Exam 3 Flashcards
What are the functions of the hindbrain?
Hindbrain - Contains medulla, pons, and cerebellum. Involved with non-conscious function.
- medulla: autonomic functions, including respiration, cardiac function, reflexes. Part of the reticular system (wakefulness, arousal). Part of the brain stem.
- pons: acts as a bridge. It relays signals from the forebrain to the cerebellum. Also part of the brain stem.
- cerebellum: governs motor coordination that produces smooth movements.
What are the functions of the midbrain
Midbrain - Contains the substantia nigra (SN).
- SN pars compacta: provides input to the basal ganglia and supplies dopamine to the striatum. It’s involved with voluntary motor control and some cognitive functions.
- SN pars reticulata: provides output functions. Relays signals from basal ganglia to the thalamus
What are the functions of the forebrain?
Forebrain - Contains the cerebral cortex, basal ganglia (not SN, yes striatum, globus pallidus, and subthalamic nucleus), limbic system (hippocampus, amygdala), and diencephalon (thalamus, hypothalamus)
- cortex: involved in processing and interpreting information.
- basal ganglia: includes the striatum, globus pallidus, and subthalamic nucleus. Involved in voluntary motor control and some cognitive functions.
- limbic system: includes amygdala that is tied to emotions and the hippocampus that is tied to memory.
- diencephalon: includes thalamus that acts as a ‘relay station’ to and from the cortex and the hypothalamus that is involved with non-concious functions (internal homeostasis, emotions, hormonal control, direct neural regulation).
Our senses receive information that is passed through the thalamus to the cortex and back. Within these cortico-thalamic loops, decisions about how to interpret and act on sensory information is made. Damage to the cortex can affect movement, speech, and personality.
What are the pathogenic conditions that involve the different brain regions?
cerebellum - undergoes neurodegeneration in spinocerebellar ataxias, meaning movements become jerky.
basal ganglia - the SN pars compacta undergoes cell loss during parkinson’s
cortex - schizophrenia is considered a disease of the frontal cortex and involves excess dopamine (?)
What is the structural basis of the blood-brain barrier?
Endothelial cells (facing blood) have very tight junctions in between them, which is the reason why we have the BBB in the first place. Beneath (on the brain side) the endothelial cells is a basement membrane.
Astrocytes are a key structural component. They form the lower part of the BBB.
What is the basic structure of a neuron? What are the roles of glial cells in the brain (astrocytes, oligodendrocytes, microglia)?
Structure -
- Dendrites are projections that receive signals from other neurons
- Soma contains the nucleus
- Axon connects soma to synaptic bouton
- Myelin sheaths insulate the axon
- Synaptic bouton contains the vesicle that fuses with the membrane in order to release the neurotransmitters into the synaptic gap/cleft. This release is triggered by electrical depolarization of the neuron (Na+)
Astrocytes - Provide growth factors and antioxidants to neurons. They also remove excess glutamate (too much glutamate can harm neurons). Also support the blood-brain barrier
Oligodendrocytes - Produce the myelin sheath that insulates axons.
Microglia - Similar to macrophages. They provide growth factors and clear debris by phagocytosis. Also play a role in neuroinflammation.
What are the principles of EPSPs, IPSPs, and action potentials?
Action potential - action potentials are always going to be the same size. The size of a signal is more about the # of action potentials (more rapidly or slowly). Larger diameter axons give faster rates (the rate is proportional to the diameter). The current is carried by a nerve fiber, or bundle of axons.
EPSP - Excitatory post-synaptic potential. It depolarizes the neuron (more positive), but not enough for an action potential. It’s like a little blip, but needs more Na+ to enter the cell in order to fully depolarize to trigger an action potential.
IPSP - Inhibitory post-synaptic potential. Makes the neuron more negative, so that the same signal that caused an action potential before is no longer able to. So what would’ve been an action potential is now just an EPSP.
