Prinsip-prinsip aksi obat

SugiyantoLab. Farmakologi & Toksikologi

Fak. Farmasi UGM

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Principles of Drug Action

General Overview

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A few drugs act by virtue of their physicochemical properties, e.g. laxative agent (MgSO4), general anesthetics (based on its lipid solubility (?), osmotic diuretics (mannitol)

Some drugs act as false substrates (sulphonamides) or inhibitor for certain transport systems (cardiac glycosides) or enzymes (NSAIDs)

Most drugs produce their effects by acting on specific protein molecules, usually located in the cell membrane. These proteins are called receptors

Prinsip aksi obat

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Receptor, Agonist & Antagonist

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Receptors normally respond to endogenous chemicals in the body.

These chemicals are either synaptic transmitter substances (neurotransmitters) or hormones, for example acetylcholine, epinephrine, insulin, aldosterone etc.

Chemicals or drugs that activate receptors and produce a response are called agonist.

Drugs or chemicals that combine to receptors but do not activate them are called antagonist

Receptors

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They are protein molecules which are normally activated by neurotransmitters or hormones.

Many receptors have now been cloned and their amino acid sequences determined.

The 4 main type of receptors are:1. Agonist-gated receptors are made up

from subunits which form a central ion channel (e.g. nicotinic receptor)

2. G-protein-coupled receptors form a family of receptors with seven membrane-spanning helices

Receptors

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3. Nuclear Receptors (Intracellular receptors, Protein Synthesis-regulating Receptors) for steroid hormones and thyroid hormones

4.Kinase-linked receptors (Ligand-regulated Enzymes) adalah reseptor permukaan membran yg biasanya mempunyai aktivitas kinase tirosin intrinsik, sebagai contoh: reseptor insulin, reseptor sitokin dan reseptor faktor pertumbuhan

Reseptor asetilkolin nikotinik :

Suatu protein pentamer yang terdiri dari 5 subunit yaitu 2βγδ

Terkait dengan kanal Na+ berlokasi di neuromuscular

junction, ganglia otonom, medula adrenal, dan CNS

pertama kali dikarakterisasi dengan kemampuannya mengikat nikotin04/21/23 7

Reseptor GABA

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Contoh reseptor terkopel protein G

Reseptor asetilkolin muskarinikReseptor adrenergikReseptor dopaminReseptor angiotensin

merupakan keluarga terbesar reseptor permukaan selmenjadi mediator dari respon seluler berbagai molekul,

seperti: hormon, neurotransmiter, mediator lokal, dll.merupakan satu rantai polipetida tunggal, keluar masuk

menembus membran sel sampai 7 kali disebut memiliki 7 transmembran

Reseptor terkopel Protein G

Some examples of Nuclear Receptor (Protein synthesis-regulating Receptors)

ReceptorReceptor Location (Unliganded)Location (Unliganded)

Thyroid HormoneThyroid Hormone 100% Nucleus100% Nucleus

Retinoic AcidRetinoic Acid ~95% Nucleus~95% Nucleus

Vitamin DVitamin D 75% Nucleus75% Nucleus

EstrogenEstrogen 95% Nucleus95% Nucleus

GlucocorticoidGlucocorticoid 90% Cytosol90% Cytosol

AndrogenAndrogen 90% Nucleus90% Nucleus

MineralocorticoidMineralocorticoid ~40% Nucleus~40% Nucleus

Contoh Kinase-linked Receptor (Ligand-regulated Enzymes)

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Drug-receptor Interactions

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The activation of receptors by an agonist is coupled to the physiological or biochemical responses by transduction mechanisms that often (but not always) involve molecules called second messengers (for example Ca2+, inositol triphosphate, diacylglycerol and cAMP)

The interaction between a drug and the binding site of the receptor depends on the complementary of “fit” of the 2 molecules.

The closser the fit and the grater the number of bonds (usually non-covalent), the stronger will be the attractive forces between them, and the higher the affinity of the drug for the receptor.

Aktivasi GPCR (G protein-coupled receptor) melalui sistem fosfolipase

merupakan salah satu mekanisme transduksi signal yang penting

diawali dg pengikatan suatu ligan pada reseptor mengaktivasi enzim fosfolipase C membelah PIP2 menjadi

IP3 dan DAG

PIP2 = fosfatidil inositol bis-fosfat merupakan hasil

degradasi fosfatidil inositol pada membran sel dg bantuan enzim PI kinase

IP3 = inositol trifosfat berikatan dengan reseptor spesifik

pada retikulum endoplasmik yang tekait dg kanal Ca++ memicu pelepasan kalsium intrasel kontraksi sel, pelepasan hormon/neurotransmiter, eksositosis

DAG = diasil gliserol mengaktivasi protein kinase C memfosforilasi residu serine/threonin kinase pada sel target

lumen ofendoplasmic

reticulum

Activated G subunit

PI 4,5-biphosphate(PI(4,5)P2)

inositol1,4,5-triphosphate

(IP3)

G-protein linkedreceptor

Open IP3-gatedCa++ channel

ActivatedPhospholipase C

Activated PKC

diacylglycerol

Signal molecule

Ca++

Cara kerja reseptor insulin dlm pengambilan glukosa

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Specificity & selectivity

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The ability of a drug to combine with one particular type of receptor is called specificity.

