Antagonist: Affinity (0)
– Partial agonist: Affinity + IA (0-1)
– Inverse agonist: Affinity + IA (0 to -1)

29. Drug Mechanisms
• Receptor interactions
• Non-receptor mechanisms

30. Receptor Interactions
Agonist Receptor
Agonist-Receptor
Interaction
Lock and key mechanism

31. Receptor Interactions
Receptor
Perfect Fit!
Induced Fit

32. Receptor Interactions
Antagonist Receptor
Antagonist-Receptor
Complex
DENIED!
Competitive
Inhibition

33. TYPES OF RECEPTORS
1.Ion- channel receptors(Ionotropic)
2.G- protein coupled
receptors(Metabotropic)
3.Enzyme – linked receptors
4.Nuclear receptors/transcription/cytosolic
5. Enzymes as Receptors
33

35. Ion channel receptor
 These cell surface receptors, also called ligand
gated ion channels, enclose ion selective
channels (for Na+, K+, Ca2+ or Cl¯ ) within their
molecules.
 Agonist binding opens the channel and causes
depolarization/hyperpolarization/ changes in
cytosolic ionic composition, depending on the ion
that flows through.
 Ex; - Nicotinic Cholinergic, GABAA, glycine
(inhibitory AA), excitatory AA-glutamate (kainate,
NMDA and AMPA) and 5HT3 receptors fall in this
category.

36. 3/8/2024 ThepowerpointTemplates.com 36

37. Ion channels

38. Ligand gated ion chanels
Fastest intracellular responce, ms
Binding of ligand - opening of chanel - ion (K+, Na+) in or out of cell - responce
Ligands
Fast neurotransmittors
ex. Acetylcholine (nicotinic reseptors)
Nobel prize chemistry 2003,
Roderick MacKinnon “for structural and mechanistic studies of ion channels”.
http://nobelprize.org/chemistry/laureates/2003/press.html
Membrane
(Phospholipides)
Ion chanel
Ligand binding sites

39. G protein coupled receptor

40. G-Protein coupled receptors

41. G-Protein coupled receptor
• Membrane bound receptors which are
bound to effector system through
G-proteins.
• These are hetero trimeric molecules
having 3 subunits α,β and ϒ.
• Based on α-sub unit they are further classified
into 3 main varieties Gs, Gi and Gq
41

42.  Gs : Adenylyl cyclase activation, Ca2+ channel
opening
 Gi : Adenylyl cyclase inhibition, K+ channel
opening
 Go : Ca2+ channel inhibition
 Gq : Phospholipase C activation

43. 3/8/2024 ThepowerpointTemplates.com 43

44. •
There are three major effector pathways through which GPCRs function
1. Adenyl cyclase: cAMP system: Activation of AC results in
intracellular accumulation of second messenger cAMP which
functions through cAMP dependant protein kinase (PKA). The PKA
phosphorylates and alters the functions of many enzymes, ion
channels, transporters and structural proteins.
2. Phospholipase-C: IP3-DAG pathway: Activation of
Phospholipase- C(PLc) hydrolises the membrane PIP2 to generate IP3
and DAG. IP3mobilizes Ca2+ and DAG enhances protein kinase C
(PKc) activation by Ca2+
3. Ion channel regulation: The activated G-proteins can also open or
close ionic channels specific for Ca2+ ,K+ or Na+, without the
intervention of any second messenger like cAMP or IP3 and bring
about depolarization/hyperpolarization/changes in intracellular Ca2+

45. 3/8/2024 ThepowerpointTemplates.com 45

46. 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

47. 3/8/2024 ThepowerpointTemplates.com 47

48. IP3-DAGpathway
• Main Results:
– Mediates /modulates contraction
– Secretion/transmitter release
– Neuronal excitability
– Intracellular movements
– Eicosanoid synthesis
– Cell Proliferation
– Responsesare opposite in caseof PLc
inhibition

49. Transmembrane enzyme-linked
receptors
 Utilized primarily by peptide hormones.
 Made up of a large extracellular ligand binding
domain connected through a single
transmembrane helical peptide chain to an
intracellular subunit having enzymatic property.
 Examples are—insulin, epidermal growth factor
(EGF), nerve growth factor (NGF) and many
other growth factor receptors.

