pharmacodynamics pacific

8/8/2019 Pharmacodynamics PACIFIC

1/119

Principles ofPrinciples of

Pharmacology:Pharmacology:

PharmacodynamicsPharmacodynamics

Dennis Rosete, M.D.Dennis Rosete, M.D.

Philippine Society ofPhilippine Society of

Experimental and ClinicalExperimental and Clinical

PharmacologyPharmacology


2/119

Learning Objectives:Learning Objectives:

Understand the theoretical basis of drug-Understand the theoretical basis of drug-receptor interactions.receptor interactions.

Understand the determinants and types ofUnderstand the determinants and types of

responses to drug-receptor interactionsresponses to drug-receptor interactionsincluding the graded dose-response curve.including the graded dose-response curve.

Define potency and efficacy.Define potency and efficacy. Understand how to compare drug potencyUnderstand how to compare drug potency

and efficacy.and efficacy. Understand measures of drug safety.Understand measures of drug safety. Understand the consequences of receptorUnderstand the consequences of receptor

regulationregulation


3/119

DRUGDRUG MANMAN

TwoTwoINTERACTIONINTERACTION WayWay

RelationshipRelationship

PHARMACODYNAMICS:PHARMACODYNAMICS:ActionActionEffectEffect

PHARMACOKINETICSPHARMACOKINETICS

AbsorptionAbsorptionDistributionDistributionMetabolismMetabolismEliminationEliminationExcretionExcretion


4/119

A. PharmacodynamicsA. Pharmacodynamics

Study of the biochemical andStudy of the biochemical andphysiological effects of drugs andphysiological effects of drugs and

their mechanism of action.their mechanism of action.

Refers to the actions of a drug onRefers to the actions of a drug on

the body.the body.

What a drug does to the bodyWhat a drug does to the body


5/119


drug-receptor interactionsdrug-receptor interactions

dose-response phenomenadose-response phenomena

mechanisms of therapeutic andmechanisms of therapeutic and

toxic actiontoxic action


6/119

A drug receptor is a . . .A drug receptor is a . . .

. . . macromolecular. . . macromolecularcomponent of the cellcomponent of the cellwith stereospecificitywith stereospecificity

and with which a drugand with which a druginteracts in a lock-and-interacts in a lock-and-key fashion initiating akey fashion initiating achain of events that leadchain of events that lead

to a pharmacologicalto a pharmacologicalresponse.response.
http://opt/scribd/conversion/tmp/scratch500/C:/Documents%20and%20Settings/dennis.rosete/My%20Documents/Teveten/Eprosartan.exe


7/119


8/119

Cell Membrane has protruding receptors waiting for a drug

The Cell Membrane


9/119

Ligand-gated IonLigand-gated Ion

ChannelsChannels


10/119

G-protein coupledG-protein coupled

receptorsreceptors


11/119


receptorsreceptors

Membran

e


12/119


receptorsreceptors


13/119

Receptor-enzymeReceptor-enzyme

Catalyticsite

Binding site


14/119

Cytosolic-NuclearCytosolic-Nuclear

receptorsreceptors


15/119

Terminologies

Receptor affinity - tendency of adrug to combine with a receptor

Receptor specificity - tendency ofa drug to combine with a specific

type of receptor and none other.


16/119

ReceptorsReceptors

Receptors are responsible forReceptors are responsible for

selectivity of drug actionselectivity of drug action

Beta receptors (B1 vs B2)Beta receptors (B1 vs B2) Histamine receptors (H1 vs others)Histamine receptors (H1 vs others)

Angiotensin receptors (AT1, AT2)Angiotensin receptors (AT1, AT2)

Cycloxygenase enzyme receptorsCycloxygenase enzyme receptors(COX1, COX2)(COX1, COX2)


17/119

Active vs InactiveActive vs Inactive

statesstates Active states initiate cellActive states initiate cell

signaling.signaling.

