TDM and Toxicology Flashcards
General Indications for TDM
- For drugs with no directly measurable clinical e.g. BP or biochemical e.g. temperature, BG, PT, TFT response
–> monitor by measuring the actual drug concentration in blood
(assume effects correlate with blood concentrations) - Variable pharmacokinetics (difficult to predict appropriate dose for individuals due to variations in ADME)
- formulation
- DDI e.g diuretics affect Li excretion
- genetic variation e.g. CYP450
- renal impairment (less excretion of gentamicin), liver impairment (less metab of phenytoin)
- environment e.g. smoking induces CYP1A2 (theophylline clearance) - Narrow therapeutic range (minimum effective conc - minimum toxic conc)
- therapeutic index = TD50/ED50 (larger = safer drug)
- but within range doesn’t mean safe!!
- -> elderly sensitivity (e.g. digoxin), comorbidities (e.g. hypoK enhances digoxin effects), protein binding, drug metabolites - Overdose symptoms similar to disease being treated
- digoxin toxicity and CHF both cause nausea, anorexia, arrhythmias
- gentamicin and gram -ve septicaemia both cause renal damage
Timing of TDM
Initiation or change of medication
Suboptimal clinical response despite apparently adequate dosage
Suboptimal control (deterioration) in previously stable patients
Multi-drug regimens with known DDI
Blood sampling
Time:
- usually at trough
- varies based on drugs – may be pre-dose or post-dose sampling
- important to have info about sampling time and time of last dose when interpreting
Steady state = 5 half lives
Routine TDM in hospitals
CNS drugs
- phenytoin, valproate, carbamazepine, phenobarbital
Antiobiotics
- amikacin, gentamicin, vancomycin
Lithium, digoxin, theophylline, methotrexate, cyclosporin A
Gentamicin: toxicity effects, indication for TDM, method of TDM
Aminoglycoside antibiotic
**Nephrotoxicity and Ototoxicity
Elimination by renal excretion of unchanged drug
- very short t1/2 (2-3hrs) if normal renal fx
Indication: prolonged t1/2 (up t1/2 100hrs) in renal impairment
TDM:
- conventional multiple daily dosing –> measure peak and trough levels after 3rd or 4th dose
- once daily/extended interval therapy (effective and limit risk and simplify dosing/monitoring) –> measure 6-14 hrs after 1st dose – use HARTFORD NORMOGRAM to determine subsequent dosing interval
Not indicated in normal RFT, no concurrent nephrotoxic drugs/contrast media use, <60, <5-7 days planned therapy
Phenytoin: side effects, indication for TDM, factors affecting concentration
Anticonvulsant
Indication: Narrow therapeutic range – non-linear dose-concentration relationships (small changes in dose/PK can lead to disproportionate rise in concentrations)
Side effects: drowsiness, ataxia, nystagmus
Variable hepatic metabolism by CYP enzymes
DDI:
- inhibit CYP e.g. amiodarone, cimetidine –> toxicity
- induce CYP e.g. carbamazepine, rifampicin –> risk of breakthrough seizures
Protein binding >90% (unbound fraction = therapeutic effect)
- displace phenytoin from albumin e.g. valproic acid, carbamazepine, phenobarbital –> transient increase in therapeutic effect
- altered protein binding in hypoalbuminaemia, uraemia, pregnancy
Cyclosporine: toxicity, indication for TDM, method of TDM
Calcineurin inhibitors (prevention of graft rejection)
Narrow therapeutic range; variable PK
Toxicity = nephrotoxic, hepatotoxic (mimics rejection) – interact with other nephrotoxic drugs leading to additive effects
TDM:
- WHOLE BLOOD (not serum)
- measure C2 (2hr post-dose) –> best correlation with AUC which gives better prediction of risk
- needs very accurate timing since measuring beyond 2hrs can yield very different results
Therapeutic range varies with organ transplanted and time elapsed since transplantation
Digoxin: indication for toxicity, method of TDM, factors affecting concentration, management of toxicity
For management of cardiac failure and AF
- inhibits membrane bound Na-K ATPase
Indication: Overlapping features of clinical disease and overdose e.g. nausea, vomiting, anorexia, cardiac arrhythmias, green/yellow vision
Indication: Narrow therapeutic range
- arrhythmia 1.2-2.6 nmol/L
- heart failre 0.6-1.3 nmol/L
TDM:
- t1/2 = 40hrs so steady state = 8 days
- sample at least 6 hrs post-dose (after completion of distribution to cardiac tissue - too early = high conc before distribution; too late = low conc due to metabolism)
