Pharm Neuro: Seizures, Dementia & Parkinson's

pathophysiology of seizure disorder

excess glutamate receptor excitatory activity, excess Ca or Na ion conductance, and inadequate GABA receptor inhibitory activity (balancing issue due to abnormal discharge of cerebral neurons)

other neurons recruited relates to seizure type

therapeutic approach to seizure disorders

decrease glutamate activity and increase GABA inhibitory activity

what is the approach to decrease glutamate activity?

decrease activity of voltage gated channels (Na or Ca)

which drugs decrease activity of Na channels, decreasing glutamate activity?

phenytoin, carbamazepine, lamotrigine

which drugs decrease Ca channel activity, decreasing glutamate activity?

ethosuximide, lamotrigine

what is the approach to increase GABA inhibitory activity? what drugs do this?

increase GABA A (maybe B) receptors activity

benzodiazepines (lorazepam)

tonic-clonic seizure tx

Carbamazepine, lamotrigine, valproate

absence seizure tx

ethosuximide, valproate, lamotrigine

myoclonic and atonic seizure tx

valproate, lamotrigine

what two medications can be used in all seizures?

valproate, lamotrigine

what can carbamazepine be used for?

partial seizures, generalized tonic-clonic seizures

what can ethosuximide be used for?

generalized absence seizures

what seizures can gabapentin and phenytoin be used for?

partial

if there is no underlying seizure cause, what are the RFs for recurrence?

structural CNS lesion

abnormal EEG

partial seizure type

FHx

postictal motor paralysis

what is the recurrence rate for patients with 2+ seizure RFs?

100%

what is the recurrence rate for patients with no seizure RFs?

10-15%

which seizure medication has capacity limited enzyme pathway?

phenytoin

what happens when seizure drugs are protein bound?

inactive - only free drug is active

what % for phenytoin is protein bound?

90%

what % of valproate is protein bound?

about 90%. but metabolism is not capacity limited

autoinduction of seizure drugs causes what to occur? what medication demonstrates this?

increase P450 enzymes concentrations (CYP1A2, 2C9, 2D6, 3A4)

carbamazepine mainly after 2-3mo (some with phenytoin)

what are some drug indication guidelines for seizure medications?

AAN, ILAE, NICE, SIGN

what are some acute SEs of anti-seizure drugs that can occur?

w/ higher concentrations: ataxia, sedation, diplopia

idiosyncratic: rash, liver toxicity, marrow toxicity

chronic SEs of anti-seizure drugs

peripheral neuropathy, cerebellar atrophy, weight gain

osteoporosis

Carbamazepine, phenytoin, and valproate use for 6 months is comparable to chronic corticosteroid use and can lead to what SE?

osteoporosis

how should a patient be switched between seizure medications?

up-titrate new drug to seizure control or minimum effective dose

THEN

down-titrate drug being replaced, continuing to increase new drug as needed

what impacts can anti-seizure drugs have in women of child-bearing age?

teratogenicity

BCP interactions

reduced fertility

valproate impacts in PG

neural tube defects

impaired cognitive development

seizure treatment considerations in children

more rapid seizure control

higher dosing relative to weight

lamotrigine (lamictal) MoA & Indications

blocks sustained repetitive neuron firing and prolongs inactivation of Na channels (maybe Ca channels) used for mono therapy or add-on in generalized or partial seizures

lamotrigine SE/ADRs

dizziness, N/V

ataxia

blurry/double vision

rash

osteoporosis

how does lamotrigine impact other anti-seizure medications?

decreases carbamazepine and phenytoin

increases valproate

what anti-seizure drug should folate be taken with?

lamotrigine

carbamazepine class, indication & moa

tricyclic anti-seizure drug for generalized tonic-clonic and partial seizures that works by decreasing synaptic release glutamate and inhibiting Na channels

carbamazepine SE/ADRs

nausea, HA

ataxia

hyponatremia

arrhythmia

alopecia

bone marrow suppression

osteoporosis

carbamazepine PG

D

lactation: no

phenytoin (dilantin) class, indications & moa

cyclic ureides anti-seizure drug for partial and generalized tonic-clinic seizures that limits repetitive firing of neurons and inhibits Na channels

phenytoin (dilantin) SE/ADRs & PG

gingival hyperplasia

folic acid, Vit D deficiency

peripheral neuropathy

nystagmus, ataxia

hypotension

decreased mentation

osteoporosis

overdose -> death

PG D

which medication needs close dental follow up and good dental hygiene?

