Departemen Farmakologi Fakultas Kedokteran UNISSULA POISONS, &

 Every natural or synthetic chemical can cause injury if the dose is high enough.  Poisons are chemicals that can injure or impair body functions.  Toxins are mostly described as substances produced by microorganisms.  Venoms are substances injected by one species into another.  Venoms and toxins are mostly proteins or polypeptides.  Many of toxins and poisons are alkaloids (drugs of plant origin).

KLASIFIKASI KERACUNAN MENURUT CARA TERJADINYA 1. Self poisoning • Minum obat dengan dosis >> tapi dengan pengetahuan dosis ini tidak berbahaya • Hanya untuk menarik perhatian, tidak untuk bunuh diri, sering insektisida 2. Attempted suicide Ada maksud untuk bunuh diri, sering barbiturat & hipnotik-sedatif 3. Accidental poisoning Jelas kecelakaan, tanpa faktor kesengajaan, sering terjadi pada anak usia <5 tahun 4. Homicidal poisoning Tindakan kriminal KLASIFIKASI KERACUNAN MENURUT MULA WAKTU TERJADINYA

1. Keracunan akut Terjadi mendadak  diagnosa lebih mudah ditegakkan Sering mengenai banyak orang Gejala sering menyerupai sindrom penyakit (toxidrom)

2. Keracunan kronik Gejala timbul perlahan & lama sesudah pajanan  diagnosis sulit ditegakkan Ciri khas : zat penyebab diekskresi >24 jam, t1/2 panjang  akumulasi Manifestasi kronik pada tertentu oleh zat kimia dg t1/2 pendek akibat akumulasi (ex : nekrosis papila ginjal akibat analgesik) Route of exposure : Direct contact Ingestion Inhalation Toxicokinetics

Toxicodynamics

Toksikokinetik & Toksikodinamik  Toksikokinetik: ADME suatu (racun)  Volume of distribution  Volume semu suatu senyawa didistribusi ke seluruh tubuh  Large Vd (>5 L/kg), co., antidepresan, opioid, verapamil, propranolol, antipsikotik, antimalaria  Small Vd (<1 L/kg), co., salisilat, etanol, litium, fenitoin  Klirens Volume plasma yang dibersihkan dari obat per satuan waktu  Klirens total = klirens ginjal + klirens hepar + klirens organ lain  Pasien keracunan  Obat melukai epitel barier saluran cerna ↑ absorpsi obat  Kapasitas hepar untuk memetabolisme obat terbatas ↑ obat di sirkulasi  Kapasitas ikatan protein plasma terbatas ↑ obat bebas dalam sirkulasi

TOXICOKINETICS & TOXICODYNAMICS

 Toxicokinetics, which is analogous to pharmacokinetics, is the study of the absorption, distribution, metabolism, and excretion of a xenobiotic under circumstances that produce toxicity or excessive exposure.  Toxicodynamics,which is analogous to pharmacodynamics, is the study of the relationship of toxic concentrations of xenobiotics to clinical effect.  Xenobiotics are all substances that are foreign to the body.

ABSORPTION

 Absorption is the process by which a xenobiotic enters the body. Both the rate (ka) and extent of absorption (F) are measurable and important determinants of toxicity.  The rate of absorption often predicts the onset of action, whereas the extent of absorption (bioavailability) often predicts the intensity of the effect and depends, in part, on first-pass effects. A xenobiotic must diffuse through a number of membranes before it can reach its site of action.  Absorpsi adalah proses di mana xenobiotik memasuki tubuh. Baik laju (ka) dan tingkat penyerapan (F) merupakan penentu toksisitas yang terukur dan penting.  Tingkat penyerapan sering memprediksi onset aksi, sedangkan tingkat penyerapan (bioavailabilitas) sering memprediksi intensitas efek dan tergantung, sebagian, pada efek first-pass. Xenobiotik harus berdifusi melalui sejumlah membran sebelum dapat mencapai tempat kerjanya. DISTRIBUTION  Volume of distribution (Vd) is the proportionality term used to relate the dose of the xenobiotic the individual receives to the resultant plasma concentration.  Measure of how much drug is located inside & outside of the plasma compartment.  Once bound to plasma protein, a xenobiotic with high binding affinity will remain largely confined to the plasma until elimination occurs.  Most plasma measurements of xenobiotic concentration reflect total drug (bound plus unbound). Only the unbound drug is free to diffuse through membranes for distribution or for elimination.  Volume distribusi (Vd) adalah istilah proporsionalitas yang digunakan untuk menghubungkan dosis xenobiotik yang diterima individu dengan konsentrasi plasma yang dihasilkan.  Ukur berapa banyak obat yang terletak di dalam & di luar kompartemen plasma.  Setelah terikat dengan protein plasma, xenobiotik dengan afinitas pengikatan yang tinggi akan tetap terbatas pada plasma sampai eliminasi terjadi.  Sebagian besar pengukuran plasma konsentrasi xenobiotik mencerminkan total obat (terikat plus tidak terikat). Hanya obat tanpa batas yang bebas difusi melalui membran untuk distribusi atau untuk eliminasi. DISTRIBUTION  Large Vd (>5 L/kg) : antidepressant, opioid, verapamil, propranolol, antipsychotic, antimalaria.  Small Vd (<1 L/kg), co., salicylate, ethanol, litium, phenytoin.  If the Vd is large (>1 L/kg), it is unlikely that hemodialysis, hemoperfusion, or exchange transfusion would be effective because most of the xenobiotic is outside of the plasma compartment.  Specific therapeutic maneuvers in the overdose : alter xenobiotic distribution by inactivating and/or enhancing elimination to limit toxicity  (a) manipulation of serum or urine pH (salicylates); (b) use of chelators (lead); and (c) the use of antibodies or antibody fragments (digoxin).  Vd besar (> 5 L / kg): antidepresan, opioid, verapamil, propranolol, antipsikotik, antimalaria.  Vd kecil (<1 L / kg), co., Salisilat, etanol, litium, fenitoin.  Jika Vd besar (> 1 L / kg), tidak mungkin hemodialisis, hemoperfusi, atau transfusi tukar akan efektif karena sebagian besar xenobiotik berada di luar kompartemen plasma.  Manuver terapeutik spesifik dalam overdosis: mengubah distribusi xenobiotik dengan menonaktifkan dan / atau meningkatkan eliminasi untuk membatasi toksisitas (a) manipulasi pH serum atau urin (salisilat); (b) penggunaan chelators (timbal); dan (c) penggunaan antibodi atau fragmen antibodi (digoxin). ELIMINATION

