Parikinsonian Drugs Flashcards
What are the three main dopaminergic pathways in the brain and what do they control?
Nigrostriatal - movement
Mesolimbic- emotion
Tuberoinfundibular- regulates hormone secretion
What are the two families of Dopamine receptors
D1 family- D1 and D5
D2 family- D2, D3, D4
What causes Parkinsons?
Familail Parkinsons- 8%, SNCA gene.
Idiopathic- 92%, oxidative stress, environmental, environment+ risk genes.
What are the cardinal signs of Parkinsons?
Rest tremor, Rigitidity, Postural Abnormality and Bradykinesia. Unilatateral, spreads to both sides, drugs treat the symptoms not the degeneration.
List 4 non motor symptoms of Parkinsons
Autonomic dysfunction- impotence, postural hypotension. Cognitive dysfunction- pain, depression, sleep disturbances.
Describe the pathophysiology of Parkinsons
Alpha synuclein is a protein of the CNS that faciliatets exocytosis of neurotransmitters, In Parkinsons, the alpha synuclein is abnormally formed so aggregates in clumps. This impairs neuronal function and enetually leads to neurone death. The alpha-synuclein aggregates are called Lewys Bodies. They principally aggregate in the substantia nigra but also form in the locus coerulus, dorsal vagus nucleus and the nucleus basilis of mynert (coordinates previos experience and expection with vision, top down processing).
Describe the staging of Parkinsons
Stages 1-3 are asymptomatic. Dorsal motor nucleus of vagu (parasympathetic to vsicera), raphe nucleus (affecting RAS), locus ceorulus (secretes NA in response to stress) and then the SNpC are affected.
Stages 4-6 are symptomatic. Amygdala, nucleus basils of Mynert, hippocampus and then the rest of the cortex are affected.
Need to lose 80-85% of dopaminergic neurons and deplete 70% of striatal dopamine to cause motor symptoms.
Explain the rationale of L-DOPA with Carbidopa.
Dopamine cannot be given because it is too polar to cross the BBB. L-DOPA can cross the BBB to be converted to dopamine by DOPA decarboxylase. But 95% would first be converted to dopamine by periphery DOPA decarboxylase. Carbidopa, also polar, is given as a peripheral DOPA decarboxylase inhibitor.
Describe side effects of L-DOPA
Effet declines with time because the effect depends on sufficient DOPA decarboxylase within nigro-striatal neurons being present to convert the L-DOPA.
Acute- nausea (give domperidone), hypotension, psychological effects
Chronic- dyskinseas (but disappear if treatment withdrawn) and on-off effects
Why might you use a D2 agonist for Parkinsons?
Problems?
Give 2 examples and their structures
Can be used in adjunct with L-DOPA. Longer duration of action, smother response- independent f dopaminergic neurons.
Common side effects include nausea, hallucinations and psychological problems. Rarely cause constipation and dyskinesias.
Older drugs, like bromocriptine, have Ergot structures which cause heart valave problems.
Newer drugs, like Ropinerol, don’t have Ergot structures but cause addictive behaviours like gambling.
What is deprenyl? What is it used for? Side effects?
A selective MAO-B inhibtiro (MAO-B dominates in dopaminergic areas of CNS). Also known as selegiline. Side effecst are rare but include nausea, hypotension and psycholigal problmes like confusion.
What is resagiline?
A new drug for Parkinsons that may slow the degenerative process by promoting anti-apoptsosi genes.
What are tolocapone and entacapone? How do their MOAs differ?
They are bothh COMT inhibitors. In the CNS this prevents breakdown of dopaimine by COMT. Howevever entacapone also acts in the periphery but in a different way. In the periphery, COMT usually converts L-DOPA to 3-0-menthly-DOPA, which comepetes for the same transport system across the BBB as L-DOPA. There entacapone can be given with LDOPA to reduce dosage needed.
