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PR3153 CNS > Pharmacology - Seizures and Epilepsy > Flashcards

Pharmacology - Seizures and Epilepsy Flashcards

1
Q

What are the S/E common to the ASMs?

A

Dizziness
Drowsiness=Somnolence
Headache
SJS/TEN
Blood dyscrasias
Hepatotoxicity (1st gen)
Osteomalacia (1st gen)
- Increased CL of vit D –> secondary hyperparathyroidism
- Increased bone turnover, reduced bone density

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2
Q

Which ASMs are assoc w NV?

A

CBZ, Valproate, Lamotrigine, Levetiracetam, Topiramate

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3
Q

What are the unique S/E for CBZ?

A

Diarrhoea, constipation, stomach upset, hyponatremia + PGx assoc SJS/TEN

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4
Q

What are the unique S/E assoc w PHT?

A

Hirsutism, gingival hyperplasia, wt loss, headache, insomnia, teratogenic

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5
Q

What are the unique S/E assoc w valprate?

A

Alopecia, ataxia, tremor, stomach upset, diarrhoea, wt gain, irregular or painful menstruation, pancreatitis, hyperammonemia, encephalopathy, suicidal ideation

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6
Q

What are the unique S/E assoc w lamotrigine?

A

Ataxia, tremor, asthenia, headache

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7
Q

What are the unique S/E assoc w levetiracetam?

A

Asthenia, ataxia, headache, irritability, aggression

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8
Q

What are the unique S/E assoc w topiramate?

A

Ataxia, cognitive dysfn (psychomotor slowing, speech, memory), wt loss, abdo pain, glaucoma, kidney stones, hyperammonemia, depression

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9
Q

What is the MOA of CBZ and PHT?

A

Inhib voltage gated Na+ channels
Decrease Na+ influx into cells
Decrease ability to generate AP
Decrease neuronal excitability

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10
Q

What is the MOA of valproate?

A
  1. Inhib voltage gated Na+ channels
    - Decrease Na+ influx into cells
    - Decrease ability to generate AP
    - Decrease neuronal excitability
  2. Inhib low voltage T-type Ca2+ channels
    - Decrease influx of Ca2+ into cells
    - Inhib exocytosis of excitatory neurotransmitters
    - Decrease neurotransmission, neuronal excitability
  3. Inhib GABA transaminase (enzyme which breaks down GABA)
    - More GABA available to bind to GABA rece
    - Opening of Cl- channels, Cl- influx
    - Hyperpolarisation of membrane potential
    - Reduced ability to generate AP –> recuced neuronal excitability
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11
Q

What is the MOA for levetiracetam?

A

Binds to SV2A protein in walls of vesicles that contain glutamate
Impair synaptic release of glutamate
Reduce neuronal excitability

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12
Q

What is the MOA of lamotrigine?

A

In addition to blockage of voltage dep Na+ and Ca2+ channels, inhib glutamate and impedes sustained repetitive neuronal firing

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13
Q

What are the indications for lamotrigine?

A

Adjunctive for partial seziures and generalised seizures
Monotherapy for typical absence seizures
Adjunctive or initial thera for Lennox-Gastaut syndrome

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14
Q

What are the indications for Levetiracetam?

A

Adjunctive thera for
- Partial onset seizures
- Myoclonic
- Primary GTC

Monothera for partial onset in NEWLY Dx epilepsy

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15
Q

What are the indications for topiramate?

A

Block voltage dep Na+ and Ca2+ channels
Block AMPA rece –> inhib excitatory neurotransm
Reduce neuronal excitability

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16
Q

What are the indications for topiramate?

A

Monotherapy for partial seizures, GTC

Adjunctive thera for Lennox-Gastaut syndrome

Migrain prophylaxis in adults

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17
Q

What is the MOA of benzodiazepines?

A

Bind to GABA rece @ regulatory site
- Potentiates Cl- influx
- Cl- influx hyperpolarises mem
- Reduce ability to gen AP
- Reduce excitability of cortex
Still req GABA (enhances inhib effect of GABA neurotransm)

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18
Q

Why are barbiturates more dangerous than benzodiazepines?

A

Linear r/s between barbiturate dosing/[ ] and CNS depression effects vs benzodiazepines hit a ceiling

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19
Q

What is the MOA of barbiturates?

A

Similar to benzodiazepines except that it binds to GABA rece at a site distinct from benzos and GABA

Still req GABA (enhances inhib effect of GABA neurotransm)

20
Q

Describe the PK of PHT.

A

A:
- F: 95%
- Absorption reduced at doses >400mg/dose (split)
- Absortion reduced by enteral feeds –> space apart by 2h

D:
- Highly albumin bound (~90%)
- Vd: 0.7L/kg (0.5-0.8)

M:
- ~100% hepatic CL

E:
- t1/2: 12-60h
- Non-linear PK - 0 order kinetics

21
Q

What are the points to note for phenytoin?