 Removal of a parent compound from the body (elimination) begins as soon as the xenobiotic is delivered to clearance organs such as the liver, kidneys, and lungs.  As expected, the functional integrity of the major organ systems (cardiovascular, lungs, renal, hepatic) are major determinants of the efficiency of xenobiotic removal and of therapeutically administered antidotes.  Penghapusan senyawa induk dari tubuh (eliminasi) dimulai segera setelah xenobiotik dikirimkan ke organ pembersihan seperti hati, ginjal, dan paru-paru.  Seperti yang diharapkan, integritas fungsional sistem organ utama (kardiovaskular, paru-paru, ginjal, hati) adalah penentu utama dari efisiensi penghapusan xenobiotik dan penangkal terapeutik yang diberikan secara terapeutik. ELIMINATION

 Elimination can be accomplished by biotransformation to one or more metabolites, or by excretion from the body of unchanged xenobiotic.  Lipophilic (nonpolar) xenobiotics are usually metabolized in the liver to hydrophilic metabolites, which are then excreted by the kidneys.  Metabolic reactions, catalyzed by enzymes, categorized as either phase I or phase II, generally result in pharmacologically inactive metabolites; active metabolites may have different toxicities than the parent compounds.  Eliminasi dapat dicapai dengan biotransformasi menjadi satu atau lebih metabolit, atau dengan ekskresi dari tubuh xenobiotik yang tidak berubah.  Lipofilik (nonpolar) xenobiotik biasanya dimetabolisme di hati menjadi metabolit hidrofilik, yang kemudian diekskresikan oleh ginjal.  Reaksi metabolik, dikatalisasi oleh enzim, dikategorikan sebagai fase I atau fase II, umumnya menghasilkan metabolit yang tidak aktif secara farmakologi; metabolit aktif mungkin memiliki toksisitas yang berbeda dari senyawa induknya. DRUG METABOLISM

Active Drug to Inactive Metabolite hydroxylation Phenobarbital Hydroxyphenobarbital

Active Drug to Active Metabolite

acetylation Procainamide N-acetylprocainamide Inactive Drug (prodrug) to Active Metabolite converted hydrolisis Clopidogrel 2-oxo-clopidogrel Active metabolite Active Drug to Reactive Metabolite Acetaminophen Reactive metabolite

Toksidrom Racun Suhu HR RR TD Status mental Pupil Kulit Contoh Opioids Euforia, Morfin, somnolens, heroin, koma oksikodon Simpato Agitasi, delirium, diafore Kokain, mimetik psikosis, kejang, sis amfetamin, halusinasi teofilin, kafein, efedrin Antikoli Delirium, Flushin Ipratropium, nergik psikosis, kejang, g, antihistamin halusinasi, koma, kering , TCA, atropin Organof Confusion, Diafore Malation, osfat fasikulasi, koma sis paration, ekotiofat, soman Barbitur Somnolens, Benzodiazep at, ataksia, koma in, alkohol, hipnotik barbiturat -sedatif

TOXICANTS THAT AFFECT TEMPERATURE

Hyperthermia & Hypothermia TOXICANTS THAT AFFECT RESPIRATION

Bradypnea & Tachypnea TOXICANTS THAT CAUSE HEMOLYSIS Immune & Nonimmune Mediated TOXICANTS THAT AFFECT THE CARDIOVASCULAR SYSTEM Vascular tone, heart conduction, pulse

 Hypertension  Hypotension  Conduction abnormalities & heart block  Bradycardia  Tachydysrhythmia  Pulse

TOXICANTS THAT AFFECT THE AUTONOMIC NERVOUS SYSTEM Toxicants that Act as Cholinergic Blockers

