MEDICINE AND SURGERY "F"
Course of LABORATORY MEDICINE
Toxicology

TOXICOLOGY
      The analysis of exogenous substances, usually in the serum is routinely carried out in the clinical laboratory for several different reasons: the concentration of drugs is measured in order to assess whether the therapeutic regime is appropriate, and to avoid overdosage; recreational drugs or their metabolytes are measured because of forensic reasons, as are poisons. Toxic substances present in the environment or contaiminating the patient (e.g. because of its job) are measured for preventive as well as diagnostic reasons. All these substances have reference values of zero, i.e. they should be absent in the body fluids of healthy people.
 
      ESSENTIAL CONCEPTS OF PHARMACODYNAMICS
      Drugs are administered by several route (e.g. oral, intramuscular, intravenous, etc.) and are transported by the blood to their target organs or cells. The rate of absorption is usually limited by diffusion: the peak blood concentration may be immediate (in the case of intravenou administration) or may be delayed by some hours (in the case of oral administration).
      As soon as the drugs appears in the blood the processes of its metabolic transformation and excretion also start. Urinary excretion is usually proportional to the drug concentration in the serum and obeys an exponential (i.e. first order) kinetic law. Enzymatic transformation (generally by the liver followed by excretion via the bile or the urine) is saturable and obeys a zero order kinetic law.
      Each drug has a characteristic therapeutical range (i.e. a range of serum concentration in which it exerts its therapeutic action) and a toxic threshold (the serum concentration at which toxic or undesired effects appear). The therapeutic index is the ratio between the toxic and therapeutical concentrations and is widely different for different drugs: e.g. valium, when used as an ansiolytic is a very safe drug, with therapeutic index >100, whereas lithium ion, only has 2. The dosage, and therefore the therapeutic index of a drug, however, may vary depending on the clinical indications. For example, valium may be used as an antiepileptic drug, ad doses several tens of times higher than those used for its ansiolytic activity. In these cases its therapeutic index is substantially lower.
 
      SPECIMEN COLLECTION AND ANALYTICAL METHODS
      Determination of the serum (or other biological fluid) concentration of a drug is indicated if: (i) the therapeutc index is low; (ii) absorption or excretion exhibit large interindividual variability (especially in the presence of liver or kidney diseases); (iii) non-compliance or abuse by the patient are suspected; (iv) unexpected toxic effects appear.
      The appropriate sample is usually the serum; in some cases the urine,bile or other body fluids. In some cases the drug concentration is effectively measured; in other cases a characteristic metabolyte is measured instead.
      Analytical methods typically used in clinical toxicology include: chromatography (e.g. high pressure liquid chromatography; gas chromatography); potentiometry; spectrophotometry; mass spectrometry; radio-immunoassay and ther immunological methods.

      DRUGS THAT MOST COMMONLY REQUIRE TOXICOLOGICAL ANALYSES
      Some drug categories require toxicological determinations, because of essentially two main reasons: (i) the therapeutic index is low, thus even small deviations from mean values may cause risk; or (ii) the pharmacodynamics exibits high inter-individual variability.
 
      MEASUREMENT OF DRUG CONCENTRATIONS
     
Drug Dose Ther./Toxic Metabolyte specimen method
Methotrexate Methotrexate serum
Tacrolimus Tacrolimus whole blood Chromatography (HPLC)
Cyclosporine Cyclosporine Chromatography (HPLC)
Phenytoin 10 ug/ml / >20 ug/ml
Barbiturates 20 ug/ml Barbiturates serum spectrophotometric
Carbamazepine
Lithium ion 0.8 mEq/l / 1.5 mEq/l Lithium ion serum electrochemical
Digoxin 0.5ng/ml / 5 ng/ml Digoxin serum immunological
Quinidine 10-20 ug/ml / >5 ul/ml Quinidine serum immunological
Theophylline 2 ug/ml / >30 ul/ml Theophylline serum immunological

 
      DOSAGE OF RECREATIONAL DRUGS
     
Drug Toxic level Metabolyte specimen method
Ethanol 80 mg/dl Ethanol, acetaldehyde serum, expired air gas chromatography, enzymatic
Amphetamines Amphetamines serum immunological
Cocaine Benzoylecgonine serum Chromatography (HPLC)
Opiates Morphine, Heroine Chromatography (HPLC)
Cannabis delta 9 tetrahydrocannabinol urine Chromatography (HPLC)

 
DOSAGE OF POISONS AND ENVIRONMENTAL TOXICANTS
     
Substance Toxic level Metabolyte specimen method
Lead > 30ug/dl Lead ion serum electrochemical
Carbon monoxide HbCO/total Hb > 0.2 Carboxy-hemoglobin blood spectrophotometric
Arsenicals Arsenic Blood, skin, nails Atomic absorption spectrometry



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