3.5 Therapeutic Drug Monitoring and Clinical Toxicology

Therapeutic Drug Monitoring and Clinical Toxicology

Clinical Chemistry includes endocrinology and toxicology as a tested subtopic. On the MTLE, toxicology questions combine chemistry (which method, which specimen, which interference) with patient safety (chain of custody, antidote timing, critical values). This section begins with therapeutic drug monitoring and common acute poisonings, then covers alcohols and the osmolal gap, drugs of abuse testing, heavy metals, pesticides, and cyanide.

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1. Therapeutic Drug Monitoring (TDM) and Common Acute Poisonings

Therapeutic Drug Monitoring (TDM) involves measuring circulating drug concentrations to personalize dosing regimens for pharmaceuticals characterized by a narrow therapeutic index (where the effective therapeutic concentration is close to the toxic concentration).

Pharmacokinetic Fundamentals

• Steady-State Concentration ($C_{ss}$): Occurs when the rate of drug administration equals the rate of drug elimination. Achieving steady state requires 5 to 7 elimination half-lives ($t_{1/2}$) following initiation of therapy or dosage adjustment. TDM sampling is uninterpretable until steady state is reached.
• Sample Timing:
  • Trough Concentration: Drawn immediately prior to the next scheduled dose (within 15-30 minutes before administration). Represents the lowest drug concentration in the dosing interval; critical for assessing therapeutic efficacy and avoiding accumulation toxicity.
  • Peak Concentration: Drawn after drug distribution into tissues is complete (distribution equilibrium). For intravenous infusions, drawn 30 to 60 minutes post-infusion; for oral medications, drawn 1 to 2 hours post-ingestion.

Critical Monitored Drugs

Clinical Toxicology

• Acetaminophen (Paracetamol) Toxicity: Acetaminophen is metabolized primarily by hepatic glucuronidation and sulfation. In overdose, these pathways saturate, shunting excess drug to cytochrome P450 (CYP2E1), producing the highly reactive, electrophilic intermediate $N$-acetyl-$p$-benzoquinone imine (NAPQI). NAPQI depletes protective hepatic glutathione stores and binds covalently to hepatocyte macromolecules, causing massive centrilobular hepatic necrosis. Serum concentrations drawn 4 to 24 hours post-ingestion are plotted on the Rumack-Matthew Nomogram to predict hepatotoxicity. Antidote: $N$-acetylcysteine (NAC), which serves as a glutathione precursor and glutathione substitute, neutralizing NAPQI; most effective when started within 8 hours of ingestion.
• Salicylate (Aspirin) Toxicity: Toxic ingestions stimulate the medullary respiratory center (producing an initial respiratory alkalosis) and uncouple mitochondrial oxidative phosphorylation (accumulating lactate, pyruvate, and acetoacetate, generating a high anion gap metabolic acidosis). The classic presentation in adults is a mixed respiratory alkalosis and metabolic acidosis. Monitored via the Trinder reaction (ferric nitrate forms a purple chromogen).
• Carbon Monoxide (CO): Measured directly as carboxyhemoglobin (COHb) via multi-wavelength co-oximetry. Normal nonsmokers have <1.5-2% COHb; smokers have 4-9%; toxicity manifests at >15-20% (headache, dizziness, nausea); lethal at >50%. Antidote is 100% normobaric or hyperbaric oxygen, which shortens COHb half-life from 320 minutes (room air) to 80 minutes (100% $O_2$) or 20 minutes (hyperbaric chamber).

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2. Alcohols and the Osmolal Gap

Ethanol

• Enzymatic method: Alcohol dehydrogenase (ADH) oxidizes ethanol to acetaldehyde while reducing NAD+ to NADH. The rise in absorbance at 340 nm is proportional to the ethanol concentration. Headspace gas chromatography is the forensic reference method.
• Specimen rules: Clean the venipuncture site with povidone-iodine or soap and water, not an alcohol pad. Keep the tube stoppered and fill it, because ethanol is volatile. Serum or plasma ethanol is about 1.1 to 1.2 times whole-blood ethanol because serum contains more water, so a medicolegal report must state the specimen type.
• Philippine law: The Anti-Drunk and Drugged Driving Act of 2013 (RA 10586) and its implementing rules use a blood alcohol concentration of 0.05% for drivers of private vehicles of up to 4,500 kg gross weight, and 0.0% for drivers of trucks, buses, motorcycles, and public utility vehicles.

