Mkgrady8 Neuro 5 Extrapyramidal Dysfunction

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basic characteristics of parkinson's disease (PD)

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resting tremor, rigidity and stooped posture, akinesia and bradykinesia; immobility, underactivity, facial immobility, reduced blinking, difficulty in visual focusing, difficulty arising from a chair and beginning to walk; autonomic dysfunction (excessive salivation and increased sweating); dementia; depression

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causes of PD

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idiopathic most of the time; iatrogenic= induced by antipsychotic drugs; similar clinical syndromes produced by viral or other encephalitis, arteriosclerosis, carbon monoxide poisoning, and chronic manganese intoxication; pathogenesis= DOPAMINERGIC MECHANISMS IN EXTRAPYRAMIDAL SYSTEM DISRUPTED= there is a degeneration of dopaminergic neurons with cell bodies in the substantia nigra pars compacta (SNc) and terminals in striatum (caudate and putamen)

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PD treatment

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by enhancing dopaminergic activity and by reducing influence of striatal cholinergic neurons; DRUG THERAPY OF PD ODIFY ACTIVITY OF THESE 2 TRANSMITTER SYSTEMS; L-DOPA

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L-DOPA: how does it work

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CAN CROSS BBB via the neutral aa transporter converted to dopamine in remaining neurons; there may be a compensatory increase in DA synthesis by surviving neurons; essentially all effects of L-DOPA due to dopamine formed by action of dopa decarboxylase; 95-98% of L-DOPA CONVERTED TO DOPAMINE IN THE PERIPHERY and generally L-DOPA co administered with a peripherally acting decarboxylase inhibitor to prevent this conversion; the BENEFICIAL EFFECTS of dopamine in PD MEDIATED VIA DOPAMINE D2 RECEPTORS (postsynaptically on striatal neurons)

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L-DOPA: action in CNS

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ameliorate the akinesia and rigidity of PD; tremor more resistant but can be significantly reduced (anticholinergics can be combined with levodopa to reduce tremor); improvement of posture, gait, associated movements, facial expression, speech, handwriting, swallowing, etc; mood changes (e.g. depression and apathy) somewhat relieved; mental function improved; adverse effects such as dyskinesias and psychiatric disturbances produced

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L-DOPA effect on cardiovascular system

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orthostatic hypotension of central origin, tolerance with continued treatment; arrhythmias (beta receptor) and tachycardia, increased incidence of arrhythmias in susceptible persons but still low, INCIDENCE DECREASED WHEN L-DOPA COMBINED WITH CARBIDOPA

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L-DOPA effect on GI system

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nausea, vomiting, and anorexia (tolerance develop if dose increased slowly); incidence of 80% with L-DOPA alone reduced to 20% by combo with carbidopa

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L-DOPA endocrine effects

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inhibition of prolactin secretion

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major side effect of L-DOPA

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dyskinesias (abnormal involuntary movements) due to the central action of DA; reduction of dose REVERSES this; can cause behavioral and personality changes due to CENTRAL action of L-DOPA

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L-DOPA: precautions and drug interactions

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CONTRAINDICATED IN PTS WITH= narrow angle glaucoma, ACUTE PSYCHOSIS OR SEVERE PSYCHONEUROSIS, and in pts with endocrine, renal, hepatic, CV or pulmonary disease, cardiac arrhythmia, and myocardial infarction; PYRIDOXINE (B6) reverses action of L_DOPA due to enhancement of peripheral conversion to dopamine (effect prevented by carbidopa); MAO inhibitors combined with L-DOPA result in hypertensive crisis; phenothiazines and butyrophenones (dopamine blockers) counteract therapeutic effect of L-DOPA, reserpine also by preventing storage of dopamine

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Carbidopa: what does it do, when is it used

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inhibits decarboxylase but does not cross the BBB in amounts high enough to affect the enzyme in brain; generally given in fixed dose combo with L-DOPA; the trade name for the combo is SINEMET and comes in various ratios of L-DOPA to carbidopa

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carbidopa: advantages of addition of carbidopa

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reduced dose of levodopa (by 75%); markedly diminished nausea and vomiting; diminished cardiac side effects; achieve therapeutic level much more rapidly; reduced fluctuation of L-DOPA reaching CNS; avoid pyridoxine effect; overall therapeutic efficacy of L-DOPA enhanced

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unresolved effects of peripheral decarboxylase inhibitors

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orthostatic hypotension (central mechanism); dysknesias that appear earlier, more severe, and persist longer; adverse mental effects may appear earlier

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motor fluctuations with L-DOPA therapy