 Anticholinergic-Synonyms  Cholinergic blockers / Antimuscarinic / Antiparasympathetic / Cholinolytic / Parasympatholytic / Antispasmodic / Spasmolytic / Cholinergic neurons :  Include all sympathetic and parasympathetic preganglionic neurons and nerve supply to the adrenal medulla.  Parasympathetic postganglionic neurons (autonomic effector sites).  Sympathetic postganglionic neurons which innervate sweat glands.  Sympathetic postganglionic neurons which innervate vessels in skeletal muscle and produce vasodilation when stimulated. TOXICANTS THAT AFFECT THE AUTONOMIC NERVOUS SYSTEM Toxicants that Act as Cholinergic Blockers

Introduction to Anticholinergic Introduction to Solanaceae, Agents : Solanine, Solanidine,  Nondepolarizing Blockers at Solanocapsine, as well as Atropine Muscarinic (Cholinergic) and Atropine-like Toxins in the Receptors Solanaceae :  Atropine and Scopalamine  Physalis spp. - Ground Cherry  Atropa belladonna - Belladonna  (Members of the Solanaceae) Plant  Matrimony Vine  Henbane (Hyoscyamus niger)  Cestrum spp. - Jessamines  Datura stramonium - Jimson Weed  Solanum spp. - Nightshade Group  Anticholinergic Mushrooms TOXICANTS THAT AFFECT THE AUTONOMIC NERVOUS SYSTEM Toxicants that Act as Cholinergic Blockers

Direct muscarinic antagonist (drugs) : Inhibit ACh release :  Antihistamine  Alfa-2 adrenergic agonist  Atropine  Botulinum toxins  Carbamazepine  Crotalidae venoms  Clozapine  Elapidae β-  Phenotiazine  Scopolamine  TC antidepressant  Trihexyphenydyl TOXICANTS THAT AFFECT THE AUTONOMIC NERVOUS SYSTEM Toxicants with Cholinomimetic Effects

Cause ACh release  Alfa 2 adrenergic antagonist  Guanidine  Aminopyridines  Muscarine  Black widow  Pilocarpine  Carbachol

Toxicants with Muscarinic Effects but No Nicotine

Introduction to Muscarinic Toxicants  Muscarinic - Histaminic Mushrooms : Amanita muscaria  Slaframine TOXICANTS THAT AFFECT THE AUTONOMIC NERVOUS SYSTEM

Inhibitors of Cholinesterase

 Edrophonium  Organophosphorus (organic phosphorus) and N- methylcarbamate insecticides  Neostigmine  Physostigmine  Anabaena flos-aquae - Blue-green Algae TOXICANTS THAT AFFECT THE AUTONOMIC NERVOUS SYSTEM

Toxicants with Nicotinic Effects

 Nicotine Nicotiana spp. -Tobacco Lobelia Conium - Poison Hemlock Lupinus - Lupine or Bluebonnet Sophora - Mescal Beans Gymnocladus dioica - Kentucky Coffe Tree Laburnum anagyroides - Golden Chain  Levamisole  Imidacloprid TOXICANTS THAT AFFECT THE AUTONOMIC NERVOUS SYSTEM

Toxicants with Nicotinic Effects

 Indirect neuronal nicotinic agonist : Chlorpromazine Ethanol Ketamine Local & volatil anesthetic  Levamisole  Imidacloprid TOXICANTS THAT AFFECT THE AUTONOMIC NERVOUS SYSTEM Nicotinic Antagonist / Cholinolytics

 Direct nicotinic antagonist :  Alfa  Coniine  Cystine  Gallamine  Hexamethonium  Nicotine  NMBA non-depolarizing  Succinylcholine TOXICANTS THAT AFFECT THE AUTONOMIC NERVOUS SYSTEM Nicotinic Antagonist / Cholinolytics

 Indirect neuronal nicotinic antagonist :  Physostigmine  Tacrine  Galantamine TOXICANTS THAT AFFECT NEUROTRANSMITTER Affect Neurotransmitter