What are the major amino acid neurotransmitters in the CNS?
Amino acid:
1. GABA - A major inhibitory neurotransmitter in the brain. It depresses neuronal excitability by increasing the flux of Cl- ions into the neuron. GABA-A is an ion channel. Drugs that interact with GABA are generally CNS depressants. Dysfunction of GABA transmission plays a role in epilepsy, spasticity, and addiction/alcohol.
2. Glycine (not talked about much) - Similar to GABA, but in the spinal cord
3. Glutamate (opp. of GABA) - A major excitatory neurotransmitter in the brain. Excess of glutamate can cause neuronal damage due to letting too much Ca2+ into the cell. Glutamate receptors are ion channels (AMPA, NMDA) and GPCRs. Too much glutamate may result in epilepsy and schizophrenia.
What are the major non-amino acid neurotransmitters in the CNS?
Non-amino acid:
1. Acetylcholine - ACh acts on muscarinic and nicotinic receptors. It is predominant within the basal forebrain, pons, cortex, and basal ganglia. Dysfunction in ACh transmission may result in cognitive function decline, nicotine dependence, and movement disorders. Drugs targeting ACh are cholinesterase inhibitors.
2. Dopamine (DA) - DA is predominant in the midbrain (SN pars compacta and ventral tegmental area). Dysfunction in DA transmission may result in schizophrenia, Parkinson’s, addiction, depression, and ADHD. Drugs will target D1-D5 receptors (GPCRs) and the DAT. Targeting DAT increases extracellular DA, which can produce euphoria (inc. risk of addiction). Too much DA can result in schizophrenia, not enough can result in Parkinson’s.
3. Norepinephrine - NE is predominant in the pons (locus coeruleus). Dysfunction in NE transmission may result in memory loss, depression, addiction, and pain. NET inhibitors are used to treat depression, since depression is thought to involve a NE deficiency.
4. Serotonin; 5-HT - Predominant in the midbrain/pons (raphe nuclei). Dysfunction in serotonin signaling may result in depression, mood disorders/anxiety, and schizophrenia. Drug targets are different serotonin receptors (14 GPCRs, one gated ion channel, and SERT) depending on the indication.
What are the mechanisms by which drugs can modulate neurotransmission in the CNS (with examples)?
- Post-synaptic receptor. Can be agonist or antagonist.
- Transporter. To control the amount of neurotransmitter in the synapse.
- Metabolism. To breakdown/slow down breakdown of neurotransmitter
What are the symptoms and neuropathology of MS?
MS - an immune-related (inflammatory) disorder that involves destruction of the myelin sheath that surrounds neuronal axons, primarily in the spinal cord & brain. In place of this destruction, scarring accumulates.
Symptoms: Many different symptoms that vary from patient-to-patient. It depends on where this myelin breakdown is.
- Visual problems
- Numbness, tingling
- Fatigue, motor weakness
- Difficulty walking, gait problems, ataxia
- Pain
- Dizziness, vertigo
What are some environmental and genetic factors that are associated with elevated MS risk?
- Age (peak incidence is people in their 30s)
- Geography (lower exposure to sunlight, decreased 25-hydroxyvitamin D levels)
- Viral infections (Epstein-Barr Virus: an infection can lead to an immune response against the antigen. That particular protein looks similar to one of our own proteins, so the immune response may also cross-react with one of our own proteins) People with a particular HLA phenotype have an increased risk of MS if they have EBN antigen
- Environmental insults (urbanization) after age 15
- Cigarette smoking increases risk and severity of MS
- Genetics (highest risk in twins, which may indicate a polygenic mode of inheritance)
It is a connection of environment and genetics that results in MS.
What are the different clinical forms of MS?
Relapsing-remiting MS (RRMS) - About 85% of cases. Relapses of neurological dysfunction lasting weeks/months affecting the brain, optic nerves, and/or spinal cord. Initial symptoms disappear, but there’s less remission with each relapse
Secondary progressive MS (SPMS) - The damage is permanent and progressively worsening. There is less inflammation than RRMS. Little remission seen here.
