Pharmacotherapy of Tone Disorders

Question 1

What is the principle of PD therapy?

Answer 1

To increase dopaminergic tone and decreasing cholinergic tone–balancing act.

Question 2

Peripheral and central side effects of Sinemet?

Answer 2

Peripheral: N/V, posteral hypotension, cardiac irregularities

Central: dyskinesias, psychiatric disturbances (can treat with clozapine), on/off phenomenon, sleep disturbances (somnolence), impulse control disorder (gambling, hypersexuality)

Question 3

Bromocriptine

Answer 3

Ergot-dervied older dopamine D2 receptor agonist.

Slightly less effective than L-DOPA but less likely to cause dyskinesias.

Side effects similar to L-DOPA but more psychiatric effects like delusions/hallucinations.

Question 4

Ropirinole

Answer 4

Non-ergot dopamine D2 receptor agonist.

Question 5

Pramiprexole/Rotigotine

Answer 5

Non-ergot dopamin D3/D2 receptor agonists.

Question 6

Apomorphine

Answer 6

Non-selective (D1/D2) dopamine receptor agonist for severe “off” episodes of akinesia.

VERY STRONG EMETIC–administer anti-emetic prophylactically.

Question 7

Tolcapone and Entacapone

Answer 7

Tolcapone - central/peripheral COMT inhibitor

Entacapone - peripheral COMT inhibitor

May reduce dose requirements for Sinemet.

Hepatotoxicity limits use of Tolcapone–reserved for those non-responsive to Entacapone.

Question 8

Stalevo

Answer 8

L-DOPA + carbidopa + entacapone

Question 9

Selegiline and Rasagiline

Answer 9

Irreversible MAO-B inhibition. Rasagiline more potent.

Effective monotherapy in EARLY PD but acts as adjunct to help with fluctuating responses to L-DOPA.

Question 10

Trihexyphenidyl and Benztropine

Answer 10

Muscarinic anticholinergic drugs.

Dest avoided in elderly due to potential for confusion.

Question 11

Treatment principle for Huntington’s?

Answer 11

To minimize chorea/dyskinesia by decreasing dopaminergic tone and increasing cholinergic tone.

Antipsychotic drugs to treat movement disorders, delusions/hallucinations (Haloperidol, Quetiapine) and depression (SSRIs).

Question 12

Tetrabenazine

Answer 12

Reversible VMAT2 inhibitor (vesicular monoamine transporter type 2).

Side effects of depression, increased suicide risk

Question 13

Treatment for Wilson’s Disease

Answer 13

Copper chelation and increased renal output.

Penicillamine - side effects of BM suppression and protential for cross-reactivity with penicillin

Trientine - for those intolerance of penicillamine

“Trien to increase output of copper PENnies”

Question 14

Spasticity vs. spasm

Answer 14

Spasticity = increased muscle tone due increased velocity-sensitive stretch reflexes (hyperactive stretch reflex) in UMN syndrome –> tone depends on resting level of discharge of alpha, which is regulated by gamma neurons. Treat with spasmolytics.

Spasm = involuntary muscle contraction of skeletal muscle, often due to local tissue trauma or muscle strain

Question 15

Benzodiazepenes

Answer 15

Diazepem most commonly used.

Increases GABAa receptor activation –> greater neuronal inhibition.

Used to treat both spasticity and spasm.

Question 16

Baclofen

Answer 16

GABAb analogue –> GABAb receptor agonist (GABAb receptor is GPCR).

Less than sedation than diazepam but also reduces pain. Seizures/hallucinations if withdrawn rapidly.

Oral and intrathecal administration. Advantage of intrathecal administration is reduced peripheral effects.

“Can administer Baclofen on the BACk.”

Question 17

Tizanidine

Answer 17

alpha2 adregenergic receptor–but mechanism of relief for spasticity not fully understood.

CYP1A2 metabolism–be careful of drug interactions like fluoroquinolone.

Question 18

Dantrolene

Answer 18

RYR antagonist that acts DIRECTLY/SPECIFICALLY on skeletal muscles (instead of smooth muscles due to specific isoform expression) to inhibit Ca2+ induced Ca2+ release from SR.

Can also be used for malignant hyperthermia in the setting of reaction to anesthesia of NMJ blocking agents.