ANALGETIKA

Hendra Wana Nur’aminDepartemen Farmakologi

Fakultas Kedokteran Universitas Lambung Mangkurat

• Pain “unpleasant sensory and emotional experience.”

• Analgetic any member of the group of drugs used to achieve analgesia — relief from pain

Analgetic• Non Steroid Anti-inflamatory Drugs (NSAIDs)• Opioid

NON STEROID ANTIINFLAMATORY DRUGS (NSAIDs)

Indikasi

Common Pharmacological Effects

• Analgesic (CNS and peripheral effect) may involve non-PG related effects

• Antipyretic (CNS effect) • Anti-inflammatory (except acetaminophen) due

mainly to PG inhibition

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Steroids work here

Steroids work here

NSAIDs work here

COX-1

COX-2

COX-3

• COX-1 membentuk prostaglandin (proses normal tubuh) proteksi mukosa lambung

• COX-2 berperan dalam peradangan• COX-3 varian dari COX-1, yang terdistribusi di sistem saraf pusat.

Tidak mempengaruhi lambung paracetamol

• Efek samping AINS terhadap asmaPenghambatan COX mengarahkan metabolisme asam arakidonat ke arah jalur lipoksigenase  leukotrien bronkokonstriksi

• COX 2 Selektif celecoxib, rofecoxib, valdecoxib.Penghambatan secara selektif terhadap COX-2 mengkatalisis pembentukan tromboksan A2 (pembekuan darah dan bersifat vasokonstriktor  blood clots

Untuk mengatasi efek obat NSAID terhadap lambung:• digunakan setelah makan• dalam bentuk bersalut selaput jangan digerus atau

dikunyah • Gangguan lambung sebelumnya, bisa diiringi

penggunaannya dengan obat-obat yang menjaga lambung seperti antasid, golongan H2 bloker seperti simetidin atau ranitidin, golongan penghambat pompa proton seperti omeprazol atau lansoprazol, atau dengan sukralfat.

FARMAKODINAMIK

SALISILAT• Indikasi : analgetik & antipiretik, pada sakit

kepala, nyeri sendi ringan-sedang, nyeri otot & saraf

• Sistemik, enteral: Aspirin, Na-salisilat, diflunisal, salsalat

• ES: iritasi saluran cerna salut enterik Aspirin : pencegahan infark miokard anti

agregasi platelet

ASAM FENILPROPIONAT• Indikasi: analgetik, antipiretik, antiinflamasi• Ibuprofen > aspirin: efektif untuk dismenor• Naproxen, fenoprofen, keteoprofen, flurbiprofen

antiinflamasi penyakit sendi

DERIVAT ASAM ASETAT• Indometasin: antiinflamasi penyakit sendi, dan PDA pada

neonatus• Toksik sebagai antipiretik dan analgetik• Tolmetin pengganti indometasin• Sulindak

DERIVAT PIRAZOLONMetampiron, fenilbutazon & oksifenbutazon• ES: diskrasia darah (leukopenia, agranulositosis, anemia

aplastik)• Alternatif terapi dari kolkisin

Asetaminofen (Paracetamol)• Efek analgetik & antipiretik (+)• Efek antiinflamasi (-)• Bekerja pada COX-3

OBAT LAIN

Asam mefenamat & diklofenak, meklofenamat• Analgetik, antipiretik & antiinflamasi• Asam mefenamat: meredakan nyeri ringan

sampai sedang sehubungan dengansakit kepala, sakit gigi, dismenore primer, termasuk nyeri karena trauma, nyeri otot dan nyeri sesudah operasi

EFEK SAMPING

SALISILAT• Iritasi GI (perdarahan, mual, muntah) 20%• Menurunkan ES :

• buffered & enteric coated• diberi bersama makanan, dan• konsumsi air yang banyak

• SSP salisilism (tinitus, penurunan pendengaran, vertigo)

