Drugs for Movement Disorders
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62 terms
Terms | Definitions |
|---|---|
 What is the main motor output pathway in the NS? | PYRAMIDAL TRACT -Corticospinal tract |
| What are the 2 main modifying pathways that influence the motor output pathway? | Extrapyramidal system--basal ganglia, reticular formation, vestibular nuclei, red nucleus -starting, stopping, and coordination of movements -maintenance of muscle tone and posture Outputs of the Cerebellum -coordination of muscle groups in skilled movement |
| What plays a role in gating proper initiation of movement and muscle tone? | BASAL GANGLIA |
| What is responsible for sensory motor coordination? | CEREBELLUM |
| What is responsible for basic movements and postural control? | BRAINSTEM CENTERS |
| What is responsible for planning, initiating, and directing voluntary movements? | MOTOR CORTEX |
| What makes up the basal ganglia? | -Caudate Nucleus -Putamen -Globus Pallidus |
| What is dopamine input to the basal ganglia via? | NIGROSTRIATAL PATHWAY -contains 75-80% of DA in brain -arises from DA cell bodies in SN -terminates in axonal boutons in basal ganglia -each DA neuron forms 500,000 boutons |
| what does MORE activity in the INDIRECT pathway result in? | LESS MOVEMENT |
| What does MORE activity in the DIRECT pathway result in? | MORE movement |
| which DA receptors are excitatory? inhibitory? | D1--excitatory--DIRECT pathway D2--inhibitory--INDIRECT pathway |
| Symptoms of Parkinson's Disease? | -Rhythmical RESTING TREMOR -Increased muscle tone--RIGIDITY -HYPOKINESIA and BRADYKINESIA -POSTURAL INSTABILITY -Possible dementia |
| What is the biochemical basis of PD? | LOSS OF DA NEURONS -primarily in SN and loss of DA terminal fields in basal ganglia =LOSS OF NIGROSTRIATAL DA SYSTEM |
| What are the most rapidly aging neurons in the brain? | DA neurons!! |
| What percentage of DA neurons must be lost before see sx? Why can you lose so many before any loss in fx? | 70-80% -DA that's released from boutons lasts longer (less reuptake) and influences more receptors -Increased synthesis of DA -Increased release of DA per bouton -Increased receptors |
| In regards to DA pathways, what is the biggest problem in PD? | -HYPERACTIVITY of INDIRECT PATHWAY -lose balance between indirect and direct pathway |
| What is L-DOPA? What are some of its features? | -Immediate precursor in the biosynthesis of DA (aka AFTER the rate-limiting step!) -penetrates brain and converted by AAAD to DA -75-85% of pts respond immediately and dramatically to LDOPA -Improvements in rigidity and akinesia -NO CHANGE in dementia and postural instability -Plasma conc peaks after 1-2 hours--half life 1 to 3 hours -If take L DOPA alone only 1-3% gets to brain because AAAD decarboxylates into DA in gut and in blood--can cause NE and Epi side effects!! (autonomic effects, anorexia, nausea, vomiting, tachycardia, hypotension, depression, anxiety, agitation, insomnia) |
| What can you do to lessen the conversion of L-DOPA to DA peripherally? | Give L-DOPA with a peripheral AAAD inhibitor that can NOT cross BBB--CARBIDOPA -Carbidopa + L-DOPA=SINEMET |
| What is the benefit of time release L-DOPA treatment? | Avoid the peaks and valleys (hyper and hypokinesia) |
| What kinds of food can interfere with the absorption of L-DOPA? | -Foods high in protein -Take L-Dopa at least 30 minutes before eating or 1 hour after eating -Take with full glass of water -L-DOPA is absorbed in the small intestine |
| What is a big problem with Sinemet treatment after 5-7 years? | On-Off phenomena--unpredictable, sudden as use higher and higher doses as DA neurons die off more and more |
