THERAPEUTIC DRUGS

The therapeutic drugs included

are the more popular ones
and the ones that usually
measured in toxicology
laboratories for the purpose
of therapeutic drug
monitoring (TDM).
 Cardiotropic Drugs
These drugs are used for congestive heart failure and
for cardiac arrhythmia. The representative drugs are
as follows.

Digitalis glycosides: digoxin and digitoxin

Digitoxin is converted to active metabolite digoxin.
Procainamide (Pronestyl) – active metabolite is NAPA
Quinidine – fluorometrically measured

Lidocaine (Xylocaine)- local anesthetic

Propranolol (Indiral)- toxic effect same as Raynaud’s

phenomenon
 Anticonvulsants
Anticonvulsants are given for seizure disorders.
The most common anticonvulsants prescribed
by clinicians are as follows:
Phenobarbital – for generalized clonic-tonic seizures
Phenytoin (Dilantin)- decreases excitability by blocking Ca and
Na ions
Primidone (Mysoline) – active metabolites are phenobarbital and
PEMA (phenylethylmalonamide)
Ethosuximide (Zarontin) – desmethylmethosuxemide as active
metabolite
Carbamazepine (Tegretol) – active metabolites are 10,11 epoxide
form and 10,11 dihydroxy form
Valproic acid (Depakene) – enhances GABA-mediated inhibitory
systems
 Antiasthmatics
This drug is used for asthma, a form of chronic obstructive
pulmonary disease which is commonly allergic in nature.
There are many types of antiasthmatics. Among these are the
following:
Theophylline
Theophylline acts as a phosphodiesterase inhibitor.
Phosphodieterase allows high levels of cAMP to build up
promoting bronchodilation.
Metabolites are 1,3 dimethyluric acid & 3-
methylxanthine

Albuterol
Albuterol (Ventolin) is also a bronchodilator which acts as a β
adrenergic-agonist.

Antihistamines
Steroids
Steroids e.g., prednisone are also found to be effective against
asthma.
 Anti-inflammatory Drugs
The most popular anti-inflammatory drugs that are commonly
assayed in the laboratory are the following:

Acetaminophen (Tylenol) – inhibits PG synthetase to block

pain impulse generation; analgesic and antipyretic; highly
toxic to the liver

Acetylsalicylic acid (Aspirin) – NSAID; inhibits PG synthesis

via cyclooxygenase pathway; anticoagulant at low doses;
analgesic & antipyretic; toxicity is detected with tinnitus,
muffled hearing, sensation of fullness of ears

Naproxen (Naprosyn)

Ibuprofen (Motrin)
 Immunosuppressives
Immunosuppressive agents are usually indicated for autoimmune
diseases to reduce the inflammation. The more popular ones are
cyclosporin, prednisone, and cyclophosphamide (Cytoxan) which is
cytotoxic.

Cyclosporin is the drug of choice for the maintenance of allografts

e.g., liver, kidney and heart.
The therapeutic range of this drug is 250 – 800 ng/mL in whole
blood and 50 – 300 ng/mL in plasma.
Cyclosporin acts by inhibiting selectively T helper cell function
with sparing and augmentation of the T suppressor cell
populations.
It inhibits T helper cell production of interleukin-2. Cyclosporin is
metabolized in the liver through cytochrome P-450 IIIA.

Its frequent side effects are nephrotoxity and lymphoma.

 Drugs for Manic Depression
Manic depressants are used to psychiatric affective disorders.
The more common the drugs listed in the blood are:

Lithium – competes with ions & membrane receptors; for

bipolar disorders (manic-depressive disorders); for chronic
cluster headache

Tricyclic antidepressants (TCAD)

Amitriptyline
Imipramine
Nortriptyline
Desipramine
Doxepin
Neuroleptics and Antipsychotic Major
Tranquilizers
Neuroleptics and antipsychotic major
tranquilizers are used to treat acute
schizophrenia, and to suppress agitated
states. The two classes of antipsychotics
are:

Phenothiazines: chlorpromazine,
thioridazine, fluphenazine (Prolixin)
Chlorpromazine blocks post-synaptic receptors for
serotonin and dopamine.

