Post on 16-Mar-2022
THERAPEUTIC DRUG MONITORING FORANTIEPILEPTIC DRUGS & LITHIUM
SAMARINA MUSAAD
samarina.musaad@Labtests.co.nzsamarinam@adhb.govt.nz
Overview…
Introduction: Old versus newA few groups of AEDs
Why TDM?Common themes & examplesPitfalls in AED TDMOCPs & pregnancyAssaysThe role of the pathology laboratory in monitoring AEDsScenariosSummary & “golden rules”Lithium
Resources: Lexi-interact (uptodate), ILAE guidelines (provided), BPAC statementwww.bpac.org.nz “Prescribing issues associated with anticonvulsant medication forepilepsy”.
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Introduction
New versus old
Newer AEDs (e.g. vigabatrin, lamotrigine, topiramate) have wider therapeutic indices,fewer side effects, and simpler kinetics compared to older drugs(e.g. phenytoin, carbamazepine, valproate)
Group & example Mechanism of action Comment
Barbiturates-phenobarbital CNS suppressant Its sedative effect limits its use
Benzodiazepines*-clonazepam CNS suppressant Long term use is discouragedbecause they cause tolerance anddependency
Carboxamides-carbamazepine,oxcarbazine
Inactivates Na channels Carbamazepine’s activemetabolite (epoxide) is equallypotent and is responsible for 10-40% activityOxcarbazine is better toleratedthan carbamazepine
Fatty acids-Na valproate,vigabatrin
Multiple mechanisms (selectivelyinactivates Na channels, ↑brain GABA,against Ca currents)
Assays for vigabatrin are notreadily available
Hydantoins-phenytoin,fosphenytoin
Inactivates Na channels TDM is most usefulFosphenytoin is an injectableprodrug for phenytoin
Triazines-lamotrigine Not fully understood# Newer drug
Introduction A few groups…
• *Diazepam is used for status epiplepticus, rarely paraldehyde• # probably selectively inactivates Na channels
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ILAE guidelines Patsolas et al2008
Why TDM?
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Why TDM?
Common reasons to check blood levels
I. Assessing complianceII. There is a change in pharmacokinetics e.g. pregnancy, adding another
drug, uraemia, changing a drug formulationIII. Clinical suspicion of toxicityIV. Need to re-adjust the dose
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Louis 2009
Why TDM?
& establish an individual’stherapeutic baseline
or an unexpected changein response
or dose increases
Common themes to remember:
Peak levels for assessing toxicity & trough levels for assessing compliance
Start monitoring after steady state is expected to have been achieved
Most are metabolised by the liver (with some exceptions e.g. exceptions vigabatrin)
Doses need adjustment in hepatic impairment and severe renal impairment (the latter decreasesprotein binding)
T1/2 changes with concomitant use of a CYP inducer or inhibitor
Consider organ specific function tests/monitoring based on potential side effects
Many are highly protein bound in plasma so drugs often compete for protein binding e.g.valproate displaces phenytoin increasing its free fraction
High loading doses can cause paradoxical intoxication in which seizures worsen
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Drug Absorption/elimination and
metabolism
Side effects Symptoms oftoxicity
Specialconsiderations
Carbamazepine(Tegretol)
Slow & erratic/hepatic
Gastrointestinal(vomiting, diarrhoea),skin (rash),
neurological,neutropenia, &hyponatraemia
Visual (blurred vision,
diplopia, nystagmus) &neurological(drowsiness, ataxia)
-Potent CYP inducer-Active metabolite canaccumulate causingtoxicity even in thepresence of“therapeutic” levels ofthe parent drug-Monitor every 2 monthsuntil levels are stable-Decreases FT4 levels(unknown clinicalsignificance)- Causes SIADH #
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Examples…
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Patsalos et al 2008
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Drug Absorption/elimination
andmetabolism
Side effects Symptoms oftoxicity
Specialconsideration
s
Phenytoin(dilantin)Fosphenytoin is aninjectable solubleprodrug
Slow andoftenincomplete/Hepaticglucuronidation; 25%unchanged inurine
Cosmetic(gingivalhyperplasia,hirsutism), folatedeficiency#, &low BMD*
Visual (double
vision) &neurological(confusion, ataxia)
-Potent inducer-Clearancefollows 1st orderkinetics before itreverts to 0order kinetics-Fosphenytoin(cerebyx) to betested at least 2hrs after IV and4 hrs after IMadministration
• *Reduction in bone mineral density is partly due to induction of CYP 450 causing ↑ Vit D catabolism• #By inhibiting intestinal absorption
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Silverman et al 1988
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Drug Absorption/elimination
andmetabolism
Side effects Symptoms oftoxicity
Specialconsiderations
Na Valproate(epilim, valproicacid)
Rapid andnear completeabsorption/hepatic
Gastrointestinal(nausea, vomiting,diarrhoea),neurological(headache,dizziness), rash, &depression
Hepatictoxicity ´ toxicencephalopathy
-Broadspectruminhibitor ofCYP and UGT-glucuronidation-Can bemeasured atleast 8 hrs postdose to trough
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Drug Absorption/elimination
andmetabolism
Side effects Symptoms oftoxicity
Specialconsideration
s
Phenobarbital Slow butcomplete/hepatic; 25%excretedrenallyunchanged
Sedation,tolerance
Confusion,delirium,somnolence
-Potentinducer
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Drug Absorption/elimination
andmetabolism
Side effects Symptoms oftoxicity
Specialconsideration
s
clonazepam Wellabsorbed/Hepatic andrenallyexcreted
CNSsuppression,paradoxicaleffects(anxiety,sweating),amnesia
Coma, ataxia,somnolence
-long acting
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Drug Absorption/elimination
andmetabolism
Side effects Symptoms oftoxicity
Specialconsideration
s
Lamotrigine Quick efficientoralabsorption/hepaticglucuronidationfollowed byrenal excretion
Rash, nausea Dizziness,ataxia,blurred vision,vomiting, &statusepilepticus
