neuro exam 3

___________ is the white coating of the eyes.

a. iris

b. cornea

c. choroid

d. sclera

d.

What does the ciliary body produce?

aqueous humor

____________ is the crystal clear portion that let light in.

a. iris

b. cornea

c. choroid

d. sclera

b.

_________ is located between lens and cornea and is a circular opening of it is called the pupil.

a. iris

b. cornea

c. choroid

d. sclera

a.

___________ is between retina and the sclera, and contains connective tissue and blood vessels to provide nutrition to the eye.

a. ciliary body

b. cornea

c. choroid

d. sclera

c.

What is the measurement of fluid pressure inside the eye? What is the avg in adults?

IOP—> ~15mmHg in adults

What is the only modifiable risk factor for glaucoma?

elevated IOP

What drugs increase IOP?

• anticholinergics (ex: oxybutynin, tolterodine, benztropine, antihistamines, tricyclic antidepressants)

• chronic glucocorticoid therapy (topical and systemic)

• topiramate

Explain how aqueous humor is produced, flows, and recycled?

• idk how imp

1. produced in ciliary body

2. circulates around lens—> to pupil—> to anterior chamber

3. flows out anterior chamber into trabecular meshwork (80-85%)

4. other 15-20% of humor drains by uveoscleral pathway

If not managed, what may glaucoma progress to?

blindness

Angle refers to the filtration angle between the iris and the cornea.

What’s the difference between open and closed-angled glaucoma?

• basically—> key difference is how fluid drains from the eye

• open: slowed exit of aqueous humor through trabecular meshwork—> slowly develops over time

  • think—> like a slowly draining sink

• closed: iridocorneal angle completely closed—> flow stopped—> rapid/painful pressure increase

  • think—> like putting a stopped in a sink and blocking it

List the medications used for glaucoma tx:

• b-blockers

• a2 agonists

• prostaglandin analogs

• rho kinase inhibitors

• carbonic anhydrase inhibitors

• cholinergics

List the beta-blockers used for glaucoma tx:

• are they selective or non-selective?

• betaxolol- b1 selective

• carteolol- nonselective

• levobunolol- nonselective

• timolol- nonselective

What are the advantages/disadvantages to using betaxolol for glaucoma tx?

• advantage—> b1 selective, so less likely to cause pulmonary ADRs

• disadvantage—> less efficacious because b2 receptors are predominant in the eye

MOA of b-blockers used for glaucoma tx:

blocks aqueous humor production

aqueous humor production is through activation of what receptors in what pathway?

through activation of b receptor Gs-cAMP-PKA pathway

List the a2 agonists used for glaucoma tx:

• apraclonidine

• brimonidine

a2 agonists bind to pre/post synaptic a2 receptors to cause what effects?

• presynaptic: decrease NT release= decrease IOP

• postsynaptic: stimulate Gi pathway= decrease cAMP= decrease aqueous humor production

ADRs of a2 agonists used for glaucoma?

• idk how imp

• CNS depression

• ocular/skin allergy

List the prostaglandin analogs used for glaucoma tx:

• latanoprost

• bimatoprost

• travoprost

• latanoprostene bunod

What is the MOA of prostaglandin analogs?

• What type of receptor does it bind to? ionotropic? g-coupled?

• What effects are seen?

• PGF_2a analogs—> bind to PGF receptors

  • PGF_2a receptors are GPCRS

  • effect the G_q- PLC-IP₃- Ca²⁺ pathway

• effects:

  • altered ciliary muscle tension—> increases outflow

  • digestion of extracellular matrix that impedes outflow—> increases outflow

Latanoprostene bunod has what group on its structure to increase outflow?

nitric oxide donating group

ADRs of prostaglandin analogs:

• darkening of iris

• increase length/# of eyelashes

What drug is a rho kinase inhibitor? MOA and effects?

• drug: Netarsudil

• MOA: inhibits rho kinase (which regulates the cytoskeleton of the trabecular meshwork) —> increases outflow

List the carbonic anhydrase inhibitors used for glaucoma tx:

• which is systemic?

• dorzolamide

• brinzolamide

• acetazolamide—> systemic, barely used/tolerated

What role does carbonic anhydrase play in aqueous humor production?

• catalyzes the formation of carbonic acid from H20 and CO2

• carbonic acid needed to make bicarbonate (HCO3-)

• bicarb is ESSENTIAL for aqueous humor production

Inhibiting carbonic anhydrase leads to ___________ aqueous humor production.

a. increase

b. decrease

b.

