Pharmacodynamics

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.

2. Pharmacodynamics

3. What is Pharmacodynamics?
What the drug does to the body when it
enters?
Defination.:
Itisthestudyofbiochemicalandphysiological
effectsofdrugandtheirmechanism of
actionatorganlevelaswellascellular
level.

12. MECHANISM
OF DRUG
ACTION

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

14. 1. Enzymes

15. Enzymes
Enzymesare biological molecules (proteins) that act
as catalysts and help complex reactions occur
everywhere in life

18. Nonspecific inhibition: Denaturationof
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
Adrugmayinhibita
particularenzymewithout
affecting others and
influencethatparticular
substrate-enzymereaction
ultimatelytoinfluencein
theproductformation
Normal
Drug + Enzyme

20. i) Competitive Inhibition
Thedrugbeingstructurallysimilarcompeteswiththe
normalsubstrateforthecatalyticbindingsiteofthe
enzymesothattheproductisnotformedora
nonfunctionalproductisformedandanewequilibrium
isachievedinthepresenceofthedrug.

21. (ii)Noncompetitive Theinhibitorreacts
withanadjacentsiteandnotwiththe
catalyticsite,butalterstheenzymeinsucha
waythatitlosesitscatalyticproperty.

23. 2. Ion Channnel

24. Ion channels arepore-forming membrane
proteinswhose functionsincludeestablishing
arestingmembrane potential,shapingaction
potentialsandotherelectricalsignalsbygatingthe
flowofionsacrossthecellmembrane.

26. Ionchannelsarepresentinthemembranes ofall
cells.
Ionchannelsareconsideredtobeoneofthetwo
traditionalclassesofionophoricproteins,withthe
otherclassknownasiontransporters(including
thesodium-potassium pump,sodium-calcium
exchanger,andsodium-glucosetransportproteins,
amongstothers)

27. 3. Transporters
Thisproteinalsofunctionsasatransporterinthe
blood–brainbarrier.P-gptransportsvarious
substratesacrossthecellmembraneincluding.
Substratesaretranslocatedacrossmembrane by
bindingtospecifictransporters(carriers)–Solute
CarrierProteins(SLC)
Pump themetabolites/ionsIthedirectionof
concentrationgradientoragainstit

28. Drugsinteractwiththesetransport
system
Examples:Probenecid(penicillinand
uricacid),Furosmide(Na+K+2Cl-
cotransport),Hemicholinium(choline
uptake)andVesamicol (active
transportofAchtovesicles)

30. 4. Receptors
Drugs usually do not bind directly with enzymes,
channels, transporters or structural proteins, but
act through specific macromolecules –RECEPTORS
Definition:Itisdefinedasamacromoleculeor
bindingsitelocatedoncellsurfaceorinsidethe
effectorcellthatservestorecognizethesignal
molecule/drugandinitiatetheresponsetoit,but
itselfhasnootherfunction,e.g.G-proteincoupled
receptor

31. Agonist:Anagentwhichactivatesareceptorto
produceaneffectsimilartoathatofthe
physiologicalsignalmolecule,e.g.Muscarineand
Nicotine)
Antagonist:anagentwhichpreventstheaction
ofanagonistonareceptororthesubsequent
response,butdoesnothaveaneffectofitsown,
e.g.atropineandmuscarine
Some Definitions

32. Inverseagonist:anagentwhichactivatesreceptorsto
produceaneffectintheoppositedirectiontothatofthe
agonist,
Partialagonist:Anagentwhichactivatesareceptorto
producesubmaximaleffectbutantagonizestheactionofafull
agonist,e.g.pentazocine.
Ligand:anymoleculewhichattachesselectivelytoparticular
receptorsorsites(onlybindingoraffinity)

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(orIntrinsicActivity)–ability
ofabounddrugtochangethe
receptorinawaythatproducesan
effect;somedrugspossessaffinity
butNOTefficacy
DR Complex Effect (E)

