Pharmacology L4: Parkinson's Disease Flashcards
What are 5 etiology for Parkinson’s Disease?
- Age: the most important risk factor
- Family history for PD
- Male gender
- Environment? Exposure to manganese and iron, pesticide/herbicides, well water, rural farming(?)
- Trauma, emotional stress, repetitive head injury(?)
What are the 4 symptoms of Parkinson’s Disease?
Remember: “TRAP”
- Tremor at rest,
- Rigidity (Very challenging = no fluidity of movement) of limbs,
- Akinesia,
-
Postural problems (leading to loss of balance)
- Forward tilt of trunk region, shuffling gait, rigidity of extremities, short steps
Relative new disease (100yrs)
Exposed to poisons on a regulate basis (PD developed/correlation from industrial revolution) = theory
Most common form is idiopathic “____” (shaking palsy).
paralysis agitans
Without treatment, PD progresses over 5-10 years to a _____ state with patients unable to care for themselves.
rigid akinetic
Death may result from complications of immobility, including______ or ____.
aspiration pneumonia; pulmonary embolism
_____ has radically altered and postponed this outcome, but overall mortality remains higher than in the general population.
Pharmacology
What is the cure/treatment for PD?
While there are treatments to manage symptoms, there is NO cure for the degeneration dopaminergic neurons (substantia nigra pars compacta)
What is the cause of PD?
due to the selective loss of dopaminergic neurons in the substantia nigra of the brain.
What is the substantia nigra?
the major origin of dopaminergic innervation of the striatum, a main function of which is regulation of posture and muscle tone.
What does post-mortem brains of PD patients have?
only 10% of normal dopamine levels
What can also be found in dopaminergic neurons in PD patients?
Lewy bodies (a-synuclein) may also found in dopaminergic neurons – synuclein is involved in vesicular recycling, so loss may prevent DA from being packaged effectively.
About 60-80% loss of dopaminergic neurons occurs before ______ symptoms are seen.
motor
What is the problem with proteins behaving badly to nervous systems?
Improperly deposited = disruption of movement (between and within neurons) = trigger for neuronal death Plaque
What does a substantia nigra in a PD patient look like?
Darkly tinted cells (dopaminergic neurons) are reducing
What does DA look like in normal and PD patients?
Effective treatment may include increasing ____ or decreasing of the effects of ____ within the brain, so that initial balance is somewhat restored.
DA; ACh
What is the dopamine in CNS synapse?
What could ideally be done to increase dopamine concentrations in the synapses?
What is drugs that can be converted into dopamine?
- Levodopa (L-Dopa), a precursor of dopamine, is the major initial drug used in treatment.
- It can cross the blood-brain barrier, is presumed to be taken up by dopaminergic neurons which convert it to dopamine centrally.
- Dopamine itself cannot cross the BBB.
- This would increase the concentration of dopamine available for use in the CNS.
What are anti-parkinson drugs?
Why should Levodopa (L-dopa) be taken with Carbidopa?
Carbidopa protects the conversion of L-dopa to dopamine (esp. in periphery) so that it can be converted in CNS
What does COMT work in PD?
What are drugs that inhibit the metabolism of dopamine?
- Rasagiline, a selective MAO-B inhibitor, may slow the normal degradation of dopamine in the brain and preserve it for recycling into vesicles.
- Use of sustained release preparations of L-DOPA or addition of COMT inhibitors, such as entacapone, may counteract fluctuations of L-DOPA.
- Due to gliosis, more MAO-B is found in the brains of patients with PD; MAO-B activity levels are doubled in the substantia nigra in PD and correlate with the percentage of dopaminergic cell loss.
What is the theory of dopamine receptor agonists?
Theory: these compounds would act directly on postsynaptic dopamine receptors even if presynaptic dopamine-releasing neurons have degenerated.
In PD, there is greater loss of ____ (D1/D2) receptors relative to ____(D1/D2) subtype; recall that DA is largely modulatory in its effects in the substantia nigra.