ADRs of topical and systemic carbonic anhydrase inhibitors:

topical: sulfa allergy, burning, blurred vision

systemic: sulfa allergy, rash, ataxia, confusion, loss of appetite, n, kidney stones, hematologic toxicity

List the cholinergic agents used for glaucoma tx:

• pilocarpine

• carbachol

What is the MOA and ADRs of cholinergic agents?

• MOA: direct agonists—> activate muscarinic receptors and cause contraction of iris sphincter and ciliary muscle

  • results: iris—> miosis—> increases drainage of fluid—> decrease IOP

  • ciliary muscles relax—> lens thickens

• ADRs: pupil constriction, HA

What are the 3 layers of a tear?

1. oil layer—> prevents evaporation

2. aqueous layer—> nourishes cornea, conjunctiva, eyelids, eyes in general

3. mucous layer—> binds water from aqueous layer to keep eye wet

Describe ocular lubricants:

• admins?

• designed to do what?

• many admin: gels, alcohols/polymers, mineral oil

• designed to lubricate cornea/conjunctiva, enhance tear activity, and reduce fricition

What medication can be used for chronic dry eye disease?

cyclosporine

Define each of the following terms:

• cyclophilin

• calcineurin

• nuclear factor of activated T-lymphocytes (NFAT)

• immunophilin

• cyclophilin- cytoplasmic receptor protein (CpN)

• calcineurin- a phosphate (CaN)

• nuclear factor of activated T-lymphocytes (NFAT)- intracellular protein which requires translocation from cytosol to nucleus

• immunophilin- cellular protein that has strong affinity towards an immunosuppressant and forms complex

What is the MOA of cyclosporine?

1. cyclosporine forms complex with cyclophilin (cytoplasmic receptor protein)

2. complex then binds to calcineurin (a phosphatase)

3. this inhibits calcineurin-mediated dephosphorylation of NFAT (nuclear factor of activated T-cells)

4. then inhibits the next step of calcineurin-catalyzed dephosphorylation which is required for translocation to nucleus

5. ultimately inhibits NFAT from synthesizing interferons

PRACTICE:

What class of drugs should not be considered if the patient has a sulfa allergy?

a. beta-blockers

b. a2 agonists

c. carbonic anhydrase inhibitors

d. rho kinase inhibitors

c.

What is dementia?

defines the loss of cognitive functioning (thinking, remembering, reasoning) and behavioral abilities that interfere with a person’s daily life and activities

Does mild cognitive impairment (MCI) warrant a dementia diagnosis?

no! not everyone with MCI will develop dementia (about 15% do)

What is vascular dementia (VaD)?

• how to reduce risk?

• treatment?

• refers to any dementia that is primarily caused by cerebrovascular disease or impaired cerebral blood flow

• reduce risk—> antihypertensives, antithrombotic therapy

• treatment—> cholinesterase inhibitors, memantine

What is frontal lobe dementia?

• any current cure?

• neuropathologically and clinically heterogeneous disorder characterized by focal degeneration of the frontal and/or temporal lobes

• no current “cure”—> tx aimed at s/sx relief

What is the most common pathology of dementia and is defined as a gradual progressive dementia?

Alzheimer’s Disease

Early Onset Alzheimer Disease (EOAD) is age < ____.

Late Onset Alzheimer Disease (LOAD) is age ≥____.

EOAD is age <65

LOAD is age ≥65

What is the exact etiology of AD?

• exact is not known!!! several genetic/environmental factors and hypothesizes

Which genes are most strongly associated with Alzheimer's disease risk, and what biological processes do they influence?

• APOE and ABCA7—> most substantial heritable contributor to genetic risk

  • role: lipid metabolism

• TREM2, CLU, and PICALM

  • role: implicated in amyloid plaque formation, tau pathology, neuroinflammation

What are the key genetic mutations associated with dominantly inherited Early-Onset Alzheimer's Disease (EOAD) and Late-Onset Alzheimer’s Disease (LOAD)

• EOAD

  • dom inherited alterations in chromosomes 1,14, 21 that impact amyloid precursor protein (APP)

• LOAD

  • APOE*4 allele (one copy/heterozygous less risk then two copies/homozygous)

What is Apolipoprotein E (APOE)?

• fxn?

• binds to what?

• APOE*4 allele is associated with what?

• Difference between APOE*4, APOE*3, APOE*2?

