acetazolamide

During case presentations, student presented that a patient was taking acetazolamide for hydrocephalus until she could get in for surgery, I was unaware of this use for it so needed to look into it more:

hydrocephalus: disorder of excessive amount of cerebrospinal fluid which accumulates in the ventricles and subarachnoid space

• CSF is produced by the choroid plexus -- epithelium and connective tissue in cerebral ventricles
• epithelial cells produce CSF using active transport which is dependent upon carbonic anhydrase
• CSF production is generally constant unless intracranial pressure is increased (absorption matches the production)
• production rate ~20mL/hour, complete turnover 3-4 time a day
• hydrocephalus results from imbalance between inflow and outflow
• obstruction of circulation
• inadequate absorption
• overproduction
• leads to increased intracranial pressure and ventricular dilation
• etiology: congenital, neural tube defects, CNS malformations, intrauterine infections, choroid plexus carcinoma, infections, tumors, post-hemorrhagic
• symptoms: headache, N/V, personality/behavior changes, lethargy
• bradycardia, hypertension, altered respiratory rate
• macrocephaly
• compression of cranial nerves
• Progressive (need to manage or will get worse)
• most effective treatment: surgical drainage using a ventriculostomy shunt (prevents excess accumulation of CSF, shunts CSF to either systemic circulation or peritoneum)
• Medical therapy:
• diuretics: furosemide and acetazolamide decrease CSF production
• used for short periods in slowly progressive hydrocephalus that is too unstable for surgery or until surgery can be done
• diuretics generally not effective for infants
• acetazolamide can be used for: acute mountain sickness, edema, glaucoma, retinal edema,
• need to dose adjust for renal impairment, caution in liver disease (can induce coma
• Mechanism of action: inhibits carbonic anhydrase from catalyzing the reversible hydration of carbon dioxide and dehydration of carbonic acid
• delays abnormal paroxysmal excessive discharge from CNS neurons and affects promotion of diuresis and urinary alkalinization
• adverse effects: metabolic acidosis, stevens Johnson syndrome, hepatic necrosis, agranulocytosis, thrombocytopenia, angle-closure glaucoma
• monitoring: CBC and electrolytes

prazosin for ptsd

PTSD: disorder that develops after exposure to traumatic event involving actual or threatened injury to themselves or others

• presents as: intrusive thoughts, nightmares, flashbacks, avoidance of reminders of the traumas, sleep disturbances
• leads to dysfunction in life
• 70% of patients with PTSD have sleep disturbances
• Mechanism unknown:
• increased central nervous system noradrenergic activity might contribute to pathophysiology
• elevated levels of norepinephrine disturb REM sleep and increase non-REM sleep
• prazosin decreases the arousal produced by norepinephrine in response to a stressor
• specific involvement of postsynaptic alpha 1 adrenoreceptor
• nightmares usually present during light sleep and disturb REM sleep
• prazosin has a role (mechanism unknown) in regulating REM sleep
• diagnosis made if having still having symptoms at least 4 weeks after traumatic event
• early initiation of treatment is best
• can be treated with SSRI's, SNRI's, TCAs, MAOIs, atypical antidepressants, second generation antipsychotics (augmentation).
• alpha-adrenergic receptor blocker: prazosin
• acts centrally (crosses BBB-highly lipophilic) and peripherally
• reduces nightmares
• improves sleep
• 1 mg at bedtime, gradually increase to 3-15 mg as tolerated
• avoid sudden d/c (can result in rebound hypertension)
• often used in conjunction with one of the antidepressant options (^ usually SSRIs)
• use in caution in patients with hypotension, prone to orthostatic hypotension
• studies show well-tolerated and successful improvement in symptoms of PTSD
• side effects: hypotension, dizziness, lightheadedness, orthostatic hypotension, sedation, syncope

Valacyclovir Prophylaxis for wrestling

Question from provider --
Is there evidence to support using valacyclovir prophylactically for wrestlers? (prevention, NOT suppression)

