Movement Disorder Drugs

Question 1

Parkinson’s Disease - pathophysiology

Answer 1

Basal ganglia in the brain is responsible for many aspects of coordination of movement. The substantia nigra is one structure within the basal ganglia. Neurons in the substantia nigra release dopamine. Neuronal projections lead to presynaptic inhibitory D2 receptors on cholinergic interneurons in the putamen and caudate nucleus (also in basal ganglia). In Parkinson’s disease these projections in the substantia nigra are progressively lost, leading to inappropriate increased levels of released acetylcholine, causes overactivity in the caudate nucleus and putamen, thus leading to muscular rigidity and tremors.

The exact cause of the loss of these neuronal projections is not well understood but thought to be oxidative in nature.

Known causes: age, brain trauma, tumors, infection/encephalitis, toxin exposure (environmental or otherwise consumed) incl manganese, CO.

Due to redundancy of neuronal connections, no symptomology until 70% of these projections are lost.

Can occur over the age of 40, but usually presents late 50s/early 60s

Question 2

Drug therapy for Parkinsons (general characteristics)

Answer 2

Drug therapy will affect either actions of dopamine or acetylcholine

Early stage Parkinsons: drugs will work PREsynaptically

Later stage Parkinsons: drugs will work POSTsynaptically

Question 3

dopa decarboxylase

Answer 3

MOA: catalyzes the removal of a carboxyl group from dopa (specifically, l-dopa “levodopa”), thus converting it to dopamine

• if dopa decarboxylase acts on levodopa (converts to dopamine) in the periphery, it will become trapped there because DOPAMINE DOES NOT CROSS THE BBB

Question 4

does dopamine cross the blood-brain barrier?

Answer 4

NO!

Question 5

levodopa

Answer 5

MOA: direct replacement dopamine therapy

precursor to dopamine which can cross the BBB

90% destroyed in the gut

Question 6

dopa decarboxylase inhibitors (2)

Answer 6

• carbidopa

- benserazide

Question 7

carbidopa/levodopa combination drug

“sinemet”

Answer 7

combination drug for parkinsons given orally

MOA:
levodopa=dopamine precursor which crosses BBB
carbidopa= inhibits conversion dopa to dopamine

when taken together, a greater amount of dopa leaves the gut, greater availability of dopa to cross BBB

Question 8

amantadine

Answer 8

MOA: causes PREsynaptic release of dopamine

• not effective in later stage parkinsons bc stored supply of dopamine is already low or depleted

Question 9

postsynaptic dopamine agonists (list of 4)

Answer 9

bromocriptine - partial D1 agonist / full D2 agonist

pergolide - D1/D2 agonist

pramipexole - highly selective D2 agonist

ropinirole - highly selective for D2 agonist, also given for “restless leg syndrome”

Question 10

COMT inhibitors

Answer 10

MOA: increase levels of dopamine by inhibiting catechol-0-methyltranferase which degrades dopamine

• entacapone- only active peripherally
• tolcapone- active in periphery and CNS; BLACK BOX warning for hepatotoxicity

Question 11

selegiline

Answer 11

MOA: MAO type B inhibitor. metabolites include amphetamine and methamphetamine, both of which are indirect acting dopamine agonists (presynaptic uptake causes release of more dopamine)

Question 12

trihexlphenidyl

Answer 12

MOA: inhibits acetylcholine in key excitatory pathways

• usually used as an adjunct with dopaminergic drugs to control excess SLUDE from Ach activity
• sometimes used to treat early, mid parkinsons

Question 13

benztropine

Answer 13

MOA: centrally-acting antimuscarinic

• used to control the “cosmetic” effects of excess SLUDE (ie. leaky bladder, excess salivation)

Question 14

diphenhydramine

Answer 14

MOA: antihistamine/H1 antagonist, also blocks reuptake of dopamine

• adjunct therapy for parkinsonism

Question 15

ethopropazine

Answer 15

MOA: unusual phenothiazine with marked anticholinergic properties

• adjunct therapy for parkinsonism

Question 16

procyclidine

Answer 16

MOA: atropine-like muscarinic antagonist

• adjunct therapy for parkinsonism, useful to manage rigidity and excessive salivation (sialorrhea)

Question 17

general side effects of dopaminergic drugs

Answer 17

• GI: nausea/vomting/anorexia (think antipsychotic drugs that decrease dopamine are anti-emetic and cause weight gain)
• CV: orthostatic hypotension, tachycardia (DA receptors on heart)
• involuntary movements (ataxia, choreiform movements)
• neuroleptic malignant syndrome from sudden decreases in DA levels (sim antipsychotics); therefore caution with missed doses or major changes in dosing or withdrawal)
• drug interactions:CAUTION with any drug that is also directly or indirectly dopaminergic
  
  • MAO-I (hypertensive crisis),
  • vitamin B6 (increases dopa decarboxylase activity in gut thus increases peripheral dopamine levels)

Question 18

side-effects of chronic use dopaminergic drugs

Answer 18

• dyskinesias
• end-of-dose failure
• on-off-phenomenon (day-to-day fluctuations in symptomatic control due to over-exertion)

Question 19

Amyotrophic Lateral Sclerosis (ALS) Pathophysiology

Answer 19

exact cause unknown. Too much glutamate and NMDA activation

characterized by progressive muscular weakness assoc with progressive degeneration of spinal, bulbar and cortical neurons.

ultimate cause of death due to loss of diaghramatic control and respiratory compromise

Question 20

riluzole

Answer 20

MOA: inhibits glutamate release presynaptically, blocks postsynaptic NMDA, kainate-type glutamate receptors, inhibits voltage-dependent Na channels

• antispasmodic used for ALS. can increase survival up to 60 days

Question 21

baclofen

Answer 21

MOA: GABA-B agonist

• GABA-B receptors are g-coupled presynaptic receptors; binding of GABA inhibiting release of glutamate which ultimately inhibits spasticity
• antispasmodic used for ALS

Question 22

tizanidine

Answer 22

MOA: alpha-2 agonist. antispasmodic action assumed to come from increasing presynaptic inhibition of motor neurons

• used for spasticity in ALS, MS, or post-stroke

Question 23

Muscarinic antagonists for ALS (list of 5)

Answer 23

dicyclomine
flavoxate
oxybutinin
oxyphencyclimine
trihexylphenidyl

• used to control “cosmetic effects” of SLUDE

Question 24

Huntington’s disease pathophysiology

Answer 24

• genetic autosomal dominant disorder affects the neostriatum
• The Huntingtin gene provides the genetic information for a protein that is also called “huntingtin”. Expansion of a CAG triplet repeat stretch within the Huntingtin gene results in a different (mutant) form of the protein, which gradually damages cells in the brain, through mechanisms that are not fully understood.
• in huntingtons disease, peptide is malformed and may repeat 100x, not cleared by body well
• characterized by incoordination and cognitive decline and severe psychosis
• avg age onset 35-45, but ranges from 2-80
• treatment is symptomatic

Question 25

Drug interactions of Dopaminergic agonists

Answer 25

Vitamin B6- increases dopa decarboxylase in gut
MAOI- hypertensive crisis
other dopaminergics- additive effects