Anticonvulsants and Anti-Parkinsonians

Okay WARNING of course our professor for this section was older than dirt so he's so out of date it's crazy. So this is not the PANCE deck, this is the test deck!!

Seizures

The clinical manifestation of an abnormal and excessive excitation of a population of neurons

Epilepsy

A tendency towards recurrent seizures unprovoked by systemic or neurologic insults

Tonic-clonic, absence, status epilepticus, atypical (myoclonic, atonic)

Types of generalized seizures

simple, complex, partial evolving to generalized

Types of partial seizures

Tonic-clonic (grand mal)

Which type of seizure is characterized by an aura, epileptic cry, LOC and loss of postural tone, tonic spasm of the entire body, synchronous clonic movements that are followed by confusion and sleep

synchronous, bilateral, high voltage polyspike

EEG changes for Grand Mal

Absence (petit mal)

Which type of seizure characteristically occur in childhood and includes a 5-10 sec LOC that looks like day dreaming and may have local/widespread clonic movements

with epilepsy, with acute disorders affecting the brain, after rapid withdrawal of anticonvulsants

Status epilepticus may develop in patients…

local, unilateral discharge

EEG change for simple partial Seizures

Simple partial

Which type of seizure is characterized by consciousness and is often limited to certain muscles, specific sensory changes, or autonomic activity (may spread causing progressive symptoms - jacksonian march)

Complex partial

Which type of seizure is characterized by impaired consciousness, stereotype movements, and flashbacks that usually originate in the temporal or frontal lobes

bilateral or unilateral changes

EEG changes in complex partial

Drugs, EtOH, DM, fever, anoxia, brain tumor, head trauma, photosensitivity (television, raves, etc), hormone; vascular (SAH, ischemic strokes), infectious (meningitis, etc), trauma (epidural hematoma), autoimmune (SLE), metabolic (hyponatremia, glucose), Ecclampsia

For seizure with a KNOWN etiology (28%) what are some triggers?

Ion conductance of neuronal membranes, Defects in GABA neuronal circuitry (Decreased GABA), overactivity of glutamatergic transmission

What is happening at the neuronal level for seizures?

phenobarb, primidone, ethosuximide

Which AEDs decrease the excitability of the focus?

phenytoin, phenobarb, carbamazepine, valproate

Which AEDs prevent the spread of nervous activity?

valproate, Benzos, phenobarb, primidone

Which AEDs enhance inhibitory mechanisms?

Sedation at therapeutic doses (NOT phenytoin), blood dyscrasias (NOT benzos), teratogenic potential, may induce CYP450s,

Common Characteristics of AEDs

antacids and antihistamines (decrease absorption)

DDIs for AEDs

Phenytoin

The 1st drug for seizures that is the drug of choice for grand mal seizures (also used for partial, status epilepticus, trigeminal neuralgia)

Inhibits sodium channels reactivation (potassium potentiates this)

MOA for phenytoin

Highly bound, slow oral absorption, Zero order kinetics

PK rules for Phenytoin

10-20 (therapeutic), 20+ (Nystagmus, thought disorders, sedation, diplopia), 30+ (Loss of coordination, confusion, hyperactivity), 40+ (lethargy, stupor, coma)

Describe the ranges for Phenytoin

hirsutism, blood dyscrasias, teratogenic, gingival hyperplasia, osteomalacia

ADRs for phenytoin

Grand mal, partial, trigeminal neuralgia (#1 draft pick)

Uses for carbamazepine

inhibits Na+ reactivation, inhibits Ca2+ influx

MOA for carbamazepine

Slowly absorbed, 70% bound, 10-20 hr t1/2, liver microsomal enzyme activity

PK for Carbamazepine

teratogenic, Aplastic anemia, agranulocytosis, involuntary motor activity (elderly), temporary taste disorder, OD symptoms (dizziness, diplopia, drowsiness, ataxia, slurred speech)

ADRS for Carbamazepine

tonic-clonic, partial seizure, #1 choice for seizures in infants

Uses for Phenobarb

Enhances the binding of GABA (inhibits voltage-gated Ca2+ currents to prevent NT release)

MOA for phenobarb

Slowly absorbed, 50% bound, 50-140 hr T1/2, liver metabolism, induces p450s for tetracycline and other antibiotics

PK of phenobarb

sedation, depression of Cardio and respiration, hepatotoxicity, megaloblastic anemia, osteomalacia, NOT teratogenic but enhances phenytoin

ADRs for phenobarb

saliva

How do you test AED levels

Tonic-clonic, complex partials

Uses of primidone

Rapidly and completely absorbed after oral, 5-15 t/12, 2 active metabolites (phenobarb and PEMA)

