โดยรศ . ดร . ทั�ศนีย� ปั ญจานีนีทั�

หมวดว�ชาเภสั�ชว�ทัยาและพิ�ษว�ทัยาภาคว�ชาว�ทัยาศาสัตร�การแพิทัย� คณะว�ทัยาศาสัตร� มหาว�ทัยาล�ยร�งสั�ต

เภสั�ชพลศาสัตร์�

Discovery

Phase I

Preclinical

Phase II

Phase III

Approval

Post marketing surveillance

6 years 6 years 2 years

Preclinical Clinical Approval

Compound Success Rate by StagesCompound Success Rate by Stages

Safety and dosage (20-80 healthy volunteers)

Efficacy and side effects (100-300 patient volunteers)

Adverse reactions (1000-5000 patients)

Laboratory and animal testing

Target validation and lead discovery

(250 lead compounds)

(5 drug candidates)

(1 drug)

(>104 compounds)

Source: Pharmaceutical Industry Profile 2001

5-10 years

Withdrawal

Cost >$800m

Success 1 in 5,000

Bacteria, 1.6 Mb, ~1600

genes[Science 269: 1995]

1995Bacteria,

1.6 Mb, ~1600 genes

[Science 269: 1995]

1995

Eukaryote, 13 Mb,

~6K genes [Nature 387: 1997]

1997Eukaryote, 13

Mb, ~6K genes

[Nature 387: 1997]

1997

1998Animal,

~100 Mb, ~20K genes

[Science 282: 1998]

1998Animal,

~100 Mb, ~20K genes

[Science 282: 1998]

Human, ~3 Gb, ~100K

genes[Science 291, 2001]

2001Human,

~3 Gb, ~100K genes

[Science 291, 2001]

2001

Malaria, ~23 Mb,

~5,300 genes[Nature 419, 2002]

2002Malaria, ~23 Mb,

~5,300 genes[Nature 419, 2002]

2002Anopheles gambiae,

~270 Mb, ~15,189 genes[Science 296, 2002]

2002Anopheles gambiae,

~270 Mb, ~15,189 genes[Science 296, 2002]

2002

Proteins

Chemicallibrary

results

SAR analyses

Combi-chemsynthesis

Assign pharmacophore

ADME / Tox workup

In vitroADME / Tox

Don’t delay triage ofcompounds that aren’t

“drug-like”

Proteins

Chemicallibrary

results

SAR analyses

Combi-chemsynthesis

Assign pharmacophore

Proteins

Chemicallibrary

results

SAR analyses

Combi-chemsynthesis

Assign pharmacophore

ADME / Tox workup

In vitroADME / Tox

Don’t delay triage ofcompounds that aren’t

“drug-like”

In vitroADME / Tox

Don’t delay triage ofcompounds that aren’t

“drug-like”

ว�ตถุ$ปัระสังค�1.อธิ�บายค$ณสัมบ�ต�และโครงสัร(างของ

ต�วร�บยา2. อธิ�บายกลไกการสั+งสั�ญญาณ

เข(าไปัในีเซลล� 3. ยกต�วอย+างต�วร�บยาทั.สั/าค�ญ 4 ชนี�ด

4. อธิ�บายการหนี(าทั.และการทั/างานีของสัารข�0นีทั$ต�ย ภูม�และโปัรตนีจ

บทัทั. 8ต�วร�บยา

(DRUG RECEPTOR)

I. บทันี/าII. ปัระเภทัของยาแบ+งตามการออกฤทัธิ�3

21. แบบต(องมต�วร�บยาทั. จ/าเพิาะเจาะจง

ligand: receptor

2.2 แบบออกฤทัธิ�3ทั�.วไปัosmotic agents

antacids metal chelators

antiseptics ยาสัลบ(general anesthetics)

