Parkinson's Disease Drugs

What are the six therapeutic strategies for Parkinson's disease (PD)?

1. Give more dopamine

2. Have cells give more dopamine

3. Have body destroy less dopamine

4. Give something like dopamine

5. Give something to activate motor cortex in another way

6. Neuroprotection

Compare the permeability of dopamine and levodopa (L-dopa)

Dopamine does NOT cross the BBB

Levodopa DOES cross the BBB, small %

Describe the absorption of levodopa

Rapidly absorbed from GI

Absorption delayed with food due to competition for import

What percent of levodopa enters the brain unaltered and what does this mean for dosing?

Only 1-3% enters the brain unaltered

This means that large doses are required for therapeutic benefit

What does levodopa have the best efficacy with?

Can ameliorate all clinical symptoms, but best efficacy seen with BRADYKINESIAS

Why can levodopa cross the BBB?

It is more hydrophobic than dopamine which allows it to cross the BBB and also improves bioavailability

How is levodopa converted to dopamine in the brain?

By the action of an aromatic L-amino acid decarboxylase enzyme called DOPA decarboxylase

Levodopa is a PRODRUG

How is levodopa transported across the BBB?

By a carrier protein called L-amino acid transporter (LAT)

What are GI effects of levodopa?

Anorexia, nausea, and vomiting (up to 80%)

How can the GI effects of levodopa be decreased?

Decrease incidence with divided doses or concomitantly with food or antacids

What should be avoided with levodopa?

Avoid antiemetics as they reduce efficacy

What are CV effects of levodopa?

Arrhythmias due to increased peripheral catecholamines

Postural hypotension

What is a common adverse effect of levodopa in most long-time users?

Dyskinesias

What are adverse behavioral effects of levodopa?

Depression, anxiety, hallucinations, nightmares, etc.

Describe the on-off phenomenon of levodopa

Response fluctuations of the medication

Off = marked akinesia

On = improved motility, but marked dyskinesia

What is a notable DDI of levodopa?

Pyridoxine enhances peripheral metabolism of levodopa, DECREASING therapeutic effect

Who should levodopa NOT be given to?

Patients taking MAO-A inhibitors (hypertensive crisis)

Psychotic patients, some glaucomas, those with peptic ulcers, or history of questionable skin lesions

What is the MOA of carbidopa?

AAAD (DOPA decarboxylase) inhibitor

Inhibits conversion of levodopa to DA in the periphery

Describe the permeability of carbidopa

Does NOT cross BBB

Sinemet

1:10 mix of carbidopa:levodopa

What is the MOA of Sinemet?

Blocking the peripheral metabolism of levodopa SIGNIFICANTLY increases therapeutic levels reaches in the brain

Reduces the daily requirement of levodopa by up to 75%

Parcopa

A formulation of carbidopa/levodopa that slowly dissolves in the mouth and is swallowed

Stavelo

Carbidopa/levodopa with a COMT inhibitor

3x combination

Amantadine

Symmetrel

What is the MOA of amantadine?

Multiple effects including enhancing release of DA from neurons and delaying reuptake

Antiviral agent interfering with uncoating viral DNA within a host cell

Compare the efficacy of amantadine to levodopa

Amantadine is less efficacious than levodopa and has a short lived effect

What are CNS adverse effects of amantadine?

Restlessness, depression, hallucinations, confusion

What CNS effect is present in amantadine OD?

Acute toxic psychosis

What is another adverse effect of amantadine?

Peripheral edema that responds to diuretics

When should amantadine be used with caution?

Use with caution in patients with seizures or heart failure

What does amantadine block?

NMDA-type glutamate receptor to increase dopamine release and block dopamine reuptake

What is the MOA of selegiline?

Selective, irreversible MAO-B-specific inhibitor

CYP N-dealkylated to methamphetamine to cause a release of DA from neurons

Slows break down of DA

When is selegiline used?

In patients with declining levodopa response

Minor efficacy as sole agent

Compare rasagiline to selegiline

More potent than selegiline, especially in preventing MPTP-induced PD

How is rasagiline used?

Used alone or in combination with Sinemet

When should MAO-B inhibitors be used with care?

In patients on TCAs as they may increase peripheral side effects of Sinemet

What drugs are COMT inhibitors?

Tolcapone

Entacapone

What is the MOA of COMT inhibitors?

Inhibit peripheral metabolism, levodopa elimination decreases, brain penetration is enhanced

When are COMT inhibitors useful?

MAY be useful with fluctuating response, smooth it out and prolong "on" time

Which COMT inhibitor is more potent?

Tolcapone

Which COMT inhibitor is preferred and why?

Entacapone due to DECREASED hepatotoxicity

What are adverse effects of COMT inhibitors?

Increased ADE from levodopa due to more in circulation

What do proparglymines block?

The ability of MAO-B to deaminate DOPA

What is the active form of selegiline?

S stereoisomer

What part of the COMT inhibitors' structure is important for hydrogen bonding to the COMT receptor site?

Hydroxyl groups on the phenyl ring

What is unique about the metabolism of entacapone?

Isomerization

Trans is active form, which is metabolized to the cis form which is inactive

What drugs are dopamine receptor agonists?

Bromocriptine

Ropinirole

Describe bromocriptine

Ergoline derivative

D2 receptor agonist

Describe the bioavailability and excretion of bromocriptine

Orally bioavailabile

Excreted in bile and feces

Describe ropinirole

Non-ergoline derivative

Relatively pure D2 receptor agonist

Describe the efficacy of ropinirole

Effective as MONOtherapy early in PD

Effective in COMBINATION therapy with levodopa in advanced PD

Describe the metabolism of ropinirole

Metabolized by CYP1A2

What are GI adverse effects of DA agonists?

Anorexia and vomiting

Peptic ulcer bleeding

How can the GI effects of ropinirole be minimized?

Minimized with food

What are CV adverse effects of DA agonists?

Postural hypotension

What CV effects of DA agonists are an indicator to stop therapy?

Arrhythmias

What are mental adverse adverse effects of DA agonists?

Confusion, hallucinations, delusions, etc. more common than with levodopa

Describe the permeability of apomorphine

Lipophilic enough to pass the BBB, but dopamine cannot

What makes apomorphine hard to administer?

First-pass metabolism and severe side effects

What are severe side effects of apomorphine?

Nausea, dyskinesias, chest pain, and more

Describe the affinity for dopamine of non-ergoline dopamine receptor agonists

Have more affinity for D2 than other dopamine receptors

What is another way in which the motor cortex can be activated?

Cholinergic muscarinic receptor antagonists

Cholinergic neurons in striatum generally act to inhibit output to the motor cortex

What is PD characterized by?

Selective and progressive loss of DA neurons leading to physical symptoms

What is DA neuron death due to?

Oxidative stress

Mitochondrial toxicity

Apoptosis

What drug classes also demonstrate anti-apoptotic activity?

Antioxidants/MAO inhibitors (proparglyamines)

What drugs are mitochondrial enhancers?

Creatine phosphate

CoEnzyme Q10

What is the MOA of creatine phosphate?

Affects mitochondrial ATP synthesis and transferring of phosphates

Enhances mitochondrial function, increasing ATP

What is the MOA of coenzyme Q10?

Affects the electron transport chain

Enhances mitochondrial function, increasing ATP

How does minocycline work as an antiapoptotic agent?

Inhibits microglial activation

Blocks caspase-1 and -3 to block apoptosis