Study analyzed the use of valacyclovir over a 10 year period (2003-2012) in participants at a 28-day wrestling camp in Minnesota for collegiate wrestlers
(Not a RCT) but looked at comparison of outbreaks of herpes gladiatorum from HSV-1 infection between subjects using valacylovir for prophylaxis or not using prophylaxis
3-4% had a known history of HSV-1 infection
29.8% seropositive for HSV-1
use of valacyclovir for prophylaxis --> ~87% reduction in outbreaks
started treatment 3 days before the start of camp and continued treatment through the end of the camp (28 days)
valacylcovir was dosed at 1 gm once daily
subjects also required to take other precautions such as daily skin checks and showers after physical contact
2793 total subjects over 10 years  --> 224-334 subjects annually
23. 1 outbreaks/year on average vs. 3.6 outbreaks/year during study (majority of outbreaks occurred in those not using antiviral prophylaxis)
~1 outbreak/year among the users of antiviral prophylaxis

of the total subject sample size, 2221 available for individual data assessment over 8 year period
71% on prophylactic antivirals
67 with a known history of HSV-1, of these, 9 had outbreak (13.4%)
only 1.1% of total had outbreak with no history of HSV infection

conclusion:
higher usage of prophylactic valacyclovir correlates with reduced number of outbreaks
valacyclovir suppresses seroconversion and reduces shedding of virus
team-wide usage of antiviral prophylaxis is appropriate
proven more efficacious than acyclovir 400 mg BID

Reference:
Prophylactic Valacyclovir to Prevent Outbreaks of Primary Herpes Gladiatorum at a 28-Day Wrestling Camp: A 10-Year Review

Anderson, B. J. MD; McGuire, Dennis P. PhD; Reed, Megan DC ATC; Foster, Monique M.Ed ATC; Ortiz, Deanna ATC

Clinical Journal of Sport Medicine  

Issue: Volume 26(4), July 2016, p 272–278

 

Recommendation: recommend antiviral prophylaxis with valacyclovir

dose --> unsure (the study used 1 gm once daily, but the FDA approved dose for SUPPRESSION is 500 mg once daily

vasopressin receptor antagonists

Vasopressin (ADH) Receptor Antagonists

• treatment of hyponatremia
• alternative or addition to fluid restriction and sodium chloride administration
• vasopressin receptors:
• V2: antidiuretic response
• V1a: vasoconstriction
• V1b: adrenocorticotropic hormone release
• selective free water diuresis (aquaresis) -- do not affect excretion of sodium or potassium
• increased urine output
• decreased urine osmolality
• restoration of serum sodium levels
• increases thirst significantly - limits sodium rise
• oral -- selective V2: tolvaptan (29:1 ratio, V2:V1a)
• IV -- blocks V2 and V1a: conivaptan
• tolvaptan: warnings -- should not be used longer than 30 days -- risk of hepatotoxicity, should not be used in liver disease
• conivaptan: concerns with V1a block leading to hypotension and increased risk of variceal bleeding in cirrhosis patients (vasopressin is used to treat active bleeds), also may worsen renal function in cirrhosis patients -- terlipressin (V1a agonist to treat hepatorenal syndrome)
• have been studied in hyponatremia due to SIADH, heart failure, and cirrhosis
• should NOT be used in patients who are hyponatremic and volume depleted (repletion with saline is primary therapy)
• do not correct sodium too quickly -->  osmotic demyelination of nerves
• no more than 8 mEq/L in 8 hours or 12 mEq/L in 24 hours
• slower rates in malnutrition, alcoholism, advanced liver disease
• only initiate in hospital setting to monitor serum levels
• adverse effects: increased thirst, dry mouth, polyuria
• substrate of cyp3A4 = many DDI's
• monitoring: serum sodium, rate of sodium increase, serum potassium, volume status, signs of hepatotoxicity/ hepatic function test
• half-life ~ 12 hours
• onset of action 2-4 hours, peak at 4-8 hours
• cost:
• 15 mg tablets (wty: 10) = $4293.70

Reversal for factor Xa inhibitors

Question from patient:

Currently on dabigatran for anti-coagulation therapy. Patient stated he may be switching insurance plans which may cause him to have to switch from dabigatran to rivaroxaban or apixaban. Patient expresses concern about whether reversal agents exist for these drugs or not.

