Parkinson's Disease

State the disorders of motor function

PD (hypokinetic), Huntington's disease (hyperkinetic). Tics (Tourettes disorder), tardive dyskinesia (caused by chronic antipsychotic treatment), MSA (multiple systems atrophy), PSP (progressive supranuclear palsy), restless leg syndrome

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What are the symptoms of PD?

Resting tremor, rigidity, bradykinesia, postural instability, stooped posture, GI/genitourinary dysautonomia, orthostatic hypotention, cognitive decline (time course of disease is unpredictable)

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Outline the incidence of PD

Common in aging population (40+). Incidence increases until 7th decade of life, equal in men/women, no specific racial/environmental incidence

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Outline the pathology of PD

Loss of dopamine containing neurones in substantia nigra. Results in loss of terminals in caudate – putamen (striatum)

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The pathology of PD can be confused with which diseases?

Multiple systems atrophy, progressive supranuclear palsy, striato-nigral degeneration

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How is the diagnosis of PD confirmed?

By pathology at post-mortem. Loss of dopamine neurones in substantia nigra. Need post-mortem in presence of Lewy Bodies. Loss of neurones in non-dopamine brain areas

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Compare features of a PET scan for a patient with PD

Commas not seen clearly, indication of reduced uptake of dopamine with little dopamine transporters

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Outline the direct route for the basal ganglia

Cortex (glutamate +) - putamen (GABA -, GPe/STN) - GP interna (GABA - ) - VA/VL thalamus (glutamate +) - back to cortex

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Outline the indirect route in the basal ganglia

Cortex (glutamatate +) - putamen (GABA -) - GP externa (GABA -) - STN (glutamate +) - GP interna (GABA -) - VA/VL thalamus (glutamate +) - back to cortex

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What are the non-motor components of PD?

Bladder, bowels, sweating, drooling, speech, swallowing, sleep disturbance, somnolence/insomnia, hypotension, depression, anxiety, panic attacks, dementia, impotence, postural instability, pain

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Describe features of predisposition

Sporadic (no clear pattern of inheritance), inherited (glucocerebrosidase/susceptible gene). Dysfunction of proteasome (protein build up), altered mitochondrial function (decreases ATP generation/free radicals), altered lysosomal pathways (autophagy)

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Which therapy is used based on the pharmacology of PD?

Dopamine replacement therapy

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Describe features of striatal neurochemical imbalance in D

SNc to striatum (leads to reduced DA (D1/D2) receptor activation in striatum), increased ACh. Dysfunction of basal ganglia motor circuit. D2-R, striatal cholinergic interneuron dis-inhibited (increased muscarinic ACh receptor activation in striatum)

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What are the treatments for PD?

L-DOPA, dopamine agonists, MAOB inhibitors, COMT inhibitors, anticholinergics. Other - surgery, foetal transplants, stem cells, neurotrophic factors

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Describe features of L-DOPA

Gold standard treatment for PD, precursor for dopamine, use of dopamine replacement therapy, introduced in 1960s, combined with decarboxylase inhibitor in 1970s, problems with long term treatment. E.g. madopar, sinemet

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Outline how L-DOPA interferes with the dopamine metabolic pathway

Tyrosine (TH) - L-DOPA (AADC) - dopamine - MAO to DOPAC (COMT) to HVA or dopamine - COMT + MAO to HVA

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What are the side effects of L-DOPA?

Anorexia, nausea, vomiting, insomnia, agitation, postural hypotension, dizziness, tachycardia, arrhythmia, reddish colouration of urine

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What are the side effects with chronic L-DOPA?