| What are some drug interactions with L-DOPA? | -Should NOT be given with MAO-A or Non-specific MAOI--combo could lead to elevated peripheral NE levels and hypertensive crisis -should not be given to psychotic patients--can exacerbate disorder -anticholinergics can decrease absorption |
| Side effects of Bromocriptine (Parlodel) | Anorexia, nausea, vomiting, confusion, hallucinations, delusions |
| What is the benefit of adding a DA agonist to L-DOPA? | Increases basal level of DA activity so don't have to give as high of dose of L-DOPA=Less side effects |
| What are the second generation DA agonists? | ROPRINIROLE and PARAMIPEXOLE -Stimulate D3 receptors more than D2 -reduce "OFF" time when used with L-DOPA |
| How are Paramipexole and Ropinirole metabolized? | Paramipexole--Excreted unchanged in urine Ropinirole--Liver |
| Side effects of 2nd generation DA agonists? | Fatigue, nausea, postural hypotension, somnolence, constipation, insomnia -Sleep attacks--sudden and without warning |
| Characteristics of Apomorphine? | -D1 and D2 agonist -SubQ -Rapid onset, Short duration -RESCUE THERAPY when "off" |
| What benefit do COMT inhibitors provide for PD tx? | -Inhibit further metabolism in the periphery of L-DOPA so that can give smaller dose |
| What are some COMT Inhibitors? | TOLCAPONE, ENTACAPONE Tolcapone--Long-acting, give 2-3 times per day Entacapone--Short-acting, given with each dose of Sinemet |
| What is the Entacaponse-L-dopa-carbidopa combo called? | STALEVO |
| Side effects of COMT inhibitors? | dyskinesias, diarrhea, nausea, hallucinations Tolcapone--Liver toxicity Entacapone--turns urine ORANGE |
| What role does amantadine play in PD tx? | -Enhances DA release and decreases its uptake -Alone in early tx or later in combo with L-DOPA for dyskinesias -Can cause red or purple skin blotches |
| What role does Deprenyl (Edepryl) play in PD tx? | -MAOB Inhibitor -Minimal effects alone--helps a little with "on-off" effects when used with L-DOPA |
| What is a newer and more effective MAO-B inhibitor? | Rasagiline -reduces breakdown of dopamine -Metabolized by CYP -Used cautiously at reduced levels with antidepressants that increase serotonin levels |
| When are anticholinergics typically used in PD tx? | -Seldomly used -Young patients with severe Tremor and Dystonia -ANTIMUSCARINICS may be used to improve TREMOR and RIGIDITY but little effects on bradykinesia--Trihexyphenydyl HCl, Benztropine mesylate, Benadryl -Usually used at the beginning early PD stages or in combo with L-DOPA |
| Side effects of anticholinergics? | Drowsiness, mental slowness, restlessness, confusion, agitatoin, dry mouth, blurry vision |
| In general, what are the main recommendations for the treatment of someone with PD?? | 1) Initially use AMANTADINE, PRAMIPEXOLE, or ROPINIROLE (in young patients anticholinergics) 2) Add or move to L-DOPA (SINEMET) when symptoms increase. Use as LOW DOSE as possible 3) When L-DOPA becomes less effective combine with DA AGONISTS or COMT INHIBITORS or AMANTADINE |
| What can continuous pacing stimulation with DBS lead to? | -Reduced output from STN |
| What is Tremor defined as? | -Repetitive, rhythmic oscillatory movements that tend to be REGULAR in AMPLITUDE and FREQUENCY |
| What is essential tremor? | -Enhanced physiological tremor -genetic component, progressive -made worse by anxiety, fatigue, caffeine |
| What are some medications for Postural tremor? | BETA BLOCKERS try first -propranolol, metoprolol, nadolol PRIMIDONE -antiseizure -best for hand tremor. start low and work your way up Sometimes... Pregabalin, topiramate, gabapentin (seizure meds) Benzodiazepines--alprazolam (xanax) Wine Botox |
