principles of drug action
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Principles of Drug Action. Prinsip-prinsip aksi obat Sugiyanto Lab. Farmakologi & Toksikologi Fak . Farmasi UGM. General Overview. - PowerPoint PPT PresentationTRANSCRIPT
Prinsip-prinsip aksi obat
SugiyantoLab. Farmakologi & Toksikologi
Fak. Farmasi UGM
04/21/231
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)
04/21/2312 Reseptor Insulin
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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