For any cell, there is anFor any cell, there is anequilibrium between active anequilibrium between active an

inactive states. The inactiveinactive states. The inactive

state usually predominates.state usually predominates. Each state has its own affinity.Each state has its own affinity.


18/119


Onset of action-time it takes to reachOnset of action-time it takes to reach

minimum effective concentration (MEC)minimum effective concentration (MEC)

Peak action occurs when drug reaches itsPeak action occurs when drug reaches its

highest blood/plasma concentrationhighest blood/plasma concentration

Duration of action-length of time drug has aDuration of action-length of time drug has a

pharmacologic effectpharmacologic effect


19/119


20/119

AGONIST /

ANTAGONIST

AGONIST a drug thatbinds to receptors and

produce an effect.

ANTAGONIST a drugthat binds to receptors

and prevent an agonistfrom producing aneffect.


21/119

ReceptorsReceptors

Receptors mediate the actions ofReceptors mediate the actions ofpharmacologic antagonistspharmacologic antagonists

Mimics the chemical configurationMimics the chemical configurationof the natural chemical in the bodyof the natural chemical in the body

May displace the usual partnersMay displace the usual partnerswhen in excessive quantities or withwhen in excessive quantities or withincreased affinityincreased affinity
http://opt/scribd/conversion/tmp/scratch500/C:/Documents%20and%20Settings/dennis.rosete/My%20Documents/Teveten/Eprosartan.exe


22/119


Refers to the actions of aRefers to the actions of a

drug on the bodydrug on the body

drug-receptor interactionsdrug-receptor interactions dose-response phenomenadose-response phenomena

mechanisms of therapeuticmechanisms of therapeuticand toxic actionand toxic action


23/119

Definitions and ConceptsDefinitions and Concepts

SelectivitySelectivity: differential: differential

responsiveness among the drugsresponsiveness among the drugs

multiple effectsmultiple effects

DoseDose: amount administered: amount administered

Posology: concerned with thedosage or amount of a druggiven in the treatment of

disease. EfficacyEfficacy: the property of a drug to: the property of a drug to

achieve the desired responseachieve the desired response


24/119

EfficacyEfficacy


25/119

Graded dose-responseGraded dose-response

curvescurves Individual responses to varying dosesIndividual responses to varying doses

Concepts to remember:Concepts to remember:

Threshold:Threshold: Dose that produces a just-Dose that produces a just-noticeable effect.noticeable effect.

EDED5050 :: Dose that produces a 50% ofDose that produces a 50% of

maximum response.maximum response.

Ceiling:Ceiling: Lowest dose that produces aLowest dose that produces a

maximal effect.maximal effect.


26/119

Dose-response curveDose-response curve

Dose

R

espon

s

e 0

20

40

60

80

100

0 200 400 600 800 1000


27/119


Dose

R

espon

s

e

0

20

40

60

80

100

0.1 1 10 100 1000 10000

10 0


28/119

= Agonist

0

20

40

60

80

10 0

0 . 1 1 1 0 10 0 1 0 0 0 1

10 0


29/119

= Agonist

0

20

40

60

80

10 0

0.1 1 10 100 10 00 1

100


30/119

= Agonist

0

20

40

60

80

100

0.1 1 10 100 1000 10

100


31/119

= Agonist

0

20

40

60

80

0.1 1 10 100 1000 10

100


32/119

= Agonist

0

20

40

60

80

0.1 1 10 100 1000 10

100


33/119

= Agonist

0

20

40

60

80

0.1 1 10 100 1000 10

100


34/119

= Agonist

0

20

40

60

80

0.1 1 10 100 1000 10


35/119


Dose

R

espon

s

e 0

20

40

60

80

100

0.1 1 10 100 1000 10000

Ceiling

ED50

Threshold

ED50


36/119

Determinants ofDeterminants of

ResponseResponse Intrinsic EfficacyIntrinsic Efficacy

((): Power of a drug): Power of a drug

to induce a response.to induce a response. Number of receptorsNumber of receptors

in the target tissue.in the target tissue.


