2Patient Presentation Chief Complaint HPI "I have trouble getting myself started, and it takes me longer to do things."HPIJoan Miller is a 58-year-old, right-handed woman who presents to the neurology clinic because of stiffness on her right side over the last 6 months. It takes her longer to do things because it takes more effort to get movement started, and her muscles feel stiff. For the last year, she feels that she does not think as quickly and it takes her longer to remember things. She also complains of constipation and decreased libido for over a year. Recently, it has become difficult to read because the words occasionally look blurry. These symptoms have affected her job performance as a high-school gym teacher, resulting in her contemplating early retirement.
3Patient PresentationSix months later, Ms. Miller returns to the clinic. Her medications include multivitamin daily, eye emollient ointment (Refresh PM), Metamucil 1 tablespoon twice daily, pramipexole 1 mg 3 times dailyHer libido, slowness, stiffness, and thinking have improved. She is better able to perform her job, enjoys the work, and is no longer planning her retirement. Her constipation has improved marginally. She continues to complain of blurred vision but has not been to the ophthalmologist. She now complains of itchy eyebrows and scalp. The patient reports no side effects from the medicine. However, her husband complains that her personality has changed because she shops excessively, often buying duplicates of things, which is straining their budget.
4IntroductionA neurodegenerative disorder caused by progressive death of selected dopaminergic neurons in the CNS.The pathology of this disorder leads to deteriorating motor,autonimic,cognitive and psychiatric function. First described by James Parkinson in his classic 1817 monograph, "An Essay on the Shaking Palsy,“
5Epidemiology Affects between 100 and 200 per 100,000 people over 40 Over 1 million people in North America aloneUncommon in people younger than 40Incidence of the disease increases rapidly over 60 years, with a mean age at diagnosis of 70years
7PathophysiologyDopaminergic cells originating in substantia nigra pars compacta and terminating in the caudate & putamen (nigrostriatal pathway ) are lost gradually during the course of the disease.Pateints initially become symptomatic after 70%-80% cell loss in these area.Accounts for development of rigidity & akinesiaMay contribute to cognitive symptoms.Factors contributing to autonomic dysfunctionDegeneration of the intermediolateral columns of spinal cordDegeneration of the sympathetic and parasympathetic gangliaLoss of brainstem serotonergic & noradrenergic cellscontribute to depressive symptomsFormation of Lewy bodiesFound in cortex, brainstem and basal forebrain in individuals with preclinical and advance PDEnclosed bodies containing eosinophils and cytosolic proteinsNonspecific finding; may be unrelated to PD process
8Motor features of Parkinson disease Cardinal manifestationsCraniofacialMusculoskeletalGaitVisual
9Cardinal manifestations TremorCoarse, slow “pill rolling” seen in upper extremitiesMore prominent at restUsually occurs in one arm at first, then spreads to the contralateral arm.BradykinesiaGeneralized slowness of motionDifficulty initiating movementFacial maskingDecreas swallowingRigidityCogwheelingMuscle stiffness, fatigue and weaknessResistance observed during passive motion a limb.Postural instabilityAlterations in balance and equilibriumContributes to falls & injuries
11Musculoskeletal Micrographia Dystonia Myoclonus Stooped posture (camptocormia)Kyphosis ScoliosisDifficulty turning in bed
12NONMOTOR SYMPTOMS Cognitive dysfunction and dementia Psychosis and hallucinationsMood disorders including depression, anxiety, and apathy/abuliaSleep disturbancesFatigueAutonomic dysfunction ????Olfactory dysfunction (Smell sensory)Pain and sensory disturbancesDermatologic findings (seborrhea)
13STAGES Hoehn and Yahr Scale SymptomsStagesUnilateral involvement only, minimal or no fx impairmentStage I:Bilateral involvement, without impairment of balanceStage II:Evidance of postural imbalance, some reduction in activities ,capable of leading independentStage III:Severely disabled, unable to walk and stand unassisted , markedly incapacitatedStage IV:Restricted to bed or wheelchair unless aidedStage V
14TreatmentThe pharmacologic treatment of PD can be further divided intoNeuroprotectiveSymptomatic therapy.
15SYMPTOMATIC THERAPY The decision to initiate symptomatic medical therapy in patients with PD is determined by the degree to which the patient is functionally impaired.The timing of this decision varies greatly among patients but is influenced by a number of factors, including :The effect of disease on the dominant handThe degree to which the disease interferes with work, activities of daily living, or social and leisure functionThe presence of significant bradykinesia or gait disturbancePersonal philosophy regarding the use of drugs
16SYMPTOMATIC THERAPYThe major drugs available for symptomatic therapy includeLevodopaMAO B inhibitorsDopamine agonistsCOMT inhibitorsAnticholinergic agentsAmantadine
17LEVODOPALevodopa (L-dopa) is well established as the most effective drug for the symptomatic treatment of idiopathic or Lewy body PD.It is particularly effective for the management of akinetic symptoms and should be introduced when these become disabling and are uncontrolled by other antiparkinsonian drugs.Tremor and rigidity can also respond to levodopa therapy, but postural instability is less likely to do.
