Autonomic pharmacology

Dopamine related Drugs in Parkinson's Disease

Catechol-O-methyltransferase (COMT) inhibitors:^101,108,128
- Catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) catalyze transformation of dopamine (and L-DOPA).^101,108,128
  - Specifically, COMT catalyzes methyl group transfer from S-adenosyl-L-methionine resulting in, for dopamine, a pharmacologically inactive 3-methoxytryptamine and in the case of L-DOPA, 3-O-methyl DOPA.
  - As noted earlier, L-DOPA administration (oral) is associated with about 99% catabolism, by the action of aromatic L-amino acid decarboxylase; however, concurrent administration of carbidopa, an aromatic L-amino acid decarboxylase inhibitor, reduces peripheral L-DOPA to dopamine conversion.
    - However, carbidopa administration also results in increased likelihood of L-DOPA conversion to 3-O- methyl DOPA.
    - The therapeutic rationale for administration of COMT inhibitors then is blockade of peripheral L-DOPA transformation to 3-O-methyl DOPA. As a result of COMT inhibition both L-DOPA half-life is extended and an increased amount of each L-DOPA dose reaches the brain.
- Examples of COMT inhibitors include tolcapone (Tasmar) and entacapone (Comtan).^101,108,128
  - Tolcapone (left) and Entacapone (right)
  - These agents reduce clinical symptoms of "wearing off" in patients receiving L-DOPA/carbidopa therapy.
  - Both clinical efficacy and mechanism of action of these agents are similar.
  - Generally, entacapone is preferable to tolcapone because tolcapone administration has been associated with a low incidence of hepatic and hematological adverse effects. ^101,108,128
    - Tolcapone administration may result in a dose-dependent elevation of hepatic aminotransferase which occurs in about 1% to 3% of cases.
    - Moreover, acute fulminant liver failure may rarely occur.
    - Because of this hepatic effect, tolcapone administration should be accompanied by ALT/AST (ALT, alanine transaminase; AST, aspartate aminotransferase) monitoring every 2-4 weeks for the first half-year and "periodically" after that.
    - As a further precaution, tolcapone should not be prescribed to individuals with pre-existing liver disease and its administration halted if ALT/AST levels exceed 2 times the upper limit of normal. [The aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio may be used as both an indicator of liver damage and facilitate differentiation between liver damage potential causes.]
    - Tolcapone exhibits a long duration of action; by contrast, entacapone duration of action is approximately 2 hours and may be given along with each dose of L-DOPA/carbidopa. Tolcapone acts both centrally and peripherally; whereas, entacapone acts peripherally.
- Adverse effects:^101,108,128
  - Adverse effects associated with COMT inhibition may be in part due to increased L-DOPA.
    - These effects include dyskinesia, confusion, and nausea. A temporary initial reduction in L-DOPA dosage (about a 30% reduction) in the first two days will typically either avoid or reverse these complications.
    - Some other adverse effects include abdominal pain, diarrhea, orthostatic hypotension, sleep disorder, and orange urinary discoloration.
    - As noted earlier, tolcapone has been associated with acute hepatic failure on rare occasions.
      - This side effect is of sufficient concern to require, in the United States, a signed patient consent along with liver function monitoring.
- Stalevo is a combination drug consisting of L-DOPA along with carbidopa and entacapone. An advantage of this preparation is simplification of the drug regimen, allowing consumption of a reduced number of tablets per day.¹²⁸

There are two principal forms or isoenzymes of monoamine oxidase (MAO).

These forms are designated MAO-A and MAO-B.

Both isoforms are present in the periphery and inactivate intestinal monoamines.

However, MAO-B is the principal form found in the stratum; furthermore, this form is the form responsible for oxidative catabolism of brain dopamine.

Percentage of total MAO-A and MAO-B enzymatic activity in some human tissues^{135,135a,135b,135c}
Tissue	MAO-A Percent Activity	MAO-B Percent Activity
Brain	<20%	>80%
GI Tract	>80%	<20%
Kidney	25%	75%
Lung	55%	45%
Platelets	<5%	>95%

The rationale for use of MAO-B inhibitors is that they may increase steady-state dopamine levels and thus mitigate reduced striatal dopamine effects.
MAO-B inhibitors at appropriate doses are relatively selective and are classified as irreversible inhibitors of monoamine oxidase.
- If these agents are used alone, as monotherapy, some symptomatic motor benefit is likely to occur.
- Also, MAO-B inhibitors in combination with carbidopa/L-DOPA enhance the carbidopa/L-DOPA effect.

