Pakistan Society Of Chemical Pathologists
Distance Learning Programme In Chemical Pathology
Lesson No 19
Therapeutic Drug Monitoring And Toxicology
(Short Name: TDMT)
BY
Surg Commodore Aamir Ijaz
MCPS, FCPS, FRCP (EDIN)
Professor Of Pathology /
Consultant Chemical Pathologist
Bahria University Medical & Dental College /
PNS SHIFA Karachi
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BCQs
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Q 1:
Liver is the principal site of xenobiotic metabolism.
This metabolism takes place in two phases; phase I and
Phase II. Which of the following metabolic processes is a
Phase II reaction of xenobiotic metabolism:
a.
b.
c.
d.
e.
Hydrolysis
Hydroxylation
Oxidation
Reduction
Sulfation
e. Sulfation
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Q 2:
Enzyme Induction and Enzyme Inhibition are two
important aspects of drug metabolism. Which of the
following phenomena is mostly related to Enzyme Inhibition
and NOT to Enzyme Induction:
a.
b.
c.
d.
e.
Decreased pharmacological effect
Increased cytochrome-P450
Increased drug action
Increased phospholipids
Toxicity due to metabolites
c. Increased drug action
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Q 3:
You want to improve your TDM facilities by obtaining
important information regarding patients undergoing the test. While
collecting sample for TDM which of the following information is
LEAST important:
a.
b.
c.
d.
e.
Alcoholism
Diabetes mellitus
Other drug intake
Pregnancy
Smoking
b.Diabetes mellitus
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Q 4: A transplant patient is on a combination maintenance
immunosuppression therapy of cyclosporine, sirolimus and
corticosteroids. Which of the following is the best sampling regimen
for simultaneous TDM of all these drugs:
a.
b.
c.
d.
e.
C0 (Trough) level
C2 (2 h post dose) levels
C6 (6 h post dose) levels
Peak level
Random sample
a.C0 (Trough) level
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Toxicology
Three sub-branches
• Clinical Toxicology
•
Drugs of Abuse
•
Doping
(Details can be found in ppt prepared by Dr Mahreen Hassan)
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Q 5:
Androgens are one of the most common hormones used as
doping agents by athletes to improve performance. The most
reliable method for detection of exogenous testosterone is:
a.
b.
c.
d.
e.
HCG stimulation test
LH measurement
Measurement of dihydrotestosterone
Ratio of 13C to 12C in urine by isotope ratio mass spectrometry
Ratio of testosterone glucuronide to epitestosterone glucuronide (T/E ratio) in urine
d. Ratio of 13C to 12C in urine by isotope ratio mass spectrometry
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Q 6: A 32 y male has been brought to the A&E of a hospital with
drowsiness and ataxia. He has urinary retention, dry mouth and red
skin. His pupils are dilated, pulse is 120/min, temperature 1010F
and bowl sounds are sluggish. Casualty Medical Officer suspects
some ‘poisoning’. Please help him selecting the most probable
cause of these clinical features in the patient:
a.
b.
c.
d.
e.
Barbiturate poisoning
Ephedrine poisoning
Ethanol intoxication
Poisoning by an antihistamine
Withdrawl of heroin
d. Poisoning by an antihistamine
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Q 7:
An unfortunate couple died in an accident of carbon
monoxide (CO) poisoning as a result of fire on the lower floor.
Husband and wife were 78 y and 72 y of age, respectively.
Surprisingly their 23 y old grandson who was also sleeping in
another room on the same floor remained unconscious for 48 h but
survived and discharged fit. His carboxyhaemoglobin measured in
the hospital lab was initially touching 55%. Which of the following
factors could be the most important reason which led to this very
poor outcome in the old couple:
a.
b.
c.
d.
e.
Higher carboxyheamoglobin level
Increased binding of CO to mitochondrial enzymes
Increased half-life of CO
Lower PO2
Pre-existing impaired Cardiovascular function
e. Pre-existing impaired Cardiovascular function
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Q 8: A person died in suspicious conditions and his body
was exhumed after two months to rule out arsenic
poisoning. His hair and other body parts were sent for
analysis of arsenic. Please select the most suitable
instrument for this test:
a.
b.
c.
d.
e.
Atomic absorption spectrophotometer
Electrochemiluminescence
HPLC
Ion Selective Electrode Analyser
Routine Clinical Chemistry Analyser
a. Atomic absorption spectrophotometer
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Q 9:
A farmer has been brought in A&E in
semi-conscious state. His pupils are constricted
(pin-point). Please select the most appropriate
blood test for this patient:
a.
b.
c.
d.
e.
