Factors Influencing Toxicity

Factors Influencing Toxicity

• Individual reactions to drugs or substances can sometimes be unpredictable, termed idiosyncratic responses.
• Idiosyncratic responses are uncommon and hard to trace to genetic predispositions or other causes like the state of the immune system.
• Toxicity depends on factors such as:
  • Form and chemical activity
  • Dosage and relationship to time
  • Exposure route
  • Species
  • Life stage, such as infant, young adult, or elderly adult
  • Gender
  • Ability to absorb the substance
  • Metabolism
  • Distribution within the body
  • Excretion
  • Individual health, organ function, and pregnancy status
  • Nutritional status
  • Presence of other chemicals
  • Circadian rhythms at the time of substance administration

Form and Innate Chemical Activity

• A substance's form impacts its toxicity, particularly for metallic elements, also known as heavy metals.
• Mercury vapor's toxicity differs greatly from methyl mercury and while Cr3+ is relatively nontoxic, Cr6+ causes skin or nasal corrosion and lung cancer.
• A substance's innate chemical activity differs greatly.
• Hydrogen cyanide binds to cytochrome oxidase, resulting in cellular hypoxia and rapid death.
• Nicotine binds to cholinergic receptors in the CNS, altering nerve conduction and gradually inducing paralysis.

Dosage

• Dosage is critical in determining if a substance is an acute or chronic toxicant where virtually all chemicals can be acute toxicants if administered in large enough doses.
• Toxic mechanisms and target organs differ for acute and chronic toxicity.

Exposure Route

• The way a toxic substance exposure happens determines toxicity and chemicals can be highly toxic by one exposure route, but not others.
• Ingested chemicals absorbed from the intestine distribute first to the liver and detoxify immediately.
• Inhaled toxicants immediately enter the general blood circulation, distributing throughout the body before liver detoxification.

Absorption

• A substance's ability to be absorbed is essential to systemic toxicity.
• Nearly all alcohols are readily absorbed when ingested, unlike most polymers.
• Absorption rates and extent of depend on a chemical's form and exposure route.
• Ethanol is readily absorbed from the gastrointestinal tract but poorly absorbed through the skin.
• Organic mercury, unlike inorganic lead sulfate, is readily absorbed from the gastrointestinal tract.

Factors Related to the Organism: Species

• Toxic responses vary based on the species of organism due to metabolic, anatomical, or physiological differences.
• Rats cannot vomit and expel toxicants before they are absorbed; humans and dogs are able to vomit.
• Selective toxicity refers to differences in toxicity between two simultaneously exposed species and is the basis for drugs and pesticides.
• Insecticides are lethal to insects but relatively nontoxic to animals, and antibiotics are selectively toxic to microorganisms while virtually nontoxic to humans.

Factors Related to the Organism: Life Stage

• Age/life stage determines response to toxicants.
• Infants/elderly are more sensitive than young adults.
• Parathion is more toxic to young animals, and nitrosamines are more carcinogenic to newborn or young animals.

Factors Related to the Organism: Gender

• Gender can influence toxicity through physiological differences in pharmacokinetics and pharmacodynamics.
• Gender also plays a role in alcohol metabolism and its toxic effects due to differences in ADH and ALDH enzyme activity levels between men and women.
• Women generally have lower ADH and ALDH enzyme levels, resulting in slower metabolism and increased toxicity.
• Pharmacodynamic differences include women having greater sensitivity and enhanced effectiveness to beta blockers, opioids, and antipsychotics.
• Male rats are 10x more sensitive to liver damage from DDT than females and female rats are 2x as sensitive to parathion as are male rats.

Metabolism

• Metabolism/biotransformation converts a chemical from one form to another by a biological organism and a major factor in determining toxicity where metabolism products are known as metabolites.
• The two types of metabolism include:
  • Detoxification
  • Bioactivation

Metabolism: Detoxification and Bioactivation

• In detoxification, a xenobiotic is converted to a less toxic form and it's a natural defense mechanism that generally converts lipid-soluble compounds to polar compounds.
• In bioactivation, a xenobiotic is converted to more reactive or toxic forms.
• Cytochrome P-450 (CYP450), an enzyme pathway used to metabolize drugs, may be decreased in the elderly.
• Drugs like phenytoin/carbamazepine have less pronounced effects; CYP450 metabolism can be inhibited by many drugs.

Distribution Within the Body

• Distribution of toxicants and toxic metabolites within the body determines toxicity locales.
• A major determinant of whether a toxicant will damage cells is its lipid solubility: lipid-soluble toxicants readily penetrate cell membranes.
• Many toxicants are stored in fat tissue, liver, kidney, and bone, and blood is the main distribution avenue. Lymph also distributes some materials.