18LEVODOPAMechanism Levodopa is converted to dopamine by dopa decarboxylase for use in striatal neurons.Role in Therapy useful for motor symptom is Stage II-V disease
19LEVODOPA Formulations Levodopa is combined with a peripheral decarboxylase inhibitor carbidopaAdvantage of combination;Carbipoa to block its conversion to dopamine in the systemic circulation and liver (before it crosses the blood-brain barrier) in order to prevent nausea, vomiting, and orthostatic hypotension.Carbipoa increase F of levodopa to penetrate the CNS. Need app mg\ day of carbidopa to effectively block the peripheral conversion of levodopa.The combination drug carbidopa/levodopa (immediate-release Sinemet) is available in tablets of 10/100, 25/100, and 25/250 mgControlled release formulation has 70% bioavailability of immediate release 25\100mg, 50\200 mg.
20Controlled release levodopa preparations are less completely absorbed and require a dose up to 30 percent higher to achieve an equivalent clinical effect. The clinical effect of each tablet is typically less dramatic than for immediate release preparations, since controlled release formulations reach the brain more slowly. This presents a disadvantage in assessing the response of patients just beginning therapy. As a result, it is recommended that therapy be initiated with an immediate release preparation with a subsequent switch to controlled release if desired. Both the immediate and the controlled release formulations appear to maintain a similar level of symptom control after several years of use
21Dosing Initial:25/100 mg two to hree times daily with meals avoid high fat meals ???.Interfere with abs. of levodopa in GI tract.Total daily dose of carbidopa/levodopa can be titrated carefully upward over several weeks to a full tablet of 25/100 mg three times daily as tolerated.If pt fail to respond to >1000 mg levodpa reconsider PD diagnosis.
22Adverse effects Nausea, somnolence, dizziness, and headache are among the more common side effects that may accompany treatment with levodopa, but they are not likely to be serious in most patients.More serious adverse reactions to levodopa (mainly in older patients) may include confusion, hallucinations, delusions, agitation, and psychosis.Levodopa may also induce a mild to moderate elevation in serum homocysteine levels which in turn may be associated with an increased risk of hip fractures in elderly patients.
23Adverse effects Motor fluctuations Occur in at least 50 percent of patients after 5 to 10 years of treatmentCalled (the wearing-off phenomenon): involuntary movements known as dyskinesia, abnormal postures of the extremities and trunk known as dystonia
24MAO B INHIBITORS selegiline MechanismSelegiline irreversibly and selectively inhibits monoamine oxidase (MAO) type B inhibitor the oxidative metabolism of dopamineRole in Therapyis modestly effective as symptomatic treatment for PD and may have neuroprotective properties (preclinical disease).Adjunctive treatment in Stage I-IV. May use lower doses of levodopa and dopamine agonist.
25Selegiline Dosing 10 mg per day ; 5 mg qam and 5mg at lunch Metabolized by liver to …. (to avoid insomnia).However, lower doses are sufficient to induce MAO B inhibition, and 5 mg once a day in the morning is currently recommended.Doses higher than 10 mg daily are of no additional benefit and may result in nonselective MAO inhibition, thereby placing the patient at risk of hypertensive crisis in the absence of dietary restrictions.
26Selegiline Adverse effects Nausea and headacheamphetamine metabolites of selegiline can cause insomniaAugment levodopa toxicitiesPotential food- drug interaction (tyramine)Potential drug-drug interaction (SSRI)
28DOPAMINE AGONISTSPergolide has been voluntarily withdrawn from the United States market and is best avoided because it is associated with a risk of cardiac valve problems.Injectable apomorphine has been approved by the United States FDA for treatment of motor fluctuations in PD section on Dopamine agonists.AdvantageUnlike levodopa-carbidopa ,these drugs are direct agonists thatdo not require metabolic conversiondo not compete with amino acids for transport across the gut or into the braindo not depend upon neuronal uptake and release.longer duration of action .
29DOPAMINE AGONISTS Role of Therapy Monotherapy in early disease (younger pt) to delay the time to start levodopa.Less effective monotherapy for sever stages >stage 3
30DOPAMINE AGONISTS Role of Therapy Monotherapy — Dopamine agonists (DAs) were initially introduced as adjunctive treatment for advanced PD complicated by reduced levodopa response, motor fluctuations, dyskinesia, and other adverse effects of levodopa. However, the hypothetical concern that free radicals generated by the oxidative metabolism of dopamine contribute further to the degeneration of dopaminergic neurons has prompted some investigators, despite lack of conclusive evidence, to advocate the early use of DAs as an levodopa-sparing strategy.With this approach, treatment with levodopa can be postponed and saved for a later time in the course of the disease, when disability worsens and the less effective agonists no longer provide adequate benefit.This strategy is based upon the unproven concept that the long-term duration of a given patient's responsiveness to levodopa is finite and that the drug, like money in a savings or retirement account, should be rationed. However, whether reduced responsiveness to levodopa over time is due to a decline in drug response or progression of underlying PD is currently uncertain.
