toxicology TDM

Question 1

Main functions of a clinical toxicology lab

Answer 1

1. therapeutic drug monitoring ( TDM)
2. ID of drugs in acute intoxication
3. Urine testing for drugs of abuse or performance enhancers
4. testing for environmental or occupational exposure

Question 2

Therapeutic drug monitoring

Answer 2

analysis, assessment, and evaluation of circulating concentrations of drugs in Serum,
Plasma, or Whole blood

Question 3

Main purposes of TDM

Answer 3

ensure drug dosage is within the Therapeutic Range - The range that produces the
maximum therapeutic benefit

identify when the drug is outside of the therapeutic range
•Too low - drug inefficiency
•Too high - toxicity

Not used for all drugs

Question 4

Indications for Therapeutic Drug Monitoring (TDM)

When is it necessary?

Answer 4

• Drugs with low therapeutic index (ie. Narrow range between therapeutic and toxic levels)
• Start or change in therapy
• Neonates/ infants due to maturing renal and hepatic functions
• During illness
• When a drug is unexpectedly ineffective or toxic
• When a new drug is added due to possible drug interactions

Question 5

Factors to consider in TDM

Answer 5

• Route of administration ( ex. orally, muscular injection)
• Rate of absorption
• Distribution of the drug within in the body
• Metabolism ( liver)
• Rate of elimination (kidney)

Question 6

protein bound vs free drug

Answer 6

Only free drug can give a biologic response

Not protien bound drug

Question 7

Pharmacodynamics

Answer 7

study of the biochemical and physiological effects of drugs

and the mechanisms of their actions

Question 8

site of action

Answer 8

site at which a drug acts to initiate a specific biological effect

Drug action is usually mediated through receptors such as cellular enzymes and
structural or transport proteins

Question 9

Pharmacokinetics definition & how its used

Answer 9

activity or fate of drugs in the body over a period of time.

•Takes into account all of the factors that determine concentration of a serum drug
level (absorption, distribution, metabolism and excretion).

•Assists the health care provider in establishing or modifying a dosage regimen for
each patient.

•Uses mathematical modelling to determine the drug concentration in circulation
Drug concentrations will swing back and forth between a maximum (peak) and minimum
(trough) concentration level.

Goal:
•To get the peak and trough levels within the therapeutic range.
•To make sure the peak is not in the toxic range

Question 10

steady state

Answer 10

intake and elimination of a drug are in equilibrium

5 to 7 doses of a drug are usually required to achieve a steady state

Question 11

factors affecting blood levels of a drug physiologial & non

Answer 11

Physiological Factors:
•Absorption into blood (IV, IM, orally)
•Distribution in body tissues
•Metabolism by liver
•Excretion by the kidney
•Maturation or aging
•Organ disease (liver & kidney esp.)
•Diurnal variation (daily fluctuations)
•Drug interactions

Non-physiological Factors:
•Drug formulation
•Medication Errors
•Patient compliance

Question 12

during drug therapy what is affected by a patients history

Answer 12

A- Absorption
D- Distribution
M-Metabolism
E- Excretion

Question 13

routes of administration

Answer 13

intravenous **
-most direct & effective delivery to sites of action

intramuscular (IM) injection
Subcutaneous (SC) injection

Transcutaneous

• absorbed through skin
• ex. transdermal patch

rectal delivery

• ex. suppository
• used in infants or when oral delivery is not possible

Oral administration **

• Most common method
• Least invasive

Question 14

Drug Absorption for oral drugs; efficiency of absorption from GI tract depends on:

Answer 14

efficiency of absorption from GI tract depends on:
•Dissociation from its administered form
•Solubility in gastrointestinal fluids
•Diffusion across gastrointestinal membranes

Question 15

drug absorption ( Dissolution)

Answer 15

• Tablets and capsules must dissolve before being absorbed

* Liquid solutions absorbed more rapidly

Question 16

drug absorption ( solubility )