• Aspirin menghambat agregasi platelet KI diberikan bersama antikoagulan lain

• Hipersensitif, asidosis respiratorik, asidosis metabolik • Gangguan hepar & ginjalAsetaminofen• Dosis tinggi: hepatitis, nekrosis hepar

NSAIDs lain• Iritasi GI • Diatasi dengan H2 blockers, omeprazol & misoprostol • Interaksi: antihipertensi (diuretik, antagonis B-

adrenergik, ACE inhibitor)• Gangguan ginjal & hepar, SSP

PENGHAMBAT SELEKTIF COX-2

Celecoxib, Rofexocib• Aman terhadap saluran cerna cocok untuk penderita

dispepsia• Meningkatkan kejadian penyakit kardiovaskular

NSAIDs

COX-2 specific NSAIDs: • Rofecoxib (Vioxx®)

• Launched in 1999• Marketed in 86 countries: 2.5 bill.$ /year• Recent trial to test Rofecoxib for efficacy in colorectal polyps treatment revealed an

increased risk of heart disease (+ 50%) after 18 month continuous use• Sept. 2004: Merck voluntarily withdrew Vioxx® from the market pending further

investigation.

• Celecoxib (Celebrex®)• April 2005: FDA required Pfizer to include a “boxed warning” indicating a potential

risk of cardiovascular side effects

• Valdecoxib (Bextra®)• April 2005: FDA required Pfizer to withdraw Bextra® from the market due to

unfavorable risk vs. benefit profile (mostly already known adverse skin reactions)

FARMAKOKINETIK

Opioid Analgesics

Opiates:• Alkaloids derives from Papaver somniferum• Already used 4000 B.C. (opius greek: “little juice”)• 1805: Morphine isolated (morpheus: Greek god of dreams)• 1874: synthesis of heroin (introduced in 1898 by Bayer as a cough medicine)• Opium tincture heavily used during civil war• Opiates freely available in the US until 1914• 1914: Harrison Act

Prevented physicians from maintaining addiction

Morphine was

first isolated by Friedrich Wilhelm Serturner in 1805.

Sertürner named his discovery after Morpheus, the Greek god of

dreams. Morpheus is the son of Hypnos,

the god of sleep.

RESEPTOR OPIOID

• Reseptor µ : analgetik, depresi napas, miosis, euforia, penurunan motilitas usus• µ1 : hanya di SSP

• µ2 : di perifer

• Reseptor κ : analgetik, depresi napas, miosis, sedasi < reseptor µ

• Reseptor δ : depresi napas • selektif untuk enkefalin

FARMAKODINAMIK

• Analgetik & narkosis• Analgetik muncul sebelum penderita tidur• Pada pasien nyeri, sedih gelisah euforia• Pada orang normal disforia

• Sedasi• Bila diberi bersama hipnotik & sedativa dan

antiemetik amnesia • Antitusif

• Bekerja di reseptor opioid pusat batuk SSP• Kodein, hidrokodon (+)• Dekstrometorfan (+) bukan di reseptor opioid

• Depresi pernapasan• Menurunkan respon batang otak terhadap CO2• Hati-hati jika diberikan bersama anestesi umum &

hipnotik-sedativa• Mual

• Merangsang CTZ

• Efek endokrin • aktivasi reseptor µ opioid

• Menghambat pelepasan LRH (mens tidak teratur & impotensi)

• Menghambat diuresis• Aktivasi reseptor κ opioid

• Menghambat ADH meningkatkan diuresis

• Miosis • Efek pusat di nukleus Edinger Westphal nervus III

• Efek kardiovaskular• Menurunkan TD• Bradikardi • Vasodilatasi, hipotensi & gatal lepasnya histamin

• Imunosupresi • Efek sentral menekan sistem imun : NK sel

Opioid Analgesics

Opiates:Morphine:

• CNS: • Sedation and drowsiness• Nausea (direct stimulation of the chemoreceptor trigger zone)• Cough suppressant (suppressive effect on medulla; independent of analgesic effect)

• Eyes: • Pupillary constriction (stimulate parasympathetic portion of the oculomotor nucleus)

• Respiratory system: • Strongly suppressive on all phases (frequency; volume)

• GI: • Decreased peristaltic movements, increased sphincter tonus => constipation

• Urinary tract: • Increased smooth muscle cell tone => urinary retention

Withdrawal symptoms:• Mostly autonomic hyperactivity: diarrhea, vomiting, chills, cramps, pain…

Opioid Analgesics

Codeine (3-methoxy-morphine):• Better oral absorption than morphine• Only 20% of analgesic effect of morphine

(does not increase significanly by increasing the dose)• Little euphoria => rarely addictive• GI and respiratory effects similar to morphine

(=> codeine and dihydrocodeine are widely used as antitussive)

Dextromethorphane (DXM):• Synthetic morphine derivative• Equally antitussive as codeine• Does not act through opioid receptors• No analgesic or GI effects

Opioid Analgesics

Heroin (diamorphine):• Diacetylated morphine• Used in UK as analgesic

(~2x more potent than morphine)

Hydrocodone (Vicodin®):• Often combined with NSAIDs

Meperidine (Pethidine):• Actions similar to morphine• Much shorter duration => used during labour

Methadone:• Actions similar to morphine• Significantly longer duration (t1/2 = >24 h) => less psychological dependence• Used to treat morphine and heroin addiction

Fentanyl:• High potency (allows use in transdermal delivery systems)• Short lasting: used in anesthesia and in patient-controlled infusion systems

Opioid Analgesics

Opiate antagonists:• Naloxone:

• Short acting• Rapidly reversed opoid-induced analgesia and

respiratory suppression• No effect if no opioids are present• Used to treat opiate overdoses and to improve breathing

in newborns whose mothers received opioids• Induces severe withdrawal symptoms in opioid addicts

• Naltrexone:• Similar to naloxone, but much longer duration of action • Used to “protect” detoxified addicts by preventing any

opioid effect if the patient relapses

TOLERANSI• Perlu dosis lebih tinggi untuk menghasilkan efek

farmakologi Diperantarai oleh reseptor µ opioid dan dilawan dengan

antagonis opioid Perubahan selular masih belum jelas Dapat terjadi toleransi silang

Morfin >< metadon; meperidin

KETERGANTUNGAN FISIK• Menyebabkan abstinence

atau withdrawal syndrome

• Menyebabkan gangguan otonom, somatik, endokrin, psikologis.

• Nyeri dan tidak menyenangkan tapi TIDAK MENGANCAM NYAWA

PENYALAHGUNAAN• Menyebabkan mood

positif EUFORIA• Tidak terjadi pada dosis

terapi

Opioid

• Keracunan obat-obat golongan opioid banyak terjadi karena kecanduan atau penyalahgunaan.

Gejala-gejala:• mual, muntah • pusing• kulit dingin• pupil kecil• depresi nafas• koma

Opioid Poisoning

Opioid

Penatalaksanaan: • Bila ada depresi

nafas, berikan nalokson HCl

• Bila tidak ada depresi nafas, simptomatik saja.

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References• Basic & Clinical Pharmacology by Bertram G. Katzung(11th Edition). The

McGraw-Hill Companies Inc, 2009• Goodman & Gilman’s Manual of Pharmacology and Therapeutics (11th ed),

2008• Farmakologi dan Terapi FK UI (edisi 5). Jakarta: FK UI, 2007• DiPiro JT, et al. Pharmacotherapy: A Pathophysiologic Approach 6th Ed. San

Fransisco: McGraw Hill, 2005• Morgan GE. Clinical Anesthesiology, 4th Edition. McGraw-Hill Companies,

Inc, 2006

05/03/2023 46Contact: hendranuramin@gmail.com