A brief review of managing anti seizure medications in patients with other comorbidities and comedications.

1. Managing Epilepsy in
Patients with Comorbidities
Dr Pramod Krishnan
Consultant Neurologist and HOD,
Department of Neurology,
Manipal Hospital, Bengaluru.

2. Introduction
• Studies have reported a higher prevalence of stroke, diabetes, heart disease,
high blood pressure, asthma, chronic bronchitis, stomach/intestinal ulcers,
arthritis, thyroid conditions, migraine, Alzheimer’s disease and cancer in
persons with a history of epilepsy.
• Epilepsy was also associated with an increased prevalence of psychiatric
disorders, especially anxiety and depression.
• Comorbidities can be a direct cause of epilepsy, as with stroke, be in complex
relationship with epilepsy, as with psychiatric disorders, or be associated with
no apparent relationship as, for example, with heart disease

4. GABAergic:
Prolongs Cl- channel opening: Phenobarbitone
Opens Cl- channel more often: Clobazam
Inhibits GABA transaminase: Vigabatrin
Blocks synaptic GABA reuptake: Tiagabine
Ca channel blockers:
High voltage activated channel:
Gabapentin, Pregabalin
Low voltage activated channel:
Ethosuximide
Zonisamide:
Blocks Na channels.
Blocks T type Ca channel.
Potentiates GABA
Fast inactivation of VGSC:
PHT, OXC, CBZ.
Slow inactivation of VGSC:
LCS, Eslicarbazepine.
Others: LTG, VPA, TPM,
FBM, ZSN, Rufinamide.

5. Patient oriented
choice of AED
Disease oriented
choice of AED
Patient factors
Drug
Epilepsy
Physiological variables: age,
gender, weight
Comorbidities
Concomitant drugs
Psychosocial variables
Seizure type: focal, generalised
Epilepsy Syndrome: LGS, JME
EEG and other clinical
features.
Pharmacokinetics
Pharmacodynamics
EBM: RCTs, meta-analysis,
guidelines.
Expert opinion
Pharmacogenomics.
Clinical experience

10. Adverse effects of First Generation AEDs

11. Adverse effects of Second Generation AEDs

12. Adverse effects of Third Generation AEDs

13. ASDs in Cardiac Disease

14. Acute therapy with ASDs
• Acute therapy with PHT can cause arrhythmias and hypotension.
• Risk is higher in cardiac patients and with rapid infusion.
• ECG and BP monitoring is recommended.
• The use of intravenous PHT or fosphenytoin is contraindicated in patients
with severe heart disease and second or third degree atrioventricular block.
• LEV and VPA are preferred as they can be infused rapidly without any adverse
cardiac effects.

15. Chronic therapy with ASDs
• CBZ, OXC and PHT should be used with caution in patients with heart
disease, and they should be avoided in the event of atrioventricular
conduction dysfunction.
• PGB should be used with care in cases of heart failure due to left ventricular
systolic dysfunction.
• In general, enzyme inducing AEDs should be avoided because of their many
interactions with drugs that are commonly used in heart disease.

16. Cardiac patients
Avoid phenytoin
Arrhythmia, Hypotension, Conduction block.
Ticlopidine, Amiodarone, OAC increases PHT levels
PHT reduced Digoxin, Frusemide, Losartan levels
Caution with
Valproate
Affects platelet function
Salicylates increase free fraction of VPA
VPA increases Nimodipine levels by 50%
Avoid
Carbamazepine
Ticlopidine, Diltiazem, Verapamil increase level of CBZ
Hyponatremia when used with diuretics
Avoid Enzyme
inducing agents
Reduce level of statins, CCBs, beta-blockers, OACs
LEV, LTG, TPM, ZSN, GBP.

18. Lung disease
Avoid BZDs, PB Can cause respiratory depression. Needs monitoring.
Caution with
Phenytoin
Can aggravate respiratory depression, esp as IV
infusion.
BZDs in children Can increase bronchial secretions.
Avoid Enzyme
inducing agents
Reduce level of theophylline and vice versa.
LEV, VPA, LTG, TPM, ZSN, GBP.

19. SmPC= summary of product characteristics

20. ASDs in Liver disease
• In chronic treatment, the most suitable AEDs are those with a low level of
protein binding and limited hepatic metabolism: GBP, LEV, OXC, PGB and
TPM.
• However, in the event of severe liver disease, it may also be necessary to
adjust the dose of these AEDs because of concomitant renal dysfunction.
• For this reason, in the presence of severe liver disease it is advisable to reduce
the normal dose of LEV by 50% and the normal dose of TPM by 30%.
• OXC has low protein binding and a lower potential for enzyme induction
compared to CBZ.

