OBAT YANG BEKERJA

TIDAK MELALUI IKATAN RESEPTOR-OBAT

Dr. DATTEN  BANGUN MSc,SpFKD ADMAR JAS A t MSiDrs ADMAR JAS,Apt,MSi

Bagian Farmakologi dan Terapeutik,Fakultas KedokteranFakultas Kedokteran

Universitas Sumatera Utara

How drug act ?Paul Ehrlich :Paul Ehrlich :

Corpora non agunt nisi fixata

A drug will not workUnless it is bound

Dengan apa berikatan ?

- Protein Molecules- DNA = antimikroba

= anti neoplasma= karsinogen

--- RECEPTOR

Are there any drugs that do not fit the drug-receptormodel?model?

• Disrupting of Structural Proteins e.g. vinca alkaloids for cancer, colchicine for gout

• Being Enzymesg ye.g. streptokinase for thrombolysis

• Covalently Linking to Macromolecules• Covalently Linking to Macromoleculese.g. cyclophosphamide for cancer

R ti Ch i ll ith S ll M l l• Reacting Chemically with Small Moleculese.g. antacids for increased acidity

Bi di F M l l A• Binding Free Molecules or Atomse.g. drugs for heavy metal poisoning, infliximab (anti-TNF)

= Vinca alkaloid:-memblok fase M (mitotic)pada sel kankerp

e.g. streptokinase for thrombolysis= Being Enzymes

g p y

=Covalently Linking to Macromolecules in cancer=Covalently Linking to Macromolecules in cancer cells-------> Cyclophosphamide

=Reacting Chemically with Small Molecules

e.g. antacids for increased acidity

= Binding Free Molecules or Atomse.g. - drugs for heavy metal poisoning,

- infliximab (anti-TNF)infliximab (anti TNF)

= Osmotic diuretic,,e.g. – mannitol; increase the osmolarity

of body fluid-------promote diuresis,reduce cerebral edema

HOW DO DRUGS WORK BY UNCONVENTIONAL MECHANISMS OF ACTION ?

• Being Nutrientsit i i le.g. vitamins, minerals

• Exerting Actions Due to Physical Propertiese.g. mannitol (osmotic diuretic), bulk laxatives

• Working Via an Antisense Actione.g. fomivirsen for CMV retininitis in AIDS

• Being Antigens g ge.g. vaccines

•Having Unknown Mechanisms of Action•Having Unknown Mechanisms of Actione.g. general anesthetics

Are there any MORE drugs that do not fit the drug-receptor model?

= petroleum jelly physical form= petroleum jelly--- physical form= PABA ----------- absorption of UV rays= activated charcoal--- adsorptive property activated charcoal adsorptive property= 131 I,radioisotopes------ radioactivity= Potassium permanganate-- radioactivity= Cholestyramine---- sequestration of

cholesterol in the gut= Mesna® scavenging of reactive metabolites= Mesna®,scavenging of reactive metabolites

of cyclophosphamide Mesna:( mercaptoethanesulfonate):

Receptor Regulation

Receptor Numbers - Not static- High turnover - formed Conti-g

- removed Upregulation

Conti-nuously

- Upregulation.- down regulation - delayed effect of

antidepressant.- Tolerance in

opioid.

Receptor RegulationSensitization or Up-regulation

1. Prolonged/continuous use of greceptor blocker;example:

- adrenergic blocker pada hypertension-----the number of receptor increase----abrupt stopping of the drug----------hypertensive crisishypertensive crisis

2. Inhibition of synthesis or release of2. Inhibition of synthesis or release of hormone/neurotransmitter – Denervation of preganglionic fiber

Desensitization or Down-regulation,ord t ti f t iadaptation or refractoriness

1 P l d/ ti f1. Prolonged/continuous use of agonist---- misal;- heroine; an agonist in endorphine

receptor------- the number of receptordecrease----- drug tolerancedecrease drug tolerance

- if happen rapidly---- tachyphylaxis- salbutamol in asthma

2. Inhibition of degradation or uptake of agonistagonist

Receptor regulation (cont)• Down-regulation

• Increases receptor internalization and degradation• Slower onset and more prolonged effect than• Slower onset and more prolonged effect than

desensitization• Occurs over hours or days

I i t i d d d i th t t l # f• Is an agonist-induced decrease in the total # of cell-surface receptors

• Intensity and duration of action of EGF, PDGF, and other agents that act via tyrosine kinase receptorother agents that act via tyrosine kinase receptor are limited because of this process

• Cells responsiveness to ligand is correspondingly diminisheddiminished

Molecular and cellular determinantsf d l i iof drug selectivity

Selectivity of drug action can be conferred by:Selectivity of drug action can be conferred by:1. Cell- type specificity of receptor subtypes2 Cell-type specificity of receptor-effector2. Cell-type specificity of receptor-effector

couplingExample:Example:Ad 1.a) Drug that act on DNA synthesis

(ex (cytostatics)---------(ex.(cytostatics)---------will have a lot of side-effects .

1.b). Drug that act on cell-type restricted processlike acid generation in stomach,may have fewerlike acid generation in stomach,may have fewerside-effect

The more restricted the cell-typedistribution of the receptor targetedof a drug,the more selective the drugis likelyto be

Ad 2. Voltage-gated calcium channels are ubiquitously expressed in the heart, BUTcardiac pace-maker are a relatively more sensitive to the effect of calcium channel blockers than are cardiac ventricular muscle cells,t a a e ca d ac e t cu a usc e ce s,

WHY??

