Sweatman - Epilepsy Drugs Flashcards
(93 cards)
1
Q
Which anti-convulsant should NOT be used in pregnant women?
A
- Valproic acid
- With women of child-bearing age, should be concerned about whether or not they are pregnant when you initiate therapy
2
Q
What is fetal hydantoin syndrome?
A
- Gp of defects to fetus via teratogenic effects of Phenytoin or Carbamazepine
- Intrauterine growth restriction w/small head (microcephaly) and minor dysmorphic craniofacial features + limb defects (skeletal malformations particular to fingers/hands, incl. hypoplastic nails of fingers and/or toes)
- May have developmental delay, intellectual disability
- Heart defects and cleft lip may also be seen
3
Q
What is the 1st-line drug for acute, prolonged epileptic crisis?
A
- Lorazepam
- NOTE: while you control epilepsy with subsequent drugs, their physico-chemical characteristics are that they cannot be given as a bolus, and you want to terminate the epileptic rxn now
4
Q
7-y/o child w/o any hx of brain damage, but who had mild speech delay and hyperkinesia started having brief episodes of fixed gaze and falls. In sleep, the parents observed tonic fits. Which of the following is most appropriate to tx this pt?
A
- Valproate
- He said this is absence?
5
Q
What drug can elicit gingival hyperplasia as a symptom?
A
- Phenytoin
- NOTE: Cyclosporine, dihydropyridine Ca-channel blockers can also cause this (i.e., Nifedipine)
6
Q
What drug is used in tx of epilepsy that works by INH Ca channels?
A
- Gabapentin (alpha-2-delta-1 subunit)
- NOTE: Pregabalin (alpha-2-delta-1 subunit), Oxcarbazepine (possibly), and Zonisamide (Type-T) also do this
7
Q
What is the MOA of Valproate?
A
- INH the breakdown of GABA, INC its time in the synaptic cleft —> slightly unusual MOA
8
Q
What drug gets dose adjusted over time to maintain appropriate serum levels?
A
- Carbamezepine bc it induces its own metabolis via CYP -> activity reaches a pt where it’s maximally induced, so you don’t keep INC dose
- Phenytoin also a self-inducer, but may not be as much as Carbamezepine
9
Q
Metabolic acidosis secondary to AED tx is most likely to occur with which drug?
A
- Topiramate: INH carbonic anhydrase, so bicarb retained in urine flow
- Can also get formation of kidney stones
10
Q
Which drug exhibits zero-order kinetics?
A
- Phenytoin
- Linear elimination: constant amt eliminated per unit time, so half-life changes as you INC dose
- NOTE: high-dose ASA also exhibits zero-order kinetics
11
Q
Routine CBC reveals neutrophil count of <0.5 x 10^9/L; what is the most likely causative agent?
A
Carbamazepine
12
Q
57-y/o woman being tx’d for epilepsy has petechiae on lower legs and a number of recent bruises. What drug is she on?
A
- Valproic acid: can cause thrombocytopenia
13
Q
For which pt would HLA-B genotyping be prudent if considering Carbamazepine therapy?
A
Asian
14
Q
56-y/o man with epilepsy complains of weakness, SOB on exertion. He is tachycardic, with pale skin. What AED is he on?
A
- He is anemic
- He is taking Felbamate
15
Q
What is the pro-drug for Phenytoin?
A
Fosphenytoin
16
Q
What 2 drugs share the same pharmacology as Valproate?
A
- Divalproex
- Valproic acid
17
Q
What is the drug list for anti-convulsants (table)?
A
18
Q
What are the seizure classifications (table)?
A
- Many of the drugs have specific indications in regards to types of seizures they are used to treat
- This relates underlying pathophys of seizure and MOA of respective drug
19
Q
What is the pathophys of seizures?
A
- Start discretely, then spread to neighboring regions
- High-frequency bursts of AP’s: influx of EC Ca, then depolarization = activation of voltage-dependent Na channels, generating repetitive AP’s
- Hypersynchronization: hyperpolarizing after-potential via GABA receptors or K+ channels
- Surrounding (normally) INH neurons opposed by:
1. INC in EC K+
2. Ca in presynaptic terminals -> INC NT release
3. Activation of NMDA excitatory neurons
4. Cell swelling, and changes in tissue osmolarity
20
Q
What are the 3 MOA’s of the anti-convulsants? How do these vary by seizure type?
