University of Santo Tomas-Legazpi
College of Health Sciences
Medical Technology Program
WRITTEN REPORT
Subject:
Clinical Chemistry Lecture II
Topic/Lesson:
a. Therapeutic Drug Monitoring
b. Toxicology
Audience:
3rd Year BSMT students
Reporters:
All 3BSMT1 students
Medium of Reporting:
Recorded Video through Zoom
Learning Objectives:
(Therapeutic Drug Monitoring)
a. To know the characteristics of drugs which makes therapeutic drug monitoring essential
b. To determine the mechanism of drugs and its factors of influence
c. To name the therapeutic category related to therapeutic drugs.
(Toxicology)
a. To define toxicology and know the different Toxicants
b. To define mechanism of toxicants
c. To discuss the laboratory methods used to evaluate toxicity.
Preparation:
a. The 3BSMT1 students divided the tasks into designated groups.
b. Each group are tasked to work on their appointed topic by making a slide presentation and to
record their report discussion
c. The 3BSMT1 block officers assigned point persons that will manage tasks and will compile the
outputs form the groups for the whole class:
o Powerpoint presentation in-charge
o Video Editor
o Written Report in-charge
Reference:
Bishop, M. L., Duben-Engelkirk, J. L., & Fody, E. P. (1996). Clinical chemistry: Principles,
procedures, correlations. Philadelphia: Lippincott.
Report Content:
See next page
A.THERAPEUTIC DRUG & MONITORING
3BSMT1
CONTENTS:
01. ROUTES AND ADMINISTRATION
02. ABSORTION
03. FREE VERSUS BOUND DRUGS
04.
05.
06.
07.
➢
OVERVIEW
08. PHARMACOGENOMICS
DRUG DISTRIBUTION
09. CARDIOACTIVE DRUGS
DRUG ELIMINATION
10. ANTIBIOTICS
PHARMACOKINETICS
Presented by 3 BSMT-1
11. ANTIEPILECTIC DRUGS
SAMPLE
Contents
COLLECTION
SAMPLE
COLLECTION
12. PSYCHOACTIVE DRUGS
13. IMMUNOSUPPRESSIVE DRUGS
14. ANTINEOPLASTICS
01. ROUTES AND ADMINITRATION
Therapeutic Drug Monitoring (TDM)
Involves the analysis, assessment, and
evaluation of circulating concentrations of drugs
in serum, plasma, or whole blood.
• The purpose of these actions is to ensure that
a given drug dosage produces maximal
therapeutic benefit and minimal toxic adverse
effects.
• With certain drugs, however, the correlation
between dosage and therapeutic effects or
toxic outcomes is weak, and it is difficult to
predict what dose should be used. In this
situations, trial, and error, in conjunction with
direct observation, may work.
• The standard dosage is statistically derived
from observations in a healthy population.
• Disease states may produce altered
physiologic conditions in which the standard
dose does not produce the predicted
concentration in circulation. In these cases,
individualizing a dosage regimen is
warranted.
Common indications for TDM:
✓ The consequences of overdosing and
underdosing are serious.
✓ There is a small difference between a
therapeutic and a toxic dose.
✓ There is a poor relationship between the
dose
of
drug
and
circulating
concentrations but a good correlation
between circulating concentrations and
therapeutic or toxic effects.
✓ There is a change in the patient’s
physiologic state that may unpredictably
affect circulating drug concentrations.
✓ A drug interaction is or may be occurring.
✓ TDM helps in monitoring patient
compliance.
A drug must be at the proper concentration at its
site of action to provide therapeutic benefit. It
would be excellent to measure drug concentration
at the site of action.
● Bioavailability is defined as the unaltered
percentage of the injected dose as it
enters systemic circulation.
● The goal of most therapeutic regimens is
to acquire (blood, plasma, or serum)
concentration
Drugs can be administered by several routes:
a. Intravenous (IV) - Directly into the
circulation
b. Intramuscular (IM) - Into the muscles
c. Subcutaneous (SC) - Under the skin
d. Transcutaneous - Inhalation or absorbed
through the skin
e. Suppository - Rectal delivery
02. ABSORPTION
Factors affecting the efficiency of absorption for
orally administered drugs:
1. Dissociation from administered form
2. Solubility in gastrointestinal fluids
3. Diffusion
across
gastrointestinal
membranes
Two types of drug absorption
● Passive
● Active
Factors alter absorption rates:
●
●
●
●
Changes in intestinal motility
pH
Inflammation
Presence of food or other drugs
(coadministration of drugs such as antacids,
kaolin, sucralfate, cholestyramine, and
antiulcer medications)
Drug absorption rate may change with:
● Age
● Pregnancy
● Pathologic conditions
METABOLISM
●
Certain drugs are subject to significant hepatic
uptake and metabolism during passage
through the liver aka first pass metabolism.
Variations are examined in the discipline of
pharmacogenomics.
Genetic variation, fatty/cirrhotic liver may affect
the capacity to metabolize drugs.
Biotransformation - enzymatic process in the
liver
●
●
●
03. FREE VERSUS BOUND DRUGS
Free or unbound drug fraction- only fraction that can
interact with its site of action and result in a biologic
response, also termed as active.
•
•
•
Albumin - major protein constituent in
plasma; changes in concentration can affect
the free versus bound status of many drugs.
High free fraction - toxic adverse effects
Low free fraction - no therapeutic benefit
These fractions occur secondary to changes in blood
protein content such as in inflammation,
malignancies, pregnancy, hepatic disease, nephrotic
syndrome, malnutrition, and acid-base balance.
Plasma alpha-1-acid glycoprotein- binding of
drugs (propranolol, quinidine, chlorpromazine,
cocaine, benzodiazepines)
- Concentration of substances that compete for
binding sites affects the fraction of free drug
(e.g., urea, bilirubin, hormones)
05. DRUG ELIMINATION
Plasma free fraction of a parent drug/metabolites is
subject to glomerular filtration, renal secretion, or
both.
-
-
For those drugs not secreted or subject to
reabsorption, the elimination rate of free drug
directly relates to the glomerular filtration rate.
Decreases in glomerular filtration rate directly
result in increased serum half-life and
concentration. amino-glycoside antibiotics
and cyclosporine
First-order elimination: △C/△T = -Kc
04. DRUG DISTRIBUTION
● Free fraction of circulating drugs
● Highly hydrophobic drugs can easily transverse
cellular membranes and partition into lipid
compartments
● Ionized species diffuse out of the vasculature
● Volume of distribution index:
Vd = D/C
where: Vd = volume of distribution (L)
D = IV injected dose (mg or g)
C = Concentration in plasma (mg/L or g/L)
-
From the integration of equation △C/△T = kC yields this formula.
From it, we can
calculate
the
elimination
constant or, if k is
known, we can
determine
the
amount of drug
that
will
be
present after a
certain time.
EXAMPLE:
The concentration of gentamicin is 10 μg/mL at
12:00. At 16:00, the gentamicin concentration is 6
μg/mL. What is the elimination constant (k) for
gentamicin in this patient?
Half-Life
●
This represents the time needed for the
serum concentration to decrease by one-half.
●
From the just-cited example, the half-life of
gentamicin in this patient would be calculated
as follows:
06. PHARMACOKINETICS
● Is defined as the activity of drug(s) in the body
as influenced by absorption, distribution,
metabolism, and excretion.
● Figure 30-3 is an idealized plot of elimination
after an IV bolus
In this same patient on the same day, what would be
the predicted serum concentration of gentamicin at
midnight (24:00)?
●
Figure 30-5 is a plot of serum concentration
as it would appear after oral administration of
a drug.
●
●
●
Most drugs are not administered as a single
bolus but are delivered on schedule basis
(e.g., once every 8 hours).
