Analgesik-Antipiretik & Antiinflamasi PDF

ANALGESIK-ANTIPIRETIK dan ANTIINFLAMASI (NONSTEROID ANTIINFLAMASI) ANALGESIK : menghilangkan/mengurangi nyeri ringan sampai sedang ANTIPIRETIK : menurunkan demam ANTIINFLAMASI : menanggulangi keradangan Analgesics Definition Drugs that selectively inhibit...

ANALGESIK-ANTIPIRETIK dan ANTIINFLAMASI (NONSTEROID ANTIINFLAMASI) ANALGESIK : menghilangkan/mengurangi nyeri ringan sampai sedang ANTIPIRETIK : menurunkan demam ANTIINFLAMASI : menanggulangi keradangan Analgesics Definition Drugs that selectively inhibit the perception (sensation) of the pain Classification 1- Peripheral (miscellaneous): - Causal - Non-causal 2- Central: - Narcotic - Non-narcotic Types of Pain Superficial: - Stimulation of skin & mucous membranes - Fast response Deep: - Arises from muscles, joints, tendons, heart..etc. - Slow response Peripheral Analgesics Causal Non-causal -Treat the cause - Not treat the cause Example: Examples: Atropine (antispasmodic) 1- Local anaesthetics (for superficial tumor) 2- Counter-irritant (apply pain that counteract or mask the original one e.g. acupuncture)  Classification of Analgesics Analgesics Mild Strong Analgesics Analgesics Aspirin Ibuprofen Opium Heroin Codeine Acetaminophen Central Analgesics Non-narcotic Narcotics - NSAID The class - Opioids (morphine & morphine like drugs) Examples 1- Natural (as codeine) 1- Aspirin 2- Semi synthetic e.g. 2- Paracetamol di-hydromorphine& 3- Diclofenac diacetylmorphine 4- Piroxicam (heroin) 3- Synthetic e.g. 5- Ibuprofin pethidine 6- Ketoprofin 4- Endogenous opiates as endorphins & encephalins Central Analgesics Non-narcotic Subcortical “thalamus” Narcotics Site of Cortex & thalamus action No antagonist Antagonist Naloxone, nalorphine & levallorphan Dull pain e.g. headache, toothache & Uses Sever & deep pain e.g. backache cancer, MI & anginal pian Low Potency High No addiction. ↑in bleeding tendency Side effect Addiction & ulcer MOA ‡ of opiates receptors Inhibits prostaglandin synthesis (m, k ,s, d) and relief the by inhibition of cycloxygenase pain through the release of enzyme endorphines & encephalins Screening Methods For Analgesics Principle Pain is induced to a suitable animal and the response of the animal to the painful stimuli is recorded before and after administration Screening methods Narcotics: 1- Thermal method a- Hot plate b- Tail flick 2- Mechanical method Screening methods Non-narcotic: 1- Electrical method 2- Chemical ( Writhing method) Hot – plate Material Animal: Mouse Instrument: Hot plate analgesiometer Painful stimulus: Heat (55°C) Drug used: Morphine Tail-flick Material Animal: Mouse Instrument: Tail-flick analgesiometer Painful stimulus: Heat (by apply a beam of light 130°C) Drug used: Morphine Writhing Method Principle: The painful stimulus is induced by IP injection of an irritant substance (e.g. acetic acid) Writhing: Stretching of the body, withdrawing of the limb, retraction of the abdomen & the stomach touches the ground Writhing Method Material Animal: Mouse Painful stimulus: Chemicals e.g. acetic acid Drug used: NSAID e.g. Na salicylate Drug Onset of writhing No. of writhing Acetic acid (control) Na salicylate (100mg/kg) Na salicylate (200mg/kg) ANALGESIK OPIOID : sifat seperti Opium/Morfin menghilangkan nyeri sedang sampai berat dapat menimbulkan adiksi  Cedera Jaringan Pelepasan mediator kimia Vasokostriksi Hist, Kinin, PG (sementara) vasodilatasi permeabilitas nyeri demam kapiler ↑ eritema edema nyeri panas (kongesti (penimbunan (uj. syaraf& (vasodi darah) car&sel) bengkak) latasi) hilangnya fungsi  Stimulus Gangguan pd membran sel Phospholipase inhibitors Phospholipids Corcoticosteroids Phospolipase Fatty acid substitution (diet) Arachidonic acid NSAID. ASA Lipoxygenase inhibitors Cyclo-oxygenase Lipoxygenase Leukotrienes Receptor level antagonists LTB4 LTC4 / D4 / E4 Prostaglandins Thromboxane Prostacyclin Alteration of vascular Phagocyte permeability, bronchial Leukocyte attraction, constriction, increased modulation activation secretion Colchicine Bronchospasm, Inflamasi congestion, Inflamasi mucus plugging Enzim Siklo-Oksigenase Siklo – oksigenase 1 (COX-1) : Lambung , Usus, Ginjal, Platelet Siklo– oksigenase 2 (COX-2) : inflamasi  Nonselective COX Inhibitors Salicylicacid derivates : aspirin, sodium salicylates, salsalate, diflunisal, sulfasalazine, olsalazine Para-aminophenol derivatives : acetaminophen Indole & indene acetic acids : indomethacin, sulindac Heteroaryl acetic acids : tolmetin, diclofenac, ketorolac Arylpropionic acids : ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin Anthranilic acids (fenamates) : mefenamic