Parkinson's Disease: Pharmacology & Movement Disorders

Pharmacology of Parkinson's Disease Drugs

• DA neurons (medium spiny neurons) originate in the substantia nigra (SN) of the midbrain and project to the corpus striatum where they release DA.

Characteristic Movement Disorders of Parkinson's Disease

• Tremor is a cardinal sign and occurs at rest, not during voluntary movement.
• Pill rolling looks like they're rolling a pill between their thumb and index finger.
• Diphenhydramine Muscarinic receptor antagonist is given for experiencing tremor predominant disease except in elderly due to anticholinergic effects.
• Rigidity presents as lead pipe limb resistance that is uniform or ratcheted limb resistance where jerky movement occurs in response to constant force.
• Bradykinesia is slowness of movement and is found in every case of PD and is the most handicapping symptom.
• Postural dysfunction includes poor balance and frequent falls and occurs in the later stages of the disease.
• Masklike faces present as a lack of facial expressions.

Stages of Parkinson's Disease Disability

• Stage 1 presents as mild, unilateral symptoms.
• Stage 2 presents as bilateral symptoms, but no balance issues.
• Stage 3 presents as postural instability and mild posture imbalance.
• Stage 4 presents as severe disability with bilateral involvement and pronounced postural instability with a loss of independence.
• Stage 5 involves being wheelchair-bound or bedridden.

Levodopa Dosing Recommendations

• The honeymoon period is when Levodopa is working very well for 2 - 5 years.
• The "On-off" effect includes sudden changes in mobility due to fluctuating levodopa levels.
• In early PD, Levodopa is predictable and effective, so doses are given every 12 hours.
• In late PD there are fewer terminals which limit the amount of DA created from levodopa so end-of-dose early wearing off occurs, so doses are given every 8 hours.
• In advanced stages higher doses of levodopa are used with short duration, creating on-off effects.
• Combination therapy is used so off-time is decreased.
• Take levodopa more often in smaller doses every 4 hours, up to 5x/day.
• Enzyme inhibitors and direct dopamine receptor agonists,are used in combination therapy.

BBB Permeability of Levodopa, Carbidopa, and Dopamine

• Levodopa is the only drug that crosses the BBB and is converted into DA by DDC in neurons.
• Carbidopa prevents peripheral conversion of levodopa to dopamine.
• Carbidopa does not cross the BBB but enhances levodopa's effectiveness by inhibiting DDC occurring outside the BBB.
• Dopamine does not cross BBB.

Site of MAO-B

• MAO-B is primarily found in the outer mitochondrial membrane and in glial brain cells near dopaminergic synapses.

Levodopa/Carbidopa Counseling Points

• Take on an empty stomach or with a carbohydrate meal due to proteins compete for absorption.
• Can cause tardive dyskinesia and nausea and vomiting.
• Use 5HT3 antagonist antiemetics and do not use phenothiazines, DA antagonists.
• Increase in DA causes an increase in reward areas of the brain, which causes some people to have impaired impulse control like gambling, drugs, or buying and this disappears when switched to other drugs.
• Dyskinesia is caused by upregulation of D2 receptors as dopamine neurons die.

Molecular Pathophysiology of Parkinson's Disease

• Degeneration of DA-producing neurons in the substantia nigra.
• Formation of alpha-synuclein containing structures known as Lewy bodies (dementia).
• Mitochondrial dysfunction is linked to the presence of alpha-synuclein.
• TOM is a transporter that moves proteins from mitochondria to intermembrane space.
• Alpha-synuclein proteins look similar to the proteins that TOM should be passing though which causes destruction of the mitochondria from inside out.
• Neurons in the substantia nigra express more alpha-synuclein than neurons in the surrounding midbrain and also have a higher state of oxidation to begin with.
• There is a destructive feed forward cycle which causes cell-wide dysfunction.

Types of Parkinson's Disease

• Brain-first top-down type.
• Body-first bottom-up type.

Role of a-Synuclein and Autophagy in Parkinson's Disease

• Autophagy is an essential catabolic mechanism that delivers misfolded proteins and damaged organelles to the lysosome for degradation.
• If cells can't recycle their trash, bad things happen.

Levodopa MOA/Notes

• Levodopa is extensively metabolized to dopamine by dopa decarboxylase also called AADC.
• Metabolism happens mainly in the periphery, so the DA doesn't get to the brain as much.