Butyrophenones: haloperidol (Haldol)

 Chemotherapeutic Agents
Chemotherapeutic agents are antineoplastic, i.e., they are used to treat
cancer. Generally, these drugs are toxic to the body. In fact, it is this
toxicity which is used to kill cancer cells which are rapidly dividing. One
of the more popular ones is methotrexate.

Methotrexate is a folic acid antagonist. It inhibits the enzyme dihydrofolate

reductase.
It also inhibits polynucleotide ligase involved in DNA synthesis and
repair. Serum levels are not usually monitored except in toxicity.
Among the toxic effects are hematologic e.g., leukemia and
thrombocytopenia. It can also cause gastrointestinal, hepatic,
pulmonary, dermatologic, and neurologic problems.

Eucovorin has been used in high doses of methotrexate in individuals with

tumors which do not respond to normal doses of methotrexate.
Eucovorin rescues the normal cell while allowing methotrexate to kill the
tumor cells. Methotrexate has been used also as an immunosuppressive
for psoriasis, rheumatoid arthritis and some collagen vascular diseases.
Drugs of Abuse
One of the functions of a clinical toxicology
laboratory is to screen for drug abuse
from patients or from individuals who are
applying for jobs or travel abroad.

It also done in medico-legal cases.

Most of these drugs are basic except

barbiturates (acidic).
Opiates
These are basic compounds that are
structurally made up of tertiary amines and
contain benzene rings.

Examples are:
Morphine
Codeine
Heroin
Naloxone (Narcan)
Methadone
Propoxyphene (Darvon)
Tranquilizers

Diazepam (Valium)

Oxazepam
Sedative-hypnotic
This includes the barbiturates which are
derived from barbituric acid. Barbituric
acid is a condensation product of urea
and malonic acid.

Phenobarbital (long-acting barbiturate)

Amobarbital (intermediate-acting barbiturate)
Pentobarbital (short-acting barbiturate)
Thiopental (ultra-short-acting barbiturate)
Dopaminergic Pathway Stimulants

Cocaine

Benzoylegonine (less active metabolite)

Amphetamine
Amphetamine
Methamphitamine
Methylphenidate (Ritalin, which is used to
treat hyperactive children)
Hallucinogens

Phencyclidine

Methaquaalone

LSD (lysergic acid diethylamide)

THC (tetrahydrocannabinol)
POISONS
Early diagnosis of acute poisoning
with toxic substances
is important for
proper management of the patient
e.g., identifying the correct
antidote.
 Alcohols
Ethanol
Ethanol is the most common toxic substances
involved in medico-legal cases.

It is also the most common drug of abuse.

It has a sedative-hypnotic effect. Fatal dose is

generally 300 – 400 mL of pure alcohol consumed
in less than 1 hour.
Acute ethanol intoxication results in decreased
inhibition, incoordination, blurred vision, slurred
speech, stupor, coma, seizure and even death.
 Measurement of Ethanol
Conway Microdiffusion.
This is an excellent screening method. Ethanol is allowed to react
with potassium dichromate and sulfuric acid to form chromium
(III) sulfate (green).

Alcohol Dehydrogenase (Enzymatic) Method.

The ethanol reacts with nicotinamide adenine dinucleotide (NAD)
to form acetaldehyde and NADH. This is done
spectrophotometrically.

Fluorometric/Colorimetric.
The NADH produced by the alcohol dehydrogenase reaction is
allowed to react with tetrazolium dye to form a fluorescent or
colored reduced dye.

Gas Chromatography. This is used to separate and identify the

different alcohols e.g., methanol, ethanol and isopropanol. The
internal standard used is η-propanol.

