DSA33 - Treatment of Movement Disorders

(Dopamine/Anti-ACh) agents are superior for PD Treatment, while (Dopamine/Anti-ACh) agents primarily help with tremors BUT not bradykinesia

Dopamine; Anti-ACh

Generally, the (earlier/later) therapy is initiated, the longer the delay until debilitating morbidity occurs

earlier

What are the 3 basic principles for PD Treatment?

1. Prevent disease progression

2. Prevent need to start L-DOPA

3. Minimize s/e of L-DOPA

Levadopa/Carbidopa (L-DOPA, Sinemet) MoA

Dopamine Replacement (converted to dopamine in catecholamine neurons via the enzyme DOPA-decarboxylase)

Carbidopa is added to L-DOPA therapy in Parkinson disease because it does what?

Inhibits peripheral L-aromatic amino acid decarboxylase (DOPA decarboxylase)

Levadopa/Carbidopa (L-DOPA, Sinemet) Tx

Common for Parkinson's, but less preferred

Levadopa/Carbidopa (L-DOPA, Sinemet) S/E

N/V ==> DYSKINESIA (Chorea, Ballismus, Athetosis, Tics/Tremor) + Dysrhythmia (increased Catecholamines) + Behavior Changes

What is a very common S/E when L-DOPA dose is too high?

Choreiform Movements

Why can't anti-emetics be used to treat N/V seen with L-DOPA S/Es?

B/C blockade of DA receptors worsens Parkinson's

T/F - Haloperidol/other DA-receptor blockers CAN be used to treat Dyskinesia seen with L-DOPA S/Es

FALSE

What can you treat the L-DOPA behavior disturbances with, if not with conventional antipsychotics (b/c of their anti-DA action)?

Atypical antipsychotics (Olanzapine)

Why is L-DOPA sometimes necessary in PD Treatment?

B/C DA itself cannot penetrate the CNS

Why is L-DOPA NOT a popular initial Treatment for PD?

When L-DOPA therapy fails, adequate control of symptoms by any combination of drugs becomes extremely difficult.

What happens when L-DOPA therapy fails (after 4-5 yrs)?

1. Response fluctuations (dyskinesia/akinesia)

2. End of Dose failure (time before next dose)

3. "On-off" Periods (Akinesia periods)

Define Neuroleptic Malignant Syndrome

High fever

Sweating

Confusion

Renal failure

Increased CPK

Due to antipsychotics/Sudden termination of L-DOPA (sudden reduction in brain DA function)

What should be done if Anti-psychotic (D2 receptor antagonists) cause "Drug-Induced Parkinsonism"?

-Reduce dose/Switch drug

-Add Anti-ACh

-Add Amantadine

What is the typical progression for EARLY Tx of PD?

Start with MAO-B Inhibitor and/or D2 Agonist --> L-DOPA if need be later

What is the benefit of administering Levodopa & Carbidopa together (aka Sinemet)?

Reduces dose of L-DOPA b/c MORE GETS TO BRAIN --> fewer peripheral side effects

What does MAO-B do?

It's the primary isoenzyme that degrades DA in the striatum

Selegiline MoA

MAO-B Inhibitor - inhibits DA metabolism in the striatum

Selegiline Tx

Early Parkinson's (slow progression) - more ADJUNCTIVE to improve response to L-DOPA

Selegiline S/E

Insomnia & Behavioral changes (due amphetamine & methamphetamine metabolites); C/I with TCAs & SSRIs (risk of serotonin syndrome)

What is another more dangerous metabolite of Selegiline? Why is it more dangerous?

Desmethylselegiline; may be anti-apoptotic

Define Serotonin Syndrome

A potentially life threatening syndrome that can occur with any medication that increases levels of serotonin --> profound sympathetic activity with hyperthermia

Rasagiline MoA

MAO-B Inhibitor - inhibits DA metabolism in the striatum

Rasagiline Tx

Early Parkinson's (slow progression) - MORE neuroprotective than Selegeline

Rasagiline S/E

Not as severe as Selegiline (NOT converted to amphetamine)

Why is there little risk of a hypertensive crisis with MAO-B Inhibitors (unlike non selective MAO inhibitors)?

