A. Toxicology is the study of toxic drugs or poisons.

A toxicant (poison) is any substance that, when taken in

sufficient quantity, causes sickness or death. Toxicity is a relative term used to compare one substance with
another; a toxic substance is one with a toxicity defined as “extremely” or “super” toxic.

B. Specific drugs considered to be toxicants are composed of several categories. Some of these
drugs are also considered to be therapeutic in nature.

1. Analgesics are anti-inflammatory agents and painkillers. These drugs are also considered to be therapeutic.
a. Salicylate (aspirin) is considered toxic at a serum level of >90 mg/dL 6 hours following ingestion. The
time since ingestion must be known to determine severity of toxicity.
(1) Salicylate intoxication results in the following: stimulation of the respiratory system with initial
respiratory alkalosis, conversion of pyruvate to lactate, inhibition of oxidative phosphorylation, and breakdown
of fatty acids to produce ketoacids. Eventually, metabolic acidosis occurs.
(2) Renal clearance of salicylate can be increased by forced alkaline diuresis.
b. Acetaminophen, if present in serum at 300 mcg/mL 2 hours after ingestion, induces hepatic toxicity. Again,
time since ingestion is critical in determining acetaminophen intoxication.
(1) Intoxication results in hepatocystic necrosis 3 to 4 days after overdose because of the inability of the liver
to adequately conjugate the metabolite of acetaminophen (i.e., acetamidoquinone) to glutathione. High levels
of acetamidoquinone in the liver induce hepatocyte death.
(2) Antidote. The effective antidote for acetaminophen overdose is Nacetylcysteine, which is thought to act as
a glutathione substitute and binds to the metabolite.
2. Barbiturates are short-acting (pento-, secobarbital); intermediate-acting (amo-, β-, butabarbital); and long-
acting (phenobarbital) sedatives that exert a tranquilizing effect through their depressant effect on the CNS.
The barbiturates can be considered as substances of abuse or as analgesics.
a. Barbiturate intoxication results in cardiac arrest and respiratory depression through its effect on the CNS.
b. There are no real antidotes for barbiturate overdose except the establishment of an open airway, aiding
respiration, and maintaining cardiac output.
3. Narcotics (opioids) are compounds include heroin, morphine, codeine, and methadone. Most of these drugs
are habit forming and can be considered drugs of abuse.
a. Intoxication. The toxic effects of overdose include depression of respiration caused by a decreased
sensitivity to carbon dioxide and coma. Heroin is metabolized by the liver to form morphine and is excreted by
the kidney as morphine glucuronide.
b. Antidote. The effective antidote for narcotic overdose is naloxone, a narcotic antagonist.
4. Pesticides exist as organic complexes, organophosphates (largest single group of pesticides), and
carbamates. These compounds inhibit AChE, which results in specific effects on the heart and respiratory
centers, muscle cramps, and certain CNS effects.
a. Intoxication. The method used for the determination of pesticide poisoning is the examination of PChE (an
isoenzyme of AChE found in serum).
b. Antidote. The effective antidote for pesticide poisoning is atropine sulfate.
5. Carbon monoxide is a tasteless gas with 200-fold greater affinity for hemoglobin than oxygen.
a. Intoxication. During carbon monoxide poisoning, hemoglobin cannot adequately exchange carbon dioxide
for oxygen because of the increased amount of carboxyhemoglobin present. Suffocation and death follow.
b. Antidote. The effective antidote for carbon monoxide poisoning is removal of the source of carbon
monoxide or removal of the victim from the source.
6. Metal poisoning includes intoxication by the heavy metals lead, arsenic, and mercury.
a. Lead poisoning is most typically caused by lead paint ingestion or continuous exposure to lead in the soil.
(1) Intoxication. Lead is found primarily in RBCs in intoxicated victims but produces widespread effects, such
as gastrointestinal irritation, weight loss, kidney damage, convulsions, and in children, altered cognition and
encephalopathy. Death occurs because of peripheral vascular collapse or brain involvement.
(2) Antidote. Administration of ethylenediaminetetraacetic acid (EDTA), penicillamine, and other lead
chelates that bind the lead and allow it to be excreted by the kidney. Examination of urinary ALA levels and
RBC protoporphyrins can determine the occurrence of lead poisoning after serum and urine lead levels
have returned to normal.
b. Mercury (mercury salts) is found in antibacterial agents, photographic reagents, pesticides, and batteries.
