FARMAKODINAMI Dr. dr. nurdiana, Mkes Lab. Farmakologi FKUB

EFEK / RESPON Px DOSIS (R/) DOSIS YG DIMINUM Fisiologik Patologik Faktor-2 FK A D M E Fisiologik Patologik Genetik Umur Interaksi KONSENTRASI OBAT DI TEMPAT KERJA Faktor-2 FD reseptor homeostatik EFEK / RESPON Px terapeutik toksik

Food-Drug Interaction For example, a drug that causes chronic nausea or mouth pain may result in poor intake and weight loss

PRINSIP KERJA OBAT Obat tidak menimbulkan fungsi baru, tetapi mempengaruhi/memodulasi fungsi yang sudah ada Tidak ada obat yang mempunyai efek tunggal (efek terapeutik dan efek samping) Efek obat ditentukan oleh interaksinya dengan proses biologi di tubuh  mengubah kecepatan kegiatan faal tubuh Drugs do not produce new function modify existing functions

EFEK OBAT (farmakologi): Efek terapi  efek obat yang dikehendaki untuk tujuan terapi, timbul pada dosis terapi Efek samping efek obat yang tidak dikehendaki, timbul pada dosis terapi, sering merugikan, dapat berupa efek farmakologi yang lain atau reaksi hipersensitif (alergi) Efek toksik  efek obat yang tidak dikehendaki, timbul pada dosis toksik/ supramaksimal

Tolerans : terjadi pada tingkat f.kinetik & f.dinamik Resistens Takhifilaksis Idiosinkrasi

Sinergisme : Efek kombinasi dari 2 (/lebih) Sinergisme : Efek kombinasi dari 2 (/lebih) macam obat yang saling menunjang Addisi : Bentuk sinergisme obat dimana efeknya merupakan efek penambahan obat tersebut (mis. 1+1=2) Potensiasi : Bentuk sinergisme obat dimana efeknya lebih besar dari efek penambahan masing-masing obat (mis. 1+1>2) Antagonis : Efek 2 macam obat yang berlawanan

Bound Free Free Bound ABSORPTION Free Drug EXCRETION Bound Drug LOCUS OF ACTION “RECEPTORS” TISSUE RESERVOIRS Bound Free Free Bound ABSORPTION Free Drug EXCRETION SYSTEMIC CIRCULATION Bound Drug BIOTRANSFORMATION

EFEK OBAT INTERAKSI OBAT DENGAN RESEPTOR PADA SEL SUATU ORGANISME PERUBAHAN BIOKIMIAWI DAN FISIOLOGI RESPON (KHAS UTK MASING-MASING OBAT)

Farmakodinami mempelajari : Efek obat (biokimiawi & fisiologis) pada sistim biologik serta mekanisme kerjanya Efek obat : Sebag besar ok interaksi obat dg reseptor, sebagian lagi tdk melalui resept Reseptor obat : Makromolekul (protein) pada sistim biologik yang dapat merubah fungsi sistim tsb ok interaksinya dg obat

Definisi Efficacy Potency Derajat kemampuan obat menghasilkan respon yang diinginkan Potency Jumlah obat yang dibutuhkan untuk menghasilkan respon terhadap obat Digunakan untuk membandingkan komponen kandungan di dalam golongan obat

Definisi Effective Concentration 50% (ED50) Lethal Dose 50% (LD50) Concentration of the drug which induces a specified clinical effect in 50% of subjects Lethal Dose 50% (LD50) Concentration of the drug which induces death in 50% of subjects

Definisi Therapeutic Index Margin of Safety Measure of the safety of a drug Calculation: LD50/ED50 Margin of Safety Margin between the therapeutic and lethal doses of a drug

Dose-Response Relationship Drug induced responses are not an “all or none” phenomenon Increase in dose may: Increase therapeutic response Increase risk of toxicity

RESEPTOR  UNTUK LIGAND ENDOGEN OBAT hormon nerotransmiter AGONIS : SUBSTANSI YANG EFEKNYA MENYERUPAI SENYAWA ENDOGEN/LIGAND ANTAGONIS : MENGHAMBAT EFEK SUATU AGONIS DI TEMPAT IKATAN AGONIS Kompetitif Non kompetitif