37/119

Full vs Partial agonistsFull vs Partial agonists

These terms are tissue dependentThese terms are tissue dependent

Receptor densityReceptor density

Cell signaling apparatusCell signaling apparatus Other receptors that are presentOther receptors that are present

Drug historyDrug history


38/119

Full vs Partial agonistsFull vs Partial agonists

0

20

40

60

80

100

0.1 1 10 100 1000 10000

Full Agonist

Partial Agonist

Dos

%

Effe

ct


39/119

Two types ofTwo types of

antagonismantagonismcompetitive (reversible) antagonistcompetitive (reversible) antagonist drug molecule that will compete with andrug molecule that will compete with an

agonist for binding to the receptoragonist for binding to the receptor

response is abolished or diminished as longresponse is abolished or diminished as long

as the antagonist can successfully competeas the antagonist can successfully compete

with the agonist for the receptor sitewith the agonist for the receptor site

competition can be overcome by floodingcompetition can be overcome by flooding

the receptor site with a very largethe receptor site with a very large

concentration of agonist and full responseconcentration of agonist and full response

can be restoredcan be restored


40/119

Two types ofTwo types of

antagonismantagonismnoncompetitive (irreversible)noncompetitive (irreversible) a drug molecule which binds to thea drug molecule which binds to the

receptor and does not dissociatereceptor and does not dissociate

and cannot be displaced byand cannot be displaced byincreasing agonist concentrationincreasing agonist concentration

Effectively, some of the receptorsEffectively, some of the receptors

become inactivated and the fullbecome inactivated and the fullresponse cannot occur, althoughresponse cannot occur, although

some pharmacologic activity of thesome pharmacologic activity of the

agonist is usually still present.agonist is usually still present.

120


41/119

= Agonist =

0

2 0

4 0

6 0

8 0

100

- 10 .5 - 10 - 9 .5 - 9 - 8 .5 - 8 - 7 .5 - 7 - 6 .5

12 0


42/119

= Agonist =

0

20

40

60

80

10 0

-11 -10 -9 -8 -7

12 0


43/119

= Agonist =

0

20

40

60

80

10 0

-11 -10 -9 -8 -7

120


44/119

= Agonist =

0

20

40

60

80

100

-11 -10 -9 -8 -7

12 0


45/119

= Agonist =

0

20

40

60

80

10 0

-1 1 -1 0 -9 -8 -7

120


46/119

= Agonist =

0

20

40

60

80

100

-11 -10 -9 -8 -7

100

120


47/119

= Agonist =

0

20

40

60

80

100

-11 -10 -9 -8 -7


48/119

CompetitiveCompetitive

0

200

400

600

800

1000

1200

-11 -10 -9 -8 -7

IC50

log [antagonist]

Eff

e

ct


49/119

= Agonist =


50/119

= Agonist =


51/119

= Agonist =


52/119

= Agonist =


53/119

= Agonist =


54/119

= Agonist =


55/119

= Agonist =


56/119

CompetitiveCompetitive

antagonistsantagonists

0

20

40

60

80

100

0.1 1 10 100 1000 10000

A CB

Dos

Respon s

e


57/119

NoncompetitiveNoncompetitive


Dos

Respon s

e

0

20

40

60

80

100

0.1 1 10 100 1000 10000

A

C

B

Chemical andChemical and


58/119

Chemical andChemical and

PhysiologicPhysiologic


Physiologic:Physiologic: Two drugs haveTwo drugs have

opposite effects through differingopposite effects through differingmechanismsmechanisms