A

Highly albumin bound ~90%
- But in low albumin –> free phenytoin increases.
- May be displaced by valproic acid
- Original Winter-Tozer eqn etx used to est free PHT lvl in presence of hypoalbuminemia & renal impairment (found to not corr well)
- New studies to consider pt’s disease, dynamic parameters but still not ideal

Capacity limited CL = CL dep on [ ]
Increase [ ] –> Decreased CL. Metabolic enzymes saturated. [ ] increment NOT proportional to dose increment.

Relative narrow therapeutic range (plasma [ ] 40-100micromol), saturation kinetics & consequent non-linearr/s bet dose & plasma [ ]

22
Q

What is the difference for saturation concerns between PHT and valproate (sodium)?

A

PHT: saturation of metabolic enzymes
Valproate: saturable plasma protein binding

23
Q

Describe the PK of CBZ.

A

A:
- F: 75-85%
- Mean Tmax: 12h (tab), 24h (CR), 2h (susp)
- Food ingestion does not affect absorption

D:
- Highly protein bound: 75-80%
- Vd: 1.4L/kg (1-2Lkg)
- Crosses placental barrier
- [ ] in breastmilk is 25-60% of plasma levels

M:
- 100% hepatic, 99% by CYP3A4
- 30+ metabolites, active metabolite is CBZ10, 11-epoxide

E:
- t1/2: 6-15h
- 72% renal, 28% faeces

24
Q

What are the points to note for CBZ?

A

Autoinduction of CYP3A4 enzymes. Induces own meta. CL increases, CBZ [ ] declines and stabilises in accordance w new CL & t1/e
Accel elim of other drugs as well
Req uptitration of dose
DO NOT start at desired maintenance dose at first. Gradually increase over a few weeks. Maximal autoinduction usually occurs 2-3 weeks after dose initiation

25
Q

What are the DDI assoc w CBZ?

A

CYP3A4 inhib & substrate - Clarithromycin: increase serum [CBZ]

CYP3A4 inhib: increase serum CBZ

Warfarin: decreases warfarin meta

Can worsen anaemia

26
Q

Who are the special populations in CBZ?

A

Pregnancy: Teratogenic
- Switch to lamotrigine or levetiracetam

Renal impairment: Not major route of elim (1-3%)
- Renal toxicities incl interstitial nephritis and hyponatremia (Use w caution)

Hepatic impairment: Use w caution
- Can cause hepatotoxicity since primarily metabolised by liver

Elderly: Beer’s List (list of drugs to be used w caution in pts >65y)
- Cause or exacerbate SIADH (syndrome of inadequate antidiuretic hormone secre) or hyponatremia
- Increased risk of psychiatric effects

27
Q

What are the CI w CBZ?

A

Concomitant use of MAOis
Bone marrow depression

PGx: HLA-A*1502 & 3101 alleles
- If +ve: Avoid both CBZ and PHT shld be avoided as well
- If -ve: can be initiated on CBZ but shld be monitored durg 1st 12 weeks

Caution:
- Elderly
- Renal impairment
- Hepatic impairment

28
Q

Describe the PK of valproate.

A

A:
- F: 90% relative to IV dose

D:
- Strongly bound to plasma proteins ~90-95%
Competition for binding e.g. PHT, warfarin, NSAIDs.
Displaced by endogenous compounds (uraemia, hyperbilirubinaemia)
- Free fraction: ~10%
- Vd= 0.15L/kg

M:
- Primarily hepatic via glucuronidation, mitochondrial β-oxidation and α-hydroxylation

E:
- t1/2: 9-19h in adults

29
Q

What to take note of w valproate?

A

Saturable protein-binding within therapeutic range
↓protein binding at higher [ ], higher free fraction of drug w low albumin. Watch out for pts w low protein status (higher free fraction than anticipated)

30
Q

What are the DDI assoc w valproate?

A

↓ [ ] of other antileptic drugs- Displaces other antiepileptics –> free drug higher than expected –> ↑CL
- Req dose adjustment

Warfarin: ↑ serum [warfarin]
- Valproate inhib CYP2C9 which metabolises S-warfarin

Azelastine (nasal), Orphenadrine: Enhance CNS depression

Hydroxyzine, opioid agonists: Enhance CNS depression

Carbapenem, Mefloquine: ↓ serum [valproate]

Lamotrigine, lorazepam: valproate ↑ serum [ ] of drugs

31
Q

What are the CI assoc w valproate?

A

Pregnancy + Migraine prophylaxis

Severe hepatic impairment

PGx: rare mutations in POLG (codes for mitochondrial DNA polymerase chain gamma –> Alpers-Huttenlolocher syndrome (AHS) + risk of dev fatal VPA-hepatotoxicity

Urea cycle disorders, particularly OTC deficiency + risk of hyperammonemic encephalopathy

32
Q

Who are the special populations wrt valproate?

