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
TOXICANTS THAT AFFECT THE AUTONOMIC NERVOUS SYSTEM
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
Toxicants that Act as Cholinergic Blockers
TOXICANTS THAT AFFECT THE AUTONOMIC NERVOUS SYSTEM
Direct muscarinic antagonist (drugs) :
Antihistamine
Atropine
Carbamazepine
Clozapine
Phenotiazine
Scopolamine
TC antidepressant
Trihexyphenydyl
Toxicants that Act as Cholinergic Blockers
Inhibit ACh release :
Alfa-2 adrenergic agonist
Botulinum toxins
Crotalidae venoms
Elapidae β-neurotoxins
TOXICANTS THAT AFFECT THE AUTONOMIC NERVOUS SYSTEM
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
TOXICANTS THAT AFFECT THE AUTONOMIC NERVOUS SYSTEM
Edrophonium
Organophosphorus (organic phosphorus) and N-
methylcarbamate insecticides
Neostigmine
Physostigmine
Anabaena flos-aquae - Blue-green Algae
Inhibitors of Cholinesterase
TOXICANTS THAT AFFECT THE AUTONOMIC NERVOUS SYSTEM
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
TOXICANTS THAT AFFECT THE AUTONOMIC NERVOUS SYSTEM
Indirect neuronal nicotinic agonist :
Chlorpromazine
Ethanol
Ketamine
Local & volatil anesthetic
Levamisole
Imidacloprid
Toxicants with Nicotinic Effects
TOXICANTS THAT AFFECT THE AUTONOMIC NERVOUS SYSTEM
Nicotinic Antagonist / Cholinolytics
Direct nicotinic antagonist :
Alfa bungarotoxin
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 8-10jam 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
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
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.
PATHOPHYSIOLOGY OF ENVENOMING
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).
PATHOPHYSIOLOGY OF ENVENOMING
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.
PATHOPHYSIOLOGY OF ENVENOMING
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?!