Response can be irregularResponse can be irregular

Chemical:Chemical: No receptors areNo receptors areinvolvedinvolved


59/119

Allosteric AntagonismAllosteric Antagonism


60/119



61/119



62/119


ll i iAll t i t i t


63/119

Allosteric antagonistsAllosteric antagonists

11

0

20

40

60

80

100

0.1 1 10 100 1000 10000

A

Dos

Respon s

e


64/119


65/119

Receptor regulationReceptor regulation

Reduced responsivity: ChronicReduced responsivity: Chronicuse of an agonist can result in theuse of an agonist can result in thereceptor-effector systemreceptor-effector systembecoming less responsivebecoming less responsive

Increased responsivity: ChronicIncreased responsivity: Chronicdisuse of a receptor-effectordisuse of a receptor-effector

system can result in an increasedsystem can result in an increasedresponsiveness upon re-exposureresponsiveness upon re-exposureto an agonist.to an agonist.


66/119

THREE MOST IMPORTANTTHREE MOST IMPORTANTPROPERTIES OF A DRUG:PROPERTIES OF A DRUG:

EFFICACYEFFICACY

SAFETYSAFETY

QUALITYQUALITY

P ti fP ti f


67/119

Properties of aProperties of a

biological systembiological system

Potency:Potency: Dose of drugDose of drug

necessary to produce a specifiednecessary to produce a specified

effect.effect. Dependent upon receptor density,Dependent upon receptor density,

efficiency of the stimulus-responseefficiency of the stimulus-response

mechanism, affinity and efficacy.mechanism, affinity and efficacy.

Magnitude of effect:Magnitude of effect: EfficacyEfficacy


68/119


69/119

Relative PotencyRelative Potency

Dos

Effe c

t

0

20

40

60

80

100

0.1 1 10 100 1000 10000

A B


70/119

Relative EfficacyRelative Efficacy

0

20

40

60

80

100

0.1 1 10 100 1000 10000

Relative

Efficacy


71/119

PotencyPotency- biological activity of a drug per unit of weigh- biological activity of a drug per unit of weight

Example 1:Example 1:

drug Adrug A drug Bdrug B drug Cdrug C

1 ng1 ng 100 mg100 mg 1 g1 g

These 3 drugs differ in potency butThese 3 drugs differ in potency but

have identical or similar effects.have identical or similar effects.

Definitions andDefinitions and


72/119

Definitions andDefinitions and

ConceptsConcepts Dose intensity relationshipDose intensity relationship::

manner in which the intensity ofmanner in which the intensity ofthe effect in the individualthe effect in the individual

recipient relates to doserecipient relates to dose

Dose frequency relationshipDose frequency relationship::manner in which the number ofmanner in which the number of

responders among a populationresponders among a population

of recipients relates to dose.of recipients relates to dose.


73/119

FIGURE A.

DOSE-FREQUENCY CURVE


74/119


75/119

THREE MOST IMPORTANTTHREE MOST IMPORTANTPROPERTIES OF A DRUG:PROPERTIES OF A DRUG:

EFFICACYEFFICACY

SAFETYSAFETY

QUALITYQUALITY


76/119

Therapeutic IndexTherapeutic Index

TI = LD50 / ED50TI = LD50 / ED50

LD Lethal DoseLD Lethal Dose

(lethal in 50% of animals)(lethal in 50% of animals) ED Effective DoseED Effective Dose

(therapeutic effect in 50%)(therapeutic effect in 50%)

Closer Ratio is to 1 = GreaterCloser Ratio is to 1 = GreaterDanger ToxicityDanger Toxicity


77/119


78/119

Safety index: LDSafety index: LD11/ED/ED9999

-20

0

20

40

60

80

100

0.00

01

0.00

10.

01 0. 1 110 10

01K 10

K10

0K

Sleep Death

LDLD11

EDED9999

Therapeutic index:Therapeutic index:


79/119

Therapeutic index:Therapeutic index:

LDLD5050 /ED/ED5050

-20

0

20

40

60

80

100

0.00

01

0.00

10.