A

Pregnancy
- Epilepsy and Bipolar disorder: CI unless no suitable alt
- Migraine prophylaxis: CI

Child bearing age (F)
- CI unless conditions of pregnancy prevention programme fulfilled

Males:
- Increase risk of neurodev disorders in children born to men treated w valproate in the 3mo prior to conception

Renal impairment: No dose adj
Hepatic impairment
- Mild-moderate: Not reco
- Severe: CI

Paeds
- Lower ini dose
- <3y.o. assoc w hepatotoxicity

Elderly: Lower ini dose, monitor for ADRs

33
Q

What are the unique S/E assoc w benzodiazepines?

A

Severe respi depression (esp w alc)

Tolerance and dependence
- Tolerance: body needs higher dose to get same effect
- Dep: can dev –> withdrawal - disturbed sleep, rebound anziety, tremor, convulsions
- Must withdraw gradually

Ataxia, dysarthria, nystagmus, confusion, amnesia, suicidal ideation

34
Q

How do we reverse respi depression from benzodiazepines?

A

Flumanezil (a benzo antagonist) - bind to benzo site, does not activate in the manner benzo does –> no potentiation of GABA

35
Q

What are the S/E unique to barbiturates?

A

Dose dep CNS depression
Severe withdrawal symptoms
Suicidal ideation

36
Q

Is flumanezil effective in treating barbiturate overdose?

A

No

37
Q

Describe the PK of levetiracetam.

A

A:
- F ~100%

D:
- Highly sol & permeable
- < 10% protein binding

E:
- 66% renal
- t1/2: 4-8h
- PK profile linear w low intra & interpt var

38
Q

Describe the PK of lamotrigine.

A

A:
- PO chewable tab (mainly used in paeds)
- F = 100%

D:
- 55% protein bound

M:
- 100% hepatic

E:
- t1/2 generally shorter in children
- t1/2 sig ↓ by coadmin w carbamazepine, phenytoin // ↑ by coadmin w valproate
- t1/2: 18-30h

Linear PK

39
Q

Describe the PK of topiramate.

A

A:
- PO ROA
- F ≥ 80%

D:
- 15% protein bound

E:
- Long t1/2: 20-30h
- Predom renal CL (30-55%)

Linear PK

40
Q

What are the dosing concerns with lamotrigine?

A

Risk of srs cutaneous rxn w
- High starting doses
- Rapid dose escalation
- Concomitant valproate

Slowly titrate, follow PIL

41
Q

What are the DDI assoc w lamotrigine?

A

Carbamazepine, phenytoin:
- ↓t1/2 –> lower exposure

Valproate:
- ↑t1/2 –> prolong exposure
- Increased risk of srs cutaneous rxn

42
Q

Discuss cutaneous skin rxns wrt ASM use

A

ASMs induce skin rxns by unknown mech. Hypothesised to be due to aromatic ring forming an arene-oxide intermediate (immunogenic upon interaction w proteins or cellular macromolecules)
- All 1st gen ASMs except valproate, oxacarbazepine
-Non-aromatic: valproate, levetiracetam, gabapentin, topiramate

43
Q

Of the new generation ASMs which are hepatic CL dependent and which are not?

A

LTG: 100% hepatic

Levetiracetam and Topiramate are more renal dominant

44
Q

Discuss reproductive concerns wrt ASMs

A

Women w epilepsy shld be referred to specialist care
- Discussion on fertility, contraception, family planning issues
- Early discussion on family planning

Potential risk to fetus (if pt has un controlled seizures)
Teratogenic potential of ASMs

Use of OC
- Potent enzyme inducers may render OC ineffective, alt methods req
- For pts on lamotrigine, OC may lower [lamotrigine] –> breakthru seizures

45
Q

Discuss pregnancy wrt to ASMs.

A
  • Levetiracetam and lamotrigine are safer options during pregnancy
  • 1st gen ASMs and topiramate assoc w ↑ risk of major cogenital malformations (dose dep for CBZ, PB, topiramate)
  • Neurodev risk for all the same pop as above except CBZ
  • ↑risk of neurodev disorders (NDDs) in children born to men treated w valproate in 3mo prior to conception
    Counsel potential risk, need for effective contraception (incl for female partner) while using and for 3mo after stopping treatment.
    Do not donate sperm during and 3mo after stopping treatment. If planning to father a child, consult dr to discuss alt. In case of pregnancy, contact dr.
46
Q

Discuss lactation wrt ASMs.

A
  • All breast feeding women on ASM thera shld be encouraged to breastfeed
  • Not indicated poorer outcome, pending long term outcomes

PR3153 CNS (13 decks)

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