Carbidopa MOA/Notes

• Carbidopa improves the bioavailabilty of levodopa in the brain by inhibiting dopa decarboxylase in the periphery.
• This allows more L-Dopa to cross BBB.
• Carbidopa cannot use the same transporter system as levodopa.

R-Selegiline (Deprenyl) MOA/Notes

• Covalently bonds to and irreversibly inhibits MAO-B, which metabolizes dopamine in the brain.
• A triple bond makes it irreversible.

Safinamide (Xadago) MOA/Notes

• Selective and reversible inhibition of MAO-B and activity-dependent Na channel antagonism.
• Add-on therapy to DA agonists or levodopa.
• Being reversible means it is distinguishable.

Tolcapone (Tasmar) MOA/Notes

• Inhibits COMT in both the brain and the periphery which prevents metabolism of dopamine

Apomorphine (Apokyn) MOA/Notes

• Non-ergot dopamine receptor agonist and the red part of the image is dopamine.
• Extremely lipophilic.

Amantadine (Symmetrel) MOA/Notes

• Promotes release of DA from neuronal storage sites and inhibits DA reuptake DAT.
• Very rigid structure means increased lipophilicity and preventing metabolism where it can't fit into any enzyme.

Rivastigmine (Exelon) MOA/Notes

• Pseudo-irreversible ACHEI and inhibits both butyrylcholinesterase and acetylcholinesterase.

Etiology of Parkinson's Disease

• Primarily associated with older age.
• Genetic and environmental factors. -Toxin exposure causes generation of reactive oxygen species thus cell death. -Exposure to pesticides or heavy metals, and drinking well water.

Key Feature of Parkinson's Disease

• Degeneration of dopaminergic neurons projecting from the substantia nigra SN to the striatum nigrostriatal pathway.
• Dopaminergic neurons mediate motor activity and make dopamine During this process, oxygen radicals are created, which cause more cellular damage.
• Additional involvement occurs in neurons in autonomic ganglia, basal ganglia, spinal cord, neocortex, limbic system emotions, enteric nervous system gut.

Pathophysiology Histologic Features

• Depigmentation of DA-producing neurons caused by a loss of SN neurons where Dopaminergic loss leads to increased symptom severity.
• Presence of Lewy bodies in the remaining SN leads to aggregation of proteins which form abnormal structures in abnormal areas.
• Early stages of PD results in compensatory mechanism where there is Upregulation of DA synthesis by neurons that are still working and Downregulation of synaptic DA reuptake from synaptic cleft.

List of Drugs to Avoid With Parkinson's Disease

• Medications that block DA receptors. Antipsychotics like Haloperidol.
• Metoclopramide.
• Phenothiazine antiemetics like prochlorperazine, promethazine, thiethylperazine
• Initiate plan for early stages.
  • No medications.
  • Anticholinergic medications.
• Moderate stage
  • More disability so must have pharmacologic treatment.
  • Consider levodopa, but could hold off.
• Advanced stage
  • Levodopa and other agents.

Complications of Levodopa Therapy and Management

Dyskinesia

• Involuntary jerky movement of the neck/head/UE/LE
• Occurs during “ON” period due to peak DA level in SN
• May occur 6 months after starting tx
• Ach worsens it!
• Lower L-dopa dose and give more frequently
• Use Sinemet CR
• Add DA agonist or amantadine
• Do not use cholinergic drugs

End-of-dose "wearing off" effect (motor fluctuation)

• Symptoms return before the next dose is given
• Less and less DA-ergic neurons result in L-dopa lasts less time
• Give smaller doses more frequently
• Switch to CR formulation
• Give regular Sinemet 1st thing in AM
• Add MAO-B or COMT inhibitor or DA agonist

"Delayed-On" and "No-On” Response

• Due to delayed gastric emptying or decreased absorption in duodenum
• Take on an empty stomach
• Use ODT formulation
• Avoid CR formulation
• Chew or crush IR tablet
• Use apomorphine SQ as a rescue

"Freezing"

• Sudden inhibition of LE motor function during “ON” period
• Increased risk of falls
• Increase L-dopa/carbidopa dose
• Add DA agonist or MAO-B inhibitor

"Off-Period" Dystonia

• Sustained muscle contraction usually in LE
• Occurs usually in AM when drug levels are low
• Administer CR formulation at bedtime

Understanding Drugs in Treating Parkinson's

• L-Dopa in blood crosses BBB and is converted to DA by DDC, available for use.
• DA cannot cross the BBB, only L-Dopa can.
• Dopamine breakdown is done by monoamine oxidase B and COMT.
• Medications that inhibit breakdown will target both of these and are used to prolong DA lifespan.

