DOPA-LEVODOPA

What is the main toxicity associated with entacapone?

Liver toxicity

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With what other neurotransmitter does dopamine share its biosynthetic pathway?

Glutamate

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Describe features of Parkinson's disease?

First described by James Parkinson in 1817. 2nd most common neurodegenerative disease (after AD). Affects 0.1% of general population, rising to 2% of those >80 years (>4 million worldwide). Death occurs within 10-15 years

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What are the treatment options for PD?

Pharmacological (monotherapy, adjunct therapy), surgical (gene therapy, foetal implants, deep brain stimulation, stem cells). Rehabilitation

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Outline dopamine biosynthesis

L-tyrosine - (tyrosine hydroxylase) - L-DOPA - (DOPA decarboxylase) - dopamine

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Outline dopamine metabolism

Use COMT to get 3-methyoxytyramine then MAO-B to get homovallinic acid. Or MAO-B to get DOPAC then COMT to get homovanillinic acid

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What does DOPAC stand for?

3,4-dihydroxyphenylacetic acid

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Describe features of dopamine storage

Packed into vesicles at presynaptic terminus. Fuse with membrane and release dopamine into synaptic cleft

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Catecholamines are stored as what?

ATP complexes. 4:1 ratio. Keeps osmotic pressure of solution low (although concentration ~2.5M). ATP acts as co-transmitter in adrenergic synapses (purinergic synapses)

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Describe the structure of dopamine receptors

Heptahelical structure consisting of amino acids. N-terminus outside cell and C-terminus inside cell. GCRP (cascade reaction in cell). Lipid structure to maintain structure within phospholipid bilayer

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Describe features of the dopamine receptor subtypes

Dopaminergic neurones are inhibitory. 5 subtypes. D1/D2 (control neuromotor activity), D3/4/5. D1 (stimulates adenylyl cyclase (not in SN). D2 (reduces cAMP production (present in SN)

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Describe features of the pharmacology of PD

Prevent not possible (ageing/genetics/no biomarkers for disease onset). Strategy is to replace lost dopamine. Dopamine will not cross BBB. Balancing act (too much/dyskinesia, too little/akinesia). Minimising side effects is important

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Why is the brain impermeable to dopamine?

Dopamine is too polar to cross the BBB

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Describe the absorption of L-DOPA

Dopamine cannot cross BBB into CNS. L-DOPA is more lipophilic and can cross BBB. In the brain, L-DOPA is metabolised into dopamine using DOPA decarboxylase

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Outline the structure and features of L-DOPA

Half-life of 1-2 hrs. Metabolised by DOPA decarboxylase. Initial dosage interval 6-8 hours. Eventually required 1-2 hours (end of dose 'wearing off' effect). Functional groups include catechol ring, COOH and amine

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What is the dosages for different therapies when using L-DOPA?

Monotherapy - 6-8 g/day, over 2-4 doses, increases every 1-2 hrs. Adjunct therapy - 0.5g/day (Carbidopa). Doses taken on empty stomach (competition of amino acids for neutral amino acid transporter in gut)

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Describe features of toxicity with L-DOPA treatment

Motor fluctuations and dyskinesia (50% of patients after 5 years). End of dose effects (on-off periods). Non-motor symptoms - vomiting, nausea, domperidone. Nigral neurone toxicity (increased ROS)

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Why is nausea the main side effect of L-DOPA?

Only a small amount of L-DOPA crosses the BBB. The remaining dose is left in the PNS which is metabolised, causing nausea

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Describe the features of COMT inhibitors in adjunct therapies (1)

Inhibits metabolism of L-DOPA in PNS. Used for patients with motor fluctuations. Increased F/time between dosing. Lower L-DOPA dose and increase half-life. Benefits (reduced off time/L-DOPA dose, improved motor impairment/disability)

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Describe the features of COMT inhibitors in adjunct therapies (2)

Side effects include increased dyskinesia, nausea, vomiting, diarrhoea, hallucinations and discoloured urine (red colour/not harmful/metabolism of dopamine)

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Give two examples of COMT inhibitors

Tolcapone (causes liver toxicity/second line treatment with strict monitoring) and entacapone (first line treatment with strict monitoring)

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Describe the features of MAO-B inhibitors in adjunct therapies (1)

Inhibition of dopamine metabolism in the brain. Two forms of MAO (A - GIT/periphery/liver, B - brain). Increased dopamine at synapse. Decreased L-DOPA dose, dyskinesias, early use delays need for L-DOPA by 9-12 months

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Describe the features of MAO-B inhibitors in adjunct therapies (2)

Side effects include confusion, hypotension, nausea. Contra-indications include postural hypotension, frequent falls and dementia

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Give two examples of MAO-B inhibitors

Selegiline and rasagiline (structures similar to dopamine)

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Describe the features of DOPA decarboxylase inhibitors in adjunct therapies (1)

Inhibit peripheral metabolism of L-DOPA to dopamine. Doesn't cross BBB (no CNS effect). Increases F (no effect on t 1/2). Lowering of L-DOPA dose (L-DOPA alone 6-8g/day, 0.5g/day with Carbidopa, reduced peripheral symptoms-nausea/vomiting/CV effects)

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Describe features of Carbidopa

Lodosyn. Sinemet (adjunct with L-DOPA). Stalevo (adjunct with L-DOPA plus entacapone). 75 mg/day (taken with L-DOPA). Side effects from dopamine overstimulation

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Describe features of Benserazide

Madopar (UK, not in USA). 75 mg/day with L-DOPA. No effect upon its own. Side effects arise from dopamine overstimulation

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DOPA-LEVODOPA

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