They don't greatly affecting degradation of catecholamines in other brain regions or in the periphery

Why should Nonselective MAOIs NOT be used for PD?

Would lead to hypertensive crisis when combined with L-DOPA therapy

Pramipexole MoA

Direct Dopamine Agonists - Affects D3 (part of D2 family) as neuroprotective agent

Pramipexole Tx

Early AND Advanced Parkinson's (slow progression) - monotherapy or combo w/ L-DOPA

Pramipexole S/E

May produce N/V, mental disturbances (compulsivity) + Psychotomimetic effects; exacerbate schizophrenia

Ropinirole MoA

Direct Dopamine Agonists - selective for D2

Ropinirole Tx

Early AND Advanced Parkinson's (slow progression) - monotherapy or combo w/ L-DOPA

Ropinirole S/E

May produce N/V, mental disturbances (compulsivity) + Psychotomimetic effects; exacerbate schizophrenia

What are the specific behavioral side effects of Dopamine Agonists?

-Addictive behaviors

-"Out-of-character" behaviors for pt (gambling, overtly sexual activities, etc.)

-Compulsive behaviors

Entacapone MoA

Catechol-O-Methyl Transferase (COMT) Inhibitor - active in periphery

Entacapone Tx

Parkinson's - used to smooth response to L-DOPA (may permit lowering dose) by reducing 3 O-MD

Benztropine MoA

Antimuscarinic/Anticholinergics (CNS Active - aka more lipid soluble)

Benztropine Tx

Parkinson's/Side effect of DA Antagonist - improve tremor & rigidity BUT not bradykinesia

Benztropine S/E

Dry mouth, urinary retention, constipation; C/I = prostatic hyperplasia, obstructive GI disease, glaucoma , WORSENS DEMENTIA

Biperiden MoA

Antimuscarinic/Anticholinergics (CNS Active - aka more lipid soluble)

Biperiden Tx

Parkinson's/Side effect of DA Antagonist - improve tremor & rigidity BUT not bradykinesia

Biperiden S/E

Dry mouth, urinary retention, constipation; C/I = prostatic hyperplasia, obstructive GI disease, glaucoma , WORSENS DEMENTIA

Trihexyphenidyl MoA

Antimuscarinic/Anticholinergics (CNS Active - aka more lipid soluble)

Trihexyphenidyl Tx

Parkinson's/Side effect of DA Antagonist - improve tremor & rigidity BUT not bradykinesia

Trihexyphenidyl S/E

Dry mouth, urinary retention, constipation; C/I = prostatic hyperplasia, obstructive GI disease, glaucoma , WORSENS DEMENTIA

Amantadine MoA

Miscellaneous (may influence synthesis, release, or reuptake of DA) - may have anticholinergic and glutametergic effects

Amantadine Tx

Parkinson's

Amantadine S/E

Insomnia, restlessness, depression, GI disturbances, Toxic psychosis; C/I = seizure disorders, congestive heart failure

Bromocriptine MoA

Ergot Alkaloid (Ergot-derived dopamine agonist)

Bromocriptine Tx

Parkinson's (more outmoded nowadays due to S/Es)

Bromocriptine S/E

Vasospasm; Psychotomimetic and dyskinetic; PROFOUND N/V

What is the general principle in Treating Huntington's Disease?

Decrease DA instead of increasing GABA (this will in turn decrease negative input to GABA neurons --> indirectly allows for GABA levels to rise)

Tetrabenazine MoA

Blocks VMAT2 uptake process (NOT competitive) --> reduces DA in storage vesicles/reduces DA release

Tetrabenazine Tx

Early Huntington's

Tetrabenazine S/E

Blunts emotionality & thought process; May produce depression

Although Antipsychotics (such as competitive D2 receptor antagonists) can be used to treat Huntington's, what are some significant side effects of these drugs?

Parkinson-like Syndrome, Dystonias, Neuroleptic Malignant Syndrome

How are the S/Es of D2 Antagonists Treated?