• APOE—> a fat-soluble transporter

• responsible for transporting cholesterol in the blood/brain and interacts with b-amyloid binds to NFTs

• APOE*4 allele associated with modified clearance and increased deposition of Ab in AD

  • APOE*4- risk factor for EOAD and LOAD

  • APOE*2- lower risk of AD

  • APOE*3- protective effect from AD development

What is one gene that actually reduces the risk of AD/ EOAD development?

A673T (a rare APP mutation)

PRACTICE:
Genetic susceptibility to late-onset AD is primarily linked to which of the following?

a. apolipoprotein E4 genotype

b. presenilin gene mutations

c. amyloid precursor protein mutations

d. apolipoprotein E2 genotype

a.

T/F: the exact pathophysiologic mechanisms of AD are unknown.

true—> there are signature lesions made of amyloid plaques and NFTs in the brain’s cortical areas and medial temporal lobe structures tho

What is the amyloid cascade hypothesis of AD?

• imbalance of what?

• results in?

• what’s unknown about it?

• imbalance between the production and clearance of b-amyloid peptides

  • results in accumulation/aggregation—> plaque formation—> AD development

• unknown if presence of ab is the primary pathology or changes are a marker of an alternate pathology

What are tau proteins?

What are NFTs?

How are NFTs correlated with dementia?

• tau proteins provide structural support (to microtubules)

• NFTs are composed of abnormally hyperphosphorylated tau proteins (microtubules now can’t fxn properly)

• NFT density tends to correlate with severity of dementia

what is one of the most prominent neurotransmitter defects in AD?

cholinergic abnormalities (aka loss of acetyl choline)

What is the cholinergic hypothesis in AD?

BASICALLY—> a theory that loss of cholinergic neurons and neurotransmitter dysfunction (e.g., acetylcholine) contributes to cognitive/memory impairments in AD

What are the main limitations/flaws of the Cholinergic Hypothesis?

• Cholinergic neurons are just one of many pathways damaged in AD.

• cholinergic cell loss is a secondary consequence of AD pathology

What do cholinergic therapies do in AD?

minimize/ improve symptoms

Explain what the inflammatory mediator hypothesis for AD is.

• BASICALLY—>proposes that chronic brain inflammation plays a key role in Alzheimer’s disease

  • β-amyloid has direct neurotoxicity AND triggers an immune response that indirectly damages neurons.

  • Inflammation represents a failed attempt to clear amyloid.

In addition to acetyl choline, what neurotransmitter abnormalities have been seen in AD?

• glutamate

• serotonin

There is a causal association between what disease and incidence of AD?

• CV and vascular disease (ex: high cholesterol, HTN)

  • vascular disease may accelerate amyloid deposition and reduce clearance of amyloid b

With what stage of AD does functioning fluctuate from day to day?

a. mild

b. moderate

c. severe

b.

What are some cognitive symptoms of AD?

• memory loss

• aphasia (impaired communication)

  • circumlocution, anomia

• apraxia (can’t sequence movements)

• agnosia

• disorientation

• impaired executive fxn

What are some functional symptoms of AD?

• inability to care

  • eating, toileting, bathing, dressing

What are some neuropsych symptoms of AD?

• depression

  • hallucinations, delusions

• behavioral disturbances

  • aggression

  • uncooperativeness

  • wander

  • repetitive manners

Screening for AD is done at what age regardless of symptoms?

mini-Cof or MoCA is rec at age 65 regardless of symptoms

What are the 4 screening assessments available for AD?

(idk how imp)

• mini-mental state examination

• montreal cognitive assessment

• mini-cog

• saint louis university mental status exam

What are the 2 categories of biomarkers in AD?

• which is early changing versus late changing?

• what do they help do? diagnose?

FYI: Biomarkers are measurable substances or processes in the body that indicate normal or abnormal conditions

1. Core 1 (early-changing)

   • includes b-amyloid and T1

   • help identify presence of AD

2. Core 2 (later-changing)

   • includes T2 biofluid and tau PET

   • help confirm AD diagnosis

What is the definitive diagnosis for AD?

is a clinical diagnosis!!!! (looks at symptoms, history, cognitive tests, imaging)

What is the goal of pharm therapy in AD?

tx cognitive difficulties symptomatically and preserve pt. function for as long as possible

Current AD treatments ______ seem to prolong life, cure AD, or halt/reverse processes of the disorder.

a. do

b. do not

b.

List all the pharm options for cognitive symptoms of AD:

• just an overview, don’t memorize

• cholinesterase inhibitors

  • Donepezil, Rivastigmine, Galantamine

• NMDA receptor antagonists

  • Memantine

• cholinesterase inhibitor + NMDA receptor antagonist

  • Donepezil + memantine

• anti-amyloid monoclonal antibody (mAb)

  • Donanemab

  • Lecanemab

What is the indication of cholinesterase inhibitors?