Answer 16

• Weak acids are absorbed well in stomach (due to gastric acidity)
• Weak bases best absorbed in intestine (pH is more alkaline)

Question 17

drug absorption (Diffusion)

Answer 17

Absorption occurs in predictable manner in healthy people
•Absorption rates can be altered by changes in:
•Intestinal mobility
•pH
•Inflammation
•Presence of food or other drugs

Absorption rates can also be affected by:
•Age
•Pregnancy
•Pathologic conditions

Question 18

drug bioavailability

Answer 18

The bioavailability is the fraction of a drug dose that is absorbed into the
systemic circulation

**In order to be useful, a drug’s bioavailability needs to be greater than 70%

Question 19

First pass effect

Answer 19

Drugs administered orally are absorbed in the small intestine and are carried by the
portal vein directly to the liver.

•Some drugs have a high hepatic excretion rate whereby low amounts reach the 
systemic circulation (low bioavailability).

first-pass effect - extensive metabolism of a drug with a high
hepatic extraction rate by the liver before it reaches systemic circulation

Question 20

drug distribution ( protein bound )

Answer 20

• Drug distribution occurs after a drug enters the vascular department.
• Many drugs bind to protein in the blood
• Acidic drugs are primarily bound to albumin
• Basic drugs are primarily bound to globulins

Question 21

drug distribution ( free drugs)

Answer 21

Only the free (unbound) fraction of drug can interact with the site of action & cause
biologic response.

•Free drug is also termed active

Percentage of free drug depends on physiologic & biochemical parameters:
•Inflammation, malignancies, pregnancy, hepatic disease, nephrotic syndrome, malnutrition, acid–
base disturbances
•Concentration of other substances competing for binding sites (eg. other drugs, urea, bilirubin,
hormones)

Example: Phenytoin
•In a healthy individual: 90% bound; 10% free
•In uremic patients: 20-30% free
•Drug dose would need to be adjusted in uremic patients

Question 22

drug metabolism by liver

Answer 22

All substances absorbed from intestine enter hepatic portal system
Metabolism involves the biotransformation and excretion of the drug

Rate of metabolism can vary between different patients as well as with the same patient
at different times and in different circumstances

Question 23

Biotransformation

Answer 23

•Chemical alteration of a xenobiotic within the body that generally enhances the xenobiotic’s aqueous solubility and excretion.( makes drugs water soluble & easier to excrete in urine )

**•The main biochemical pathway for drug metabolism is the hepatic mixed-function
oxidase (MFO) system
Converts lipophilic non-polar molecules to more polar water-soluble forms

patients with liver disorders may require lower dosages

Question 24

Pharmacogenomics

Answer 24

study of genetic variations in patient drug metabolism pathways and
development of drug therapies to compensate for genetic differences impacting therapy
regimens

• Responders
• Patients benefitting from therapeutic and desired effects of the drug
• Nonresponders
• Patients not benefitting from therapeutic and desired effects of the drug

Question 25

Pharmacogenomics - (CYP450)

Answer 25

Cytochrome P-450 •Gene group family that affects drug metabolism •Family of enzymes within the hepatic mixed-function oxidase (MFO) system * Three variations most often linked to differences in drug metabolism: * CYP2D6 * CYP2C9 * CYP34A * If a patient metabolizes slowly - less drug given to prevent toxic concentrations * If a patient has increased rates of metabolism - higher dose given to maintain therapeutic levels

