Poisoning: Actions, Decontamination, Elimination

General Poisoning Actions

• Assess airway, breathing, and circulation initially
• First aid should be given for any immediate life-threatening toxic effects
• Blood samples are needed to assess and correct acid/base balance, electrolyte disturbances, BGLs, and drug levels
• Oxygen may be administered; IV access must be established and the patient placed on a cardiac monitor
• Agents must be identified and clinical features noted
• Antidotes should be administered when necessary

Methods to Decontaminate Patients

• Rinse eyes and wash skin to remove toxins
• Gastric lavage aims to empty the stomach of ingested substances
• Forced emesis can be used to induce vomiting
• Bowel irrigation cleanses the entire bowel
• Activated charcoal can adsorb certain toxins in the gastrointestinal tract

Enhancing Drug/Toxin Elimination

• Dialysis uses a semi-permeable membrane to filter toxins; requires small molecular weight, low protein binding, small Vd, and water solubility
• Urinary alkalinization enhances elimination for drugs filtered in the glomerulus; best for drugs with small Vd and that are weakly acidic
• Activated charcoal can be used for small molecule, lipid-soluble toxins with small Vd and low protein binding

Common Antidotes

• Paracetamol: N-acetylcysteine
• Cyanide: Hydroxocobalamin
• Heroin: Naloxone
• Iron: Desferrioxamine
• Methanol: Fomepizole
• Diazepam: Flumazenil

Methanol Sources

• Windshield wiper fluid, de-icing products, paint removers, and shoe dyes
• Embalming fluid and cosmetic nail products containing methyl acetate

Methanol Toxicity and Clinical Presentation

• Methanol is metabolized into formic acid, causing toxic effects
• Intoxication, blindness from optic nerve damage, GI issues (N/V/D), and neurological symptoms
• Results in metabolic acidosis

Methanol Metabolic Pathway

• Methanol is broken down into formaldehyde by the enzyme alcohol dehydrogenase (ADH)
• Next formaldehyde is broken down into formic acid by aldehyde dehydrogenase (ALDH)
• Both steps can be inhibited by Fomepizole or Ethanol, competitive inhibitors

Identifying Methanol Poisoning

• Anion gaps and metabolic acidosis are typically present due to formic acid formation
• Increased osmol gap

Determining Methanol Concentration

• The conversion factor for estimating methanol concentration is 3.2
• Step 1 Calculate the osmolarity (Osm)
• Step 2: Determine Osm gap
  • Osm gap calculation: (Measured Osm) – (Calculated Osm)
  • An abnormal osm gap is above 15
  • A very high osm gap is above 25, which is when empiric fomepizole (Antizol) should be considered
• Step 3 – Estimate methanol alcohol concentration as 3.2 multiplied by the osm gap.

Methanol Treatment Notes

• Half-life of methanol changes based on the situation
  • No treatment increases the half life to 3 hours
  • Fomepizole extends this to 54 hours

Hemodialysis for Methanol Poisoning

• Hemodialysis eliminates methanol and formate from the body with a half-life of 2.5 hours
• Indicated if:
  • pH <7.25
  • Failure of renal function leads to electrolyte changes not responding
  • Vision changes
  • Hemodynamic instability
  • Toxic alcohol levels = >50mg/dl
  • If getting fomepizole, increase the dose

Fomepizole Treatment

• Competes with methanol for alcohol dehydrogenase (ADH), preventing toxic metabolite production
• Has an 8k fold greater binding affinity to ADH
• Indicated with methanol levels >20mg/dl

When Dosing Fomepizole

• Dosing: 15mg/kg IV x 1 dose, then 10mg/kg q12h x 4 doses, then 15mg/kg q12h until ethylene glycol level <20mg/dl OR pH improves
• IRRITATING to the veins, so dilution is necessary in 100ml of 0.9% NS or D5W
• Redose q4h if the patient needs hemodialysis due to Fomepizole's low VD and degree of protein binding

