9/20 Movement Disorder Drugs - Dorovkov

Question 1

drugs for PD

Answer 1

1. levodopa
2. dopamine agonists
3. MAO-B inhibitors
4. COMT inhibitors
5. anticholinergics
6. amantadine

Question 2

PD characteristics and symptoms

Answer 2

progressive disorder of movement occuring most commonly in elderly (mean onset: 55yo; onset variable 50-80)

• resting tremor (abates with voluntary/intentional movement)
• muscle rigidity
• bradykinesia (slow movement)
• impairment of postural balance leading to distubance of gait/falling

within 10-20 yrs, total immobility for most patients

• death from PD usually due to complications related to immobility (ex. aspiration pneumonia, CV/cerebrovasc disease)

Question 3

neuropathology of PD

Answer 3

• loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) in basal ganglia
• decrease in number of DA terminals in striatum

Question 4

proposed causes of PD

Answer 4

1. genetic
2. environmental
3. oxidative stress (free radicals)
4. aging

Question 5

genetic factors for PD

Answer 5

contribution of identified genetic factors approx 10%

• protein degradation (Parkin)
• mitochondrial function (PINK1)
• response to oxidative stress (DJ1)
• LRRK2 (kinase with many domains)

most predispose to early onset of PD (< 50yo)

Question 6

at what stage of SN cell loss do PD symptoms manifest?

why?

Answer 6

PD symptoms appear at advanced stage of cell loss (80% loss)

• there is likely an adaptive increase in dopamine receptors in response to cell death
• when this effect “maxes out”, adaptation/compensation fails and symptoms appear

Question 7

environmental factors for PD

risk factors

protective stuff

Answer 7

in 1980s, people developed sx similar to PD after using synthetic recreational drug MPPP, later found to be contaminated with MPTP

• MPTP is metabolized to free radical MPP+ → oxidative stress resulting in cell death

mechanism: MPP+ inhibits ComplexI → ATP decrease → cell death

others: pesticides, heavy metals, vitD deficiency

protective stuff: exercise, coffee, cigarettes, anti-infl drugs, elevated levels of uric acid

Question 8

oxidative stress

Answer 8

possible that metabolism of DA → free radicals which lead to oxidative stress

[dopamine → DOPAC + hydrogen peroxide]

• if H2O2 is not deactivated fast enough, produces free radicals → cell death

Question 9

basic principle of treatment

Answer 9

facilitate dopaminergic neurotransmission

• exogenous DA precursors
• drugs to increase release of endog DA
• direct DA agonists
• inhibitors of DA metabolism

Question 10

L-Dopa

Answer 10

Levodopa

single most effective agent in treating PD

natural pathway: Tyr → Dopa → dopamine

• pretty much pharmacologically inert, buuuut
  
  • L-Dopa is converted to dopamine via decarboxylation
• unlike dopamine, penetrates bbb

Question 11

metabolism of levodopa

Answer 11

levodopa → dopamine [L-a.a. decarboxylase] → 3,4 dihydroxyphenylacetic acid (DOPAC) [monoamine oxidase, aldehyde dehydrogenase]

• all three substances can be degraded by COMT

levodopa can be turned into melanin

dopamine can be norepinephrine

Question 12

Levodopa PK

absorption: where/how?

pl concentration and half life

Answer 12

rate and extent of absorption depend on:

• rate of gastric emptying
• pH of gastric juice
• time of exposure to degradative enzymes of gastric/intestinal mucosa

transported into brain by active transport system

• competes with dietary protein → transport is reduced with high protein diet

peak pl concentration occurs 1-2hr after oral dose

half-life is 1-3hr

Question 13

metabolism of levodopa

enzymes involved, metabolites formed, characteristics

implications

Answer 13

metabolized in peripheral tissues by…

• L-aromatic a.a. decarboxylase (L-AAD, 60%)
  
  • → dopamine. does not enter CNS.
• catechol-O-methyltransferase (COMT, 10%)
  
  • → 3-O-methyl-dopa, which competes with levodopa for transport into brain (15hr half life)

implications:

1. administered alone, less than 1% makes it into CNS
2. peripheral conversion produces side effects

Question 14

carbidopa

Answer 14

L-aromatic amino acid decarboxylase inhibitor (L-AAD inhibitor)

• doesn’t penetrate bbb
• serves purpose of increasing fraction of levodopa that remains unmetabolized by L-AAD in peripheral tissues such that it’s available to enter CNS
  
  • increases plasma half-life and plasma conc of levodopa
  • allows for lower dosing → lower side effects!

