GENERAL PHK hhhgggffgggHAR. dynamics.ppt

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1. 1.3. Pharmacodynamics
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•Thestudyofthebiochemicalandphysiological
effectsofdrugsandthemolecularmechanisms
bywhichtheseeffectsareproduced
•Isthestudyofwhatdrugsdotothebodyandhow
theydoit

2. Mechanism of Drug Action
Physicalaction
Massofthedrug(inbulklaxatives),adsorptive
property(activatedcharcoal),osmoticactivity
(mannitol)
Chemicalaction
Antacids,chelatingagents(BAL,EDTA)
Throughproteintargets
(Ion channels, carrier molecules, enzymes,
receptors)
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3. Protein Targets for drug action
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Anycellularmacromoleculetowhichadrug
selectivelybindstoelicititspharmacological
effect
Receptors:E.g.adrenergicreceptorstargetedby
adrenaline
Ionchannels:E.g.voltagegatedNa
+
channels
targetedbylocalanesthetics
Enzymes:E.g.angiotensin-convertingenzyme
targetedbycaptopril
Carriermolecules(transporters):E.g.Proton

4. READING ASSIGNMENT: Drug
receptor interaction
Occupation, Activation, Specificity, spare
receptors, maximal response,…
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5. Drug-receptors interaction and signal
transduction
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6. 6
Interactionwithreceptors
Receptor-Ligandsinteractioncanbe:
Agonists(fullandpartial):ligandthatcanbindtoa
particularreceptortoinitiateacellularresponse
Antagonist:ligandthatcanbindtoaparticular
receptor,butitcanNOTinitiateacellular
response
Affinity:abilityofaligandtobindareceptors
Intrinsicactivity:itistheabilityofdrugtobringa
response

7. Potency and Efficacy
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Potencyisrelatedtothesizeofthedose
necessarytoproducecertaineffect
ItisafunctionofEC
50(comparingEC
50ofdrugs);
thelessconc.required,themorepotentthe
drug
Efficacyistheabilityofadrugtoproduce
maximumeffect
Therelativeefficacyoftwodrugsthatelicitthe
sameeffectcanbemeasuredbycomparingtheir
maximumeffects

8. 8
Intrinsicactivity(IA):
Determinestheefficacyofadrug
IA=1Fullagonist(producemaximaleffects-
highefficacy)
0<IA<1Partialagonist(produceonlysub-
maximaleffects)
IA=0Antagonist(Noefficacy)

9. 9
•Drug B is the most potent (smaller
EC
50)
•Drug A, C and D have equal
maximal efficacy
•Drug B sub-maximal efficacy
•Drug A is more potent than Drug C
& D
•Which drug is the least potent?

10. Dose Response Curve for reversible
competitive antagonism
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Shift agonist log dose.
response curve
to the right, ↑EC
50 without
change in
slope ( compet.
antagonist reduce
potency)
No change in maximal effect

11. Irreversible Competitive
antagonism
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Theantagonistdissociatesveryslowly,ornot
atall,fromthereceptors,asaresultnochange
intheantagonistoccupancytakesplacewhen
theagonistisapplied-duetocovalentbond
Resultsindownwardshiftindoseresponse.
furtherdepressionofthemaximalresponseof
theagonist

12. Non-Competitive Antagonism
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Agonistintheabsence(a)andthepresence
(b,c,d)ofincreasingdosesofanon-
competitiveantagonist
The antagonist bind other than the active site of the
receptor
Prevent agonist receptor binding and activation
Decrease maximal response
Block can not overcome by
increasing agonist
EC
50is unchanged

13. Therapeutic range/window
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Therangeofplasmaconcentrationsthatare
associatedwithoptimumresponseandminimal
toxicityinmostpatients
Thegoaloftherapyistomaintaindrug
concentrationswithinthetherapeuticrangeatall
times

14. 14
Therapeutic Index
An estimate of a drugs margin of safety.
Mathematically: LD=low dose &ED =desired effects

15. Drug-Druginteraction
Definedasthemodificationsoftheeffectsofone
drugbypriororconcomitantlyadministered
anotherdrug(poly-pharmacy)
Drug-Druginteractioncanresultin
•Increased effect
Increased therapeutic effectgood
Increased toxic or adverse effectbad
•Decreased effect
Decreased therapeutic effectbad
Decreased toxic effectgood
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16. Druginteraction
Definedasthemodificationsoftheeffectsof
onedrugbypriororconcomitantly
administeredanotherdrug(poly-pharmacy)
Atpharmacokineticlevel
•Occuratdispositionlevel(ADME)
Atpharmacodynamiclevel
•Onedruginterfereswiththeinteractionofanotherdrugat
itstargetsite(atthelevelofreceptors),or
•Drugchangesinsomewaytheanticipated
pharmacologicresponseofanotherdrug
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17. Drug-Drug interaction may alter drug effect
by
Additive effect: 1+1=2
•E.g. ephedrine + aminophylline
Synergistic effect1+1>2
•Eg. trimethoprim+ sulfamethoxazole
Potentiation effect1+0>1
•Eg. Amoxacillin+ clavulanicacid
Antagonism1+1=0 or <1
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18. DrugAntagonism:
Effectofonedrugisdiminishedorcompletely
abolishedinthepresenceofanother
Physiological/functional
Actingondifferentreceptorstoproduce
oppositeeffects
E.g.histamineandadrenaline
Pharmacologicalantagonism
Antagonismtakesplaceatthereceptorlevel
Eg.Flumazenilantagonizeeffectofdiazepam
Chemical:Dimercaprol(BAL)chelateswithHg
Physical:Charcoaldecreaseseffectofstrychnine
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19. Adverse Drug Reactions (ADR)
ADR:anyresponsetoadrugthatisnoxiousand
unintendedandthatoccursatnormal/overdoses
usedforprophylaxis,diagnosisortherapy
Predictableadverseeffects
Sideeffects:Observedattherapeuticdose
Toxiceffects:Effectsobservedatlarger
concentrations
oAcutetoxicity:acuteadministrationoflargerdoses
atonce
oChronictoxicity:usuallywithprolongedand
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20. AdverseDrugReactions…
Unpredictableadverseeffects
Hypersensitivityreactions:abnormalresponse
duetoantigenicnatureofsomedrugs
Idiosyncraticreactions: unusual or
exaggeratedreactiontoadrug(mostlygenetically
mediated)
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21. Clinical Management of toxicities
Involves a stepwise approach
1.Stabilization of the patient
•Maintenance of patient Airway, Breathing, and
Circulation (ABCs)
2. Clinical evaluation (history, physical examination &
laboratory tests)
3. Prevention of further absorption, exposure
•Washingeyesandskin
•Prevention/reductionofabsorption(GI
decontamination)
4. Enhancement of eliminationof the suspected toxin
5. Administration of an antidote
•Substances that counteract the effect of a drug or toxin
6. Supportive careand follow-up21