3 .1 ต�วร�บยาทั.เปั4นีโปัรตนีอยู+ระหว+างเย5.อห$(มเซลล�

Ligand + receptor (binding site)

response

IV. การจ�บระหว+างโมเลก$ลยาก�บต�วร�บยา 41. Specificity :

stereospecificity receptor binding site4.2 พิ�นีธิะระหว+างยาก�บต�วร�บยา

- hydrogen, ionic, hydrophobic, Van der Waals reversible

- covalent: irreversible anticancer:DNA, anticholinesterase

Beta-blockerBeta-blocker

stereospecificity

Beta-agonistBeta-agonist

- Drug Receptor I nteracti ons- Drug Receptor I nteracti ons (Molecularlevel) (Molecularlevel)

Affinity vs. Efficacy

D+R DRresponse

Affinity=k1/k2Efficacy=k3Drug with high affinity, less Drug with high affinity, less amount of drug is required = amount of drug is required = high potencyhigh potencyEfficacy (or Intrinsic Activity)Efficacy (or Intrinsic Activity) – ability of a bound drug to change – ability of a bound drug to change the receptor in a way that produces an effectthe receptor in a way that produces an effect

k1 (association constant)

2 (dissociation constant)

3k

The dose-response The dose-response curvecurveThe dose-response The dose-response curvecurve

Effects of drug-receptor Effects of drug-receptor bindingbindingEffects of drug-receptor Effects of drug-receptor bindingbinding

••Full AgonistsFull Agonists: : Compounds that are able Compounds that are able to elicit a maximal to elicit a maximal response following response following receptor occupation and receptor occupation and activationactivation..••Partial AgonistsPartial Agonists::Compounds that can Compounds that can activate receptors but activate receptors but are unable to elicit the are unable to elicit the maximal response of the maximal response of the receptor systemreceptor system..

AgonistsAgonistsAgonists

% M

axim

um

E

ffec

t

[Drug]

Agonist

Antagonist

Partial agonist

100

80

60

40

20

0

1 10010 1000

Agonist

Antagonist

Partial agonist

100

80

60

40

20

0

1 10010 1000

[Drug]

Agonist

Antagonist

Partial agonist

100

80

60

40

20

0

1 10010 1000

Agonist

Antagonist

Partial agonist

100

80

60

40

20

0

1 10010 1000

0.5 1.0 2.0 4.0 8.0 ug/ml0.5 1.0 2.0 4.0 8.0 ug/ml

100%74%

47%

11%

Effect of acethylcholine on isolated ileumEffect of acethylcholine on isolated ileum Ach (agonist) + muscarinic receptor ileum contractility

WHAT’S YOU SEE?

AntagonistsAntagonistsAntagonistsAntagonists• Antagonists

– produce their effects by blocking the action of an agonist, or an endogenous ligand at that receptor

• Competitive antagonistsCompetitive antagonists– Reversible binds to same receptor as agonist– The maximal response of the agonist is not decreased.– Shift dose-effect for agonist to right parallel– The blockade can be overcome by increasing the agonist concentration

• Noncompetitive antagonistsNoncompetitive antagonists– Shift dose-effect for agonist to right– Effect can not be overcome by sufficient dose (decrease in maximum

effect)

100 Maximum

Pretreated withcompetitiveantagonist50

LowDose of morphine

High LowDose of morphine

High

100

50 Pretreated withnoncompetitiveantagonist%

eff

ect

100 Maximum

Pretreated withcompetitiveantagonist50

LowDose of morphine

High LowDose of morphine

High

100

50 Pretreated withnoncompetitiveantagonist%

eff

ect

100 Maximum

Pretreated withcompetitiveantagonist50

LowDose of morphine

High LowDose of morphine

High

100

50 Pretreated withnoncompetitiveantagonist%

eff

ect

AntagonistsAntagonistsReceptorAgonistAntagonist

X X X XX X X X

. กลไกการสั+งสั�ญญาณเข(าเซลล(transmembrane signal transduction)

61. เก�ด secondary messenger: G- protein/cAMP, G-protein/phosphoinositide systems6.2 เก�ดการควบค$ม ion channels6.3 เก�ดการเปัล.ยนีแปัลง polypeptides

64 เก�ด phosphorylation cascade

ตารางทั. 8 .2 ต�วร�บยาและกลไกการสั+งสั�ญญาณเข(าเซลล�

Ion-channel ReceptorIonIon--channel Receptorchannel Receptor

1. 1. IonIon--channelschannels binding site coupled to ion channelbinding site coupled to ion channel

transmitter (or drug) gates the channeltransmitter (or drug) gates the channel Ions flow down conc. gradientIons flow down conc. gradient

