PRINSIP-PRINSIP TOKSIKOLOGI Dr.dr. Nurdiana, MkesTOKSIKOLOGI : Ilmu yang mempelajari efek samping bahan kimia termasuk obat terhadap organisma hidupArea toksikologi khusus yang ptg utk kedokteran :Forensic toxicology kombinasi kimia analitik dan toksikologi dasar yang memperhatikan aspek medikolegalClinical toxicology fokus pada penyakit yang disebabkan atau secara unik berhubungan dengan substansi toksik

What is a Poison?

All substances are poisons;there is none that is not a poison. The right dosedifferentiates a poison and a remedy.Paracelsus (1493-1541)

Measures of Toxicity

Toxicity of chemicals is determined in the laboratoryThe normal procedure is to expose test animalsBy ingestion, application to the skin, by inhalation, gavage, or some other method which introduces the material into the body, orBy placing the test material in the water or air of the test animals environment

Measures of Toxicity

Toxicity is measured as clinical endpoints which includeMortality (death)Reproductive tox (teratogenesis,reproduction performance,perinatal and postnatal tox)Carcinogenicity (ability to cause cancer), and,Mutagenicity (ability to cause heritible change in the DNA)

Duration of Exposure

Three terms are commonly used to describe the duration of dose(s)

AcuteSubchronic

Chronic

Duration of Exposure:Acute Exposure

Application of a single or short-term (generally less than a day) dosing by a chemicalAnimal: mouse, rat, female,maleExamination: death animal in a 14 day period(weight, behavioral, lethargy, food consumption etc)Information: LD50,target organ, reversibility, dose-response

Measures of Toxicity:The Median Lethal Dose

LD50The amount (dose) of a chemical which produces death in 50% of a population of test animals to which it is administered by any of a variety of methods

mg/kgNormally expressed as milligrams of substance per kilogram of animal body weight

Measures of Toxicity:The Median Lethal Concentration

LC50The concentration of a chemical in an environment (generally air or water) which produces death in 50% of an exposed population of test animals in a specified time frame

mg/LNormally expressed as milligrams of substance per liter of air or water (or as ppm)

Fig. 16.5, p. 400

ToxicityLD50 measured in mg/kg of body weight LD50ExamplesSupertoxic < 0.01mg dioxin, botulism, mushroomsExtreme. Toxic 15g water, table sugar

Duration of Exposure:Subchronic Exposure

Toxic symptoms are expressed after repeated applications for a timeframe less than half the life expectancy of the organism (90 days)Examination: body weight, food consumtion, respiratory and cardiovascular distress, motor and behavioral abnormalities etcAt the end of the 90-day blood and organ collected for analysis

Duration of Exposure:Chronic Exposure

Expression of toxic symptoms only after repeated exposure to a chemical in doses regularly applied to the organism for a time greater than half of its life-expectancyMice : 18 m 24 mRats : 2-2.5 y

What is a Response?

Response (symptoms) could be on the molecular, cellular, organ, or organism level (interference w/receptor,membrane function,cellular energy production, biomolc, calsium homeostasis etc) Local vs. Systemic Reversible vs. Irreversible Immediate vs. Delayed Graded vs. Quantal degrees of the same damage vs. all or none

Primary Routes of ExposureThere are three primary routes by which organisms are exposed to pesticides

OralDermalInhalation

Primary Routes of Exposure: Oral ExposureAny exposure which occurs when the chemical is taken in through the mouth and passes through the gastrointestinal tract

ADME (target organ adverse effect is dependent upon the concentration of active compound at the target site for enough time ), Not all organs are affected equally, greater susceptibility of the target organ, higher concentration of active compound Liver, Kidney Lung, Neurons, Myocardium, *Bone marrow

Primary Routes of Exposure: Dermal Exposure

Exposure of the skin Animal : back (0.5 of liquid ang 0.5 g of solid, 1-inch square, one intact and two abraded skin sites, 4 h)Examination: erithema,edema, corrosive action

Primary Routes of Exposure:Inhalation ExposureOccurs when a chemical is breathed into the lungs through the nose or mouth