37. Receptors –contd.
Two essential functions:
–Recognitionof specific ligandmolecule
–Transductionof signal into response
Two Domains:
–Ligandbinding domain
–Effectors Domain –undergoes functional
conformational change

38. Receptors –contd.
Cellsurfacereceptorsremainfloatedincell
membranelipids
Functionsaredeterminedbytheinteraction
oflipophillicorhydrophillicdomainsofthe
peptidechainwiththedrugmolecule
Non-polarhydrophobicportionoftheamino
acidremainburiedinmembranewhilepolar
hydrophilicremainoncellsurface

39. Hydrophilicdrugscannotcrossthe
membraneandhastobindwiththepolar
hydrophilicportionofthepeptidechain
Bindingofpolardrugsinligandbinding
domaininducesconformationalchanges
(alterdistributionofcharges and
transmittedtocouplingdomaintobe
transmittedtoeffectordomain

40. Receptors –contd.
DrugsactonPhysiologicalreceptors
and mediate responses of
transmitters,hormones, autacoids
andothers–cholinergic,adrenergic
orhistaminergicetc.
Drugsmayactontruedrugreceptors
-Benzodiazepinereceptors

41. The Transducer mechanism
Mosttransmembranesignalingisaccomplishedbya
smallnumberofdifferentmolecularmechanisms
(transducermechanisms)
Largenumberofreceptorssharethesehandfulof
transducermechanismstogenerateanintegrated
response
Mainly4(four)majorcategories:
1.GPCR
2.Receptorswithintrinsicionchannel
3.Enzymelinkedreceptors
4.Transcriptionfactors(receptorsforgeneexpression)

44. A) G-protein Coupled
Receptors
Largefamilyofcellmembrane receptors
linked to the effector
(enzyme/channel/carrierproteins)through
oneormoreGTPactivatedproteins(G-
proteins)
Allreceptorshascommon patternof
structuralorganization
Themoleculehas7α-helicalmembrane
spanninghydrophobicaminoacidsegments
–3extraand3intracellularloops

46. GPCR

47. GProtein–theseareproteinsthatbindtothe
guanine nucleotide(GTP –guanosine
triphosphate,GDP–guanosinediphosphate)
HydrolysisofGTPreleasesaphosphategroup
whichcanactonothermolecules–transmits
thesignal
GTP>GDP+P

49. Gproteinshavethreesubunits–α(alpha),
β(beta),andγ(gamma).
βandγsubunitsaretightlyboundtogether.
αbindstoGTP

50. Ligandbindingtothetransmembraneproteincausesa
conformationalchangeandreleaseoftheαsubunit
TheαsubunitexchangesGDP>GTPandbecomes
active
Theαsubunitmeetsatargetandphosphorylatesit
(addsaphosphategroupfromGTPconvertingitto
GDP–thisishydrolysisofGTP)
Hydrolysis=cleavage
Phosphorylation=additionofaphosphategroup

51. Ligands
•Monoamines e.g. dopamine, histamine,
noradrenaline, acetylcholine (muscarinic)
•Nucleotides
•Lipids
•Hormones
•Glutamate
•Ca
++
G-protein-coupledreceptors(7-TMreceptors)

52. NowtheαsubunitisboundtoGDP,it
becomes inactiveagainand re-
associateswiththetransmembrane
proteinandtheβandγsubunits

54. Second Messengers
Secondmessengers –thesearemolecules
thatrelaysignalsfromreceptorsonthecell
surfacetotargetmoleculesinsidethecell
ExamplesincludeIP
3,Ca
2+
,cAMP
Allowsforamplificationofthesignal

55. 3.6 Signal transduction pathway
a) Interaction of receptor with G
s-protein
G
S-Protein -membrane bound protein of 3 subunits (a, b, g)
-a
Ssubunit has binding site for GDP
-GDP bound non covalently
bg
a
GDP
3.G-protein-coupledreceptors(7-TMreceptors)

