Pharm E1- Neuro

What is continuous seizure activity w/o the regaining of mental status (neurological emergency secondary to cerebral ischemia)?

Status epilepticus

What is abnormal behavior that results from abnormal discharges of cortical neurons?

seizure

What is epilepsy?

symptom of disturbed electrical brain activity, w/ periodic recurrence of seizures w/ or w/o convulsions

What are treatment options for epilepsy?

AEDs, vagal nerve stimulator, surgery, and ketogenic diet

How do ketogenic diets help epilepsy?

lower pH / acidosis → higher threshold / harder for seizure to occur

Are AEDs disease modifying?

no

What are the main groups of drugs to treat epilepsy?

Na channel blockers, CCBs, GABA enhancers, glutamate blockers, carbonic anhydrase inhibitors, hormones

AEDs that inhibit which calcium channel are the best for treating absence seizures (ethosuximide)?

T calcium channels

Which GABA receptor is more important in the treatment of seizures?

GABA A (facilitates passage of Cl^-)

What drugs modify the NMDA glutamate receptor site?

Felbamate & Levetiracetam

What drugs modify the AMPA/Kainate glutamate receptor set

topiramate

What group of drugs increases the concentration of H ions and decrease the pH, which increases the seizure threshold?

carbonic anhydrase inhibitors

What drug?

• inhibit Na channels

• highly protein bound to albumin

• Michaelis mentan pharmacokinetcs- half life increases as dose& serum conc. increases

• CYP3A4 & 2C inducer

• requires TDM

Phenytoin (Dilantin)

What is the first line agent for generalized and partial seizures?

Phenytoin (Dilantin)

What are SEs of Phenytoin (Dilantin)?

SJS, rash, lethargy, blurred vision, hirsutism, gingival hyperplasia, vit D deficiency & osteomalacia

Why should phenytoin be avoided IM & IV? (use fosphenytoin instead)

high risk of phlebitis and CV complications

What drug?

• Na channel blocker

• induces its own metabolism; half life shortens as enzymes are upregulated

• induces CYP3A4, 2C9, 2C19

• also has anticonvulsant activity

• requires TDM & monitor LFTs

Carbamazepine (Tegretol)

What are SEs of Carbamazepine (Tegretol)?

diplopia, dizziness, elevated LFTs, hyponatremia, bone marrow suppression

Both drugs cause hyponatremia, but which one is the bigger offender & more likely to cause SIADH?

Oxcarbazepine

What is Oxcarbazepine (Trileptal) MOA?

Na channel blocker

What is the MOA of valproic acid (Depakote)?

Na channel inhibitor, Ca channel inhibitor, GABA enhancer

What SEs are seen with Valproic Acid (Depakote)?

GI disturbances (MC), hepatotoxicity (monitor LFTs), CYP interactions, sedation, ataxia, tremor, weight gain, pancreatitis, thrombocytopenia, & teratogenic (neural tube defect)

What drug is teratogenic and can cause neural tube defects if given during pregnancy?

Valproic acid (Depakote)

What drugs are Benzodiazepines?

Diazepam (Diastat)

Lorazepam (Activan)

Midazolam (Versed)

Clonazepam (Klonopin)

Clobazam (Onfi)

What is the most common IV agent for acute seizures?

Lorazepam (Ativan)

What drugs?

• enhance GABA A activity & increase Cl^- influx

• C-IV

• go to agents for acute seizures (PR/IN/IM/IV); PO better for prevention

• SEs: sedation (MC) & withdrawal seizures

Benzodiazepines

What is the drug of choice for neonatal seizures?

Phenobarbital (luminal)

What drug?

• activate GABA A to increase Cl^- influx

• C-IV

• rarely used d/t ADRs; reserved for refractory status epileptics or those who failed other AEDs

Phenobarbital (luminal)

What side effects are seen with phenobarbital?

sedation & CNS depression; paradoxical reaction in children (inc excitation)

requires TDM

What drug is used IV for status epileptics and can induce a “pentobarb coma”?

