Therapeutic Drug Monitoring (TDM) and Toxicology Flashcards
What is therapeutic drug monitoring?
Measuring and monitoring circulating levels of a drug (or its metabolites) in serum, plasma or whole blood
To ensure that drug dosage is in therapeutic range and not toxic or ineffective
Not required for most drugs as safe and effective dosages are known
What is toxicology?
The study of adverse effects due to exposure to toxins such as xenobiotics, poisons and toxins
What are xenobiotics?
Xenobiotics are chemicals and drugs not normally produced in the body, but are capable of entering biochemical pathways.
Usually refers to drugs and environmental chemicals.
It is estimated that some 50-60% of patients are ____________ with respect to their medication. Which means?
Non-compliant.
Patient not responding or not taking their drugs.
What causes someone to be in treatment recovery or have rising drug levels?
Drug overdose.
What does it mean when there is an underdose?
Patient is not taking enough drug to be of therapeutic value.
What does narrow therapeutic range refer to and what are the implications?
- If narrow range or close to toxic range.
2. Level should be in range to be maximally effective.
What is the implicates of “suspected tolerance”?
It means dose may have to be raised to obtain same therapeutic effect if drug tolerance developed.
Can the symptoms of disease be similar to the toxic symptoms of the drug?
Yes it can. E.g. If drug and disease both cause nausea, so monitor to be sure the drug is working.
Is oral dosage always related to plasma concentration?
No, sometimes oral dosage may not be related to plasma concentration. Amount of drug taken not directly transferable to plasma concentration.
How does therapeutic drug monitoring affect the treatment?
- If can be used to determine the course of treatment.
2. Response to drug determines future doses or if use of different drugs or treatments are needed.
What is Pharmacokinetics?
Pharmacokinetics: Study of drug disposition in the body, including how and when drugs enter the circulation, how long they remain in the blood, and how they are ultimately eliminated from the body
Used to modify drug doses for blood levels
How does a therapeutic drug vary in concentration in the blood?
Peak versus trough: concentrations of drugs oscillate between maximum (peak) and minimum (trough) concentrations
What is T½ (half-life)?
T½ (half-life):
Time needed for drug concentration to decrease by half
Describe steady state in therapeutic drug monitoring.
Drug concentration remains in equilibrium after multiple drug doses
Usually reached after 5-7 doses
Dosage adjusted so both peaks and troughs are within therapeutic range
List the different routes of drug administration (6).
Routes of Drug Administration
IV, IM, on the skin, inhalation, oral, or epidermal
What is absorption and what affects it?
Absorption
- Process in which drugs enter the bloodstream
- GI tract longer than IV administration
- Food, drugs, and illness may inhibit
What does distribution mean in terms of TDM and Toxicology?
Distribution
Spread of drug through circulatory system to organs and tissues throughout the body
How are a lot of drugs metabolized|?
- Metabolism: Drug is transformed into an easily excretable water soluble form
- Many drugs first pass through the liver
What are ways drugs are eliminated from the body (elimination)?
Elimination:
- The kidneys excrete the free form of drug in urine (great sample for testing)
- Removal also via lungs, GI, etc.
When should samples be collected: a) in general b) for oral doses?
- Timing is crucial for collection of drug levels. Timing is drug dependent.
- Administration route can alter timing:
a) Peak levels can be collected one hour post dose for orally administered doses, and trough levels immediately before next dose
\What are free (active) versus bound drugs (in the plasma)?
Free (active) versus bound drug:
- Free drugs interact with sites of action and result in biological response
- Drugs can form complexes with serum constituents like albumin (bound)
What can affect the concentration of free versus bound drugs?
Concentrations of proteins can impact concentrations of free versus bound drugs
What type of tube is used for TDM or toxicology?
Lithium heparin tubes with no gel used for many drugs
What is the result if the collection tube has gel in it for TDM?
Gels may absorb drug creating falsely low values.
What types of tubes should NOT be used?
EDTA, citrate, or oxalate are generally unacceptable.
What is lithium used for?
Lithium is used as lithium carbonate for treatment of manic depressive psychosis or bipolar disorders.
How does the drug lithium get metabolized? Timing of peak?