With this type of administration, serum
concentration of drug oscillates between a
maximum (peak drug level) and minimum
(trough drug level).
Approximately to 7 doses are required before
a steady-state oscillation is acquired. The
basis of this number is demonstrated in
Figure 30-6.
Responders
● Are the patients benefiting from the
therapeutic and desired effects of the drug
Nonresponders
● Do not demonstrate a beneficial and desired
therapeutic effect from the initiation of a given
drug regimen.
The therapeutic effectiveness of drugs in responders
and nonresponders has recently been attributed to
the interindividual variation in the genetic
polymorphisms.
● One of the most prominent gene families that
affect drug metabolism is the cytochrome
P450 (CYP450) family.
● The three most often linked to differences in
degrees of drug metabolism are CYP2D6,
CYP2C9, and CYP3A4.
● This information can then be used to
personalized drug doses tot the degree that
is appropriate for the CYP450 profile of the
patient.
09. CARDIOACTIVE DRUGS
These drugs are the ones
most
used
to
treat
congestive heart failure
and cardiac arrhythmias.
07. SAMPLE COLLECTION
✓ Timing of specimen collection is the single
most important factor in TDM.
o A commonly use drug that is an
exception to this rule is digoxin.
✓ Serum or plasma is the specimen of choice
✓ Care must be taken that the appropriate
container is used when collecting specimen.
o Certain drugs tend to be absorbed
into the gel of certain serum separator
collection tubes; it is necessary to
follow vendor recommendations.
✓ Heparinized plasma is suitable for most drug
analysis
✓ The calcium-binding anticoagulant may
interfere with the analysis
✓ EDTA, citrated and oxalated plasma are not
usually acceptable specimens.
08. PHARMACOGENOMICS
The effectiveness of a drug over the population that
uses it can be divided into categories of patients
defined as responders and nonresponders.
It can be classified into different classes:
1. Class I - Rapid Na+ channel blockers
(Procainamide, Lidocaine, Quinidine)
2. Class II - Beta receptor blockers
(Propranolol)
3. Class III - K+ channel blockers (Amiodarone)
4. Class IV - Ca2+ channel blockers
(Verapamil)
A. CARDIAC GLYCOSIDES
(Digitalis & its Derivatives)
1. Digoxin and Digitoxin
B. PROCAINAMIDE (PRONESTYL)
●
• Mechanism of Action
Functions by inhibiting membrane Na+, K+ -ATPase
(causes a decrease in intracellular potassium,
resulting in increased intracellular calcium in cardiac
contractility)
● Toxic Adverse Effects
○ Nausea
○ Vomiting
○ Visual disturbances
○ Cardiac effects (premature
ventricular contractions – PVC and
atrioventricular node blockage)
● Dosage Regimen
○ Requires assessment of serum
concentrations after initial dosing to
ensure that effective and nontoxic
serum concentrations are achieved
● Peak Serum Concentration
○ 8-10 hr after an oral dose correlates
with tissue concentration. (Peak
levels collected before this time are
misleading and not valid)
● Immunoassay - used to measure total
digoxin concentration in serum
❖ Elimination of digoxin occurs primarily
by renal filtration of the plasma free
form
❖ In circulation, 25% is protein-bound
and the rest is sequestered into
muscle cells
❖ its therapeutic actions and toxicities is
influenced by the concentration of
serum electrolytes (low serum
potassium and magnesium potentiate
digoxin actions)
❖ Thyroid status also influence the
action of digoxin:
o Hyperthyroid patients:
resistance
o Hypothyroid patients: more
sensitive
●
Class I antiarrhythmic drug - useful in treating
supraventricular or ventricular arrhythmias
Peak Plasma Concentration - About 1 hr.
❖ Undergoes N-acetylation in the liver to
form N-acetylprocainamide (NAPA)
which is the active metabolite
❖ Toxic side effects related to Systemic
Lupus Erythematosus (SLE)
❖ Gastrointestinal absorption is rapid and
complete
❖ Absorbed procainamide is about 20%
bound to plasma proteins
C. QUINIDINE
●
●
●
Class I antiarrhythmic, similar uses of
procainamide
Toxic Adverse Effects
○ Nausea
○ Vomiting
○ Abdominal discomfort
○ Cardiovascular toxicity - PVCs may see
at twice the upper limit of therapeutic
range.
Peak Serum Concentration on Two most
common formulations:
○ Quinidine sulfate (gastrointestinal
absorption is complete and rapid)
● 2 hr. after an oral dose
○ Quinidine gluconate
● 4-5 hr. after an oral dose
●
●
Can be determined by:
○ Chromatography
○ immunoassay
○ fluorometrically (common)
Monitor by trough level - ensure within
therapeutic range.
❖ Undergoes hydroxylation in the liver
❖ Two most common formulations:
o Quinidine sulfate
(gastrointestinal absorption is
complete and rapid)
o Quinidine gluconate
❖ Absorbed quinidine is 70 – 80%
bound to serum proteins
❖ Elimination is through hepatic
metabolism
D. DISOPYRAMIDE (NORPACE)
E. LIDOCAINE (XYLOCAINE)
●
●
●
●
Class I antiarrhythmic, use as an
antiarrhythmic is in the acute control and
prevention of ventricular arrhythmias after
acute myocardial infarction.
○ major use as an antiarrhythmic is in
the acute control and prevention of
ventricular arrhythmias after acute
myocardial infarction.
Local anesthetic
Unlike procainamide and quinidine, lidocaine
does not cause QRS and Q-T prolongation
(Roden, 2006)
Toxic side effects
o Convulsions
o Coma
o Respiratory depression (CNS effects)
o Bradycardia
o Hypotension
❖ Lidocaine can cause heart block and
congestive heart failure, limiting its
use in critical care patients (Roden,
2006).
❖ A local anesthetic
❖ 90% dose undergoes N-dealkylation
in the liver
❖ Urinary excretion is 10%
❖ Not protein-bound
❖ Not stored in tissues
Commonly used as quinidine substitute when
quinidine adverse effects are excessive
● Primary toxicities
○ Anticholinergic effects (>4.5 µg/mL)
■ Dry mouth
■ Constipation
○ Cardiac Effects (>10 µg/mL)
■ Bradycardia
■ Atrioventricular node
blockage
● Peak Serum Concentration
○ 1-2 hr.
● Can be determined by:
○ Chromatography
○ Immunoassay
• Gastrointestinal is complete and rapid
F. PROPRANOLOL (INDIRAL)
❖ Eliminated by renal filtration, and to a
lesser extent, by hepatic metabolism
❖ Conditions with low glomerular
filtration rate, half-life is prolonged and
serum concentrations rise.
●
Class II antiarrhythmic β receptor–blocking
drug
●
Toxic effect:
○ Bradycardia
○ Arterial insufficiency (Raynaud’s type)
○ Hypotension
○ AV block
○ Nausea
○ Vomiting
○ Pharyngitis
○ Bronchospasm
○ Thrombotic thrombocytopenic purpura.
○ Marrow suppression (rare)
H. VERAPAMIL
●
●
❖ Approximately 93% is protein bound.
❖ Propranolol is metabolized in the liver
❖ 0.5% excreted in the urine unchanged
❖ Toxic effects
o Hypotension
o ventricular fibrillation
o Constipation
o Peripheral edema.
❖ Approximately 90% is plasma protein
bound
❖ Drug undergoes extensive metabolism
in the liver, where norverapamil, an
active metabolite, is produced.
❖ Eliminated approximately 75% of the
active components are eliminated by
the kidney and ≈25% through the GI
tract.
G. AMIODARONE
● Class III antiarrhythmic drug, which markedly
prolongs the action potential mainly by blocking
potassium channels in cardiac muscle.
● Oral loading dose
o 1200 - 1600 mg/day with a maintenance
dose of 200 to 400 mg/day.