phenytoin - gingival hyperplasia

fosphenytoin

prodrug for phenytoin given as IM or IV for status epilepticus

valproic acid (depakote) class, indications & moa

anticonvulsant for seizures (generalized tonic-clonic, absence, myoclonic, tonic), Mania, mood stabilization, migraine px

increases GABA concentration pre- and post- synapse

valproic acid (depakote) SE/ADRs & PG

drowsiness, sedation

nausea

tremor

hepatotoxicity, pancreatitis

osteoporosis

weight gain

PG D

valproic acid (depakote) dosing

divided doses if >250mg/day oral

ethosuximide (zarontin) class, indications & moa

succinimide anti-seizure medication for petit mal or absence seizures in children

reduced low-threshold Ca currents

ethosuximide (zarontin) SE/ADRs

N/V, anorexia, hiccups

drowsiness

blood dyscrasia

SLE

ethosuximide (zarontin) substrate

CYP3A4 (inducers of this with decrease drug effects; inhibitors of this will increase drug effects)

topiramate (topamax) indications & moa

generalized tonic-clonic, partial, absence seizures and migraines

reduced voltage gated Na currents, enhance GABA A receptor currents and inhibits glutamate receptor

topiramate (topamax) SE/ADRs & PG

dizziness, nausea, nystagmus, in-coordination

cognitive dysfunction

metabolic acidosis

nephrolithiasis

PG D

what interferes with BCPs?

topiramate (topamax)

what is a weak carbonic anhydrase inhibitor?

topiramate (topamax)

abrupt discontinuation of what drug can cause seizures?

topiramate (topamax)

levetiracetam (keppra) indications

myoclonic, partial-onset and tonic-clonic seizures

levetiracetam (keppra) SE/ADRs

increase BP

AKI

CNS depression, Behavior problems

muscle weakness

eosinophilia, hematologic changes

SJS-TEN

levetiracetam (keppra) dosing

up-titrate and down-titrate

renal dosing GFR<80

lorazepam (Ativan) class, indications & moa

benzodiazepine for anxiety, operative amnesia, status epilepticus

potentiates GABA A receptor

lorazepam (Ativan) SE/ADR & PG

sedation, dizziness, confusion, coma

hypoactive reflexes

respiratory depression

PG D

what medication is contraindicated in sleep apnea and acute narrow angle glaucoma?

lorazepam

lorazepam dosing may need to be decreased if it is used chronically with what drug?

valproate

categories of dementia medications

acetyl cholinesterase inhibitors

NMDA receptor antagonists

anti-amyloid

pathophys of Alzheimer's

acetylcholine deficit in hippocampus

excess glutamate signaling -> increased NMDA receptor Ca channel activity -> secondary cascades -> neuronal cell death

alzheimer's therapeutic approach

inhibit acetylcholine metabolism (inhibit acetylcholinesterase)

reduce cell death by inhibiting NMDA receptor activity

donepezil (aricept) class, indications & moa

CNS acetylcholinesterase inhibitor that increases acetylcholine concentration in hippocampus for Alzheimer's dementia - slows progression

donepezil (aricept) SE/ADR

insomnia, HA

diarrhea, anorexia

hypotension

cholinergic crisis (N/V, salvation, sweating, bradycardia)

what medication may pose an increased risk for extra-pyramidal reactions with co-administered anti-psychotics?

donepezil (aricept)

memantine (Namenda) class, indications & moa

NMDA receptor antagonist prevents excess Ca ion influx for moderate-severe alzheimers

memantine (Namenda) SE/ADRs

confusion, fatigue, HA, hallucinations, aggression

HTN

what two Alzheimer's medications can be co-administered?

donepezil and memantine

aducanumab-avwa (aduhelm) class, indications & moa

anti-amyloid monoclonal antibody for mild cognitive impairment or Alzheimer's

reduces amyloid beta plaques in cerebral vasculature

aducanumab-avwa (aduhelm) SE/ADRs

ARIA (amlyoid related imaging abnormalities) or ARIA-E (edema) or ARIA-H (hemosiderin)

AMS (confusion, delirium, disorientation, HA, visual disturbances) - often within 8 months

which medication can cause ARIA and AMS?

aducanumab-avwa (aduhelm)

what medications requires a brain MRI before treatment, week 7 and 12?

