Pharm I-2

Question 1

Autosomal dominant inherited disorder
◦ Caused by expansion of a CAG
trinucleotide repeat (glutamine) of the
huntingtin gene on chromosome 4

Answer 1

Huntington’s Disease

Question 2

◦ Functional overactivity in dopaminergic
nigrostriatal pathways

Answer 2

Huntington’s

Question 3

GABA and glutamic acid decarboxylase are
markedly reduced in the basal ganglia (BG)
of HD

Answer 3

Huntington’s

Question 4

depletes cerebral DA by preventing
intraneuronal storage
◦ Built up gradually
◦ Adverse effects may include hypotension, depression,
sedation, diarrhea, and nasal congestion

Answer 4

Reserpine

Question 5

depletes cerebral DA, less
troublesome side effects
◦ Inhibits VMAT2, but precise mechanism unknown

Answer 5

Tetrabenazine

Question 6

Develops in early childhood, no progression or
dementia
Treatment is symptomatic

Answer 6

Benign hereditary chorea

Question 7

Withdrawal of offending substance – levodopa,
antimuscarinics, amphetamines, lithium, phenytoin,
oral contraceptives

Answer 7

Drug-induced chorea

Question 8

for those intolerant or unresponsive to
haloperidol, may cause cardiac arrhythmias

Answer 8

Pimozide

Question 9

Cause an imbalance in DA/ACh output
from nigrostriatum (↑ACh)

Answer 9

Acute dystonic rxns
extra-pyramidal symptoms

Question 10

◦ Characterized by a variety of abnormal movements
◦ Can be irreversible, usually older patients
◦ Complication of long-term neuroleptic (antipsychotic)
or metoclopramide treatment
◦ Pharmacologic basis unclear, increasing the dose of
neuroleptics often acutely relieves the dyskinesia, but
paradoxically also causes it in the long term
D2 receptor hypersensitivity hypothesis

Answer 10

Tardive dyskinesia

Question 11

More focal or segmental, usually younger pts
◦ Same treatment as above, but anticholinergics also
effective
◦ May respond to local injections of botulinum A toxin

Answer 11

Tardive dystonia

Question 12

Characterized by unpleasant creeping
discomfort that seems to arise from deep in
the legs and sometimes the arms
May resolve with correction of coexisting
iron deficiency

Answer 12

Restless leg syndrome

Question 13

Hepatolenticular
degeneration

Answer 13

Wilson’s Disease

Question 14

Autosomal recessive inherited
neurodegenerative disorder
Marked by reduced serum copper and
ceruloplasmin concentrations and increased
copper concentration in the basal ganglia
and viscera
◦ Globus pallidus and putamen

Answer 14

Wilson’s Disease

Question 15

Treatment involves removal of excess
copper and maintenance of copper balance.
◦ Penicillamine (dimethylcysteine)
◦ Trientene hydrochloride
◦ Zinc sulfate

Answer 15

Wilson’s disease

Question 16

Acts as AMPA receptor antagonist,
blocking glutamate site
◦ Also blocks kainate receptors and Na+
channels and enhances GABA currents
◦ Highly pleiotropic (acting at multiple sites)
Used for focal seizures or adjunct for
absence and tonic-clonic seizures
Long half-life (20 hrs)

Answer 16

Topamax

Question 17

Antagonizes the glycine site on the
NMDA receptor and modulates
GABAA receptors
Very potent
Lacks sedative effects (unlike many AEDs)

Answer 17

Felbamate

Question 18

Associated with rare but fatal aplastic
anemia – restricted for use in only
extreme refractory epilepsy

Answer 18

Felbamate

Question 19

Major inhibitory transmitter in the CNS

Answer 19

GABA

Question 20

post-synaptic, specific recognition
sites, Cl- channels
Multiple binding targets

Answer 20

GABA-A

Question 21

presynaptic autoreceptors, also
postsynaptic, mediated by K+ currents

Answer 21

GABA-B

Question 22

Bind GABAA receptors, increasing
chloride influx, hyperpolarizing the
neuron’s membrane potential
◦ Increase frequency of Cl- channel opening

Answer 22

Benzodiazepines

Question 23

Also increases GABA activity in the
reticular formation leading to inactivation
of T-type Ca2+ channels, hence its use for
absence seizures

Answer 23

Clonazepam

Question 24

Barbiturate used for focal seizures, especially in
neonates. Oldest of the currently used AEDs
◦ Refractory status epilepticus
Increases the mean open duration of the Clchannel without altering channel conductance or
opening frequency
Very strong sedation, cognitive impairment,
behavioral changes
Induces p450, very long half-life (up to 2d)
Tolerance, risk of dependence

Answer 24

Phenobarbital

Question 25

prodrug, metabolized to phenobarbital

Answer 25

Primidone

Question 26

Elevates GABA levels by irreversibly inhibiting the enzyme responsible for its breakdown GABA-transaminase ◦ Restricted use in US due to risk of permanent vision loss

