TOXICOLOGY AND THERAPEUTIC DRUG MONITORING

• Alcohol


  Common CNS depressants that cause disorientation, euphoria, confusion and may progress to unconsciousness, paralysis and even death
• Symptoms of alcohol intoxication


  Begin when the concentration is >0.05% w/v (>50 mg/dl blood alcohol)
• Ethanol (Grain Alcohol)


  Most common abused drug, most ethanol is converted to acetic acid
• Methods for testing alcohol


  Enzymatic (AD), GLC and osmometry
• Increased in GTT, AST, AST/ALT ratio (>2.0), HDL and mean corpuscular volume with alcohol consumption
• Detection limit for alcohol


  12 hours
• Fatal dose of alcohol

  300-400ml of pure alcohol consumed in less than one hour
• Toxic blood alcohol levels

  250-400 mg/dl
• Methanol (Wood Alcohol)


  Commonly used solvent and a contaminant of homemade liquors, converted to formaldehyde then formic acid in the liver
• Fatal dose of methanol

  60-250 ml
• Isopropanol (Rubbing Alcohol)


  Metabolized to acetone
• Fatal dose of isopropanol

  250 ml
• Ethylene Glycol (1,2 Ethanediol)


  Common constituent of hydraulic fluid and anti-freeze, converted to oxalic acid and glycolic acid, leads to deposition of calcium oxalate crystals in renal tubules
• Fatal dose of ethylene glycol

  100 grams
• Carbon Monoxide (CO)


  Colorless, odorless, tasteless gas produced by incomplete combustion, very toxic, binds to heme proteins impairing oxygen transport and inhibiting cellular respiration
• Indicator of CO toxicity

  "Cherry-red" color of the face
• Sample for CO testing

  EDTA whole blood
• Arsenic


  Component of ant poisons, rodenticides, paint and metal alloys, common homicide or suicide agent, expresses toxicity by binding to thiol groups in proteins
• Cadmium


  Utilized in electroplating and galvanizing, significant environmental pollutant, causes destruction of type 1 epithelial cells in the lung and decreased resistance to bacterial infections
• Lead


  Component of household paints, potent enzyme inhibitor, combines with bone matrix and persists, causes encephalopathy, birth defects, compromised immunity, and behavioral changes
• Toxic blood lead levels

  >70ug/dl (definitive lead poisoning)
• Samples for lead testing

  • Whole blood, urine, hair
• Testing for lead poisoning


  Analysis of morning urine for delta ALA, serum or plasma should not be used
• Tests for lead


  • Graphic furnace AAS (children), inductively coupled plasma emission spectrophotometry (ICPES, anodic stripping voltametry), zinc protoporphyrin or free RBC protoporphyrin
• Mercury


  Binds with proteins and is an enzyme inhibitor, has the ability to "amalgamate" with other substances, presence in blood may result in loss of glomerular integrity
• Samples for mercury testing


  • Whole blood (organic mercury), urine (inorganic mercury)
• Method for mercury testing


  Reinsch test
• Amphetamines


  Therapeutically used for treating narcolepsy and attentional deficit disorder, increases mental alertness and physical capacity, anorectic property, structurally related to dopamine and cathecolamines, 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') is a popular recreational abused drug, acute intoxication causes hyperpyrexia, toxic effects include hypertension, cardiac arrhythmias, convulsions, pancytopenia
• Anabolic steroids


  Chemically associated to the male hormone testosterone, improves athletic performance by increasing muscle mass, toxic effects include chronic hepatitis, atherosclerosis, abnormal platelet aggregation, cardiomegaly
• Cannabinoids


  The naturally occurring cannabinoids are marijuana and hashish, Tetrahydrocannabinol (THC) is the most potent psychoactive substance, impairs short term memory and intellectual functions, THC-COOH can be detected in urine for 3-5 days after single use, up to 4 weeks for chronic users, physiologic effects include reddening of the conjunctiva and tachycardia
• Cocaine (Crack)


  Alkaloid salt that can be taken directly or by inhalation, derived from coca plant, potent CNS stimulant that elicits a sense of excitement and euphoria, increases physical activity, easily passes placenta and mammary glands, Prozac is used to inhibit its action, can be detected in urine for up to 3 days after single use, up to 20 days for chronic users, toxic effects include hypertension, arrhythmias, seizures, myocardial infarction, urine metabolite is benzoylecgonine
• Opiates


  Capable of analgesia, sedation and anesthesia, derived from opium poppy, include natural substances like opium, morphine, codeine, and synthetic forms like heroin, hydromorphone, oxycodone, meperidine, methadone, propoxyphene, pentazocine, fentanyl, heroin is highly addictive, morphine binds to mu-receptors in the limbic system producing analgesic effect, morphine and meperidine increase liver and pancreatic enzymes, methadone is a nonbicyclic drug that binds with morphine in the brain, darvon overdose combined with alcohol is a major cause of drug-related death, morphine and codeine are commonly tested, major metabolites are N-acetylmorphine (heroin) and morphine, antagonist for opiate overdose is nalaxone (narcan), toxic effects include respiratory acidosis, myoglobinuria, cardiopulmonary failure
• Therapeutic Drug Monitoring (TDM)

  Involves the analysis, assessment and evaluation of circulating concentrations of drugs in serum, plasma or whole blood, a quantitative procedure performed for drugs with a narrow therapeutic index, to ensure maximal therapeutic benefit and minimal side effects, to achieve a constant serum level of the drug that will be therapeutic, allows for the safe use of drugs that would otherwise be potentially toxic, most drugs have a half-life independent of their concentrations, the half-life of the drug determines the time to reach the steady-state or average concentration, only the free fraction of the drugs can interact with the site of action and result in a biologic response, the Mixed Function Oxidase (MFO) system is the biochemical pathway responsible for the greatest portion of drug metabolism
• Indications for TDM


  • The consequences of overdosing and underdosing are serious
  • There is a small difference between a therapeutic and toxic dose
  • There is a poor relationship between the dose of drug and circulating concentrations but a good correlation between circulating concentrations and therapeutic and toxic effects
  • There is a change in the patient's physiologic state that may unpredictably affect circulating drug concentrations
  • A drug interaction is or may be occurring
  • It helps in monitoring patient compliance
• Routes of drug administration

  • Intravenous
  • Oral
  • Intramuscular
  • Subcutaneous
  • Inhalation
  • Suppository
  • Transcutaneous
• Intravenous route


  Associated with 100% bioavailability, all the drugs enter the bloodstream (1.0 bioavailable fraction)
• Oral route


  Should achieve 0.7 bioavailability fraction
• Intravenous administration


  The distribution and elimination rates are constant
• Five pharmacological parameters that determine serum drug concentration

  • Liberation
  • Absorption
  • Distribution
  • Metabolism
  • Excretion
• Absorption of drugs


  Therapeutic dose must be optimally attained, most drugs are absorbed by passive diffusion, absorption occurs in the intestine, factors affecting absorption include changes in intestinal movement, pH, inflammation, presence of food or other drugs