Headspace analysis. This is measurement of ethanol in vapor. The

ethanol is allowed to evaporate by warming and the vapor
collected is analyzed.
Ethylene Glycol.
Ethylene glycol (1,2 ethane-diol) is the predominant ingredient in
anti-freeze used in car radiators.

Methanol.
Methanol is also known as wood alcohol. It is widely used as
solvents in paints, varnishes and paint removers.

Poisoning occurs in patients who ingest “methylated spirits or

methanol-containing anti-freeze.

Poisoning with methanol is more dangerous than ethanol

poisoning.

It is metabolized by liver alcohol dehydrogenase to form

formaldehyde and formic acid which can result in ocular toxicity.

Toxic levels methanol are within the range of 60 – 250 mL.

Sometimes, 15 mL methanol may already cause death.
 Measurement of Methanol

Copper Oxidation Method.

Methanol is oxidized by copper to
formaldehyde which resorcinol to form a
rose red color solution.

Chromotropic Acid (CTA) Colorimetric Method.

Methanol is oxidized by permanganate to

form formaldehyde which then reacts with
CTA to form a violet complex.
 Cyanide
Cyanide inhibits cellular respiration by binding with the
respiratory enzymes of the electron transport system
(especially cytochrome a + a3). It binds iron in the ferric
state (cyanoferric complex) of cytochromes and
hemoglobin. With cyanide, hemoglobin is converted into
cyanmethemoglobin.

Cyanide produces tissue hypoxia. An anaerobic environment

causes an increase in lactic acid (metabolic acidosis).
Death is very rapid.

The antidotes are amyl nitrite, sodium nitrite, sodium

thiosulfate and methylene blue. They are capable of pulling
cyanide ions from the body.
 Carbon Monoxide
This is the most common gaseous poison and is released
from automobile engines. It is found in the free state in
manufactured gas (coal gas), but not in natural gas.

It binds with hemoglobin being 210 times stronger than

oxygen, to form carboxyhemoglobin. It causes tissue
hypoxia with the brain and the heart being the most
susceptible targets.

Carbon monoxide causes a shift to the right of the

hemoglobin-oxygen-dissociation curve.

Acute poisoning may be diagnosed by the appearance of a

cherry red color of the face. The most effective antidote is
100% oxygen.
 Measurement of CO
Measurement of carbon monoxide may be done by any of
the following modalities. The specimen of choice is
whole blood.

Release of CO from the hemoglobin complex followed by

direct or indirect measurement of CO:
Gasometric techniques
Gas chromatography
Microdiffusion
Infrared spectrophotometry

Estimation of carboxyhemoglobin by its typical color or

absorption bands (Absorption maxima of 568 – 572 nm
and 538 – 540 nm)
Spectrophotometric
Spectrographic
Color comparison
 Arsenic
Arsenic is a favorite homicidal poison. It is considered a “protoplasmic
poison” because it combines with proteins in the protoplasm of the cell. It
does this by virtue of its affinity for sulfhydryl groups. The reaction results
in precipitation of the proteins.

Arsenic is used in ant poisons, rodenticides, herbicides, weed killer,

insecticides, paints, wood preservatives, ceramics, etc.

Arsenic poisoning can cause cyanosis, hypotension, tachycardia and

ventricular arrhythmia. In pregnant women, arsenic can cross the
placenta.

The major toxicologic forms of arsenic are as follows:

1. Inorganic arsenicals e.g., sodium arsenate and lead or copper arsenite
2. Organic arsenicals e.g., carbasone and tryparsamide
3. Arsine gas in industries. This is the most dangerous form.

Arsenic poisoning can be detected by the garlic odor of the breath and the
metallic taste in the patient’s mouth. Treatment includes gastric lavage,
dicumarol, and BAL (British Antilewisite) which makes arsenic
water-soluble.
The specimen of choice for this poison is urine. Blood is not
used. Measurement is done by the Reinsch test. The
metallic copper in the presence of acid will reduce arsenic
to its elemental form. Deposits of copper produced will
form a visible, dark film.