01 0. 1 110 10

01K 10

K10

0K

Sleep Death

d ff


80/119

PHARMACOLOGYisdefined as:

from the Greek word

pharmakon poison

Adverse effects

T i l i


81/119

Terminologies

Toxicology: deals with the toxic orpoisonous effects produced by drugs

Side Effects - other effects of drugs(may be positive or negative)


82/119

According to the WHO definition,According to the WHO definition,


83/119

According to the WHO definition,cco d g o e O de o ,anan adverse reactionadverse reaction is anyis anyuntoward medical occurrence in auntoward medical occurrence in a

patient:patient:

1. that is harmful or noxious to1. that is harmful or noxious tothethe bodybody

2.2. unintendedunintended

3.3. may arise even from themay arise even from theadministration of the usualadministration of the usualrecommended dose range of therecommended dose range of the

drug.drug.


84/119

Excluding


85/119

Serious adverse eventSerious adverse event

DeathDeath

DisabilityDisability Prolonged hospitalizationProlonged hospitalization

Congenital defectCongenital defect Life threatening conditionLife threatening condition


86/119

Type A (augmented/predictable) reactions

Expected extensions of an individual drugs known

pharmacologic properties and are responsible for the

bulk of ADEs encountered.

Even though their incidence and morbidity is high,

they are rarely life-threatening, although they can

produce significant disability.

Drug Allergy


87/119

Causes of Type A reactions


88/119

Causes of Type A reactions

1. Pharmaceutical causes

- Drug quantity

- Drug release

2. Pharmacokinetic causes

- Drug absorption - Drug elimination

- Drug distribution - Drug metabolism

3. Pharmacodynamic causes

- Drug receptors

- Homeostatic mechanisms

- Disease


89/119

Type B (bizarre/unpredictable) reactions

Type B reactions include idiosyncratic reactions,

immunologic or allergic reactions (e.g.anaphylaxis),

and carcinogenic/teratogenic events.

While uncommon, are often among the most

serious and potentially life-threatening of all

ADEs, and are a major cause of important

drug-induced disease.

Adverse


90/119

Adverse

reactions which

only occur with

long term use

Special Groups ofSpecial Groups of


91/119

patientspatients

Pediatric patientsPediatric patientsGeriatric patientsGeriatric patients

Patients with hepatic insufficiencyPatients with hepatic insufficiency

Patients with renal insufficiencyPatients with renal insufficiency Pregnant patientsPregnant patients

Nursing mothersNursing mothers

FDA Classification of DrugFDA Classification of DrugS f tS f t


92/119

SafetySafety

era ogen c ecera ogen c ec --adversely affect fetaladversely affect fetal


93/119

adversely affect fetaladversely affect fetal

development.development.

Probably the mostrenowned isPhocomelia, thename given to theflipper-like limbswhich appeared on

the children ofwomen who tookthalidomide

era ogen c ecera ogen c ec --adversely affect fetaladversely affect fetal


94/119

adversely affect fetaladversely affect fetal

development.development.

Pediatric and Geriatric patientsPediatric and Geriatric patients possible dose adjustments;possible dose adjustments;


95/119

possible dose adjustments;possible dose adjustments;

safetysafety

Hepatic and renal insufficiencyHepatic and renal insufficiencyibl dpossible dose


96/119

possible dosepossible dose

adjustments; dialysabilityadjustments; dialysability

Hepatic failureHepatic failure


97/119

Hepatic failureHepatic failure

urs ng mo ersurs ng mo ers somesomedrugs are excreted indrugs are excreted in


98/119

drugs are excreted indrugs are excreted in

breastmilkbreastmilk


99/119

OverdoseOverdose

Beyond theBeyond the

maximum dosagemaximum dosage

Could beCould be

intentionalintentional(suicidal) or(suicidal) or

accidentalaccidental

(medication error)(medication error)

Antidote?Antidote?

i


100/119

Precautions

Ability to operateAbility to operate

machinerymachinery

Are there sedatingAre there sedating

effects?effects?

