8 Parkinson's and Alzheimer's Flashcards
What is the pathophysiology of Parkinson’s disease?
Loss of Dopamine (DA) neurons in the substantia nigra pars compacta
Decreased DA neurotransmission in basal ganglia
4 major clinical features of Parkinson’s disease
Bradykinesia - slowness of movement
Muscle rigidity (cogwheel rigidity) - esp elbows and knees
Resting tremor
Impairment of postural balance, gait
Secondary Sx of Parkinson’s disease
Dementia/cognitive deficits, depression, anxiety, difficulty speaking
What is the most common etiology of Parkinson’s?
Idiopathic
Not as genetically linked as Alzheimer’s but research into Parkin gene and alpha-synuclein gene as possible markers
What is MPTP?
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Street drug —> late stage Parkinson’s basically overnight
Being used in animal studies for Parkinson’s research
Symptoms of Parkinson’s become apparent once _______% of the DA neurons in the substantia nigra have been lost
70-80%
What are Lewy bodies?
Intracellular aggregation of alpha-synuclein and other proteins (histological sign of Parkinson’s)
Why does a section of the substantia nigra in a Parkinson’s patient appear less pigmented than a normal brain?
Because DA is a precursor for melanin, so loss of DA neurons means loss of pigmentation as well
How is the nigrostratal and basal ganglia circuitry disturbed in Parkinson’s?
Loss of DA neurons in SNPC
—> Over-activity of indirect pathway and under-activity of direct pathway
—> Increased GABA input into thalamus
—> Decreased glutamate input into cortex
—> Inability to control movement
Why are anticholinergics used as an adjunct in Parkinson’s treatment?
The DA neurons normally inhibit GABA in the corpus striatum at the same time as cholinergic interneurons enhance GABA activity
In Parkinson’s the loss of DA inhibition means over excitation of GABA by ACh, so anticholinergics are used to balance it out
What are the different targets for drugs used to treat Parkinson’s?
Increase brain DA levels (L-dopa)
Inhibit DA metabolism in the brain (MAO-B and COMT)
Stimulate brain DA D2 receptors (dopamine agonists)
In the periphery, inhibit the conversion of L-dopa to DA (Carbidopa) and the metabolism of L-dopa by COMT
What drug is used to increase DA levels?
L-Dopa (Levodopa, Dopar, Larodopa)
L-3,4-dihydroxyphenylalanine
“Replacement” Therapy
Why do we give L-dopa rather than dopamine for replacement therapy?
Dopamine does not cross BBB
L-Dopa readily crosses BBB is is then converted to DA in the neuron
Peripheral effects of L-Dopa
Nausea and vomiting
Clinical uses of L-Dopa
Improvement of PD symptoms for 3-4 years (esp Bradykinesia)
Not all patients respond well (or can tolerate) - ~33%
Effectiveness of L-dopa will go down over time, so other drugs need to be added eventually
Why does L-dopa get less effective over time?
Does not affect progression of DA neuron degeneration
Once you’ve lost enough DA neurons, it just doesn’t matter how much L-dopa you add
As effectiveness of L-dopa goes down, have to add other drugs
L-dopa is not as effective in _________ Parkinson’s
Drug-induced (MPTP)
What are the pharmacokinetics of L-dopa?
Orally administered - absorption is delayed by food, amino acids
Short half-life - needs to be taken 3-4x/day
Need high doses b/c only 1-3% gets into the CNS
What is Sinemet?
Combo of L-Dopa and Carbidopa
Carbidopa inhibits the dopa-decarboxylase enzyme that converts L-dopa to DA in the periphery, but doesn’t cross the BBB
SO, peripheral conversion is inhibited but not in the brain
Decreases the dose of L-dopa needed and decreases peripheral effects (N/V)
Side effects of L-dopa/Carbidopa
Tend to increase as disease progresses
GI: N/V
• Divided doses will help decrease GI effects
• Avoid antiemetics that block DA D2 receptors (Prochlorperazine)
CV: postural hypotension, arrhythmias, HTN
Dyskinesia develop over time - treat by reducing L-dopa
Behavioral: depression, anxiety, agitation, sleep problems
• Psychosis possible - treat with atypical antipsychotics
What is the On-Off Phenomenon?
Fluctuations in clinical response
Occurs in patients on successful L-dopa therapy
“On” = improved mobility
“Off” = akinesia (due to falling drug levels)
What can you do to avoid the On-Off phenomenon?