Question 26

Drug excretion

Answer 26

``` Can occur through different routes: •Biliary •Intestinal •Pulmonary •Renal ---> Major pathway of elimination for most soluble drugs ``` * Decreased renal function causes increased serum drug concentrations * Creatinine clearance or GFR can be measured to assess kidney function for many drugs : decreased renal function = increased serum drug conc.

Question 27

Decreased Elimination

Answer 27

Elimination depends on glomerular filtration & renal secretion decreased GFR ( or decreased creatinine clearance ) will increase the drug half- life & plasma concentration decreases in the plasma drug concentration as first order process with an exponential rate of loss

Question 28

Preanalytical Factors Affecting TDM Results

Answer 28

* Dose accuracy ( drugs degrade over time) * Sample collection at appropriate time ( peak or trough) * Specimen collection and handling ( serum preferred for most ) * Physiologic changes in the patient failure to give/consume full dose

Question 29

Specimen collection

Answer 29

•Accurate timing of collection is the most important factor in TDM******** * Trough Levels - collected right before the next dose * Tested to ensure the drug concentration stays within therapeutic range * Peak Levels - collected shortly after an administered dose * Exact time will differ depending on type of drug and how it is administered * 1 hr after orally administered dose * Tested to screen for drug toxicity * Acceptable specimens: Serum, heparinized plasma * Unacceptable specimens: EDTA (1 exception) , citrate and oxalate

Question 30

Analytical Factors Affecting TDM Results

Answer 30

* Method Selectivity * Ability of a method to detect the compound of interest ( only detect drug) * Interfering Substances * Metabolites of the drug * Human-anti-mouse antibodies (HAMA) - can interfere with immunoassays * Heterophile antibodies- can interfere with immunoassays •Presence of interfering substances can lead to inappropriate changes in drug dosing

Question 31

TDM of cardioactive drugs - Digoxin

Answer 31

treatment of arrhythmias restores cardiac contration in congestive heart failure steady state concentration in cardiac tissue ( 10-15x that in plasma) - specimen should be collected 8 hrs or more after dose to allow distribution equilibrium in tissue - 2-3 hr peak in plasma -6-10 hr peak in tissue ( if taken too early may be interpreted as toxic bc of plasma levels & they incorrectly receive a lower dose next time ) methods of analysis - Immunoassay

Question 32

TDM of Antibiotics - Aminoglycosides

Answer 32

•Kill aerobic gram-negative bacteria •Poorly absorbed from intestinal tract - Given intravenously or intramuscularly •Accumulation occurs with any impairment of glomerular filtration ( kidney issues) - Dose corrections must be made in this case( drug is mainly excreted through the kidney)

Question 33

TDM of Antibiotics- Choramphenicol

Answer 33

* Kill aerobic gram-positive bacteria * Rapidly absorbed in gastrointestinal tract * Peak concentration at 1-2 hours after oral dose * 50% protein-bound ( 50% free) * Increased concentrations with hepatic disease ( affected by liver) * No significant decrease in clearance with renal disease ( doesn't get affected by kidney as much) * Methods of analysis: * Immunoassay * HPLC ( high performance liquid chromatography )

Question 34

TDM Antibiotics- Vancomycin

Answer 34

* Used against gram-positive and some gram-negative bacteria * Useful against methicillin-resistant staphylococcus (MRSA) and cornybacteria * Treat endocarditis and sepsis * Poorly absorbed when given orally; given by IV infusion •Reduced clearance can occur with impaired renal function leading to toxic concentrations

Question 35

TDM Antifungal Antibiotics- Azoles

Answer 35

Main class in which TDMis useful Methods of analysis: •HPLC •LC/MS

Question 36

TDM Antiepileptic Drugs - Phenobarbital

Answer 36

* Treatment of all seizures except absence seizures( patient blanks/stares off) * Absorption is slow but complete * 40-60% is protein-bound * Dose given orally * Decreased clearance of drug occurs when renal and hepatic functions are decreased. * Toxicity can include drowsiness, fatigue, depression and reduced mental capacity

Question 37

TDM Antiepileptic Drugs - Phenytoin ( Dilantin)

Answer 37

