farmakodinami dasar
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FARMAKODINAMI Dr. dr. nurdiana, Mkes Lab. Farmakologi FKUB DOSIS (R/) DOSIS YG DIMINUM Faktor-2 FK A D M E KONSENTRASI OBAT DI TEMPAT KERJA Faktor-2 FD reseptor homeostatik EFEK / RESPON Px terapeutik toksik Fisiologik Patologik Genetik Umur Interaksi 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 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) 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 LOCUS OF ACTION “RECEPTORS” Bound ABSORPTION Free TISSUE RESERVOIRS Free Bound Free Drug Bound Drug SYSTEMIC CIRCULATION BIOTRANSFORMATION EXCRETION 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 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) 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 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 Antagonis ireversibel ikatan dg reseptor dpt digeser oleh agonis (Emax sama, ED50 beda) ikatan dg reseptor kuat, Emax lebih rendah FUNCTIONAL ANTAGONISTS 1. Physiologic Antagonists 2. 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 *RESEPTOR TRANSMEMBRAN - IKT. ENZIM - KANAL ION - IKT. G-PROTEIN *RESEPTOR DI SITOSOL KOMUNIKASI SEL INTRA SEL ANTAR SEL TRANSDUKSI SINYAL MOLEKUL LIGAND 1ST messenger RESEPTOR ( TARGET SEL) EFEKTOR 2nd messenger (cAMP, IP3, DAG) EFEK BIOLOGI Komunikasi sel Classification Receptor Transduction Mechanisms 1. 2. 3. 4. 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 In G X Y P gene Change in the Receptor activation cons.of second messenger of a G protein G prot regulation of an enzyme or ion channel Inactivation mechanism The Major Effectors and Intracellular Second Messengers in GPCR Systems Effector 2nd messenger adenylyl cyclase cyclic AMP (cAMP) phospholipase C calcium, DAG, and phosphoinositide (IP3) Obat dan Efek D +R DR Efek agonis adr beta Gs GDP GTP ATP GDP Adenilat siklase GTP Enzim ATP cAMP R2C2 Protein kinase 2C ADPEnzim-PO4 2R 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 Protein RNA mRNA R drug Plasma Speed of responses Agonist vs antagonist K+1 Ag + R K-1 Ag K+1 Ant + R K-1 Ant Response 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 BASAANTASIDA Mg(OH)2, Al (OH)3 PERUBAHAN SIFAT OSMOTIK DIURETIK OSMOTIKUREA, MANITOL GLISEROLMENGURANGI OEDEM SEREBRAL GANGGUAN FUNGSI MEMBRANANESTESI UMUMETER HUBUNGAN DOSIS-RESPON Graded dose-responses One tissue/organ can yield the full response range Response Full agonist Agonist concentration [A] •Emax & ED50 Response Emax ½ Emax I I I I ED50 I I I ED100 Log concentration [A] I Therapeutic and Toxic Effects are Dose-Related: Phenobarbital Sleep ED50 Death LD50 Dose of Phenobarbital Autonomic Pharmacology Central Nervous System (CNS) Peripheral Nervous System Somatic Nervous System Autonomic Nervous System (ANS) Sympathetic Branch Parasympathetic Branch “Feed or Breed” “Fight or Flight” Autonomic Nervous System Characteristics 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 Cholinergic 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 Neruroeffector junction Space between nerve cells Specialized synapse between two nerve cells or a nerve cell and an organ Neurotransmitter Chemical messenger that conducts a nervous impulse across a synapse PREGANGLION POST GANGLION PARASIMPATIS Otot jantung ACH NIC ACH MUS Otot polos < < Glandula MEDULLA ACH NIC ACH MUS < SPINALCORD SIMPATIS Kel. Keringat < ACH NIC < < NE alpha beta ACH NIC < D1 D < ACH NIC < EPINEPRINE SIMPATIS Otot jantung Ot.polos p darah SIMPATIS Pemb. Darah Ginjal ADRENAL MEDULLA ACH NIC < VOLUNTARY MOTOR NERVE SOMATIC Otot rangka Neurotransmission Neurotransmitters Acetylcholine 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 [email protected] [email protected]