MOVEMENT DISORDERS

I. Parkinson’s Disease – progressive/chronic/degenerative disorder

a. Pathophysiology: ↓Substantia nigra pars compacta → ↓DA to caudate & putamen → ↑Ach → Rigidity
b. Causes: CNS disease/injury, environmental toxins (CO, manganese, MPTP in heroin)
c. Symptoms: anosmia (may precede), rigidity, tremor (fine motor 1st), bradykinesia, shuffling/magnetic gait
d. Cosmetic symptoms: polyuria, urinary urgency, excessive salivation = sialorrhea (caused by ↑Ach)
II. Antiparkinson Agents – work to either ↑DA levels or effects or to ↓ACh effects
a. Side Effects of ↑DA
i. Nausea & Vomiting (most common) – effects of DA in CTZ, , ↓Vitamin/nutrient (Esp. elderly)
ii. Anorexia
iii. Choreiform movements (rapid, irregular, jerky movements), Ataxia
iv. Orthostatic hypotension – β2 agonist effects of DA
v. Tachycardia – β1 agonist effects of DA
b. Side Effects of Withdrawal
i. Neuroleptic Malignant Syndrome – Levodopa withdrawn abruptly
1. Downregulation of DA receptors w/Levodopa → depleted DA effects when withdrawn
c. Side Effect of Long-term Rx
i. Dyskinesia
ii. End-of-dose failure (shortening of effectiveness of each dose)
iii. On-off phenomenon (large day to day fluctuation in symptomatic control w/exertion, fatigue)
iv. Secondary levodopa failure (effect drops off after 2-5 years)
d. Drug Interactions:
i. Vitamin B6 - ↑DOPA decarboxylase activity in GIT → ↓DA bioavailability
ii. MAOIs - ↓DA breakdown → ↑Risk of Acute HTN, stroke
e. Last Resort Treatment: Deep Brain Stimulation
ANTIPARKISON AGENTS
Drug MOA Uses/Side Effects
DA REPLACEMENT Levodopa = precursor to dopamine Early stage treatment (palliative)
Levodopa (L-DOPA) (Tyr→DOPA→DA→NE→Epi) - Indirect/presynaptic dopamingerics
Carbidopa
Carbidopa = DOPA decarboxylase inhibitor Carbidopa → ↓Gut destruction & ↓Peripheral
used in combo (Sinemet) (cannot cross BBB) side effects of Levodopa
Early stage treatment (palliative)
- Indirect/presynaptic dopaminergic releaser
DA RELEASER Anti-viral (Influenza A & Rubella)
- Adjunct to Levo/Carbidopa
Amantadine ↑ DA presynaptic release
- so levo builds up the DA in the terminal
and amantadine releases it
COMT INHIBITORS Early stage treatment (palliative)
Catechol-O-methyltransferase inhibitors →
Entacapone - Indirect/presynaptic dopaminergic
↓presynaptic DA degradation → ↑DA availability
Tolcapone Hepatotoxic – no longer used
Monoamine oxidase B inhibitor →
↓ presynaptic DA degradation → ↑DA availability
MAO-A = Alimentary (peripheral) – 5HT/NE/DA metab Early stage treatment (palliative)
MAO-B INHIBITOR
MAO-B = Brain – selective for DA metab - Indirect/presynaptic dopaminergic
Selegiline
Drug Metabolites: - Adjunct to Levo/Carbidopa
amphetamine, methamphetamine
­ DA release
Anticholinergics
Early stage treatment (palliative)
Trihexyphenidyl
Inhibits ACh activity in excitatory pathways -Adjunct to dopaminergics or for mild cases
↓ Cosmetic effects (urinary, salivation)

Central-acting mAChR antagonist Early stage treatment (palliative)

Benztropine Improves tremor & rigidity -Adjunct to dopaminergics or for mild cases
NO effect on bradykinesia ↓ Cosmetic effects (urinary, salivation)

Atropine-like activity Early stage treatment (palliative)

Procyclidine ” tremor, excessive sweating & salivation (sialorrhea) -Adjunct to dopaminergics or for mild cases
Also prescribed for drug-induced parkinsonism ↓ Cosmetic effects (urinary, salivation)
 DA Agonsist
Late stage treatments (palliative)
Ergots – less favorable - Direct acting/postsynaptic dopaminergic
Bromocriptine Full D₂ - Activates receptor directly
Partial D₁ agonist - Use when there is almost no Dopaminergic neurons for
Levodopa to work on
Greater incidence of psychiatric side effects
Late stage treatments (palliative)
- Direct acting/postsynaptic dopaminergic
Ergots – less favorable - Activates receptor directly
Pergolide
D₂ & D₁ agonist - Use when there is almost no Dopaminergic neurons for
Levodopa to work on
Greater incidence of psychiatric side effects

Late stage treatments (palliative)

- Direct acting/postsynaptic dopaminergic
Non-Ergots – more favorable - Activates receptor directly
Pramipexole - Use when there is almost no Dopaminergic neurons for
Selective D₂ agonists
Levodopa to work on
Greater incidence of psychiatric side effects
Late stage treatments (palliative)
- Direct acting/postsynaptic dopaminergic
- Activates receptor directly
Non-Ergots – more favorable - Use when there is almost no Dopaminergic neurons for
Ropinirole
Selective D₂ agonists Levodopa to work on
Greater incidence of psychiatric side effects
Rx for Restless Leg syndrome
Other Adjuncts

Diphenhydramine H1 antihistamine, also blocks DA reuptake

III. Amyotrophic Lateral Sclerosis (ALS)

a. Pathophysiology: progressive muscular weakness from degeneration of spinal, bulbar & cortical neurons
i. Loss of descending inhibitor inputs to spinal cord → spasticity
b. Symptom:
i. muscle atrophy
ii. spasticity
1. caused by increased release of Glutamate
iii. respiratory compromise
c. Treatment: antispasmodics & anti-musarinics
ANTISPASMOTICS / MUSCLE RELAXANTS
Drug MOA Uses Side Effects Other
Pre-synaptic: inhibits Glut release

Post-synaptic: Glut receptor inhibitor

Riluzole ALS Nausea, vomiting ↑Survival by ~60 days
(NMDA & kainate-type)

V-G Na+ channel blocker

GABAB agonist (pre-syn GCPR) Drowsiness GABA-A = Cl- channels, post-
ALS spasticity synaptic, inhibitory
Baclofen ↓ presynaptic Glut release → Lightheadedness GABA-B = GCPR, presynaptic,
Neuropathic pain
↓ spacticity Dizziness inhibitory
ALS/MS/Post-stroke spasticity Drowsiness Clonidine – another α2
α2 agonist → presynaptic inhibition of Neuropathic pain, Insomnia – Orthostatic HTN agonist, also used for
Tizanidine
motor neurons no next day drowsiness or Dizziness neuropathic pain as a patch
hangover Asthenia (weakness) (esp. for pain with Shingles)
 ANTIMUSCARINICS
Dicyclomine
Oxyphencyclimine
To treat “Cosmetic Symptoms” under muscular control
Trihexyphenidyl
For urinary incontinence, urgency
Flavoxate
Oxybutynin

IV. Huntington’s Disease – AD disorder, degeneration of neostriatum (Caudate), avg. age of onset = 35-45
a. Genetics: Malformed Hunting tin protein due to AG trinucleotide repeat
i. Anticipation: ↓ age of onset & ↑severity w/subsequent generations
b. Symptoms: incoordination, prominent cognitive decline (psychosis)
c. Treatments: only palliative/symptomatic (antipsychotics, antispasmodics, antimuscarinics)