1st line for mild-moderate AD

Name the cholinesterase inhibitors:

• donepezil

• rivastigmine

• galantamine

What are the ADRs of cholinesterase inhibitors in general?

• dizzy

• syncope

• bradycardia

• atrial arrhythmias

• sinoatrial and AV block

• MI

• n/v/d

• anorexia

• weight loss

ADRs specific to donepezil?

• peptic ulcer disease

• GI bleeding

• insomnia

• vivid dreams/ nightmares

ADRs and Counseling points with Rivastigmine?

• ADR: allergic dermatitis

• admin: take with food

MOA of each of the following:

• donepezil

• rivastigmine

• galantamine

idk how imp

• donepezil- specifically/reversibly inhibits acetylcholinesterase

• rivastigmine- psuedo-irreversible inhibitor of butyrylcholinesterase and acetylcholinesterase

• galantamine

ADR and counseling points of Galantamine?

• ADR: serious skin reactions

• admin: take with meals

MOA of Memantine:

uncompetitive antagonist of the NMDA glutamate receptor

ADRs and counseling points with Memantine (Namenda)?

• ADRs: HA, confusion, dizzy, hallucinations, constipation

• admin: can take w/ or w/out food, can open capsule and sprinkle contents on applesauce

Combination therapy is done for what kind of AD?

moderate-severe

Namzaric is a combination of what 2 drugs?

donepezil + memantine

What drugs are anti-amyloid monoclonal antibodies used in AD?

• Donanemab

• Lecanemab

What is the main ADRs assoicated with Donanemab and Lecanemab?

• ARIA (amyloid-related imaging abnormalities)

• infusion related rxns

How often is each anti-amyloid mAb dosed?

• Donanemab- q 4 weeks

• Lecanemab- q 2 weeks

Contraindications to taking anti-amyloid mAbs?

homozygous for APOE e4 allele

When is pharm therapy for neuropsychiatric symptoms started?

is tx permanant or temporary?

• when nonpharm has failed!!

• temporary tx

If an antidepressant must be used in AD, what is the DOC? what antidepressant should be AVOIDED?

• SSRIs (sertraline, citalopram) most common used in AD

• AVOID Tricyclic antidepressants (anticholinergic activity)

What is the BBW on antipsychotics?

increased mortality in elderly patients with dementia related psychosis

What antipsychotics can be considered in AD?

• aripriprazole

• risperidone

• olanzapine

• quetiapine

Brexipiprazole is FDA approved for ________________________.

agitation with dementia

Suvorexant is approved in patients with mild-to-moderate AD for what?

insomnia

Understand the categories of multiple sclerosis and the MS patient population that are affected by each category

1. relapsing-remitting MS (RRMS)

   • temporary periods called “relapses”

   • attacks followed by period of remission

   • ~85% of pts.

2. primary progressive MS (PPMS)

   • symptoms get worse with no remission period

   • ~10% of pts.

3. secondary progressive MS (SPMS)

   • slowly worsening of symptoms and fxn

   • 50% of pts. with RRMS convert to SPMS within 10-20

4. progression-relapsing (PRMS)

   • rare (~5% of pts.)

   • worsens from onset of 1st symptom

What are some lab tests for MS?

• CSF analysis

• MRI

• optic neuritis

• gadolinium

What does the Gadolinium test identify?

contrast agent to identify new lesions and disruption of the BBB

Answer the following about Interferon-B 1b drugs:

	Betaseron	Avonex	Plegridy
Dose			XXXXXXXXXX
Frequency
ROA

	Betaseron	Avonex	Plegridy
Dose	250 mcg	30 mcg	XXXXXXXXX
Frequency	every other day	once weekly	every 2 weeks
ROA	SQ	IM	SQ

Which medication was the first oral DMT and its contraindications?

• Fingolimod (sphingosine-1-phosphate receptor agonist)

• C/I:

  • Class Ia and III anti antiarrhythmic agents

What medication needs genetic testing for CYP2C9 polymorphisms?

Siponimod

Which medication has a black box warning for hepatotoxicity and teratogenicity?

Teriflunomide

What medications have a lifetime cumulative dose?

• Cladribine

• Mitoxantrone

What is the treatment of Pseudobulbar Palsy (aka emotional outbursts, dysphonia, dysphagia)?

Nuedexta (dextromethorphan and quinidine)

What medication should be used cautiously if a patient is depressed?

IFN and natalizumab