departemenfarmakologi fakultas kedokteranunissula of poisons _ antidotes 9...toksisitas yang terukur...

Departemen Farmakologi

Fakultas Kedokteran UNISSULA

POISONS, VENOMS & TOXINS

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 suicideAda maksud untuk bunuh diri, sering barbiturat &

hipnotik-sedatif

3. Accidental poisoningJelas kecelakaan, tanpa faktor kesengajaan, sering

terjadi pada anak usia <5 tahun

4. Homicidal poisoningTindakan kriminal

KLASIFIKASI KERACUNAN MENURUT MULA WAKTU TERJADINYA

1. Keracunan akutTerjadi mendadak diagnosa lebih mudah ditegakkanSering mengenai banyak orangGejala sering menyerupai sindrom penyakit (toxidrom)

2. Keracunan kronikGejala timbul perlahan & lama sesudah pajanan

diagnosis sulit ditegakkanCiri khas : zat penyebab diekskresi >24 jam, t1/2 panjang akumulasiManifestasi kronik pada organ tertentu oleh zat kimiadg t1/2 pendek akibat akumulasi (ex : nekrosis papilaginjal akibat analgesik)

Route of exposure :

Direct contact

Ingestion

Inhalation

Toxicokinetics

Toxicodynamics

Toksikokinetik & Toksikodinamik

Toksikokinetik: ADME suatu toxin (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

Phenobarbital Hydroxyphenobarbitalhydroxylation

Active Drug to Active Metabolite

Procainamideacetylation

N-acetylprocainamide

Inactive Drug (prodrug) to Active Metabolite

Clopidogrelconverted

2-oxo-clopidogrel

Active Drug to Reactive MetaboliteAcetaminophen Reactive metabolite

hydrolisisActive

metabolite

Racun Suhu HR RR TD Status mental Pupil Kulit Contoh

Opioids Euforia, somnolens, koma

Morfin, heroin, oksikodon

Simpatomimetik

Agitasi, delirium, psikosis, kejang, halusinasi

diaforesis

Kokain, amfetamin, teofilin, kafein, efedrin

Antikolinergik

Delirium, psikosis, kejang, halusinasi, koma,

Flushing, kering

Ipratropium, antihistamin, TCA, atropin

Organofosfat

Confusion, fasikulasi, koma

Diaforesis

Malation, paration, ekotiofat,soman

Barbiturat, hipnotik-sedatif

Somnolens, ataksia, koma

Benzodiazepin, alkohol, barbiturat

Toksidrom

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

Hypertension

Hypotension

Conduction abnormalities & heart block

Bradycardia

Tachydysrhythmia

Pulse

Vascular tone, heart conduction, pulse

TOXICANTS THAT AFFECT THE AUTONOMIC NERVOUS SYSTEM

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 blood vessels in

skeletal muscle and produce vasodilation when stimulated.

Toxicants that Act as Cholinergic Blockers


Introduction to Anticholinergic

Agents :

Nondepolarizing Blockers at

Muscarinic (Cholinergic)

Receptors

Atropine and Scopalamine

Atropa belladonna - Belladonna

Plant

Henbane (Hyoscyamus niger)

Datura stramonium - Jimson Weed

Anticholinergic Mushrooms

Introduction to Solanaceae,

Solanine, Solanidine,

Solanocapsine, as well as Atropine

and Atropine-like Toxins in the

Solanaceae :

Physalis spp. - Ground Cherry

(Members of the Solanaceae)

Matrimony Vine

Cestrum spp. - Jessamines

Solanum spp. - Nightshade Group



Direct muscarinic antagonist (drugs) :

Antihistamine

Atropine

Carbamazepine

Clozapine

Phenotiazine

Scopolamine

TC antidepressant

Trihexyphenydyl


Inhibit ACh release :

Alfa-2 adrenergic agonist

Botulinum toxins

Crotalidae venoms

Elapidae β-neurotoxins


Introduction to Muscarinic Toxicants

Muscarinic - Histaminic Mushrooms : Amanita muscaria

Slaframine

Toxicants with Cholinomimetic Effects

Toxicants with Muscarinic Effects but No Nicotine

Cause ACh release

Alfa 2 adrenergic antagonist

Aminopyridines

Black widow spider venom

Carbachol

Guanidine

Muscarine

Pilocarpine


Edrophonium

Organophosphorus (organic phosphorus) and N-

methylcarbamate insecticides

Neostigmine

Physostigmine

Anabaena flos-aquae - Blue-green Algae

Inhibitors of Cholinesterase


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 with Nicotinic Effects


Indirect neuronal nicotinic agonist :