❖ Toxic effects can be profound and
include
➢ Symptomatic bradycardia
➢ Heart block
➢ Fatal pulmonary fibrosis
➢ Hepatitis
➢ Visual field disturbances
➢ Optic
nerve
neuropathy
photodermatitis
➢ Mainly
hypothyroidism
but
sometimes
hyperthyroidism.
(Passman et al, 2012)
❖ Approximately 96% is plasma protein
bound
❖ Excretion is very slow by skin, biliary
tract, and lacrimal glands.
Class IV antiarrhythmic drug
Oral loading dose
o 1200 - 1600 mg/day with a
maintenance dose of 200 to 400
mg/day
10. ANTIBIOTICS
a. AMINOGLYCOSIDES
• Aminoglycosides are group of chemically
related antibiotics used for the treatment of
infections with gram-negative bacteria that
are resistant to less toxic antibiotics.
•
The most encountered in a clinical setting are
gentamicin, tobramycin, amikacin, and
kanamycin.
•
All share a common
mechanism of action but
vary in effectiveness against
different strains of bacteria.
All share a common
nephrotoxicity
and
ototoxicity.
•
•
The ototoxic effect involves disruption of
inner
ear
cochlear
and
vestibular
membranes, which results in hearing and
balance impairment. These effects are
irreversible.
•
Cumulative effects may be seen with
repeated
high-level
exposure.
Nephrotoxicity is also of major concern.
•
Aminoglycosides impair the function of
proximal tubules of the kidney, which may
result in electrolyte imbalance and possibly
proteinuria. These effects are usually
reversible; however, extended high-level
exposure may result in necrosis of these
cells and subsequent renal failure.
•
Toxic
concentrations
are
usually
considered any concentration above the
therapeutic range.
•
Not
well
absorbed
from
the
gastrointestinal tract, administration is
limited to the IV or IM route; therefore,
these drugs are not used in an outpatient
setting.
•
Aminoglycosides are eliminated by renal
filtration. In patients with compromised
renal function, appropriate adjustments
must be made based on serum
concentrations.
•
Chromatography and immunoassay are
the primary methods used for aminoglycoside
determinations.
b. VANCOMYCIN
•
VANCOMYCIN is a glycopeptide antibiotic
that is effective against gram-positive cocci
and bacilli.
•
Because of poor oral absorption, vancomycin
is administered by IV infusion.
•
Unlike other drugs, a clear relationship
between serum concentration and toxic
adverse effects has not been firmly
established. Many of the toxic effects occur in
the therapeutic range.
•
It is assayed by immunoassay
and
chromatographic
methods.
•
The major toxicities of vancomycin are redman syndrome (characterized by an
erythemic flushing of the extremities),
nephrotoxicity, and ototoxicity.
•
The renal and hearing effects are like those
of the aminoglycosides.
•
It appears that the nephrotoxic effects occur
more frequently at trough concentrations that
are greater than 10 g/mL. The ototoxic
effect occurs more frequently when peak
serum concentrations exceed 40 g/mL.
•
Because vancomycin has a long
distribution phase, in most instances, only
trough levels are monitored to ensure the
serum drug concentration is within the
therapeutic range.
•
Vancomycin is primarily eliminated by
renal filtration and secretion
11. ANTIEPILEPTIC DRUGS
●
●
●
●
Used in Epilepsy, Convulsions, and
Seizures
Used as prophylactics
A second generation has been introduced in
clinical practice as “supplemental therapy” to
more traditional drugs
Most AEDs are analyzed by chromatography
or immunoassay and measure the free or
bound drug in a serum or plasma sample.
FIRST GENERATION ANTIEPILEPTIC DRUGS
a. PHENOBARBITAL
●
●
●
Circulating protein bound: 50%
Elimination: Hepatic metabolism
Common adverse effects:
○ Drowsiness
●
●
●
●
●
●
●
○ Fatigue
○ Depression
○ Reduced mental capacity
Administered as oral preparation
Slow acting barbiturate that effectively
controls several types of seizures
Peak serum concentration peaks in 10
hours after oral dose
Compromised renal/hepatic function =
decreased rate of elimination
Half life: 70-100 hours
A potent inducer of the hepatic MFO
system.
After initiation of therapy, dose adjustment is
usually required after the induction period is
complete. (For most individuals, this is 10-15
days after the first dose)
•
•
•
•
Reduced protein binding can occur with;
anemia with hypoalbuminemia, and co
administration of other drugs.
Major toxicity of Phenytoin—- Seizures
Seizures of a patient during treatment may
be
subtherapeutic
or
toxic
concentrations.
In many situations however, the effective
range must be individualized to suit the
clinical situation.
Primidone (inactive form)
○ After absorption, this drug is rapidly
converted to its active form.
○ Is used instead of phenobarbital when
steady-state kinetics is needed to be
established quickly.
○ Rabidly absorbed
○ Both Primidone and Phenobarbital
need to be measured to assess the
total potential amount of phenobarbital
in circulation.
Fosphenytoin (injectable form)
○
○
○
rabidly metabolized in serum,
releasing the parent drug.
This conversion takes 75 minutes.
Most immunoassay do not detect the
proform, thus complete conversion is
needed first before evaluation
c. VALPROIC ACID
b. PHENYTOIN “DILANTIN”
•
•
•
•
•
•
•
•
•
Circulating protein bound: 87-97%
Elimination: Hepatic metabolism
Common adverse effect:
o Hirsutism (excessive hair growth)
o gingival hyperplasia
o vitamin D deficiency
o folate deficiency
Administered as: Oral preparation
Gastrointestinal absorption: variable and
sometimes incomplete
Commonly used treatment for seizure
disorders
A short-term prophylactic agent in brain
injury to prevent functional tissue loss
Can be displaced with other high protein
bound drugs
Unbound/free fraction is biologically active in
total serum concentration
●
●
●
●
●
Circulating Protein bound: 93%
Elimination: Hepatic metabolism
Common adverse
effects:
o Nausea
o Lethargy
o Weight gain
Administered as oral
preparation
Gastrointestinal absorption: rapid and
complete
●
●
●
●
●
Used as a monotherapy for the treatment of
petit mal and absence seizures.
Determination of serum concentration is done
to ensure that toxic levels are not present
High
serum
levels—
pancreatitis,
hyperammonemia,
hallucinations
(<200μg/mL)
Hepatic dysfunction occasionally occurs in
some patients even at therapeutic serum
concentrations, therefore hepatic indicators
should be checked frequently for the first 6
months after initiation of therapy.
Free fraction is more reliable index of
therapeutic and toxic concentrations
●
Plasma concentrations greater than 15 g/mL
are associated with hematologic dyscrasias
and possible aplastic anemia.
e. ETHOSUXIMIDE “ZERONTONON”
●
●
●
Commonly used for control of petit mal
seizure
Administered through oral preparation
TDM of ethosuximide is done to ensure that
serum concentrations are in the therapeutic
range.
d. CARBAMAZEPINE “TEGRETOL”
●
●
●
●
●
●
●
●
●
●
●
Circulating protein bound: 70-80%
Elimination: Hepatic metabolism
Idiosyncratic adverse effects:
o Rashes
o Leukopenia (Most serious)
o Nausea
o Vertigo
o Febrile reaction
Administered as: Oral preparation
Less frequently used because of its serious
toxic adverse effects
An inducer of its own metabolism, thus
frequent plasma levels must be analyzed on
initiation of therapy until induction period has
come to completion
Carbamazepine toxicity is diverse and
variable
Effects occur in a dose-dependent manner,
others do not.
Leukocyte count and liver function testing
during the first two weeks of therapy to detect
possible toxic effects.
Mild, transient liver dysfunction is commonly
seen.