MAO-B Inhibitors

• Drug class to start with at early stages, 50s-60s usually. Rasagiline, selegiline, safinamide.
• MOA: inhibit MAO-B in the brain which then inhibits DA degradation and results in prolonged dopaminergic activity.
• Rasagiline and Selegiline are IRREVERSIBLE inhibitors of MAO-B which Can be used as monotherapy in early PD.
• Safinamide is a REVERSIBLE inhibitor of MAO-B and Cannot be used as monotherapy, must add on only to carbidopa/levodopa.
• Has to be add on therapy because reverse inhibition of MAO-B makes safinamide less efficacious
• Administer in morning and no later than noon due to adverse effects like difficult to fall asleep

Selegiline Metabolism

• Selegiline undergoes first-pass hepatic metabolism via CYP2B6, 2C19 to form amphetamine metabolites so use Selegiline ODT to bypass first-pass metabolism
• ADR includes agitation, insomnia, hallucinations, orthostatic hypotension, and is similar among all drugs
• Rasagiline and safinamide are better tolerated, and do not produce amphetamine metabolites
• Drug-Drug Interactions include SSRIs
• Use with meperidine is contraindicated due to risk of serotonin syndrome

Anticholinergics

• Trihexyphenidyl, benztropine.
• MOA: blocks Ach in SN and restores Ach/DA imbalance.
• Indications: can be used as monotherapy for tremor, used as an add-on for dystonia symptoms.
• Contraindications: narrow-angle glaucoma, BPH, GI obstruction.
• Side Effects: blurred vision, dry mouth, urinary retention, constipation.
• Avoid in elderly and patients with cognitive deficits, but better for younger patients.
• DDI: other anticholinergics, drugs that cause decreased GI motility, cholinesterase inhibitors like alzheimer's disease

Amantadine

• MOA: unknown; possibly increases DA release from presynaptic terminals and inhibits NMDA receptors.
• Adverse Effects: livedo reticularis purple discoloration in the upper and lower extremities and is 100% renally eliminated, not ideal for bad kidney function.
• Doses must be reduced with renal dysfunction CrCl < 50.
• Do NOT stop abruptly!
• DDI includes anti-Influenza effect by intranasal flu vaccine.
• Formulations include ER capsule once a day at bedtime.
• ER tablet is once a day in morning.
• IR tablet, capsule, and syrup are 2-3 times/day.

Dopamine Agonists

• Apomorphine, pramipexole, ropinirole, rotigotine, bromocriptine only ergot derivative.
• MOA: directly stimulate postsynaptic DA receptors D1, D2, D3 in corpus striatum.
• Indications: adjunct to carbidopa/levodopa to reduce frequency of “OFF” periods.

Adverse Effects Of Dopamine Agonists

• Apomorphine requires premedication with antiemetic trimethobenzamide.
• Bromocriptine increases risk of pulmonary fibrosis.
• Avoid in patients with cognitive problems or dementia.
• Do NOT abruptly discontinue!
• Do not drink alcohol containing products like alcoholic beverages or mouthwash because it causes a disulfiram reaction.

Carbidopa/Levodopa

• MOA: more L-dopa to the brain with less peripheral ADRs.
• Carbidopa is peripherally acting L-amino acid decarboxylase inhibitor.
• Carbidopa does not cross BBB unless you have a carbidopa dose of at least 75 mg/day. Indication its considered the gold standard.
• Do NOT abruptly stop!

Decreased Absorption

• High protein diet competes in gut and BBB for L-dopa absorption.
• Must have high carbohydrate and no protein snack if needed.
• Iron supplements can decrease absorption of levodopa
• Do not use vitamin B6 pyridoxine because it causes peripheral conversion of L-dopa to DA

COMT Inhibitors

• Tolcapone, entacapone, opicapone.
• MOA inhibit COMT enzyme to reduce conversion of L-dopa to DA, increasing central L-dopa availability and prevents breakdown of dopamine.
• Tolcapone inhibits peripheral and central COMT Entacapone and opicapone inhibit peripheral COMT
• Don't have anti-PD effect on their own; DON'T administer without L-dopa NEVER MONOTHERAPY

Adverse Effects of COMT Inhibitors

• Tolcapone causes fatal hepatotoxicity.
• Strict LFT monitoring first 6 months is recommended or patients must sign a consent form and Use only if do not respond to other treatment.
• Tolcapone and entacapone causes brownish-orange urine discoloration and delayed diarrhea

Adenosine A2A Antagonist

• Istradefylline facilitates dopamine receptor signaling, thereby normalizing motor function.
• Do not use in severe hepatic impairment.

