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

Roflumilast

Roflumilast (Daliresp)

• phosphodiesterase inhibitor --> increase levels of intracellular cAMP in lung cells --> decreased neutrophil and eosinophil cell counts
• decrease inflammation, promote airway smooth muscle relaxation
• used for COPD associated with chronic bronchitis
• demonstrated significant improvement in FEV1 and reduction of rate of COPD exacerbations in comparison to placebo
• failed to show benefit in patients with emphysema
• has not been compared to other phosphodiesterase inhibitors
• has been studied as add-on therapy to long-acting beta agonist and long-acting anti-muscarinic
• uncertain in asthma
• 500 mcg orally once daily
• no renal dose adjustments, use caution in mild hepatic impairment, contraindicated in mod-severe hepatic impairment
• metabolized by liver, cyp 3A4 and 1A2
• take with or without food
• avoid use with strong cyp450 inducers
• may increase risk of depression/suicidal thoughts
• may cause diarrhea, nausea, headache, back pain
• can cause weight LOSS/decreased appetite
• initial response takes approx. 4 weeks
• NOT for ACUTE bronchospasm -- this is not a bronchodilator
• roflumilast PREVENTS exacerbations
• should be reserved for refractory disease
• data is less convincing than the effects of standard of care LABA and LAMA
• can be used as add-on to standard of care prevention
• cost 30 day supply = $354.17

References:

Product Information: DALIRESP(TM) oral tablets, roflumilast oral tablets. Forest Laboratories, Inc., St. Louis, MO, 2011.

Stoller J. Management of exacerbations of chronic obstructive pulmonary disease. UpToDate. Barnes P (Ed). Accessed on: 17 November 2016. 

Ferguson G. Management of stable chronic obstructive pulmonary disease. UpToDate. Stoller J (Ed). Accessed on: 17 November 2016.

 

sulfa allergy

Sulfonamide Allergy --

• second most common drug allergy (second to penicillin)
• sulfonamide moity = SO2NH2
• antimicrobials: arylamine + aromatic ring on sulfa core = forms analog of para-aminobenzoic acid --> essential for antimicrobial action but also contributes to hypersensitvity reactions
• nonantimicrobial agents -- do not contain arylamine: diuretics (furosemide, HCTZ, acetazolamide), hypoglycemics (glyburide), anti-inflammatories (celecoxib, sulfasalazine), anti-hypertensives, sumatriptan 
• sulfone: dapsone, not a sulfonamide but hypersensitivity reaction is clinically similar
• HIV increases susceptibility to sulfonamide reactions
• most commonly presents as fever and mobilliform rash 
• develops within 1-2 weeks of initiation of therapy
• can be mild but also can progress to organ failure
• generally avoid drugs in the class, however, if clinically necessary, patients can undergo desensitization
• generally takes 1-2 for symptoms to resolve
• if re-exposed, symptoms may develop more rapidly within 1-2 days
• antibiotics are associated with Stevens-Johnson Syndrome and toxic epidermal necrolysis
• patients must STRICTLY AVOID
• re-exposure may be fatal
• non-antibiotics are not associated with SJS/TEN
• minimal evidence of cross-reactivity between antibiotic and non-antibiotic sulfonamides
• predisposition to drug hypersensitivity reactions in general is more predictive
• need to assess what type of reaction patient had (distinguish between fever/rash vs SJS/TEN)
• if need to desensitize (administer small and increasing doses under careful medical supervision), usually for patients who have type 1 IgE mediated reactions

Reference: 

Montanaro A. Sulfonamide allergy in HIV-uninfected patients. UpToDate. Adkinson NF (Ed). Accessed on: November 16 2016.

cyanocobalamin

Patient came in to pick up cyanocobalamin injection and Amy and I provided administration education:

Indication: (vitamin B12) deficiency, pernicious anemia, hyperhomocysteinemia

Dosage: 

• deficiency: 1000 mcg/day orally, if oral route not adequate, initial treatment is the same as it is for pernicious anemia 
• malabsorption: 100 mcg IM or SC for 6-7 days, then give same amount alternating days for 7 days, then every 3-4 days for another 2-3 weeks, then 100 mcg monthly for life
• malabsorption: 1000 mcg IM daily for 10 days or daily for 3-7 days followed by weekly injections for 3-4 weeks
• pernicious anemia: 100 mcg IM or SC daily for 6-7 days, then give same amount alternating days for 7 days, then every 3-4 days for another 2-3 weeks, then 100 mcg monthly for life
• malabsorption: 1000 mcg IM daily for 10 days or daily for 3-7 days followed by weekly injections for 3-4 weeks