A
- PARTIAL and SECONDARILY GENERALIZED tonic-clonic seizures:
1. Limit sustained, repetitive firing of neurons by promoting inactivated state of voltage-gated Na channels (MOA of local anesthetics)
2. Pre- or post-synaptic enhancement of GABA-mediated synaptic INH via pre- or post-synaptic action - ABSENCE seizures: INH of voltage-activated Ca channels responsible for T-type Ca currents
21
Q
Which drugs target voltage-gated Na+ channels? How does this MOA work?
A
-
Prolong inactivation of Na+ channels, reducing ability of neurons to fire at high frequencies (LVZ - PCT)
1. Bind to specific components of Na channel, preventing action, even in presence of membrane depolarization - Multimeric transmembrane-spanning channel complex normally exists in closed state -> when the membrane is depolarized, various subunits rapidly reconfigure to open ion channel to free mvmt of Na+
1. Almost immediately, inactivation gate swings across open pore to rapidly terminate ion passage
2. Normally, various components reconfigure into closed, but activatable state
22
Q
Which anti-convulsants enhance GABA action? How?
A
- Several mechanisms, but all produce greater quantum yield of GABA release w/e/neuronal impulse:
1. Benzodiazepines/barbiturates bind separately at sites on multimeric ion channel complex to modulate activity of endogenous GABA (post-syn)
2. Gabapentin acts pre-syn to promote GABA release
3. Vigabatrin and Valproate reduce metabolism of GABA - NOTE: GABA is principle INH NT in the brain
23
Q
Which drugs act via Ca-channel blockade? How?
A
- Reduce flow of Ca through T-type Ca channels
- Reduce pacemaker current underlying thalamic rhythm in spikes and waves seen in generalized ABSENCE seizures
- Both Na- and Ca-channel blockers diminish effects of glutamate, the principal stimulatory NT in the brain
24
Q
How do AED’s affect the high-frequency firing characteristic of seizures?
A
- Phenytoin, Carbamazepine, and sodium valproate all markedly reduced number of AP’s elicited by current pulses -> diminish atypical neuronal activity, reducing seizure activity, as seen on an EEG
- NOTE: in absence of drug, a series of high-frequency AP’s filled entire duration of current pulse
25
What psych concern should you be conscious of with all of the anti-convulsants? How can you monitor this?
- **Suicidal ideation**: INC incidence, according to FDA
- According to clinical trials, behavioral effect observed _1-24 weeks_ after starting drug
- MONITOR all pts for emerging or worsening depression or suicidial thoughts/behavior
1. _Educate pts/caregivers about risks_, and advise to immediately report emergence of worsening of depression, suicidal, or self-harm thoughts/beh
- _Minimally effective drug levels_ should be used
26
How effective are current anti-convulsants?
- Current drugs _control seizures in ONLY 50% of pts_, with another 25% helped somewhat
- AE's vary from minimal impairment to death from aplastic anemia or hepatic failure
1. Can limit pt adherence, and be responsible for tx discontinuation
27
What are 2 clinical guidelines for anti-convulsant therapy?
- 1) Use _single-agent therapy_; substitution preferred with Rx failure, rather than additive tx
- 2) # of these drugs require monitoring of serum drug level, but these levels provide only guidance; _clinical assessment of effect vs. toxicity_ is paramount
28
What is the MOA of Carbamazepine?
INH Na+ channels
29
What is the MOA of Clonazepam?
GABA allosteric agonist
30
What is the MOA of Ethosuximide?
INH T-type Ca channels
31
What is the MOA of Felbamate?
INH NMDA; enhance GABA
32
What is the MOA of Gabapentin?
INH alpha-2-delta-1 subunit of Ca channel
33
What is the MOA of Lacosamide?
INH Na+ channels
34
What is the MOA of Lamotrigine?
INH Na+ channels
35
What is the MOA of Levetiracetam?
Unknown
36
What is the MOA of Oxcarbazepine?
INH Na+; possible INC K+ and DEC Ca effects
37
What is the MOA of Phenytoin?
INH Na+ channels
38
What is the MOA of Pregabalin?
INH alpha-2-delta-1 subunit of Ca channel
39
What is the MOA of Topiramate?
- INH N+ channels
- INC K+ current
- INC GABA
- DEC glutamate activity
40
What is the MOA of Valproate?