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after 5 yrs of L-DOPA therapy some type of unpredictable fluctuation in clinical response occurs in 50% of pts (difficult to manage); freezing episodes= periods of sudden immobility; wearing off effect= relief of symptoms lasts only 2-3 hrs rather than 4-5 hrs, smaller, more frequent doses helpful; peak dose dyskinesias APPEAR 1-2 HRS AFTER A DOSE, helpful to decrease individual doses and give more frequently; on off phenomenon= UNPREDICTABLE MOTOR FLUCTUATIONS FROM A STATE OF MOBILITY (ON) TO A STATE OF IMMOBILITY (OFF) AND BACK AGAIN, addition of agonists or selegiline to L-DOPA or apomorphine (a direct dopaminergic agonist)

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controversy concerning L-DOPA therapy

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occurence of these fluctuations has caused the controversy; some clinicians think these problems related to duration of therapy with L-DOPA and recommend prescribing anticholinergics or amantadine initially in less disabled pts; others suggest reduced effect of L-DOPA due to progression of PD and recommend L-DOPA given early; a conservative approach= initially prescribe other agents, and reserve L-DOPA for pts that do not respond to anticholinergics of amantadine; combo of L-DOPA with other agents relatively common

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therapeutic use of antichoinergic drugs

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muscarinic receptor antagonists in CNS= can correct balance between dopaminergic and cholinergic influences in striatum; anticholinergics used alone or in combo with L-DOPA or amantadine; tremor, rigidity, and bradykinesia improves but these drugs much less effective than L-DOPA, usefulness limited by side effects and become less effective with prolonged use; often effective for control of EPS (extra pyramidal syndrome) (by antipsychotic drugs)

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side effects of anticholinergics

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peripheral anticholinergic= dry mouth, mydriasis, cycloplegia, tachycardia, constipation, urinary retention; central anticholinergic= disruption of memory, insomnia, restlessness, delirium, paranoid reaction, hallucinations; some have antihistaminic effects (diphenhydramine), producing drowsiness and dizziness

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specific anticholinergic agents

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benztropine, procyclidine

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amantadine: therapeutic use

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an antiviral agents, has a beneficial effect on PD and drug induced EPS; releases dopamine from intraneuronal stores and decreases re uptake and has direct agonist and anticholinergic actions; tolerance to its action develops within a few weeks; frequently combined with anticholinergic agents or L-DOPA

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amatadine: side effects

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usually well tolerated; produces anticholinergic effects and increases peripheral and central adverse effects of anticholinergic drugs; 25% of pts develop difficulty in thinking, confusion, lightheadedness, hallucinations, and anxiety; when given with L-DOPA increases psychotic reactions; edema of the feet, ankles, and legs, reversible with time; caution in pts with renal impairment since 90% of amantadine excreted in urine

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apomorphine: therapeutic use

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dopamine agonist; been tried as continuous subcutaneous therapy to supplement oral L-DOPA in pts with response fluctuations (domperidone reduces emetic action)

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bromocriptine: therapeutic use

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dopamine agonist; especially useful with L-DOPA to reduce motor fluctuations (caused by L-DOPA), works on D2 receptors; effective alone (but often not used alone); dose of L-DOPA reduced when combined with bromocriptine; less tendency to produce dyskinesias

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bromocriptine: adverse effects

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all reversible upon discontinuation; minimized by slowly building up dose over 2-3 months to develop tolerance (to nausea, hypotension); nausea and vomiting (controlled by domperidone); hypotension common, tolerance develops with time; constipation; digital vasospasm on cold exposure; psychiatric disturbances (e.g. nightmares, hallucinations, paranoid delusions), more common and severe than with L-DOPA; dyskinesias like those of L-DOPA but less frequent; erythromelalgia= red, tender, warm, edematous lower extremities; contraindications= psychiatric illness or recent myocardial infarction

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ropinirole: therapeutic use, side effects, precautions

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direct acting D2 receptor agonist; side effects= light headedness and fainting with slowed heart beat, nausea, drowsiness, dystonias, and hallucinations; precautions= ciprofloxacin reduces excretion of ropinirole (increasing its circulating levels)

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preamipexole: therapeutic use, side effects

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direct acting DA receptor agonist with selectivity for D3/D4 DA neurons, also exerts a neuroprotective effect; may be co administered with sinemet; side effects= orthostatic hypotension, nausea, drowsiness

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selegiline: therapeutic use, side effects

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a monoamine oxidase B inhibitor; MAO-B preferentially metabolizes dopamine without altering metabolism of NE and serotonin; consequently it causes enhancement of L-DOPA effects; addition to L-DOPA/carbidopa resulted in modest reductions of motor fluctuations in pts (but this effect decline after 6-12 months); investigators proposed using early combo of selegiline and L-DOPA as initial therapy in newly diagnosed PD; a recent study of PD cases found pts who received it alone or with tolcapone reached a predetermined level of disability more slowly than subjects who took tolcapone alone or placebo (i.e. it delays progression of early PD); minimal adverse effects, can cause insomnia and mental disturbances including hallucinations