Primary progressive MS (PPMS) - About 15% of cases. This at first resembles SPMS. These individals are already in the progressive phases that did not cross the threshold until the damage was permanent.
Clinically isolated syndrome (CIS) - The first auto-immune episode that crosses the threshold, leading to symptoms. This episode lasts longer than 24 hours.
**the progressive phase involves cytodegeneration where there is loss of myelin, axons, and oligodendrocytes.
What are the autoimmune and degenerative phases of MS?
Autoimmune phases - Antigens that are released from the CNS or cross-reactive foreign antigens are presented to B and T cells in the lymph nodes. More B and T cells migrate to the CNS and they carry out immune functions, releasing antibodies and cytokines, at the CNS sites.
Degenerative phases - Due to the immune function damage in the CNS, antigens are released that further prime immune cells to then cause more damage (also in periphery).
It’s a vicious cycle.
What autoimmune responses are involved in MS?
Dendritic cells present CNS antigens. Different T cells are activated from this antigen presentation. Dendritic cells also stimulate B cells from this. The activated B and T cells will then migrate to the BBB, but they can’t get in. α4-integrin mediated binding allows for the penetration of the BBB, so the B & T cells enter the brain. The B cells mature into plasma cells that produce antibodies that attack the antigens on the antigen presenting cells. The active T cells interact with antigen presented by MHC on the surface of neurons, oligodendrocytes, and microglia. Once the T cells bind, they release cytokines (inc. perforin and granzyme that lead to oligodendryocyte destruction) and stimulate macrophages, which leads to death to the myelin sheath.
What are the effects of demyelination on axon conductive properties?
- Demyelination causes action potentials to slow down due to slowed propagation of the current from the loss of insulation from the myelin sheaths. So we no longer have sustained conduction.
What are the steps involved with remyelination? What role does remyelination play in MS pathology?
- After the damage has been done, there is migration of neuronal stem cells and oligodendrocyte progenitor cells (OPC) to the lesion. This leads to the replacement of damaged neurons and oligodendrocytes that remyelinates the axon.
- During demyelination, oligodendrocytes are lost and macrophages enter. Astrocytes enter and start to form scars.
- OPCs are recruited and mature to oligodendrocytes. These then produce new myelin, but this ultimately fails, leading to scarring by astrocytes called astrogliosis.
- The re-establishment of the myelin sheath is good, but it’s not as strong as the original myelin.
What are the pathogenic mechanisms that are current or potential targets for MS therapies?
Immune system targets:
- T cell binding/penetration of BBB -> α4-integrin antibodies, IFN-β
- T cell/APC interactions -> altered peptide ligands that interfere with this interaction
- cytokines -> antibodies that are specific to cytokines to neutralize them
Remyelination targets:
- Agents that facilitate OPC recruitment or promote OPC differentiation
How can gadolinium-enhanced MRI be used to visualize lesions in MS patients?
Gadolinium penetrates the brain in regions where the BBB is compromised. We can see where in the brain there is ongoing damage. This is useful for active damage and autoimmune events during a relapse phase, but it would recede during the remission phase as there is remyelination.
What are the symptoms, pathophys, and treatments of Guillain-Barré syndrome?
Acute, inflammatory neuropathy. This is peripheral, not in the CNS (like MS).
symptoms - starts in lower extremities. See weakness that ascends to proximal muscles and upper extremities. Can progress to total paralysis w/ death from respiratory failure in days. Generally peaks at 10-14 days.
pathophys - autoimmune attack on peripheral nerves by circulating antibodies, resulting in demyelination.
treatment - ventilation (if respiratory difficulty), plasmapheresis (to eliminate auto-antibodies), and intravenous immunoglobulin administration.