Agonis obat yang mampu berikatan dg reseptor dan menimbulkan efek (afinitas +, aktivitas intrinsik +) Antagonis obat yang mampu berikatan dg reseptor tetapi tidak dapat menimbulkan efek (afinitas +, aktivitas intrinsik - ) Antagonis kompetitif ikatan dg reseptor dpt digeser oleh agonis (Emax sama, ED50 beda) Antagonis ireversibel ikatan dg reseptor kuat, Emax lebih rendah

FUNCTIONAL ANTAGONISTS Physiologic Antagonists Chemical Antagonist

Agonists and Antagonists Physiologic ANTAGONIST A drug that binds to a non-related receptor, producing an effect opposite to that produced by the drug of interest. Its intrinsic activity is = 1, but on another receptor. Glucocorticoid Hormones  Blood Sugar Insulin  Blood Sugar

Agonists and Antagonists Chemical ANTAGONIST A chelator (sequester) of similar agent that interacts directly with the drug being antagonized to remove it or prevent it from binding its receptor. A chemical antagonist does not depend on interaction with the agonist’s receptor (although such interaction may occur). Heparin, an anticoagulant, acidic If there is too much  bleeding and haemorrhaging Protamine sulfate is a base. It forms a stable inactive complex with heparin and inactivates it.

Polar Nonpolar Polar

RESEPTOR KOMUNIKASI SEL INTRA SEL ANTAR SEL *RESEPTOR TRANSMEMBRAN - IKT. ENZIM - KANAL ION - IKT. G-PROTEIN *RESEPTOR DI SITOSOL KOMUNIKASI SEL INTRA SEL ANTAR SEL

TRANSDUKSI SINYAL Komunikasi sel MOLEKUL LIGAND 1ST messenger RESEPTOR ( TARGET SEL) EFEKTOR 2nd messenger (cAMP, IP3, DAG) EFEK BIOLOGI Komunikasi sel

Classification Receptor  Transduction Mechanisms Ion channel linked receptors e.g. Ach nicotinic (Na+) and GABA (Cl-) G protein & second messenger generation, adenylate cyclase stimulation or inhibition - cAMP, guanylate cyclase - cGMP, phospholipase C - IP3,DAG Some receptors are themselves protein kinases Intracellular receptors (e.g. corticosteroids, thyroid hormone)

Transmembrane Signaling Mechanisms = drug     Out G In  X Y P gene

Change in the cons.of second messenger Inactivation mechanism Receptor activation of a G protein G prot regulation of an enzyme or ion channel

The Major Effectors and Intracellular Second Messengers in GPCR Systems cyclic AMP (cAMP) calcium, DAG, and phosphoinositide (IP3) Effector adenylyl cyclase phospholipase C

Obat dan Efek D + R DR Efek agonis adr beta    GTP Enzim ATP ADP Gs   Adenilat  siklase GTP GDP GTP GDP Enzim ATP cAMP ATP ADP R2C2 Protein kinase 2C 2R Enzim-PO4 EFEK

Mechanism of beta-1 receptor activation in cardiac muscle

Effect of beta-2 receptor activation on smooth muscle

Effect of alpha-1 /muskarinik3(M3) receptor activation of smooth muscle contraction

Intracellular Mechanism: Steroid Nucleus XXXXXXXXXXXXX  Effects R RNA Protein mRNA    R drug Plasma

Speed of responses

Agonist vs antagonist Ag K+1 K-1 Ant + Response R R

Agonist & Antagonist

Agonist & Antagonist

PENGATURAN FUNGSI RESEPTOR BILA SUATU SEL DIRANGSANG TERUS MENERUS OLEH AGONISNYA  DESENSITISASI BILA RANGSANGAN PADA RESEPTOR BERKURANG SECARA KRONIK, MISAL PEMBERIAN  BLOCKER JANGKA PANJANG  SUPERSENSITIVITAS (HIPERAKTIVITAS) TERHADAP AGONIS

Faktor faktor yg mempengaruhi Farmakokinetik & Farmakodinamik Umur : bayi, lansia Interaksi : makanan, obat Farmaseutik Farmakokinetik Farmakodinamik

Individual patient variations in drug responses Body weight and composition Age of client(young and old) Diet and Nutrition Ethnic origin Genetics Pathophysiology(eg. Kidney disease, liver disease etc.) Immunity Psychology Environment

