destruction of DA neurons in the substantia nigra pars compacta that provides innervation to the striatum (caudate and putamen)

correlated with destruction of basal ganglia system involved in motor control

80% of DA neurons are lost by the time the symptoms of the disease appears

70% of DA neurons are lost by the time the symptoms of the disease appears

Signals from Putamen->Globus externa->subthalmic nuclei -> globus interna ->Cortex

reduce the excitatory outflow from the thalamus to the cerebral cortex at striatum level

Signals from putamen -> GP-interna to thalamus -> then to cortex.

increase the excitatory outflow from the thalamus to the cortex.

stimulation of the direct pathway (movement enabling)

net result is the increase movement

net result is the paucity of movement

inhibition of the indirect pathway (movement inhibiting)

Levodopa

Ropinirole

selegiline

carbidopa

tolcapone

selegiline

rasagiline

entacapone

Ropinirole

trihexiphenidyl

pramipexol

Amantadine

Levodopa on its own, DA cannot cross BBB

Carbidopa is an inhibitor of AADC.

Carbidopa prevents the conversion of levodopa to DA in GI and peripheral tissues leading to an increased availability of this drug in the CNS.

Inc. DA transmission by enhancing the synthesis of DA in the surviving neurons of the substantia nigra pars compacta.

motor fluctuations in advanced Parkinson’s disease

Parkinson’s disease and Restless Legs Syndrome

Parkinsonism

Drug-induced extrapyramidal disorders

DA receptor agonists (agonists at D2 and D3 receptors)

Longer duration of action 8-24 h and given orally

non-peptide molecules, they do not compete with levodopa for transport across BBB

peptide molecules, they compete with levodopa for transport across BBB

enhance dopaminergic neurotransmission by activating presynaptic DA receptors

These drugs do not require enzymatic conversion by AADC and, therefore, can be effective late in the course of PD.

Initial therapy with these drugs have less risk of developing dyskinesia and motor fluctuations when compared to levodopa therapy

use for PD and Restless Legs Syndrome

INHIBITORS OF DA METABOLISM - MOA

selectively and irreversibly inhibit MAO-B (MAO isoform @striatum)

These drugs DONT block peripheral catecholamines thus can safely use with levodopa

Their efficacy is due to the enhancement- of DA metabolism in the striatum

can potentiate the effectiveness of levodopa therapy when use in combination

Selegiline is metabolized to methamphetamine and amphetamine.

Rasagiline is metabolized to methamphetamine and amphetamine.

Selegiline: should NOT co-administered with the analgesic meperidine.

Both Block CMOT - blocking DA and levodopa metabolism

Tolcapone is only distributed into peripheral tissues

decrease the peripheral metabolism of levodopa & increasing central uptake and brain concentrations of DA.

Entacapone can cross the blood-brain barrier and inhibit COMT in the brain.

Tolcapone has a longer duration of action than entacapone

Both metabolized by the liver and eliminated in the feces and urine.

Adjunct to levodopa/carbidopa in idiopathic Parkinsonism

Increase the peripheral metabolism of levodopa, Decrease central uptake and brain concentrations of DA

Antimuscarinic agents that block muscarinic receptors and reduce cholinergic tone in the CNS

Modify the activity of striatal cholinergic interneurons that regulate the interactions of neurons of the direct and indirect pathways

These drugs reduce bradykinesia more than tremors.

Use for Drug-induced extrapyramidal disorders and adjunct in Parkinsonism

antiviral agent used for influenza and MILD-Parkinson’s disease

Blocks cholinergic & NMDA glutamate receptors and increase DA release

has little or no effect on tremor but is effective against rigidity and bradykinesia

More efficacious than levadopa and tolerance develops more readily

Neurons in the substantia nigra pars compacta project to the dorsal striatum

This pathway contains 79% of the brain’s DA

This is the pathway that degenerates in Parkinson’s disease

This is the pathway that degenerates in Alzheiemers  disease