Excretion

• The site and rate of excretion is a major factor affecting the toxicity of xenobiotics.
• The primary excretory organ is the kidney, followed by the GI tract and the lungs.
• Xenobiotics are also excreted in sweat, tears, and milk.
• A large volume of blood serum is filtered through the kidney where lipid-soluble toxicants are reabsorbed and concentrated in kidney cells.
• Impaired kidney function slows down elimination of toxicants and increases their toxic potential.

Health Status

• An individual's health plays a major role in determining toxicity levels and types.
• Pre-existing kidney/liver diseases and pregnancy are associated with physiological changes in kidney function that could influence toxicity.

Nutritional Status

• Nutritional status determines who develops toxicity.
• Consuming mercury-absorbed fish can result in mercury toxicity and selenium is an antagonist.
• Some vegetables accumulate cadmium from soil, antagonized by zinc, and grapefruit inhibits the p450 drug detoxification pathway, making some drugs more toxic.

Other Factors: Presence of Other Chemicals

• The presence of other chemicals at the same time, earlier, or later may:
  • Decrease toxicity via antagonism
  • Add to toxicity via additivity
  • Increase toxicity via synergism or potentiation
• Antidotes counteract poisons through antagonism (atropine counteracts poisoning by organophosphate insecticides).
• Alcohol can enhance the effect of antihistamines/sedatives and a synergistic interaction between butylated hydroxytoluene(BHT) and certain oxygen concentrations results in lung damage.

Managing Poisoning or Intoxication

• Holistic management considerations for toxic exposures encompass:
  • Resuscitation and stabilization
  • Toxic diagnosis
  • Therapeutic interventions
  • Decontamination
  • Enhanced elimination of absorbed toxins
  • Antidotes
  • Supportive care

What is a Poison?

• A poison is any substance that is harmful to the body that capable of causing illness or death when introduced/absorbed.
• Even properly prescribed medications can become harmful if they aren't taken as prescribed.

Poisoning

• Poisoning is a common medical emergency that occurs when a substance interferes with typical body functions after it is swallowed, inhaled, injected, or absorbed.
• Types of poisoning:
  • Deliberate
  • Accidental
  • Environmental
  • Industrial exposures

Poisoning Causes

• Substances that act as poisons include:
  • Cleaning products
  • Household products, such as nail polish remover and other personal care products
  • Pesticides
  • Metals, such as lead/Mercury which are found in old thermometers/batteries
  • Combined or misused prescription and OTC drugs
  • Contaminated food
  • Plants, such as poison ivy and poison oak
  • Venom from certain snakes

Symptoms of Poisoning:

• Symptoms include:
  • Vomiting
  • Diarrhea
  • Nausea
  • Redness or sores around the mouth
  • Drooling or dry mouth
  • Dilated or constricted pupils
  • Rash
  • Confusion
  • Shaking or seizures
  • Trouble breathing
  • Unconsciousness/fainting

Resuscitation and Stabilization

• First priorities for resuscitation are ABC's (airways, breathing, & circulation).
• Vital signs including pulse and hypoglycemia must be corrected and unresponsive patients, empirically treat with a coma cocktail.
• Provide oxygen, naloxone, dextrose 50W (D50W), and 100mg thiamine.
• Adults require 50 ml of D50W; children require 1 g/kg glucose (4ml/kg D25W or 10ml/kg of D10W).
• Thiamine is not usually administered to children.

Toxicological Diagnosis

• Gather as much exposure information and determine the patient's intent.
• Examine:
  • Undress patient completely
  • Check clothing for objects/substances
  • Assess general appearance
  • Examine the skin for bruising, cyanosis, flushing
  • Assess ABCDE (airway, breathing, circulation, disability, exposure)
• Consider toxicological investigation and screens in evaluating children.

Gastric Emptying

• For emesis: use syrup of ipecac where 15ml is for 1-12 year olds, and 30 ml is for adults. Repeat if no emesis in 12hrs.
• 90% vomit within 20 minutes of the first dose; 97% vomit with the second dose, where usually 3−5 episodes of emesis resolve in two hours.
• If protracted emesis occurs, consider toxin as etiology
• Orogastric lavage: 36-40 French tube (adults), 22-24 French tube (children) where from the chin to xiphoid it is confirmed with air insufflation.
• Lavage with room temperature water until it runs clear.
• Use charcoal before tube withdrawal.