Pentobarbital (Nembutal)

What drug has limited use d/t fatal aplastic anemia, hepatotoxicity, and drug interactions and is used only in refractory epileptic patients?

Felbamate (Felbatol)

What is the drug of choice for absence seizures?

(*Test Q)

Ethosuximide (Zarontin)

What is Ethosuximide’s MOA?

inhibit neuronal Ca channel

What drug?

• structure related to GABA- may enhance GABA synthesis & interact with Ca channels

• adjust in renal failure

• main SE- CNS depression

• adjunctive AED & can treat neuropathic pain

Gabapentin (Neurontin) & Pregabalin (Lyrica)

Pregabalin is a _____

C-V

What is Lamotrigine’s (Lamictal) MOA?

inhibit sodium channels, inhibit glutamate release, & modulation calcium channels

What drug?

• AED- less sedation than other meds

• metabolism inhibited by VPA (higher levels- lower dosage);

• induced by carbamazepine & phenytoin (lower levels- increase dosage)

Lamotrigine (Lamictal)

What SEs are seen with Lamotrigine (Lamictal)?

SJS, dizziness, ataxia, N, V

What drug?

• bind to synaptic SV2A & prevent glutamate release

• becoming first line for epilepsy; used as adjunctive for partial seizures

• 60% renal elimination - adjust w/ renal issues

Levetiracetam (Keppra)

Which AED is associated with increased aggression, especially in children?

Levetiracetam (Keppra)

What drug?

• anticonvulsant- treats seizures & migraine prevention

• adjust for for renal

• SE: impaired concentration

Topiramate (Topamax)

What is the MOA of Topiramate (Topamax)?

block Na channels, enhance GABA, antagonize AMPA/Kainate

carbonic anhydrase inhibitor - induce mild metabolic acidosis (increase seizure threshold

What drug?

• AED- targets Na channels & binds CRMP-2 (prevents hyperexcitability)

• C-V

• SE: inc PR interval, HA, ataxia, N/V

Lacosamide (Vimpat)

What is a treatment algorithm for status epilepticus?

immediate- secure airway, circulation, protect from injury

early 0-10 min- IV lorazepam, Diazepam PR, Midazolam IN

if unresponsive- phenytoin or fosphenytoin

if unresponsive- Levetiracetam or phenobarbital

if unresponsive- VPA or additional phenobarbital

if unresponsive - general anesthesia or pentobarbital coma

When can a patient stop AED therapy?

seizure free 2-5 yrs on AEDs

single seizure type

normal neuro exam / no brain lesions

normal EEG after treatment

*withdraw slowly, esp benzodiazepines & barbiturates

What are the most common reactions to epileptic treatment?

sedation, dizziness, blurred vision, difficulty concentrating, ataxia (fall risk!)

What AEDs cause less drowsiness than other agents?

Lamotrigine & VPA

What drug is rarely used in school aged children due to interference with learning?

phenobarbital

What would not be a good AED drug to prescribe in a patient with a history of mental illness due to psychosis & suicide attempts observed in clinical trials?

Levetiracetam

What drugs have a a risk of SJS/TEN and should be discontinued immediately with any sign of a rash?
(*test Q)

Oxcarbazepine & lamotrigine

What drug causes aplastic anemia and is reserved for refractory seizure activity?