Question 15

levodopa + carbidopa

Answer 15

Sinemet

carbidopa: levodopa at fixed 1:4 or 1:10 ratio (1 =25mg)

Question 16

adverse effects of levodopa tx

GI

Answer 16

without peripheral L-AAD inhibitor (carbidopa), 80% of patients experience…

• anorexia
• nausea
• vomiting (stimulation of emetic center located in brainstem OUTSIDE OF BBB)

combo with carbidopa? reduction of GI effects to 20% of patients!

Question 17

adverse effects of levodopa tx

cardiovascular

Answer 17

• arrhytmias
• postural hypotension (activation of vascular DA receptors)
• admin with nonspecific MAO inhibitors improves levodopa action, could lead to hypertensive crisis

hypotension and hypertension? whaaaat?

• at low concentrations, levodopa has affinity for certain subtypes of receptors
• subtypes affected change at high concentrations

Question 18

adverse effects of levodopa tx

CNS effects

Answer 18

desired

• decrease in tremor, rigidity, bradykinesia

undesired

• abnormal involuntary movements (dyskinesias)
• psych disturbances : confusion, hallucinations, anxiety
  
  • conventional antipsychotics (phenothiazines) effective but worson Parkinsonism
  • clozapine (atypical) does not worsen Parkinsonism, can be used

Question 19

long term effects of levodopa tx

Answer 19

1. response fluctuations

• 50% pts after 5 years
• 70% pts after 15 years

2. end of dose deterioration aka wearing off (predictable)
3. on-off phenomenon (unpredictable)
4. increase in side effects

• dyskinesias
• psych disturbances

may require adjunctive tx

Question 20

end of dose deterioration

Answer 20

predictable

in early PD, duration of beneficial effects of levodopa exceeds plasma lifetime of drug

• implication: nigrostriatal dopamine system retains some capacity to store/release DA (“buffering” effect”

after long term use of levodopa tx, “buffering” capacity appears to be lost → pt’s motor state can fluctuate dramaticaly with each dose

• “wearing off” phenomenon: each dose of levodopa effectively improves mobility for 1-2 hr, but sx return rapidly at the end of the dosing interval

Question 21

on/off phenomenon

Answer 21

unpredictable

patients fluctuate rapidly between feeling no apparent effects (“off”) and feeling effects (“on”) of their meds

• off periods: marked akinesia alternative over couse of few hours
• on periods: improved mobility, often marked dyskinesia

mechanism is unknown → prob result of brain response to variation in levodopa levels & alteration in fx of dopamine receptors

severe off-period that wont respond to other measures?

apomorphine

Question 22

levodopa

drug interactions

Answer 22

• pyridoxine (B6) : enhances extracerebral metabolism of levodopa
• MAO-A inhibitors : accentuate peripheral effects (can cause hypertensive crisis)

Question 23

levodopa

contraindications

Answer 23

psychotic patients

angle-closed glaucoma (bc can increase IOP)

• chronic angle-open? OK, as long as IOP is controlled/monitored

active peptic ulcer (GI bleeding)

hx of melanoma (levodopa is precursor of melanin!)

Question 24

secondary pharmacologic tx of PD

agonists

Answer 24

1. pramipexole: D3 agonist, non-ergot-derivative
2. ropinirole: D2 agonist, non-ergot derivative
3. bromocriptine: D2 agonist, ergot derivative
4. pergolide: D1&D2 agonist, ergot derivative

• all act as agonists at dopamine receptors

not as effective as levodopa at fighting sx of PD, BUT some key advantages:

• don’t compete for active transport with other compounds
• less motor fluctuations in pts (signif less dyskinesia, esp in younger pt)
• less response fluctuations than levodopa as well

Question 25

distribution of dopamine receptors and effect on drug action

Answer 25

agonists selectively affect certain (not all) DA receptors → can lead to limited adverse effects

Question 26

bromocriptine

Answer 26

D2 agonist

ergot derivative

• used in combo with levodopa/carbidopa for advanced disease to smooth on/off response fluctuations

adverse effects

• GI, dyskinesia, orthostatic hypotension, arrhythmias
• hallucinations and confusion (more common/severe bc of presence of lysergic acid moiety)

ergot adverse effects (vasoconst)

• pleuropulmonary fibrosis
• retropritoneal fibrosis
• erythromelalgia (block/infl of blood vessels)
• digital vasospasm (constriction of finger sm arteries)

Question 27

ropinirole

pramipexole

Answer 27

ropinirole

• metabolized by CYP1A2 → drugs also metabolized by liver can reduce clearance

pramipexole

• excreted largely unchanged in urine

both:

• effective as monotx in patients with mild disease
• effective as means of smoothing response fluctuation in patients on levodopa tx with more adv disease

adverse effects:

• GI effects, dskinesia, orthostatis hypotension/arrhythmias, hallucinations/confusion
• rare: narcolepsy-like tendency to pass out at inapprop times

