Year 2002 Paper two: Questions supplied by Jo 1

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1 Year 2002 Paper tw: Questins supplied by J 1 Questin 40 Which ne f the fllwing is least likely t imprve the n-ff phenmenn in a patient with Parkinsn s disease currently treated sixth-hurly with levdpa/carbidpa and selegiline? A. Reducing the time between dses f levdpa/ carbidpa B. Intrductin f a dpamine agnist C. Intrductin f a catechl-o-methyltransferase (COMT) inhibitr D. Increasing each dse f levdpa/ carbidpa E. Intrductin f a sustained-release frm f levdpa/ carabidpa Answer: Learning Issues: 1) Parkinsn s disease 2) Treatment and side effects Parkinsn s Disease (PD) - Bradykinetic neurdegenerative mvement disrder - Peak age nset >60 years ld - Males > females - Cardinal features: (need 2 ut f 4 fr dx) Rigidity Bradykinesia Rest tremr (present in >85%) Gait disturbance - Other features: Ansmia Autnmic dysfunctin (may als be treatment related) Psychiatric features (depressin, dpamine-related hallucinatins) Sleep disturbance Dementia Dyskinesia and mtr fluctuatin (Levadpa related) - Subtypes Idipathic (75%) Genetic/ familial clusters (< 5%) Others eg ther neurdegenerative disease/ drugs/ CVA - Pathlgy (degree relates well with mtr symptms and dementia) Degeneratin f dpaminergic pathways (dpamine deficiency) and chlinergic sensitivity in basal ganglia Neurns accumulate synuclein prtein -> lewy bdies (especially lfactry and brain stem -> midbrain) Brain atrphy (limbic/ paralimbic structures; anterir cingulate gyrus) A few general statements abut PD: - An early nset resting tremr especially if unilateral suggests idipathic PD - Early nset cgnitive decline, neurpsychiatric symptms r autnmic dysfunctin suggests syndrmes with Parkinsnian features usually earlier age f nset and less respnsive t levadpa - Drug induced parkinsnism (mainly neurleptics, metclpramide, manganese, CO) clsely resembles idipathic except the tremr is generally less prminent. This ften reslves with drug cessatin if it persists, the patient may already have been in the prcess f develping PD

2 Year 2002 Paper tw: Questins supplied by J 2 - Diffuse lewy bdy dementia (DLB) clsely assciated with PD, there is cntrversy whether it is a spectrum f disease Hwever tend t have actin rather then rest tremr Rapidly fading respnse t levadpa Marked early neurpsychiatric features Treatment PHARMACOLOGICAL Symptmatic 1) dpamine supply - Levadpa + carbidpa/ benserizide 2) Dpamine agnist - Direct stimulatin f dpamine receptrs 3) metablism f dpamine - MAO inhibitrs - COMT inhibitrs 4) Antichlinergics Neurprtective Mstly experimental MAO inhibitr selegiline (shwing prmise but cnflicting data) Chrnic NSAIDS Oestrgen in pst-menpausal wmen Cenzyme Q10 (anti-xidant) Mincycline (antibitic) DRUGS AND SIDE EFFECTS DRUG MECHANISM SIDE EFFECTS Dpamine Can be used 1 st line Nausea Dizziness Levadpa: Headaches Precursr f dpamine which crsses BBB Smnlence Levadpa/ Carbidpa (Sinemet) Levadpa/ Benzaseride (Madpar) Sustained release frmulatins available but less cmpletely absrbed s need 30% mre t achieve same respnse Carbidpa/ benzaseride: Peripheral decarbxylase inhibitr which prevents peripheral cnversin t dpamine in systemic circulatin Start with small dses TDS with meals With dementia: start with smaller dses due t susceptibility t psychiatric cmplicatins Mst with idipathic PD - Gd respnse - if n/minimal respnse with mderate dses, recnsider dx r revise it t ther subtype eg MSA hmcysteine -> risk hip # In lder patients - Hallucinatins/ delusins - Cnfusin - Agitatin Lng term use: Within 5-10 years, up t 50% develp mtr fluctuatins, dyskinesias and dystnia Cncerns re neurtxic effects f levadpa in vitr Dpamine agnists Can be used 1 st line and mntherapy but mst will need levadpa in a few years (OR) adjunctive in advanced PD where Similar t levadpa Peripheral edema cmmn

3 Year 2002 Paper tw: Questins supplied by J 3 Brmcryptine Caberglide Perglide Pramipexle Rpinirle Apmrphine (used IV as rescue therapy) MAO-B inhibitrs Selegiline Rasagiline COMT inhibitrs Entacapne Tlcapne Antichlinergics Benztrpine there is levadpa respnse and levadpa cmplicatins Direct stimulatin f dpamine receptrs - N need cnversin - N cmpetitin with ther amin acids fr gut absrptin - Lnger duratin f actin Can be used as mntherapy in very early PD Cmbinatin f selegiline and levadpa prduces better Sx cntrl than levadpa mntherapy Slws xidative metablism f dpamine thus may levadpa-induced side effects eg dyskinesia and psychiatric effects Levadpa extenders thus useless as mntherapy - peripheral methylatin f levadpa (entacapne) - central methylatin f levadpa (tlcapne) Dpamine depletin prduces state f chlinergic sensitivity s chlinergic drugs exacerbate PD symptms and in chrnic use (rare in thse using levadpa alne) PRL Sleep attacks with pramipexle Valvular heart disease with perglide and cabergline (secndary activatin f sertnin receptrs activatin and vergrwth) s they shuld be avided Ergt-related side effects rare - Raynaud - Erythrmelalgia - Retriperitneal/ pulmnary fibrsis risk f impulse cntrl disrders eg pathlgical gambling Nausea Headache Insmnia Wrsen side effects f levadpa Cnfusin in elderly (very cmmn) Avid simultaneus SSRI r TCA Frm dpaminergic effects thus nausea Hallucinatins Cnfusin Dyskinesia Pstural hyptensin Orange urine Abnrmal LFTS and hepattxicity (nly tlcapne) Memry impairment Cnfusin