acid, meclofenamic acid Enolic acids : oxicams (piroxicam, meloxicam) Alkanones : nabumetone  Selective COX-2 Inhibitors Diaryl-substituted furanones : rofecoxib Diaryl-substituted pyrazoles : celecoxib Indole acetic acids : etodolac Sulfonanilides : nimesulide ASPIRIN Asam Asetil Salisilat = Asetosal Batang pohon willow (Leroux; 1829)  Antipiretik Prototipe dari NSAID Penghambat non-selektif COX-1 & COX-2  Farmakodinamik Efek Analgesik : menghambat sintesis PGE&PGI Efek Antipiretik : memperbaiki fungsi termostat di hypothalamus, hambatan sintesis PGE2 me ↑ pengeluaran keringat, vasodilatasi perifer Efek Antiinflamasi : hambatan sintesis PGE2 & PGI2 tidak menghambat migrasi sel  Efek pada darah : waktu perdarahan >> hipoprotrombinemia platelet disfungsi  menghambat agregasi Efek pada metabolisme : dosis >  hiperglikemia  glukosuria  Efek pada kelenjar endokrin : – dosis >  hiperglikemia – rangs hypothalamus  steroid bebas darah > Efek pada SSP : – dosis >  intoksikasi – salisilismus  pusing, bingung, tinitus, vertigo  Efek anti Gout : – dosis > (5 gr)  hambt reabs  urikosurik – dosis < (1-2gr)  hambt sekresi  eks < Efek pada G.I. tract : – iritasi lokal: difusi kembali asam lambung ke mukosa  kerusakan jaringan – sistemik: hambatan sints PGE 2 & PGI 2 (hambatan sekresi asm lambung & merangsang sekresi mukus bersifat sitoprotektif)  Efek pada pernapasan : – dosis tx  respirasi alkalosis terkompensasi – dosis > → depresi pernafasan Efek pd hepar & ginjal : – hambatan PGE2  gangguan hemostasis ginjal – SGOT & SGPT ↑  hepatomegali, ikterus  Farmakokinetik Topikal : Asam salisilat; Metil salisilat Distribusi : – Seluruh jaringan tubuh & cairan transelular – Cairan sinovial, spinal, peritoneal, liur, ASI – Menembus sawar otak & uri Metabolisme : di hepar Ekskresi : - Urine >>>> - Keringat > - Empedu >  Efek samping : Iritasi lambung Allergi Kemungkinan peningkatan perdarahan Penggunaan klinis : Analgesik- Antipiretik Demam reumatik akut Reumatoid artritis Mencegah trombus Kontra Indikasi : Ulkus peptikum Haemophylia Allergi PARA AMINO FENOL Fenasetin; Asetaminofen; Asetanilid Parasetamol Digunakan pertama tahun 1893 Menghambat sintesis PG di sentral Efek analgesik & antipiretik serupa Aspirin Antiinflamasi , alergi  Dipiron Analgesik-antipiretik Antiinflamasi lemah Penggunaan klinis : menurunkan demam  penyakit hodgkin ASAM MEFENAMAT Analgesik Antiinflamasi < ESO: iritasi lambung, diare pada px tua, hipersensitivitas, gangguan fungsi ginjal  jangan > 7 hari KI: bumil, < 14 tahun  AS. PROPIONAT Ibuprofen, Naproksen  kurang toksik Ketoprofen, As. Tiaprofenat Analgesik, Anti inflamasi 45 jm  1/hari Penggunaan klinis – reumatoid artritis – osteo artritis – spondilitis ankilosa KI: bumil  NABUMETON Pro-drug  metabolitnya aktif hambat enzim COX Tidak bersifat asam Tidak menghambat prostasiklin yang bersifat sitoprotektif ESO relatif < Penggunaan klinis: Reumatoid Artritis Osteoartritis  MELOXICAM (MOVI - COX) Selektif menghambat COX-2 Efek saluran cerna & ginjal (-) Penggunaan Klinis: Reumatoid Artritis Osteoartritis CELECOXIB (CELEBREX) Hambat PG terutama COX-2 Antiinflamasi, analgesik & antipiretik Pengaruh agregasi platelet; edema (-) Penggunaan klinis: Reumatoid Artritis, Osteoartritis Hati–hati: asma, hipertensi, gangguan jantung & ginjal, bumil, busu, < 18 tahun NIMESULIDE Golongan Sulfonanilide Antiinflamasi, analgesik & antipiretik Hambat PG terutama COX-2 Iritasi lambung < GOUT Penumpukan asam urat pada sendi-sendi, ginjal dan pada jaringan lain Pengobatan 1. Mengatasi serangan gout akut – Kolkisin – NSAID – Steroid 2. Menurunkan kadar asam urat dalam darah 1. Mengatasi serangan gout akut 2. Menurunkan kadar asam urat dalam darah, 2 cara: 1. Meningkatkan ekskresi asam urat: Probenesid Sulfinpirazon 2. Menghambat sintesa asam urat : Alopurinol Strong Analgesics Only Available by prescription Used to relieve severe pain associated with injuries, heart attacks, or chronic diseases such as cancer Most strong analgesics are derived from the opium poppy or synthetically produced Basically three types: Natural, semi-synthetic, and synthetic Morphine Naturally occurring in the poppy- Only needs to be isolated Very strong pain reliever but also very addictive (2nd to Heroin) Usually injected but can be smoked, sniffed or swallowed Commonly used in hospitals Large illegal street culture Codeine Most commonly used strong analgesic Similar to Morphine except for the replacement of a (OH- ) group for (OCH3) group Commonly used with Tylenol as a more mild analgesic 1/6 as strong as Morphine and less addictive Heroin Originally sold as cough suppressant and pain