360 - Therapeutic Drug Monitoring & Toxicology Flashcards
what is the main purpose of TDM?
to ensure that drug dosages fall within the therapeutic range to provide maximum benefit to the patient
T or F. All drugs are suitable for TD
F! not all are suited
The best candidates for TDM meets one or more of the following:
- 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.
some examples of use of TDM
- 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.
antiepileptic drugs
carbamazepine, valproic acid, phenytoin, phenobarbital, lamotrigine
antibiotics
amikacin, gentamicin, tobramycin, vancomycin
chemotherapy
busulfan, methotrexate
cardiac drugs
digoxin
immunosuppressants
cyclosporine, tacrolimus, sirolimus
antidepressants
lithium
bronchodilators
theophylline
the common factors affecting plasma drug concentration are
ADME
Absorption, Distribution, Metabolism, and Elimination
absorption
- 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
how is absorption affected if drug is administered by IV
the entire dose enters the circulation and absorption is not a factor
Bioavailability of a drug
the amount of drug absorbed compared to the amount of drug administered
distribution
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
T or F. When a drug is protein bound, it is non-active
T! free form of drug in plasma is the active form; can interact w cellular receptors
metabolism
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
These enzymes metabolize most drugs
phase I (eg. cytochrome P450 enzymes); subject to genetic variation
T or F. Most drugs are metabolized by zero order kinetics
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
these drugs follow zero order kinetics
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
elimination
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
ADME factors are influenced by these additional factors:
DEMOGRAPHICS: age, weight, sex, ethnicity, genetics
DISEASES STATES: liver, kidney, thyroid, cardiac
OTHER: dialysis, body temperature, and cardiac output
TDM collection
- 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)
an anti-inflammatory, antipyretic pain reliever
salicylate or aspirin
salicylate
- 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
interferences of salicylate Trinder’s method
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.
alternative methods to Trinder’s method for salicylate
HPLC (reference method), FPIA, salicylate hydroxylase method
an anti-pyretic pain reliever
acetaminophen (paracetamol, Tylenol, Panadol)
acetaminophen
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.
interferences of measuring acetaminophen
rare = non-specific protein binding
a CNS depressant
ethanol
ethanol
- 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
interferences of ethanol measurement
assay is reasonably specific
Isopropanol, methanol, and ethylene glycol can react, but interference is minimal (<1%)
reference method for blood alcohols
gas chromatography
gas chromatography for alcohols
- 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
Increased sensitivity of the head-space analysis can be gained by…
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
If a STAT methanol or ethylene glycol is ordered, then these are tested
sodium, urea, glucose, osmolality, and ethanol
The unaccounted osmolal gap is calculated = measured osmolality – (calculated osmolality + ethanol)
If the unaccounted osmolal gap is ≥ 5mmol/L,
then methanol and ethylene glycol tests are performed
If the unaccounted osmolal gap is ≥ 2mmol/L but < 5 mmol/L
only the ethylene glycol test is performed
If the unaccounted gap is less than 2 mmol,
neither the ethylene glycol or methanol test will be performed
Describe the relationship between the osmolal gap and blood alcohol, including the “unaccounted gap”:
increased osmolal gap = increased blood alcohol