ALT
Amylase
Cholinestrase
Gamma Glutamyl transferase
Lactate dehydrogenase
c. Cholinestrase
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SAQs
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Q:10: TDM has always been an important part of a Chemical
Pathology Lab. A Chemical Pathologist must be familiar with
certain aspects of Therapeutics for appropriate sample collection
and interpretation of data generated by drug analyses.
a. Please write FIVE clinical situations where TDM provides
maximum benefit to the patient.
b. What are FIVE pharmacokinetic parameters that are
important in TDM
.
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Suggested Answer to Q.10a
Please write FIVE clinical situations where TDM provides
maximum benefit to the patient.
(Plz see next slide)
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Clinical Situations Where TDM Provide
Maximum Benefit
TDM is most valuable when drug in question is used chronically and has narrow
therapeutic index.
Five benefits to the patient are :
• Non compliance can be recognized.
• The most appropriate drug dosing regimen can be initiated and maintained
• Patient undergoing changes in drug disposition characteristics can be
recognized.
• Therapeutic drug regimen can be adjusted during period of continuous
physiological changes.
•
Baseline concentration associated with an optimal therapeutic regimen can
be identified.
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Suggested Answer to Q.10b
What are FIVE pharmacokinetic parameters that are
important in TDM
(Plz see next slide)
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Five Pharmacokinetic Parameters that are
Important In TDM
Bioavailability. The bioavailability of a drug depends in part on its
formulation. A drug that is significantly metabolized as it first
passes through the liver exhibits a marked "first-pass effect,"
reducing the effective oral absorption of the drug. A reduction in
this first-pass effect (eg, because of decreased hepatic blood flow
in heart failure) could cause a clinically significant increase in
effective oral drug absorption.
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Five Pharmacokinetic Parameters that are
Important In TDM (Contd)
Volume of distribution and distribution phases. The volume of
distribution of a drug determines the plasma concentration reached
after a loading dose. The distribution phase is the time taken for a
drug to distribute from the plasma to the periphery. Blood taken
before completion of a long distribution phase may not reflect
levels of pharmacologically active drug at sites of action.
Examples: Digoxin, lithium.
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Five Pharmacokinetic Parameters that are
Important In TDM (Contd)
Clearance. Clearance is either renal or non-renal (usually hepatic).
Whereas changes in renal clearance can be predicted on the basis of
serum creatinine or eGFR, there is no routine liver function test for
assessment of hepatic drug metabolism.
Half-life. The half-life of a drug depends on its volume of distribution and
its clearance and determines the time taken to reach a steady state level.
After a period of 3 or 4 half-lives, the serum drug concentration will be
87.5% to 93.75% of the steady state value. Patients with decreased drug
clearance and therefore increased drug half-life will take longer to reach a
higher steady state level. In general, since non-steady state drug levels
are difficult to interpret, therapeutic drug monitoring usually involves
measurement of drug levels at steady state.
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Five Pharmacokinetic Parameters that are
Important In TDM (Contd)
Protein binding of drugs. All routine drug level analysis involves
assessment of both protein-bound and free drug. However,
pharmacologic activity depends on only the free drug
concentration. Changes in protein binding (eg, in renal failure or
hypo-albuminaemia) may significantly affect interpretation of
reported levels for drugs that are highly protein-bound. Example:
Phenytoin. When the ratio of active to total drug is increased, the
therapeutic range based on total drug level will not apply.
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Q:11: You are a Consultant Chemical Pathologist in a medium-sized lab where
Serum Lithium is estimated on an ISE analyser. The Consultant Psychiatrist is not
happy with your reports of Lithium assay because of ‘poor clinical correlation’. He has
sent his Resident to your department to sort the issues related with this test. The
Resident has some queries regarding Lithium Estimation. Please answer her queries:
a.
A patient has been put on Lithium therapy for bipolar affective disorder on
12th of Aug 2013. When the Lithium testing should be started and what is the
philosophy behind this time period?
b.
The patient is advised to take Lithium in the evening at 2000 h. At what time
his blood sample should be collected and what is the rationale for this time?
c.
What is the therapeutic range of Serum Lithium which should be achieved? Is
this range maintained to ensure drug efficacy or to monitor toxicity?
d.
If the level is not within the range, what could be the factors causing this level
other than those related to Lithium intake?