Large and persistent liver indices and/or
significant leukopenia = discontinuation of the
drug
SECOND GENERATION ANTIEPILEPTIC DRUGS
a. FELBAMATE
● Circulating protein bound: 30%
● Gastrointestinal Absorption: Nearly
completely absorbed
● Elimination: Renal and Hepatic metabolism
● Common adverse effects:
o Fatal Aplastic Anemia
o Hepatic Failure
● Administered as: Oral preparation
●
●
●
●
●
Peak serum concentrations are reached
within 1-4 hours
Known for its toxicity
Primarily indicated in severe epilepsies
(Children with Lennox-Gastaut syndrome)
As monotherapy, the half-life of Felbamate is
14-22 hours
Clearance is higher in children than that of
results
●
●
●
●
b.
Metabolism of the drug is enhanced by
enzyme inducers (Phenobarbital, primidone,
phenytoin, carbamazepine)
TMD may be indicated due to the narrow
therapeutic range
Can be considered after steady state has
been reached
Adverse side effects
○ Fatal aplastic anemia
○ Hepatic failure
●
●
●
Gastrointestinal absorption: Rapid and
complete
Half life: 15-30 hours
Therapeutic range: Individual therapeutic
ranges varies but a 2.5–15 μg/mL has been
noted as efficacious and increasing
concentration seems to correlate with
increasing risk of toxicity.
GABAPENTIN
●
●
●
Elimination: Eliminated unchanged by the
kidneys
Administered as: orally with maximum
bioavailability (60%) and is reduced when
antacids are administered concurrently
Half-life: 5-9 hours
●
●
●
●
●
●
●
●
●
c.
●
●
●
Can be indicated as monotherapy or in
conjunction with other AEDs (for patients
suffering from complex partial seizures with
or without generalized seizures)
Does not bind to serum proteins
Not metabolized hepatically
Children require 30% larger than normal
dose to maintain a comparable half-life.
(Because they eliminate the drug faster than
adults)
Multiple daily doses may be the preferred
regimen
The most likely treatment consideration in
patients with liver disease and in treating
partial onset seizures in patients with acute
intermittent porphyria
LAMOTRIGINE
Circulating protein bound: 55%
Elimination: Hepatic metabolism (Majority)
Administered as: Oral preparation
●
●
Rate of elimination: Highly dependent on
patient age and physiologic condition.
o Younger infants metabolize slowly
than older infants
o Children metabolize twice as quickly
as normal adults
o Pregnant women have an increased
mark of clearance.
Used in patients with partial and generalized
seizures
Lamotrigine clearance is also influenced by
the recognized enzyme-inducing AEDs such
as phenobarbital, primidone, phenytoin, and
carbamazepine.
Valproic acid inhibits Lamotrigine
Tailoring dosage and serum concentration is
advisable
d. LEVETIRACETAM
●
●
●
●
●
●
●
Administered as: Oral preparation nearly
entirely bioavailable
Half life: 6-8 hours
Rate of elimination: increased in children
and pregnant women
Rate of clearance: correlated with the GFR
of the patient.
Used in partial and generalized seizures
Does not bind to serum proteins
TDM is useful in monitoring compliance
and fluctuating levels during pregnancy
●
●
f. OXCARBAZEPINE
●
●
●
●
Circulating protein bound: 40% (MHD)
Elimination:
o Half-life: 2 hrs (immediate release
parent drug)
o 9 hr (immediate release derivative
MHD)
o 7-11 hr (extended-release parent
drug)
o 9-11 hr (extended-release derivative
MHD)
Excretion: Urine (>95%)
Administered as: Oral preparation
Hypothyroidism:
○ Monitor
thyroid
function
(discontinuation is associated with
return of normal thyroxine levels)
Long term:
○ Osteopenia
○ CNS-related
adverse
effects
(psychomotor
slowing,
impaired
concentration)
○ Coordination abnormalities (ataxia,
gait disturbances).
TDM though not routinely warranted but
may be beneficial in optimizing seizure
control at extreme ages, renal insufficiency,
rule out compliance and ascertain the
significance of potential drug interactions.
g. TIAGABINE
●
●
●
●
●
●
●
Adverse effects:
○ Weight gain
○ Muscle stiffness
○ Difficulty concentrating
Absorption: Peak serum time (4-6 hr) and
complete bioavailability
Cautions:
○ Hypersensitivity may occur.
○ Discontinue treatment immediately
○ Significant
hyponatremia
and
syndrome of inappropriate ADH
(SIADH). Monitor esp risk of
hyponatremia
Indicated for use as monotherapy or
adjunctive therapy in treatment of partial
seizures in adults and as monotherapy in
treatment of partial seizures in pediatric
patients (4 yrs &) above with epilepsy.
●
●
●
Protein bound: 96%
Peak plasma concentration: 45 min
Administered orally
Adverse effects:
o Somnolence
o Asthenia
o Lightheadedness
o Impaired concentration
o Depression
o Suicidal thoughts/behavior
Half-life: 7-9 hrs
Excretion: Urine (25%), Feces (63%)
Used in combination to treat partial seizures.
Although, it is exactly unknown how this drug
works, but it increases the amount of natural
chemicals in the brain that prevent seizure
activity.
●
Cautions:
○
○
●
Patients treated with any AED for any
indication should be monitored for
emergence
or
worsening
of
depression and unusual mood
changes.
●
TDM can be useful in dose adjustment or
optimization of topiramate and thus required
for patient with concomitant AED therapy.
●
Should be monitored since controlling the
occurrence of seizures some individuals
respond well outside the range of serum
levels and display optimal response while
others may display toxicity even if it is within
the therapeutic range.
●
Cautions:
Clearance of tiagabine is reduced in
patients with liver disease, dosage
reduction may be necessary.
TDM can be useful due to variable
metabolism
and
potential
drug-drug
interactions
○
Kidney stones reported with therapy.
○
Increase fluid intake, increases the
urinary output lowering the conc of
substance
involved
in
stone
formation.
○
Coadministration with valproic acid
increases risk of hyperammonemia
(with or without the encephalopathy)
h. TOPIRAMATE
●
●
●
●
●
●
●
●
●
Protein bound: 13-17% (IR), 15-41% (ER)
Indicated for:
o Monotherapy for partial onset or
primary generalized tonic clonic
seizures
o Adjunctive therapy: partial onset
seizures for adults and pediatric
patients
o Adjunctive
therapy:
seizures
associated with Lennox - Gaustat
syndrome
Absorption: Bioavailability (80%)
Peak serum concentration: 1-4 hr (IR), 24
hr (ER)
Elimination: Excreted in Urine (70-80%)
Half-life: 21 hr (IR), 31 hr (ER)
Administered: Orally
Adverse effects:
o Decrease memory
o Abnormal vision
o Speech disorder
o Metabolic acidosis
An antiepileptic drug used to manage
seizures and prevent migraines (by reducing
neural pathway excitability)
i.
ZONISAMIDE
●
Protein bound:
40%
Peak
plasma
concentration ; 2-6hr
o concentration: 2-5 mcg/mL
Administered orally
Elimination: Half life for plasma (63 hr), RBC
(105 hrs)
Excreted in: Urine (63%), Feces (3%
▪ Renal clearance: 3.5 mL/min
●
●
●
●
●
●
Adverse effects:
o Feeling sad or empty
o Trouble sleeping
o Suicidal thoughts/ideation
o Irritability
o Unsteady
walking/trouble
coordination
Dosing modifications:
with
o
Renal impairment - slower titration
and more frequent monitoring is
advised.
o Not recommended if patient’s GFR is
less than 50 mL/min
● Hepatic impairment:
○ Slower titration and more frequent
monitoring is advised.
● High ammonia levels - in blood can affect
mental activities (slow mental alertness),
cause vomiting and unusual tiredness.
