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 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 organ 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 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

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 blood 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-neurotoxins
 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 spider venom  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 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 8-10
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 :
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 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
 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,
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 METHANOL
ETHANOL
 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 METHANOL
Toxicokinetics
 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 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
History, symptoms
suggestive of poisoning
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
D5W at 10 mL/kg/30 min.
Infuse:10% ETOH in D5Wat1.5mL/ kg/h
to maintain level100-150mg/dL
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
 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 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.
 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 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
Complement 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.
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 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.), 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)
 NEUROTOXIN
5. 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 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?!