loss of the dopaminergic neurons in the basal ganglia, as well as non-dopaminergic neurons (progressive disease)

-D2 antagonists primarily work at the limbic system, but they can also work on D2 receptors in the basal ganglia: PARKINSONS SYNDROME!

symptomatic therapy: therapy to reduce/fix symptoms of parkinsons disease

-neuroprotection: protect the neuron from getting damaged (prevent the loss of neurons)

When 80% of the neurons are lost. We will see akinesia, bradykinesia, tremors, rigidity, pill rolling and loss of imbalance

-may have cognitive defects because of loss of other neurons as well

Levodopa (AAAD inhibitor, COMT inhibitor), Dopamine receptor agonists

-adjunct: muscarnic antagonists, MAO B inhibitors, amantadine

-levodopa is a prodrug that can get metabolized to dopamine, peripherally and centrally

-levodopa is taken into the bloodstream by amino acid active transport

-DA cannot go through the blood brain barrier, so this becomes a problem when levodopa is broken down in the periphery. In addition, dopamine in the periphery can cause hypotention, tacycardia (indirect and direct), and nausea and vomitting (sensed from the CTZ as a toxin in the blood stream)

-used with levodopa

-blocks the breakdown of levodopa in the periphery

-increases the half life of levodopa and fraction is available for the CNS

-carbidopa is an example

-levodopa + carbidopa = Sinemet

-used with carbidopa and levodopa

-increases the plasma half life of levodopa and fraction available for the CNS

- blocks the peripheral conversion to 3-O-methyl dopa

Tolcapone can block COMT in the periphery and centrally. This is an advantage because it retards the breakdown of dopamine LONG ACTING. Causes diarrhea and hepatoxicity

-entacapone: only works periphery, shorter acting but no hepatoxicity

-hallucinations, confusion, anorexia

-dyskinesia (50% of after 5 years)

-motor fluctuations :on-off phen. and wearing off

-dopamine metabolism: the metabolite of dopamine is a free radical, so it is actually neurotoxic

-no pherpherial effects like seen with levodopa

-no free radicals

-don't need combination therapy 

-less dyskinesia

-don't have to take on an empty stomach

-selective for Dopamine receptors

***longer half life (no on-off phen.), 1st line therapy

-nausea/vomiting, hallucinations and confusion, (due to limbic system) peripheral edema, somnolence, and impulse control disorders 

****ADDING WITH LEVODOPA CAN DECREASE DYSKINESIA and MOTOR FLUCTUATIONS

-D2, D3, D4 agonists

-bromocriptine, pergolide, cabergoline

-Pergolide was taken off the market because it activates 5HT2B which causes proliferation of the valve and pulmonary hypertention. Cabergoline does not do this because its not for parkinsons; instead it is used to decrease prolactin (at low doses)

-D2 and D3 agonists

-ropinirole and pramipexole can be used for restless leg syndrome

rotigotine: patch: withdrawn

-apomorphine

-used as a rescue drug: used when a patient has an on-off phenomenon 

agonist at D2

-SC: have to give an antiemetic pre and post dose

-Neuroleptic malignant syndrome

***we should taper down the drug if we have to stop the use of the drug

Levodopa

Dopamine receptor agonist

-may want to give levodopa to a dopamine agonist after a few years so we can avoid neurotoxicity 

-levodopa and carbidopa have short half lives. When patients take these drugs, they get relief from symptoms, but when the drugs wear off, the symptoms come back

-to prevent this we might see sinemet dosed q 3 hours, or it can be formulated as a sustained release preparation

-If add a COMT inhibitor, we can increase the half life

-MAO B inhibitor at low and moderate doses

-irreversible

-does not inhibit catecholamine metabolism (no food warning: no problem with tyramine)

-amphetamine like metabolites (anorexia, insomina)

-interactions with SSRI and meperidine

-effective as monotherapy in early stages

Rasagiline (Azilect)

MAOB inhibitor

-does not have amphetamine like metabolites

-effective in monotherapy in early stages

-reduces tremor (often monotherapy)

-ADRs: confusion, impaired memory (CENTRAL)

peripheral antimuscarinic effects (dry mouth, urine retention)

-antiviral

-for rigidity and bradykinesia

-MOA: increase dopamine release, NMDA receptor antagonist, muscarinic receptor antagonist (POSSIBLE MECHANISMS)

-ADRs: dizziness, insomnia, confusion, hallucinations

-to slow the disease progession

-MAOB inhibitors: may inhibit yield of free radicals

-Ropinirole and pramipexole: activation of presynaptic D2 receptors reduces endogenous DA production and reduces oxidative stress (post and presynaptic receptors)

*****CoenzymeQ10: antioxidant; centrol role in mitrochondrial function