● Recommended as adjunctive therapy in
adults. In pediatric patients below age of 16
efficacy and safety has not yet been
established.
● Because of the potential to cause CNS
depression
as
well
as
other
cognitive/neuropsychiatric adverse events, it
should be used with caution if used in
combination with other CNS depressants.
●
●
Determination of serum lithium is commonly
done by ion-selective electrode
Flame emission photometry and atomic
absorption are also viable methods
B. TRICYCLIC ANTIDEPRESSANTS
●
●
●
●
●
●
Used to treat:
o Depression
o Insomnia
o Extreme apathy
o Loss of libido
Imipramine, amitriptyline, and doxepin are
the most relevant
Desipramine and nortriptyline are active
metabolic products of imipramine and
amitriptyline
Orally administered drugs with a varying
degree of absorption
Peak serum concentrations are reached in
the range of 2–12 hours
Highly protein bound
12. PSYCHOACTIVE DRUGS
C. OLANZAPINE
A. LITHIUM
●
●
●
●
●
●
●
An orally administered drug used to treat
manic depression (bipolar disorder)
Cationic metal that does not bind to proteins
Distribution is uniform throughout total body
water
Eliminated predominately by renal filtration
and is subject to reabsorption
Serum concentrations in the range of 0.5–1.2
mmol/L are effective in a large portion of the
patient population
Serum concentrations in the range of 1.5–
2mmol/L may cause:
a. Apathy
b. Lethargy
c. Speech difficulties
d. Muscle weakness
Serum concentrations greater than 2 mmol/L
are associated with:
a. Muscle rigidity
b. Seizures
c. Coma
●
●
●
●
●
A thienobenzodiazepine derivate which
effectively treats:
o Schizophrenia
o Acute manic episodes
o Recurrence of bipolar disorders
It can be administered as fast-acting
intramuscular injection
o Dose: 2.5-10 mg per injection.
It is more likely administered orally and is
85% absorbed while the approximately 40%
is inactivated by first-pass metabolism.
Women and nonsmokers tend to have
lower clearance. Consequently, a higher
serum concentration of olanzapine than with
men and smokers.
TDM may help in optimizing clinical response
while balancing it with adverse effects
B. TACROLIMUS
13. IMMUNOSUPPRESSIVE DRUGS
A. CYCLOSPORINE
●
●
●
●
●
●
●
Cyclic
polypeptide
that
has
potent
immunosuppressive activity.
Its primary clinical use is suppression of hostversus-graft
rejection
of
heterotopic
transplanted organs.
○ administered as an oral preparation
with absorption in the range of 5%50%;
○ and peak concentrations within 1 to 6
hours.
> 98% of circulating cyclosporine is protein
bound
○ cyclosporine appears to sequester in
cells, including erythrocytes.
○ evaluation of plasma cyclosporine
concentrations requires rigorous
control of specimen temperature
(highly temperature dependent RBC
content)
Whole blood specimens are used.
Cyclosporine is eliminated by hepatic
metabolism---half-life of approximately 12
hours.
Adverse effects of cyclosporine are primarily
o Renal tubular
o Glomerular dysfunction, which may
result in hypertension.
Chromatographic methods are available
and provide separation and quantitation of
the parent drug from its metabolites.
●
Orally administered immunosuppressive drug
that is 100x more potent than cyclosporine.
○ both
drugs appear
to have
comparable
degrees
of
nephrotoxicity.
○ both drugs are > 98% bound to
proteins in the plasma
● Gastrointestinal uptake is highly variable with
peak plasma concentrations
achieved in 1-3 hours.
● Half-life of 10-12 hrs
○ eliminated almost exclusively by
hepatic metabolism,
○ metabolic products are primarily
secreted into bile for excretion.
● Increased immunoreactive tacrolimus may be
seen in cholestasis
● Most common method is high-performance
liquid
chromatography-tandem
mass
spectrometry
● Whole blood concentrations correlate well
with therapeutic and toxic effects and are the
preferred specimen for tacrolimus TDM.
● Adverse effects associated with tacrolimus
toxicity include
o Anemia
o Leukopenia
o Thrombocytopenia
o Hyperlipidemia
C. SIROLIMUS
●
●
●
●
●
●
●
Antifungal agent with
immunosuppressive
activity
Once-daily
oral
administration
Plasma
concentrations are affected extensively by
intestinal and hepatic first-pass metabolism
Half-life of 62 hours and is predominantly
metabolized in the liver
92% of circulating sirolimus is bound
Whole blood is the ideal specimen
Subsequent monitoring is performed by
collecting trough specimens on a weekly
basis for the first month followed by a
●
●
biweekly sampling pattern in the second
month.
Adverse effects associated with toxicity
include
o Thrombocytopenia
o Anemia
o Leukopenia
o Infections
o Hyperlipidemia
Measured using chromatographic methods or
by high-performance liquid chromatography–
tandem mass spectrometry
●
immunoassay, though immunoassays are
generally considered less specific
Cross reactivity between MPA and its active
metabolite (AcMPAG) should be taken into
account along with the clinical picture when
evaluating a dosage regimen.
14. ANTINEOPLASTICS
D. MYCOPHENOLIC ACID
●
●
●
●
●
●
●
●
●
●
Mycophenolate mofetil (Myfortic)
Prodrug that is rapidly converted in the liver
to its active form, mycophenolic acid (MPA)
A lymphocyte proliferation inhibitor
Administered orally and absorbed under
neutral pH conditions in the intestine
Interindividual variation of gastrointestinal
tract physiology influences the degree of
absorption of MPA
o Peak concentrations are generally
achieved 1 to 2 hours post dose
Once in circulation, MPA is 95% protein
bound
MPA is primarily eliminated by renal excretion
(>90%)
Half-life of approximately 17 hours
Toxicity may cause
o Nausea
o Vomiting
o Diarrhea
o Abdominal pain
Plasma
MPA
and
its
metabolites'
concentrations can be assayed using
chromatography or, more commonly,
●
Assessment of the therapeutic benefit and
toxicity of most antineoplastic drugs is not
aided by TDM because correlations between
plasma concentration and therapeutic benefit
are hard to establish
●
In addition, the therapeutic range for many of
these
drugs
includes
concentrations
associated with toxic effects.
●
Many of these agents are rapidly metabolized
or incorporated into cellular macromolecular
structures within seconds to minutes of their
administration.
●
Considering that most antineoplastic agents
are administered intravenously as a single
bolus, the actual delivered dose is more
relevant than circulating concentrations.
B. TOXICOLOGY | 3BSMT1
CONTENTS:
01. EXPOSURE TO TOXINS
02. ROUTES OF EXPOSURE
03. DOSE-RESPONSE
RELATIONSHIP
04. ANALYSIS OF TOXIC AGENTS
05. TOXICOLOGY OF SPECIFIC AGENTS
06. TOXICOLOGY OF THERAPEUTIC
Presented by 3 BSMT-1
DRUGS
Contents
02.ROUTES OF
EXPOSURE
01. EXPOSURE TO TOXINS
According to available data, 50% of poisoning
cases came from suicide attempts which also
happens to have the highest mortality rate.
Accidental exposure accounts for about 30%
where such cases occur most frequently among
children. Accidental drug overdose also falls
under this category, and it is relatively common
among adolescents and adults. Finally, the
remaining percentage came because of
homicide and occupational exposure. The later
typically occurs in industrial or agricultural
settings. It is currently drawing more concerns as
we continue to learn more about the effects of
various chemical agents currently being used.
●
Toxins
Are substances that are harmful to living
organisms. Its key differentiating feature is
that it exclusively uses for substances that
can only be produced through biological
synthesis
Xenobiotics
○ Are exogenous chemical compounds
known to have adverse effects on living
organisms. These chemical compounds
are characterized by their triggering
mechanism which involves environmental
exposure.