Toxin Adsorption in Gut

• Includes activated charcoal, multiple dose-activated charcoal, cathartics, whole-bowel irrigation.
• Activated charcoal:
  • Is most appropriate for GI tract decontamination via toxin adsorption in gut lumen.
  • Is safe for adults and children, with a dose of 1g/kg.
  • Is indicated if any drug is known to absorb or after unknown ingestions by patients with protected airways.
• Multi-dose activated charcoal is sufficient for one dose and is indicated for ingestion of large doses, substances that form bezoars, slow-release toxins, toxins that slow gut function, toxins with enterohepatic or enteroenteric circulation.
  • Repeat dose is 0.25-0.5g/kg.
• Cathartics:
  • Osmotic cathartics are given with activated charcoal, using 70% sorbitol (1g/kg) or 10% magnesium citrate, and shown to reduce transit time of activated charcoal.
  • Clinical data don't suggest that it limits toxins bioavailability or changes patient’s outcomes.

Enhanced Elimination

• Enhanced elimination includes:
  • Alkalinization
  • Forced diuresis
  • Hemodialysis/hemoperfusion

Enhanced Elimination:Alkalinization

• It is beneficial in certain ingestions: 2-4-D (herbicide), phenobarbital, chlorpropamide, salicylates, methanol.
• It's achieved by an IV dose of bicarbonate at 1-2 mEq/kg, followed by intermittent boluses or continuous bicarbonate drip for urine pH 7.5-8.

Enhanced Elimination: Hemodialysis/Hemoperfusion

• Dialysis is for specific toxins: salicylates, methanol, ethylene glycol, lithium, theophylline, amanita (mushrooms).
• Benefits include removing toxins already absorbed by the gut and removing the parent compound and active metabolite.
• Is less effective in cases with larger volume of distribution (>1 L/kg), larger molecular weight, or is highly protein-bound.
• Hemoperfusion is used to decontaminate a patient's systemic circulation.
• It uses a filter filled with activated charcoal into a dialysis circuit.
• Advantages include alleviating constraints of protein binding and molecular size, where toxins must be absorbed by charcoal and have a low distribution volume.

Poison Prevention

• Only take medications that are prescribed by a healthcare professional.
• Never take more or frequent doses of medications to try to get faster/more powerful effects, especially pain medication, and never share or sell prescription drugs.
• Follow the label directions when giving or taking medicines.
• At night, turn on a light to check the amount of medicine.
• Keep medicine in its original bottles/containers and monitor use prescribed to children/teenagers for ADHD and similar.

Important to Consider

• Is paracetamol the safest pain reliever?

What is an Antidote?

• An antidote is a therapeutic substance used to counteract toxic actions of a specified xenobiotic, reducing the health service burden of poisoning cases.

Antidote: Definition

• Antidote is derived from the Greek word "Antididonai" meaning "given against" and it is defined as a chemical, especially a drug, limiting a poison’s effects.

Antidote

• A substance that counteracts a form of poisoning where anticoagulants are reversal agents.
• A toxin is injected in small animal doses, where antibodies are extracted for particular toxins.
• Antivenom results that are used to counteract venom are produced by certain snakes/spiders/venomous animals.

How Does Antivenom Work?

• Small, non-lethal venom doses are injected into an animal, usually a horse/sheep, allowing the immune system to make antibodies against the venom.

Classification of Antidotes

• By mode of action:
  • Physiological/pharmacological antidote
  • Physical antidote
  • Chemical antidote

Physical Antidote

• These agents interfere with poison using physical, rather than chemical, properties:
  • Adsorbing: Adhesion of atoms, ions or molecules from a gas, liquid, or dissolved solid to a surface which creates a film of adsorbate on the surface of the adsorbent. Example: activated charcoal as a universal antidote.
  • Coating: A mixture of egg and milk makes a coat over the mucosa.
  • Dissolving: 10% alcohol/glycerine on carbolic acid performs the following:
    • Dilution that reduces the carbolic acid concentration at contact site, lessening chemical burn severity and tissue damage.
    • Barrier formation that forms alcohol/glycerin protective barrier over the affected area.

Chemical Antidote

• It interacts specifically with a toxicant, neutralizing it.
• Metal chelators combine with metals to form complexes that are eliminated by kidneys with 2 mechanisms:
  • Complex formation where the antidote makes a complex with toxicant, making it unavailable to cross the membrane/interact with receptors
  • DMSA (dimercaprol/dimercaptosuccinic acid) are sulfohydryl compounds that bind metals, like arsenic acid/lead.

Chemical Antidote: Metabolic Conversion

• Metabolic detoxification into a less toxic product where nitrate reacts with hemoglobin and cyanide to form cyanomethaemoglobin (less toxic than cyanide) and interfere with cyanide access to cytochrome oxidase system.