killer10 times stronger than Morphine Incredibly addictive (many times, other strong analgesics are needed for withdrawal) Heroin Synthesized from Many other problems morphine in a are associated with esterification reaction heroin addiction with acetyl chloride including as It is absorbed by the prostitution and AIDS. brain very quickly resulting in a potent high Other Synthetic Strong Analgesics Vicodin Is solution of acetaminophen and hydrocodone (the latter being the stronger) Hydrocodone is addictive and can cause highs. Usually taken orally Stronger than codeine but not as strong than Morphine  Synthetic Strong Analgesics (Opioids) The active area of morphine has been identified and can be synthesized. This has produced many synthetic analgesics and has allowed scientists to eliminate some of the harmful side effects of more natural analgesics. Demerol Demerol (Meperidine) Used for moderate to severe pain and to stop muscle spasms. Usually injected or taken orally.  Methadone Compared to most strong analgesics it is weaker. Has been synthesized to not have euphoric properties and mild withdrawal effects but is still addictive. Used as an analgesic but most commonly to help in the withdrawal for Heroin addicts. Mechanism of Strong Analgesics The human body contains “natural opiates” in the brain called endorphins These are produced in the body during extreme conditions such as “running high” and extreme injuries. When these are absorbed by receptors in the brain the body feels analgesia and the pain is reduced. Mechanism of Strong Analgesics cont. Opiates derived from the poppy act in the same way as endorphins but are not natural to the human body. The “high” is produced because of the absorption of opiates is quicker than endorphins Drugs such as naloxone act to fill the receptors in the brain but are not analgesics and thus are used to prevent overdoses on analgesics. Endorphins are not used as analgesics because the cannot be stored and are unstable.  Side Effects of Strong Analgesics Short term Long Term Dulling of Pain Addiction and very strong Euphoria withdrawal effects Slow Nervous system Constipation Slowed heart rate Loss of libido Loss of cough reflex Disruptions in Nausea menstruation “Cross-tolerance” Overdoses can lead to death Loss of appetite Possibility of stroke Problems associated with Overall slowdown of buying street drugs i.e. biological systems sharing needles AIDS and prostitution.  Local Anesthetics -- Cocaine Cocaine used in 1885 as a local anesthetic. Extracted from the plant Erythoxylum coco ([1R-(exo,exo)]-3-(Benzoyloxy)-8-methyl-8- azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester  History of Cocaine Coca leaves have been chewed by South American Indians for thousands of years. There were used to induce feelings of euphoria Was banned by Spanish settlers in the 1500s but the ban was repealed when it became apparent that slaves worked harder while on it United States cocaine was used in soft drinks until it was classified as narcotic in 1914 Clinically used as a local anaesthetic for eye operations and in modified synthetic forms for dental treatment (novocaine) and sore throats (benzocaine)  Cocaine The leaves of the coca plant contain 0.6% - 1.8% alkaloidal cocaine To extract, cocaine leaves are soaked in kerosene and sulfuric acid HCl is added creating cocaine hydrochloride, which can be extracted as powdery flakes or rocks  Clinical Action Acts as a reuptake blocker for the monoamines dopamine, norepinephrine and serotonin interacts with serotonin and muscarinic acetylcholine receptors and the sodium channels influence on the axonal voltage-gated sodium channels that provides cocaine's local anaesthetic properties  Effects of Cocaine Subjective Physiological Euphoria Increased heart rate Increased Increased respiration sociability rate Increased energy Increased body Hyper vigilance temperature Increased blood pressure Pupil dilation  Derivatives of Cocaine Cocaine is too addictive and in appropriate for medicinal use Two derivatives of cocaine are widely used as local anesthetics – Procaine or Novacaine – Lidocaine  Procaine (Novacaine) Novacaine Principal use in dentistry for temporary numbing of mouth area First synthesized in 1905 and was the first injectable man-made local anesthetic Restricts blood vessels, reducing bleeding  Lidocaine Lidocaine First modern local anesthetic agent Sodium channel blocker Administered parenterally for ventricular arrhythmias, subcutaneously for minor surgical procedures, and topically to mucosal surfaces prior to invasive procedures  why where what who how TERIMA KASIH