Felbamate

What drugs should be routinely monitored with CBCs and for sx such as fever, sore throat, mouth ulcers, unusual bleeding/bruising due to possible ADRs such as agranulocytosis, leukopenia, neutropenia, etc?

carbamazepine, felbamate, VPA, phenytoin

What drugs can cause hepatitis / hepatic failure and should be routinely monitored w/ CBCs & LFTS?

carbamazepine, felbamate, phenytoin, VPA (worst one; MC under 2 y/o)

Which AEDs require therapeutic drug monitoring (TDM)?

carbamazepine, phenobarbital, VPA, phenytoin

What forms of birth control are not affected by AEDs?

depo shots & IUDs

What AEDs decrease the effectiveness of OCs?

phenytoin, phenobarbital, carbamazepine, oxcarbazepine, felbamate

What condition is a slowly progressive neurodegenerative disorder caused by too little dopamine & has 4 cardinal features: tremor, rigidity, hypokinesia, & postural instability?

Parkinson’s Disease (PD)

What are 2 main targets for treatment of Parkinson’s?

COMT- metabolizes L DOPA

MOA-B- breaks down dopamine

What can be used as a diagnostic test for Parkinson’s?

response to levodopa or apomorphine

What treatments can be used for early, uncomplicated PD?

Neuroprotection: MAO-B inhibitors, DA agonists

Sx: anticholinergics, MAO-B inhibitors, COMT inhibitors, DA agonists (Ergot & non ergot), DA precursors

What class of drugs irreversibly inhibits MAO-B to reduce metabolism of DA to decrease radical formation/oxidative stress (neuroprotective)?

MAO-B inhibitors

What drugs are MAO-B inhibitors?

Selegiline & Rasagiline

What drug?

• MAO-B inhibitor

• treats early PD, delays need for levodopa

• metabolized to amphetamine derivatives, shows positive on drug screen

• SEs: orthostatic hypotension (fall risk), serotonin syndrome, agitation, insomnia, hallucinations

Selegiline (Eldepryl, Zelapar)

What drug?

• MAO-B inhibitor

• reduces functional decline of PD

• not metabolized to amphetamine derivates, fewer SE

• risk for serotonin syndrome

Rasagiline (Azilect)

What do both MOA-B inhibitors present a risk for?

serotonin syndrome

What foods should be avoided with MOA-B inhibitors due to risk of tyramine reaction?

Fava beans, aged cheeses, red wine, sausage, salami, etc

What drugs?

• used for sx tx in early PD w/ minimal hypokinesia

• blocks Ach in SNc → dec tremor

• avoid in patients w/ cognitive impairment; not great for elderly

• SE: dry mouth, constipation, blurred vision, etc

• reduce gradually due to rebound sx

Anticholinergics

What drug?

• Unclear MOA- amphetamine like action to release DA, anticholinergic, NMDA antagonist

• used as mono or combo tx in early mild PD → can help manage levodopa induced dyskinesia

• reduce in renal impairment

• se: dizziness, anxiety, insomnia, N, V, anticholinergic

• can develop tolerance

Amantadine (Symmetrel)

What drugs may be used as first line monotherapy for PD but are not as effective as cabidopa/levodopa?

Dopamine agonists (ergot & non ergot derivatives)

What class of drugs is Bromocriptine (Parlodel)?

Ergot derivative

What drugs are non-ergot derivatives?

Pramipexole (Mirapex)

Ropinirole (Requip)

Rotigotine (Neupro) - transdermal patch

Apomorphine (Apokyn) - SQ

What are possible SEs of ergot derivatives?

pleuro/retroperitoneal fibrosis and valve regurgitation

What drug?

• most effective tx for sx of PD; eventually all pt’s require

• crosses BBB

• SE: N, V, orthostatic hypotension, hallucinations, insomnia, somnolence, depression

Levodopa / Carbidopa (Sinemet)

What can affect the absorption of levodopa/carbidopa (Sinemet)?

amino acids (compete for absorption; not absorbed as well if taken at same time as proteins)

What forms does Levodopa/Carbidopa come in?

Sinemet, Sinemet CR, Parcopa (ODT)

What should be given along with levodopa to prolong conversion to DA and allow levodopa to act centrally while reducing AE?

Carbidopa

What drug lengthens the half life of levodopa/carbidopa when given in combo?

Entacapone

What drugs?