Classically, administration of MAO inhibitors or even MAO-A inhibitors is associated with the warning that ingestion of foods containing tyramine may precipitate hypertensive reactions.
- These reactions occur because tyramine, a vasopressor, is normally inactivated in the G.I. tract by MAO which, when inhibited, allows tyramine access to the blood.
  - Such dietary tyramine limitations do not apparently apply to MAO-B inhibitors, at least at the recommended doses.
As a reminder, specificity in drug action is intimately tied to drug concentration.
- In this case, MAO-B inhibitors target the MAO-B isoenzyme; however, at higher MAO-B inhibitor concentrations of the MAO-A isoenzyme is also subject to inhibition. Some examples of nonspecific MAO inhibitors include tranylcypromine, phenelzine, and isocarboxazid.
  - Selegiline (deprenyl) is an example of a selective MAO-B inhibitor.
Selegiline (Deprenyl)
Rasagiline (Azilect)
- Selegiline administration tends to reduce mild ""on-off"" or ""wearing-off"" effects associated with L-DOPA treatment.
- In addition, selegiline prolongs the L-DOPA antiparkinsonism effect.
  - The dosage range which supports selective MAO-B inhibition is less than or equal to 10 mg/day.
- With respect to side effects, although selegiline appears well-tolerated in mild Parkinson's disease.
  - Unfortunately, in those patients with more advanced disease or who exhibit underlying cognitive impairment, selegiline make worsen adverse motor and cognitive effects associated with L-DOPA treatment.
  - Also, selegiline metabolites include amphetamine and methamphetamine. These metabolites may induce anxiety, insomnia as well as other unwanted side effects.
- A more potent MAO-B inhibitor has been introduced and allows for once-daily dosing.
  - This agent Rasagiline (Azilect) is approved for both initial monotherapy and adjunctive treatment (FDA approval in 2009) .
    - Its metabolite does not exhibit amphetamine-like properties of selegiline.
    - As monotherapy Rasagiline increases daily ""on"" time by about two hours.
    - It is more selective for MAO-B compared to MAO-A by a factor of about 14.¹³³
  - Selegiline and Rasagiline: Cytochrome P450-mediated Metabolism¹³⁴
  - Neither selegiline nor Rasagiline should be administered to individuals receiving meperdine.
    - As a further caution, these agents should not be used to treat patients receiving either trycyclic antidepressant or serotonin reuptake inhibitors since, at least in theory, such combination might promote ""serotonin syndrome."
    - Finally, combination of L-DOPA administration and administration of a nonselective MAO inhibitor should be avoided because the combination might cause hypertensive crisis possibly as a result of peripheral norepinephrine accumulation.
- Zydis selegiline is a special selegiline formulation, an orally disintegrating, freeze-dried tablet which dissolves on contact with saliva and is directly absorbed by the oral mucosal.
  - This route of administration avoids the hepatic ""first-pass"" metabolism effect. As a consequence, both increased selegiline blood levels and reduced plasma levels of amphetamine-like metabolites are noted.

Anticholinergic Agents (Cholinergic Antagonists):^101,128
- The presence of cholinergic interneurons within the striatum provides a context for use of muscarinic cholinergic antagonists for management of Parkinson's disease.^101,128
  - These antagonists were used pervasively prior to the introduction of L-DOPA.
  - Muscarinic receptor subtypes have been described and most likely all five subtypes are present in the striatum.
  - Anticholinergic drugs used in the management of Parkinson's disease include:
    - trihexyphenidyl (Artane)
      - Trihexyphenidyl (Artane)
    - benztropine mesylate (Cogentin)
      - Benztropine (Cogentin)
    - diphenhydramine hydrochloride (Benadryl)
      - Diphenhydramine (Benadryl)
    - biperiden (Akineton)
      - Biperiden (Akineton)
    - orphenadrine (Norflex) and
      - Orphenadrine (Norflex)
    - procyclidine (Kemadrin)
      - Procyclidine (Kemadrin)
  - These agents exhibit some ("modest") antiparkinsonian activity and are therefore considered either in management of early Parkinson's disease or as adjunctive to dopamimetic drugs.
  - Anticholinergic drugs appear helpful in management of rigidity and tremor associated with Parkinson's disease but appear of limited value in managing bradykinesia.
- Adverse effects associated with these agents occur mainly as a result of their anticholinergic characteristics.^101,128
  - Side effects are reversible and subside following drug discontinuation.
  - In terms of broad categories, the two principal side effects of concern are sedation and mental confusion.
    - Anticholinergic effects such as constipation and urinary retention may also be present as well as blurred vision secondary to cycloplegia.
    - Additional adverse effects include depression, irritability, excitement, confusion, hallucinations, insomnia, and restlessness.
Amantadine (Symmetrel, Symadine):^101,128
- Amantadine (Symmetrel)
- Amantadine (Symmetrel) is usually classified as an antiviral agent which has utility in treating influenza A.
  - However, this drug is also effective in managing Parkinson's disease.
    - The mechanism may involve both an influence on striatal dopamine release and through an anticholinergic mechanism.
      - Because of its limited efficacy in managing Parkinson's disease, amantadine may be useful in initial treatment of mild disease.
      - Furthermore, beneficial effects may be of limited duration, perhaps only lasting a few weeks.
      - Therapeutic actions of amantadine include improvement in the tremor, rigidity, and bradykinesia associated with Parkinson's disease.
  - Adverse effects include anticholinergic presentations, dizziness, sleep disturbances, nausea and vomiting and lethargy; however, these effects are not always observed and when they are, appear mild and reversible.
    - Other adverse effects include confusion, excitement, agitation, and hallucinations; these effects are also reversible upon drug discontinuation.
    - A dermatological side effect, livedo reticularis, may occur with amantadine administration but subsides within about a month following drug discontinuation. Other dermatological adverse effects have also been noted.
    - A complication associated with amantadine administration is peripheral edema which is responsive to diuretics and not associated with cardiac, hepatic, or renal dysfunction. Other non-CNS-related effects include heart failure and orthostatic hypotension and accordingly, amantadine should be used only cautiously in patients with a history of heart failure.

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