Osmolal Gap

$\text{Calculated osmolality} = 2[\text{Na}^+] + \frac{\text{glucose (mg/dL)}}{18} + \frac{\text{BUN (mg/dL)}}{2.8}$

• Osmolal gap = measured osmolality − calculated osmolality. A gap above about 10 mOsm/kg suggests unmeasured osmoles such as ethanol, methanol, ethylene glycol, isopropanol, or mannitol.
• Measure with a freezing-point depression osmometer. A vapor-pressure osmometer does not detect volatile alcohols and will miss the gap.
• Ethanol raises the measured osmolality by about 1 mOsm/kg for every 3.7 to 4.6 mg/dL, so subtract its expected contribution before blaming a toxic alcohol.

Toxic Alcohols

Fomepizole (or ethanol) blocks alcohol dehydrogenase so methanol and ethylene glycol are not converted to their toxic acids; hemodialysis removes both the parent alcohol and its acids.

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3. Drugs of Abuse: Screening, Confirmation, and Specimen Integrity

• Screening uses immunoassays (automated EMIT or CEDIA methods, or lateral-flow cassettes) with a cutoff concentration. Results are reported as negative or presumptive positive.
• Cross-reactivity limits screening specificity. Examples: pseudoephedrine and other sympathomimetics in amphetamine assays, and poppy seeds in opiate assays. A presumptive positive therefore needs confirmation by a method that identifies the specific compound, such as GC-MS or LC-MS/MS, usually at a lower cutoff than the screen.
• Analytes measured in urine:

• Specimen validity: The collector checks temperature within 4 minutes of voiding and inspects color and volume. The laboratory tests creatinine, specific gravity, pH, and oxidants. Low creatinine and low specific gravity suggest dilution or substitution; abnormal pH, nitrites, or oxidizing agents suggest adulteration.
• Chain of custody: Every transfer of the specimen, from collection through sealing with tamper-evident tape, transport, accessioning, aliquoting, and testing, is documented with date, time, and signatures on the custody and control form. A break in the chain can invalidate a legally defensible result. RA 9165 requirements for Philippine drug testing laboratories are covered in the related-laws section.

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4. Heavy Metals, Pesticides, and Cyanide

Lead

• Specimen: Whole blood in a trace-element-free EDTA tube (royal blue or tan top). Methods include graphite furnace atomic absorption, inductively coupled plasma mass spectrometry (ICP-MS), and anodic stripping voltammetry for point-of-care testing.
• Biochemistry: Lead inhibits delta-aminolevulinic acid dehydratase (urine ALA rises) and ferrochelatase (zinc protoporphyrin rises). It also inhibits pyrimidine 5'-nucleotidase, which produces coarse basophilic stippling on the blood smear, and it causes a microcytic anemia.
• Interpretation: No blood lead level is considered safe for children. The US CDC lowered its blood lead reference value for children to 3.5 µg/dL in 2021.

Mercury and Arsenic

• Mercury: Inorganic and elemental mercury are monitored in urine (preferably 24-hour); methylmercury from fish is monitored in whole blood. Artisanal small-scale gold mining, which uses mercury to amalgamate gold, is a recognized exposure source in the Philippines.
• Arsenic: Urine is the preferred specimen for recent exposure. Speciation separates nontoxic seafood arsenic (arsenobetaine) from toxic inorganic arsenic. Hair and nails record chronic exposure, and transverse white nail bands (Mees lines) are a classic sign.

Organophosphate and Carbamate Insecticides

• These compounds inhibit acetylcholinesterase, so acetylcholine accumulates and produces a cholinergic crisis: miosis, salivation, lacrimation, bronchorrhea, bradycardia, vomiting, diarrhea, and muscle fasciculations.
• Laboratory tests:
  • RBC (true) acetylcholinesterase reflects the synaptic enzyme and is the better marker of the severity of exposure.
  • Plasma pseudocholinesterase (butyrylcholinesterase) falls faster and is a sensitive early marker, but it is less specific because liver disease, pregnancy, malnutrition, and inherited variants also lower it.
• Treatment: Atropine, plus an oxime such as pralidoxime for organophosphates. Carbamate inhibition is spontaneously reversible.

Cyanide

• Cyanide inhibits cytochrome c oxidase, so cells cannot use oxygen. The result is a severe lactic acidosis with high venous oxygen content. Sources include smoke from burning plastics and wool, improperly processed cassava, and sodium nitroprusside infusions.
• Whole-blood cyanide results take too long to guide emergency care, so a high lactate in a smoke-inhalation victim prompts empirical treatment with hydroxocobalamin, which binds cyanide to form cyanocobalamin.

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5. Toxicology Quick Reference