21. Liver disease
Avoid PB, also BZD
As acute therapy as they can aggravate hepatic
encephalopathy
VPA is
contraindicated
Causes hepatotoxicity
Caution with PHT Increase in free fraction due to hypoalbuminemia
Avoid LTG
LEV is preferred for acute therapy.
LEV, GBP, OXC, TPM, PGB for chronic therapy.
CBZ, Ethosuximide, PB, BZD, PHT, TGB, ZNS can be
used cautiously as chronic therapy.

22. Renal disease
Avoid TPM, ZNS In patients with history or risk of nephrolithiasis.
Avoid LEV, reduce
dose
As acute management, in view of mainly renal
elimination.
GBP, OXC, LEV,
LTG, PB, PGB,
TPM, ZNS
As chronic therapy, use cautiously, with dose
adjustment.
After dialysis Dose supplementation is usually required.
BZD, VPA, CBZ, PHT, TGB.

24. Disorder Most preferred Less preferred/ Avoid
Liver transplant LEV, TPM, GBP, PGB. Enzyme inducing ASDs. Avoid LTG, VPA.
Renal transplant BZD, LTG, VPA ASDs with renal excretion. Enzyme inducing
ASDs.
Porphyria LEV, PGB, GBP. Also OXC. Caution with BZD. Avoid CBZ, LTG, PB, PHT,
PRM, TGB, TPM, VPA, ZNS.
BMT LEV, LTG, TPM, GBP Avoid CBZ, OXC, PB, PRM.
VPA should be avoided during the engraftment
phase (2-6 weeks).
Hypothyroidism LEV, LTG, ZNS, PGB, BZD, GBP Enzyme inducing ASDs. Use OXC, VPA and
TPM with caution.
• VPA only causes a minimal reduction of cyclosporine and tacrolimus levels.
• Cyclosporine binds largely to plasma proteins, and this can significantly increase the free fraction of
ASDs that have a high percentage of protein binding.
• Azathioprine, mycophenolate and muromonab-CD3 (OKT3) are not significantly affected by ASDs.

26. ASDs and bone health.
• In patients >65 years of age, those taking AEDs are 75% more likely to
experience a fall than those not taking AEDs.
• Patients with epilepsy have double the fracture risk compared to controls.
• Risk of falls and fractures is more with polytherapy.
• Enzyme-inducing AEDs and PHT in particular accelerate vitamin D
catabolism and increase bone turnover.
• Potent inducers of cytochrome P450 have worst effect on BMD: PHT, PB,
CBZ.
• Even 1 year of PHT monotherapy reduced BMD significantly.
• VPA has mild negative effects on bone health.

27. ASDs and Bone health
• WWE have 2-6 times higher risk of fractures.
• Risk with LEV and LTG is much lower.
• Regular exercise and cessation of smoking should be followed.
• Monitor Bone mineral density every 2 years in all postmenopausal WWE.
• Calcium (1,000 mg) and Vitamin D (800 U) supplements should be given to all
postmenopausal WWE and those on enzyme-inducing ASDs for > 3 years.

28. Disorder Most preferred Less preferred/ Avoid
Obesity TPM, ZNS. Avoid VPA, CLB, CBZ, GBP, PGB, PER.
HIV LEV, PGB, TPM, GBP. BZD, LTG, OXC, VPA, ZNS. Avoid CBZ, PB, PHT, PRM.
Stroke LEV, LTG, OXC, GBP, TPM. Enzyme inducing ASDs and VPA, as they interfere with
salicylates, OACs. They may also delay recovery.
Migraine TPM, VPA, ZSN, PGB, GBP,
LTG
-
Skin rash LEV, GBP, PGB, TPM, VPA,
PER, LCM
LTG, OXC, CBZ, PHT, PB
Neuropathic
pain
PGB, GBP, CBZ, OXC, PHT -

29. ASDs and Infections.
Enzyme-inducing AEDs reduce the concentration of praziquantel and albendazole by over 50%.
Isoniazid inhibits the metabolism of CBZ, PHT and VPA, and can cause toxicity.
Conversely, Rifampicin reduces the plasma concentration of CBZ, LTG, PB, PHT and VPA.

