TOXICOLOGY

Study of poisons.
 POISON
Any substances that can cause a
harmful effect upon exposure.
PHARMACOLOGY
Deals with the study of drug
action and drug conversion by the
body.
THERAPEUTIC
DRUG
MONITORING
 involves the analysis, assessment and
evaluation of circulating concentrations of
drugs in serum, plasma or whole blood.
It is quantitative procedure performed for
drugs with a narrow therapeutic index.
To ensure that a given drug produces
maximal therapeutic benefit and minimal
side effects; to achieve constant serum
level of the drug that will be therapeutic.
It 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.
MIXED FUNCTION OXIDASE (MFO) system
is the biochemical pathway responsible
for the greatest portion of drug
metabolism.
 FOUR MAJOR DISCIPLES OF
TOXICOLOGY
1. MECHANISTIC TOXICOLOGY
Elucidates the cellular and biochemical
effects of toxins
It provides a basis for rationale therapy
design and the development of test to
assess the degree of exposure of
poisoned individuals.
2. DESCRIPTIVE TOXICOLOGY
Uses the results from animal experiment
to predict what level of exposure will
cause harm in humans.
Risk assessment
3. FORENSIC TOXICOLOGY
Medico legal consequences of
exposure to a toxin.
Major focus is establishing and
validating the analytical performance of
the methods used to generate evidence
in legal situations.
4. CLINICAL TOXICOLOGY
Study of interrelationship between toxin
exposure and the disease state.
Emphasizes not only diagnostic testing but
also therapeutic intervention.
FUNCTIONS OF TOXICOLOGY:
TDM
Identification of drugs in acute
intoxication
Urine testing for drugs of abuse
Testing for toxins from environmental
or occupational exposure
INDICATIONS FOR TDM:
1. The consequences of overdosing and
underdosing are serious.
2. There is a small difference between a
therapeutic and toxic dose.
3. There is a poor relationship between the dose
of drug and circulating concentrations.
4. There is a change in the patients physiologic
state that may unpredictably affect circulating
drug concentrations.
5. A drug interaction is or may be occurring.
6. It helps in monitoring patient compliance.
ROUTES FOR ADMINISTRATION:
The circulatory system is a convenient route that can
effectively deliver most drugs to its site of action.
Intravenous route of administration is associated
with 100% bioavailability all the drugs enter the
bloodstream.
Orally administered drug should achieved 0.7
bioavailability fraction.
When drugs are intravenously (most immediate
route) administered, the distribution and elimination
rates are constant.
ROUTES: IV, oral, IM, Subcutaneous, Inhalation,
suppository, and transcutaneous.
EXPOSURE TO TOXINS:
INTENTIONAL SUICIDAL ATTEMPTS
50% of poisoning cases
Most frequent in children.

ACCIDENTAL EXPOSURE
30% of poisoning cases
Drug overdose of either therapeutic or illicit
Most frequently in adult remainder cases are due
to homicide or occupational exposure that occurs
in industrial and agriculture setting.
 FACTORS INFLUENCING ABSORBENCY
OF TOXIN FROM GIT
1. Rate of dissolution
2. Gastrointestinal motility
3. Resistance to degradation in GIT
4. Interaction with other substances.
 TOXICITY RATING SYSTEM
TOXICITY RATING LETHAL ORAL DOSE IN AVERAGE
ADULT
SUPER TOXIC < 5 mg/kg

EXTREMELY TOXIC 5 50 mg/kg

VERY TOXIC 50 500 mg/kg

MODERATE TOXIC 0.5 5 g/kg

NON TOXIC > 15 g/kg

FOR YOUR SEATWORK:

DIFFERENTIATE ACUTE
FROM CHRONIC
TOXICITY.
ACUTE VS. CHRONIC TOXICITY
Term used to relate the duration and frequency of
exposure to the toxic effects.

ACUTE TOXICITY
Associated with single, short term exposure to a
substance.
CHRONIC TOXICITY
Associated with repeated exposure for extended
periods of time. It is also due to an accumulation
of the toxicant.
FIVE PHARMACOLOGICAL
PARAMETERS THAT
DETERMINE SERUM DRUG
CONCENTRATION
1. LIBERATION
It the release of drug
2. ABSORPTION
It is the transport of drug from the site of
administration to the blood.
3. DISTRIBUTION
Refers to the delivery of the drug to the tissues.
4. METABOLISM
It is the process of chemical modification of the drug
by cells.
5. EXCRETION
Is the process by which the drug and its metabolites
are excreted from the body.
 ABSORPTION
For a drug to achieve therapeutic dose, it must
be at the proper concentration at its site of
action.
Most drugs are absorbed by passive diffusion
the drug must be in a hydrophobic state
(nonionized)
Some drugs require uptake by transport
mechanisms intended for dietary constituents.
Drug absorbed from the intestine enter the
hepatic portal system all the blood from the GIT
is routed through the liver before it enters into
the general circulation.
 Tablets and capsules require dissolution
before being absorbed; liquid solutions are
rapidly absorbed.
Weak acids are absorbed in the stomach;
weak bases in the intestines.
Changes in the absorptive characteristics of
the drugs may be due to age, pregnancy or
pathologic conditions.
FACTORS AFFECTING ABSORPTION: changes
in intestinal movement, pH, inflammation
and the presence of food or other drugs.
 DISTRIBUTION
The locations where the drugs are effective
are in the body tissues, not generally in the
blood.
Drug diffuse widely through the body,
frequently reaching higher concentrations in
tissues than in blood.
The relationship between tissue and blood
levels is termed the distribution space.
A large distribution space indicates that much
of the drug moves into the tissues than stays
in the circulation.
 EXCRETION
The rate at which a particular drug is
cleared from the circulation is dependent
not only on the type of drug itself, but also
on a patients capacity to metabolize and
excrete it.
All drugs are excreted either unchanged in
the urine, or excreted as metabolites of the
patient drug.
Some drugs enter the enterohepatic
circulation and excreted in stool.
CAUSES OF DRUG TOXICITY:

