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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