Rapid/ rapidly reversibleRapid/ rapidly reversible

Examples: Nicotinic acetylcholine receptor: coupled to sodium channel drugs: nicotine, curare

GABA receptor: coupled to chloride channel drugs: sedative-hypnotics

G protein-coupled receptorsG proteinG protein--coupled receptorscoupled receptors

2. G protein2. G protein--coupled coupled

receptor coupled to G proteinreceptor coupled to G protein

G protein activates G protein activates effectoreffector

Large family all with 7 membraneLarge family all with 7 membrane--spanning regionsspanning regions

Receptor coupled to G protein, and G Receptor coupled to G protein, and G protein stimulates protein stimulates effectoreffector

Slower than ionSlower than ion--coupledcoupled

Examples:Examples: Cholinergic Cholinergic muscarinicmuscarinic

55--HT (serotonin)HT (serotonin)

OpioidOpioid

DopamineDopamine

NorepinephrineNorepinephrine

Receptor

G protein

Precursor

Ionchannel

Secondmessenger

Effectorenzyme

Receptor

G protein

Precursor

Ionchannel

Secondmessenger

Effectorenzyme

Receptor Tyrosine kinaseReceptor Tyrosine Receptor Tyrosine kinasekinase

3. 3. LigandLigand--regulated regulated enzyme receptorenzyme receptor

integral protein is outer integral protein is outer membranemembrane--receptor receptor domaindomain

Tyrosine Tyrosine kinasekinase domain domain phosphorylatephosphorylate target target protein protein

ligand ex. Insulin, Epidermal growth factor EGF, platelet-derived growth factorPDGF, Atrial natriureticfactor ANF

Intracellular hormone receptorIntracellular hormone receptorIntracellular hormone receptor

4. protein synthesis4. protein synthesis--regulating receptorregulating receptor bind to DNAbind to DNA---->at Hormone >at Hormone

Responsive Element HREResponsive Element HRE------>transcription>transcription------>protein >protein synthesissynthesis------>Altered cell >Altered cell functionfunction

ligandligand exex.. GlucocorticoidGlucocorticoid,,minerocorticoidminerocorticoid,, sex steriodsex steriod,,vitamin Dvitamin D,, thyroid hormonethyroid hormone

slower, longer effectslower, longer effect

Second messengersSecond messengers

Are many:Are many: CalciumCalcium

cGMPcGMP

PhosphoinositidesPhosphoinositides(IP(IP33, , diacylglyceroldiacylglycerol))

cAMPcAMP (cyclic (cyclic adenosine 3,5adenosine 3,5--monophosphate)monophosphate)

Tolerance and sensitizationTolerance and sensitization

The effects of a drug may change with The effects of a drug may change with repeated administrationrepeated administration

Tolerance Tolerance ((การ์ทนยาการ์ทนยา )) Decreased response with repeated administration Decreased response with repeated administration

agonist (desensitization)agonist (desensitization)

Receptor Receptor down regulationdown regulation (decrease number or (decrease number or response)response)

A higher dose is required to produce the original A higher dose is required to produce the original effect effect

CrossCross--tolerancetoleranceTachyphylaxisTachyphylaxis = = การ์ทนยาท�� เก�ดอย�างร์วดเร์�วการ์ทนยาท�� เก�ดอย�างร์วดเร์�ว

SensitizationSensitization Increased response with repeated Increased response with repeated

administration of antagonistadministration of antagonist

Receptor Receptor up regulationup regulation (increase response)(increase response)

A lower dose is required to produce the A lower dose is required to produce the original effectoriginal effect

Cross sensitizationCross sensitization

Tolerance and sensitization (cont.)Tolerance and sensitization (cont.)