Note that antimony, bismuth mercury, and selenium can also

reduce copper. They also yield positive result in the
Reinsch test. The test, however, is not satisfactory if the
concentration of the metal is low.
 Mercury
These are four toxicological forms of mercury namely:
Elemental mercury (metallic) - HgO
Mercurous mercury- Hg+
Mercuric mercury- Hg+2
Organic mercury or alkyl mercury (an environmental
pollution)
With the exception of mercurous mercury, these forms of
mercury are poorly absorbed in the gastrointestinal tract.

Poisoning occurs when they are inhaled or absorbed

through the skin. This causes respiratory and central
nervous system toxicity. Mercury prefers to deposit in
the kidney.
Mercury undergoes covalent binding with protein
sulfhydryl groups, producing non-specific enzyme
dysfunction, inactivation and denaturation. Treatment
includes gastric lavage or emesis and use of
dimercaprol or penicillamine.

The specimens used in the measurement of mercury

could be:
24-hour urine: for acute toxicity of elements, inorganic,
and most organic forms

blood: for short-chain alkyl mercury compounds which

are excreted through bile

hair: for chronic mercuric exposure

 Iron
Iron poisoning is common in young children and results
from ingestion of iron containing products. The
poisoning is characterized by acute mucosal damage
especially with large doses of iron.

Toxic levels result in hepatic cell damage, shock, lactic

acidosis, cyanosis, convulsion, shock, renal and
hepatic failure, and death.

The toxic signs include vomiting melena, abdomenal

pain, hematemesis and severe gastroenteritis.

Iron poisoning is diagnosed by measuring serum iron

and total iron binding capacity (TIBC).
 Lead

Lead is encountered in industrial exposure and in

lead-containing paints and plasters. It is either inhaled or
ingested. Cumulative poisoning dose of 0.5 mg/day
(0.5g/day) absorption is fatal. Permissible blood levels in
children is only 10 ug/dL.

The half-life of lead is 32 years. The bone is the largest body

compartment or reservoir of lead (endogenous intoxication).
Typically, lead poisoning is characterized by hypochromic
normocytic anemia.

Lead interferes with hemoglobin synthesis. It affects heme

synthesis by blocking the action of dALA synthetase, ALAS
or DALA dehydrase, corproporhyrinogen decarboxylase and
ferrochelatase.
Treatment is done using dilute magnesium sulfate or
sodum sulfate to remove lead, o r chelating agents
like dimercaprol and pencillamine.

Inorganic lead poisoning is characterized by:

Increased ALA in urine
Decreased ALAD activity in red blood cells
Increased free erythrocyte protoporphyrin (FEP)
Increased Zn protoporphyrin (an excellent
screening test)

The zinc protoporphyrin/heme ratio is used to

diagnose chronic lead exposure. It has a poor
sensitivity. AAS is most accurate for lead. The
more common methods used are as follows:
Colorimetric using diphenylthiocarbazone
(dithizone) to form a red complex
Polarography
AAS
 Organophosphates and Carbamates
Organophosphates are esters of phosphoric acid. Carbamates are
synthetic derivatives of carbonic acid. Both interfere with
neurotransmission and are widely used as pesticides in
agriculture. Both inhibit the enzyme acetyl cholinesterase which
hydrolyze the neurotransmitter acetyl choline.

The symptoms of poisoning are usually parasympathetic

manifestations e.g., salivation, lacrimation, urination and
defecation (SLUD), pupillary constriction, bradycardia and
bronchoconstriction.

Treatment or choice includes respiratory support, lavage, emesis,

and pralidoxime.
Diagnosis is made through:
Erythrocyte acetyl cholinesterase level (more specific)
Plasma pseudocholinesterase level (more sensitivity).