Poisons
○ Are also exogenous agents that causes
adverse effects on living organisms. The
key difference is that the term poison is
used when referring to harmful substances
produced by animals, plants, and certain
minerals and gases.
●
Toxins can enter the body through a
variety of methods, the most common of
which are: ingestion, inhalation, and
transdermal absorption.
●
Toxin intake is the most common of them
in the clinical context. To have a systemic
effect, most poisons must be absorbed
into circulation.
●
Toxins
are
absorbed
from
the
gastrointestinal tract through a variety of
methods. Some are absorbed by dietary
nutrient-processing
enzymes.
The
majority, however, is absorbed through
passive diffusion and this is how it works.
●
The chemical must be able to overcome
cellular boundaries. Because hydrophobic
chemicals can diffuse through cell
membranes, they can be absorbed
anywhere along the gastrointestinal tract.
●
Passive diffusion of ionized compounds
across membranes is not possible. In
stomach acid, weak acids can become
protonated. As a result, a nonionized
species is produced that can be absorbed
in the stomach.
●
Weak bases, on the other hand, favor
absorption in the intestine, where the pH is
mostly neutral or slightly alkaline.
●
Other factors, such as the rate of
dissolution,
gastrointestinal
motility,
resistance to degradation in the
gastrointestinal tract, and interactions with
other substances, can influence the
absorption
of
toxins
from
the
gastrointestinal tract.
○
●
●
07. TOXICOLOGY OF DRUGS OF ABUSE
●
Toxins that are not absorbed from the
gastrointestinal tract have no systemic
effects, but they can cause local symptoms
like diarrhea, bleeding, and nutritional
malabsorption, which can lead to systemic
problems because of toxin exposure.
o
indicator of toxic effects specific for
certain toxin
b. LIVER CELLS TOXIN
o
GGT and ALT activity is monitored
to asses substances exerting early
toxic effects by damaging liver cells
03. DOSE-RESPONSE
RELATIONSHIP
“THE DOSE MAKES THE POISON”
- Paracelsus (pioneer of using chemicals
in medicine)
●
●
●
The statement became the fundamental of
dose-response relationship
Index relative to toxicity must be
established to assess their potential to
cause a pathologic effect
There are different indices developed based
on the predicted response (ex. Death in
xenobiotic)
DOSE-RESPONSE RELATIONSHIP
-
there is an increase in the toxic response as
the dose increase.
toxic
response
is different
from
individuals at the same dose.
i.
●
Individual-dose relationship
changing health effects based on the change
in xenobiotic exposure levels
ii. Quantal-dose response relationship
● change in health effects of a defined
population based on the changes in the
exposure to xenobiotics
ACUTE & CHRONIC TOXICITY
●
●
CUMULATIVE FREQUENCY HISTOGRAM
-
evaluating data with toxic responses over
range of doses will give more in-depth
characterization.
a. TOXIC RESPONSE
o
associated with an early pathologic
effect at lower than lethal doses.
i.
●
relates the duration and frequency of
exposure to observed toxic effects.
dose-response relationship differs for the
same xenobiotic
ACUTE TOXICITY
associated with a single, short-term exposure
to a substance
● sufficient to cause immediate toxic effects
ii.
CHRONIC TOXICITY
● associated with repeated frequent exposure
for extended periods for greater than 3
months to years
● insufficient to cause acute response
●
●
related to accumulation of the toxicant or the
toxic effects within the individual.
affects different body systems
04. ANALYSIS OF TOXIC
AGENTS
●
Specimen containers and lids should also be
devoid of contaminating organic and
inorganic agents that may interfere with
analytical testing
●
Exercise precautions to prevent loss of toxic
agents due to in vitro volatilization and
metabolism.
PROCEDURE
TOXICOLOGY TESTING
●
●
●
●
●
●
●
●
●
performed to screen for the presence of a
number of agents that might be present
○ drug screens
○ heavy metal panels
targeted testing
performed on urine or blood specimens
recognize the toxic agents exhibit unique
absorption, distribution, metabolism, and
elimination kinetics or toxicokinetics
must be coordinated with the selection of
specimen type and timing of collection
relative to the time of exposure
might
be
performed
when
an
environmental risk of exposure is known
○ industrial workers
○ chemical plants
to support the investigation of an
exposure
○ chemical spill
○ suicide attempt
to comply with occupational regulations
or guidelines
○ OSHA (Occupational Safety and
Health Administration)
to confirm clinical suspicions of
poisoning
○ arsenic
○ cyanide
COLLECTION, HANDLING, & STORAGE
●
Patient clothing, skin, hair, collection
environment (e.g., dust, aerosols, antiseptic
wipes), and specimen handling variables
(e.g., container, lid, preservatives) are
common sources of external contamination
●
Concentrated acids are commonly used as
urine preservatives
Analysis of toxic agents in a clinical setting is a twostep procedure.
i.
Screening test
● rapid, simple, qualitative procedure
● detect specific substances or classes of
toxicants
● procedures have good analytic sensitivity but
lack specificity
● qualitative screening tests that provide a
result of positive (drug is present) or negative
(drug is absent).
ii.
Confirmatory tests
● more specific method
● quantitative and the concentration of the
substance in the specimen is reported
Immunoassays are commonly used to screen
for drugs.
● specific for a single drug (e.g.,
tetrahydrocannabinol [THC])
● detect drugs within a general class
(e.g., barbiturates and opiates).
Variety of analytical methods can be used for
screening and confirmatory testing
➢
Thin-layer chromatography (TLC)
● relatively simple, inexpensive method
● detecting various drugs and other organic
compounds
➢
Gas chromatography (GC)
● widely used and a well-established technique
for qualitative and quantitative determination
of many volatile substances
● reference
method
for
quantitative
identification of most organic compounds
➢
Inductively
coupled
plasma-mass
spectrometry
(ICP-MS)
or
atomic
absorption (AA) methods
●
Inorganic compounds, including speciation,
may be quantitated
4. Analytic Methods that can be used for the
determination of ethanol in serum
a. Enzymatic
b. GC
c. Osmometry (Most commonly used)
05. TOXICOLOGY OF
SPECIFIC AGENTS
CARBON MONOXIDE
1. Produced by combustion of carboncontaining substances
2. Primary Environmental Sources
a. Gasoline Engines
b. Improperly Ventilated Furnaces
c. Wood or Plastic Fires
3. Colorless, Odorless, and Tasteless gas
4. . Carboxyhemoglobin
a. When carbon monoxide binds to
hemoglobin
b. Has a cherry-red appearance
5. Considered a very toxic substance
a. Because both carbon monoxide and
oxygen compete for the same
binding site
6. 6. Expresses its toxic effects by causing
a leftward shift in the oxygen-hemoglobin
dissociation curve
7. Major toxic effects of carbon monoxide
exposure are seen in organs with high
oxygen demand such as the BRAIN and
HEART
Many chemical agents encountered on a regular
basis have potential adverse effects. The focus
of this section is to survey the commonly
encountered nondrug toxins seen in a clinical
setting, as well as those that present as medical
emergencies with acute exposure.
ALCOHOL
1. Toxic Effects are both general to specific
2. Exposure to alcohol causes:
a. Disorientation
b. Confusion
c. Euphoria
d. Unconsciousness
e. Paralysis
f. Death
3. Ethanol consumption is a leading cause
of:
a. Economic Problems
b. Social Problems
c. Medical Problems
4. Compromises function in
a. Various Organs
b. Tissues
c. Cell Types
d. Liver (The most sensitive organ)
DETERMINATION OF ALCOHOL
1. Must be accurate and precise
2. Serum, Plasma, and Whole Blood are
acceptable specimens
a. Sealed specimens can be
refrigerated or stored at room
temperature for up to 14 days
3. Ethanol uniformly distributes in total
body water, serum, greater water content
than whole blood, and a higher
concentration per unit volume
REFERENCE METHOD
I.