| What kind of tremors are present ONLY during movement? | Kinetic or Intentional Tremor -Usually associated with cerebellar damage -Toxic effect of alcohol and other drugs -NO KNOWN TX |
| What are the 2 parts of the movement disorder associated with HD? | -Presence of Involuntary movements--CHOREA -Impairment of voluntary movements |
| What does HD involve the selective degeneration of? | -Basal Ganglia neurons--Especially GABA and ACh neurons |
| What is the effect of HD on DA terminals? | No effect--DA release may be NORMAL or slightly ELEVATED |
| What structures make up the STRIATUM? | Caudate Nucleus Putamen |
| What DA pathway degenerates first in HD? | INDIRECT PATHWAY=Too much activity (in late stages lose direct too--get more PD-like sx) |
| Have drugs that increase GABA and ACh activity been successful in tx of HD?? | NO!! |
| What can drugs that decrease DA activity do in HD? | -Help manage and decrease abnormal movements -Reserpine, Tetrabenazine--INHIBIT UPTAKE INTO VESICLES--deplete DA vesicle sores -Haloperidol, chlorpromazine--BLOCK DA RECEPTORS--tardive dyskinesia--involuntary movements -Clozapine--tx early cases of RIGID HD |
| What can depression in HD be tx with? | Fluoxetine (for OCD too) Serotonin blockers--Sertraline (zoloft), paroxetine (paxil) Tricyclic antidepressants--amitriptyline (Elavil) |
| What can the spastic effects (from loss of GABA) in HD tx with? | Benzodiazepines--DIAZEPAM (valium) |
| What helps with movements in late stages of HD? | NOTHING LDPA is sometimes used |
| What is Wilson's Disease? | -RECESSIVELY inherited -Disorder of COPPER METABOLISM -Characterized by LIVER DAMAGE and DAMAGE TO NEURONS -muscle tremors, bizarre movements--can be confused with CHOREA and DYSTONIA -FATAL if untreated -Increased concentration of Copper in brain, cornea, and liver--leads to hepatic and neurologic dysfunction |
| How is Wilson's Disease treated? | -Decrease copper concentrations--CHELATION, REDUCE ABSORPTION -Life-long tx -PENICILLAMINE--chelator. Comlexes with copper leading to it's removal by URINARY EXCRETION -TRIENTINE--can be used if develop intolerance to Penicillamine -POTASSIUM DISULFIDE with meals--sometimes used in combination with others to decrease Cu absorption -ZINC ACETATE (Galzin)--induces intestinal production of metallotionein--high affinity for copper. Blocks Cu absorption. Newly ingested Cu does not reach circulation and is excreted in stool FIRST--Start with Chelating agent for a few weeks THEN--move to maintenance on Galzin alone |
| What mutation causes Wilson's Disease? | -mutation near the ATP binding site in the copper-regulating protein ATP7B |
| What are other hyperkinetic movement disorders like ballismus, chorea, dystonia, and tics tx with? | DA depleting drugs--RESERPINE or TETRABENAZINE Neuroleptics--DA receptor blockers--HALOPERIDOL, Chlorpromazine, Perphenazine, fluphenazine, clonidine Benzodiazepines--DIAZEPAM, CLONAZEPAM Antiseizure--carbamezepine SOME people respond to anticholinergics (EXCEPT CHOREA)--used mostly with DYSTONIA |
| What does Tourette's syndrome usually respond to? | halloperidol Clonidine alternatives--atypical antipsychotics risperidone, olanzapine milder forms--benzodiazepines |
| What can focal dystonias be tx with? | BOTOX--muscle paralysis by blocking ACh release Injection lasts several months and can be done for up to 15 years |
| What id RLS usually tx with? | ROPINIROLE or other DA agonists |
| Which movement disorders have GOOD pharmacologic tx? | WILSON'S DYSTONIAS PD |
| Which movement disorders have poor tx options? | HD TREMOR Others |
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