Toxicology and TDM Flashcards
When is TDM most useful?
- Chronic medication
- Narrow therapeutic index
- Significant risk from toxicity or under-dosing
- Variable pharmacokinetics
- Adherence monitoring
Pre-analytical factors affecting TDM results
- Dosage uniformity - may vary pill to pill
- Timing - need to decide if trough, peak, post-distributive phase, and generally presumed in steady state
- Sample type - serum separator gel may adsorb some drug from plasma eg PHT
- Within individual BV eg albumin
Analytical factors affecting TDM results
- Availability of standardised reference materials
- Selectivity of methods for drugs - varies between methods; due to similarities between the molecular structure of drugs within the same class, drugs and endogenous compounds and drugs and their (active or inactive) metabolites
- Method precision relative to target concentration range
- Interfering substances in sample
Total vs free phenytoin levels - utility/indications?
Phenytoin is highly albumin bound. In chronic liver disease, when albumin falls, total phenytoin in the reference interval may actually represent high free phenytoin and low bound phenytoin, resulting in toxicity. Free phenytoin levels may more accurately represent therapeutic levels while avoiding toxicity.
%age of carbamazepine that is protein bound
80%
%age of phenytoin that is protein bound
90-95%
Principal site of elimination of carbamazepine
Liver
Active metabolite of carbamazepine and clinical importance?
Carbamazepine-10,11- epoxide. In kids, this can accumulate and cause toxicity, even when carbamazepine levels are within therapeutic range.
Drug interactions with CBZ
- Inducers increase metabolism - phenytoin
- Competitive inhibitors of metabolism increase CBZ levels - erythyromycin
Trough levels are usually monitored for therapeutic CBZ levels. When are peak levels indicated and when should they be taken?
When toxicity is suspected. Sample 4-8 hours after ingestion. Toxic levels are usually >15 ug/mL.
Toxic phenytoin level
> 20 ug/mL
35 - ppt seziures
Principal metabolite of valproic acid
2-n-propyl-3-ketopentanoic acid. Active.
%age valproate protein bound
93%
Toxic levels of valproate?
> 100 ug/mL - hepatic and encephalopathic
Valproate has a ______ half-life and is cleared ___________
Valproate has a SHORT half-life and is cleared RAPIDLY.
How does valproate interfere with phenobarbital?
Inhibits non-renal clearance.
How does valproate interfere with phenytoin?
Competes for protein binding, reducing total phenytoin concentration while free drug levels remain the same.
Your lab’s valproate/phenytoin/CBZ method
PETINIA - particle-enhanced turbidimetric inhibition immunoassay
Your lab’s digoxin method
Competitive immunoassay with chemiluminescent detection (digoxin competes with digitoxin bound to paramagnetic particles for binding to acridinium ester labelled mouse antibody).
Is gentamycin toxicity reversible?
Only if dose is reduced and toxicity does not persist beyond two weeks.
Main toxicit(ies) from gentamycin?
- Vestibular and cochlear sensory nerve cell degeneration
- Renal tubular necrosis
Main concentration related drug toxicity from vancomycin?
Auditory nerve damage
How is gentamycin monitored?
Both trough and peak concentrations
How is vancomycin monitored?
Trough concentrations.
Pre-analytical factor with gentamicin levels?
Heparin containing tubes - heparin complexes with gentamicin which can interfere with immunoassays.
Thiopurine drugs
6-mercaptopurine
Azathioprine
6-Thioguanine
Causes of increased sensitivity to digoxin?
Hypokalaemia
Hypomagnesaemia
Hypercalcaemia
Failure of digoxin concentration to correlate with toxicity may be due to concurrent disturbances in these electrolytes.
Timing of digoxin measurement?
Peak tissue concentration - 8 hours or more after the dose
Interpretation of a high digoxin level taken prior to 8 hours post dose?
Could simply be due to incomplete distribution to tissues
Safe therapeutic plasma concentration of digoxin?
0.8-2 ng/mL
What is the safe digoxin level in heart failure?
0.5-0.8 ng/mL, up to 1.2 ng/mL no increase in mortality.
Does digibind interfere with digoxin measurement?
YES
Normal paracetamol metabolism?
In liver, to glucuronides (60%), sulfates (30%) and by CYP450 enzymes to NAPQI (10%)
What is NAPQI?
N-acetyl-benzoquinone imine. A highly reactive and toxic (usually minor) metabolite of paracetamol.
Usual pathway for metabolism of NAPQI?
Glutathione conjugation with subsequent transformation back to cysteine and mercapturic conjugates of paracetamol
What happens in paracetamol overdose?
Sulfation pathway overwhelmed and is channelled into CYP450 pathway. Increased NAPQI formation eventually depletes glutathione. NAPQI is then free to cause hepatonecrosis.
Timing of hepatic damage post paracetamol overdose?
Hepatic necrosis begins 24-36 hrs after ingestion and peaks at 72-96 hrs after ingestion.
Apart from hepatic necrosis, what other clinical features of paracetamol OD might there be?
Non-specific nausea, vomiting, abdo pain.
Metabolic acidosis
Coma
Specific therapy for paracetamol overdose and how does it work?
N-acetylcysteine. A substitute for glutathione as well as possibly replenishing hepatic glutathione and enhancing sulfate conjugation.
Timing of NAC therapy - when is it most effective?
Within 8 hours of ingestion (ie ideally prior to onset of liver damage)
What is the Rumack-Matthew nomogram?
Relates timing and dose of paracetamol ingestion to the probability of hepatic necrosis.
Caveats when using Rumack-Matthew nomogram?
- Do not use blood levels taken prior to 4 hours after ingestion (ensure the entire dose is absorbed before using nomogram).
- Assumes single acute rather than chronic ingestion - toxicity occurs at lower drug levels with chronic ingestion.
- Not useful if time of ingestion unknown/unreliable - just treat!
- If co-ingestion of drug that delays paracetamol absorption - wait 4 hours, see if symptoms from co-ingested drug to determine if significant effect on paracetamol expected before using nomogram
- In underweight, alcholics, pts on CYP450 inducers - increased susceptibility to paracetamol toxicity. Some practitioners lower the line on the nomogram by 50-70%.
Indications for NAC in chronic supratherapeutic ingestion?
Increased transaminases and paracetamol level > 10ug/mL.
Paracetamol methods
- Immunoassay with spectrophotometry
- Enzymatic (arylacylamide amidohydrolase)
- Chromatographic methods (reference procedure)
- POC lateral flow immunoassay (but limited PPV)
Limitations of paracetamol immunoassay and spectrophotometry
Interference by bilirubin/bilirubin metabolites
Some methods detect non-toxic and toxic metabolites - need to choose a method that measures only parent drug
Limitations of enzymatic paracetamol assay
Interference by NAC, bilirubin, IgM paraproteins