Our patient: 1000 mcg/1 mL daily x 7 days SC, then weekly x 4 weeks, then monthly

Counseled patient on:

• how to swab vial, pull back air into syringe, inject vial and draw out correct dose and get rid of air bubbles
• locations for injection: buttocks, arm, side of thigh, and abdomen
• after discussing options with patient, it was decided that the abdomen would be easiest to adminster
• explained rotation of sites and avoiding 2 in circumference around bellybutton 
• pinching skin and injecting at 45 degree angle
• avoiding surface veins
• pointing needle bevel in correct angle
• if fluid comes back out of injection site, needle was not into SQ tissue far enough 
• how to dispose of needle (Tide container and return to pharmacy)
• injection site reactions 
• printed off visual aid on how to do SQ inj.

precautions with inj: anaphylaxis, angioedema

monitoring parameters: hematocrit, reticulocyte count, vitamin b12, folate, iron

absorption: SQ - rapid vs. oral which is slow and variable

distribution: liver and bone marrow

metabolism: biliary, enterohepatic cycling

excretion: renal

vitamin b12 deficiency:

• macrocytic red blood cells
• hypersegmented neutrophils
• pancytopenia
• neurologic symptoms: dementia, weakness, parasthesias
• alcoholics and bariatric surgery at higher risk
• often coexists with folate deficiency
• non-toxic, excreted in urine if excess

levels > 300 pg/mL = normal

200-300 = borderline result

<200 = low/deficient

OTC question

• 20 year old female came in asking for "Mucinex" which was recommended to her by her PCP
• Patient initially provided no other information
• Asked patient about what kinds of symptoms she was having
• patient stated she is having sinus/nasal/head congestion which is causing pressure build up within her ears
• it was recommended to her by myself and Chayla that she goes with a decongestant product such as Mucinex D (guiafenesin and pseudoephedrine) as her symptoms were mostly sinus congestion vs chest congestion (which is a behind the counter product)
• patient is college student and noted that she needs to buy generic due to cost issues and asked why we did not suggest one of the products OTC and what the difference between them is
• we explained to her that the products with decongestant were the behind the counter products
• since she was still hesitant to go with the product we were suggesting, we asked more questions and she revealed more information
• we found out that she has an undiagnosed "thyroid issue" currently that her doctor is trying to figure out and did not want her to take anything with pseudoephedrine in it due to cardiovascular side effects
• we then suggested that she goes with mucinex DM (guiafenesin and dextromethorphan) although this may not be the most efficacious product based on her symptoms, it is the safest option

Pseudoephedrine: 

Mechanism of action -- decongestant by alpha-adrenergic stimulation of receptors in vascular smooth muscle causing constriction of dilated arterioles in nasal mucosa leading to reduction in blood flow to inflamed nasal passages

Adverse effects: 

cardiovascular --  pseudoephedrine has been reported to cause atrial fibrillation, hypertension, tachycardia, myocardial infarction

should be used in caution in the follow disease states: hyperthyroidism, arrhythmia, diabetes, elderly, glaucoma, ischemic heart disease, renal failure

hyperthyroidism can cause tachycardia

if this was the condition our patient is being worked up for, it would be best for her to avoid a product with pseudoephedrine in it as it can cause further tachycardia and hypertension

patients should be counseled that this drug can cause insomnia, anxiety, nervousness, restlessness

all of which can make hyperthyroid symptoms worse as well

Balanitis

Balanitis: inflammation of the glans penis

• more common in African Americas and Hispanics
• usually occurs in uncircumcised males
• symptoms usually occur over 3-7 days 
• presents as pain, tenderness, may have erythematous lesions, may have discharge, prutitis
• can progress to edema and scarring --> phimosis (tightening of the prepuce which constricts the opening of the foreskin)
• could result in systemic symptoms: joint pain, painful glands, sores on other parts of body, fatigue

Causes: 

• infections: candida, anaerobes, aerobes (strep), STD's (HPV, HSV, trich, syphillis, gonorrhea), mycobacterium, HIV
• skin disorders/pemphigoid (psoriasis, seborrheic dermatitis)
• cicinate balanitis (lichen sclerosis/balanitis xerotica obliterans
• Zoon's balanitis
• carcinoma in situ
• poor hygiene
• fixed drug eruptions
• reactive arthritis
• obesity
• trauma
• contact dermatitis/irritant/allergy

Treatment:

candida infection: 