• inc central levodopa & prolong half-life by prevent breakdown through inhibiting peripheral COMT

• only as adjunct w/ levodopa/carbidopa (reduce l-dopa by 25%)

• contraindication: MOA-AIs

COMT inhibitors

What SE is seen with COMT inhibitors?

urine discoloration (brown/orange)

What drugs are COMT inhibitors?

Tolcapone (Tasmar)

Entacopone (Comtan)

What is the black box warning for Tolcapone (Tasmar)?

hepatotoxicity - monitor LFTs

treatment algorithm for parkinsons

What drug is associated with a “honeymoon” that works great at first and then loses it’s effect?

L-dopa

What are the refractory sx of PD (dysarthria, dysphagia, freezing) treated with?

levodopa oral soln, apomorphine, surgery, PT

What drugs can be added to PD treatment when the medications start wearing off due to loss of presynaptic neurons?

entacapone, DA agonist, MAO-B inhibitor, apomorphine injections, duodenal L dopa infusions

administer Sinemet more frequently or switch to oral soln or sinemet CR

What can be added to PD treatment for “off” dystonia?

DA agonist, rotigotine, botox

add bedtime dose of sinemet CR & take first thing in the morning

What can be added to treatment for PD if meds unpredictably wear on-off?

DA agonist or try a different one, MOA-Bi, COMTi, protein redistribution (separate meals), sinemet oral soln, apomorphine injections, continuous duodenal l dopa infusion

*trial and error

How can PD treatment be modified for dyskinesias associated with peak dose or “on” (too much DA/too much effect)?

lower sinemet dose or discontinue agents that potentiate L dopa (COMTi / MAO-Bi)

add DA agonist, amantadine, clozapine, or propranolol

How can PD treatment be modified for biphasic dyskinesias?

short dosing interval to produce over lapping of effects; add DA agonist; switch to CR

What condition is the progressive loss of hippocampus and cortical cholinergic neurons associated with memory and cognition?

Alzheimer’s Disease (AD)

What drugs?

• treat mild-mod AD by preventing breakdown of post synaptic Ach to enhance cholinergic transmission (helps improve memory and cognition)

• SE: cholinergic toxidrome- DUMBBBELS

Cholinesterase inhibitors (ChEI)

What drugs are cholinesterase inhibitors?

Donepezil (Aricept)

Rivastigmine (Exelon)

Galantamine (Razadyne)

Tacrine

What drug?

• cholinesterase inhibitor specific for AChE over BuChE

• high plasma protein binding & long half life (70 h)

• CYP interactions (ketoconazole, quinidine)

• reduced response in long term use

Donepezil (Aricept)

What drug?

• cholinesterase inhibitor for both AChE & BuChE

• short plasma half life (1-1.5 hr) but covalently binds ChE to stick around longer

• twice daily dosing

• sustained effect in long term use

Rivastigmine (Exelon)

What drug?

• cholinesterase inhibitor very specific for AChE

• moderate half life (7h); twice daily dosing

• reduced response in long term use

• CYP drug interactions

Galantamine (Razadyne)

What drug?

• NMDA glutamate receptor antagonist - prevents Ca entry = less stress & reduced excitatory activity

• tx mod-severe AD

• well tolerated; improve cognitive function & daily activities

• long half life; minimal drug interactions

Memantine (Namenda)

What condition is an inflammatory/demyelination disease of the CNS producing progressive neurological symptoms and plaques/sclerosed areas?

Multiple Sclerosis (MS)

What are the 3 categories of treatment for MS?

exacerbations - shorten duration & lessen severity

disease modifying therapy (DMT)

symptom management

How are MS exacerbations managed?

IV methylprednisolone w/in 2 wks of sx onset

Plasma exchange if severe

DMTs reduce relapse rates & white matter lesions in MS, but how long does it take to have an effect on symptoms in MS patients?

1-2 yrs