Pharmacological Antidote

• Counteracts by producing the opposite pharmacological effects.
• May neutralize/antagonize effects by:
  • Preventing the formation of toxic metabolites
  • Facilitating rapid or complete elimination
  • Competing the toxicant's action at a receptor site
  • Blocking receptors responsible for the toxic effect
  • Aiding in restoring normal function

How Do Antidotes Work?

• The harmful effect of poisons/toxic chemicals depends on dose, route of administration, toxin type, and exposure duration.
• Classification is made based on mechanism of action that reduces toxicity based on four functions:
  • Reducing the toxin level which occurs by acting directly on the toxin/drug to reduce its concentration, and includes its increased elimination as well as:
  • Specific binding involving immunotherapy, chelation, bio-scavenger therapy
  • Nonspecific antidotes where toxin levels are reduced by preventing absorption in the gastrointestinal tract

How Do Antidotes Work: Blocking the Action Site

• This achieves an alteration of the toxin's receptor site or modifications in enzyme activity.
• Ethyl alcohol competes with methyl alcohol molecules for alcohol dehydrogenase, reducing toxic metabolites.
• Oximes used for organophosphorus poisoning work on the principle of enzyme reactivation.

How Do Antidotes Work: Reducing the Level of Toxic Metabolites

• Antidotes reduce the toxic effects of poisons by neutralizing/converting the metabolites into less toxic forms.
• N-acetyl cysteine is used for paracetamol poisoning to convert toxic metabolites into another form, to reduce hepatic toxicity
• Sodium thiosulfate reverses cyanide poisoning to convert toxic metabolites to less toxic substances.

How Do Antidotes Work: Counteracting Harmful Toxin Effects

• This occurs by directly inhibiting/reducing its effect where atropine reduces the muscarinic effects of organophosphorus poisoning and decreases toxic effects on the body tissues.
• Vitamin K (Warfarin toxicity), folinic acid (methotrexate overdose), and pyridoxine (isoniazid (INH) overdose) operate by this principle.

When Should Antidotes Be Administered?

• It is difficult to provide guidance on administering an antidote in an emergency due to variation of: the time until presentation, mechanism of action, and toxicokinetic properties of the antidote. This causes maximum benefits to be uncertain and time-dependent.

Common Drugs and their Antidotes

• Activated charcoal (universal antidote) is used for oral/nonspecific poisons.
• Calcium chloride is used for black widow spider bite poisoning.
• Acetylcysteine is used for acetaminophen/paracetamol poisoning.
• Flumazenil is used for benzodiazepine overdose.
• Naloxone is used for opioid poisoning.
• Atropine sulfate is used for carbamate and organophosphate poisoning.
• Dimercaprol is used for inorganic mercury, gold, and arsenic toxicity.
• Methylene blue is used for drug-induced methemoglobinemia.
• Digoxin immune fab reverses digoxin toxicity.
• Pralidoxime is used for anti-cholinesterase poisoning.
• Calcium salts are used for fluoride toxicity.
• Heparin is used for ergotamine toxicity.
• Snake antivenom is used for cobra bites.
• Sodium thiosulfate is used for cyanide toxicity.
• Vitamin C is used for mercury toxicity.
• Thiamine/vitamin B1 is used to reduce toxicity caused by alcohol poisoning.
• Sodium bicarbonate is used for chlorine gas inhalation poisoning.
• Protamine sulfate is used for heparin toxicity.
• Penicillamine is used for arsenic, gold, lead, zinc, and copper toxicity.
• Mesna is used for cyclophosphamide toxicity.
• Deferoxamine is used for iron toxicity.
• Beta-blockers are used for theophylline toxicity.
• Prussian blue is used for thallium toxicity.
• Intralipids are used for toxicity due to local anesthetic agents.
• Hyperbaric Oxygen Therapy (HBOT) is used for carbon monoxide and cyanide poisoning.

Antidotes: Miscellaneous

• Fresh frozen plasma/vitamin K (phytomenadione) reverses Warfarin overdose.
• Chelators like Ethylenediaminetetraacetic acid (EDTA) and Dimercaptosuccinic acid (DMSA) reverse heavy metal poisoning.
• Cyproheptadine reverses toxicity due to serotonin drugs/serotonin syndrome.
• Benztropine with diphenhydramine hydrochloride (DPH) reduce extrapyramidal reactions caused by antipsychotic drugs.
• Octreotide reverses toxicity due to oral hypoglycemic (low blood glucose levels) drugs.
• Calcium gluconate reverses toxicity from calcium channel blocker drugs and burns from hydrofluoric acid.
• 5% acetic acid/vinegar reverses ammonia and urea toxicity.
• Yohimbine or atipamezole can reverse Amitraz toxicity.