Chlorpromazine

Ethanol

Ketamine

Local & volatil anesthetic

Levamisole

Imidacloprid

Toxicants with Nicotinic Effects


Nicotinic Antagonist / Cholinolytics

Direct nicotinic antagonist :

Alfa bungarotoxin

Coniine

Cystine

Gallamine

Hexamethonium

Nicotine

NMBA non-depolarizing

Succinylcholine


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 8-10jam overdosis. Cek fungsi hepar & asetaminofen blood levels

Atropin Antikolinesterase intoksikasi: organofosfat, karbamat

Dosis awal 1-2 mg, IV, bila tidakada respon: dosis didobel tiap 5-10 menit; end-point: ↓ wheezing & sekresi paru

Bikarbonatsodium

Membrane-depressant cardiotoxic drugs (TCA, kuinidin)

1-2 mEq/kg IV bolus

Kalsium Fluorida, calcium channel blockers

Mulai dengan 15 mg/kg IV; dosisbesar bila severe CCB overdosis

Hidroksokobalamin

Sianida Dosis dewasa 5 g IV selama 15 menit. Mengubah sianida menjadisianokobalamin

Glukagon Beta bloker 5-10 mg IV bolus dapat mengatasihipertensi 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, metaproterenol

Infus 25-50 mcg/kg/min IV

Flumazenil Benzodiazepin Dosis dewasa 0.2 mg IV, diulang bila perlumax. 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 besarbila keracunan propoksifen, kodein, fentanil

Fisostigmin Delirium akibat obatantikolinergik

Dosis dewasa 0.5-1 mg IV. Efek hanyatransient (30-60 menit), dosis efektifterendah dapat diberikan bila gejala munculkembali. Jangan diberikan pada TCA overdosis

Pralidoksim Organofosfatkolinesterase inhibitor

Dosis dewasa 1 g IV diulang tiap 3-4 jam jikaperlu atau constant infusion 250-400 mg/jam

Antidotum khusus hanya

tersedia untuk kurang dari

2-3% kasus !!!!

Manipulasi pH urinAlkalinisasi 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 (inaktifmetabolit) ~ 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. 4gram/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 denganpemberian berikutnya.

2. ALCOHOL

ADME :

Absorpsi cepat dari saluran cerna

Water-soluble molecule

Cmax : 30 menit (puasa); ♀ > ♂

(lower total body water content pada ♀)

Vd : 0.5-0.7 L/kg

ADME :

Mudah menembus sawar

darah otak

Metabolisme di hepar

(90%) asetaldehida

Eliminasi via paru-paru &

urin

ETHANOL VS METHANOLEthanol 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

ETHANOL

Time of admission and patient’s

condition : Ethanol (alcohol in

drinks) is rapidly absorbed and

clinical features after overdose such

as flashing, drunk, CNS depression

and GI dysfunction occur within 1-2

hours. In this poisoning, the patient’s

condition is gradually improved.

Drunkenness and vasodilatation :

patient is drunk with flashing,

talkative and aggression,

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.

METHANOL

Time of admission and patient’s

condition : toxic alcohols especially

methanol, it will be detoriated over the

time, even after 24 hours.

Drunkenness and vasodilatation : toxic

alcohols, no sign of drunk is observed

and a state of shock with chill and cold

extremities are noted.

ETHANOL VS METHANOLETHANOL

Ophthalmic manifestations : pupils are

usually meiotic and there is no visual

defect.

Smell of ethanol : >>>

Tachypnea and acidemia : Acidemia is of

good laboratory finding in differential

diagnosis of toxic alcohol & the non-

toxics. The body respond to acidemia is

tachypnea and hyperventilation.

However, in ethanol poisoning, mild

acidemia may occur, but is usually self

limited and is improving with

supportive treatment.

Blood glucose and electrolytes :

hypoglycemia & hypokalemia due to

vomiting may occur in ethanol

intoxication.

METHANOL

Ophthalmic manifestations : pupils are

mydriatic and there is a retard or no

response to light.

Smell of methanol : <<<

Convulsions and CNS symptoms : CNS

symptoms, particularly convulsions are the

signs of severity of toxic alcohol

intoxications.

Tachypnea and acidemia : >>>

Serum alcohols levels : practically is less

important as the time passes (hours after)

and even may be confusing.

Blood glucose and electrolytes :

hyperglycemia & hyperkalemia due to

acidosis.

ETHANOL VS METHANOLToxicokinetics

Ethanol is well absorbed orally. It

rapidly distributes throughout the

body and crosses the BBB.

