Anticonvulsant and Antiparkinson Drugs

Question 1

Definition of Epilepsy

Answer 1

A family of chronic neurologic disorders caused by development of a persistently low seizure threshold, manifested by periodic, unpredictable seizures.

Prevalence of 1% by age 20, and 3% by age 80

70% are on anticonvulsants
20% undergo surgery
10% is intractable

Question 2

Principles of pharmacotherapy

Answer 2

Treatment is symptomatic
Most anticonvulsants have low therapeutic index
Pharmacokinetics are important

Question 3

Na channel targeting AEDs

Answer 3

Phenytoin
CARBAMAZEPINE (1974)
Lamotrigine
Fosphenytoin
Lacosamide

Question 4

Ca2+ channel targeting AEDs

Answer 4

ETHOSUXIMIDE 1960
Gabapentin
Pregabalin

Question 5

SV2A receptor AEDs

Answer 5

LEVETIRACETAM 1999

Question 6

AEDs with multiple targets

Answer 6

VALPROATE 1987
Felbamate
TOPIRAMATE 1996
Zonisamide

Question 7

GABAa receptor AEDs

Answer 7

Phenobarbital
Primidone
DIazepam
Clonazepam
Clorazepate

Question 8

GABA transporters AEDs

Answer 8

Tiagabine

Question 9

GABA transaminase AEDs

Answer 9

Vigabatrin

Question 10

Potassium Channel Opener AEDs

Answer 10

Retigabine

Question 11

AMPA receptor antagonist AEDs

Answer 11

Perampanel

Question 12

1st mechanism of AED action

Answer 12

They enhance the inactivation of Na+ channels

Carbamazepine (Tegratol)
Topiramate (Topomax)

Question 13

Carbamazepine (Tegratol)

Answer 13

Induces P450 - chronic treatment shortens half life from 36 to 8-12 hours.

Common adverse reactions include diplopia, ataxia, and drowsiness.

Can also be used for neuropathic pain and treatment of bipolar disorder.

Question 14

Topiramate (Topomax)

Answer 14

Fructose-like (analogous)
Has multiple mechanisms of action including Na channel blocking, increase of affinity of GABA for its receptors, and blocks AMPA-type glutamate receptors

Half life is 21 hrs which is mostly just excreted unchanged in the urine

Can be used for migraine prophylaxis
Broad spectrum anticonvulsant, and widely used

Causes sleepiness, dizziness, balance issues, and often resolved over time

Question 15

2nd mechanism of AED action

Answer 15

Blocking of Ca channels

Ethosuximide (Zarontin) is used to accomplish this.

Question 16

Ethosuximide (Zarontin)

Answer 16

Drug of choice for absence epilepsy (A type of seizure that involves brief, sudden lapses in attention)

T-type Ca channels are not involved in transmitter release? What does this mean?

No plasma protein binding

Half life of 40-60 hours with renal excretion

Question 17

3rd mechanism of AED action

Answer 17

Enhancement of GABAergic inhibition

Drugs used to accommodate this:
Tiagabine
VALPROATE
Vigabatrin
Lorazepam

Question 18

Valproate (Depakote)

Answer 18

Broad spectrum anticonvulsant that has a sustained release form (Divalproex Na)

Hepatotoxicity - Contraindicated in hepatic disease, and children younger than 2

Mixed mechanism that also blocks Na channels

Can also be used for bipolar, migraine, and prophylaxis

Question 19

AEDs that induce metabolism of other drugs

Answer 19

Carbamazepine
Phenytoin
Phenobarbital

Question 20

AEDs that inhibit metabolism of other drugs

Answer 20

Valproate

Felbamate

Question 21

AEDs that are highly protein bound

Answer 21

Valproate

Phenytoin

Question 22

3A4*1B

Answer 22

A P450 isoform that causes increased toxicity and decreased clearance of some AEDs. Mostly found in African Americans (53-69%), and Caucasians (4-11%).

Drugs this enzyme acts on are:
Carbamazepine
Ethosuximide
Clonazepam
Lamotrigine
Topiramate
Tiagabine

Question 23

Most common by seizure type

Answer 23

Partial Complex: Carbamazepine, Tiagabine, levetiracetam

Generalized Tonic-Clonic: Valproate

Absence: Valproate (if t-c also present)

Myoclonic: Valproate

Question 24

Basal Ganglia Disorders

Answer 24

Parkinsonism - Degeneration of dopaminergic neurons in substantia nigra pars compacta

Huntington’s Disease - Degeneration of cholinergic and GABAergic striatal neurons

Ballism - Damage to one subthalamic nucleus (often due to vascular accident)

Tardive Dyskinesia - Iatrogenic disorder due to long term treatment with antipsychotics

Question 25

Parkinsonism

Answer 25

Motor Symptoms:
resting tremor, cogwheel rigidity, brdykinesia, stooped posture

Slowly Progressive:
Affecting approximately 1 million Americans with onset at about 60 years of age

First disease of the brain to have molecular basis of degeneration of >40% of nigral dopaminergic neurons

Question 26

Treatment 1 for Parkinsonism

Answer 26

Replace lost Dopamine with L-DOPA and Carbidopa
L-DOPA + Carbidopa = Sinemet (Dopamine Precursor)

Can cause nausea and cardiac arrhythmias

Question 27

Long term effects of L-DOPA

Answer 27

Dyskinesias, end of dose deterioration, On-Off effect

Hallucinations, delirium, depression and sleep disturbances can be treated with Clozapine, which is a D2 agonist that blunts psychotic effects

Question 28

Treatment 2 for Parkinsonism

Answer 28

Directly activate Dopamine receptors in striatum

Drugs:
Ropinirole (Requip), a D2 receptor agonist, well absorbed orally with a 6 hr half life. Fewer dyskinesias than L-DOPA. Can be used initially or in combination with L-DOPA but causes nausea from orthostatic hypotension, and mental confusion with impulsive behavior and hallucinations.

Rotigotine (Neupro patch), got FDA approval in 2016 and available as a transdermal patch

Question 29

Treatment 3 for Parkinsonism

Answer 29

Scavenge free radicals and inhibit MAO-B

Drug:
Selegiline (Eldepryl)
Metabolized to methamphetamine stimulating DA release, MAO-B found in 5HT but not DA neurons in Sub. Nigra

Drug interactions with tricyclic antidepressants and SSRIs can cause serotonin syndrome (hyperthermia, hypertension, and rigidity)

Question 30

Huntington’s Disease

Answer 30

Caused by triplet repeat expansion of Huntingtin

Autosomal dominant inheritance

GABAergic & cholinergic striatal neurons die

Treated with Tetrabenazine = VMAT2 inhibitor