aducanumab-avwa (aduhelm) - due to ARIA

aducanumab-avwa (aduhelm) administration

IV

dextromethorphane/quinidine (neudexta) class & indications

NMDA receptor antagonist for psuedobulbar affect (PBA) and off-label for agitation and aggression in dementia

dextromethorphane/quinidine (neudexta) moa

may bind to sigma-1 receptors in brain

quinidine is used to delay metabolism

dextromethorphane/quinidine (neudexta) SE/ADRs

D/V

Dizziness, weakness

cough

peripheral edema

serotonin syndrome

dextromethorphane/quinidine (neudexta) contraindications

prolonged QTc, HF, AV block

*get ECG

grapefruit juice

Parkinson's Disease (PD)

loss of dopaminergic cells in substantial nigra - NT imbalance -> prominent motor changes and widespread neurologic symptoms with involvement of vagus N, spinal cord and peripheral autonomic system

PD symptoms

motor: tremor, rigidity, akinesia/bradykinesia, postural instability, gait abnormalities

nonmotor: sleep disturbances, fatigue, speech, pain, dysesthesia, vision, autonomic (drool, dysphagia, ortho hypotension), psych (A&D, dementia, psychosis)

motor fluctuation, akathisia, dyskinesia

PD severity: unified PD rating scale (UPDRS)

1: mention, behavior, mood

2: ADLs

3: motor

4: complications of therpay

5: modified Hoehn & Yahoo stage (symptom severity)

6: Schwab & England ADLs

does dopamine cross BBB?

no

levodopa metabolism

by dopadecarboxylase (DDC) in plasma -> reducing levodopa available to cross BBB into CNS

by COMT in serum and CNS to 3-OMD that crosses BBB but isn't effective -> blocking COMT in CNS leaves more levodopa to be converted to dopamine

carbidopa blocks DDC

classes for PD

anticholinerics

NMDA receptor antagonist

MAO-B inhibitors

dopamine agonists and supplements

COMT inhibitors

how do anticholinergics work in PD?

decrease D and Schedule imbalance -> increase D levels relatively

how do NMDA receptor antagonists work in PD?

modulate levodopa impact on NMDA receptors -> bradykinesia, rigidity, tremor

how do MAO-B inhibitors work in PD?

MAO-A metabolizes NE, serotonin, dopamine

MAO-B selectively metabolizes dopamine

inhibition -> increase CNS dopamine levels

how do dopamine agonist and supplements work in PD?

agonists stimulate dopamine receptors directly

dopamine supplement - replacement therapy

how do COMT inhibitors work in PD?

decrease levodopa metabolism to 3-OMD allowing more to be metabolized to dopamine

benzotropine (cogentin) class, indications & moa

anticholinergic for PD and extrapyramidal symptoms

inhibits ACh receptor

benzotropine (cogentin) SE/ADRs

dry mouth

blurry vision

constipation, urinary retention

sedation, cognitive impairment, hallucinations

orthostatic hypotension

temperature insensitivity

what PD symptoms does benzotropine (cogentin) help?

tremor and drooling but not as effective for bradykinesia, rigidity and gait

what medication should be avoided in patients over 70yo?

benzotropine (cogentin)

and caution in dementia

amantadine (symmetrel) class, indications, moa

NMDA receptor inhibitor for mild PD symptoms that decreases levodopa injury to NMDA receptor

amantadine (symmetrel) SE/ADRs

nausea, dizziness, hallucinations, restlessness, insomnia

livedo reticularis, peripheral edema

orthostatic hypotension

amantadine (symmetrel) dosing

dose by CrCl

avoid in CKD and elderly (anticholinergic)

Osmolex ER

long acting formulation of amantadine (symmetrel) for PD dyskinesia and drug-induced extra-pyramidal symptoms

selegiline (eldepryl) class, indications & moa

MAO-B inhibitor for PD and depression

at therapeutic doses for PD it inhibits MAO-B enzyme -> rise in available dopamine in CNS

selegiline (eldepryl) SE/ADRs

N/D

confusion, HA, hallucinations

dyskinesias, jitteriness

orthostatic hypotension

selegiline (eldepryl) contraindications

bipolar disorder

other drugs, alcohol, tyramine (higher dose -> HTN crisis)

selegiline (eldepryl) formulations & dosing

oral disintegrating tablet or capsule

limit 10mg/day

topical patch (achieves higher doses)

ropinirole (requip) class, indications & moa

non-ergot-derived dopamine (D3) agonist (directly stimulates D3 receptor) for PD and restless leg syndrome

initial therapy alone or add-on to levodopa/carbidopa