Dabigatran reversal agent -- praxbind (idarucizumab), FDA approved

Under investigation:
andexanet alfa -- antidote/reversal agent for factor Xa inhibitors (rivaroxaban, apixaban, edoxaban)

• decoy receptor -- has higher affinity to factor xa inhibitor than factor xa (binds to drug)
• not active against dabigatran
• 2015 -- first RCT:
• ages 50-75 years
• primary endpoint: % change in anti-factor xa activity measured by chromogenic assay of factor xa activity
• secondary endpoints: proportion of patients with 80% reduction in anti-factor xa activity, change in unbound inhibitor plasma concentration from baseline, change in thrombin generation
• patients either given apixaban 5 mg BID x 3.5 days (steady state) or rivaroxaban 20 mg once daily x 4 days, then randomized to andexanet alfa or placebo
• andexenet alfa given either as IV bolus or IV continuous infusion
• apixaban given bolus of 400 mg with or without continuous infusion at 4 mg/min
• rivaroxaban given bolus of 800 mg with or without continuous infusion of 8 mg/min
• results:
• anti-factor xa activity rapidly decreased within 2-5 minutes with both apixaban and rivaroxaban compared to placebo after 1 IV bolus, activity persisted for approx. 2 hours
• all patients who received full dose treatment had at least 80% reduction in anti-factor xa activity, no patients in placebo group achieved this
• conclusion: effectively and safely reversed apixaban and rivaroxaban
• was expected to be approved/released in 2016, however, in August 2016 FDA required more information from manufacturer (Portola Pharmaceuticals) regarding the manufacturing process and additional information to support inclusion of edoxaban and enoxaparin to finalize the review
• Portola is addressing these issues and re-submitting but unknown how long this will take
• phase 3b/4 study: ANNEXA-4, open label confirmatory study in patients on either apixaban, rivaroxaban, edoxaban, or enoxaparin who present with acute major bleeding
• plans to be released in 2022

Currently -- only PARTIAL reversal with either FEIBA, prothrombin complex concentrates (PCC)*four factor or recombinant factor VII

Donepezil for Balance/gait

patient prescription for donepezil for "balance & gait"

• Reversible cholinesterase inhibitor --> increased concentration of acetylcholine
• approved for dementia/Alzheimers
• The degeneration of cholinergic systems may contribute to impairments in gait and balance
• adverse effects: diarrhea, nausea, vomiting, muscle cramps, insomnia, fatigue .
• due to cholinergic effects, it is hypothesized that treatment with donepezil should improve balance and gait, so far studied in Parkinson's disease
• Randomized, double-blind cross over trial compared donepezil x 6 weeks 10 mg max per day with 3 week washout period in subjects with Parkinson's disease who fall more than 2 times per week
• primary outcomes: daily falls 
• treatment with donepezil reduced falls by half compared to placebo
• small sample size: 23 subjects

Studies currently ongoing to evaluate cholinergic augmentation for balance and gait:

• Randomized, double-blind cross over trial compared donepezil 2.5 mg 2/day x 3 weeks then 4/day for 6 weeks with a 6 week washout period between treatment periods in subjects with Parkinson's disease 
• primary outcome: root mean square of mediolateral sway when standing and variability of stride duration when walking two minutes
• Randomized, double-blind, placebo controlled trial will compare donepezil to placebo in older adults with cognitive problems (subjects in early stages of dementia -- NOT Parkinson's disease)
• primary outcomes: improvements in gait velocity, reduction in gait variability
• hypothesis -- donepezil will be effective for fall prevention in older adults with cognitive impairments

atomoxetine for adhd

Atomoxetine: (why is this the most efficacious for adhd vs. other SNRIs?)

• selective norepinephrine reuptake inhibitor
• only FDA approved SNRI for adhd
• used as second-line therapy after trial of atl east 2 stimulant agents 
• slower onset of action than stimulants (does not work immediately, takes ~2 weeks to see effect)
• no abuse potential
• less potential to cause growth effects in comparison to stimulant agents
• good for comorbid anxiety disorders, tics
• adverse effects: nausea, anorexia, insomnia, sedation, liver toxicity, priapism
• metabolized through cyp 2D6
• need to be dose reduced in hepatic impairment
• no renal dose adjustments
• potential for drug drug interactions with 2D6 inhibitors or inducers
• pathogenesis of ADHD: involved with hypoactivity of dopamine and norepinephrine in frontal-subcortical circuits in brain
• atomoxetine works strictly on norepinephrine
• other SNRIs (duloxetine and venlafaxine) work on serotonin and norepinephrine
• mostly work on serotonin, starts to work on norepinephrine only with HIGH doses
• more efficacious to use an SNRI that has more effect on norepinephrine vs serotonin as that is the catecholamine affected in ADHD
• there is weak evidence to use duloxetine in ADHD although not FDA approved for this use
• 1 RCT compared duloxetine to placebo showed some benefit, but further studies needed
• no RCTs comparing duloxetine to atomoxetine