56. G-proteins and Effectors
Large number can be distinguished
by their α-subunits

57. GPCR -3 Major Pathways
1.Adenylylcyclase:cAMPpathway
2.PhospholipaseC: IP3-DAG
pathway
3.Channel regulation

58. Adenylylcyclase:cAMP
pathway

59. 2. PhospholipaseC:IP3-DAG pathway

60. Physiological function likes,
mediates/modulates contraction,
secretion/transmission
release,eicosenoides synthesis,
neuronalexcitability,intracellular
movements, membrane function,
metabolism,cellproliferationetc.

61. 3. Channel regulation
ActivatedG-proteinscanopenorcloseionchannels–Ca++,
Na+orK+etc.

62. Theseeffectsmaybewithoutinterventionofanyof
abovementioned2
nd
messengers –cAMPor
IP3/DAG.
Bringaboutdepolarization,hyperpolrizationorCa
++changesetc.

63. Gs–Ca++channelsinmyocardiumandskeletal
muscles
GoandGi–openK+channelinheartandmuscle
andcloseCa+inneurons.

64. Physiologicalresponseslikechangesin
inotropy,chronotropy,transmitter
release,neuronalactivityandsmooth
musclerelaxationfollow.

65. Receptorsfoundtoregulateionicchannels
throughG-proteins

67. B) Intrinsic Ion Channel
Receptors

68. Intrinsic Ion Channel
Receptors
Mostusefuldrugsinclinicalmedicineactby
mimickingorblockingtheactionsof
endogenousligandsthatregulatetheflowof
ionsthroughplasmamembranechannels
Thenaturalligandsincludeacetylcholine,
serotonin,aminobutyricacid(GABA),andthe
excitatoryamino acids(eg,glycine,
aspartate,andglutamate)

69. Thesecellsurfacereceptors,alsocalledligand
gatedionchannels,encloseionselectivechannels
(forNa*,K*,Ca2*orCl-)withintheirmolecules.

70. Agonistbindingopensthechanneland
causes depolarization/hyperpolarization
/changesincytosolicioniccomposition,
dependingontheionthatflowsthrough.

71. Thenicotiniccholinergic,GABA-A,glycine
(inhibitory),excitatoryAA(kainate,NMDAorN-
methylD-aspartate,quisqualate)and5HT3
receptorsfallinthiscategory

72. 3. Enzyme-linked
receptors

73. Theagonistbindingsiteandthecatalytic
sitelierespectivelyontheouterandinner
faceoftheplasmamembrane
Thesetwodomainsareinterconnected
throughasingletransmembranestretchof
peptidechain.
Therearetwomajorsubgroupsofsuch
receptors.

74. Enzyme Linked Receptors
2 (two) types of receptors:
1.Intrinsic enzyme linked receptors
Protein kinase or
guanylcyclasedomain
2.JAK-STAT-kinasebinding receptor

75. a. Intrinsic enzyme receptors
The intracellular
Domainiseitheraproteinkinaseorguanyl
cyclase.
Inmostcasestheproteinkinasespecifically
phosphorylates tyrosineresidues on
substrateproteins,
e.g.insulin,epidermalgrowthfactor(EGF),
nervegrowthfactor(NGF)receptors,butin
fewitisaserineorthreonineproteinkinase.

77. Inthemonomericstate,thekinase
remainsinactive.
Agonistbindinginducesdimerizationof
receptormoleculesandactivatesthe
kinasetoautophosphorylatetyrosine
residuesoneachother,increasing
theiraffinityforbindingsubstrate
proteinsandcarryingforwardthe
cascadeoftyrosinephosphorylations.