 Dopaminergic  GABAergic  Glutamatergic  Serotonergic

DEFINITION OF AN ANTIDOTE

 ‘Medicine given to counteract the action of poison’ (Shorter Oxford Dictionary)  ‘Therapeutic substance used to counteract the toxic action of a specified xenobiotic’ (Meredith et al.,1993)  ‘Substance used to treat poisoning which has a specific action depending on the poison’ ANTIDOTUM RACUN PEMBERIAN Asetilsistein Asetaminofen Hasil terbaik bila diberikan 8-10 jam overdosis. Cek fungsi hepar & asetaminofen blood levels Atropin Antikolinesterase intoksikasi: Dosis awal 1-2 mg, IV, bila tidak organofosfat, karbamat ada respon: dosis didobel tiap 5- 10 menit; end-point: ↓ wheezing & sekresi paru Bikarbonat Membrane-depressant 1-2 mEq/kg IV bolus sodium cardiotoxic drugs (TCA, kuinidin) Kalsium Fluorida, calcium channel Mulai dengan 15 mg/kg IV; dosis blockers besar bila severe CCB overdosis Hidroksokobala Sianida Dosis dewasa 5 g IV selama 15 min menit. Mengubah sianida menjadi sianokobalamin Glukagon Beta bloker 5-10 mg IV bolus dapat mengatasi hipertensi dan bradikardi Fomepizole Metanol, etilen glikol 15 mg/kg; diulang tiap 12 jam ANTIDOTUM RACUN PEMBERIAN Deferoksamin Garam besi Jika keracunan berat: 15 mg/kg/jam IV; 100mg deferoksamin dapat mengikat 8.5 mg besi Esmolol Teofilin, kafein, Infus 25-50 mcg/kg/min IV metaproterenol Flumazenil Benzodiazepin Dosis dewasa 0.2 mg IV, diulang bila perlu max. 3 mg. jangan diberi pada pasien kejang, benzodiazepin dependence, atau TCA overdosis Nalokson Obat narkotik Initial 0.4-2 mg IV, IM, atau SC. Dosis besar bila keracunan propoksifen, kodein, fentanil

Fisostigmin Delirium akibat obat Dosis dewasa 0.5-1 mg IV. Efek hanya antikolinergik transient (30-60 menit), dosis efektif terendah dapat diberikan bila gejala muncul kembali. Jangan diberikan pada TCA overdosis Pralidoksim Organofosfat Dosis dewasa 1 g IV diulang tiap 3-4 jam jika kolinesterase inhibitor perlu atau constant infusion 250-400 mg/jam Antidotum khusus hanya tersedia untuk kurang dari 2-3% kasus !!!! Manipulasi pH urin Alkalinisasi urin (dg bikarbonat)  untuk keracunan salisilat, fenobarbital Asidifikasi urin  tidak dianjurkan karena ES fungsi ginjal & jantung  rhabdomyolysis; presipitasi myoglobin di tubulus ginjal Diuresis paksa  tidak dianjurkan karena ES volume overload & abnormalitas elektrolit Dekontaminasi Saluran cerna : Activated charcoal  mengikat racun sblm diabsorpsi; charcoal tidak mengikat ion besi, litium, atau potassium Induksi emesis  tidak efektif bahkan berbahaya Bilas lambung: hanya boleh dilakukan pada pasien sadar; orogastric atau nasogastric tube diameter besar, larutan 0.9% saline hangat Katartik: whole bowel irrigation dengan polyethylene glycol electrolyte solution dapat mempercepat waktu pengosongan lambung; PO 1-2 L/jam selama beberapa jam hingga rektal efluent jernih 1. PARACETAMOL (ACETAMINOPHEN)

Self-poisoning pada dewasa & accidental poisoning pada anak-anak ADME : Absorpsi di usus halus

Cmax : 30-60 menit Metabolisme di hepar  acetaminofen sulfat & glukuronida (inaktif metabolit) ~ 95% Metabolisme oleh CYP2E1 metabolit reaktif N-acetyl-p- benzoquinone imine (NAPQI) ~ 5% Vd: 0.9L/kg

T1/2 eliminasi: 1.5-3 jam Eliminasi: ginjal Dosis untuk nyeri akut & demam: 325-500 mg 4x/hari (max. 4 gram/hari) Dosis 15 gram  fatal TANDA & GEJALA KERACUNAN PARASETAMOL (ASETAMINOFEN)

Gejala awal : anoreksia, mual, & muntah Setelah 24-48 jam: ↑ PT (prothrombin time) & transaminase Nekrosis hati yang nyata Gagal hati Ensefalopati Kematian Konsentrasi serum 4-24 jam postingestion  nomogram Rumack-Matthew TERAPI KERACUNAN PARASETAMOL (ASETAMINOFEN)

ANTODOTUM : N-ASETILSISTEIN Berbau sulfur Pada pasien keracunan awal tanpa hepatoksisitas  N- asetilsistein mereplesi glutation & mendetoksifikasi NAPQI (mencegah hepatotoksisitas) ~ 8 jam postingestion Pada keracunan lanjut dengan hepatotoksisitas  N- asetilsistein mempercepat proses penyembuhan fungsi hepar & menurunkan mortalitas & transplantasi hepar Pemberian : 18 dosis selama 72 jam EFEK SAMPING N-ASETILSISTEIN

Rash Urtikaria Reaksi anafilaksis (jarang) Reaksi hipersensitivitas

Umumnya bersifat sementara dan tidak terjadi lagi dengan pemberian berikutnya. 2. ALCOHOL

ADME : ADME : Absorpsi cepat dari saluran cerna Mudah menembus sawar darah otak Water-soluble molecule Metabolisme di hepar C : 30 menit (puasa); ♀ > ♂ max (90%)  asetaldehida (lower total body water content pada ♀) Eliminasi via paru-paru & Vd : 0.5-0.7 L/kg urin ETHANOL VS METHANOL Ethanol is made by fermentation of sugar or by the hydration of ethene. Ethanol is commonly found in households in the form of alcoholic beverages. Ethanol is also used for manufacturing paints and varnishes, as a carrier in various medications, as a disinfectant, in some types of thermometers, as a fuel substitute, and in some forms of antifreeze.

