Dr. DATTEN BANGUN MSc,SpFK Drs ADMAR JAS A t...
Transcript of Dr. DATTEN BANGUN MSc,SpFK Drs ADMAR JAS A t...
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