50. ENZYME LINKED RECEPTORS
a. Intrinsic enzyme receptors
Intracellular domain is either protein
kinase or guanyl cyclase
Ex:Insulin,EGF,NGF
b.JAK-STAT-Kinase binding receptors
No intrinsic catalytic domain but agonist
induced dimerization affinity for cytosolic
tyrosine kinase protein
Ex:cytokines,growth hormone.
50

51. 3/8/2024 ThepowerpointTemplates.com 51

52. Transmembrane JAK-STAT
binding receptors
Many cytokines, growth hormone, prolactin,
interferons, etc. act through this type of receptor

53. Receptors regulating gene expression
(Transcription factors, Nuclear
receptors)
These are intracellular (cytoplasmic or nuclear) soluble
proteins which respond to lipid soluble chemical
messengers that penetrate the cell.
 The liganded receptor diamer moves to the nucleus and
binds other co-activator/co-repressor proteins which
have a modulatory influence on its capacity to alter gene
function.
 All steroidal hormones (glucocorticoids,
mineralocorticoids, androgens, estrogens, progeste-
rone), thyroxine, vit D and vit A function in this manner.

54. 3/8/2024 ThepowerpointTemplates.com 54

55. • Enzymes as receptors
• Ex- ACE,AchE,DHFR
• Angiotensin Converting Enzyme
• Acetylcholinesterase Enzyme
• DiHydroFolate Reductase Enzyme
3/8/2024 ThepowerpointTemplates.com 55

56. FUNCTIONS OF RECEPTORS
• To propogate signals from outside to
inside
• To amplify the signal
• To integrate various extracellular and
intracellular regulatory signals
• To adapt to long term changes in
maintaining homeostasis
56

57. RECEPTOR REGULATION
↓ Response ↑ Response
 Tolerance  Up regulation
 Tachyphylaxis  Supersensitivity
 Down regulation
 Desensitisation

58. Full responce
Spare receptors
Full agonist
Weak responce
Partial agonist
Full responce
Spare receptors - Partial agonist

59. Desensitization
 Receptor mediated response to drugs often
desensitise with time.
After reaching an initial high response, the
effect diminishes over seconds or minutes
even in the continued presence of the
agonist.
 Reversible

60. 3/8/2024 ThepowerpointTemplates.com 60

61. Tolerance
 Reduction in responsiveness as a
consequence of continued drug
administration

62. Tachyphylaxis
 Rapid reduction in responsiveness
as a consequence of drug
administration
 Eg; Nitroglycerin

63. Down regulation
 Decrease in no of receptors
• receptor internalization and
E n d o c t o s i s
 Eg; Beta2 agonist in asthma

64. •Prolonged occupation of receptors by a
antagonist may increase the number
of receptors
•Externalisation of receptors from inside
the cell surface
•When the antagonist is withdrawn
 the elevated number of receptors can
produce an exaggerated response..
Receptor Upregulation

65. SUPERSENSITIVITY
exaggerated response following
chronic reduction in receptor
stimulation

67. Diseases Resulting from
Receptor Malfunction

68. Autoimmune
 Nicotinic cholinergic receptors 
myasthenia gravis
 Insulin receptors  insulin-resistant
diabetes mellitus
 TSH receptor  Grave’s disease
(activation)
 TSH receptor  Atropic thyroiditis
(blocking)

69. Non-receptor Mechanisms
• Chemical action- neutralisation,
chelation
• Physical action-osmosis,
• adsorption,
• demulcents,
• Pro tectives

70. Non-receptor Mechanisms
• Placebo
• Counterfeit mechanism- sulfa drugs
• Protoplasmic poison- antiseptics
Formation of antibodies

71. THANKYOU
71