Increase in DA receptors and remaining neurons fire faster 

(Almost 80% depletion of dopamine in target area) 

Idiopathic, free radical exposure (Carbon monoxide, manganese, or oxidative damage), MPTP (attempted meperidine) 

MPTP converted to active form of MPP+ by monoamine oxidase -- taken up by dopaminergic nerve terminals -- inhibits complex 1 of mitochondria -- oxidative stress and free radicals -- neurons of nigrostriatal pathway die 

Antipsychotic drugs

Genetic: mutation of alpha synuclein and parkin 

If there is a severe loss in dopaminergic neurons, there will not be enough left to convert DOPA to dopamine 

Signs of improvement once therapy is begu might take several weeks; optimal benefit may take as long as 1-2 months 

First symptoms to improve

Mode and vigor

Bradykinesia and akinesia (most effective)

Tremor

L-DOPA is rapidly absorbed from intestine; rate is influenced by gastric emptying rate, local pH, and food

about 1-3% reaches brain; rest is metabolized by DOPA-decarboxylase 

Presence of DOPA decarboxylase inhibitor, carbidopa, much more enters brain 

Tolerable doses diminish with time; efficacy diminishes 

GI side effects: anorexia, nausea, vomiting; lessened with carbidopa (give with meals or divide dose); due to primarily activation of CTZ in medulla

Cardiovascular Effects: orthostatic hypotension (centrally mediated), tachycardia - conversion of DOPA to NE; less prominent when given with carbidopa 

Short term

N/V/anorexia; lessened with carbidopa

Can be decreased by giving drug with or after meals or by dividing dose

Tolerance to the effect - due primarily to activation of CTZ in medulla 

Orthostatic hypotension, short term effect

Lessend when given with carbidopa

Also tachycardia because dopamine --> NE 

Dyskinesias: facial grimacing, restless feet syndrome; can produce choreoform movements; combination may be more likely to cause dyskinesias

Psych and Behavioral side effects: nightmares/anxiety; increased dose will cause paranoia, hallucinations, and mania; related to overstimulation of dopamine receptors 

Response fluctuations - sometimes related to L-DOPA intake timing; may be managed by using dopamine agonists, altering diet, and by using slow release dopamine

Long term effect of L-DOPA requiring altered dose

Restless feet syndrome, facial grimacing

May be fleeting or severely debilitating

Patient often enjoys mood effect

Tolerance does not develop dyskinesias; using with carbidopa might actually increase dyskinesia incidence

anxiety/nightmares

Long term effect that might require dose adjustment 

Aphrodisiac effect may be related to improved mood; dopamine also involved in hypothalamic and pituitary function 

Long term effect of L-DOPA

sometimes related to L-DOPA intake timing (wearing off, end of dose akinesia)

May be managed by using dopamine agonists, alteration of diet, or by using slow release L-DOPA 

Drug holidays may help manage some neurological or behavioral side effects 

L-DOPA is gradually withdrawn from a period of 3-21 days

When the patient gets back on the drug, they'll often need lower doses 

Pyridoxine is a co factor of DOPA decarboxylase, but still shouldn't have an effect with carbidopa

L-DOPA is not to be used with MAO inhibitor A --> hypertensive crisis 

psychotic patients or closed angle glaucoma (conversion to NE), open angle glaucoma, cardiac disease, peptic ulcer disease 

Avoid in patients with history of melanoma

After taking DOPA for many years, drug may begin to wear off --> change to controlled release 

Takes longer to work so you might want to combine with short release DOPA too 

Do not have toxic metabolites

Directly active dopamine receptors

Used in patients unresponse to Sinnemet

Some doctors may use it as a first line drug because there are less dyskinesias

Begin with low doses of Sinnemet and then add dopamine agonist 

Oral

Ergot alkaloid

Low doses --> hyperprolactinemia

Excreted in bile and feces

First line drug for Parkinsonism -- less likelihood of dyskinesias and response fluctuation; may be used in combo with L-DOPA but doses must be optimized 

CV effects - possibility of hypotension; ergots -- erythromelalgia and digital vasospasm; serious may involve stroke or MI

GI effects - anorexia/nausea/vomiting reduced when meds taken with food; constipation, indigestion, peptic ulceration with bleeding and reflux esophagitis 

Dyskinesias are less than L-DOPA/Carbidopa

Mental disturbance: hallucinations are more common with bromocriptine (bc bros like drugs) 

Fibrosis (bc bros like to be thick)

Pramipexole (Mirapex) and Ropinirole (Requip)

Dopamine agonists with fewer side effects

Been used more widely but no evidence of better efficacy over bromocriptine

More likely to cause sudden sleep episodes 

CV side effects less common but a common reaction is hypotension 

Can also cause dyskinesias and hallucinations 

Monoamine oxidase inhibitor B

Retards breakdown of dopamine and prolongs effects of DOPA 

Some evidence in animal models that it reduces progression of the disease

Used as adjunctive therapy and may allow DOPA dose reduction 

May reduce mild on/off symptoms 

Inhibits only one form of monoamine oxidase so it's tolerated

Nonspecific inhibitors of MAO should be avoided because in combo with L-DOPA, can cause hypertensive crisis 

The drug is contraindicated in patients taking tricyclic antidepressants and serotonin uptake blockers and meperidine (Demerol) -- serotonin syndrome

Antiviral drug that causes DA release in striatum

May also block muscarinic and glutamate receptors

Used in initial treatment or late in treatment to control L-DOPA induced dyskinesias; benefit may be transient 

N/V/D in 15% of patients

Adverse CNS: restlessness, agitation, hallucination

Livedo reticularis: peripheral vascular condition - reddish blue skin

Peripheral edema

Avoid in patients prone to seizure and who have congestive heart failure 

CNS effects such as drowsiness, restlessness, hallucination

Side effects can be predicted from autonomic pharm - may be additive with other drugs with antimuscarinic properties 

Avoid use in prostatic hypertrophy, obstructional GI, and glaucoma 

COMT inhibitor

Converts DOPA to 3-o-methyldopa which has 0 effect in Parkinsons

Make DOPA more available to the brain 

Increase duration of DOPA effect 

May be beneficial in treating wearing off phenomena 

May be necessary to reduce level of DOPA to minimize dyskinesias and other dopamine related side effects 

Requires frequent blood tests to monitor liver function

COMT inhibitor

Make more DOPA available to brain and prolong its action; therefore might increase dyskinesias and other DA related side effects 

COMT inhibitors are never used alone; may be beneficial in treating wearing off phenomena 

3 - 8 years; can give with direct acting dopamine agonist - acts directly and therefore does not need the presynaptic neuron 

SE of dopamine agonists similar to L DOPA 

1) Begin treatment when symptoms begin; early treatment decreases mortality

2) For mild to moderate symptoms use anticholinergic or amantadine

3) For more severe, use Sinnemet, little reason to use L-DOPA alone; may be used in combo with anticholinergic/amantadine or with dopamine agonists (will prolong treatment after Sinnemet is no longer effective)