Drugs to Treat Cognitive Disorders for Alzheimer's Disease

Alzheimer's Facts:

• Know the rate of increase in AD past the age of 65.
• For every 5-year age group beyond 65, the percentage of people with AD doubles.
• Alzheimer's is the most dominant form of dementia
• Other major causes of dementia: Lewy body and multi-infarct.
• Know the pathologic changes that occur in AD, including fMRI measurement of whole brain blood flow.
• AD involves progressive degeneration of both white and gray matter in the brain.
• fMRI shows decreased blood flow in AD brains

Damage of Neurons Caused By Alzheimer's Disease

• Know the first type of neurons damaged by AD, the neurotransmitter involved, and the presence of plaques and neurofibrillary tangles in the cytosol of neurons. Know the role of tau protein.

• First type of neurons damaged: cholinergic

• Neurotransmitter: acetylcholine

• Beta-amyloid plaques form from fragments of amyloid precursor protein (APP), which clump together and disrupt neurons. Neurofibrillary tangles occur when tau protein becomes defective, causing microtubules to collapse.

• What brain nucleus is damaged early in Alzheimer's disease: Nucleus basalis frontalis

• Know two brain areas damaged that affect short- and long-term memory. The hippocampus stores short-term memory up to 2 years.

• Cortical projections store long-term memory.

• The difference between AD and Lewy Body Dementia:

• AD starts in cholinergic neurons and spreads to other types of neurons

• LBD starts in cholinergic neurons and stays there Identify the enzyme responsible for metabolizing acetylcholine into choline and acetate.

  • Acetylcholinesterase (AChE) breaks down acetylcholine, terminating its signal in cholinergic neurons.

How do acetylcholinesterase inhibitors improve memory and cognitive function?

• Acetylcholinesterase inhibitors reversibly block AChE, increasing acetylcholine These drugs do not reverse AD but they only temporarily improve cognitive function.

Effects of Acetylcholinesterase Inhibition

• Identify the PNS side effects that can result from inhibition of acetylcholinesterase throughout the body. SLUDGE symptoms Salivation, Lacrimation, Urination, Defecation, Gl upset, Emesis Nausea, diarrhea, muscle cramps, bradycardia, and worsening of asthma or COPD

• Which product offers a transdermal patch after patients cannot swallow?

• Rivastigmine (Exelon) used for severe mostly

• Which drug in theory can enhance cognition by inhibiting two types of acetylcholinesterase? Rivastigmine (Exelon) inhibits AChE and butyrylcholinesterase BuChE

• Which cholinesterase inhibitor drug can theoretically provide added cognitive benefit by stimulating nicotinic receptors and inhibiting another type of acetylcholinesterase?

• Galantamine (Razadyne): Positive allosteric modulator at nicotinic receptors and boosts the effects of acetylcholine and therefore cognition

Understand the mechanism of NMDA channels to contribute to the pathophysiology of dementia.

• NMDA receptors allow excessive calcium entry, leading to neuronal cytotoxicity in AD.
• Know the term of the antagonist mechanism of memantine (Namenda) on NMDA channels.
• What divalent cation is prevented from entering through NMDA channels?
• Memantine (Namenda) is a uncompetitive NMDA antagonist that blocks excessive calcium influx. It prevents excess calcium Ca²⁺ from entering neurons through NMDA channels. Most effective treatment regimen with memantine is Memantine + an acetylcholinesterase inhibitor. Identify symptoms improved by antipsychotics in patients with AD and it helps with agitation, hallucinations, and delusions in AD patients.
• Difference in dosing of antipsychotics between young adults and elderly patients with dementia: Elderly patients require half the dose of young adults due to increased sensitivity and risk of side effects

Understand b-Amyloid Hypothesis of Alzheimer's Disease

Sleeping issues

• Sleeping less than 6 hours a night is associated with an increase in B-amyloid in the brain.
• The glymphatic system washing B amyloid out of the brain while you sleep, being overall most active during deep, non rem sleep.
• This activity decreases during aging. Inhibiting B secretase BACE 1 is an strategy for pharmacological intervention