Significant route of exposure for aquatic organisms

Not of toxicological concern until it crosses from the lung into the body (unless the chemical is corrosive)

PREVENSI DAN TERAPI KERACUNAN

Untuk kepentingan klinik, semua agen toksik dibagi 2 klas :Agen toksik yang memerlukan terapi spesifik atau ada antidotnyaAgen toksik yang tidak memerlukan terapi spesifikSebag. besar obat dan bahan kimia lain Tx simtomatik

fungsi vitalKeracunan obat terutama Tx supportivePrinsip penting dalam toksikologi klinik : Treat the patient, not the poison

Terapi keracunan akut :Mempertahankan fungsi vitalMengusahakan konsentrasi racun di jaringan yang penting serendah mungkin dg cara mencegah absorbsi dan meningkatkan eliminasi

Mencegah absorbsi racun selanjutnya dengan :Emesis -merangsang pharynx di bag.posterior-Ipecac-ApomorphineGastric lavageChemical adsorbtion activated charcoal

Inaktivasi bahan kimia-antidote-netralisasi asam atau basaPurgation- Katartik - WBI : whole bowel irrigationBila keracunan melalui inhalasi atau kulit :-pindahkan pasien dari sumber racun-bersihkan kulit yang terkena dg air-pakaian yg terkena racun dilepas

Bila kena mata secepatnya irigasi dg air selama 15 menitMENINGKATKAN ELIMINASI RACUN - Biotransformasi atau - Ekskresi lewat empedu- Ekskresi lewat urin- DyalisisANTAGONIS ATAU INAKTIVASI BAHAN KIMIA YG DISERAP

Ingested toxin: A poison that is consumed orally.Poisoning by IngestionAbout 80% of all accidental ingestions of poisons occur in children 1 to 3 years of age Most result from household productsPoisoning in adults is usually intentional, although accidental poisoning from exposure to chemical in the work place also occurs.Toxic effects of ingested poisons may beimmediate or delayed, depending on the substance ingested

Common Types of Household Poisons

Assessment and ManagementThe primary goal of physical assessment of poisoned patients is to identify the poisons effects on the three vital organ systems most likely to produce immediate morbidity and mortality:Respiratory systemCardiovascular systemCentral nervous system

Five Signs of Major ToxicityComaCardiac dysrhythmiasGI disturbancesRespiratory depressionHypotension or hypertension

HISTORYWhat was ingested? (obtain samples of substance, vomitus)Route of intoxication?When was the substance ingested?How much of the substance was ingested?Use of alcohol or other possibly potentiating substances?Was an attempt made to induce vomiting?Has an antidote or activated charcoal been administered?Patterns of drug habituation or abuse?Does the patient have a psychiatric history pertinent to suicide attempts or recent episodes of depression?

Physical ExamPay special attention to:Skin condition (cyanosis, pallor, wasting, needle marks, staining)Pupil responses, impaired visionSigns of caustic ingestion, burningAmount of salivation, breath odor, presence of vomitusBreath sounds for evidence of aspiration, atelectasis, pulmonary secretionsCardiac dysrhythmiasAbdominal pain

General Principles of ManagementPrevent aspiration, consider intubationReduce or prevent absorptionDO NOT induce vomiting in most casesUse of gastric lavage and/or activated charcoal may be preferredMaintain airway, breathing and circulationGastric Lavage A method of GI decontamination that may be superior to ipecac-induces emesisAdvantages:Immediate recovery of a portion of the gastric contents (if performed within 1 hour of ingestion)Control of lavage durationDirect access for administration of activated charcoal

Tehnik gastric lavageUse large bore (36-40 French) orogastric tube, smaller 24-28 French NG tube may be too small to remove gastric contentsPlace the patient in left lateral Trendelenburg to minimize chance of aspirationInsert tube through mouth into esophagus and advance until tip is placed in the stomachCheck tube placement by insufflation of air into stomach with syringe while auscultatingInfuse 150-200 mL aliquots of tap water or NS in adults, 50-100 mL >5 yearsDrain stomach contents after each infusion, return volume should be approximately equal to what was infusedContinue until return fluid comes back clearFollow with activated charcoal

Potential complications gastric lavage:Patient agitationInadvertent tracheal intubationEsophageal perforationAspiration pneumonitisFluid and electrolyte imbalances in pediatric patients

Activated charcoal:A medication that works by binding to certain poisons, preventing them from being absorbed into the body.Used only for ingested toxins.