Ethanol also crosses the placenta.

Ethanol is metabolized by hepatic

alcohol dehydrogenase, and its

metabolites can be excreted in the

urine, along with unmetabolized

parent compound.

Toxicokinetics

Methanol is rapidly absorbed through

GIT, so the average absorption half -

life is 5 minutes and reaches

maximum serum concentration

within 30 – 60 minutes & well

dissolves in body water.

Methanol is not toxic by itself, but its

metabolites are toxic.

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

Ethanol is suspected of inhibiting N-

methyl-d-aspartate glutamate receptors

in brain cells and the related

production of cyclic guanosine

monophosphate

Clinical Signs

Clinical signs : CNS depression,

ataxia, lethargy, sedation,

metabolic acidosis.

Clinical Manifestations

• Initiate within 0.5 – 4 hours of

ingestion & include nausea, vomiting,

abdominal pain, confusion, drowsiness

& CNS suppression. Patients usually do

not seek help at this stage.

• After a latent period of 6 – 24 hours

that depends on the dose absorbed,

decompensate metabolic acidosis occur

which induces blurred vision,

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

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

3. Akamprosat

Disetujui FDA

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 ketergantunganalkohol

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 terlihatbeberapa hari setelah dosis terakhir

DI: fenitoin, INH, antikoagulan oral

ES: meningkatkan enzim transaminase hepar

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

MANAGEMENT AT ED

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

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.

MANAGEMENT AT ED

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

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

MEDIKASI – ETHANOL

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

Ingestion > 0.4 mg/kg

History, symptoms

suggestive of poisoning

Ethanol: Loading dose: 10% ETOH in

D5W at 10 mL/kg/30 min.

Infuse:10% ETOH in D5Wat1.5mL/ kg/h

to maintain level100-150mg/dL

Ethanol Oral : loading dose: 0.8-1

mL/kg PO of 95% ETOH in 6 oz of

orange juice over 30 min.

Average maintenance doses:

0.15 mL/kg/h PO of 95% ETOH

Fomepizole 15mg/kg over 30 min, then

10mg/kg q12hX4 doses & Folate

1mg/kg iv (max 50mg) q4h

NaHCO3 1mEq/kg iv (severe acidosis)

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

http://www.cjem-online.ca/v4/n1/p34

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 >>>

menimbulkan depolarisasi pada

motor end plate depolarisasi

lebih lama otot kehilangan

respon berkontraksi terjadi

fasikulasi kelumpuhan (flaccid

muscle paralysis).

Insektisida fosfat ester malathion, parathion

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

Matamiosis

Kelenjar : meningkatnya sekresi kelenjar

eksokrin (keringat, bronkus, air mata,

lambung dan usus)

Efek nikotinik : efek terhadap otot rangka dan

ganglion.

ANTI CHOLINE-ESTERASE

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

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)

TREATMENT OF ACUTE POISONING : OPIOID COMPETITIVE ANTAGONISTS

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.

6. BENZODIAZEPINE POISONING

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 SNAKES 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

neurotoxin

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.

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.


Haemostasis : bleeding and blood clotting disturbances

Procoagulant enzymes activate intravascular coagulation coagulopathy

& incoagulable blood. Procoagulants of Colubridae, Australasian Elapidae,

Echis, & 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).


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 Viperidae, 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 ENVENOMINGComplement Activation

Elapid and some colubroid venoms activate complement (“cobra venom

factor” is the snake’s C3b), whereas some viperid venoms activate the

classic pathway.

Complement activation affects platelets, the blood coagulation system,

and other humoral mediators.

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.


NEUROTOXINSchematic 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.), taipoxin (O. scutellatus).

Other toxins : botulinum toxin, tetanus neurotoxin.

2.Voltage-gated calcium channel :

Snake toxins : calciseptine (Dendroaspis spp.), beta-bungaratoxin

(Bungarus spp.)

Other toxins : omega-conotoxin (marine snail, Conus spp.);

3.Pre-synaptic membrane : Snake toxins: phospholipase A2 toxins.

4.Pre-synaptic ACh receptor: Snake toxins : candoxin (Bungarus candidus)

NEUROTOXIN5. Voltage-gated potassium channels : Snake toxins: dendrotoxins

(Dendroaspis spp.)

6. Acetylcholine : Lysis by exogenous acetylcholinesterase in snake venom:

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 (Crotalus 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 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.

DOSIS DAN CARA PENGGUNAAN ANTIVENOM (SABU)

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?!

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