* Controls several types of seizures and prophylactic agent in brain injury * given by intramuscular injection or orally * 90-95% tightly bound to protein once absorbed * Protein-binding can be reduced by: * Other drugs (salicylates and valproic acid) * Anemia * Hypoalbuminemia ( elderly) •Adverse effects ( too much drug) : initiation of seizures, hirsutism, gingival hyperplasia, vitamin D deficiency, folate deficiency

Question 38

TDM Antiepileptic - Valproic Acid

Answer 38

* Treatment for petit mal and absence seizures * Can also be used to treat bipolar disorder * Rapidly and almost completely absorbed after an oral dose * Peak concentration 1-4 hours after oral dose * 93% protein bound * Free drug levels increase when competition for protein-binding increases: * Uremia * Cirrhosis * Concurrent drug therapy * Adverse effects: nausea, lethargy, weight gain * Extremely high levels associated with: pancreatitis, hyperammonemia, hallucinations

Question 39

TDM Antiepileptic - Carbamazepine ( Tegretol)

Answer 39

* Treatment for seizures * Mood-stabilizing for bipolar disorder * Given orally * 80% protein bound •Reduced liver function leads to drug accumulation. •Reduced concentration can occur due to increased metabolism when the following drugs are co-administered: •Phenobarbital •Phenytoin •Valproic Acid •Has serious adverse affects, so only used when patients do not respond to other antiepileptics.

Question 40

TDM Psychoactive Drugs- Lithium

Answer 40

* Administered as lithium carbonate * Treatment of manic phase of affective disorders, mania, and manic-depressive illness * Peak concentration occurs 2-4 hours after oral dose * Cation that does not bind to protein * Primarily cleared by the kidneys * Prolonged clearance times seen with decreased renal function * Elevated concentrations cause: apathy, lethargy, speech difficulties, muscle weakness * Very elevated concentrations: renal impairment, hypothyroidism, CNS disturbances * Methods of analysis: * Flame emission photometry * Atomic absorption spectrophotometry * Ion-selective electrode * Inductively coupled plasma-mass spectrometry (ICP-MS)

Question 41

TDM Immunosuppressive Drugs - Cyclosporine

Answer 41

* Effective in suppressing: * Solid organ allograft rejection * Graft-versus-host disease following BM transplantation * Approved for use in the following organ transplants: * Renal, cardiac, hepatic, pancreatic, bone marrow * Slowly absorbed * Peak concentrations in 4-6 hours * 90% protein-bound and concentrated in RBCs * Best specimen is whole blood ** NOT SERUM * Toxicity can cause: renal tubular and glomerular dysfunction * Methods of analysis: * Non-isotopic immunoassay * HPLC * LC-MS/MS

Question 42

TDM immunosuppressive drugs - Tacromilus ( FK506)

Answer 42

* Binds to FK506-binding protein * Mainly administered orally * Narrow therapeutic index * Highly protein bound (up to 99%) * 100 times more potent than cyclosporine * all immunosuppresive drugs are whole blood Special requirement - collect 2 EDTA tubes

Question 43

TDM immunosuppressive drugs - Sirolimus

Answer 43

* Fermentation product of actinomycete Streptomyces hygroscopius isolated from soil samples on Easter Island * antifungal, antitumor, and immunosuppressive activity * used to prevent acute rejection in renal transplant patients****** * Available as an oral solution or tablet * Rapidly absorbed in GI tract (peak by 2 hours) * ~95% distributes into RBCs * Methods of analysis: * Chromatographic detection (LC-MS, LC-MS/MS, HPLC) * Automated immunoassay

Question 44

TDM antineoplastic agents- Methotrexate

Answer 44

•Used for: - Management of ALL in children - Choriocarcinoma and trophoblastic tumors in women - Carcinoma of breast, tongue, pharynx, testes - Maintenance of remission in leukemia - Treatment of severe psoriasis * Inhibits DNA synthesis * Primarily eliminated through renal excretion * Methods of analysis: - Radioimmunoassay (RIA) - Not common - Folate reductase inhibition technique - Liquid chromatography - Non-isotopic immunoassays***

Question 45

TDM Bronchodilator-Theophylline

Answer 45

* Relaxes bronchial smooth muscles to relieve or prevent asthma * also used to treat neonatal apnea * Readily absorbed after oral, rectal, or parenteral administration * 50% protein-bound once absorbed * Smoking increases the rate of metabolism and increases clearance * Clearance is prolonged in neonates and CHF patients