Toxicology and TDM

Question 1

When is TDM most useful?

Answer 1

1. Chronic medication
2. Narrow therapeutic index
3. Significant risk from toxicity or under-dosing
4. Variable pharmacokinetics
5. Adherence monitoring

Question 2

Pre-analytical factors affecting TDM results

Answer 2

1. Dosage uniformity - may vary pill to pill
2. Timing - need to decide if trough, peak, post-distributive phase, and generally presumed in steady state
3. Sample type - serum separator gel may adsorb some drug from plasma eg PHT
4. Within individual BV eg albumin

Question 3

Analytical factors affecting TDM results

Answer 3

1. Availability of standardised reference materials
2. 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
3. Method precision relative to target concentration range
4. Interfering substances in sample

Question 4

Total vs free phenytoin levels - utility/indications?

Answer 4

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.

Question 5

%age of carbamazepine that is protein bound

Answer 5

80%

Question 6

%age of phenytoin that is protein bound

Answer 6

90-95%

Question 7

Principal site of elimination of carbamazepine

Answer 7

Liver

Question 8

Active metabolite of carbamazepine and clinical importance?

Answer 8

Carbamazepine-10,11- epoxide. In kids, this can accumulate and cause toxicity, even when carbamazepine levels are within therapeutic range.

Question 9

Drug interactions with CBZ

Answer 9

1. Inducers increase metabolism - phenytoin
2. Competitive inhibitors of metabolism increase CBZ levels - erythyromycin

Question 10

Trough levels are usually monitored for therapeutic CBZ levels. When are peak levels indicated and when should they be taken?

Answer 10

When toxicity is suspected. Sample 4-8 hours after ingestion. Toxic levels are usually >15 ug/mL.

Question 11

Toxic phenytoin level

Answer 11

> 20 ug/mL
35 - ppt seziures

Question 12

Principal metabolite of valproic acid

Answer 12

2-n-propyl-3-ketopentanoic acid. Active.

Question 13

%age valproate protein bound

Answer 13

93%

Question 14

Toxic levels of valproate?

Answer 14

> 100 ug/mL - hepatic and encephalopathic

Question 15

Valproate has a ______ half-life and is cleared ___________

Answer 15

Valproate has a SHORT half-life and is cleared RAPIDLY.

Question 16

How does valproate interfere with phenobarbital?

Answer 16

Inhibits non-renal clearance.

Question 17

How does valproate interfere with phenytoin?

Answer 17

Competes for protein binding, reducing total phenytoin concentration while free drug levels remain the same.

Question 18

Your lab’s valproate/phenytoin/CBZ method

Answer 18

PETINIA - particle-enhanced turbidimetric inhibition immunoassay

Question 19

Your lab’s digoxin method

Answer 19

Competitive immunoassay with chemiluminescent detection (digoxin competes with digitoxin bound to paramagnetic particles for binding to acridinium ester labelled mouse antibody).

Question 20

Is gentamycin toxicity reversible?

Answer 20

Only if dose is reduced and toxicity does not persist beyond two weeks.

Question 21

Main toxicit(ies) from gentamycin?

Answer 21

1. Vestibular and cochlear sensory nerve cell degeneration
2. Renal tubular necrosis

Question 22

Main concentration related drug toxicity from vancomycin?

Answer 22

Auditory nerve damage

Question 23

How is gentamycin monitored?

Answer 23

Both trough and peak concentrations

Question 24

How is vancomycin monitored?

Answer 24

Trough concentrations.

Question 25

Pre-analytical factor with gentamicin levels?

Answer 25

Heparin containing tubes - heparin complexes with gentamicin which can interfere with immunoassays.

Question 26

Thiopurine drugs

Answer 26

6-mercaptopurine Azathioprine 6-Thioguanine

Question 27

Causes of increased sensitivity to digoxin?

Answer 27

Hypokalaemia Hypomagnesaemia Hypercalcaemia Failure of digoxin concentration to correlate with toxicity may be due to concurrent disturbances in these electrolytes.

Question 28

Timing of digoxin measurement?

Answer 28

Peak tissue concentration - 8 hours or more after the dose

Question 29

Interpretation of a high digoxin level taken prior to 8 hours post dose?

Answer 29

Could simply be due to incomplete distribution to tissues

Question 30

Safe therapeutic plasma concentration of digoxin?

Answer 30

0.8-2 ng/mL

Question 31

What is the safe digoxin level in heart failure?

Answer 31

0.5-0.8 ng/mL, up to 1.2 ng/mL no increase in mortality.

Question 32

Does digibind interfere with digoxin measurement?

Answer 32

YES

Question 33

Normal paracetamol metabolism?

Answer 33

In liver, to glucuronides (60%), sulfates (30%) and by CYP450 enzymes to NAPQI (10%)

Question 34

What is NAPQI?

Answer 34

N-acetyl-benzoquinone imine. A highly reactive and toxic (usually minor) metabolite of paracetamol.

Question 35

Usual pathway for metabolism of NAPQI?

Answer 35

Glutathione conjugation with subsequent transformation back to cysteine and mercapturic conjugates of paracetamol

Question 36

What happens in paracetamol overdose?

Answer 36

Sulfation pathway overwhelmed and is channelled into CYP450 pathway. Increased NAPQI formation eventually depletes glutathione. NAPQI is then free to cause hepatonecrosis.

Question 37

Timing of hepatic damage post paracetamol overdose?

Answer 37

Hepatic necrosis begins 24-36 hrs after ingestion and peaks at 72-96 hrs after ingestion.

Question 38

Apart from hepatic necrosis, what other clinical features of paracetamol OD might there be?

Answer 38

Non-specific nausea, vomiting, abdo pain. Metabolic acidosis Coma

Question 39

Specific therapy for paracetamol overdose and how does it work?

Answer 39

N-acetylcysteine. A substitute for glutathione as well as possibly replenishing hepatic glutathione and enhancing sulfate conjugation.

Question 40

Timing of NAC therapy - when is it most effective?

Answer 40

Within 8 hours of ingestion (ie ideally prior to onset of liver damage)

Question 41

What is the Rumack-Matthew nomogram?

Answer 41

Relates timing and dose of paracetamol ingestion to the probability of hepatic necrosis.

Question 42

Caveats when using Rumack-Matthew nomogram?

Answer 42

1. Do not use blood levels taken prior to 4 hours after ingestion (ensure the entire dose is absorbed before using nomogram). 2. Assumes single acute rather than chronic ingestion - toxicity occurs at lower drug levels with chronic ingestion. 3. Not useful if time of ingestion unknown/unreliable - just treat! 4. 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 5. In underweight, alcholics, pts on CYP450 inducers - increased susceptibility to paracetamol toxicity. Some practitioners lower the line on the nomogram by 50-70%.

Question 43

Indications for NAC in chronic supratherapeutic ingestion?

Answer 43

Increased transaminases and paracetamol level > 10ug/mL.

Question 44

Paracetamol methods

Answer 44

1. Immunoassay with spectrophotometry 2. Enzymatic (arylacylamide amidohydrolase) 3. Chromatographic methods (reference procedure) 4. POC lateral flow immunoassay (but limited PPV)

Question 45

Limitations of paracetamol immunoassay and spectrophotometry

Answer 45

Interference by bilirubin/bilirubin metabolites Some methods detect non-toxic and toxic metabolites - need to choose a method that measures only parent drug

Question 46

Limitations of enzymatic paracetamol assay

Answer 46

Interference by NAC, bilirubin, IgM paraproteins