1. D/C Antagonist (i.e. haloperidol/risperidone) and Sub w/ Atypical Antipsychotic

2. May also continue offending agent & address motor abnormalities with CNS Anti-ACh agent

Propanolol MoA

Beta-Blocker

Propanolol Tx

1st choice Essential Tremor (ET) - PRN or chronically (depends on severity)

Propanolol S/E

C/I in Asthma or Obstructive Lung Disease

Primidone MoA

Analog of phenobarbital (long acting barbituate) --> Enhances GABA neurotransmission

Primidone Tx

2nd choice ET (slower onset)

Primidone S/E

Drowsiness

If neither Propanolol nor Primidone is successful alone to treat ET, what can you do?

Combine the drugs

While low dose alcohol can ameliorate ET, what is danger of this?

-Tremor can worsen as EtOH wears off

-Can lead to tolerance

Which fiber carries information about the stretch on the muscle and tendons?

Ia fiber

What neurotransmitter is used to stimulate contraction of stretched muscles/inhibit antagonist muscles after Ia fibers transmits the necessary information?

Glutamate (directly excites agonist AND excites inhibitory interneuron)

What neurotransmitter is used by the inhibitory neuron to inhibit the antagonist muscle?

GABA

Baclofen MoA

Acts at GABA(B) receptors more in Spinal Cord (increases K+ conductance) --> Inhibits excitation of alpha motor neurons for antagonist muscle AND decreases glutamate for agonist muscle

Baclofen Tx

Spasms (from spinal injury, ALS, MS, or Cerebral Palsy) - given INTRATHECALLY (cord site is critical for administration)

What is used for continuous intrathecal administration of Baclofen?

Implantable osmotic pump

Baclofen S/E

BLACK BOX = Sedative-hypnotic type of withdrawal; Drowsiness, Lassitude (lack of energy), Muscle weakness, Constipation, Urinary Retention

What are some warnings with Intrathecal administration of Baclofen?

-Seizures when drop stops

-Muscle rigidity --> RHABDOMYOLYSIS (with fever & organ damage)

Tizanidine MoA

Acts at Alpha2 receptors AND decreases release of glutamate from Ia neurons in spinal cord; Clonidine analag

Tizanidine Tx

Spasticity esp for MS

Tizanidine S/E

Alpha 2 blockade in brainstem = Hypotension, Drowsiness; SEVERE HTN WITHDRAWAL

Diazepam MoA

Benzodiazepine - increases GABA by facilitating GABA at GABA(A) receptor (increases Cl- conductance)

Diazepam Tx

Spasms/Spasticity (MS & spinal lesions); may be used with Baclofen for night time MS spasm

Gabapentin MoA

Anti-neuropathic pain and antiseizure drug; Acts at Ca2+ channels (voltage dependent)

Gabapentin Tx

Spasticity from MS

Gabapentin S/E

Somnolence, dizziness, ataxia, headache & tremor

For acute muscle injury, what is usually given for pain (and also for spasms - IF there's NO SPINAL CORD INVOLVEMENT)?

Ibuprofen

Metaxalone MoA

Likely CNS mechanism (unknown)

Metaxalone Tx

Spasms - esp muscle spasms

Metaxalone S/E

Somnolence, dizziness, ataxia, headache & tremor

Methocarbamol MoA

Global CNS depression

Methocarbamol Tx

Spasms

Methocarbamol S/E

Drowsiness, Dizziness - a/w falls & Fxs (esp with elderly)

Carisoprodol MoA

Likely GABAergic - metabolized to meprobamate (used for anxiety and sleep disorders)

Carisoprodol Tx

Spasms - IV use, limited to 3 consecutive weeks

Carisoprodol S/E

Drowsiness, dizziness, potential for abuse, dependence and tolerance

Cyclobenzaprine MoA

Unknown

Cyclobenzaprine Tx

Spasms

Cyclobenzaprine S/E

Drowsiness, dizziness, urinary retention, constipation - a/w confusion & increased risk of falls

Dantrolene MoA

Skeletal muscle relaxant (interferes with release of calcium ions from sarcoplasmic reticulum )

Dantrolene Tx

Spasms - peripherally active; can reduce contractions by 75%

Dantrolene S/E

Cerebral spasticity, IV for malignant hyperthemia, external sphincter hypertonicity, muscle weakness (NOT FOR OUTPATIENT), Dose-related hepatocellular injury; NOT FOR ALS

Botulinum Toxin MoA

Acts presynaptically in acetylcholine neurons to block the release of acetylcholine --> decrease muscle contraction