INC GABA activity; INH Na+ channels
41
What is the MOA of Zonisamide?
INH Na+ and INH T-type Ca channels
42
Describe the ADME of the anti-convulsants?
- Most administered ORALLY, but some available for IV dosing
- Limited protein binding, except _Phenytoin and Valproate_ -\> issues of protein binding displacement may be significant in producing acute drug toxicity
- _Zonisamide_ accumulates in erythrocytes
- Predominantly _hepatic metabolism w/urinary elim_ of parent drug and/or metabolites -\> some have active metabolites
- Some induce **CYPs** (Carbamazepine); others INH CYPs -\> 1/2 lives may change for drug and/or concurrent agents
- _Long half-lives_
- Slow release products facilitate adherence: fewer doses/day
43
Which anti-convulsant accumulates in erythrocytes?
Zonisamide
44
Which anti-epileptic drugs exhibit extensive protein binding?
- Phenytoin
- Valproate
45
What are the key points for metabolism, CYPs, and elimination of antiepileptic drugs (table)?
- HEPATIC METABOLISM: involving _CYP's_ (phase 1) and _uridine glucuronosyl transferase_ (phase 2)
1. Concurrent agents impacting activity of these metabolic processes can alter serum drug level of concurrent AED, changing clinical effectiveness -\> _potential drug-drug interaxns_
2. Several AED's modulate enzyme activity and can alter serum levels of o/drugs, incl. inducing their own metabolism (i.e., Carbamazepine)
- For all AED's, elim of drug and/or metabolites in urine, so _renal dysfunction may be significant in regards to potential for drug accumulation_ over time
46
How is the metabolism of Carbamazepine unique? Implications?
- As tx progresses, 1/2-life of drug DEC due to INC rate of hepatic metabolism
47
Which anti-convulsants can be given IV?
- Lacosamide
- Levetiracetam
- Phenytoin
- Valproate Na
48
Which antiepileptic drugs have NO CYP interactions?
- Gabapentin, Pregabalin: NOT metabolized in liver (or at all)
- Lamotrigine (metabolized by UGT and induces UGT, however)
- Topiramate
- Levetiracetam
49
Which antiepileptics influence their own metabolism?
- Carbamazepine: CYP3A4 inducer
- Felbamate: 2C19 INH and 3A4 inducer
- Lacosamide: 2C19 INH
- Lamotrigene: _UGT inducer_
- Phenytoin: 3A4 and 2C19 inducer
- Valproate: 2C9 INH
50
Which antiepileptic is eliminated in the stool?
Phenytoin
51
Which antiepileptic drugs are metabolized by UGT?
- Lamotrigene
- Valproate Na (+2C9, 2C19)
- Zonisamide (+ 3A4)
52
For which AED's is routine monitoring of serum drug levels required?
- Carbamazepine, Ethosuximide, Gabapentin
- Phenytoin, Valproate
- NOTE: this is for _guidance_ and to see trends, rather than as an absolute
1. High serum drug levels + good control of seizures + absence of toxicity does not necessarily warrant reduction in drug dosing -\> _use clinical presentation to guide tx_
53
What are some things you should be concerned about regarding metabolism of the AED's (3)?
- _Inducers of CYP or (UGT)_ uridine 5'-diphospho-glucuronosyl-transgerase can change 1/2-life of concurrent substrate AED's (and any other drugs)
- May INH concurrent parenteral drug, but _INC levels of active metabolites_
- Some drugs _may self-induce_ (Carbamazepine) and changing their own 1/2-life, requiring dose-adjustment over time to compensate
54
What are some of the issues with Topiramate and Zonisamide?
- Weak **carbonic anhydrase INH**: renal bicarb loss (\<68% and 43%, respectively)
1. _Routine MONITORING of serum bicarb_ required
1. Promote _stone formation_ by reducing urinary citrate excretion and INC urinary pH
55
Should you abruptly terminate AED's? Why or why not?
- No: caution in adjustment of drug doses
- Discontinuation _can precipitate status epilepticus_, INC freq of seizures, and various neuro issues, like anxiety
- Clinicians must BE WARY of this if they elect to terminate tx due to severe AE's
1. Where possible, _termination should involve tapering of drug_ over period of time
56
What are some of the metabolic issues with Phenytoin?