1. Elevated concentration of free drug.

2. Abnormal response to drug after
administration
3. The presence of active drug
metabolites.
 BIOLOGICAL FLUIDS USED IN
TOXICOLOGIC
MEASUREMENTS
In using these fluids consider practicality,
timing of collection and any usable
information.
 GASTRIC CONTENT
The sample maybe collected by inducing
emesis or by performing a gastric lavage.
This fluid should not be used when the
drug is not taken orally or when 24 36
hours has elapsed after oral ingestion.
The use of this sample determines whether
the patient has actually ingested the drug
or not.
Any procedure mentioned in both
diagnostic and therapeutic.
URINE
This is frequently used because it is
very easy to obtain, simple to prepare
for analysis.
Suitable for MASS SCREENING
procedure
If however, is no of value immediately
after ingestion of the drug, is solely for
confirmation and semi quantitative
determination.
BLOOD AND SERUM
This is the MOST RELIABLE
SPECIMEN with very little chance
cross sensitivity
It is usually taken at multiple times
(serial determination) for purposes
of evaluating the effect of any
medication against intoxicant.
GENERAL PRINCIPLES OF ASSAY
TECHNIQUE
ANALYSIS OF TOXIC AGENTS
TWO STEP PROCEDURE
1. FIRST STEP (SCREENING TEST)
Rapid, simple, qualitative procedures
intended to detect specific drugs or classes
of drugs or toxicant.
Sufficiently sensitive but lack of specificity
2. SECOND STEP (CONFIRMATORY TEST)
 SPECTROPHOTOMETRIC: COLORIMETRIC
and FLUOROMETRIC
Simple and do not require complex
materials
Not all compounds from derivatives which
absorb light or that fluorescence
A metabolite of the drug may also react,
falsely elevating the value for the
medication in question.
The sensitivity of these methods does not
always allow detection at low levels.
 IMMUNOASSAYS
Use specific antibodies, only the derivatives
of interest would be measured.
Increase in complexity and cost.
More sophisticated equipment was required,
which needed more expensive reagents.
Techniques were often more complicated,
thus requiring a higher level of technician
proficiency.
Application of this method allows rapid,
accurate measurements of drugs.
 CHROMATOGRAPHY
Allows measurement of low drugs.
Measure the amount of parent drug and
metabolites
Demand considerable time and skill
Expensive equipment is required and high
degree of technical ability is called for:

THIN LAYER CHROMATOGRAPHY

Simple and inexpensive
 GAS CHROMATOGRAPHY
For qualitative and quantitative
determination
Many compounds must be first converted
to a volatile derivatives that must still be
stable at the temperature of separation.
HPLC (HIGH PERFORMANCE LIQUID
CHROMATOGRAPHY)
Must be able to detect the compound after
it comes off the column.
 Bring half lengthwise:
Define the following:
half- life
peak concentration
Pharmacodynamics
pharmacogenomics
Pharmacokinetics
therapeutic index
therapeutic range
TERMINOLOGIES
1. BIOAVALABLE FRACTIO (f)
- It is the fraction of the doses that
reaches the blood.
2. Vd of a DRUG
- represent the dilution of the drug
after it has been distributed in the body.
It is used to estimate the peak drug blood
level expected after a loading dose is
given. It is the principal determinant of
the dose.
3. FIRST PASS HEPATIC METABOLISM
- drugs that are transported to the
liver lost a fraction of its bioavailability
before the drug reaches the general
circulation.
4. FIRST ORDER ELIMINATION
- represents a linear relationship
between the amount of drug eliminated
per hour and the blood level of drug.
5. HALF LIFE
- the time required to reduce a drug level
to half of its initial value.
6. PEAK CONCENTRATION
- the highest concentration of a drug
obtained in the dosing interval.
7. PHARMACODYNAMICS
- it is the relationship between the drug
concentration at the target site and response
of the tissue.
8. PHARMACOGENOMICS
- refers to the study of genes that affect
the performance of a drug in an individual.
9. PHARMACOKINETICS
-it is the mathematical expression of the
relationship between drug dose and drug
blood level.
10. THERAPEUTIC INDEX
- the ratio between the minimum toxic
and maximum therapeutic serum
concentration
11. THERAPEUTIC RANGE
- the difference between
highest and lowest effective
dosages.
12. TROUGH CONCENTRATION
- is the lowest concentration of
a drug obtained in the dosing
interval.