Increase frequency of doses
Improve absorption of L-dopa (diet), sustained release
Add another drug (MAO-I, DA agonist)
Apomorphine (Apokyn) used as “rescue” - fast acting DA2 receptor agonist
Drug interactions possible with L-dopa
MAO-A Inhibitors - may cause hypertensive crisis
Pyridoxine (Vit B6) - increases peripheral metabolism of L-dopa, which decreases its effectiveness
Which drugs can cause a hypertensive crisis when paired with L-dopa?
MAO-A inhibitors
Which supplement will increase the peripheral metabolism of L-dopa, decreasing it’s effectiveness?
Pyridoxine (Vit B6)
Contraindications for L-dopa
Psychosis***
Closed angle glaucoma - increases intraocular pressure
Cardiac disease
Active peptic ulcer - can increase GI bleeding
Malignant melanoma - L-dopa is a precursor of melanin
L-dopa toxicity
What are the MAO-b inhibitors used to inhibit DA metabolism?
Selegiline (Deprenyl)
Rasagiline (Azilect)
Safinaminde (Xadago)
MOA for MAO-B inhibitors
Inhibits MAO-B in CNS —> reduces striata metabolism of DA
Does not affect peripheral metabolism of DA by MAO-A
May inhibit progression of PD by decreasing free radicals produced during DA metabolism
Adverse effects of MAO-BIs
Insomnia (Amphetamine like metabolites) - take in morning and noon to decrease likelihood
Severe hypertension if combined with other MAOIs (Phenelzine)
Will increase the side effects of L-dopa in late stage disease
Do NOT combine with meperidine - can lead to stupor, rigidity, agitation, hyperthermia, possible serotonin syndrome
Serotonin syndrome possible if combined with TCAs/SSRIs
Your patient is on a MAO-B inhibitor and complains of insomnia. What should you advise them to do?
Take it in the morning or at noon to decrease the likelihood
Why shouldn’t you combine MAO-BI’s with meperidine?
Can lead to stupor, rigidity, agitation, hyperthermia, possible serotonin syndrome
MAO-BIs + TCA or SSRI = __________
SEROTONIN SYNDROME
MOA for COMT inhibitors
Catecholamines-O-methyl transferable metabolizes DA and L-dopa
Inhibiting COMT prevents metabolism of DA and L-Dopa
_______ inhibits COMT in CNS and periphery, but _______ inhibits COMT in periphery only
Tolcapone (Tasmar)
Entacapone (Comtan)
Which PD drug has been associated with death from hepatic failure?
Tolcapone (Tasmar) - inhibits COMT in CNS and periphery
How does Entacapone work?
Inhibits COMT in periphery only, increasing pool of L-dopa available for transport into the brain
What is Stalevo?
Combo of L-dopa/Carbidopa/entacapone
Side effects of COMT inhibitors
Dyskinesia, confusion, nausea, hypotension, abdominal pain, sleep disturbances, ORANGE COLOR IN URINE
Which PD drugs work by acting directly on DA D2 receptors
DA Receptor Agonists
Bromocriptine (Parlodel)
Ropinirole (Requip)
Pramipexole (Mirapex)
Because these drugs act directly on the receptors, they continue to be effective as the disease progresses
What are the benefits of using DA receptor agonists?
They continue to be effective as the disease progresses
Used in combo with L-dopa during ‘on-off’ periods
Lower incidence of response fluctuations and dyskinesias
What awesome side effect do you get with Bromocriptine (Parlodel)
Erythromelalgia - swollen, itchy, red feed
It’s because it’s an ergot derivatives, so it can cause vasospasms
Your patient has a mutation in DDC and cannot synthesize DA. How do you treat them?
Bromocriptine
PD drugs that may cause narcolepsy
The newer DA agonists (Ropinirole and Pramipexole)
Newer DA agonists (Ropinirole and Pramipexole) are useful in…
Monotherapy in mild PD
Soothing response to L-dopa in late PD
DOC for restless leg syndrome (RLS)
Ropinirole
Relatively pure DA D2 agonist
Why does Pramipexole have an FDA warning?
Possible heart failure
Which DA receptor agonist is available as a transdermal patch?