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Suggested Answer to Q.11a
A patient has been put on Lithium therapy for bipolar affective disorder on 12th
of Aug 2013. When the Lithium testing should be started and what is the
philosophy behind this time period?
•
17 Aug 2013
•
Trough serum lithium level drawn no earlier than the 5 day,
but preferably no later that the 7 th day, after any lithium
dose changes
•
5-7 d are required for establishing steady state
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Suggested Answer to Q.11b
The patient is advised to take Lithium in the evening at
2000 h. At what time his blood sample should be
collected and what is the rationale for this time?
• 0800 h next morning
• Trough level is required which is after 1214 h.
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Suggested Answer to Q.11c
What is the therapeutic range of Serum Lithium which
should be achieved? Is this range maintained to ensure
drug efficacy or to monitor toxicity?
• 0.6 – 1.2 mmol/L
• To monitor toxicity
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Suggested Answer to Q.11d
If the level is not within the range, what could be the
factors causing this level other than those related to
Lithium intake?
Dehydration due to
 fever,
 watery stool,
 vomiting
 hot weather
In dehydration decreased clearance of lithium and increased blood
concentration of lithium occur.
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Q:12: Immunosuppressants are one of the most important
groups of drugs which require TDM.
a. Name FIVE immunosuprressants which are used widely
for maintenance immunosuppression in solid organ and
bone marrow transplant patients.
b. What are the sample requirements for the TDM of these
immunosuppressants?
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Suggested Answer to Q.12a
Name FIVE immunosuprressants which are used widely
for maintenance immunosuppression in solid organ and
bone marrow transplant patients.
• Cyclosporin
• Mycophenolate mofetil
• Sirolimus
• Tacrolimus
• Everolimus
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Suggested Answer to Q.12b
What are the sample requirements for the
TDM of these immunosuppressants?
Whole Blood
• Cyclosporine
• Tacrolimus
• Sirolimus
• Everolimus
Plasma for mycophenolate mofetil
(Immunosuppressants are distributed primarily within the cells)
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Q:13: You are working as Consultant Chemical Pathologist in a Stateof-the-art facility for Toxicology testing. On joining this new facility you
have identified some areas which require improvement.
a. ‘Chain of the Custody’ for specimens received from outsource
collection points is an important prerequisite for ‘Drugs of Abuse’
testing. Write some salient features of this SOP.
b. A urine sample for ‘Drugs of Abuse’ testing has been received.
What next step you would like the lab staff to take assuming
proper ‘chain of custody’ has been maintained.
c. Alcohol is one of the most common tests carried out in a
toxicology lab. How to collect a blood sample for alcohol test is a
‘Frequently Asked Question’ by collection centres.
Please write THREE most important precautions for
phlebotomist collecting blood sample for alcohol.
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Suggested Answer to Q.13a
‘Chain of the Custody’ for specimens received from
outsource collection points is an important prerequisite
for ‘Drugs of Abuse’ testing. Write some salient features
of this SOP.
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Chain of Custody
• In circumstances where the test results could be challenged in a court
of law, a chain of custody process should be maintained.
• Chain of custody starts at the time of initial patient contact.
• The specimen must be collected under controlled conditions.
• The collection facility initiates a documentation process that
accompanies the specimen to the laboratory.
• The chain-of-custody process provides:
 Clear and unique identification of the subject being tested
 Clear and unique labeling of the specimen
 Identification of all persons who handle the specimen—legible
signature required
 A historical record of events with action dates clearly stated
 Security of the specimen using a sealed, tamper-evident process
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Suggested Answer to Q.13b
A urine sample for ‘Drugs of Abuse’ testing has been
received. What next step you would like the lab staff to
take assuming proper ‘chain of custody’ has been
maintained.
Integrity of Urine Sample should be checked by :
• pH (Invalid if < 4.5 or > 9)
• Specific gravity
• Urine creatinine
• A specimen is reported as invalid if it exhibits discrepant creatinine and
specific gravity results)
• Any obvious alteration in the sample (adulteration)
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Suggested Answer to Q.13c
Alcohol is one of the most common tests carried out in a
toxicology lab. How to collect a blood sample for alcohol test is a
‘Frequently Asked Question’ by collection centres.
Please write THREE most important precautions
phlebotomist collecting blood sample for alcohol.
for
• Use alcohol free disinfectant for cleaning the vein puncture site like Benzalkonium
chloride or iodine.
• Cover it with liquid paraffin layer and stopper immediately to avoid evaporation of
alcohol.
• Collect blood in NaF tube.
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Thank You and Best Of Luck
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