No drug is truly specific but many have a relatively selective action on one type of receptor.

Drugs are prescribed to produce a therapeutic effect but they often produce additional unwanted effects which range from the trivial (slight nausea) to the fatal (aplastic anaemia)

Neurotransmitters

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Neurotransmitter substances are chemicals released from nerve terminals which diffuse across the synaptic cleft and bind to the receptors.

The neurotransmitter activates receptors, presumably by changing their conformation, and triggers a sequences of post-synaptic events resulting in, for example, muscle contraction or glandular secretion.

Following its release, the transmitter is inactivated by either degradation (e.g. acetylcholine) or reuptake (e.g. norepinephrine, GABA).

Many drugs act by either reducing or enhancing synaptic tranmission.

Hormones

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Hormones are chemicals released into bloodstream; they produce their physiological effects on tissues possessing the necessary specific hormone receptors.

Drugs may interact with the endocrine system by inhibiting (e.g. antithyroid drugs) or increasing (e.g. oral antidiabetic agents) hormone release.

Other drugs interact with hormone receptors which may be activated (e.g. steroidal anti-inflammatory drugs) or blocked (e.g. oestrogen antagonists).

Local hormones (autacoids) such as histamine, serotonin (5-HT), kinins and prostaglandins are released in pathological processes.

Hormones

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Propil tio urasil (PTU) obat antitiroidGlimepirid dan glibenklamid, obat golongan

sulfonilurea, digunakan untuk memacu skresi hormon insulin (abtidiabetik)

Efek dari histamin dapat dihambat oleh antihistamin

Beberapa obat dapat menghambat biosintesis prostaglandin (obat-obat anti inflamasi non-steroid, NSAIDs)

Neurotransmitter Asetilkholin

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Asetilkholin:molekul pertama yang diidentifikasi sebagai

neurotransmitteraksinya pada sistem syaraf otonom di perifer maupun

CNSDi sistem syaraf perifer:

Neurotransmitter sistem syaraf parasimpatik (kholinergik)memiliki 2 macam reseptor yaitu nikotinik dan muskarinik

Di sistem syaraf pusat (CNS):berperan antara lain dalam regulasi belajar (learning),

memori, kontrol gerakan, dan mood (perasaan) contoh: penyakit Alzheimer (pikun) disebabkan karena degenerasi sistim kolinergik

Reseptor kanal ion (ionotropik)Teraktivasi sebagai respon terhadap ligan

spesifikSelektif terhadap ion tertentuTerlibat dalam signaling sinaptik yang cepat

(yang lambat : melalui reseptor protein G)Contoh : reseptor asetilkolin nikotinik

reseptor GABAa

reseptor glutamat (NMDA)

reseptor serotonin (5-HT3)

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Kinetics, effect and fate

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DRUG-receptor INTERACTION

Kinetics of drug-receptor interaction

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Kinetics……..

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A + R [AR] Response

Rate of association= k1 [A][R]

Rate of dissociation = k2 [AR]At equilibrium:

Rate of association = rate of dissociationk1 [A][R] = k2 [AR] k2/k1 = [A][R]/ [AR] = kD

Kinetics…. (some assumptions)

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1.reaksi antara agonis dan reseptor adalah reversibel

2. kedua reaktan tersedia dalam bentuk bebas atau terikat dan tidak termasuk bentuk lain, mis hasil degradasi yang tidak terlibat dalam reaksi tersebut

3. Semua tempat di reseptor mempunyai affinitas yg sama terhadap agonis dan independen

Plot terhadap waktu….

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d([AR]/dt = k1[A][R] – k2[AR]

Plotting of [AR] as function of time yields an hyperbolic curve and asymptotic relationships for the formation of [AR] as equilibrium was approach

DRUG-RECEPTOR INTERACTION

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Difference in configuration

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Protein binding & drug effect

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Agonist & Antagonist

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Affinity & efficacy

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Competitive antagonism

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Type of antagonism

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Competitive antagonism: atropine, ipratropium, hyoscine for ACTH-receptor

Irreversible antagonism: phenoxybenzamine for α-adrenoceptor

Non-competitive antagonism: Ca-channel blockers

Chemical antagonism: protamine vs heparin

Physiological antagonism: prostacyclin against thromboxane A2

Kinetics of drug-receptor interaction

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Type of receptors

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Activation of receptor

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The role of Second messengers

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Farmacokinetics

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Adverse effect of drugs

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Adverse effect of drugs

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Adverse effect of drugs

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