OBAT YANG BEKERJA MELALUI RESEPTOR : Contoh : OBAT YANG BEKERJA PADA SISTEM SARAF OTONOM AGONIS NOREPINEFRIN  RESEPTOR ADRENERGIK 1 ADRENALIN/EPINEFRIN RESEPTOR ADRENERGIK  DAN  SALBUTAMOL  RESEPTOR ADRENERGIK 2 ASETILKOLIN  RESEPTOR NIKOTINIK DAN MUSKARINIK ANTAGONIS/BLOCKER PRAZOSIN  ANTAGONIS RESEPTOR ADRENERGIK 1 PROPRANOLOL  ANTAGONIS RESEPTOR ADRENERGIK 1 ATROPIN  ANTAGONIS RESEPTOR MUSKARINIK

OBAT YANG BEKERJA TIDAK MELALUI RESEPTOR : PERUBAHAN ASAM BASAANTASIDA  Mg(OH)2, Al (OH)3 PERUBAHAN SIFAT OSMOTIK  DIURETIK OSMOTIKUREA, MANITOL GLISEROLMENGURANGI OEDEM SEREBRAL GANGGUAN FUNGSI MEMBRANANESTESI UMUMETER

HUBUNGAN DOSIS-RESPON Graded dose-responses One tissue/organ can yield the full response range Full agonist Response Agonist concentration [A]

Emax & ED50 Emax ½ Emax ED50 ED100 Response Log concentration [A] I I I I I I I I ED50 ED100 Log concentration [A]

Therapeutic and Toxic Effects are Dose-Related: Phenobarbital Sleep Death % Responding ED50 LD50 Dose of Phenobarbital

Autonomic Pharmacology Central Nervous System (CNS) Peripheral Nervous System Somatic Nervous System Autonomic Nervous System (ANS) Sympathetic Branch Parasympathetic Branch

Autonomic Nervous System Characteristics “Fight or Flight” “Feed or Breed”

ANS Anatomy & Physiology The nerves of the ANS exit the CNS and subsequently enter specialized structures called “autonomic ganglia” Preganglionic fibers Pass between the central nervous system and the ganglia Postganglionic fibers Pass between the ganglia and the effector organ

Sympathetic versus Parasympathetic Sympathetic ganglia Located close to the spinal cord or midway between the spinal cord and the effector organ Parasympathetic ganglia Located close to or within the walls of the target organs

Cholinergic and Adrenergic Fibers Fibers that release acetylcholine All preganglionic and postganglionic of the parasympathetic division Adrenergic Fibers that release norepinephrine Most postganglionic fibers of the sympathetic division are adrenergic, but some are cholinergic

Neurochemical Transmission No actual physical connection exists between two nerve cells or between a nerve cell and the organ it innervates Synapse Space between nerve cells Neruroeffector junction Specialized synapse between two nerve cells or a nerve cell and an organ Neurotransmitter Chemical messenger that conducts a nervous impulse across a synapse

< < < < < < < < < < MEDULLA SPINALCORD PREGANGLION POST GANGLION PARASIMPATIS Otot jantung Otot polos Glandula SIMPATIS Kel. Keringat Ot.polos p darah Pemb. Darah Ginjal SOMATIC Otot rangka ACH NIC ACH MUS < < MEDULLA SPINALCORD < ACH NIC ACH MUS < < ACH NIC < NE alpha beta ACH NIC < D1 D < ACH NIC < EPINEPRINE ADRENAL MEDULLA ACH NIC < VOLUNTARY MOTOR NERVE

Neurotransmission

Neurotransmitters Acetylcholine Norepinephrine Preganglionic nerves of sympathetic nervous system Preganglionic and postganglionic nerves of the parasympathetic nervous system Norepinephrine Postganglionic nerves of the sympathetic nervous system

Acetylcholine For cholinergic synapses acetylcholine molecules combine with cholinergic receptor molecules Nicotinic Receptors Produces an excitatory response Muscarinic Receptors Produce an excitatory or inhibition, depending on where the target receptors are found

Norepinephrine For adrenergic synapses norepinephrine molecules combine with adrenergic receptor molecules Alpha Receptors Blood vessels Beta Receptors Heart Lungs

selamat belajar farmako@fk.unibraw.ac.id nurdianafarmako@yahoo.com