- Metabolism highly variable
- _Zero-order elimination_: 1/2-life varies w/drug dose, making clinical use of this agent problematic
- Issues of _protein binding displacement_ and CYP-mediated drug-drug interactions
1. Highly variable induction of CYP's 3A4, 2C9, and 2C19
2. Age, cigarette smoking, and hepatic status are confounding factors
57
What are some of the AE's with Phenytoin?
- _CNS effects_: most commonly nystagmus, but also headache, ataxia, incoordination
1. Drowsiness NOT common at therapeutic levels
- **_GINGIVAL HYPERPLASIA_**: \>15% of long-term pts
- DERM EFFECTS (rare; \<5%): range from measles-like rash to SJS, TEN, DRESS (_possible with most AED's_)
1. Hypertrichosis, **_hirsutism_**: generally confined to extremities, but can affect trunk/face (may be irreversible; rarely with Carb, Lamo, Zonis)
- _HEME_ CHANGES: may occur, but _uncommon_ for pt taking phenytoin to devo severe blood dyscrasia (_potentially life-threatening_)
58
What are some of the issues with Carbamazepine?
- _CNS effects_ (esp. during initial tx phase): dizziness, drowsiness, ataxia, blurred vision; _sedation upon initiation_ and dose escalation
- HEME CHANGES: routine _monitoring required_ due to 5-8 fold INC risk of **agranulocytosis** (BBW; life-threatening) or aplastic anemia
- DERM EFFECTS (rare; \<5%): measles-like rash to SJS, TEN, DRESS
- Miscellaneous: dry mouth, constipation, N/V (common to many AED's)
59
How is HLA-B 1502 genotyping relevant to AED tx? For which drugs?
- Whole blood EDTA testing to ID **Asian pts** at-risk of _SJS and TEN_ (SNP change in HLA-B 1502 allele, placing carrier at INC risk of immune system-mediated AE's)
1. **Carbamazepine**, Phenytoin, Fosphenytoin, Lamotrigine
- May be prudent to advise carriers to avoid Carb and structurally related anticonvulsants like Phenytoin, Oxcarbazepine, and possibly Lamotrigine
60
What are some of the issues with Valproic acid?
- _CNS effects_: related to infusion rate -\> somnolence, dizziness, paresthesias, asthenia, headache
- HEME CHANGES: **thrombocytopenia**, prolonged bleeding time
- DERM EFFECTS (rare): measles-like rash to SJS, TEN, DRESS
- Miscellaneous: N, diarrhea, **hepatotoxicity** (rare, but occurs most commonly in KIDS)
61
What are the side effects of Clonazepam?
- Somnolence (37%)
- Ataxia, dizziness, fatigue (about 10% each)
62
What are the side effects of Ethosuximide?
- Somnolence
- Dizziness
- Headache
- N/V
- Diarrhea
- GI upset
63
What are the side effects of Felbamate?
- **BBW**: aplastic anemia, bone marrow suppression, hepatic disease
- N/V (25%)
- Constipation (12%)
64
What are the side effects of Gabapentin?
- Somnolence (20%)
- Dizziness, ataxia, fatigue (15% each)
65
What are the side effects of Lacosamide?
- Dizziness
- Headache
- Diplopia
- N/V
66
What are the side effects of Lamotrigine?
- **BBW**: serious rash (TEN/SJS)
- Dizziness (38%)
- Diplopia
- Ataxia
- Blurred vision
- Rhinitis
67
What are the side effects of Levetiracetam?
- Headache
- URTI
- Somnolence
68
What are the side effects of Oxcarbazepine?
- Dizziness/diplopia (50% each)
- Headache
- N/V
- Nystagmus, somnolence, ataxia
69
What are the side effects of Pregabalin?
- Dizziness
- Somnolence
- _Peripheral edema_
70
What are the side effects of Topiramate?
- Dizziness, fatigue
- Ataxia, _paresthesias_, abnormal vision/psychomotor slowing
71
What are the side effects of Zonisamide?
- Somnolence
- _Anorexia_
- Dizziness
72
What is Fosphenytoin?
- _Pro-drug_ dosed in phenytoin equivalents
1. _150mg fosphenytoin = 100mg_ phenytoin: DOSE ADJUSTMENT important when transitioning b/t these products
- Process unaffected by concurrent drug therapy
73
What are the pregnancy categories for the potentially teratogenic AED's? Abnormalities described?
