Money for Old Rope Parkinson Management

5.3 – “Money for Old Rope”: Par Parkinson kinson management (L (Levodopa, evodopa, carbidopa, entacap entacapone, one, tolcapone, sele selegiline, giline, ropinirole, pra pramipexole, mipexole, amanta amantadine) dine) • Parkinsonism (Park & Sons bank) characterized by “pill-rolling” tremor, bradykinesia, cogwheel rigidity (cogwheel safe door), and postural instability. Most common causes is Parkinson’s disease d/t degenerative loss of dopaminergic nn in the nigrostriatal pathway. Parkinson’s disease also has non-motor abnormalities, but most medical management is focused on motor symptoms. • Note that dopamine therapies are generally contraindicated in psychotic patients, d/t central dopamine control with these conditions (crossed out painting of Van Gogh) • Levodopa (coiled rope) o Most effective treatment for treatment of Parkinson’s motor symptoms. o Dopamine doesn’t cross the BBB (bank vault threshold). Levodopa (L-DOPA) is the immediate metabolic precursor to dopamine, and does cross the BBB (rope coiled, waiting to be used, on spool with L-shaped handle; can enter the vault). Decarboxylated to form dopamine by DOPA decarboxylase. Normally, 97% of L-DOPA converted to dopamine peripherally by intestinal DOPA decarboxylase. o Dopamine is also peripherally methylated to 3-O-methyldopa by catechol-O-methyltransferase (COMT). Central COMT metabolizes L-DOPA to 3-methoxy-tyrosine. o Adverse effects: ▪ Some consequences of peripheral conversion (hostages held in lobby = peripheral effects) • Cause GI distress (bound & nauseated hostage). Results in emetic effect d/t stimulation of the chemoreceptor trigger zone; tolerance usually develops after initiating therapy. • Peripheral conversion can also cause arrhythmias – tachycardia, ventricular extrasystole, postural hypotension, a-fib (unconscious bound woman) ▪ High doses can cause behavioral changes – anxiety, agitation, insomnia, confusion, hallucinations (central effects) (confused hostage). Reducing dose can be helpful in alleviating these effects. May also co-administer with atypical antipsychotic to block central dopaminergic effects. ▪ Long-term administration characterized by • Fluctuations in clinical response occur with increasing frequency with disease progression; this “wearing off” effect may result in parkinsonian symptoms nearing the end of a dosing period (e.g. akinesia, dyskinesia) (worn out end of rope inside vault) • Fluctuations may be unrelated to dosing; can cause on-off phenomenon: periods of akinesia alternating with periods of improved mobility, with timing unrelate to dosing (light flashing on and off; robber pointing to watch for chronic use) • With disease progression, therapeutic window narrows, causing motor fluctuations with even small changes in dose. Fluctuations become unpredictable (narrowing window to make escape). • Fluctuations will often be marked by significant dyskinesias in up to 80% of patients who are on levodopa for 10+ years. May include choreoathetosis of the face & distal extremities is the most common presentation (robber twisting to sneeze) • Carbidopa o Peripheral DOPA decarboxylase inhibitor (police car on periphery). Increases central bioavailability of levodopa (L-DOPA crooks with cranks escaping from lobby into vault). ▪ Does nothing to inhibit COMT, so only about 10% of L-Dopa crosses BBB (guard on intercom shooting L-crank). o Significantly decreases peripheral Adverse effects of levodopa (freeing hostages), but exacerbates neuropsychiatric effects (not releasing delirious hostage) • Entacapone, tolcapone (entrance guy & tall guy are Al Capone bandits) o COMT inhibitors (inhibiting clerk from using intercom) o Increases plasma half-life of levodopa. Used especially as patients begin to experience motor fluctuations with levodopa/carbidopa. ▪ Entacapone only active peripherally (Al Capone gangster at entrance to vault) ▪ Tolcapone active peripherally and centrally (tall Al Capone gangster entering vault and impeding guard with intercom). o Only effective combined with levodopa; ineffective as monotherapy. o Adverse effects ▪ Tolcapone: hepatotoxicity (liver-shaped clip on gun) • Selegiline (sledgehammer) o MAO-B inhibitor. Recall MAO-B selectively metabolizes dopamine (black mouse eating dope rope in vault). Selegiline enhances levodopa availability centrally; used in conjunction with levodopa – has little effect on parkinsonism alone. • Direct dopaminergic receptor agonists o Ropinirole (double ropes in a roll) is a D2 receptor agonist; pramipexole (Robber with big pecs) Preferentially agonizes D3 receptors. Ergot alkaloids (e.g. bromocriptine) are the originals, but are rarely used nowadays d/t Adverse effects o Important role as first line monotherapy for Parkinson’s. Associated with fewer long-term response fluctuations and dyskinesias from levodopa. ▪ May also be added with a dopaminergic agonist to delay inevitable end-of-dose akathisia o Also used to treat restless leg syndrome (escapee climbing ladder and shaking legs) o May have more severe psychiatric Adverse effects than; particularly impulse control disorders (e.g. gambling, compulsive shopping, hypersexuality) (“rock and roll” tattoo) o Contraindicated with h/o psychotic illness • Amantadine (manatee) o Enhances effect of endogenous dopamine by increasing synthesis and release & inhibiting reuptake (extra dope rope crate broken open) • Benztropine & trihexyphenidyl (tri-hexagon logo on Benz outside) o Centrally acting antimuscarinics. Help restore balance of dopaminergic & cholinergic effects on basal ganglia. Can help improve tremor & rigidity of Parkinson’s, with no effect on bradykinesia (car is trembling).