Methanol (methyl alcohol) is commonly found in automotive windshield washer fluid, some gasoline additives, industrial solvents and household products (rubbing alcohol, sterno, model airplane fuel, and paint remover, printing and copy solutions, adhesives, paints, polishers, window cleaners. Alcoholic drinks that are sold in black markets may have methanol. ETHANOL VS METHANOL An important point in management of toxic alcohols, particularly methanol poisoning, is proper and early diagnosis. Since emergency estimation of serum methanol concentration is not available in most parts of the country, clinical differential diagnosis is very important. ETHANOL METHANOL  Time of admission and patient’s  Time of admission and patient’s condition : Ethanol (alcohol in condition : toxic alcohols especially drinks) is rapidly absorbed and methanol, it will be detoriated over the clinical features after overdose such time, even after 24 hours. as flashing, drunk, CNS depression  Drunkenness and vasodilatation : toxic and GI dysfunction occur within 1-2 alcohols, no sign of drunk is observed hours. In this poisoning, the patient’s and a state of shock with chill and cold condition is gradually improved. extremities are noted.  Drunkenness and vasodilatation : patient is drunk with flashing, talkative and aggression, ETHANOL VS METHANOL ETHANOL METHANOL  Ophthalmic manifestations : pupils are  Ophthalmic manifestations : pupils are usually meiotic and there is no visual mydriatic and there is a retard or no defect. response to light.  Smell of ethanol : >>>  Smell of methanol : <<<  Tachypnea and acidemia : Acidemia is of  Convulsions and CNS symptoms : CNS good laboratory finding in differential symptoms, particularly convulsions are the diagnosis of toxic alcohol & the non- signs of severity of toxic alcohol toxics. The body respond to acidemia is intoxications. tachypnea and hyperventilation.  Tachypnea and acidemia : >>> However, in ethanol poisoning, mild  acidemia may occur, but is usually self Serum alcohols levels : practically is less limited and is improving with important as the time passes (hours after) supportive treatment. and even may be confusing.   Blood glucose and electrolytes : Blood glucose and electrolytes : hypoglycemia & hypokalemia due to hyperglycemia & hyperkalemia due to vomiting may occur in ethanol acidosis. intoxication. ETHANOL VS METHANOL Toxicokinetics Toxicokinetics  Ethanol is well absorbed orally. It  Methanol is rapidly absorbed through rapidly distributes throughout the GIT, so the average absorption half - body and crosses the BBB. life is 5 minutes and reaches  Ethanol also crosses the placenta. maximum serum concentration within 30 – 60 minutes & well  Ethanol is metabolized by hepatic dissolves in body water. alcohol dehydrogenase, and its metabolites can be excreted in the  Methanol is not toxic by itself, but its urine, along with unmetabolized metabolites are toxic. parent compound.  Methanol metabolized in different phases mainly in the liver. The initial enzyme in its metabolism is alcohol dehydrogease. ETHANOL VS METHANOL

ETHANOL VS METHANOL

Mechanism of Toxicity Clinical Manifestations  Ethanol is suspected of inhibiting N- • Initiate within 0.5 – 4 hours of methyl-d-aspartate glutamate receptors ingestion & include nausea, vomiting, in brain cells and the related abdominal pain, confusion, drowsiness production of cyclic guanosine & CNS suppression. Patients usually do monophosphate not seek help at this stage. • After a latent period of 6 – 24 hours Clinical Signs that depends on the dose absorbed,  Clinical signs : CNS depression, decompensate metabolic acidosis occur ataxia, lethargy, sedation, which induces blurred vision, metabolic acidosis. photophobia, changes in visual field, accommodation disorder, diplopia, blindness & less commonly nistagmus. • Blurred vision with unaltered consciousness is a strong suspicious for methanol poisoning. FARMAKODINAMIK

http://cjasn.asnjournals.org/content/3/1/208.full TERAPI KERACUNAN ALKOHOL AKUT

Simtomatik Tujuan utama : cegah depresi pernapasan & aspirasi muntah Glukosa bila ada hipoglikemia & ketoasidosis Tiamin untuk mencegah terjadinya sindrom Wernicke- Korsakoff Dehidrasi & muntah  keseimbangan elektrolit TERAPI KETERGANTUNGAN ALKOHOL

ANTODOTUM : 1. Naltrekson 2. Disulfiram Disetujui FDA 3. Akamprosat NALTREKSON MoA : memblok reseptor μ opioid Antagonis opioid kerja panjang Dosis : 50 mg/hari, PO ES : hepatotoksik Dapat mencetuskan sindrom withdrawal akut AKAMPROSAT

Antagonis reseptor NMDA & aktivator reseptor

GABAA Dosis : 333 mg enteric-coated tablet 3x/hari Absorpsi PO buruk Makanan mengganggu absorpsinya Eliminasi di ginjal ES : gastrointestinal upset (mual, muntah, diare) & rash DISULFIRAM