Answer 26

Vigabatrin

Question 27

◦ Interferes with GABA reuptake ◦ 2nd line for focal seizures

Answer 27

Tiagabine

Question 28

Block voltage-dependent Na+ channels at high firing frequencies – use-dependent (less of an effect on physiological neuronal firing

Answer 28

Phenytoin, Carbamazepine

Question 29

Blocks voltage-dependent Na+ channels at high firing frequencies ◦ Also affects K+ channels

Answer 29

Oxcarbazepine

Question 30

Blocks voltage-dependent Na+ channels and T-type Ca2+ channels

Answer 30

Zonisamide

Question 31

Blocks voltage-dependent Na+ channels ◦ Also inhibits glutamate release and perhaps affects Ca2+ channels (pleiotropic)

Answer 31

Lamotrigine

Question 32

1st line for focal seizures, some use for tonic-clonic seizures Use-dependent Highly bound to plasma proteins, displaced by valproate Induces p450 ◦ Insignificant autoinduction of its metabolism ◦ Metabolic capacity saturated easily at therapeutic levels

Answer 32

Phenytoin (Dilantin)

Question 33

Adverse effects: sedation, rashes most common ◦ Gingival hyperplasia ◦ *Significant hypotension common with IV bolus

Answer 33

Phenytoin

Question 34

prodrug for phenytoin, used for IV/IM injection

Answer 34

Fosphenytoin

Question 35

A tricyclic antidepressant used for focal seizures; some use in tonic-clonic seizures Use-dependent Induces p450 Adverse effects: ◦ Sedation ◦ Hyponatremia ◦ Nausea ◦ Visual disturbances ◦ Agranulocytosis, aplastic anemia (elderly), leukopenia (10% of pts) ◦ Rash, SJS

Answer 35

Carbemazepine

Question 36

Newer drug, closely related to carbamazepine ◦ Approved for monotherapy or add-on therapy in focal seizures May also augment K+ channels Some induction of p450 but much less than that seen with carbamazepine Sedating but otherwise less toxic than carbamazepine

Answer 36

Oxcarbazepine

Question 37

Used as add-on therapy for focal and generalized seizures Also blocks T-type Ca2+ channels Very long half-life (1-3 days)

Answer 37

zonisamide

Question 38

Add-on therapy, or monotherapy for refractory focal seizures Also inhibits glutamate release and perhaps Ca2+ channels (pleiotropic) Metabolism affected by valproate, carbamazepine, phenobarbital, phenytoin Less sedating that other AEDs Adverse effects include rash, SJS, insomnia Can also be used for bipolar affective disorder

Answer 38

Lamotrigine/ Lamictal

Question 39

caused by oscillations between thalamus and cortex that are generated by T-type (transient) Ca2+ currents

Answer 39

Absence seizures

Question 40

Acts specifically on T-type calcium channels in thalamus and is very effective against absence seizures ◦ These channels are thought to act as a type of pacemaker for thalamic neurons

Answer 40

Ethosuximide

Question 41

Long half-life (40h) ◦ Slowly titrate to effect Causes GI disturbances, low sedation

Answer 41

Ethosuximide

Question 42

Act specifically on voltage-dependent Ca2+ channel subunits called α2δ Unclear how this action leads to antiepileptic effects, but inhibition of glutamate release may be one mechanism Used in add-on therapy for focal seizures with or without secondary generalization Less sedating than classic AEDs

Answer 42

Gabapentin Pregabalin

Question 43

have important inhibitory control over neuronal firing in CNS – repolarizes neuronal cell membrane to end action potentials

Answer 43

K+ Channels

Question 44

agonists decrease hyperexcitability in the brain

Answer 44

K+ Channel

Question 45

1st line for generalized seizures, also used for focal seizures Mechanism of action is controversial ◦ K+ channel agonist, increasing outward cation currents ◦ Also blocks Na + channels and enhances GABA transmission (highly pleiotropic)

Answer 45

Valproate

Question 46

Highly bound to plasma proteins Inhibits p450 Adverse effects: CNS depressant, GI disturbances, hair loss, weight gain, teratogenic, rare hepatotoxicity

Answer 46

Valproate

Question 47

Novel AED that acts on a specific type of voltage-dependent K+ channel (M channel) 3rd line for focal seizures

Answer 47

Retigabine

Question 48

Used for seizure prophylaxis and as treatment for focal seizures and primary generalized tonic-clonic seizures

Answer 48

Levetiracetam (Keppra)

Question 49

Primary action is the regulation of neurotransmitter release by binding to the synaptic vesicle protein SV2A. ◦ Reduces release of glutamate Short half-life (6-8h) Not metabolized by p450, minimal drug interactions CNS depression

Answer 49

Levitiracetam (Keppra)

Question 50

– increase their own metabolism

Answer 50

Autoinducers ◦ Phenytoin, carbamazepine, phenobarbital, primidone