D2; D1
What is Bromocriptine?
a strong agonist at D2 receptors and a partial agonist at D1
What are newer drugs such as pramipexole and ropinirole?
agonists at D2 receptor with little to no affinity for D1 or alpha adrenergic receptors.
What is Amantadine initially developed as?
Originally developed as a synthetic antiviral agent, and it was randomly found to be effective in Parkinson’s disease.
How is amantadine used?
Seems to increase dopamine release from surviving nigral neurons, mechanism is unclear.
What is the effectiveness of Amantadine as treatment?
levodopa-induced dyskinesias.
What is the function of Amantadine?
Recently, amantadine has been shown to be an antagonist at the NMDA glutamate receptor, and may play a role in neurotransmitter balance as well as reduction of excitotoxicity.
What is the benefit of Amatadine vs L-dopa, while it is less effective?
Amantadine is less effective than L-Dopa, but also has fewer side-effects. Tolerance to its benefits seems to develop after 6-8 months of use.
How can you reduce activity of acetylcholine as treatment for PD?
- Muscarinic blockers, such as atropine-like benztropine, has been used for more than 100 years, and were the first pharmacological treatments used in PD.
- They are generally less effective than levodopa, and their host of side effects (blurred vision, dry mouth, constipation, urinary retention) make them less used.
- However, they may be useful as supplementary agents, combined with L-Dopa.
How does DBS work for PD? List 3 characteristics
- By targeting the brain’s message relay centers, subthalamic nucleus (STN) or internal globus pallidus (Gpi), DBS works by stimulating the area that influences motor control.
- The system delivers electrical pulses that affect brain cell activity, blocking selected brain areas to alleviate movement problems.
- Most cases require bilateral implantations.
What is Huntington’s Chorea/Huntington’s Disease (HD)?
HD is also a neurodegenerative disease in the basal ganglia
How does the body get affected by Huntington’s Chorea/Huntington’s Disease (HD)?
- Instead of slowing movements down, the hallmark symptoms are uncontrolled writhing of the muscles in the face, trunk and neck.
- While the body’s movement is distorted continuously, there is also progressive dementia.
What is the culprit in HD?
huntingtin protein
What is the huntingtin protein?
- Found in cells throughout the body, but has most damage within basal ganglia of the brain.
- “CAG” trinucleotide repeats add glutamine residues to the protein.
- Normally, the CAG sequence repeats 11-30 times.
- People with HD may have repeats of 36- 125 times.
- Excess glutamines cause huntingtin protein to mis-fold, and not function for cellular transport as normal.
What causes the huntingtin protein to misfold?
- Excess glutamines cause huntingtin protein to mis-fold, and not function for cellular transport as normal.
- More repeats = more glutamines = more severe/earlier onset HD
What is happening to the neurons in HD?
- In post-mortem brains, there is a 75% reduction in activity of glutamic acid decarboxylase, an enzyme responsible for synthesis of GABA.
- It is thought that with GABA concentrations declining in the brain, dopaminergic circuits are allowed to operate without the usual “brake”.
How is the “brake” lost? Death of GABAergic neurons.
Top: DAergic neurons from substantia nigra usually inhibit GABAergic output from the striatum, while cholinergic neurons are excitatory.
Bottom: In HD, GABAergic neurons degenerate. Inhibitory regulation is lost, with net excitation as the result, leading to uncontrolled motor activity.
How can we treat loss of GABAergic neurons, and overactivity of dopaminergic neurons?
- General strategy is to reduce neuronal activity in key brain regions, or to antagonise dopamine activity.
- Chorea can be suppressed by using drugs which deplete dopamine and other neurotransmitters; such as tetrabenazine.
- Antagonists to dopamine receptors may also be used in patients, such as haloperidol, which improves motor function and psychosis associated with HD.
What is putative mechanisms of action of TBZ?