- Lamotrigine: CAT C
- Carbamazepine, Phenytoin, Topiramate, Phenobarbitol: CAT D
- **Valproate**: CAT X -\> greatest risk of AE's
74
Which AED's can cause fetal hydantoin syndrome? What is this?
- Carbamazepine, Phenytoin
- FEATURES: upturned nose, mild mid-facial hypoplasia, long upper lip with thin vermilion border, and digital hypoplasia
- NOTE: not all investigators are convinced of the existence of this syndrome, and similar effects have also been attributed to both Phenobarbitol
75
What abnormalities can Valproate cause in the developing fetus?
- Neural tube defects
- Clefts
- Skeletal abnormalities
- Developmental delay
- NOTE: greatest risk during pregnancy with this drug
76
What abnormalities can be seen in fetus exposed to Phenobarbitol in utero?
- Clefts
- Cardiac abnormalities
- _Urinary tract malformations_
77
What abnormalities can be seen in fetus exposed to Lamotrigine in utero?
- _INH dihydrofolate reductase_, lowering fetal folate levels
- Registry data suggest INC risk for clefts
78
What AE's can be seen in fetus exposed to Topiramate in utero?
- Cleft lip
- Cleft palate
79
What abnormalities can be seen in fetuses exposed to Carbamazepine?
- Fetal hydantoin syndrome
- _Spina bifida_
80
What are the DOC for partial, incl secondarily generalized seizures (table)?
81
What are the DOC for primary generalized tonic-clonic seizures (table)?
82
What are the DOC for absence seizures (table)?
- These 2 drugs are considered equally effective
- 50-75% of pts experience complete control
83
What are the DOC for atypical absence, myoclonic, atonic seizures (table)?
84
What is status epilepticus? Causes? Tx?
- Status epilepticus = prolonged seizure, or cluster of seizures, _w/o return to baseline_, lasting \>30 mins
1. Can be generalized tonic-clonic, complex or simple partial, absence, or subclinical
2. Up to 50% occur in pts w/epilepsy due to recent _changes in AED's or non-adherence_
3. Remainder of cases in adults most often _secondary to a stroke_
- MEDICAL EMERGENCY: **mortality from 7-40%**
85
What are some of the predictors of mortality in status epilepticus?
- Generalized seizure
- INC patient age
- Anoxic brain injury
- Stroke
- CNS infection or tumor
- Long duration of SE
- NOTE: successful outcomes require early, aggressive tx and collaboration b/t EM doc, hospitalist, neurologist
86
What are the important similarities/differences b/t benzos and Phenobarbitol?
- BOTH work on _GABA receptor, but at different sites_: barbs prolong opening time of Cl- channel and benzos shift dose-response curve for GABA
- BOTH have issues of dependence/withdrawal + devo of tolerance
- BOTH will produce _dose-related sedation_
- ONLY Phenobarbitol will induce CYP2B6, **3A4** levels
- BOTH can be given by _rapid IV admin_, unlike Phenyton or Valproate (these can be given IV, but apparently not rapidly)
87
Why is a benzo first-line tx for SE? Why are they followed up with another drug?
- Significant _reinforcement of INH effects of GABA_
- Can be _given rapidly IV_, whereas o/agents have limitations in rate at which they can be administered by this route due to physico-chemical issues (i.e., Phenytoin, Valproate)
- NOTE: can rapidly terminate SE, but _short 1/2-lives_ for these agents mean add'l drugs must be administered to provide for more sustained drug control
88
What are the 3 main MOA's of the AED's
Work on Na+, Ca2+ (T-type) channels, or reinforce GABA's action
89
What are common side effects of all AED's?
- CNS effects like sedation, dizziness, ataxia
90
What is a serious side effect assoc with MOST AED's? For which 2 drugs is this effect NOT reported?
- RASH possible with most AED's; rarely SJS
1. Asian predisposition with HLA-B 1502 allele
2. SJS NOT reported w/Clonazepam, Lacosamide
91
Which AED's have blood toxicities?
- Carbamazepine: agranulocytosis
- Felbamate: aplastic anemia, bone marrow suppression, hepatic toxicity (BBW)
- Valproate: thrombocytopenia, prolonged bleeding time
92
Which AED's are teratogens?
- Lamotrigine
- Carbamazepine
- Phenytoin
- Valproate
- Topiramate
- Phenobarbitol
93
What is the first drug for SE?
Lorazepam IV