**recovery is slow, but most surviving patients recover completely (the rest have minor motor deficits)
What are the differences between MS drugs that are used to treat acute attacks vs. disease-modifying drugs?
Acute attacks are treated with anti-inflammatory drugs:
- Methylprednisolone
- Prednisone
- Adrenocorticotropic hormone (ACTH): stimulates anti-inflammatory steroid production.
Disease modifying therapies (DMTs) reduce relapse rates and may slow the progression of disability. These alter the course of the disease.
What DMDs are used as first-line drugs for MS? What are their mechanisms of action?
interferon β1a and β1b - act in the periphery to inhibit autoreactive lymphocytes, like T cells and dendritic cells. Also acts at the BBB to inhibit the penetration by matrix metalloproteinase (MMP), which breaks down components of the BBB, thus letting in lymphocytes. (not in CNS)
glatiramer acetate - a synthetic peptide that mimics antigenic properties of myelin basic protein, which binds to APCs, resulting in the inhibition of autoreactive lymphocytes, like T cells and dendritic cells. (only in periphery)
fingolimod - S1P receptor agonist, which stimulates oligodendrocyte survival and therefore remyelination. It also interferes with lymphocyte movement out of lymphoid organs. (in periphery (lymph node) and CNS)
What DMDs are used as second-line drugs for MS? What are their mechanisms of action?
natalizumab - monoclonal antibody that acts at the BBB and is specific for α4 integrin, which usually binds with β1 integrin to produce VLA-4. Interfering/neutralizing with VLA-4 binding with its ligand interferes with B and T cell movement into the CNS.
mitoxantrone - this is an anthracenedione with cytotoxic activity. it reduces lymphocyte numbers by causing DNA strand breaks and delaying DNA repair. (periphery)
What are the new DMDs for MS? What are their mechanisms of action?
dimethyl fumarate - works in the periphery and CNS and has multiple MOAs. In the CNS, it activates Nrf2 (neuroprotective transcription factor most common in astrocytes) that increases antioxidant and anti-inflammatory pathways (glutathione biosynthesis and detoxification). Also may promote remyelination and suppress activated T cells/dendritic cells in the periphery.
rituximab (also called ocrelizumab) - targets CD20 as well. It is effective for some PPMS patients!!! That’s unique.
alemtuzamab - targets CD20, which is on the surface of B cells. (in periphery)
cladribine - cytotoxic agent that is taken up by cells. It will be phosphorylated and integrated into DNA, resulting in cell death and lymphocyte depletion.
teriflunomide - cytotoxic agent that interferes with DNA metabolism, which inhibits proliferation of peripheral lymphocytes.
What MS drugs are in clinical trials or in earlier experimental stages? What are their mechanisms of action?
firategrast - small molecule that targets α4 integrin (VLA-4). It’s active at the BBB.
amiloride - Only active in the CNS. It’s a small molecule that targets ASIC-1, which is an ion channel that is responsible for the entry of too much Ca2+. Antagonism of ASIC-1 leads to direct neuroprotective effects.
laquinimod - Only in the CNS. Not like the other imods. This stimulated BDNF, which leads to direct neuroprotective effects. Also shown immunomodulatory effects.
opicinumab - Only in the CNS. Interferes with LINGO-1, which is a protein that negatively regulates OPC differentiation. That is bad because we need more oligodendrocytes for MS.
What are features of drugs that limit their therapeutic effectiveness (ex. toxicities, induction of neutralizing antibodies)? (interferon, fingolimod, natalizumab, dimethyl fumurate, ocrelizumab, opicinumab)
PML - fingolimod, natalizumab, dimethyl fumurate
limited by neutralizing antibodies - interferon, natalizumab, ocrelizumab, opicinumab
How can you identify the structures of fingolimod, dimethyl fumarate, and cladribine?
fingolimod has a long fatty acid chain, which is what helps it get into the CNS
dimethyl fumarate looks like a mirror image of its self with methyls and esters on each end.
cladribine has a halogen on one of its rings.