Factors affecting digoxin conc
- formulation (change absorption; solution form enhances bioavailability)
- renal failure
- DDI e.g amiodarone reducing elimination (need to reduce digoxin dose by 50%), antibiotics affecting digoxin metabolism by gut flora in some people
- hypoK increase sensitivity by 50%, hyperCa and hypoMg also
- hypothyroid increase sensitivity
- elderly most sensitive
- analytical interference by digoxin-like immunoreactive substances in elderly
Management of toxicity:
- check K, Ca, Mg and TFT
- stop digoxin and treat any arrhythmia
- recheck and correct low K+ levels
- Digibind when appropriate (note gives falsely low results in Ab assay for Digoxin)
Lithium - TDM method, types of toxicity, factors affecting concentration, management
Narrow therapeutic range (0.4-1 mmol/L)
TDM: sample 12 hr post dose
Toxicity = acute (overdose): causes GI irritation; chronic (decreased excretion): neurological
Factors affecting Lithium
- change in dosage
- impaired RFT
- DDI e.g. thiazide reduce renal clearance (increase reabsorption?), NSAID reduces clearance (by reducing renal blood flow) and increase renal reabsorption of Na and hence Li, ACEi
Management
- haemodialysis (considered regardless of symptoms)
- ongoing hydration to prevent renal impairment
- monitor urine output and correct Na deficits
Toxicology: indication of drug testing
Cause of overdose/poisoning is known in most cases
- often need drug monitoring for other reasons
- -> decide discontinuation of treatment or expensive monitoring when below toxic range
- -> treatment decisions
Most frequently overdosed drugs
Ethanol/ Methanol Paracetamol Salicylates CO Heavy metals Opioids, Benzodiazepines, Antidepressants
Paracetamol (acetaminophen): normal metabolism, pathogenesis of overdose, clinical features
Common analgesic
Usual metabolism: conjugation with sulphate/glucuronide for excretion
- 10% via CYP2E1 hepatic oxidation –> produce toxic NAPQI which is detoxified by glutathione transferase (GSH)
Overdose = saturated conjugation pathways and GSH pathways –> increased NAPQI binds to proteins and cause hepatic and renal damage
Single ingestion of >150 mg/kg = toxic
- lower threshold for malnourished, chronic alcoholic, on CYP450 inducers
Clinical features of toxicity
PARACETAMOL INDUCED HEPATOTOXICITY = PEAK CONCENTRATION OF >1000 IU/L
- first 24 hrs –> GI upset, minimal symptoms
- 24-72 hrs –> ALT and AST elevation, RUQ pain; bili/PT elevated if severe
-72-96 hrs –> vomiting and sx of hepatic failure (if severe)
- >5 days -> resolution of hepatotoxicity or multiple organ failure/death
Paracetamol toxicity treatment and monitoring
Treatment:
- PROMPT N-acetylcysteine antidote (efficacy decreases if after 24 hrs ingestion) –> give to all patients with significant risk of toxicity (cysteine for glutathione synthesis; directly form adduct with NAPQI)
- full course of treatment is minimum 20 hrs (repeat ALT testing at the end of treatment - continue until parameters improve)
Rumack-Matthew Normogram
- for SINGLE INGESTION of paracetamol
- 150 treatment line (determine whether Tx needed based on concentration of drug and hrs post-ingestion)
- obtain 4 or more hrs after ingestion
- draw 2nd level 4hrs after 1st level for those that ingest extended release preparations (check for additional rise)
Salicylate Poisoning: toxicity levels, symptoms, lab results
Aspirin, wintergreen (metabolised to give salicylates)
Toxicity when >1.8 mmol/L
>7.2 mmol/L can be fatal
Symptoms: tinnitus, hyperventilation, respiratory failure, convulsions, coma
Lab results: mixed metabolic acidosis and respiratory alkalosis
Alkalinisation of urine enhances elimination
Comprehensive Drug Screening: purpose, sample used, precautions
Mass spectrometry –> broad spectrum screening to determine unknown drugs
- drugs of abuse e.g. cocaine, ketamine
Not required in a majority of cases to guide immediate therapy
- clinical management
- workplace screening
- forensic purpose
- medico-legal reasons
Sample: urine
- main elimination route for a majority of drugs
- can measure accumulated levels over a few hrs
- blood levels may not be high enough to detect due to distribution
Need precautions in collection and analysis to prevent adulteration