Understanding Strategies For Alzheimer's Treatment

• Lecanemab (Leqembi®) a humanized monoclonal antibody that binds with high affinity to soluble amyloid-beta (Aβ) protofibrils. Understand the normal and pathological functioning of tau
  • Tau may function to help shuttle AB to the outside of the neuron to prevent its interference with normal neuronal functioning (inhibit/reverse AB plaque formation) Structure/Name Prodrug of Mycophenolic acid↓

Drug of Choice to Take in Alzheimer's

Rivastigmine and tacrine increase what neurotransmitter with each use on the synaptic junction? AChE

Drugs Used to Treat Myasthenia Gravis

• Be able to identify an AChEl as working on Alzheimer's Disease or MG just by looking at the structure. The positive charge on the N indicates working on AD.
• Positive charge indicates no activity in the CNS
• Carbamate goes on serine to block activity "if I ask you this, this is what I am expecting

What Amount Of Loss Must Occur Before MG Become Present In Patients?

• 70-80% of nicotinic receptor loss. What initial sign develops in 50% of MG patients and Ptosis (drooping eyelid) Know the process of removing nicotinic receptors from the membrane Antibodies irreversibly bind to nicotinic receptors and Blocks the effects of acetylcholine: Your cells get rid of the dysfunctional ones and have to replace them. Know the mechanism of the drugs that increase acetylcholine levels Acetylcholinesterase inhibitors increase ACh levels to stimulate the remaining receptors, thereby restoring muscle strength to normal. It has fewer GI side effects: Adv of ambenonium vs neostigmine and pyridostigmine
• 20-30% of nicotinic receptors have to be there for acetylcholinesterase inhibitors to work
• What meds shouldnt be given with a NMDA inhibitor

What Amount of Loss Must Occur Before MG Become Present in Patients?

• 70-80% of nicotinic receptor loss.
• What initial sign develops in 50% of MG patients? Ptosis (drooping eyelid)

Tools used to assess cognitive function and guide treatment in neurocognitive disorders

• Mini mental state exam
• Aids in staging and decisions of drug therapy The only way to confirm a diagnosis of AD is though direct examination of the brain at autopsy or biopsy
• Classify Alzheimer's disease based on Mini Mental Status Exam and Higher score reduces severity with the reverse correct Mild score between 26-21 Moderate score between 20-10 Severe score is between 9-0

Drugs/Supplements When Using L-Dopa/Carbidopa

• Shouldnt take vitamin B6 with L-dopa/Carbidopa what does Vit B6 do and prevent

Mild cognitive impairment, you often precede an alzheimer's diagnosis and is a noticeable cognitive decline that is greater than expected for age but does not significantly interfere with daily life or independent functioning.

Recommend appropriate first-line treatments for Alzheimer's disease based on disease severity. - Evidence is not there for nonpharm. Medications that may exacerbate cognitive decline in Alzheimer's disease if combined.

Used in Moderate to Severe With Alzheimers

    - Donepezil which has some major side effects.

What if you suspect this disease. Use some first line meds option and then what would you add if that didnt work - Monoclonal ab - All are given IV - It binds to amyloid-beta plaques promote clearance in the brain

Central Nervous System Trauma

Risk Factors of CNS Trauma:

• Motor vehicle accidents
• Falls, motor vehicle accidents and Object or Unintentional Blunt Trauma
• Assaults Risk factors what most common blunt trauma what is most deadly

Pathophysiology

• What occurs in the brain after an impact axons are twisted or stretched it causes some to tear and die and how and why bleeding can occur

Classify TBI (mild, moderate and severe) and which on are more common

• Severe TBI is more life threatening, is often on ventilation due to poor cough, gag and swallow function and What's the most deadly

Severity assessment is determined by Glascow Coma Scale.

Mild: 13-15 Moderate: 9-12 Severe : less than 8

Look for responses in eyes, motor and verbal response

• Identify common associated medical complications and corresponding pharmacotherapy prophylaxis/treatment options

The number and what score the coma is.

Establish airway and the treatment can increase CPP or MAP

What score the map has to be above. Seizures and the increase or low of ICP

Chronic: if people come in with seziures years after damage that damage may start developing What side effects would you wanna prevent in the early phases and months after TBI

CPP: between 60-70 mm Hg want this high MAP: goal above 90 mm

Cognitive deficits - Know the med that can manage cognitive deficits

Nutrition

• Feeding patients needs to happen at least by the day and at most by the 7th day to decrease mortality. between 5 - 7 days test Why not start early Changes in electrolytes and fluid status may be causing more harm than good