• more common in men with diabetes mellitus --> poorly controlled blood glucose leads to proliferation of candida 
• if not diagnosed with DM and presenting with balanitis --> work up for DM (may be undiagnosed)
• if no DM --> look for other reasons to be immunocompromised (HIV, etc.)
• usually candida albicans
• presents as painful and pruritic rash with burning
• diagnose with a culture
• treat topically for 1-3 weeks
• clotrimazole
• miconazole
• nystatin (only if suspect resistance to azoles)
• oral fluconazole 150 mg x 1 dose

bacterial infections: 

• more commonly caused by anaerobes but could be caused by aerobes as well
• will present with foul-smelling discharge
• diagnose with culture
• oral antibiotics:
• metronidazole 500 mg BID x 7 days
• augmentin 375 mg TID x 7 days
• topical clindamycin BID until symptoms resolve
• if strep - treat based on susceptibility

poor hygiene:

• bathing twice daily with saline solution

dermatitis/allergy & fixed drug eruptions:

• may be caused by detergents, soaps, condoms, etc
• presents as erythema/edema , fixed drug eruptions present with lesions/plaques at time of administration of offending drug
• need to avoid agents/drugs 
• fixed drug eruptions most common with tetracyclines, salicylates, hypnotics
• treat with topical 1%  hydrocortisone cream twice daily

reactive arthritis: 

• multisystem disorder -- can affect genitourinary tract, joints, and eyes
• caused by infections organisms (chlamydia, shigella, neisseria, salmonella, HIV)
• presents with prostatitis, discharge, painful urinating
• self-limited and can last months long

circinate balanitis

• 20-40% of men with reactive arthritis can develop this, but can occur without it
• presents as greyish/white ulcer lesions
• can be mistaken for psoriasis
• treat with 1% hydrocortisone cream
• self-limited and can last months long

complications -->

phimosis (abnormal constriction of opening in foreskin), generally not an emergency

can progress to paraphimosis (trapping of foreskin behind glans penis), urologic emergency

References:

Barrisford G. Balanitis and balnoposthitis in adults. UpToDate. O'Leary M (Ed). Accessed on 11 November 2016.

Magnesium Supplementation & Diarrhea

Question: What is the maximum amount of magnesium supplementation one can take before causing diarrhea?

Background Information:

Hypomagnesemia in alcoholism --

• multifactorial -- reduced intake, pancreatic insufficiency, chronic vomiting and diarrhea, urinary wasting
• hospitalized --> often receive IV dextrose --> greater reductions in magnesium concentration

Symptomatic hypomagnesemia -- use IV

Asymptomatic hypomagnesemia -- use oral 

Typical oral repletion dose in patient with normal renal function = 240-1000 mg (20-80 mEq) of elemental magnesium in divided doses

Serum levels rise quickly, intracellular stores take longer to replete --> continue repletion for at least 1-2 days after serum levels normalize

Supplementation: 

Recommended Daily Intake --

320 mg/day = women

420 mg/day = men

Sustained-release formulations minimize renal excretion and therefore allow for the use of lower doses --> minimizes diarrhea

• magnesium chloride
• magnesium L-lactate

Immediate-release 

• magnesium oxide
• magnesium hydroxide (milk of magnesia)

chloride: 143 mg tablet

oxide: 242 mg in 400 mg tablet

hydroxide: 167 mg in 400 mg tablet or 5 mL oral suspension

citrate: 48 mg in 290 mg/5 mL oral solution

gluconate: 27 mg in 500 mg tablet

lactate: 84 mg tablet

*Bold = most likely to cause diarrhea (faster-acting)

• absorption decreases as dietary intake increases
• elderly and CKD reduce absorption
• accumulates with renal insufficiency
• choice of therapy should be determined by severity of symptoms (if present), degree of hypomagnesemia, and renal function

Clinical Answer:

Although there are no specific dosage maximum recommendations relating to a threshold for causing diarrhea, it is well-documented in the literature that sustained-release formulations reduce the risk of causing diarrhea in comparison to an immediate-release formulation. Recommend products like magnesium gluconate, chloride, or lactate vs. citrate, oxide, or hydroxide. Due to cost, it is plausible to try supplementation with magensium oxide first. If not tolerated due to diarrhea, then switch to a more sustained-release formulated product.

References: 

DiPiro J. Pharmacotherapy: A Pathophysiologic Approach, 6th Edition. Chapter 36. 

Yu A. Evaluation and treatment of hypomagnesemia. UpToDate. Goldfarb S (Ed). Accessed on: 10 November 2016.