Menyebabkan rasa tidak nyaman pada pasien yang ketergantungan alkohol Flushing, sakit kepala berdenyut, mual, muntah, berkeringat, hipotensi, & konfusi MoA: menghambat enzim ALDH ADME: Absorpsi baik melalui saluran cerna Perlu waktu 12 jam untuk full-action Proses eliminasi sangat lambat  efeknya masih terlihat beberapa hari setelah dosis terakhir DI: fenitoin, INH, antikoagulan oral ES: meningkatkan enzim transaminase hepar MANAGEMENT AT ED

1. ABCs /supportive care : Intubation, controlled ventilation, manage circulatory 2. Prevent metabolism of methanol Ethanol IV/NG tube : ethanol’s affinity is 10-20X that of methanol Fomepizole : fomepizole has affinity 8000X. 3. Enhance removal of formic acid : Folate 1mg/kg IV q4h 4. Management should be focused on correction of metabolic acidosis, coma & eye complications. Correct acidosis : Dialysis, Sodium bicarbonate 5. Remove methanol : Dialysis

Jeffrey Brent, M.D., Ph.D. Fomepizole for Ethylene Glycol and Methanol Poisoning. N Engl J Med 2009;360:2216-23. MANAGEMENT AT ED PITFALL :  Methanol is absorbed rapidly in gastrointestinal. Decontamination would be little opportunity.  Ipecac syrup-induced emesis in methanol poisoning  ↑ risk of aspiration of gastric contents by an obtunded patient.  Activated charcoal administration is ineffective  methanol is not adsorbed by activated charcoal.

Jeffrey Brent, M.D., Ph.D. Fomepizole for Ethylene Glycol and Methanol Poisoning. N Engl J Med 2009;360:2216-23. MEDIKASI – ETHANOL

1. Indikasi riwayat konsumsi “miras”, klinis & lab.  dugaan >>> 2. Sering menjadi problem memulai pemberian etanol sebelum diagnosis definitif dapat dibuat. 3. Cara pemberian etanol:  Dosis awal 10 mL/kg 10% ethanol in D5%  Dosis pemeliharaan 0,15 mL/kg/hr of 10%  Dosis 2 kali lebih besar selama dialisis  Folate 50mg iv tiap 4 jam bila keadaan pasien berat

Manual of Emergency Medicine, 4rd edition, Jon L. Jenkins & G. Richard Braen, 2000, poisoning & ingestions, page 515. MEDIKASI KERACUNAN METHANOL

AGENT INDICATIONS TREATMENT

Methanol Methanol >20 mg/dL Ethanol: Loading dose: 10% ETOH in Ingestion > 0.4 mg/kg D5W at 10 mL/kg/30 min. History, symptoms Infuse:10% ETOH in D5Wat1.5mL/ kg/h suggestive of poisoning to maintain level100-150mg/dL Ethanol Oral : loading dose: 0.8-1 Fomepizole 15mg/kg over 30 min, then mL/kg PO of 95% ETOH in 6 oz of 10mg/kg q12hX4 doses & Folate orange juice over 30 min. 1mg/kg iv (max 50mg) q4h Average maintenance doses: NaHCO3 1mEq/kg iv (severe acidosis) 0.15 mL/kg/h PO of 95% ETOH

toxicology & pharmacology, Emergency Medicine, a Comprehensive study guide, JE Tintinalli, 2004, 6th ed, section 14, page1067 MEDIKASI KERACUNAN METHANOL

http://www.cjem-nlione.ca/v4/n1/p4 3. MUSCARINIC / CHOLINERGIC POISONING

• Bila asetil kolin dilepaskan dari ujung saraf dan ditangkap reseptor, maka terjadilah aksi potensial / depolarisasi  depolarisasi cukup kuat  kontraksi otot. • Asetilkolinesterase dihambat  hidrolisis ACh <<  ↑ ACh >>>

Insektisida fosfat ester malathion, parathion menimbulkan depolarisasi pada motor end plate  depolarisasi lebih lama  otot kehilangan respon berkontraksi  terjadi fasikulasi  kelumpuhan (flaccid muscle paralysis). ANTI CHOLINE-ESTERASE

 Obat yang menghambat kerja choline esterase sehingga hidrolisis acetyl choline dihambat  kadar acetyl choline meningkat  menimbulkan efek muskarinik dan nikotinik.  Efek muskarinik : efek terhadap otot polos dan kelenjar. Otot polos : Bronkus  bronkokonstriksi dan bronkospasme Usus dan ureter  hiperperistaltik Vesica urinaria  kontraksi ANTI CHOLINE-ESTERASE

Pembuluh darah perifer  vasodilatasi Jantung  bradikardi Mata  miosis Kelenjar : meningkatnya sekresi kelenjar eksokrin (keringat, bronkus, air mata, lambung dan usus)  Efek nikotinik : efek terhadap otot rangka dan ganglion. TREATMENT OF MUSCARINIC TOXICITY