31DOPAMINE AGONISTS Dosing Bromocriptineis usually started at 1.25 mg twice a day; the dose is increased at two to four week intervals by 2.5 mg a day.Most patients can be managed on 20 to 40 mg daily in three to four divided doses, although total daily doses as high as 90 mg can be used.Pramipexoleis usually started at mg three times a day.The dose should be increased gradually by mg per dose every five to seven days.Most patients can be managed on total daily doses of 1.5 to 4.5 mg.RopiniroleIs usually started at 0.25 mg three times a day.The dose should be increased gradually by 0.25 mg per dose each week for four weeks to a total daily dose of 3 mg.After week four, the ropinirole dose may be increased weekly by 1.5 mg a day up to a maximum total daily dose of 24 mg.Benefit most commonly occurs in the dosage range of 12 to 16 mg per day.
32DOPAMINE AGONISTS Adveres effect Poorly tolerated by about 30% due toAllergyPalpitationSinus tachycardiaAgitationEdema (hands, feet, face)Plural effusion
33COMT INHIBITORS Mechanism Drugs Inhibits the enzyme catechol-O-methyl transeferase that converts levodopa to 3-O-methyldopa and converts dopamine to 3-methooxytyramineDrugsTolcapone 100mg,200mgEntacapone 200mgCarbidopoa/levodopa/entacapone
34COMT INHIBITORS Role in therapy: They are ineffective when given alone, but they may prolong and potentiate the levodopa effect when given with a dose of levodopa.These medications are mainly used to treat patients with motor fluctuations who are experiencing end-of-dose wearing "off" periods.
35COMT INHIBITORS Dosing The starting dose of tolcapone is 100 mg three times daily; the clinical effect is evident immediately, up to 600 mg/dayThe dose of entacapone is one 200 mg tablet with each dose of levodopa, up to a maximum of eight doses per day. ???mg/day
36COMT INHIBITORS Adverse effects Tolcapone The most common side effects of tolcapone are due to increased dopaminergic stimulation and include dyskinesia, hallucinations, confusion, nausea, and orthostatic hypotension. The adverse effects are managed by lowering the dose of levodopa either before or after the addition of tolcapone.Diarrhea that is poorly responsive to antidiarrheal medications appears in approximately 5 percent of patients.An orange discoloration of the urine is a common but benign adverse event.Elevations in liver enzymes may rarely occur. Monitoring???Entacapone are similar to tolcapone ADR, although entacapone has thus far not been associated with hepatotoxicity
37ANTICHOLINERGICS Mechanism Role of therapy Drugs Antagoniza muscarinic cholinergic receptors in the striatumRole of therapyUsed to control tremorDrugsTrihexyphenidylBenztropine
38ANTICHOLINERGICS Dosing Trihexyphenidyl The starting dose of trihexyphenidyl is 0.5 to 1 mg twice daily, with a gradual increase to 2 mg three times daily.Benztropine traditionally is more commonly used by psychiatrists for the management of antipsychotic drug-induced parkinsonism; the usual dose is 0.5 to 2 mg twice daily..
39ANTICHOLINERGIC Adverse effects Peripheral antimuscarinic side effects include dry mouth, blurred vision, constipation, nausea, urinary retention, impaired sweating, and tachycardia.Caution is advised in patients with known prostatic hypertrophy or closed-angle glaucoma.Discontinuation of anticholinergic drugs should be performed gradually to avoid withdrawal symptoms that may manifest as an acute exacerbation of parkinsonism, even in those in whom the clinical response has not seemed significant.
40AMANTADINE Mechanism Role of therapy Blocks presynapatic dopamine reuptake; causes release of dopamine from storage sitesSynergistic effects with levodopa and dopamine agonistsRole of therapyImproves bradykinaseia, tremor, and rigidity, in pateints with Stages I-IV disease
41AMANTADINE Dosing The dose of amantadine in early PD is 200 to 300 mg daily; there is no evidence that larger doses are of additional benefit. The main advantage of this agent is a low incidence of side effects.It is excreted unchanged in the urine and should be used with caution in the presence of renal failure.Adverse effects — Peripheral side effects include ankle edema, which are rarely severe enough to limit treatment. Confusion, hallucinations, and nightmares occur infrequently, but unpredictably, even after long periods of use without side effects. These effects are more likely when amantadine is used together with other antiparkinsonian drugs in older patients.