Additional Fomepizole Therapy

• Folinic acid/folic acid- facilitates formic acid metabolism into carbon dioxide and water
• Folinic acid: Administer 1mg/kg up to 50mg q4-6h until toxicity resolves
• Folic acid: Administer 50mg IV q4-6h until toxicity resolves

Source of Ethylene Glycol

• Ethylene Glycol can be found in antifreeze

Clinical Considerations for Ethylene Glycol Poisoning

• Causes falsely elevated lactic acid levels and the osmol gap will decrease while the anion gap increases
• Antifreeze contains fluorescein, that can be detected under a wood's lamp

Ethylene Glycol Poisoning

• Hypocalcemia can result from binding of oxalic acid
• Toxicity leads to glycolic acid, glyoxylic acid, and oxalic acid production
• Causes intoxication, renal toxicity, and metabolic acidosis

Ethylene Glycol Metabolic Pathways

• Ethylene glycol is metabolized to glycoaldehyde by alcohol dehydrogenase (ADH).
• Glycoaldehyde is metabolized to glycolic acid by aldehyde dehydrogenase (ALDH).
• Glycolic acid is converted to glyoxylic acid, ultimately forming oxalic acid.

Lab Findings for Ethylene Glycol Poisoning

• Anion gaps, metabolic acidosis, and an osmol gap are found
• Hypocalcemia occurs

Conversion Factor for Ethylene Glycol

• Conversion factor used to estimate ethylene glycol concentration is 6.2

Estimating Ethylene Glycol Concentration

• Step 1 - Calculate Osm = (2 x Na) + (Bun/2.8) + (Glucose/18) + (Ethanol level/4.6)
• Step 2 - Determine Osm gap = (Measured Osm) – (Calculated Osm)
• Step 3 - Estimate methanol alcohol concentration (mg/dl) = 6.2 x Osm Gap

Notes on Ethylene Glycol Treatment

• The half-life of ethylene glycol varies, and follows zero order elimination at higher concentration
  • With no treatment, half life is 8.5hrs
  • Fomepizole treatment results in half life of 14-17hrs with normal renal function
  • Hemodialysis results in half life of 2.5hrs

Fomepizole Treatment for Ethylene Glycol

• Fomepizole competes with methanol for metabolism via alcohol dehydrogenase (ADH), preventing the metabolism of methanol to toxic acid metabolites
• Administer when methanol levels >20mg/dl
• Administer also if reports of ingestion or osmol gap > 10-15mOsm, arterial pH <7.3, and serum HCO3 <20

Fomepizole Dosing for Ethylene Glycol

• Dosing: Administer 15mg/kg IV x 1 dose, followed by 10mg/kg q12h x 4 doses, then 15mg/kg q12h until ethylene glycol level <20mg/dl OR pH improves
• Fomepizole can be IRRITATING to the veins, so must dilute in 100ml of 0.9% NS or D5W

Adding Thiamine and Pyridoxine to Thiamine and Pyridoxine Treatment

• Thiamine - facilitates the metabolism of one of the toxic acid metabolites and glycoxylic acid, administer 100mg IV d until symptoms subsides
• Vitamin B6-facilitates the metabolism of one of the toxic acid metabolites and glycoxylic acid, administer 150 mEq in 1L of D5W and infuse at 150-200ml/Hr

Isopropyl Alcohol Source

• Found in rubbing alcohol and hand sanitizers

Clinical Considerations for Isopropyl Alcohol

• No antidote as it does not get metabolised to a toxic acid
• May notice a fruity odor due to ketosis.
• Does not get metabolised to a toxic acid metabolite like ethylene glycol and methanol

Clinical Presentation for Isopropyl Alcohol

• Associated with Intoxication and GI, causes HAEMORRHAGIC GASTRITIS

Isopropyl Alcohol Metabolic pathway

• Isopropyl Alcohol turns into acetone due to alcohol dehydrogenase (ADH)