30. Condition Choose Avoid
Cognitive dysfunction LTG, LEV, OXC, GBP, VPA BZD, CBZ, PB, PRM, PHT, TPM
Restless legs syndrome GBP, PGB, CZP. -
Glaucoma - TPM
Hyponatremia - OXC, ESL, CBZ
Gait disturbances - CBZ, PHT, PER, PB, PRM, LTG, OXC
Tremor TPM, PER VPA
Parkinson disease ZSN VPA
Cancer VPA, LEV, PER Enzyme inducing ASDs.
Heat stroke - TPM, ZSN
Atherosclerosis - Enzyme inducing ASDs.
Choice of AEDs related to comorbidities
Lee BI, et al. Clinical opinion: Earlier employment of polytherapy in sequential pharmacotherapy of epilepsy.
Epilepsy Res 2019;156:106165

31. Polycystic Ovarian Syndrome (PCOS)
2 out of 3 of the following: Other features:
Polycystic ovaries on imaging Elevated LH/ FSH ratio
Oligo/ anovulation Insulin resistance
Clinical or biochemical evidence
of Hyperandrogenism
Obesity
Prevalence of PCOS in WWE is higher (10-20%) than in women
without epilepsy (5-6%), even in those not on AEDs.
PCOS is seen in 20-50% of women taking VPA, especially those
starting valproate before the age of 20. Also seen with CBZ.

32. Only 50% of WWE with epilepsy plan their pregnancy and approximately 25%
of the unplanned pregnancies are due to contraceptive failure.
ASDs that cause
contraceptive failure
ASDs that cause
contraceptive failure at
higher doses
ASDs whose levels
fall with hormonal
contraceptives
Phenytoin Topiramate (>200 mg/d) Lamotrigine: LTG
dose may have to be
increased by 30%.
Blood level
monitoring may be
required.
Phenobarbitone, Primidone Perampanel
Carbamazepine,
Oxcarbazepine,
Eslicarbazepine
Felbamate
Clobazam Cenobamate
Rufinamide
ASDs and Contraception

33. Contraception Comment
Non- hormonal methods All AEDs
IUCD All AEDs
Combined OCPs Non enzyme inducing AEDs
Combined OCPs Enzyme inducing AEDs cause rapid estrogen
metabolism and risk of contraceptive failure. Use
higher strength of ethinyl oestradiol (50-100 ug/day).
Use additional barrier methods.
Emergency contraception Higher dose is needed in case of enzyme inducing
AEDs.
Medroxyprogesterone injections Effective, but use more frequently (every 10 weeks,
instead of 12)
Progesterone only pill Contraindicated due to high failure rate.
Midcycle bleeding indicates risk of contraceptive failure.
Avoid systemic hormonal contraceptive agents in WWE. Use barrier methods or IUCD

34. ASDs in Brain Tumor
• Avoid enzyme inducing ASDs if patient requires chemotherapy or
corticosteroids.
• Cutaneous reactions are more common in these patients, especially with CBZ,
PHT and PB.
• LEV, VPA, OXC and LTG are good options.
• GBP, PGB and ZNS as add-ons.

35. ASDs in Psychiatry

36. ASDs in Psychiatry
• Enzyme-inducing ASDs can lower the plasma levels of other psychotropic
drugs (neuroleptics, TCA, SSRIs).
• The interaction between VPA and amitriptyline or nortriptyline can cause an
increase of up to 60% in the plasma levels of these drugs.
• There are no significant interactions between ASDs and lithium.
• TCAs can inhibit ASD metabolism, causing toxicity symptoms. The same
occurs with some SSRIs such as fluoxetine, paroxetine and fluvoxamine.
• Other antidepressants such as citalopram, escitalopram, sertraline, trazodone
and venlafaxine do not have a significant effect on ASD metabolism.

37. ASDs in Psychiatry
• Most antipsychotic drugs interfere with the hepatic metabolism of ASDs to a
variable degree. Clozapine should be avoided in patients with epilepsy, while
olanzapine, quetiapine and risperidone can be used with ASDs.
• As a general rule the epileptogenic risk is low for TCAs, SSRIs and
antipsychotics alike.
• There are, however, exceptions, and certain antidepressants such as
amoxapine, maprotiline and bupropion and certain neuroleptics such as
clozapine and chlorpromazine have a higher epileptogenic risk.