Poisoning by these agents is typically the result of overexposure or ingestion.
(1) Intoxication. Effects of mercury poisoning include gastrointestinal irritation,
severe kidney damage, or neurologic symptoms.
(2) Antidote. As with lead poisoning, chelates, such as EDTA, penicillamine, or dimercaprol [also referred to
as British antilewisite (BAL)] bind the mercury and render it able to be excreted.
c. Arsenic is found in pesticides, weed killer, and some paints.
(1) Intoxication. Arsenic induces purging gastroenteritis, shredding of the stomach lining, and causes Mees’
lines in the fingernails because of keratin binding. Death typically occurs because of hemorrhagic
gastroenteritis. Because arsenic is cleared rapidly from the blood, urine is the specimen of choice for analysis.
(2) Antidote. Chelation therapy with penicillamine or BAL is effective.
7. Substances of abuse include a variety of compounds that, when found in high levels in the urine or serum,
can incriminate an individual. It is mandatory in substance-of-abuse analysis to obtain a satisfactory specimen
and to process the specimen in a secure part of the laboratory.
a. Ethanol is the most common toxicant and substance of abuse seen in patients in emergency departments in
the United States. It acts by depressing the CNS and increasing the heart rate and blood pressure. Ethanol
metabolism occurs in the liver by alcohol dehydrogenase, which converts alcohol to acetaldehyde, which is
then excreted to acetate. A blood level of 0.1 g/dL is defined as intoxicating.
b. Methanol is widely used in paints, solvents, antifreeze, and solid canned fuels. Poisoning with methanol is
typically caused by ingestion.
(1) Intoxication by methanol is considered more dangerous than ethanol poisoning because of the formation in
humans of formaldehyde and formic acid as metabolites. Formic acid formation results in metabolic acidosis,
pancreatic necrosis, and visual system impairment.
(2) Antidotes for methanol poisoning include the administration of sodium bicarbonate to treat the acidosis
and ethanol to bind alcohol dehydrogenase and block the formation of the metabolites.
c. Amphetamines are CNS stimulants that block dopamine receptors in the brain. Amphetamine metabolism
occurs in the liver and produces benzoic acid.
(1) Intoxication by amphetamines can produce severe depression, respiratory difficulties, and episodes of
paranoia.
(2) Antidote. The antidote for amphetamine overdose is forced acid diuresis.
d. Cocaine is a CNS stimulant that is metabolized by cholinesterase to form benzoylecgonine, which is
excreted by the kidney.
(1) Intoxication. Cocaine overdose produces hypertension, myocardial infarction, or seizure. Cardiotoxicity
can occur and result in sudden death following cocaine use.
(2) Antidote. There is no antidote for cocaine overdose except the passage of time and urinary excretion.
e. Cannabinoid compounds [tetrahydrocannabinol (THC), marijuana] produce psychologic effects and
are stored in fat cells. THC is excreted in the urine for an extended period of time depending on use. Overdose
of this drug is rare and is not severe enough to be life-threatening.
f. Phencyclidine (PCP, angel dust) is an abused anesthetic that is illegally used as a hallucinogen.
(1) Intoxication. This drug can produce violence, seizures, respiratory depression, or death.
(2) Antidote. Treatment for PCP overdose is diazepam. PCP is unmetabolized and excreted in the urine as
phencyclidine.
The drug screen rapidly identifies a drug or drugs present in the blood, urine, or gastric contents of a patient
suffering from toxicity. Neutral and basic drugs as well as drug metabolites are best detected in urine, whereas
acidic drugs are best found in detectable concentrations in blood and serum. Following a positive drug screen,
confirmatory methods must be used to quantitatively analyze drug levels in a patient.
1. Handheld immunoassays are the most common type of drug screen. They detect a wide variety of drugs
but cannot separate closely related compounds. Blood and urine can both be analyzed with this method.
2. Gas-liquid chromatography allows for greater sensitivity in the identification of drugs. It can be used as a
confirmatory technique for drugs detected by drug screen.