Detecting Isopropyl Alcohol Poisoning

• Normal anion gap in the presence of Isopropyl Alcohol
• Serum creatinine levels may be falsely elevated so ESPECIALLY need to be tested

Isopropyl Alcohol Conversion

The conversion factor is 6.0

Treatment for Isopropyl Alcohol

• PPI's can be prescribed to reduce the risks of hemorrhagic gastritis

Cyanide Source

• Can be found in house fires, industries and bitter almonds

MOA of Cyanide

• Binds to ferric ion in cytochrome oxidase a3 within the mitochondria and halts cellular respiration

Cyanide Clinical Presentation

Ingestion Specific symptoms

• Irritation of nose, mouth & throat
• Headache, Nausea and Vomiting

Inhaled Specific symtoms

• Rapid loss of consciousness
• Seizures
• Causes DEATH

Cyanide Metabolic Pathway

• Absorbs fast via the respiratory tract and mucous membranes as well the GI and skin.

Detecting Cyanide Poisoning

• Increased anion gap metabolic acidosis.
• Plasma lactate >8mmol/ (94% sensitive and 70% specific for significant cyanide)
• Patients from structural fires should be tested with high priority

Treatment for Cyanide Poisoning

• Detoxification is via an organosulfur molecule called rhodanese

1ST LINE TREATMENT (preferred treatment) for Cyanide Poisoning

• Hydroxocobalamin (CYANOKIT) Vitamin B12a, is safe even if the patient has not been exposed to cyanide, since it promotes regular cell function.
• Urine/skin might appear red for several days/weeks.
• Dose is 5g IV over 15mins repeat up to 15g.

2NF LINE TREATMENT for Cyanide Poisoning

• Sodium nitrite and sodium thiosulphate leads to hypotension.
• Methemoglobin can reduce oxygen carrying capacity especially from smoke inhalation.

Iron Source

• Can be caused by ingestion of iron supplements

Toxicity Specifics

• Toxicity is due to the amount of elemental iron consumed
• 60-120mg/kg is toxic

• 120mg/kg can be lethal

Indications

• Serum iron levels indicate toxicity potential
• 500-1000ug/dl is shock

• 1000 ug/dl is morbidity and mortality

Clincial Presentation for Iron Toxicity

• Early (2-6 hours) is nausea and vomiting
• Abdo pain and Haematemesis which is to vomit blood
• Late (6-24hrs) which can be from
• Hypovolaemia and Metabolic acidosis
• Shock and Acute renal failure

Treatment Considerations

• CONSULT TOXICOLOGIST WHEN ADMINISTERING DESFERRIOXAMINE

Decontamination Removal

• Whole bowel irrigation

Desferrioxamine

• It chelates with free iron and turns into ferrioxamine then eliminated via urine
• Indicated to administer if serum Fe concentration >60umol/L (335ug/dl)

Toxicity for Desferrioxamine

• can result in Pulmonary oedema if USED FOR >24HRS for treatment, so consider it's effects

Source for Organophosphate and carbamate insecticides

• Can be associated with Nerve gases, Insecticides and Herbicides

Considerations for Toxicity

Carbamate

• Neostigmine
• pyridostigmine

Organophosphates

• Industrial chemical can lead to many complications.

MOA of Toxicity

• Carbamate inhibits acetylcholinesterase which then accumulates AcH.
• Organophosphates are an Aging process irreversibly inactivate to an enzyme fast with Agents such as sarin soman and tabun

Clinical Presentation for those Exposed to organophosphates vs carbamate

• Muscarinic effects are Mainly parasympathomimetic except those exposed to sweating and vasodilation through Miosis.
• Nicotinic effects are Ach has an action on ganglia which is relatively weak compared with its effects on muscarinic receptors.