บทัทั. 9ความเข(มข(นีของยาก�บผลของยา

(CONCENTRATION-RESPONSE

RELATIONSHIPS)ว�ตถุ$ปัระสังค�•Dose response curve

•Graded dose response curve: efficacy & potency•Quantal dose response curve: therapeutic index

•Drug interaction

I. บทันี/า

รูปัทั. 91. ความสั�มพิ�นีธิ�ระหว+างผลของยาก�บความเข(มข(นีและการจ�บของยาก�บต�วร�บยา

E = Emax x C C+ EC50

II. ปัระเภทัของ agonist และ antagonistAntagonist :

•higher affinity without intrinsic activity competitive antagonist noncompetitive antagonistAgonist:•affinity + intrinsic activity

full agonistpartial agonist

DoseDose--response curveresponse curve

GradedGraded

QuantalQuantal

••Continuous scale ( increase Continuous scale ( increase dosedose……increase effect)increase effect)

••Measured in a single biologic unitMeasured in a single biologic unit

••Relates dose to intensity of effectRelates dose to intensity of effect

••Potency/efficacyPotency/efficacy

••AllAll--oror--none pharmacologic effectnone pharmacologic effect

••Population studiesPopulation studies

••Relates dose to frequency of effectRelates dose to frequency of effect

••Safety profile: therapeutic indexSafety profile: therapeutic index

Potency, efficacy and slope

01 10 100 1000 10000 100000Dose . mg ลดนี/0าตาล - - 10 20 50 100A % - 1 5 2 5 5 0 1 0 0 %

0 .5 2 2 5 3 0 5 0 5 0 %

Quantal Dose-Response Quantal Dose-Response CurveCurve

Dose 1 10 100 1,000 10,000100,000

%therapeutic 10 50 80 100response (ED50)

%Toxic 0 0 10 50 70 100response (TD50 or LD50)

TI = LD50/ED50 = 1000/10 = 100

ED50 - Median Effective Dose 50; the dose at which 50 percent of the ED50 - Median Effective Dose 50; the dose at which 50 percent of the population or sample manifests a given effectpopulation or sample manifests a given effectTD50 - Median Toxic Dose 50 - dose at which 50 percent of the TD50 - Median Toxic Dose 50 - dose at which 50 percent of the population manifests a given toxic effectpopulation manifests a given toxic effectLD50 - Median Lethal Dose 50 - dose which kills 50 percent of the LD50 - Median Lethal Dose 50 - dose which kills 50 percent of the subjectssubjectsTI - Therapeutic indexTI - Therapeutic index

Therapeutic index Therapeutic index

Therapeutic Drug Monitoring (TDM)Therapeutic Drug Monitoring (TDM)

ปฏิ�ก�ร์�ยาร์ะหว�างก�นต�อยาปฏิ�ก�ร์�ยาร์ะหว�างก�นต�อยา (Drug interactions)(Drug interactions)(outside, PKs, PDs) (outside, PKs, PDs)

การ์เสัร์�มฤทธิ์�"ก�นการ์เสัร์�มฤทธิ์�"ก�นSYNERGISM/SupraadditiveSYNERGISM/Supraadditive (1+1= 3) (1+1= 3)Sulfonamide + trimethoprim……sequential blockadeSulfonamide + trimethoprim……sequential blockade Addition/summationAddition/summation (1+1= 2) (1+1= 2) Aspirin + paracetamol as analgesic/antipyreticAspirin + paracetamol as analgesic/antipyreticPotentiationPotentiation (1+0 = 1) (1+0 = 1) Amoxicillin + calvulanic acidAmoxicillin + calvulanic acid

การ์ต#านฤทธิ์�"ก�นการ์ต#านฤทธิ์�"ก�นPhysical antagonistPhysical antagonist Activated charcoal adsorbs alkaloids and prevent their Activated charcoal adsorbs alkaloids and prevent their absorptionabsorptionChemical antagonistChemical antagonist Tetracycline + Ca++ ComplexTetracycline + Ca++ ComplexPhysiological/functional antagonistPhysiological/functional antagonist

Histamine and adrenaline on BPHistamine and adrenaline on BPReceptor/pharmacological antagonistReceptor/pharmacological antagonist

Cholinergic agonist : cholinergic antagonistCholinergic agonist : cholinergic antagonist

Thank YouThank You