Totally absorbed
Water soluble
Usually peaks from 2-4 hours after oral dose
What is the goal of TDM in administering lithium and monitoring of symptoms of intoxication?
- Concentrations are measured to ensure compliance and avoid toxicity
- Symptoms of intoxication include muscle weakness, sluggishness, and drowsiness
How is lithium tested in the laboratory? Special sample collection requirements?
- Methodology: Atomic absorption spectrophotometry and Ion-selective electrode (ISE)
- Sample: Serum or plasma with sodium heparin.
**Note: Do NOT use lithium heparin as it will interfere with accurate measurement of patient levels
What are tricyclic antidepressants used for?
Treatment of depression, insomnia, etc.
What are the overdose symptoms of tricyclic antidepressants?
Overdose can include cardiac and respiratory failure, seizures, and coma.
When does peak concentration occur and therapeutic effects are seen for Tricyclic Antidepressants?
- Peak concentrations in range of 2-12 hours
2. Therapeutic effects are not seen until 2-4 weeks after initiation of therapy
How are tricyclic antidepressants tested?
- Methodology: Immunoassays, High Performance Liquid Chromatography or Gas Chromatography
- Sample:
a)Serum or plasma without gel
Separate serum from cells as soon as possible.
b) Collect blood approximately 10 hours after the last dose
What are the various uses of cardiac drugs?
- Cardiac glycoside for treatment of congestive heart failure and disturbances of cardiac rhythm
- Used as cardiac stimulants
Name some examples of cardiac drugs.
Examples:
Digoxin (CHF), Quinidine, Procainamide, and Disopyramide (cardiac arrhythmias)
How is digoxin tested for?
Testing for Digoxin:
- Methodology: Immunoassays
- Sample:
a) Lithium heparin without gel
b) Blood is collected up to 4 hours before the next dose
What is the reference range for digoxin? What is the particular concern?
Reference Range
Therapeutic 0.8-2.0μg/L
Toxic >2.4 μg/L
NOTE: Narrow therapeutic range with toxic level close to therapeutic level
What are aminoglycosides used for?
Treatment of infections with gram negative bacteria
Name some examples of aminoglycosides.
Examples:
Gentamicin, kanamycin, amikacin and tobramycin
How are aminoglycosides typically administered?
Usually administered by IV or IM as they are not well absorbed by the GI tract
What are the main concerns regarding aminoglycosides?
Nephrotoxicity and ototoxicity
What are the main concerns regarding vancomycin?
Nephrotoxicity and ototoxicity
When does the peak concentration and 1/2 life occur for aminoglycosides?
- Peak concentrations in 1-2 hours post-dose
2. ½ life = ~2-3 hours
What are the methods of measurement for aminoglycosides?
Aminoglycosides Methods of measurement:
Chromatography and immunoassay
What is vancomycin used for and how is it administered?
Treatment of infections with Gram positive cocci and bacilli
Administered by IV
What are sample collection requirements for TDM of vancomycin?
Sample:
- Serum without gel
- Collect trough concentration within 45 minutes prior to next dose
What is the reference range for vancomycin and what condition is required before determination?
Reference range
Monitored using steady-state (no earlier than the fourth dose) trough serum concentrations
Target is 10-20 mg/L
Toxic >28 mg/L
What is theophylline used for?
Bronchodilators: Theophylline
–> Treatment of asthma and chronic obstructive pulmonary disease (COPD)
What type of sample tube is required for collection of a TDM for theophylline?
Sample is serum or plasma without gel
Given toxic levels of theophylline toxic: a) within 0-4 weeks and b) >= 5 weeks? What are the symptoms?
Toxic is:
0-4 weeks: > 10 mg/L
> 5 weeks: > 20 mg/L
Toxic levels can cause nausea, vomiting, diarrhea, cardiac problems and seizures
What is phenobarbital and it affects?
- Phenobarbital is a metabolite of primidone and mephobarbital
- Slow acting barbiturate
- Reduces synaptic transmission
- Sedative, hypnotic and anticonvulsant effects
- Decreases excitability of nerve cells
What are the sample collection requirements for phenobarbital monitoring?
Sample Tubes for Phenobarbital:
Serum or plasma without gel
List some other types of anticonvulsant drugs and their uses?