ANTIDOTES for Organophosphates and carbamate insecticides

• An oxime that reactivates cholinesterase.
• A strong nucleophile that can split the enzyme bond

Clinical Presentation for Paracetamol

• Asymptomatic for first 24hrs
• After 24hrs, anorexia, vomiting and nausea
• Liver dmg detcted >18hrs, peaks between 72-96, failure if small % are left untreated 25% develop tubular necrosis renal failure

Treatment Considerations

• Activated charcoal is most effective within 2-4hrs of ingestion of toxin
• A SPECIFIC ANTIDOTE FOR PARACETAMOL acts in several ways. This is a source of glutathione which removes NAPQi, always check on chart when ingestion was had

OPIOIDS overdose symptoms

• CNS depression can be a sign
• Sedation and Respiratory depression
• Respiratory = <12bpm is a strong negative sign and highly indicative of overdose

Action of Naloxone

• Available S3 is an opioid reversal, given intraven or
• If no response, inject up to 10mg

ABX

• Absorption onset of action due to slowing time to peak
• Distribution saturation of toxicity due to its affinity to store of fat

Traditional vs population

Pharmacokinetics overview

Traditional

• Sampling intervals of healthy members
• small numbers

Population

• Patients receiving meds
• Blood samples are at dif doses on dif times
• Pop is studies

ABX in critical environments

• Influence dosage is lipid and water soluble
• Hydrophilic usually needs to be adjusted

Cancer causing envirnomentally

• Chemicals such as abe
• Drugs known to form
• Biological or environmental

Factors

• Genetics alter cellular growth
• impairing DNA repairs

Considerations for genetic cancer mutations

• Proto-oncogenes is what is developed into cancer, that regulates cellular fucntions

Considerations for doubling cancer

Tumour supressor

• the P53 is responsible for regulating the
• Doubling time of a tumour refers to a time where the cancermass doubles to be observed

Detection of diseases through screening

• Detect pre malignant chnages and early detection

Symptoms check for TNM

• Tumour checks and what nodes are present near it in a metastasis
• Karnofsky’s checks

Chemo approaches and methods

• CURE prolonged survival and pallation is the treatment
• Surgery to remove, or radiotherapy or chemo

Chemotherapy

_ systemic therapies given in cycles _AdjUvant and NeoAdjuvant chemo to maintain the tumour or size to allow for operation

Tumor related chemo to determine the damage to tissue, or aid against it

• Antiemetic used in chemotherapy regimens
• Assess the pain in individuals and adjust to the response
• Use GCSF to stimulate neutrophil production

Signs of infection

• Treat those aggerssyl

Chemo effectiveness

• Can cause severe dmg
• Need to provide pain relief

Anticancer drug considerations

• G1 gap the cells increase as replicated
• Then the S phase to prepare M phase

Clinical considerations

• Works as “false” DNA or RNA
• targets the S phase of cell rep

Anametabolites is subdivided to foliate classes

Methotrexate, Pemetrexed. Imhibits the DFR, essential for production of purines

Adr Puirine analg

• Guanine structure act “false” substrates in DNA an RNA synthesis Myleosuppression

Adr and analogs

• Fludarabine
• cladrabin _Myelosuppression vomiting and naeses

Drug treatments

Drug interactions for patients

Adjust the med accordingly Neutropenia needs to be addressed And adjust toxicity is seen

ALkaylating agents considerations

• Work forming covalent bonds
• Attaches primairy to the 7 nitro molecule _ADR _vominit, and possible infertility

Notes on drugs

• Cycles of ifosmide needs to he converted to active form
• Infections for patient on chemotherapy are likely

platinum Drug treatment

• Agressive check list

Treatment considerations to mitosic inhabitors and vinca

Action of Taxels

_binds inhibit microtubule

Action of Doxorubicin

Thes eplanar ring structure that interfere with Dna strands.

Action of bleomycin

• This is often cytotoxic affects G2 and M phase cells, from Cu and FE

Considerations to toximity of bleocy

considerations to

MTOR inhibitor

consideration to Talidomide

• Lower il 6 Corticosteroids use to lower swelling

Aynthetic inhibits

monoclonal Antidbodies effects

Tyrosine consideration to

• Designed in sell growth to help

Nilotinib to