Rotigotine (Neupro)
Can be used for either PD or restless leg syndrome
Helps with patient compliance
Drug used for temporary relief (“rescue”) of off-periods in patients on optimized L-dopa therapy
Apomorphine (Apokyn)
Typically injected
Side effects of Apomorphine (Apokyn)
NAUSEA - patient should take an antiemetic prior to introduction (trimethobenzamide)
Avoid antiemetics that target the serotonin system (Ondansetron) —> severe HTN, LOC
Avoid antiemetics that block DA D2 receptors (Prochlorperazine)
Side effects of DA agonists
GI: Anorexia, N/V - take with meals
CV: postural hypotension (beginning of treatment); ergot derivatives = digital vasospasm, decrease dose; cardiac arrhythmias (d/c)
Dyskinesia
Mental disturbances
Erythromelalgia (Bromocriptine)
Decreased release of Prolactin
Antiviral used for influenza that also increases the release of DA and possibly inhibit DA reuptake
Amantadine (Symmetrel)
Used to treat early or mild cases of PD
What is livedo reticularis?
Reddish/blue spotting of skin
Can be caused by Amantadine (Symmetrel)
What is buzzwordy side effect of Amantadine (Symmetrel)?
Livedo reticularis - reddish/blue spotting of the skin
Other side effects: Restlessness Depression Irritability Insomnia Agitation Confusion Hallucinations Peripheral edema (give diuretics)
Your PD patient took too much Amantadine (Symmetrel). What are you worried about?
Toxic psychosis and convulsions
MOA for anticholinergics used in PD treatment
Muscarinic receptor antagonists restore DA/ACh balance in striatum
Provides modest anti-Parkinson action
Improves rigidity, tremor but little effect on bradykinesia
Used in early/late stages as adjunct to DA therapy
What anticholinergics are used for PD adjunct therapy?
Benztropine (Cogentin)
Trihexyphenidyl (Artane)
Side effects of Benztropine (Cogentin) and Trihexyphenidyl (Artane)
Anticholinergics!
Constipation, urinary retention, blurred vision, sedation, confusion
If d/c, do so gradually
What will increase the effects of anticholinergics used for PD?
TCAs and antihistamines
Alternative treatments for Parkinson’s
Neuroprotection - antioxidants, anti-apoptotic agents
Pallidotomy - decrease activity of globus pallidus
Transplants of fetal neurons or patient-derived stem cells
Gene therapy
Deep brain stimulation
Over 50% of dementia is caused by….
Alzheimer’s Disease
Risk factors for Alzheimer’s
Age
Genetics (more so than PD)
Gender (females more at risk)
Lack of education
Head injury
Symptoms of Alzheimer’s
Mild
• Confusion, memory loss
• Routine tasks become difficult
• Personality, judgement impaired
Moderate
• Difficulty with ADLs, sleep disturbance
• Anxiety, agitation
• Don’t know family anymore
Severe
• Loss of speech
• Incontinence
Alzheimer’s disease is characterized by…
Neuritic plaques (ß-Amyloidosis) - insoluble, fibrous protein aggregations outside the neurons
Neurofibrillary tangles (Tau proteins) inside the neurons
Alzheimer’s leads to the degeneration of _______ neurons
Cholinergic neurons originating int he basal nucleus of Meynert and projecting to the cerebral cortex and hippocampus
These are the neurons involved in memory and cognition
What is the major class of drugs used to treat Alzheimer’s?
Cholinesterase Inhibitors
Donepezil (Aricept)
Rivastigmine (Exelon)
Galantamine (Reminyl)
Inhibit metabolism of ACh —> increased amount of ACh in the nerve terminal
Pharmacokinetics of cholinesterase inhibitors
Well absorbed and readily penetrate the CNS
Metabolized by CYP450s
Peripheral cholinergic side effects of cholinesterase inhibitors
GI primarily
N/V/D
Stomach cramps
All three cholinesterase inhibitors used in Alzheimer’s block acetylcholinesterase, but only _________ inhibits the ACh autoreceptor to reduce reuptake
Galantamine
What is Memantine (Namenda)?
NMDA receptor antagonist (channel blocker)
Blocks the pathological activation of NMDA receptors and reduces excitotoxic effect of glutamate to slow degeneration
Used for late-stage Alzheimer’s in combo with AChE-I’s
Side effects of Memantine (Namenda)
Agitation, insomnia, urinary incontinence, UTI, and diarrhea
Competes for renal tubular secretion so monitor dose in patients with renal impairment
Memantine (Namenda) is contraindicated in patients also taking…
Meperidine, dextromethorphan
If your patient is unfortunate enough to have both PD and Alzheimer’s, what should you not give them?
Memantine (Namenda), because it may increase side effects of L-dopa