-blood levelsare linear todose-welltolerated-valproatesignificantlyincreaseslevels
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Louis 2009
Common pitfalls in AED blood monitoring and dosing
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Adjustments in context of blood level and clinical picture
(removal of the temporal lobe;VNS- vagas nerve stimulation)
Oral contraception and pregnancy
What AEDs can do to OCPs: Inducers decrease the effect of oral contraception
What OCPs can do to the AEDs: Oestrogen induces glucuronidation → so with combinedOCPs, HRT & in pregnancy renal excretion of some drugs would be increasede.g. lamotrigine
Therefore…→ a better option for contraception when taking AEDs is IUDs
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What pregnancy can do to AEDs: In pregnancy there is generally reduced drug proteinbinding and increased metabolism and clearance due to changes in body weight,hormonal effects, and the contribution of the fetoplacental unit to drug distribution
Therefore …→ total levels of highly protein bound drugs drop significantly
→ clearance of lamotrigine and valproate is significantly increased
→ monitoring at least once every trimester is recommended
Assays and relevant testsDrug Assay Other organ specific tests
Carbamazepine Immunoassay FBC & LFTs at commencement,then on regular basis*
Phenytoin Immunoassay Consider measuring albuminlevels
Na valproate Immunoassay LFTs
Phenobarbitone Immunoassay LFTs & renal function
Clonazepam LCMS Consider LFTs and FBC
Lamotrigine Immunoassay
Vigabatrin HPLC Visual field testing before andsix monthly after starting
Gel tubes are not suitable for many of these drugs*It may be more practical to monitor neutropenia by symptoms
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Role of the pathology laboratory is to provide accurate, reproducible, clinicallyrelevant results, & to be available for consultation
• Right patient at the right time
• Clinical details on request forms
• Suitable collection tubes
• Proficiency testing
• TAT
• Therapeutic ranges
• Units
• Interpretive comments
• Critical phone limits
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Pre-analytical
Analytical
Post-analytical
Practical scenarios…
• The level is “critical” but there is no specified time for the last dose, what do I do?
• Na valproate is added to “the mix”
• A paediatric neurologist calls and expresses concern over the high numberof “elevated” lamotrigine levels his patients are having
• Your laboratory has a significant flyer in your EQA program. Upon closerinspection you see that the entire method group shifted!
• Certain drug levels from the community laboratory are always low!
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In summary
• “Routine” monitoring is not recommended• AEDs have numerous and complex pharmacokinetic interactions• Educate requestors on need for relevant details on the request form• Always ask the questions: what change has there been to the patient’s
clinical/physiological state? why test? is the patient well at this level?• Levels below the upper “reference range” do not exclude toxicity or
paradoxical intoxication i.e. can still be too high for the individual
• Elevated levels do not imply toxicity
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12/02/2018s musaad 30Patsalos et al 2008
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Lithium
Naturally occurring ion; oral preparation is in the form of a lithium salt (carbonate, sulphate, chloride, or citrate)
Soluble and well absorbed in the stomach
Does not bind to plasma proteins and does not undergo hepatic metabolism
Excreted unchanged by the kidneys- clearance can increase by 50% in pregnancy
Used to treat bipolar disorder
Increases the risk of hypothyroidism in bipolar disorder
Decreases renal response to ADH
Lithium induced hyperparathyroidism (LIH) with long term treatment, mechanism unclear
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Malhi et al 2012
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• Polyuria may exacerbate hypercalcaemia in long term lithium usersMalhi et al 2012
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Side effects with long term treatment
• Renal diabetes insipidus- through resistance to ADHmay be irreversible with chronic use
Treatment- stop lithium if possible, or Rx amiloride (a K sparing diuretic that inhibits Na & lithiumreabsorption)
• Lithium induced hyperparathyroidism (LIHP)- probably changes the set point for PTH secretionincidence of hypercalcaemia in patients taking lithiumcan be 7x higher than the general populationcomparable to familial hypo-calciuric hypercalcaemiaworsened in case of concomitant diabetes insipidus
Treatment- calcimimetics, surgical removal of one or multiple adenomas, bilateral parathyroidectomy
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• Hypothyroidism- inhibits iodine uptake, iodotyrosine coupling and T4 release.8-19% of patients on lithium compared to 0.5-1% ofthe general population
Treatment- thyroxine
• Weight gain – due to polyphagia, depressive episodes (bipolar disorder),hypothyroidism
Treatment – dietary and lifestyle measures
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Malhi et al 2012
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Golden rule number 11
Be nice to the clinical pharmacist!
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Theodore Roosevelt: Courage is not having thestrength to go on it is going on when you don’thave the strength
Danny Glover
Prince
Little girl next door
FACES OF EPILEPSY
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References
Silverman AK, Fairly J, Wong R et al. Cutaneous and immunologic reactions to phenytoin. J AM ACAD DERMATOL1988;18:721-41
Malhi GS, Tanious M, Das P et al. The science and practice of lithium Therapy (Review article) ANZJP 2012;46:192-211
St.Louis EK. Monitoring Antiepileptic Drugs: A Level- Headed Approach Current Neuropharmacology 2009;7:115-119