D. Confirmatory drug tests are required to confirm and quantify those drugs found in a patient’s serum or
urine using drug-screening methods.
1. Gas chromatography/mass spectrometry is a sensitive technique used to confirm drugs detected by
screening techniques. Typically, urine samples are initially analyzed by gas chromatography to determine the
presence of compounds, then reanalyzed by mass spectrometry to examine fragments of these compounds for
relative abundance in the sample.
2. Immunoassay techniques use antibodies to detect drugs. These methods are usually automated and in the
form of enzyme immunoassays.
3. Ethanol testing is typically performed using gas chromatography. However, an enzyme assay using alcohol
dehydrogenase and measuring the increase in NADH formation following the reaction is widely used and can
be automated.
4. Heavy metal testing is most often performed by atomic absorption spectrophotometry.
E. Therapeutic drugs must be monitored to determine what doses are inadequate or excessive in the
treatment of the patient. Often, the ingested drug (called the “parent” drug) is metabolized to form an active
metabolite that produces an effect similar to the parent drug.
1. Cardioactive drugs are divided into two categories: the cardiac glycosides and the antiarrhythmic drugs.
These agents serve to maintain normal heart function.
a. Digoxin is the major cardiac glycoside and alters the force of contraction through its effect on the ATPase
pump in heart muscle. Blood specimens must be collected 8 hours after a dose of digoxin is administered,
because its peak concentration in tissue occurs 6 to 10 hours after administration. Digoxin toxicity produces
symptoms of nausea, rapid heart rate, and visual impairment. Digoxin is excreted as digoxigenin in the urine.
b. The antiarrhythmic drugs are prescribed to treat irregular heartbeat that produces inappropriate ventricular
contraction or tachycardia (increased heart rate).
(1) Lidocaine is used for the treatment of faulty ventricular contractions and arrhythmias. It binds to α1-acid
glycoprotein and is metabolized in the liver, producing two active metabolites, monoethylglycinexylidide and
glycinexylide.
(2) Procainamide is used to treat inappropriate ventricular contractions and tachycardia.
This drug is metabolized in the liver to form an active metabolite, Nacetylprocainamide, which produces the
same effect as its parent drug. Therefore, serum levels of both drugs must be analyzed.
(3) Disopyramide stabilizes the heartbeat. It is both excreted by the renal system as the unchanged drug and is
metabolized in the liver to form an inactive metabolite.
(4) Quinidine is a myocardial depressant that decreases the heart’s ability to conduct current. It is metabolized
in the liver to produce several active metabolites, including 3-hydroxyquinidine. If quinidine is added to a
digoxin therapy regimen, an interaction occurs that induces an increase in digoxin concentration.
(5) Propranolol is prescribed for atrial and ventricular arrhythmias and hypertension. It is considered to be a
beta-blocker.
2. Anticonvulsants function to alter transmission of nerve impulses within the brain to minimize the seizures
of epilepsy.
Phenobarbital is used to treat all types of seizures except absence seizures. It is effective in children and
neonates. It is metabolized in the liver, and serum concentrations increase during the administration of valproic
acid or salicylic acid.
b. Phenytoin corrects grand mal seizures. It is metabolized by the liver and can interact with several drugs that
induce increased serum concentration or increased metabolism of phenytoin.
c. Valproic acid is prescribed for absence (petit mal) seizures. Valproic acid affects many others
anticonvulsants by inhibiting their metabolism in the liver, thus increasing serum concentration.
d. Primidone is metabolized in the liver to form phenobarbital. Therefore, dual analyses must be performed to
determine the proper dosage of this drug. It is used to treat both grand mal and complex-partial seizures.
e. Carbamazepine is typically used for treatment of various seizures and facial pain.
f. Ethosuximide is prescribed for the treatment of petit mal seizures.
3. Bronchodilators act to relax bronchial smooth muscle for relief or prevention of asthma. Theophylline is
the most common in this category of therapeutic drugs and is metabolized in the liver to produce several
metabolites, including caffeine.