Drug Abuse/ Misuse/Drug Abuse/ Misuse/


101/119


AddictionAddiction

Misuse indiscriminate use of drugsMisuse indiscriminate use of drugs

(recreational purpose)(recreational purpose)

Abuse continual non-therapeutic use ofAbuse continual non-therapeutic use of

drug with resulting physical ordrug with resulting physical or

psychological dependencepsychological dependence

Addiction presence of tolerance,Addiction presence of tolerance,withdrawal, increasing dosage andwithdrawal, increasing dosage and

uncontrollable useuncontrollable use


102/119


103/119


Addi tiAddi ti


104/119

AddictionAddiction

What is Tolerance?What is Tolerance?


105/119

What is Tolerance?What is Tolerance?

Tolerance is theneed to increasethe dose ofa drug over time

in order tomaintain a givenpharmacologicaleffect

Withd lWithd l


106/119

WithdrawalWithdrawal

PhysiologicalPhysiological

PsychologicalPsychological

H bit f i dH bit f i d


107/119

Habit forming drugsHabit forming drugs

Categories of ControlledCategories of Controlled

SubstancesSubstances


108/119

SubstancesSubstances Schedule I - not approved for medical useSchedule I - not approved for medical use

and have high abuse potentialand have high abuse potential Schedule II - used medically and haveSchedule II - used medically and have

high abuse potentialhigh abuse potential

Schedule III - less potential for abuse butSchedule III - less potential for abuse but

may lead to physical or psychologicalmay lead to physical or psychologicaldependencedependence

Schedule IV - some potential for abuseSchedule IV - some potential for abuse

Schedule V - contain mod. amounts ofSchedule V - contain mod. amounts ofcontrolled substances, limited abusecontrolled substances, limited abuse

potentialpotential


109/119

DRUG INTERACTIONDRUG INTERACTION

A pharmacologic phenomenon that occursA pharmacologic phenomenon that occurswhen the action and/or effect of a given drugwhen the action and/or effect of a given drugis modified or altered significantly by anotheris modified or altered significantly by anotherdrug when these are administereddrug when these are administeredconcomitantly or sequentially.concomitantly or sequentially.

A.A. Pharmacodynamic Drug-DrugPharmacodynamic Drug-DrugInteractionsInteractions

B.B. Pharmacokinetic Drug-Drug InteractionsPharmacokinetic Drug-Drug Interactions


110/119

Pharmacodynamic DrugPharmacodynamic DrugInteractionInteraction


111/119

InteractionInteraction

Additi itAdditivity


112/119

AdditivityAdditivity

Administration of the dose of AAdministration of the dose of A

and B simultaneously gives anand B simultaneously gives an

effect equal to 20 unitseffect equal to 20 units


113/119

SynergismSynergism


114/119

SynergismSynergism

A certain dose of Drug A aloneA certain dose of Drug A alone

produces an effect equal to 10produces an effect equal to 10

units. A certain dose of Drug Bunits. A certain dose of Drug Balone produces an effect equal toalone produces an effect equal to

10 units. Administration of the10 units. Administration of the

same doses of A and Bsame doses of A and B

simultaneously produces an effectsimultaneously produces an effect

equal to 50 unitsequal to 50 units


115/119

AntagonisticAntagonistic


116/119

AntagonisticAntagonistic

AdministrationAdministration

of the dose of Aof the dose of A

and Band Bsimultaneouslysimultaneously

negates thenegates the

effect of eacheffect of each

drugdrug

P-K DrugP-K DrugInteractionInteraction


117/119

InteractionInteraction

-- due to drugdue to druginteraction at anyinteraction at anypoint during theirpoint during theirabsorption,absorption,

distribution,distribution,metabolism, ormetabolism, orexcretion resultingexcretion resultingeither in increaseeither in increaseor decrease in theor decrease in thedrugdrugconcentration atconcentration atthe site of action.the site of action.


118/119


119/119

Thank you.Thank you.