GC
a. Accurate and precise
II.
Spectrophotometric Method
o Measuring absorbances at 4-6
different wavelengths
o Most used method
CAUSTIC AGENTS
1. Found in many household products and
occupational settings
2. Exposure to strong acids and alkaline
substance cause injury
○ Aspiration
■ Pulmonary edema
■ Shock
○ Ingestion
■ Lesions in esophagus and GIT
● Perforations
● Hematemesis
● Abdominal pain
■ Metallic acidosis and alkalosis
CYANIDE EVALUATION
Assays:
1. Ion-specific electrode methods
2. Photometric analysis
3. Two-well microdiffusion separation
4. Urinary Thiocyanate concentration
○ chronic low-level exposure
evaluated
B. CYANIDE
1. Supertoxic
○ Insecticides
○ Rodenticides
2. Pyrolysis product
3. Gas or Solid in solution
4. Exposure
○ Inhalation
○ Account the significant portion
5. Ingestion
○ Common suicide agent
6. Transdermal
METALS AND METALLOIDS
I.
●
●
CYANIDE TOXICITY EXPRESSION
●
●
●
●
●
●
●
ARSENIC
Arsenic is a metalloid that may exist bound to
or as a primary constituent of many different
organic and inorganic compounds.
Exists in both naturally occurring and manmade substances; therefore, exposure to
arsenic may occur in various settings.
Environmental exposure through air and
water is prevalent in many industrialized
areas.
Occupational exposure occurs in agriculture
and the smelting industries. It is also a
common homicide and suicide agent.
Arsenic binding to proteins often results in a
change in structure and function
Because many proteins are capable of
binding arsenic, the toxic symptoms of
arsenic poisoning are nonspecific.
Many cellular and organ systems are
affected.
Fever,
anorexia,
and
gastrointestinal distress are seen with chronic
or acute ingestion at low levels. Peripheral
and central damage to the nervous system,
renal effects, hemopoietic effects, and
vascular disease leading to death are
associated with high levels of exposure.
Blood and urine are acceptable specimens to
evaluate short-term exposure.
Hair and fingernail content have been found
useful in the assessment of long-term
exposure.
II. CADMIUM
● Cadmium is a metal found in many industrial
processes, with its main use in electroplating
and galvanizing . It is commonly encountered
during the mining and processing of many
metals.
● Cadmium is a pigment found in paints and
plastics and is the cathodal material of nickel
cadmium batteries. It is a significant
environmental pollutant.
● Cadmium distributes throughout the body but
tends to accumulate in the kidney, where
most of its toxic effects are expressed.
● An early finding of cadmium toxicity is
manifested by renal tubular dysfunction.
Tubular
proteinuria,
glucosuria,
and
aminoaciduria are typically seen.
● Evaluation of excessive cadmium is most
accomplished by determination of whole
blood or urinary content using atomic
absorption spectrophotometry.
III. LEAD
● Lead
is
a
common
environmental
contaminant. It was a common constituent of
household paints before 1972 and is still
found in commercial and art paints.
● Lead is a byproduct or component of many
industrial processes. The lead content of
foods is highly variable. In the United States,
the average daily intake for an adult is
between 75 and 120 g/day.
● This level of intake is not associated with
overt toxicity. Because lead is present in all
biologic systems.
● Adults are largely tolerant to the effects of
lead compared with children.
● Lead distributes into two theoretical
compartments. One is the skeleton, which is
the largest pool. The other is soft tissue; the
average half-life in soft tissue is 120 days.
● Elimination of lead occurs primarily by renal
filtration.
● Lead exposure causes encephalopathy
characterized by a cerebral edema and
ischemia.
● Severe lead poisoning can result in stupor,
convulsions, and coma.
●
●
●
Adults are largely tolerant to the effects of
lead compared with children.
Lead distributes into two theoretical
compartments. One is the skeleton, which is
the largest pool. The half-life of lead in bone
is longer than 20 years. The other is soft
tissue; the average half-life in soft tissue is
120 days.
Several methods can be used to measure
lead concentration. Chromogenic reactions
and anodic stripping voltammetry methods
have been used, but they lack clinical utility
because they lack analytic sensitivity. At
present, graphite furnace atomic absorption
spectrophotometry (AAS) is the most
common method used.
IV. MERCURY
● Mercury is a metal that exists in three forms:
elemental (liquid at room temperature),
inorganic salts, or a component of organic
compounds.
● Inhalation and accidental ingestion of
inorganic and organic forms in industrial
settings is the most common reason for toxic
levels.
● Elemental mercury is largely not absorbed
because of its viscous liquid nature. Inorganic
mercury is only partially absorbed. Although
not significantly absorbed, inorganic mercury
still has significant local toxicity in the
gastrointestinal tract.
● Binding to intestinal proteins after ingestion of
inorganic
mercury results
in
acute
gastrointestinal disturbances.
● Ingestion of moderate amounts may result in
severe bloody diarrhea because of ulceration
and necrosis of the gastrointestinal tract.
● In severe cases, this may lead to shock and
death. Clinical findings include tachycardia,
tremors, thyroiditis, and, most significant, a
disruption of renal function.
● The renal effect is associated with glomerular
proteinuria and loss of tubular function.
● Organic mercury may also have a real effect
at high levels of exposure. However,
neurologic symptoms are the primary toxic
effects of this hydrophobic form.
●
●
●
Low levels of exposure cause tremors,
behavioral changes, mumbling speech, and
loss of balance.
Higher levels of exposure result in
hyporeflexia, hypotension, bradycardia, renal
dysfunction, and death.
Analysis of mercury by atomic absorption
requires special techniques as a result of the
volatility of elemental mercury
PESTICIDES
●
●
●
●
●
●
●
●
●
●
Pesticides are substances that have been
intentionally added to the environment to kill
or harm an undesirable life form.
Pesticides can be classified into several
categories, such as insecticides and
herbicides.
These agents have been applied to the
control of vector-borne disease and urban
pests and to improve agricultural productivity.
Pesticides can be found in occupational
settings and in the home; therefore, there are
frequent opportunities for exposure.
Contamination of food is the major route of
exposure for the general population.
Inhalation, transdermal absorption, and
ingestion because of hand-to-mouth contact
are common occupational and accidental
routes of exposure.
Pesticides come in many different forms with
a wide range of potential toxic effects.
Extended low-level exposure to low levels
may result in chronic disease states. Of
primary concern is high-level exposure,
which may result in acute disease states or
death.
Pesticide ingestion is also a common suicide
vehicle.
Insecticides are the most prevalent of
pesticides.
Based on chemical configuration, the
organophosphates,
carbamates,
and
halogenated hydrocarbons are the most
common insecticides
06. TOXICOLOGY OF
THERAPEUTIC DRUGS
I.SALICYLATES
➢ It is a direct stimulator of the respiratory
center
➢ It inhibits the Krebs cycle, which causes an
excess of pyruvate to lactic acid conversion.
Acetylsalicylic Acid (Aspirin)
● It is a commonly used analgesic, antipyretic,
& anti-inflammatory drug
Function
● It decreases thromboxane and prostaglandin
formation by inhibiting cyclooxygenase.
Adverse effect
● Interference with platelet aggregation and
gastrointestinal function
Clinical Significance
● Nonrespiratory (metabolic) acidosis
● Respiratory alkalosis
● Excess ketone formation
Treatment (Aspirin Overdose)
● Neutralize and eliminate the excess acid
● Maintain electrolyte balance
III.