Activated Charcoal Trade Names InstaChar Actidose LiquiChar SuperChar Two Types of Activated Charcoal

Contraindications to Charcoal Altered mental statusIngestion of an acid or alkaliInability to swallowHistory of recent seizuresCharcoal with Sorbitol should NOT be used in small children

Administration of Activated CharcoalShake container thoroughly.

Activated Charcoal continuedPour liquid into container.

Activated Charcoal continuedHave patient drink full dose.

Administration of Fluids and DrugsAssure airway, breathing, and circulationEstablish IV of NS If unresponsive, consider thiamine, naloxone but only if each is indicatedIf extrapyramidal effects are present, consider use of diphenhydramine 25-50 mg IV

ExtrapyramidalControl and coordinate the postural, static, supporting and locomotor mechanismsAffecting extrapiramidal tracts and characterized by involuntary movement, changes in muscle tone and abnormal posture (Parkinsons)Side effect mimics disease and caused by drugs that block dopamine receptor sites

Contaminated FoodCauses:BacteriaVirusesToxic chemicalsSeafood poisoningsCommon symptoms:Diffuse abdominal painNausea, vomiting, diarrheaRarely life threatening

Contaminated FoodBasic treatment largely supportivePerform initial and focused assessmentsCollect samples of suspected source of poisoningEstablish and maintain airwayAdminister high-flow oxygen, intubate and assist ventilation as neededEstablish IV with NS or LRContact poison control

Poisonous PlantsCommon sources of poisoning include plants, trees, and mushroomsObtain sample of suspected agentSigns of possible toxic mushroom poisoningExcessive salivation, lacrimation, diaphoresisAbdominal cramps, nausea, vomiting, diarrheaDecreasing levels of consciousnessContact poison control center for guidance, possible administration of atropine

Ethylene GlycolA colorless, odorless, watersoluble liquidCommonly used in windshield deicers, detergents, paints, radiator antifreeze, and coolantsCommonly misused by alcoholics as a substitute for ethanol

Ethylene Glycol/MethanolCommon signs and symptoms include abdominal pain, nausea, vomiting, signs of intoxication, tachypnea, hyperpneaIrreversible blindness

Methanol (Wood Alcohol)A common industrial solvent obtained from distillation of woodFound in a variety of products, such as gas line antifreeze, windshield washer fluid, paints, paint removers, varnishes, canned fuels such as sterno, and many shellacsOnset of symptoms after ingestion ranges from 40 minutes to 72 hours

TreatmentEnsure ABCsEstablish IVContact poison controlConsider sodium bicarbonate (50 mEq) if poison control unavailableConsider 30-60 mL of 86 proof ethanol p.o.Transport rapidly

EthanolImpede metabolism of ethlene glycol or methanol to toxic metabolites Competes for enzymes needed for metabolism

Strong Acids and AlkalisStrong acids and alkalis may cause burns to the mouth, pharynx, esophagus, and sometimes the upper respiratory and GI tractsIngestions of caustic and corrosive substances generally produce immediate damage to the mucous membrane and the intestinal tractAcids generally complete their damage within 1 to 2 minutes after exposureAlkalis, particularly solid alkalis, may continue to cause liquefaction of tissue and damage for minutes to hours

Signs and SymptomsFacial burnsPain in the lips, tongue, throat, or gumsDrooling, trouble swallowingHoarseness, stridor, shortness of breathShock secondary to bleeding or vomiting

ManagementEstablish an airway, consider intubation, or if necessary, cricothyrotomyContact poison controlGastric lavage or charcoal often contraindicatedIV with NS or LRRapid transport

HydrocarbonsA group of saturated and unsaturated compounds derived primarily from crude oil, coal, or plant substancesFound in many household products and in petroleum distillates

HydrocarbonsViscosity is the most important physical characteristic in potential toxicityThe lower the viscosity, the higher the risk of aspiration and associated complicationsClinical features of hydrocarbon ingestion vary widely, depending on the type of agent involved May be immediate or delayed in onset