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tolcapone: therapeutic use, side effects, precautions, drug interactions

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inhibits catachol-O-methyl transferase (COMT); COMT breaks down L-DOPA; it has central and peripheral activities; allows for presence of more L-DOPA to remain in circulation/brain; enhances effectiveness of L-DOPA by increasing time L-DOPA effective so a longer on period and a shorter off time; also reduces amount of sinemet required to reduce tremors; side effects= nausea, drowsiness, insomnia, dizziness, confusion, urine discoloration, dyskinesia; precautions= affects liver enzymes and thus liver function should be screened; drug interactions= other drugs metabolized in liver must be monitored (e.g. warfarin)

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entacapone: therapeutic use, side effects

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also inhibits COMT but only has peripheral activity; less hepatotoxicity than tolcapone; side effects= dyskinesias, nausea, confusion

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drug treatment in Huntington'd disease (HD)

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huntington's chorea is an inherited degenerative disease involving cortex and basal ganglia; dopamine levels in striatum normal or elevated (substantia nigra neurons intact); activities of enzymes catalyzing synthesis of GABA and ACh reduced in striatum; symptoms resemble some of symptoms of excessive dopaminergic activity induced by L-DOPA; attempts to treat disease with agents that enhance cholinergic of GABA activity been disappointing; dopamine receptor antagonists provide some relief; antipsychotics (phenothiazines and haloperidol) employed (results not completely satisfactory); presumably these drugs restore balance of dopamine acetylcholine GABA system; dopamine depleting agents also have a beneficial effect; reserpine or tetrabenazine sometimes useful unfortunately antipsychotics and dopamine depleting drugs can all produce iatrogenic parkinsonism

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tourette's syndrome (TS): what is it

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a multiple tic disorder with onset in early childhood between ages of 5-7 yrs; tics usually described as sudden, rapid, stereotyped, and purposeless movements of coordinated muscle groups; most common tics involve excessive eye blinking, throat clearing, head shaking, and facial grimacing; a greater centering of tics in upper body; coprolalia (obscene or socially inappropriate speech), dramatic, and infrequent manifestation; all tics aggravated by stressful environmental stimuli or settings; ADHD seems to co occur in a high proportion of cases; often viewed as a disease associated with a hyperfunctioning of DA systems since haloperidol is first line treatment and effective in 2/3 of individuals but precise cause unknown

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TS: treatment

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haloperidol; secondary choices= primazide and risperidone, some evidence that clonidine effective in haloperidol resistant individuals

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A 72 y/o man exhibits progressive tremors,bradykinesia, and muscular rigidity. Heis slow to initiate movements and shows other motor abnormalities. The most likely diagnosis of his disease isParkinson disease. L-DOPA can beprescribed for treating the sx of this pt, but this drug will have peripheralside effects. Peripheral adverse effectsof levodopa including nausea and cardiac arrhythmias, can be diminished byincluding which of the following drugs in the therapy? a. amantadine b. bromocroptine c. carbidopa d. entacapone e. ropinirole

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C

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A 65 y/o female came in to the office of herphysician complaining of tremors in both hands while at rest. The physician also noticed a mask like faceand short shuffling gait when the pt walked in. The physician determined that the pt had Parkinsonism. Which of the following antiparkinson drugs maycause peripheral vasospasm? a. amantadine b. bromocriptine c. carbidopa d. entacapone e. ropinirole

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B

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A 72 y/o man exhibits progressive tremors,bradykinesia, and muscular rigidity. Heis slow to initiate movements and shows other motor abnormalities. The most likely diagnosis of his disease isParkinson disease. The tremor ofParkinson’s disease: a. occurs at rest and is alleviated bybeta-adrenergic antagonists b. occurs at rest and worsened by bromocriptine c. occurs mainly with intentional movement and isincreased by L-DOPA d. occurs at rest and is reduced by benztropine oramantadine

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D

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Which of the following drugs are useful fortreating symptoms of Parkinson’s disease directly activates D2 receptors? a. L-DOPA b. Bromocriptine c. Amantadine d. Selegiline e. Procyclidine

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B

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A 19 y/o male carpenter has recently begunpimozide therapy for Tourette’s disorder. He is brought to the ER by his parents. They describe that he has been having ‘different appearing tics’ thanbefore, such as prolonged contraction of the facial muscle. While being examined, he experiencesopisthotonus (spasm of the body where the head and heels are bent backward andthe body is bowed forward, a type of EPS effect). Which of the following drugs would bebeneficial in reducing these symptoms? a. benztropine b. bromocriptine c. lithium d. prochlorperazine e. risperidone

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A