ACETAMINOPHEN
➢ also known as Tylenol
➢ a commonly used analgesic drug
➢ either solely or in combination with other
compounds
➢ therapeutic dosages have few adverse
effects a healthy individual
Clinical Significance
● Severe hepatotoxicity
Absorbed Acetaminophen
● it is found with a high affinity to different
proteins, resulting in a low free fraction.
➢ Renal filtration of the drug is minimal.
Most are eliminated via:
● Hepatic uptake
● Biotransformation
● Conjugation
● Excretion
Time Frame
● The onset of hepatocyte damage is relatively
long
● Serum indicators of hepatic damage are
normal until 3 to 5 days after ingestion of a
toxic dose in an average adult
Initial Symptoms
● Vague and not predictive of hepatic necrosis
Nomograms
● Predict hepatotoxicity based on serum
concentrations of acetaminophen at a known
time after ingestion.
Alcoholic Patients
● they are more susceptible to acetaminophen
toxicity
● the use of nomogram for interpretation is not
recommended
07. TOXICOLOGY OF
DRUGS OF ABUSE
I. AMPHETAMINES
➢ Amphetamine & Methamphetamine are
therapeutic drugs used for narcolepsy and
attention-deficit disorder
➢ Produce an initial sense of increased mental
and physical capacity along with a
perception of well-being.
Initial effects are followed by:
restlessness, irritability, & possibly
psychosis
➢ Abatement of these late effects is often
countered with repeated use
➢ These drugs are stimulants with a high abuse
potential.
Tolerance & psychological dependence develop
with chronic use:
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overdose (rare)
hypertension
cardiac arrhythmias
convulsions
possibly death
Compounds
chemically
amphetamines:
● Ephedrine
● Pseudoephedrine
● Phenylpropanolamine
related
Identification of amphetamine abuse
of urine for the parent drugs
to
analysis
II. METHYLENEDIOXYMETHAMPHETAMINE
➢ an illicit amphetamine derivative commonly
referred to as “ecstasy”
Routes of administration
● Orally - tablets of 50 to 150 mg
● Inhalation
● Injection
Less Frequent
● Smoking
❖ Circulating half-life - approximately 8 to 9
hours.
❖ Elimination
● through hepatic metabolism (majority),
although 20% is eliminated unchanged in
the urine
➢ Onset of effect is 30 to 60 minutes, and the
duration is around 3.5 hours.
Desired
effects
Hallucination,
Euphoria,
Empathic
and
Emotional
responses, and Increased
Visual and Tactile Sensitivity.
Adverse
effects
Headaches, Nausea, Vomiting,
Anxiety, Agitation, Impaired
Memory, Violent behavior,
Tachycardia,
Hypertension,
Respiratory
depression,
Seizures,
Hyperthermia,
Cardiac toxicity, Liver toxicity,
and Renal failure.
*Predispose to stroke and
myocardial infarction
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Steroid abuse causes an enlargement of the
heart.
➢ Heart muscle cells develop faster
than the related vasculature in this
condition. This can result in heart
muscle cell ischemia, which can lead
to cardiac arrhythmias and even
death.
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For most of them, there are several wellestablished methods for detecting the parent
drug and its metabolite.
The ratio of testosterone to epitestosterone
(T/E) is commonly used as a screening test.
High ratios are associated with exogenous
testosterone administration.
➢ Presentation of symptoms along with patient
behavior and history must be considered.
IV.ANABOLIC STEROIDS
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Anabolic steroids are a group of compounds
that are chemically related to the male sex
hormone testosterone.
In the 1930s, these synthetic compounds
were produced as a treatment for male
hypogonadism. It wasn't long before it was
discovered that using these substances
increased muscle mass.
In many instances, this results in an
improvement in athletic performance.
The acute toxic effects of these drugs are
related to inconsistent formulation, which
may result in:
High dosages
Impurities
A variety of both Physical and Psychological
effects have been associated with steroid
abuse.
Chronic use of steroids has been associated
with:
Toxic hepatitis *
Accelerated atherosclerosis
Abnormal aggregation of platelets*
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V.
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CANNABINOIDS
Cannabinoids are a group of psychoactive
compounds found in marijuana.
THC is the most potent and abundant of
them.
Marijuana or its processed form, hashish, can
be consumed or smoked.
The subjective result of exposure is a feeling
of well-being and euphoria.
It's also linked to problems with:
○ Short-term memory
○
Cognitive function.
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Chronic use can lead to;
○ Tolerance
○ Mild dependence
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THC is a lipophilic compound that is quickly
eliminated from circulation through passive
distribution into hydrophobic compartments
like the brain and fat.
As a result of the redistribution back into
circulation
and
subsequent
hepatic
metabolism, the elimination is slow.
THC in circulation has a half-life of 1 day after
a single use and 3–5 days in chronic, heavy
users.
Hepatic metabolism of THC produces
several products that are primarily eliminated
in urine.
11-nor-Δ -tetrahydrocannabinol-9-carboxylic
acid (THC-COOH) is the most common urine
metabolite.
After a single usage, this metabolite can be
identified in urine for 3–5 days, or up to 4
weeks in a chronic, heavy user after
abstinence.
The screening test for marijuana intake is
based on an immunoassay for THC-COOH.
For confirmation, GC/MS is used. Both
approaches are specific and sensitive.
Because of the low detection limit of these
assays, THC-COOH can be found in urine
because of passive inhalation.
There have been established urinary
concentration standards that can distinguish
between Passive and Direct Inhalation.
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VI.
COCAINE
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An effective local anesthetic
An alkaloid salt that can be administered in 2
ways
o Directly (insufflation or intravenous)
→ hazardous
o Inhaled as vapor when smoked
High concentrations in the blood → a potent
CNS stimulator that elicits a sense of
excitement and euphoria
Acute cocaine toxicity
VII.
Hypertension
Arrhythmia
Seizure
Myocardial infarction
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Cocaine toxicity depends on the dose and
route of administration, not on serum
concentration.
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Benzoylecgonine is the main metabolite of
cocaine, which is the primary product of
hepatic metabolism
OPIATES
➢ Class of substances capable of analgesia,
sedation, and anesthesia
➢ Have high abuse potential
➢ Chronic use leads to tolerance with physical
and psychological dependance
VIII.
PHENCYCLIDINE
●
It is a lipophilic drug that rapidly spreads
into fat and brain tissue.
● Phencyclidine (PCP) is an illicit drug with the
following properties:
○ Stimulant
○ Depressant
○ Anesthetic
○ Hallucinogenic
Adverse Effects - commonly reported at doses that
produce the desired
Subjective Effects
● Agitation
● Hostility
● Paranoia
Overdose may lead to:
● Stupor
● Coma
➢ Phencyclidine can be ingested or inhaled by
smoking PCP-laced tobacco or marijuana.
Slow elimination - result of redistribution into
circulation & hepatic metabolism
Chronic, heavy users - PCP can be detected up to
30 days after abstinence
IX.
SEDATIVES-HYPNOTICS
All therapeutic drugs that are sedatives–hypnotics or
Tranquilizers are CNS depressants
● high abuse potential
● derived from approved sources
Barbiturates & Benzodiazepines
● most common types of sedative-hypnotics
abused
Barbiturates
● have
higher
abuse
potential
than
Benzodiazepines
● hypotension can occur
All therapeutic drugs that are sedatives–hypnotics or
Tranquilizers are CNS depressants
● high abuse potential
● derived from approved sources
Barbiturates & Benzodiazepines
● most common types of sedative-hypnotics
abused
Barbiturates
●
have
higher
abuse
potential
than
Benzodiazepines
● hypotension can occur
Benzodiazepines
● commonly found in abuse and overdose
situation
Most commonly abused:
● Diazepam (Valium)
● Chlordiazepoxide (Librium)
● Lorazepam (Ativan)
Overdose
● lethargy & slurred speech
coma
● Respiratory depression - most serious toxic
effect
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