MOVEMENT DISORDERS

1. The etiology of this disease is unknown, but it is characterized by
   progressive muscular weakness resulting from the degeneration of spinal,
   bulbar and cortical neurons. The primary symptoms muscle atrophy,
   spasticity and respiratory compromise.
   

1. Antispasmodic treatments
   

   
   
   
   

   1. GABA_B agonist – baclofen (“Lioresal”) is one of the most
      useful treatments for the spasticity observed in ALS patients.

      
      

   2. Muscarinic receptor antagonists:

1. dicyclomine (“Bentyl”)
   

2. flavoxate (“Urispas” – used for urological disorders)
   

3. oxybutynin (“Ditropan” – used for urological disorders)
   

4. oxyphencyclimine (“Daricon”)
   

5. trihexylphenidyl (“Artane”)

Huntington’s Disease

1. An “autosomal dominant disorder” that is characterized by
   incoordination and cognitive decline. One of the primary brain areas
   affected is the neostriatum. The average age of onset is 35-45
   (range 2-80).

2. Treatment, unfortunately, amounts to treating the symptomology,
   which can include severe psychoses.
   

Parkinson’s Disease (Antiparkinson Agents):

I. As one textbook describes it, Parkinsonism is a progressive, chronic,
degenerative disorder involving brain regions that control such activities as
posture, balance, and locomotion. This is a disease that afflicts over 1
million Americans, usually over the age of 40. The precise cause of this
disease is unknown. In fact, the term Parkinson’s disease is usually used when
the cause is unknown. Some of the known causes that are not age-related are
brain disease or injury (such tumors, trauma, or encephalitis), and exposure
to environmental toxins such as carbon monoxide or manganese.

II. Several of the prominent symptoms are:

• rigidity
  
  tremor (noticeable first in the fine motor skills)
  

• bradykinesia
  

• altered gait

III Specifically, the appearance of the disease reflects an imbalance between
the inhibitory effects of the neurotransmitter dopamine (DA) and the opposing
stimulatory effects of acetylcholine (ACh) in the extrapyramidal system and
basal ganglia. More briefly, the lack of DA allows the actions of ACh to
predominate in these brain areas.

IV Given the neurological imbalance described above, treatment consists of
various pharmacological means of compensating for the loss of endogenous DA
(i.e., the different drugs used to treat this disease simply reflect the
different ways drugs can pharmacologically supplement the loss of dopamine:

A. Direct replacement - since DA itself does not cross the blood-brain barrier
(BBB), substitutes for dopamine must be given in the form of the precursor:

1. levodopa - can be given orally and crosses the BBB, but 90% is
destroyed in the gut

2. carbidopa or benserazide - inhibit DOPA decarboxylase, the enzyme which
converts levodopa to DA.

3. carbidopa/levodopa (Sinemet® or Atamet) - given together, a greater
amount of DA leaves the gut and is therefore available for transport to the
brain.

B. DA releasers - amantadine (not affective in advanced stages when
stored pools of DA are low)

100. Agonists at postsynaptic DA receptors – they can produce a greater
     incidence of psychiatric symptoms than L-DOPA
     

     
     

1. bromocriptine (“Parlodel” – an ergot derivative that is a full agonist
   at D2 receptors and a partial agonist at D1 receptors)
   

   
   

2. pergolide (“Permax” – another ergot derivative that is a D2 and a D1
   agonist)
   

   
   

3. pramipexole (“Mirapex” highly selective D2 agonist)
   

   
   

4. ropinirole (“Requip” – highly selective D2 agonist)
   

500. COMT inhibitors – inhibit catechol-O-methyltransferase, an enzyme
     that is responsible for degrading dopamine.
     

     
     
     
     

     1. entacapone (“Comtan”)
        

     2. tolcapone (“Tasmar”)

E. MAO type B inhibitors - selegiline (used when response to the
combination of carbidopa/levodopa begins to deteriorate; has interesting
metabolites)

F. Anticholinergics

1. trihexlphenidyl (“Artane” - inhibits ACh activity in key excitatory
pathways; can be used for treating early, mild parkinsonism or more often as
an adjunct with dopaminergic drugs).

2. benztropine - centrally-acting antimuscarinic

G. Others used in adjunctive therapy:

1. diphenhydramine - antihistamine (H₁ antag.) that also seems to
block reuptake of DA

2. ethopropazine - phenothiazine with marked anticholinergic properties (very
atypical of this class of drugs)

3. procyclidine - atropine-like activity that is particularly useful for
alleviating rigidity and excessive salivation (sialorrhea)

V. As you might imagine, the side effect profile for these drugs varies.
However, a review of the mechanism of action of the antipsychotics should help
in understanding most of the side effects listed below:

A. nausea and vomiting (most common)

B. anorexia

C. choreiform movements (rapid, irregular, jerky movements)

D. ataxia

E. orthostatic hypotension

F. tachycardia (DA directly stimulates the heart)

G. Neuroleptic Malignant Syndrome, if levodopa is withdrawn abruptly

VI. Problems associated with long-term treatment:

A. dyskinesias

B. end-of-dose failure (shortening of effectiveness of each dosage)

C. on-off phenomenon (large day to day fluctuations in symptomatic control)

D. secondary levodopa failure (effective drops off after 2-5 years)

VII. Drug interactions - two of the most noteworthy are:

A. an interaction with MAOI’s and other drugs that affect dopamine
neurotransmission (this is a very dangerous interaction that can lead to an
acute hypertensive episode and a stroke).

B. an indirect interaction that results from high levels of vitamin
B₆, which by itself increases gastrointestinal dopa decarboxylase
activity.

Category: Pharmacology Notes