4. Psychotropic or antipsychotic drugs are used to treat psychotic patients. They can be categorized in two
classes: lithium and the antidepressants.
a. Lithium treats manic-depressive illness. The mechanism of action of lithium as a mood stabilizer remains
unknown, although effects on synaptic neurotransmission are thought to be the cause. Lithium is filtered by the
renal glomerulus and eliminated as the unchanged drug.
b. Antidepressants, or tricyclic antidepressants, are used to treat depression that has no apparent organic or
social cause. Antidepressants include imipramine, nortriptyline, amitriptyline, and desipramine, all of which
are metabolized by the liver to form active metabolites. The active metabolites include desipramine (parent
is imipramine), nortriptyline (parent is amitriptyline), and 2-hydroxy-desipramine (parent is desipramine).
c. Fluoxetine is not chemically related to the tricyclic antidepressants, but has a similar effect by blocking
serotonin uptake by nerve terminals in the CNS and by platelets.
5. Antineoplastic drugs are used in the management of certain tumors, including those found in breast,
testicular, pharyngeal, and sometimes lung cancer. These agents work by inhibiting DNA synthesis.
F. Therapeutic drug monitoring (TDM) is performed to determine patient compliance to the drug-taking
regimen, to monitor drug interactions, and to monitor drugs that are used for a preventive effect.
1. Changes in drug concentrations in the body, which occur with time, are related to the course of the
pharmacologic effects. The change in drug concentration over time is described by the following steps.
a. Liberation is the release of this ingredient, followed by the process of the drug passing into solution.
b. Absorption is the process by which the drug molecule is taken up into systemic circulation. Following
absorption through the intestinal mucosa, a drug traverses the hepatic system, where some drugs undergo
substantial metabolism and elimination. This is called first-pass elimination or metabolism.
c. Drug molecules can be confined to the blood, leave the bloodstream, and enter the extravascular space, or
they can migrate into various tissues. This is referred to as distribution, a process that typically occurs
between a period of 30 minutes and 2 hours. The bioavailability of a drug is the amount of drug that is
absorbed into the system and is available for distribution.
d. Metabolism is the process of transformation of the parent drug molecule to its metabolite(s). Metabolites
are usually water soluble and can be easily excreted. Most of the metabolism occurs in the liver, where
enzymes catalyze oxidation, reduction, or hydrolysis of the drug.
e. Elimination is the process of excretion of the drug from the body. Drugs are typically excreted in the urine
but also can be eliminated in the feces, sweat, expired air, and saliva.
2. Basic principles. TDM measures drug concentrations during therapy with pharmaceutical agents.
a. A steady-state drug level (complete with peaks and troughs) exists for each drug. When a single dose of a
drug is administered orally, the blood level changes markedly over time and, at some time, the concentration in
the plasma reaches its peak (highest point) and then declines. Immediately before the next dose of medication,
a trough level occurs.
(1) For single-dose administration, the rate of decline in concentration is expressed in terms of half-life,
which is the time required for the concentration of the drug to decrease by 50% (Figure 1–6). The half-life is
different for each drug.
(2) At steady-state levels, the rate of administration of the drug is equal to the rates of metabolism and
excretion, allowing the drug level to remain constant.
G. Pharmacokinetics is the mathematical interpretation of drug disposition over time to determine proper
dosing amounts of a therapeutic drug. Pharmacokinetic responses are typically graphic plots of blood
concentration of the drug versus time, such as a dose-response curve . Three kinetic processes are used to
describe the fate of drugs in the body over a period of time and can be illustrated in a dose-response curve.
1. First-order kinetics describe absorption, distribution, and elimination of drugs. This means that the rate of
change of concentration of a drug is dependent on the drug concentration. It is represented by the first phase of
the dose-response curve.
2. Zero-order kinetics describe the rate of change of concentration of a drug that is independent of the
concentration of the drug. That is, a constant amount of drug is eliminated per unit of time. This typically
depends on the ability of the liver to metabolize the drug. This is illustrated by the second phase of the curve.
3. Michaelis-Menten kinetics state that if a drug concentration in a system exceeds the capacity of the system,
the rate of change of concentration proceeds according to the Michaelis-Menten equation.
H. Laboratory analysis of therapeutic drugs includes enzyme immunoassays and fluorescence-polarized
immunoassays. Gas chromatography and high-pressure liquid chromatography are also used, particularly as
confirmatory tests when a screening test is positive. Serum is typically the specimen of choice for drug
analysis, but urine metabolites are measured in some cases, particularly in screening tests.