ANTIDOTE = ATROPINE SULFAT  Atropine sulfate (competitive inhibitor of ACh) in muscarinic receptors  reverses cholinergic effect.  Pada bradikardi diberikan 0,5 – 1 mg iv setiap 3 – 5 menit sesuai kebutuhan tidak melebihi 0,04 mg/kgbb. Penggunaan dengan interval jangka pendek (3 menit) dan dosis yang lebih tinggi (0,04 mg/kgbb) diberikan pada kondisi klinis yang berat. Pemberian melalui trakea dengan dosis 2 – 3 x dosis iv diencerkan dalam 10 ml saline normal.  Preparate : inj 0,25 mg/mL 4. ANTIMUSCARINIC / ANTI CHOLINERGIC POISONING ANTIMUSCARINIC / ANTICHOLINERGIC 5. OPIOID POISONING

 Acute miosis (pinpoint pupils)

 Cheyne Stokes respiration

 Deep tendon reflexes increased TREATMENT OF ACUTE POISONING : OPIOID COMPETITIVE ANTAGONISTS  Competitive blocker of opioid receptor, with 10x higher affinity for  receptor than for .  Naloxone (μ, κ and δ-antagonist)  Naltrexone (μ, κ and δ-antagonist)  Nalorphine / Allylnormorphine (μ-antagonist / κ-agonist)  Dose : 0,1 – 0,2 mg (max 10 mg) iv (adult) & 0,0(05 – 0,1 mg (child)  Actions :  Precipitates withdrawal symptoms  Reverses the coma and respiratory depression of opioid overdose (naltrexone with much longer action duration) 6. BENZODIAZEPINE POISONING

ANTIDOTUM : ANTAGONIST BENZODIAZEPINE 1. FLUMAZENIL :  Flumazenil mempunyai afinitas terhadap reseptor benzodiazepine lebih tinggi dibandingkan golongan benzodiazepine sehingga bekerja dengan menempati reseptor tersebut.  Flumazenil dapat menghilangkan efek sedasi, amnesia, depresi nafas, depresi kardiovaskular dari benzodiazepine.  Onset : 1 – 2 menit (iv). Dosis : 0,1 – 1 mg/kgBB. 2. AMINOPHILIN :  Aminophilin bersifat antagonis non selektif terhadap ikatan reseptor adenosine  menyebabkan re-uptake adenosine  asetil kolin akan dilepaskan kembali sehingga pengaruh benzodiazepine terhadap SSP dapat dihilangkan.  Dosis : 1 – 2 mg/kgBB (dosis efektif untuk menghilangkan efek sedasi dari midazolam).

DANGEROUS VENOMOUS IN INDONESIA

 The dangerously venomous snakes in Indonesia are mainly from 2 families : 1. Elapidae (Cobras, Kraits, sea snakes and coral snakes). Sea snakes and Kraits are more venomous than Cobras but much less aggressive ( Krait=Ular malas in Bahasa). 2. Vipers (ular tanah, ular pohon) cause the most fatalities of all because their habits bring them into contact with humans the most. Paralysis : kraits and sea snakes Blood disorders (excessive clotting or bleeding) : vipers and colubrids Mixture (paralysis + blood disorder) : vipers and cobras hemotoxin LYMPHATIC DRAINAGE SYSTEM PATHOPHYSIOLOGY OF ENVENOMING

Local envenoming  Swelling and bruising : ↑ vascular permeability attributable to venom endopeptidases, metalloproteinase hemorrhagins, membrane-damaging polypeptide toxins, phospholipases, and endogenous autacoids released by the venom, such as histamine, 5-HT, and kinins.  Local tissue necrosis : direct action of myotoxins and cytotoxins, and ischemia caused by thrombosis; compression of blood vessels by first-aid methods such as tight tourniquets; or by swollen muscle within a tight fascial compartment (pitfall !!!!).  Myotoxins damage the muscle cell plasma membrane directly. Most are PLA2s.  Cobra cardiotoxins are low-molecular weight polypeptides with cytotoxic action. PATHOPHYSIOLOGY OF ENVENOMING

Hypotension and shock  After viper bites, leakage of plasma or blood into the bitten limb and elsewhere, massive gastrointestinal haemorrhage  hypovolaemia.  Vasodilation, especially of splanchnic vessels, and a direct effect on the myocardium  hypotension.  Profound hypotension is part of the autopharmacological syndrome that occurs within minutes of bites by D. siamensis, D. russelii, and Australasian elapids, attributable to oligopeptides (ACE inhibitors and BPPs) and vasodilating autacoids. PATHOPHYSIOLOGY OF ENVENOMING Haemostasis : bleeding and blood clotting disturbances  Procoagulant enzymes activate intravascular  coagulopathy & incoagulable blood. Procoagulants of Colubridae, Australasian Elapidae, , & Daboia species activate prothrombin, whereas those in venoms of Daboia russelii and D.siamensis also activate factorsV and X.  Thrombin-like enzymes in pit-viper venoms have a direct action on fibrinogen.  Some venoms cause defibrinogenation by activating the endogenous fibrinolytic (plasmin) system. Anticoagulant activity is attributable to venom phospholipases.  Platelet activation or inhibition results in thrombocytopenia in victims of Trimeresurus and Viridovipera species, Calloselasma rhodostoma, Deinagkistrodon acutus, and Daboia siamensis. Potentially lethal spontaneous systemic bleeding is attributable venom haemorrhagins (Zn metalloproteases). PATHOPHYSIOLOGY OF ENVENOMING Complement Activation  Elapid and some colubroid venoms activate complement (“cobra venom factor” is the ’s C3b), whereas some viperid venoms activate the classic pathway.  Complement activation  affects platelets, the blood coagulation system, and other humoral mediators. Myotoxicity  PLA2 myotoxins and metalloproteinases are principally responsible. They are present in venoms of most species of sea snakes, many terrestrial Australasian elapids, some species of krait (Bungarus), and , such as the Sri Lankan Russell’s viper (D. russelii).  Release into the bloodstream of myoglobin, muscle enzymes, uric acid, potassium, and other muscle constituents is an effect in humans of presynaptic neurotoxins. Patients may die of bulbar and respiratory muscle weakness, acute hyperkalaemia, or acute kidney injury. PATHOPHYSIOLOGY OF ENVENOMING