38. ASDs in Psychiatry
Antiepileptic treatment Psychiatric treatment
Recommended To be avoided Recommended To be avoided
Depression CBZ, GBP, LTG, OXC,
PGB, VPA
PB, PHT, PRM, TGB,
TPM
Citalopram,
Escitalopram,
Sertraline,
Trazodone,
Venlafaxine
Amoxapine,
Maprotiline,
Buproprion
Anxiety BZD, GBP, PGB, VPA LEV BZD, SSRIs -
Psychosis LTG, OXC, VPA ESM, LEV, TPM, PER Olanzepine,
Quetiapine,
Risperidone
Chlorpromazine,
Clozapine

39. Psychiatric and behavioural side effects – New vs Old AEDs
4085 patients with epilepsy:
Psychiatric and behavioural side effects occur more frequent in
patients taking LEV and ZNS than other AEDs. Lowest rates were
seen in patients taking CBZ, CLB, GBP, LTG, OXC, PTH and VPA
Chen B et al Ep Behav 2017; 76: 24-31
LEV
VPA
22%
3.5%

40. • Indian Data from AIIMS – May 2019
• A total of 12 AEDs were prescribed to 933 patients in different treatment
regimens over a period of 3 years.
• The median age of the patients was 22 years (10–77) and among them 63.5%
were men.
• Multivariate regression analysis suggested correlation between depression and
seizure frequency, total number of AEDs and their load.
• Depressive symptoms were found to be present in more than half of the
patients with epilepsy which require detailed work-up for depression.
• Levetiracetam was found to be associated with a higher incidence of
subclinical depression.

41. Psychiatric uses of anti seizure drugs
ASD Psychiatry indication
Carbamazepine Agitation, bipolar disorder, impulsivity
Clonazepam Anxiety
Diazepam Alcohol withdrawal, anxiety
Gabapentin Anxiety
Lamotrigine Bipolar disorder, refractory depression
Lorazepam Agitation, alcohol withdrawal, anxiety
Oxcarbazepine Aggression, bipolar disorder, impulsivity
Pregabalin Anxiety
Topiramate Alcohol withdrawal, binge eating
Valproic acid Monotherapy for acute mania in bipolar disorder and maintenance
therapy for Bipolar disease.
Combination therapy for acute bipolar depression.

42. ASDs in Elderly Epilepsy
Patients

43. Challenges in
therapy
Cognitive and
behavioural
issues
Hypo-
albuminemia
Bone health
Poor gastric
absorption
Reduced
renal
clearance
Reduced liver
mass and
blood flow
Presence of
Comorbid
illness
Co-
medications

44. Treatment of
Seizures/ Epilepsy
Acute
symptomatic
seizures
Unprovoked single
seizures
1. >1 Unprovoked seizure
2. Single Unprovoked
seizure with:
IEDs on EEG and /or
Epileptogenic lesion on
MRI
• Correct
underlying
cause.
• Short duration
of AEDs may be
required.
Normal EEG,
MRI
Start AED
AED therapy is
preferable
Status epilepticus
Yes
No
Levetiracetam
Sodium Valproate
Levetiracetam
Lamotrigine
Gabapentin
Sodium Valproate
Eslicarbazepine
Oxcarbazepine

45. Peri-procedural advice
• All AEDs to be continued peri-procedurally.
• Change to IV formulation if oral intake is restricted or in case of colonoscopy
etc.
• Avoid medications that reduce seizure threshold: antipsychotics
(chlorpromazine, clozapine), diphenhydramine, atropine, quinolones,
buproprion, imipenem, meperidine, or tramadol.
• Manage peri-procedural electrolyte disturbances, sleep issues.
• Dose adjustments may be necessary.

46. Valproate and thrombocytopenia
• Thrombocytopenia can occur in 5–18% of patients taking VPA.
• Risk factors: advanced age, female gender, and doses >1000 mg/d, lower
baseline platelet count, comedications with drugs that inhibit platelets.
• Adjustment of doses seems to partially reverse VPA-associated
thrombocytopenia.
• VPA-associated thrombocytopenia is usually not associated with an increased
risk of significant bleeds.
• Mechanism: unknown; it can be caused by an increased disruption of
platelets as well as by the formation of autoantibodies destroying platelets or
by decreased production due to a direct toxic effect on bone marrow.

47. Conclusion
• Comorbidities in epilepsy patients are common.
• Careful selection of ASDs that complements or atleast, does not interfere with
therapy for the comorbidity can enhance compliance and quality of life.
• Availability of numerous ASDs, especially newer ASDs gives us the option to
tailor ASDs to the patients comorbidity and its treatment.
• Enzyme inducing ASDs should be used with caution when the patient is on
other comedications.
• In general, newer ASDs are safer in hepatic disease and older ASDs in renal
diseases.

48. THANK YOU