80. Activatedreceptorscatalyzephosphorylationof
tyrosineresiduesondifferenttargetsignaling
proteins,therebyallowingasingletypeofactivated
receptortomodulateanumberofbiochemical
processes
Examples:
–Insulin-uptakeofglucoseandaminoacidsandregulate
metabolismofglycogenandtriglycerides
–Trastuzumab,antagonistofasuchtypereceptor–usedin
breastcancer

81. JAK-STAT-kinase binding receptor
Mechanismcloselyresemblesthatofreceptor
tyrosinekinases
Onlydifference-proteintyrosinekinaseactivity
isnotintrinsictothereceptormolecule
UsesJanus-kinase(JAK)family
AlsousesSTAT(signaltransducersandactivators
oftranscription)
Examples –cytokines,growthhormones,
interferonesetc.

82. JAK-STAT-kinaseReceptors

83. 4. Receptors regulating gene expression
(Transcription factors)
Incontrasttotheabove3classesofreceptors,
theseareintracellular(cytoplasmicornuclear)
solubleproteinswhichrespondtolipidsoluble
chemicalmessengersthatpenetratethecell
Thereceptorprotein(specificforeachhormone/
regulator)isinherentlycapableofbindingtospecific
genes/butiskeptinhibitedtillthehormonebinds
nearitscarboxyterminusandexposestheDNA
bindingregulatorysegmentlocatedinthemiddleof
themolecule.

85. Allsteroidalhormones (glucocorticoids,
mineralocorticoids, androgens, estrogens,
progesterone),thyroxine,vitDandvitAfunction
inthismanner.
Differentsteroidalhormones affectdifferent
targetcellsandproducedifferenteffectsbecause
eachonebindstoitsownreceptoranddirectsa
uniquepattenofsymthesisofspecificproteins.

86. Thistransductionmechanismistheslowest
initstimecourseofaction(takeshours).

87. Functions of receptors
(a)Topropagateregulatorysignalsfromoutsideto
withintheeffectorcell.
(b)Toamplifythesignal.
(c)Tointegratevariousextracellularandintracellular
regulatorysignals.
(d)Toadapttoshorttermandlongtermchangesin
maintainhomeostasis.

88. Summary of Transducers

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
Whenadrugisadministeredsystemically,the
dose-responserelationshiphastwocomponents:

90. Dose-Response Curve
dose
% response
100%
50%

91. Dose-Response Curve
Advantages:
–Awiderangeofdrugdosescaneasilybe
displayedonagraph
–Potencyandefficacycanbecompared
–Comparisonofstudyofagonistsand
antagonistsbecomeeasier

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
Whentwoormoredrugsaregivensimultaneouslyor
inquicksuccessionmaybeeitherindifferenttoeach
otherorexhibitsynergismorantagonism.
Theinteractionmaytakeplaceatpharmacokinetic
leveloratpharmacodynamic level.

96. –Additiveeffect(1+1=2)
Aspirin+paracetamol,
amlodipine+atenolol
–Supraadditiveeffect(1+1=4)
Sulfamethoxazole+trimethoprim,
levodopa+carbidopa,
acetylcholine+physostigmine
Drug Synergism (Greek: Syn-together; ergon-work)
whentheactionofonedrugisfacilitatedorincreasedbytheother,
theyaresaidtobesynergistic.
Inasynergisticpair,boththedrugscanhaveactioninthesame
directionorgivenaloneonemaybeinactivebutstillenhancethe
actionoftheotherwhengiventogether.
Synergism can be:

100. DrugAntagonism:
1.Physical:Charcoal
2.Chemical:KMNO4,Chelatingagents
3.Physiologicalantagonism:Histamineand
adrenalineinbronchialasthma,Glucagons
andInsulin
4.Receptorantagonism

101. …. Contd.
Receptor antagonism:
1.Competitive antagonism (equilibrium)
2.Competitive (non equilibrium)
3.Non-competitive antagonism

102. Drug antagonism DRC

103. Drug antagonism DRC –non-
competitive antagonism
Response
Shift to the right
and lowered response
Drug in log conc.
Agonist
Agonist
+ CA (NE)