- Phenytoin or Dilantin
Used to treat variety of seizure disorders including epilepsy - Valproic Acid
Treatment of petite mal or absence seizures - Carbamazepine or Tegretol
Because of its toxic effects, is used for seizures when a patient is not responding to other drugs - Ethosuximide
Control of petite mal seizures
What is cyclosporine used for?
Cyclosporine: Used for suppression of host-versus-graft rejection of transplanted organs.
What is the testing and sampling requirements for cyclosporine?
- Method: Immunoassays
- Sample: EDTA whole blood
Only trough specimens should be analyzed
Pre-dose sample required
What is the therapeutic reference range for cyclosporine?
Reference range:
Therapeutic (trough):100-300μg/L
Target range is dependent on transplant type, time post-surgery and immunosuppressive protocol
Name some other types of immunosuppressive drugs?
- Tacrolimus: FK-506 is 100x more potent than cyclosporine. Lower dose
- Sirolimus: Antifungal agent used as immunosuppressive drug. Potent
- Mycophenolic Acid (MPA):
Lymphocyte proliferation inhibitor
Used in renal transplants with cya or FK5
What does the antineoplastic, methotrexate do?
Antineoplastic agent that inhibits DNA synthesis
What disease does methotrexate treat?
Treat neoplastic diseases that have rapid cell proliferation
Lymphoblastic leukemia in children and other tumors and carcinomas
What is the serious concern for methotrexate?
Potential for serious toxicity, so monitoring is important to ensure drug is being cleared
What is the method of testing for the antineoplastic, methotrexate?
Immunoassay
What are the purposes of toxicology in the medical laboratory?
- Identification of drugs in acute or chronic toxicity
- Assess levels of drugs and suggest a therapy or an antidote
- Blood can be used to determine environmental or occupational toxins such as lead
- Blood and urine testing can be done to determine presence and levels of drugs of abuse
List the drugs of abuse and their main effects on a person.
- Amphetamines: speed or uppers; increases mental & physical capacities.
- Anabolic Steroids: used to increase muscle mass
- Cannabinoids: Psychotropic drug
- Cocaine: User feels energetic, euphoric & hypersensitive
- Opiates (heroin, opium, morphine, and oxycodone): analgesic, pain management
- Valium: sedatives, muscle relaxants, anesthetics & anticonvulsants.
What type of drugs screens can be done using urine?
Drug screens can be done on urine:
- Commonly lateral flow immunoassays
- Qualitative NOT Quantitative
- -> Positive or negative - Would require confirmatory follow-up testing with HPLC-MS
What drugs are screened using urine testing? What is the specificity of the testing?
Often includes: Cocaine, THC (Marijuana), Barbiturates, Benzodiazepines, Amphetamine and methamphetamine, Opiates, Oxycodone/oxymorphone, Methadone
Not specific enough to determine type of drug in class
Describe the features of point of care testing for drug screening.
Point-of-care:
- One-step urine drug screen
- Easy dipstick card format
- Results in 3 to 8 minutes
- No reagents needed
- Stores at room temperature
- Built-in controls
What are the pros and cons of using urine for sample collection?
Preferred sample for testing is urine
Pro: Easy to obtain and stable
Con: People attempt to tamper with samples as they are self-collected and often done so unsupervised
What are ways people try to adulterate the urine sample?
Adulteration of urine samples:
- The addition of agents like salts, acids, oxidizers or even water to one’s urine sample in order to obtain a falsely negative result.
- Dilution to get drug levels under detectable levels
- Substitution with non-urine substances or someone else’s urine!
How is sample verification done?
Sample Verification is done:
Is this yellow liquid actually urine?
–>Test pH, specific gravity, and creatinine
What are the uses and concerns for acetaminophen?
Acetaminophen (e.g. tylenol):
- Analgesic and antipyretic properties
- Less stomach irritation than aspirin
- Acute overdose or chronic excessive use can result in hepatotoxicity
How is the hepatotoxicity checked with acetaminophen?
Hepatotoxicity determined using time lapse between ingestion and blood level
What are the methods and sample collection requirements for toxicology of acetaminophen?
- Methodology:
Immunoassays – EMIT & FPIA
Reference method – High Performance Liquid Chromatography - Sample:
Serum or plasma from a green topped tube without gel
What is the therapeutic reference range and toxic level for acetaminophen?