What is the diagnostic criteria and types/subtypes for multiple sclerosis?
There is no single feature or criteria that is sufficient to diagnose MS. It’s important to rule our other disorders. Two of the most important factors is a dissemination in time (new lesions 30 days apart) and dissemination in space (damage that is in more than one place (2-4 regions)).
Types: Clinically isolated syndrome, relapsing remitting, secondary progressive, primary progressive, and progressive relapsing.
- The disease modifying therapy is usually for RRMS
What is the rating scale that is associated with the diagnosis of multiple sclerosis?
The Expanded Disability Status Scale (EDSS) is the standard scale that providers use to assess MS disability.
0 = normal neurological function
10 = death
4 is the average for pts presenting with MS
5 = cane, 6 = walker, 7 = wheelchair
What is the clinical course, goals of therapy, and expected outcomes of treatment with drug and non-drug therapy for MS?
Goals of treatment:
- Start early. Hopefully we can reduce neurodegeneration by starting meds early.
- Treat acute attacks aggressively to promote more complete remission
- Use disease modifying drugs (start at CIS stage if possible). We want to target inflammation by various mechanisms.
- Increase quality of life!
What oral drug therapy is used for MS (brand + generic), including side effects, and monitoring parameters?
Dimethyl fumurate (Tecfidera), Diroximel fumerate (Vumerity) - Capsule should not be opened. Monitor LFTs (hepatotoxicity) and CBCs with differential (neutropenia). It is associated with PML. May cause flushing, so pt can take an ASA 30 mins prior to the dose.
Fingolimod (Gilenya, Tascenso ODT) , Ozanimod (Zeposia), Ponesimod (Ponvory), Siponimod (Mayzent) - CV side effects!! Contraindicated with past arrhythmia diagnosis or other CV diagnoses in the past 6 months. Need to monitor ECG for the first 6 hours. Monitor CBC and pt needs routine eye exams due to risk of macular edema. D/c of the drug can result in worsening MS symptoms.
- Ozanimod: avoid use with MAO inhibitor
- Siponimod: CYP2C9 genotype testing is required before prescribing
Teriflunomide (Aubagio) - Contraindicated in pregnancy!! To the point that we will do accelerated elimination!
What injection drug therapy is used for MS (brand + generic), including side effects, and monitoring parameters?
interferon beta-1a (Avonex, Rebif), peginterferon beta-1a (Plegridy), interferon beta-1b (Betaseron, Extavia) - Flu-like symptoms can occur after injection, so pt can take APAP or NSAID prior. Also evening dosing is good for this. See psychiatric side effects (depression, suicidal thinking)!!! Monitor LFTs and TSH.
Glatiramer acetate (Copaxone) - These have injection side effects, esp. immediately post-injections, such as flushing, sweating, dyspnea, chest pain, anxiety, and itching. Also need to rotate sites due to lipoatrophy. It may be preferred if treatment is necessary in pregnancy!
What infusion drug therapy is used for MS (brand + generic), including side effects, and monitoring parameters?
Alemtuzumab (Lemtrada) - There are possible fatal infusion reactions and autoimmune conditions. Also associated with increased risk of malignancies. It is contraindicated in HIV infection due to prolonged decreased CD4 count. Need all vaccinations at least 6 weeks before starting treatment. Can premedicate prior to dose.
Natalizumab (Tysabri) - Significant association with PML. Need all vaccinations at least 6 weeks before starting treatment. Can premedicate prior to dose.
Ocrelizumab (Ocrevus) - Only drug FDA-approved for PPMS!! Contraindicated in active Hep B. Also associated with increased risk of malignancies. Need all vaccinations at least 6 weeks before starting treatment. Can premedicate prior to dose.
What are the boxed warning and REMS programs that are associated with drug therapy for MS?
