Dopaminergic/Parkinson's Disease Drugs

To Increase Dopamine Biosynthesis in the Brain: MOA and What is it used for/treats?

• Marketed in a 10:1 ratio

• Available has tablets, capsules, and enteral suspensions

• Goal of the preparation is to increase the concentration of Levodopa in the brain, which can then be metabolized to dopamine

To Increase Dopamine Biosynthesis in the Brain: MOA and What is it used for/treats?

• Indicated as an adjunct to levodopa and carbidopa to treat end-of-dose “wearing-off” in patients with Parkinson’s disease

• It is a COMT inhibitor, which will slow the breakdown of levodopa

• Plasma levels of levodopa are greater and more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone.

To Increase Dopamine Biosynthesis in the Brain: MOA and What is it used for/treats?

• Prodrug of levodopa and carbidopa

• The first and only subcutaneous 24-hour infusion of levodopa for the treatment of motor fluctuations

Dopaminergic Receptor Agonists-Ergot Alkaloids: MOA and What is it used for/treats?

• Long-acting dopamine agonist

• Indicated as adjunct therapy with levodopa/carbidopa, but found to cause cardiac valvulopathy and was withdrawn from the market

• Used only for veterinary purposes; for horses that have Cushing’s syndrome caused by decreased production of dopamine

Dopaminergic Receptor Agonists-Ergot Alkaloids: MOA and What is it used for/treats?

• Full D2 agonist and a partial agonist at D1

• Used off-label to treat restless legs syndrome 

• Inhibits prolactin secretion, and can treat galactorrhea and other prolactin related disorders

Dopaminergic Receptor Agonists-Ergot Alkaloids: MOA and What is it used for/treats?

• Long-acting dopamine receptor agonist with a high affinity for D2 receptors

• Primarily used to decrease elevated prolactin levels, which can cause menstrual changes and unwanted lactation in women as well as impotence in men

Dopamine Receptor Agonists- Morphine derivative: MOA and What is it used for/treats?

• Dopamine D2 agonist indicated to treat hypomobility associated with Parkinson’s

• It is synthesized from morphine (a rearrangement product of morphine in concentrated HCl) and it is an infusion device

• Also has been investigated as an emetic, sedative, a treatment for alcoholism and other movement disorders

Dopaminergic Receptor Agonists: Parkinson’s Disease/Restless Legs Syndrome: MOA and What is it used for/treats?

• Activates the presynaptic D2 receptor, but is more potent in activating the D3 receptor

• Allows the typical dosage of levodopa to be decreased by 30%, but patients should be warned about the possibility of hallucinations

• Marketed as the S-enantiomer, and it is excreted unchanged

Dopaminergic Receptor Agonists: Parkinson’s Disease/Restless Legs Syndrome: MOA and What is it used for/treats?

• Activates the presynaptic D2 receptor, but is more potent in activating the D3 receptor

• Extensively metabolized by CYP1A2

• Has possibility of several drug-drug interactions; inhibitors of CYP1A2 can significantly increase ropinirole plasma levels

Dopaminergic Receptor Agonists: Parkinson’s Disease/Restless Legs Syndrome: MOA and What is it used for/treats?

• First transdermal synthetic dopaminergic agonist

• Has more affinity for the D1 receptor

• Thiophene ring system aids in D2 receptor affinity and enhances the lipophilicity of the compound to allow transdermal administration

Drugs that Increase Dopamine Release: MOA and What is it used for/treats?

• Initially used as an antiviral agent in the prophylaxis and treatment of influenza A

• Usually combined with levodopa therapy when levodopa responses decline, also approved for dyskinesia

• Appears to release dopamine, stimulate the NE response, and has NMDA receptor antagonistic effects

Monoamine oxidase B inhibitors: MOA and What is it used for/treats?

• May slow progression of the clinical disease and delay the requirement for levodopa therapy

• Inhibits the metabolism of dopamine in the CNS

• Allows the dosage of levodopa to be decreased by 10-30%

• Metabolized to amphetamine and methamphetamine which can cause anxiety and insomnia

Monoamine oxidase B inhibitors: MOA and What is it used for/treats?

• Used as a monotherapy in early Parkinson’s disease or as an adjunct in more advanced cases

• CYP1A2 is the major enzyme involved in its metabolism to non-amphetamine derivatives

• May slow the rate of neuronal deterioration in Parkinsonism

Monoamine oxidase B inhibitors: MOA and What is it used for/treats?

• It combines potent, selective, and reversible inhibition of MAO-B with blockade of voltage-dependent Na+ and Ca2+ channels and inhibition of glutamate release.

• Very high therapeutic index

• Indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease (PD) experiencing “off” episodes.

Catechol O-Methyltransferase Inhibitors-COMTi: MOA and What is it used for/treats?

Must be used with caution as it can cause serious liver disease

Adjunct with carbidopa and levodopa

Most lipophilic of COMT inhibitors

Catechol O-Methyltransferase Inhibitors-COMTi: MOA and What is it used for/treats?

• Contains an oxadiazole and a pyridine

• Used as adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease (PD) experiencing “off” episodes 

• Offers the benefit of a duration of action exceeding 24h, allowing for once-daily administration

• Demonstrates the lowest risk for cytotoxicity in comparison with other COMT inhibitors