Acetaminophen Reference Range:
Therapeutic 10-20 mg/L
Toxic (4 hours after ingestion) >200 mg/L
What is Acetylsalicylic Acid (Aspirin) used for?
Also known as ASA
Pain killer, nonsteroidal anti-inflammatory drugs (NSAIDs), and platelet function activity
What are the overdose effects of acetylsalicylic acid (aspirin)?
Overdose:
- Toxicity caused by metabolic acidosis due to ingestion of the acid in ASA
- Affects central nervous system and respiratory center
- Respiratory alkalosis from hyperventilation
- Can result in coma
What is the testing methodology for acetylsalicylic acid (aspirin)?
Methodology
- Classic method is Trinder’s (photometric method):
a) Salicylate + Fe3+ → purple chromagen
b) Red on spectrophotometer at 540 nm - EMIT and FPIA
- Reference method – High Performance Liquid Chromatography or Gas Chromatography
What are the sampling requirements for acetylsalicylic acid (aspirin) TDM?
Sample
1. Serum or plasma from a green topped tube without gel
What are the therapeutic reference ranges and toxic levels for ASA?
Acetylsalicylic Acid (Aspirin) Reference Range:
Therapeutic analgesia 20-150 mg/L
Therapeutic anti-inflammatory 100-300 mg/L
Toxic: > 500 mg/L
What are the three types of alcohols measured in the laboratory and the reasons they are measured?
- Ethanol: Measurement for legal or treatment purposes
- Methanol: Windshield washer antifreeze. Optic nerves can be damaged
Treatment: correct resulting metabolic acidosis and give ethanol - Isopropanol: Volatile, flammable alcohol especially used as a solvent and rubbing alcohol
What is the main method of measurement for alcohols in the blood?
Method: Gas chromatography
What are the sample requirements for alcohol testing samples?
- Use soap and water to clean venipuncture site NOT isopropanol
- Serum or plasma tube without gel must be tightly stoppered until analysis
- Be aware of chain of custody if applicable
What are the legal, or toxic and lethal limits of these alcohols: ethanol, methanol and isopropanol?
1. Ethanol
Legal limit is 17 mmol/L
Toxic > 33 mmol/L
Lethal > 90 mmol/L
2. Methanol:
Toxic > 6 mmol/L
Lethal > 30 mmol/L
3. Isopropanol
Toxic > 12 mmol/L
Lethal > 35 mmol/LList metals typically tested and the main reason for someone to be exposed to them.
- Lead: Found environmentally in water and fish due to contaminants
- Mercury: Inhaled or ingested in industrialized areas
- Arsenic: Environmental or occupational exposure
- Cadmium: Industrial metal used in electroplating and galvanizing
What was the main method of testing of lead and the new standard of testing?
- Atomic absorption spectrophotometry has been used
- New standard is ICP-MS
Inductively couple plasma (ionized gas) – mass spectrometry
What type of tube is used for metal testing collections?
Dark blue topped tube
What is carbon monoxide?
Colourless, odourless, tasteless gas
Produced by incomplete combustion of carbon (ie: Furnace)
What is carbon monoxides affinity for hemoglobin compared to oxygen?
225x higher affinity for hemoglobin than oxygen. When carbon monoxide binds to hemoglobin it forms carboxyhemoglobin.
What % v/v of carbon monoxide in the air is lethal by suffocation?
0.4 % v/v carbon monoxide in the air is lethal by suffocation in less than 60 minutes
What is the treatment for carbon monoxide poisoning?
Treatment is 100% oxygen
What method and collection tubes are used for sampling and testing for carbon monoxide poisoning?
- Measured by spectrophotometry and gas chromatography
2. Collect full lithium heparin no gel tube
What are the reference ranges for carbon monoxide?
Carbon Monoxide Reference Range: Non-Smokers < 2% Heavy Smokers < 15% Toxic > 20% Lethal > 50%
What is the effect of the poison cyanide, its forms and where is it found in our environment?
- Very toxic substance which can cause death
- Gas, solid, or liquid form
- Found in some insecticides and from burning of urea foam plastic
What type of collection tube should be used for testing of cyanide?
Whole blood in gray top (potassium oxalate/sodium fluoride)