DO NOT HAVE ERGOT SIDE EFFECTS

Question 28

rotigotine

Answer 28

non ergot agonist

admin: once-daily transdermal patch → continuous abs

• less serum fluctuation compared to oral admin several times a day

adverse effects

• application site rxns (redness, itching) in 37% of clinical study pts

Question 29

apomorphine

Answer 29

dopamine agonist

available as subcut injection to treat severe “off” episodes in patients with advanced PD

• rapidly taken up by brain → clinical benefit within 10 min!
• highest affinity for D4 (moderate affinity for D2/3/5)

adverse effects

• emesis (vomiting/nausea) - req pretreatment with antiemetic trimethobenzamide 3 days before initial tx, continuing for 2 mo if not indef

contraindications

• antiemetics of 5HT3 receptor classs → severe hypotension, loss of consciousness

Question 30

MAOs

Answer 30

monoamine oxidases

two subtypes: A and B

• MAO-A metabolizes norepi, serotonin, dopamine
  
  • also found in liver, GI tract
• MAO-B metabolizes dopamine selectively

Question 31

MAO-B inhibitors

selegiline

Answer 31

selegiline

• irreversible MAO-B inhibitor
• selective for MAO-B at doses of 10mg/d or less
  
  • HIGHER DOSES? also inhibits MAO-A!
• modest beneficial effects when used alone
• can be used in combo with levodopa/carbidopa to decr response fluctuations in late PD patients
• how is selegiline selective?*
• retards breakdown of DA in striatum without inhibiting preipheral metabolism of catecholamines

adverse effects

• can accentuate adverse motor/cog effects of levodopa tx
• insomnia, anxiety bc metabolites include amphetamine, methamphetamines

contraindications

• shouldn’t take with analgesic meperidine → stupor, regidity, agitation, hyperthermia
• also: tramadol, methadone, cyclobenzaprine, St Johns wort
• caution with concomitant use of tricyclinc antidepressants or SSRIs → acute serotonin syndrome

Question 32

MAO-B inhibitors

rasagiline

Answer 32

• more selective MAO-B inhibitor than selegiline
  
  • NO amphetamine metabolites
• may prevent progression of disease in early PD
• use in combo with levodopa/barbidopa to decr response fluctuations in late PD patients

adverse effects [same as selegiline, BUT no insomnia etc effects bc none of those metabolites!]

• can accentuate adverse motor/cog effects of levodopa tx

​contraindications

• shouldn’t take with analgesic meperidine → stupor, regidity, agitation, hyperthermia
• also: tramadol, methadone, cyclobenzaprine, St Johns wort
• caution with concomitant use of tricyclinc antidepressants or SSRIs → acute serotonin syndrome

Question 33

neuroprotective effect of rasagiline

Answer 33

postulated to have a neuroprotective effect, poss through…

• inhibition of MAO-B conversion of MPTP → MPP+
  
  • decr synthesis of toxic metabolites
• inhibition of MAO-B conversion of dopamine → DOPAC [w formation of H2O2]
  
  • neuroprotection as a result of reducing oxidation of dopamine

Question 34

COMT inhibitors

Answer 34

tolcapone: central and periph effects

• more potent but hepatotoxic

entacapone: periph effects

• less potent, but not hepatotoxic → preferred
• adjunct to levodopa/carbidopa → allows reduction of levodopa dose by increasing half-life of levodopa, increasing availability to brian tissue
• approved for pt with late PD who have response fluctuations

adverse effects

• levodopa-related dopaminergic effects
• diarrhea, abd pain, sleep dist

contraindications

• can expect drug interaction with drugs normally metabolized by COMT

concurrent use with non-specific MAO inhibitor could limit metabolism of levodopa → contraindicated

Question 35

anti-cholinergics

Answer 35

PD patients experience dopamine loss → relatively increased effect of ACh

centrally acting muscarinics (trihyxyphenidyl, benztropine mesylate, biperiden, orphenadrine, procyclidine)

• may improve tremor/rigidity
• little effect on bradykinesia
• can try other drugs if one doesnt work well

Question 36

amantadine

Answer 36

antiviral agent

mechanism for PD is unclear; might be…

• incr in dopamine release
• blocking dopamine re-uptake
• stim dopamine receptors

benefits are short-lived, but improve: bradykinesia, rigidity, tremor. also antidyskinetic properties

• can be used as initial therapy of mild PD, adjunct therapy in patients on levodopa with dose-dep fluctuations and dyskinesias

adverse effects

• restlessness, hallucinations, confusion, sleep disturbances, nausea
• OD: acute toxic psychosis
• livedo reticularis (swelling of small veins)

use with caution in patients with hx of seizure/heart failure

Question 37

summary

Answer 37