REMS (risk evaluation mitigation strategies): Alemtuzumab, Natalizumab
What can be used to treat gait disturbances, bladder dysfunction, cognitive dysfunction, and spasticity for MS patients?
Gait disturbances - Dalfampridine (Ampyra) may improve walking speed by 3 seconds.
Bladder dysfunction - anticholinergics like oxybutynin and tolteridone. BUT these may worsen cognitive dysfunction
Cognitive dysfunction - Cholinesterase inhibitors and memantine.
Spasticity - Baclofen is approved. Also physical therapy, stretching, exercise, etc.
What type of vaccines are preferred for MS patients?
Inactivated vaccines are preferred for people with multiple sclerosis. These can be given at anytime.
It is preferred that the pts get the varicella vaccine, especially if they are going to start MS drugs that suppress cell-mediated immunity (ex. fingolimod, alemtuzumab).
If they haven’t started anything yet, we want to get their vaccines in about 6 weeks before starting immunological therapy.
How long after stopping these drugs would you need to continue contraception for MS? Fingolimod, Ozanimod, Ponesimod, Siponimod, Orelizumab, Cladribine
Ponesimod - 7 days
Siponimod - 10 days
Fingolimod - 2 months
Ozanimod - 3 months
Ocrelizumab - 6 months
Cladribine - 6 months
Please
Stop
Fingolimod
Or
Ocean
Clash
What are the physical symptoms and neuropathological underpinnings of PD, including the Braak staging of the disease?
Symptoms - resting tremor, ridigity, akinesia/bradykinesia, postural instability, mask-like appearance, speech difficulties, cognitive deficits, depression
- chronic, progressive, irreversible, disease that results from a deficit in the extrapyramidal system (basal ganglia), which is involved in noncortical voluntary motor control.
- We see Lewy bodies in the neurons and loss of neurotransmission through the nigrostriatal system (due to loss of dopamine-releasing neurons)
- there is Braak staging that represents the spreading of PD from the lower brainstem through the entire brain. There is a symptomatic threshold in stage 3 where Lewy bodies are present in the substantia nigra.
- by the time pts present with symptoms, about 50% of the nigral dopamine neurons, or 70-80% of the nerve terminals in the striatum are already lost.
How does neurotransmission from the substantia nigra to the basal ganglia get disrupted in PD?
There are two types of neurons in the striatum that lead to two different pathways:
1. D1 receptors (direct): shortest pathway.
2. D2 receptors (indirect): slower pathway, involves additional components.
In a healthy person, dopamine will be released from neurons to go onto signal in the striatum through these two pathways. This signaling favors movement (increase thalamocortical signaling). So, the loss of dopaminergic neurons in PD will disrupt this signaling to cause the motor dysfunction.
What is the role of anti-muscarinic drugs in PD therapy?
- The D2 (indirect) pathway is antagonized by acetylcholine (balance). So if we inhibit this muscarinic/cholinergic signaling, it will help regain the balance of muscarin and dopamine signaling.
These are used as adjunct therapy for tremor in PD. But need to keep the dose low in order to prevent the cognitive deficit side effect.
Why do we treat PD patients with L-DOPA and carbidopa?
L-DOPA is the gold standard for PD therapy. It is orally active and can enter the CNS (plain dopamine can’t enter the BBB). L-DOPA is neutral at a pH of 7, dopamine is not.
This boosts dopamine!
carbidopa is a peripherally-acting DOPA decarboxylase (DDC) inhibitor. This means it stops the peripheral breakdown of L-DOPA into dopamine, which allows us to decrease the dose of L-DOPA by 4x! This is especially good because it means more dopamine in the CNS and it reduces the risk of side effects, like nausea, HTN, and psychosis.
What are the challenges that are associated with L-DOPA therapy?
On/off:
- Won’t work forever. After years of L-DOPA treatment, we will see large peaks and troughs from the drug, which can produce dyskinesias and off-states.
