360 - Therapeutic Drug Monitoring & Toxicology

Question 1

what is the main purpose of TDM?

Answer 1

to ensure that drug dosages fall within the therapeutic range to provide maximum benefit to the patient

Question 2

T or F. All drugs are suitable for TD

Answer 2

F! not all are suited

Question 3

The best candidates for TDM meets one or more of the following:

Answer 3

• the serum drug level corresponds to clinical response,
• there is a small therapeutic range,
• there is variability in pharmacokinetics,
• there is no other marker for the therapeutic outcome,
• it is used for long-term therapy.

Question 4

some examples of use of TDM

Answer 4

• to establish a steady state dosage
• to assess patient compliance, e.g. antipsychotics
• to maintain therapeutic range, e.g. aminoglycosides
• if there is a change in patient health, e.g. ageing, pregnancy, weight loss, liver disease.

Question 5

antiepileptic drugs

Answer 5

carbamazepine, valproic acid, phenytoin, phenobarbital, lamotrigine

Question 6

antibiotics

Answer 6

amikacin, gentamicin, tobramycin, vancomycin

Question 7

chemotherapy

Answer 7

busulfan, methotrexate

Question 8

cardiac drugs

Answer 8

digoxin

Question 9

immunosuppressants

Answer 9

cyclosporine, tacrolimus, sirolimus

Question 10

antidepressants

Answer 10

lithium

Question 11

bronchodilators

Answer 11

theophylline

Question 12

the common factors affecting plasma drug concentration are

Answer 12

ADME
Absorption, Distribution, Metabolism, and Elimination

Question 13

absorption

Answer 13

• most drugs administered orally
• when reaches GI = must liberate from capsule, filler, etc to be absorbed
• once absorbed, the drug passes into the circulatory system and is transported via the portal vein to the liver where some of the drugs are metabolized = FIRST-PASS METABOLISM = decreases concentration of drug in circulation

Question 14

how is absorption affected if drug is administered by IV

Answer 14

the entire dose enters the circulation and absorption is not a factor

Question 15

Bioavailability of a drug

Answer 15

the amount of drug absorbed compared to the amount of drug administered

Question 16

distribution

Answer 16

Blood will distribute the drug throughout the body

Distribution factors include the size, charge, and hydrophobicity of the molecule

Acidic drugs bind primarily to albumin, and basic drugs bind primarily to globulins, particularly α-1 acid glycoprotein

change to the concentration of free drug in the plasma will affect the amount available to interact with cellular receptors in the target tissue(s)
E.g. hypoproteinemia can result in drug toxicity as increased amounts of the free drug are available

Question 17

T or F. When a drug is protein bound, it is non-active

Answer 17

T! free form of drug in plasma is the active form; can interact w cellular receptors

Question 18

metabolism

Answer 18

Enzymatic degradation of drugs occurs in the liver, GI tract, and kidney

Drugs can be metabolized from an inactive or weakly active prodrug form to an active form, or they can be metabolized from an active form to an inactive form

Metabolic processes are classified as phase I or phase II: phase I reactions modify structure by hydrolysis, oxidation, or reduction and phase II reactions conjugate the drug by sulfation or glucuronidation to water-soluble forms

Question 19

These enzymes metabolize most drugs

Answer 19

phase I (eg. cytochrome P450 enzymes); subject to genetic variation

Question 20

T or F. Most drugs are metabolized by zero order kinetics

Answer 20

F! first order

rate of change in plasma drug concentration is dependent on the concentration of the drug;
A CONSTANT PROPORTION (PERCENTAGE) of the drug is removed per unit time

Question 21

these drugs follow zero order kinetics

Answer 21

ethanol and salicylates
- rate of change in plasma drug concentration is independent of the concentration of the drug

• CONSTANT AMOUNT is eliminated per unit time = the rate of elimination is not proportional to the concentration of the drug taken

Question 22

elimination

Answer 22

drugs are excreted in urine, feces, saliva, sweat, hair, breast milk, and expired air

kidneys are a major route of elimination for water-soluble drugs, either parent compounds or metabolites

if renal function altered = will affect the clearance of drugs
- decreased renal function, the serum concentration of a drug will increase

Question 23

ADME factors are influenced by these additional factors:

Answer 23

DEMOGRAPHICS: age, weight, sex, ethnicity, genetics

DISEASES STATES: liver, kidney, thyroid, cardiac

OTHER: dialysis, body temperature, and cardiac output

Question 24

TDM collection

Answer 24

• serum or plasma preferred
• exceptions that require EDTA whole blood = cyclosporine, sirolimus, and tacrolimus
• can be collected at the peak, trough, or steady state
• some aminoglycosides need a peak and trough level as they have a narrow therapeutic range and are nephrotoxic
• dosing schedule, time of the last and next dose, and length of time on the drug must be included on req (also route of administration and other medications)

Question 25

an anti-inflammatory, antipyretic pain reliever

Answer 25

salicylate or aspirin

Question 26

salicylate

Answer 26

- aspirin - an unmeasured anion and can increase the anionic gap - concentrations above 30 mg/dL are associated with metabolic acidosis, but salicylates also stimulate the respiratory center, causing a low pCO2 - intoxication can be observed as a mixed metabolic acidosis and respiratory alkalosis - Trinder's method

Question 27

interferences of salicylate Trinder's method

Answer 27

The iron reacts with the phenolic groups of salicylates (SSA). Salicylate metabolites and structurally related drugs and they also react. diflunisal, phenothiazine and hemolysis can interfere. A blanking step lessens endogenous background. Azides will also interfere.

Question 28

alternative methods to Trinder's method for salicylate

Answer 28

HPLC (reference method), FPIA, salicylate hydroxylase method

Question 29

an anti-pyretic pain reliever

Answer 29

acetaminophen (paracetamol, Tylenol, Panadol)

Question 30

acetaminophen

Answer 30

Above therapeutic concentrations, acetaminophen is hepatotoxic and nephrotoxic. Only methods that measure acetaminophen should be used; assays for nontoxic metabolites are not recommended. Assay = a particle enhanced turbimetric inhibition assay. - particle-bound drug (PBD) competes with the drug the patient sample for binding sites on the antibody - if particle bound drug binds the antibody, insoluble aggregates are formed. - formation of aggregates is measured by turbidimetry rate and amount of particle aggregation are inversely proportional to the concentration of drug in the patient sample.

Question 31

interferences of measuring acetaminophen

Answer 31

rare = non-specific protein binding

Question 32

a CNS depressant

Answer 32

ethanol

Question 33

ethanol

Answer 33

- metabolized by the liver by alcohol dehydrogenase to acetaldehyde and converted to acetic acid - samples should be collected using alcohol-free disinfectants and remain capped as to avoid loss due to evaporation - increases the osmolal gap and is a rare cause of ketoacidosis

Question 34

interferences of ethanol measurement

Answer 34

assay is reasonably specific Isopropanol, methanol, and ethylene glycol can react, but interference is minimal (<1%)

Question 35

reference method for blood alcohols

Answer 35

gas chromatography

Question 36

gas chromatography for alcohols

Answer 36

- in closed system, alcohols such as ethanol, methanol, isopropanol, and acetone are volatile enough to be present in measurable concentrations in the air (head) space above the liquid specimen - some of this headspace is injected into a GC for analysis - head-space procedures inject into GC system a vapour sample removed from a confined space above blood in a closed container - head-space prevents contamination of the column and injector

Question 37

Increased sensitivity of the head-space analysis can be gained by...

Answer 37

the addition of salt such as ammonium sulphate to the specimen - added salt increases in the concentration of the volatile substance in the vapour phase - sample is processed with a known amount of an internal standard to normalize variation among specimens

Question 38

If a STAT methanol or ethylene glycol is ordered, then these are tested

Answer 38

sodium, urea, glucose, osmolality, and ethanol The unaccounted osmolal gap is calculated = measured osmolality – (calculated osmolality + ethanol)

Question 39

If the unaccounted osmolal gap is ≥ 5mmol/L,

Answer 39

then methanol and ethylene glycol tests are performed

Question 40

If the unaccounted osmolal gap is ≥ 2mmol/L but < 5 mmol/L

Answer 40

only the ethylene glycol test is performed

Question 41

If the unaccounted gap is less than 2 mmol,

Answer 41

neither the ethylene glycol or methanol test will be performed

Question 42

Describe the relationship between the osmolal gap and blood alcohol, including the “unaccounted gap”:

Answer 42

increased osmolal gap = increased blood alcohol