PK for primidone

SAME as phenobarb + maybe some action at Na+ channels

MOA for primidone

sedation, depression of Cardio and respiration, hepatotoxicity, megaloblastic anemia, osteomalacia, NOT teratogenic but enhances phenytoin, acute intox, acute psychotic reactions (rare)

ADRS for primidone

absence seizures, PREFERRED IN PREGNANCY

Uses for ethosuximide

Inhibits activity T-type calcium channels

MOA for ethosuxmide

rapidly absorbed by GI tract, metabolized by liver,

PKs for Ethosuximide

GI distress, transient CNS depression, blood dyscrasia (rare), bone marrow depression,

ADRs for ethosuximide

absence, tonic clonic, myoclonic, partial, chronic neuropathic pain

Uses for Valproic acid

prolonged inactivation of Na+ channel, inhibits T-type Ca2+ channels, increases GABA levels

MOA for valproic acid

completely absorbed from GI tract, highly bound, 10-15 hr T1/2, excreted in the urine after conjugation and oxidation

PK for valproic acids

GI distress, sedation, severe hepatotoxicity, teratogenic (neural tube defects), increases phenobarb

ADRs for valproic acid

Absence (clonazepam), partial (clorazepate), myoclonic (clonazepam), status epilepticus (diazepam, lorazepam)

Uses for Benzos (lorazepam, diazepam, clonazepam, clorazepate)

enhances the binding of GABA (desmethyldiazepam is the anti-convuslant metabolite)

MOA for Benzos

Well absorbed, tolerance develops in 1-6 months

PKs of Benzos

hyperactivity (children)

ADRs for benzos

partial seizures adjunct, trigeminal neuralgia, neuropathic pain (DM)

Uses for Gabapentin

binds voltage gated Ca2+ channels, does not interact with GABA receptors

MOA for gabapentin

excreted unchanged, does not affect other AEDs

PKs for gabapentin

partial seizures adjunct, bipolar depressive

Uses of Lamotrigine

Action on Na+ channels

MOA of lamotrigine

SJS, flu-like symptoms

ADRs for lamotrigine

partial seizures

Felbamate uses

aplastic anemia (may require bone marrow transplant)

ADRs for felbamate

Dopaminergic agents (levodopa/carbidopa and dopamine agonist) COMT inhibitors, MOAB inhibitors, anticholinergics, amantadine

Drugs for Parkinson’s Disease (PD)

Levodopa

What is the most effective drug for parkinsonian symptoms but requires active transport since its a large neutral amino acid

Nausea, postural hypotension, dyskinesias, motor fluctuations

ADRs of levodopa

Increases levodopa in the brain, decreases peripheral conversion

Why do we add carbidopa to levodopa?

Does not cross BBB, blocks levodopa metabolism in the periphery

Tell me about Entacapone (COMT)

Cross BBB, longer t1/2 than entacapone, hepatotoxic

Tell me about Tolcapone

N/V, orthostatic hypotension, arrhythmias

Acute ADRs of levodopa that can be controlled by lowering the dose

Dyskinesias, psychiatric disturbances (psychosis)

Chronic ADRs of levodopa that can be controlled by lowering the dose

wearing-off effect (end of dose akinesia), on-off phenomenon

irreversible levodopa ADRs

Smaller doses more frequently, drug holidays, dopamine agonists, MAOBs, sustained release formulation

Treatment for off-on phenomenon

phenothiazines (blocks benefits), Epi (potentiates ADRS, arrythmias)

DDIs for levadopa

pergolide, bromocriptine, pramipexole

Dopamine receptor agonist examples

directly stimulate dopamine receptors, no metabolic conversion, no absorption delay, longer t1/2, mono or adjunct, may delay motor fluctuations and dyskinesia

Quirks of dopamine agonists

N/V, dizziness, postural hypotension, HA, drowsiness, somnolence, dyskinesia, confusion, hallucinations, paranoia

ADRs for dopamine agonists

Irreversible MAO-B inhibition (inhibits dopamine metabolism in the brain - lessens on-off effects)

MOA for selegiline

insomnia, hallucination, nausea, DDI with TCAs and SSRI

ADRs for selegiline

tremor, bradykinesia, rigidity, dyskinesia

Which symptoms of of parkinson’s disease does amantadine treat?

enhancing release of dopamine, inhibits presynaptic uptake of catecholamines, dopamine receptor agonist, NMDA receptor blockage

MOA for amantadine (theoretically)

autonomic, psychiatric

ADRs of amantidine

Dopaminergic depletions → cholinergic overactivity

Why do anticholingergics help with parkinson’s (especially with initial therapy OR as an adjunct)

trihexyphenidyl, benztropine, ethopropazine

Common anticholinergic agents

dry mouth, sedation, delirium, confusion, hallucination, constipation, urinary retention

ADRs of anticholinergics