- These dyskinesias and on/off effects are major problems in long-term therapy with levodopa.
- We can alleviate this by infusing L-DOPA (or just continuous) instead of taking orally (pulsatile).
Prodrug conversion:
- L-DOPA is a prodrug that but be converted to dopamine by DDC in the surviving dopaminergic neurons, but because the disease is progressive, this conversion will eventually stop happening.
- We can address this by using dopamine receptor agonists, which can target postsynaptic dopamine receptors
What are the PD drugs that are ergoline and non-ergoline dopamine receptor agonists? Which ones are used for adjunct treatments vs. monotherapy?
ergoline:
- bromocriptine: D2 agonist. Used as an adjunct with L-DOPA to keep the dose down
non-ergoline: used more often
- ropinirole, pramipexole, rotigotine: D2/D3 agonists with fewer side effects. Usually monotherapies for early-stage PD, efficacy may last for 2-4 years.
*rotigotine is given through transdermal patch which allows for continuous drug delivery.
- apomorphine: mixed D1/D2 agonist. Can provide rapid relief of the on/off state, but has vomit-inducing side effects, so it’s use is limited.
What are the PD drugs that interfere with dopamine metabolism?
MAO-B converts active DA into inactive DOPAL, so we want to inhibit MAO-B. COMT also destroys DA and L-DOPA.
irreversible MAO-B inhibitors: selegiline, rasagiline
- Can be used initially as a monotherapy to delay the use of L-DOPA or as adjunct to decrease dose of L-DOPA
reversible MAO-B inhibitor: safinamide
- no proparygylamine. Used as an adjust to L-DOPA/carbidopa to reduce the dose. This is particularly useful during off episodes
COMT inhibitors: entacapone, tolcapone, opicapone
- entacapone/opicapone decrease metabolism of L-DOPA in the periphery, allowing more to reach the brain
- tolcapone works in the CNS!!! which allows levels of CNS dopamine to remain higher and increases dopamine elimination time.
What are the chemical structures of dopamine, L-DOPA, carbidopa, and selegiline?
L-DOPA - looks like dopamine but has a carboxyl group, which is what allows its access to the CNS
Carbidopa - looks like L-DOPA, but has one more amino group
selegiline - has the propargylamine (triple bond) which results in irreversible inhibition of MAO-B.
How would we recommend a patient-specific treatment plan for the management of PD? What is first line and second line?
Goals of therapy - Minimize/manage motor and non-motor symptoms, maintain highest QOL possible, preserve activities of daily living, minimize/manage adverse drug reactions
Want to rule out drug-induced PD (ex. typical antipsychotics). Start treatment when PD interferes with ADL, employment, or QOL.
- First line: Dopamine precursor (L-DOPA)
1.5 Dopamine agonist, MAO-B inhibitors (can be first line in certain patients to delay levodopa use
- Use dopamine agonist maybe if less than 60 years of and at a higher risk for dyskinesia, but avoid if over 70 years old, if they have impulse control disorder, hallucinations, cognitive impairment, or excessive daytime sleepiness (these are side effects of dopamine agonists)
- Efficacy: Levodopa/Carbidopa > DA > MAOB-I - COMT inhibitors, amantadine
How can we therapeutically manage levodopa-induced motor fluctuations?