Because :Because : =cardiac pace-makers------- - Calcium channels= ventricular muscle---------- -Natrium channels

The more receptor effector couplingThe more receptor-effector couplingmechanism differ among the others,the moreselective the drug is likely to beselective the drug is likely to be

Drug-receptor interaction• In order for a drug to interact with it’s

receptor, a drug must have thereceptor, a drug must have the appropriate:– SizeSize– Electrical Charge

Shape– Shape– Atomic composition

Drug-Receptor Interactionsg

What factors influence binding?What factors influence binding?• Molecular structure

– Isomerism – Functional groups– Rigidity

• Peptide bond distance = 3.61 angstroms– Drugs - spacial relationship betweenDrugs - spacial relationship between functional groups is typically a multiple of 3.61

C f ti l h i d t– Conformational changes in drugs occur to optimize this

Stereochemical features of drugsIsomerism

A. Cis and trans isomers in double bonds• Different physical and chemical properties----distribution in aDifferent physical and chemical properties distribution in a

biological system are different

OHOHOH

OH

trans diethylstibesterol cis-diethylstibesteroltrans-diethylstibesterolEstrogenic activity Only 7% activity

of the trans isomer

Stereochemical features of drugs

Isomerism continued

B. Conformational isomers – as a result of the rotation around single bonds between two atoms

• Energy barrier exists between these isomers that is sufficiently large that they can often be observed

• Examples: CHCH3Examples: CH3

CH

CH3CH3 CH3

CH3

H

CH3

H

Stereochemical features of drugs

Isomerism continuedB. Conformational isomers – as a result of the rotation around

single bonds between two atoms• Remember that this is an EQUILIBRUM process

HHCH3

H HHCH3

H CH3

HCH3HH

H CH3

H HCH3 H

H CH3H H

H

HHCH3

CHHCH3

HCHCH3CH3H CH3CH3

CH3

HH

HHH

CH3H

HHH

HCH3

HHHH HCH3 HH

3

HH

Anti

Lowest energyhighest population

eclipsed

highest energylowest population >>>1 in 1000

eclipsed

highest energylowest population 1 in 1000

gauche

medium energy1 of 4 population

gauche

medium energy1 of 4 population

I l l h d b di di l di l i i Intramolecular hydrogen bonding, dipole-dipole interactions and electrostatic forces in molecules can alter this distribution

Stereochemical features of drugsg

Isomerism continued

B. Conformational isomers – as a result of the rotation around single bonds between two atoms

• EQUILIBRUM process - results in CONFORMATIONAL FLEXIBILITY

• FLEXIBILITY can lead to multiple modes of action at different receptor types

• Example: Acetylcholine: muscarinic and nicotinic receptors

• This can often lead to SIDE EFFECTS due to activity at an undesirable site of action

Stereochemical features of drugs

Optical Isomerism

E ti i i ( l f t )A. Enantiomers - mirror image (plane of symmetry)

All physical properties are identical with the only difference is the direction each rotates plane polarized light

OH

OH

p p g

NH2

OH OH

NH2

OH OH

D-serineL-serine[α]D

20 = -14.7 (c=10, 1 N HCl)[α]D20 = +14.7 (c=10, 1 N HCl)

Only the “L” isomer is used in protein synthesis

Stereochemical features of drugs

Optical IsomerismB. Diastereomers - 2 or more chiral centers

2 f ( # f )• 2n = Number of diasteromers (n = # of chiral centers)• Example: Ephedrine and Pseudoephedrine

CH CHCH3

OHH

NHCH3H

CH3

HOH

NHCH3H

MP = 37-39 MP = 118-120

OHH HOH

1 gram/20 mL 1 gram/200 mL

Ephedrine Pseudoephedrinep (Erythro)

p (Threo)

Use: Hypotension Decongestant

Theory of Drug Action

Fi h ’ ‘L k d K ’ H th iFischer’s ‘Lock and Key’ Hypothesis

Every ‘lock’ has its own ‘key’If the ‘key’ is not precise, the ‘lock’ does not openThe ‘drug’ is the key that has to g yfit the target specifically and productively

Theory of Drug Action

Corollary of ‘Lock & Key’ HypothesisCorollary of Lock & Key Hypothesis

OHCH3 CH3

OCH3

OHCHC

OH

OOH

OH OH

O

OOH O

O

CH2

CH2OH CH3

CH3 OH

O

N

CH3

CH3CH2CH3

Does not explain why some ‘keys’ open doors partially? e.g., partial agonists or partially? …… e.g., partial agonists or antagonists

Theory of Drug Action

K hl d’ ‘I d d Fit’ H th iKoshland’s ‘Induced-Fit’ Hypothesis

Hand & gloveHand & glove

At least two steps …… e.g., step 1 is initial binding and step 2 is a change in Con-initial binding and step 2 is a change in structure of the receptor (and/or drug)Receptor is flexible! …… can wrap around the drug …… the zipper model is extreme

Con-forma-tiong pp

case of induced-fitAll intermediate cases do exist in nature

change