Neurotoxicity  Neurotoxic polypeptides and PLA2s of snake venoms cause paralysis by blocking transmission at the neuromuscular junction  paralysis of the bulbar muscles may die of upper airway obstruction or aspiration, respiratory paralysis.  Anticholinesterase drugs may improve paralytic symptoms in patients bitten by snakes with neurotoxins that are predominantly postsynaptic in their action (e.g., cobras & Australasian death adders)  prolonging activity of ACh at NMJ. NEUROTOXIN Schematic representation of the neuromuscular junction showing different sites of action of snake neurotoxins, other toxins, and pharmacological substances (examples indicated where relevant). 1.Synaptic vesicular proteins : Snake toxins : beta-bungarotoxin (Bungarus spp.), (O. scutellatus). Other toxins : , tetanus neurotoxin. 2.Voltage-gated calcium channel : Snake toxins : (Dendroaspis spp.), beta-bungaratoxin (Bungarus spp.) Other toxins : omega- (marine snail, Conus spp.); 3.Pre-synaptic membrane : Snake toxins: phospholipase A2 toxins. 4.Pre-synaptic ACh receptor: Snake toxins : candoxin (Bungarus candidus) NEUROTOXIN 5. Voltage-gated potassium channels : Snake toxins: (Dendroaspis spp.) 6. Acetylcholine : Lysis by exogenous acetylcholinesterase in : cobra venom (Naja spp.). 7. Acetylcholinesterase : Inhibitors of endogenous AChE in snake venom: fasiculins (Dendroaspis spp.). 8. Post-synaptic ACh receptors :  Snake toxins : alpha-bungaratoxin (Bungarus spp.), candoxin (B. candidus), azemiopsin (A. feae), waglerin (T. wagleri );  Other toxins : alpha-conotoxin (marine snail, Conus spp.); 9. Voltage-gated sodium channels :  Snake toxins: crotamine ( spp.);  Other toxins: pompilidotoxin (wasps), delta-conotoxin (Conus spp.), tetradotoxin (pufferfish).

ANTIDOTE : SNAKE ANTIVENOM

MONOVALENT POLYVALENT THAILAND ANTIVENOM Indonesia Commercial Polyvalent AV (SABU Biofarma) covers only 3 venomous snakes DOSIS DAN CARA PENGGUNAAN ANTIVENOM (SABU)

• Dosis pertama sebanyak 2 vial @ 5 ml ditambahkan ke dalam larutan fisiologis (NaCl)  menjadi larutan 2 % diberikan mealui infus dengan kecepatan 40-80 tetes per menit  diulang 6 jam kemudian apabila masih terdapat tanda – tanda envenomasi. • Perhatian khusus : Kasus neurotoksin ec. Bungarus sp : 2 vial /2 jam, dalam 100 cc NS diberikan 40-80tts/mnt Kasus Naja sp : 2 vial /6 jam dlm 500 cc (2%) NS diberikan 40-80 tts/menit Agkistrodon : 2 vial/6 jam dlm 500cc(2%) NS 40-80tts/menit • Apabila diperlukan (progresivitas memburuk) Serum Anti Bisa Ular Polivalen dapat terus diberikan setiap 24 jam sampai maksimum 80 – 100 ml. • Serum Anti Bisa Ular Polivalen yang tidak diencerkan dapat diberikan langsung secara intravena (tanpa melalui infus) dengan sangat perlahan-lahan. • Observasi ketat pasien selama satu jam SETELAH pemberian selesai. Trimeresurus albolabris

• Thailand product • Each vial price ±USD170  INDONESIA???? ANTIVENINS  Antibodies have been used to inactivate protein poisons from animals and microbes. Antivenins used to treat poisoning with snake venom are one example.  The term antivenin was used for the first antiserum for snake venom poisoning prepared for human use (Calmette, 1907). PHARMACODYNAMIC ANTIVENINS

SUMMARY

Semua zat kimia dapat bersifat sebagai racun ~ dosis yang membedakan Penanganan pasien keracunan sangat kompleks karena banyaknya variabel yang berpengaruh, namun jika tertangani dengan baik (patient-oriented approach)  jarang fatal ONE OF YOUR REFERENCES QUESTIONS?!