Occurs within 2-5 years of starting L-DOPA therapy. On-off effect and wearing of efficacy (rapid fluctuations, freezing, plasma fluctuations, limited storage of dopamine). L-DOPA induced dyskinesia (LIDs)-hyperkinetic, face/limbs, mechanism uncertain

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Describe features of amantadine (lysovir) (1)

Used with L-DOPA to reduce dyskinesia. First introduced as antiviral agent. Poorly tolerated. Multiple mechanisms (enhance dopamine release, antimuscarinic action, increase dopamine synthesis, block NMDA receptors)

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Describe features of amantadine (lysovir) (2)

Effects on bradykinesia/tremor are modest. Less effective than L-DOPA

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What are the side effects of amantadine?

Anorexia, nausea, nervousness, insomnia, dizziness, convulsions, hallucinations, blurred vision, GI disturbance, peripheral oedma (could exacerbate congestive heart failure). High doses required/poorly tolerated

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Describe features of COMT inhibition (1)

Improves duration of action of L-DOPA (e.g. entacapone given with L-DOPA as stalevo). L-DOPA (-x-) 3-OMD. Dopamine (-x-) 3-MT - HVA. Entacapone (comptess) - peripherally active, increases duration of L-DOPA response

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Describe features of COMT inhibition (2)

Tolcapone - centrally active, confers clinical benefit, allows reduction in L-DOPA usage, rarely used clinically due to hepatotoxicity

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What are the side effects of COMT inhibitors?

Nausea, vomiting, abdominal pain, constipation, diarrhoea, dry mouth, insomnia, dyskinesia (associated with L-DOPA), dizziness

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Give examples of dopamine agonists

Apomorphine (Apo-Go), rotigotine (Neupro), bromocriptine, lysuride, ropinirole (Requip), pergolide, pramipexole (Mirapexin)

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Describe features of dopamine agonist therapy

Monotherapy (less effective than L-DOPA, less dyskinesia than L-DOPA/not apomorphine). Adjunct to L-DOPA - improves response, reduces off time, reduce motor fluctuations, reduce maintainance dose of L-DOPA, reduce dyskinesia

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What are the side effects of DA agonists?

Nausea, vomiting, constipation, leg oedema (ropinirole), pain dyskinesia, hallucinations, hypotension, bradycardia, drowsiness, somnolence, sudden onset sleep, impulse control disorders

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Describe features of MAOB inhibitors (1)

Increase central dopamine function. E.g. selegiline/rasagiline (Azilect). Early treatment may delay requirement for L-DOPA. Attenuates drug-induced motor fluctuations. Permits reduction in dose for L-DOPA. May exacerbate peak-dose effects

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Describe features of MAOB inhibitors (2)

May delay progression (Adagio study). MAOB inhibitor prevents MAOB from converting dopamine into DOPAC

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What are the side effects of MAOB inhibitors?

Constipation, diarrhoea, nausea, vomiting, sore throat, hypotension, depression, confusion, psychosis, agitation, headache, tremor, dizziness, sleep disturbances

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Describe features of anticholinergics (antimuscarinic agents)

Monotherapy in mild Parkinsonism. Tremor, rigidity, less effective than L-DOPA, often used as adjunct to L-DOPA, mechanism of action - antagonise increased cholinergic activity in striatum. (PK - ACh>DA, antimuscarinic - ACh=DA)

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Give examples of antimuscarinic agents

Benzhexol, benztropine, orphenidrine (Disipal, Biorphen), procyclidine (Arpicolim, Kemadrim)

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What are the side effects of anticholinergics?

Dry mouth, blurred vision, urinary retention, GI disturbance, tachycardia, dizziness, hypersensitivity, mental confusion, excitement, psychiatric disturbances

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What are the other treatments for PD?

Surgery (pallidotomy, deep brain stimulation). Foetal transplants (rare - disease enters implanted tissues). Neurotrophic factors (GDNF - failed at clinical trial, BDNF). Stem cells

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List treatments which provide neuroprotection in PD?

Selegiline, vitamin E, riluzole, GDNF, immunophilin, GAPDH inhibitor, Jnk kinase inhibitor, cogane, dopamine agonists, rasagaline

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Parkinson's Disease

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