4 Year 2002 Paper tw: Questins supplied by J 4 (Cgentin) Trihexyphenidyl (Artane) Amantadine antichlinergics imprve symptms Useful as mntherapy in age < 70 with mainly tremr but n gait prblems r significant akinesia Antiviral, mechanism uncertain - Antimuscarinic agent - Weak dpamine agnist - Glutamate antagnist Use t treat dyskinesias Eliminatin depends n renal clearance s dse reduce in renal impairment Usually transient and mdest effect fr early/ mild PD Of little benefit adding t levadpa but great effect with levadpa added t amantadine Antimuscarinic effects - Dry muth - Blurred visin - Ur retentin/ cnstipatin - Impaired sweating - Tachycardia Often antichlinergic Livid reticularis Ankle edema NON-PHARMACOLOGICAL Exercise Educatin/ cunselling SURGICAL - Deep brain stimulatin and paiidtmy/ thalmtmy/ subthalmtmy - Patient selectin crucial - Symptms that d nt respnd t levadpa generally d nt imprve (eg pstural instability, hypphnia, drling) - Majr indicatins Idipathic PD (atypical PD des nt have a gd respnse) Gd levadpa respnse Significant, severe symptms Minimal cgnitive impairment Mtr fluctuatins - On-Off phenmenn/ alteratins - Usually in advanced PD - Nticed < 4 hurs pst dse f levadpa - Management: dse f levadpa IF n a small dse and nt having ther side effects Shrten interdse interval (mre effective, but sme may experience all r nthing with small dses: in advanced disease the pharmaclgical threshld is higher) SR (Need t dse 30% - sme studies shwed n Off time) Additin f 2 nd drug

5 Year 2002 Paper tw: Questins supplied by J 5 Dpamine agnist t Off time (brmcriptine ineffective, thers equal efficacy thugh cabergline dyskinesia) COMT inhibitrs (clinical effect immediate) MAO-B inhibitrs (seligine n Off time mdest, resiligine better) Antichlinergics and amantadine NOT helpful in mtr fluctuatins H-Pylri eradicatin (imprved levadpa absrptin) - Unpredictable freezing Sudden immbilisatin fr minutes -> falls Nt medicatin related Resistant t treatment - Sme ccasinally fail t turn On fllwing a dse f levadpa Knwn as N On respnse May be due t gastric mtility and pr absrptin Or due t prlnged Off time Can treat with prkinetic agent eg dmperidne (D2 antagnist but des nt crss BBB s des nt wrsen PD symptms like metclpramide) Dyskinesia - Invluntary abnrmal mvements - May be chreic r dystnic, affecting face, trunk, extremities and respiratry muscles - Or when severe, can be myclnic r ballistic and interfere with mvement - Often well-tlerated - Happens when patient is On and during peak dse (60-90 minutes pst-dse), may have a diphasic pattern - Direct effect f levadpa especially cmmn in thse with yung nset PD - Affects up t 40% by 5 years and with duratin f treatment - Management Avid SR frmulatins levadpa dse as much as pssible Try adding dpamine agnist and levadpa dse Amantadine (shrt term benefit) Clzapine (but watch fr agranulcytsis) Olanzepine (but may have unacceptable PD symptms and Off time) Dystnia - Sustained abnrmal pstures mainly affecting limbs but als face, neck and trunk - During Off perid - Can be painful eg early AM ft twisted in abnrmal psture due t withdrawal frm treatment - Or as akathisia (mtr restlessless eg restless legs) a few hurs after PM dse f levadpa - Management Take SR befre sleep Levadpa r dpamine agnist 1 st thing in the mrning/ middle f the night Avid taking levadpa with high prtein meals Nn-mtr symptms - Depressin: antidepressants eg SSRIs and ECT very effective

6 Year 2002 Paper tw: Questins supplied by J 6 - Psychtic features/ cnfusin: stp amantadine and antichlinergics 1 st then cnsider simplificatin f drug regime in the fllwing rder: selegiline, ncturnal dses f dpamine agnist, sustained release frmulatins, daytime dses f dpamine agnists and finally daytime levadpa If ding this wrsens PD atypical antipsychtics (quetiapine the best, clzapine als gd but risk f agranulcytsis) Risperidne and lanzepine tend t wrsen PD symptms Sme evidence suggest anti-chlinesterase inhibitrs may be useful in thse with dementia Back t the questin: The patient is n QID levadpa/ carbidpa + MAO-B inhibitr selegiline and experiencing mtr fluctuatins suggesting advanced disease. All ptins are aiming twards either increasing the dse r duratin f effect f dpamine, hwever dse f levadpa is the least effective s the answer is D.