Signs and SymptomsBurns due to local contactWheezing, dyspnea, hypoxia, and pneumonitis due to aspiration or inhalationHeadache, dizziness, slurred speech, ataxia (irregular or difficult-to-control movements), and dulled reflexesFoot and wrist drop with numbness and tinglingCardiac dysrhythmias

ManagementMost are not life-threateningOccasionally gastric lavage may be of benefitIn seriously symptomatic patients, protect the airway and establish an IV if NS or LRContact poison controlTransport

Isopropanol (Isopropyl Alcohol)A volatile, flammable, colorless liquid with a characteristic odor and bittersweet tasteRubbing alcohol is the most common household source of this agentUsed in disinfectants, degreasers, cosmetics, industrial solvents, and cleaning agents

Isopropanol (Isopropyl Alcohol)Common routes of toxic exposureIntentional ingestion as a substitute for ethanolAccidental ingestionInhalation of high concentrations of local vapor, as from alcohol sponging of febrile children (a harmful and inappropriate procedure)

Isopropanol (Isopropyl Alcohol)More toxic than ethanol but less toxic than methanol or ethylene glycolA potentially lethal dose in adults is 150 to 240 mLIn children, any amount of ingestion should be considered potentially toxicAfter ingestion, the majority of isopropanol (80%) is metabolized to acetone

Signs and SymptomsUsually present within 30 minutesCNS and respiratory depressionAbdominal painGastritisHematemesisHypovolemia

ManagementAirway maintenance and ventilatory support with 100% oxygenGastric lavageIV with NS or LR and fluid resuscitation PRNECG monitoringRapid transport

MetalsInfants and children are high-risk groups for accidental iron, lead, and mercury poisoning due to their immature immune systems or increased absorption as a function of age

Iron PoisoningApproximately 10% of the ingested iron (mainly ferrous sulfate) is absorbed each day from the small intestineAfter absorption, the iron is converted, stored in iron storage protein, and transported to the liver, spleen, and bone marrow for incorporation into hemoglobin

Signs and SymptomsHematemesisAbdominal painShockLiver failureMetabolic acidosis with tachypneaEventual bowel scarring and possible obstruction

ManagementProtect the airway and oxygenationGastric lavageCharcoal contraindicatedIV with NS or LR titrated to support the blood pressureRapid transport

Lead PoisoningMetallic lead has been used by humans for more than 5000 yearsWas not widely recognized as a potential health hazard until 1978 when it was banned from household paints in the United StatesCommon sources of lead older glazes and paints

Signs and SymptomsHeadache, irritability, confusion, and comaMemory disturbancesTremor, weakness, and agitationAbdominal pain

ManagementProtect the airwayConsider gastric lavage if it is an acute ingestionActivated charcoal is contraindicatedIV with NS or LRTransport

Mercury PoisoningMercury is the only metallic element that is liquid at room temperatureUsed in thermometers, sphygmomanometers, and dental amalgam (dental fillings)Various compounds of mercury are used in some paints, pesticides, cosmetics, drugs, and in certain industrial processesAll forms of mercury (except dental amalgam) are poisonous

Signs and SymptomsHeadache, irritability, confusion, and comaMemory disturbancesTremor, weakness, and agitationAbdominal pain

ManagementProtect the airwayConsider gastric lavage if it is an acute ingestionActivated charcoal is contraindicatedIV with NS or LRTransport

Cyanide Poisoning Pathophysiology Cyanide binds cytochrome oxidase causing cellular asphyxia

CyanideRefers to any of a number of highly toxic substances that contain the cyanogen chemical groupCyanide is present in many household itemsCyanide poisoning may result from:Inhalation of cyanide gas (most rapid effects)Ingestion of cyanide salts, nitriles, or cyanogenic glycosides Infusion of nitroprussideAbsorption in fires

CyanideFast-acting toxin - cellular asphyxiantSigns and symptoms include: burning sensation in the mouth and throat, headache, combative behavior, hypertension, tachycardia, tachypnea, pulmonary edema with respiratory depression