There are four types of LD motor fluctuations:
1. Wearing off: before the next dosing intervals, see signs of motor symptoms -> increase dose or frequency, add DA agonist, MAOI, or COMTI, switch to CD/LD
- Freezing: Inability to move due to insufficient or fluctuating DA levels -> increase dose or frequency, add DA agonist (apomorphine), add ODT CD/LD
- Delayed onset: therapeutic benefits delayed -> take LD/CD on an empty stomach, change to ODT LD/CD, avoid CR/XR LD/CD
- Peak-dose dyskinesias: involuntary body movement caused by high DA levels -> decrease dose of DA or CD/LD, add amantidine
How can we manage non-motor symptoms for a PD patient? ex. anxiety/depression, constipation, dementia, insomnia, orthostatic HTN, psychosis/delirium, sexual dysfunction
Non-motor symptoms - anxiety/depression, constipation, dementia, insomnia, orthostatic HTN, psychosis/delirium, sexual dysfunction
constipation - increase fluid intake, physical activity, stool softeners/laxatives, probiotics
insomnia - non-pharm counseling, melatonin, AVOID benzodiazepines
orthostatic hypotension - non-pharm counseling, midodrine, droxidopa, medical equipment
anxiety/depression - cognitive behavior therapy, SSRI, SNRI, AVOID benzodiazepines
dementia - cholinesterase inhibitor (donepezil, rivastigmine), AVOID anticholinergics, benzodiazepines, antihistamines, sedatives
psychosis/delirium - reduce PD medication doses (if appropriate), pimavanserin!!, atypical antipsychotics (clozapine, quetiapine), AVOID haloperidol, olanzapine, paliperidone, risperidone
What is the non-pharm therapy for PD?
- Exercise/physical therapy: it’s been shown that we should start exercise before pharmacotherapy.
- Nutritional counseling (swallowing may be difficult)
- Occupational therapy
- Psychotherapy/support groups
- Speech therapy
What are the side effects and clinical pearls for dopamine precursors, dopamine agonists, MAO-B inhibitors, COMT inhibitors, amantadine, anticholinergics
Dopamine precursors - levodopa
- Side effects: LD motor fluctuations/dyskinesia, hallucinations, N/V
- Pearls: Increased absorption on an empty stomach, but food helps with nausea. Start low dose and titrate up as side effects allow.
Dopamine agonists - non-ergot (used more), ergot
- Side effects: N/V, impulse control disorder (ICD), orthostatic HTN
- Pearls: Very low starting doses, causes fewer motor fluctuations and there are long-acting formulations
MAO-B inhibitors - rasagiline, selegiline, safinamide
- Side effects: N/V, headache, insomnia (selegiline is an amphetamine derivative), hypo/hypertension
- Pearls: dietary restrictions for tyramine-rich foods, risk of serotonin syndrome if used will serotonergic antidepressants, dextromethorphan, and serotonergic opioids
What are the side effects and clinical pearls for COMT inhibitors, amantadine, anticholinergics
COMT inhibitors - entacapone, opicapone, tolcapone
- Side effects: N/V, urine discoloration (entacapone), hepatoxicity (tolcapone)
- Pearls: used to manage LD/CD fluctuation, no benefit in early PD.
amantadine -
- Side effects: insomnia, confusion/hallucinations, livedo reticularis (rash that can be life threatening)
- Pearls: Can be used for an isolated tremor, limited use due to cognitive side effects
Anticholinergics - benztropine, trihexyphenidyl
- Side effects: confusion/dementia, blurry vision, urinary retention, dry mouth, constipation
- Pearls: limited use due to confusion & side effects. Avoid if over 65 years old. Can help with tremor symptoms.
What are the symptoms and neurological underpinnings of AD? What happens to brain volume and neurotransmitter level? What part of the brain is most impacted?
Symptoms - short term memory loss, impaired ability to learn, reason, impaired ability to carry out daily activities, confusion, untidiness, anxiety, suspicion, hallucinations, motor dysfunction
- With AD, there is a loss of brain volume.
- amyloid plaques: extracellular, consist of amyloid-β
- neurofibrillary tangles: intracellular, consist of hyperphosphorylated tau
- destruction of synapses occurs, which results in reduced levels of neurotransmitters (esp. ACh, serotonin, norepi, and DA). We also see excitotoxicity and neurotoxicity from dysregulated glutamate.
*basal forebrain is an important place that AD affects. It is involved with learning. Eventually, the disease will spread throughout the entire neocortex