Topical Fluorouracil

Patient counseling on topical fluorouracil (5-FU) for cancerous lesions:


FDA approved for: actinic keratosis, superficial basal cell carcinoma

Mechanism of Action:
anti-metabolite & anti-neoplastic agent
Topically, as fluorouracil is metabolized it blocks a methylation reaction of deoxyuridylic acid to thymidylic acid, leading to an interference in the synthesis of DNA and RNA due to a deficiency in thymine. Ultimately this leads to cell death. This mechanism occurs more potently on rapidly dividing cells (cancerous cells) due to more rapid uptake of drug.
Dosing/administration:

• actinic keratosis: apply to lesions with either 0.5-5% cream BID for 2-6 weeks
• 0.5% microsphere formulation once daily for 4 weeks
• superficial basal cell carcinoma: apply to lesions with 5% cream BID for 3-12 weeks

*can be used off-label for other cancers

Common adverse effects: alopecia, photosensitvity, hand-foot syndrome, maculopapular inflammation, temporary reversible onycholysis and onychodystrophy, telangiectasia, scarring

Pregnancy category: X

Even though topical - can still cause drug interactions:
phenytoin/fosphyentoin - 5FU may increase phenytoin levels
gemcitabine - may increase 5FU levels
leucovorin - may increase toxicity associated with 5FU
vitamin K antagonists - 5Fu may increase serum concentrations of warfarin

ADME: Cmax ~ 1 hour after application of cream

Cost:

• Cream: $180.00-2997.18, varies based on brand and strength of product
• Solution: $75-111.33 

Counseling Pearls:

• Use non-metal applicator or gloves to apply. If used hands, wash hands immediately after application
• Try to shower/bath before application. If apply before, let areas dry, wait awhile before showering/bathing
• May cause sun sensitivity -- make sure to cover up, use sunscreen, avoid tanning beds
• Avoid application to mucous membranes (eyes, nose, mouth) or irritated skin
• May cause inflammation or allergic contact dermatitis
• chemotherapeutic drug -- cannot be disposed of in regular trash (ex: take back to pharmacy for disposal)
• Should be handled by pregnant or women of child-bearing age
• can cause birth defects
• do not use with occlusive dressings

Basal cell carcinoma background information:

• skin cancer that arises from the basal cell layer of the epidermis
• choice of treatment depends on size, location, and pathology of lesions
• Alternative therapies: surgical excision, Mohs surgery, electrodesiccation and curettage, cryosurgery, imiquimod. photodynamic therapy, radiation therapy, intralesional interferon, intralesional 5-FU, intralesional bleomycin
• treatment with 5FU --
• should be restricted to superficial lesions in non-critical areas
• low cure rates with non-superficial or high-risk lesions
• contraindicated for nodular lesions
• has long-term favorable cosmetic results compared to other therapy options
• although scarring may occur
• second-line therapy after electrodesiccation and curettage (first-line therapy) for superficial lesions
• Prognosis is usually excellent due to lesions being relatively slow growing tumors
• metastasis is rare, mortality is low, but morbidity is high
• if metastasis occurs --> poor prognosis
• can cause severe disfigurement, can destroy bone and cartilage, may cause ulcers leading to wound care
• 15% of patients will develop a new subsequent skin cancer within 1 year

References:

Product Information: fluorouracil IV injection solution, fluorouracil IV injection solution. Sandoz Inc (per DailyMed), Princeton, NJ, 2011.

Chartier T. Treatment and prognosis of basal cell carcinoma at low risk of recurrence. UpToDate. Stern R (Ed). Accessed on: 11/9/16

Management of rosacea

Pharmacist counseled patient on topical metronidazole for rosacea and I was unaware of this indication for this drug, so I researched more about it -->

Rosacea:

• Chronic and relapsing inflammatory skin disorder
• Clinical features: 4 subtypes
• Erthematotelangiectatic: transient erythema, inflammatory skin lesions, telangiectasias (tiny blood vessel pattern on skin), dry/scaly
• Papulopustular: inflammatory papules and pustules, persistent erythema
• Phymatous: skin hypertrophy resulting in disfigurement
• Ocular: conjunctivities, blepharitis, chalazion, stye formation
• features of multiple types may occur spontaneously
• Management:
• Avoidance of flushing triggers (alcohol, sunlight, stressors, extreme temperatures)
• frequent moisturizing
• gentle cleansing
• avoid irritating topical products (toners, exfoliation
• Pharmacological management:
• Erthematotelangiectatic: topical brimonidine gel
• vasoconstrictive alpha 2 adrenergic receptor agonist
• Papulopustular
• Mild-moderate: 
• topical metronidazole - mechanism unknown, improvement may occur after 2-4 weeks of therapy, full results at 8-9 weeks, relapse may occur after discontinuation --> may need long-term therapy
• topical azelaic acid - dicarboxylic acid with anti-inflammatory properties, available as cream, foam or gel, improvement may be seen within 2 weeks but full results at 12-15 weeks, may cause skin irritation (avoid in sensitive skin)
• topical ivermectin 1% cream - anti-inflammatory and anti-parasitic, well-tolerated, may use for up to 1 year
• other therapies (not first-line): topical permethrin, topical retinoids, topical clindamycin, benzoyl peroxide, sulfacetamide-sulfur
• Moderate-severe:
• oral tetracyclines (tetracycline, doxycycline, minocycline): due to anti-inflammatory properties (not anti-microbial)
• doxy or mino 50-100 mg BID or tetracycline 200-250 mg BID for 4-12 weeks
• do not give to children < 9 yeras old (reduced bone growth, tooth discoloration)
• may have occasional break-through flares that can be treated with short-courses of therapy.
• may combine with topical metronidazole
• alternatives: macrolide antibiotics (clarithromycin, azithromycin, erythromycin), oral metronidazole
• Refractory: 
• oral isotretinoin -- teratogenic, need to be prescribed through iPLEDGE program, 0.5-1 mg/kg/day for 5-6 months
• laser/light therapy
• Ocular: 
• topical and oral antibiotics (metronidazole, tetracyline, erythromycin)
• topical cyclosporine
• Phymatous:
• isotretinion 0.3-1 mg/kg/day for 12-28 weeks
• laser ablation, surgical interventions
• Pediatric - treat similar to adults but avoid tetracyclines

References: Maier L. Management of rosacea. UpToDate. Dahl M (Ed). Last updated: 14 June 2016. Accessed on: 8 November 2016.

Vivotif

Typhoid Vaccine (Salmonella typhi)

Background information:

• most prevalent in impoverished areas with poor sanitation (usually Africa & Asia)
• humans are only reservoir
• more common in children and young adults
• 200-300 cases in US per year (80% due to travel)
• onset within 5-21 days of ingestion
• clinical presentation:
• week 1: fever, bacteremia
• week 2: abdominal pain, rose spots on trunk and abdomen
• week 3:hepatosplenomegaly, intestinal bleeding, perforation, peritonitis
• may cause septic shock
• gradually resolves over weeks-months
• lab findings: anemia, leukopenia (more common in adults), leukocytosis (more common in children, if seen in adults --> sign of intestinal perforation), abnormal LFT's

Vivotif - live enteric coated capsule vaccine

Mechanism of action: S. typhi penetrate intestinal mucosa and enter systemic circulation through the lymphatic system. Live vaccine causes cell autolysis before strain becomes virulent due to lack of enzyme, UDP-4 galactose epimerase

Administration:

Primary immunization: 1 capsule on days 1,3,5,7 (total of 4 doses)

*must complete at least 1 week prior to potential exposure

Re-immunization: repeat full course every 5 years

Approved for > 6 years and older

(Oral)

Swallow capsule whole after placing into mouth, do not chew or open

Take with cold/lukewarm beverage

Take 1 hour prior to meal

Avoid alcohol 1 hour before or 2 hours after adminstration (alcohol may disrupt enteric coating)

Not for routine vaccination

Limit to: travelers to areas with recognized risk, person with intimate exposure to household contact with S. typhi fever or known carrier, lab technicians with frequent exposure to S. typhi

*carrier = excretion of organism in stool or urine > 12 months after acute infection

Adverse effects: headache, skin rash, abdominal pain, nausea, fever, diarrhea

Contraindications: hypersensitivity to any ingredient in vaccine, congenital or acquired immunodeficiency (live vaccine), acute febrile illness

Should not be used to TREAT typhoid fever or chronic typhoid carriers

Not all will be completely protected by vaccine -- travelers should still take precautions to avoid contact or ingestion of potentially contaminated food or water

Drug interactions:

• effect may be reduced by some antibiotics (postpone vaccine until 3 days after cessation of antibiotic)
• immunosuppressants (methotrexate, mercaptopurine, leflunomide, etc.) 
• TB skin test -- live vaccine may diminish effect of skin test, postpone skin test 4-6 weeks apart from administration of live vaccine

Pregnancy: C, delay until 2nd or 3rd trimester if possible

Cost: $106.02

References:

Vivotif (typhoid vaccine) [prescribing information]. Redwood City, CA: PaxVax Inc.; September 2016

http://www.cdc.gov/vaccines/hcp/vis/vis-statements/typhoid.html. Last reviewed: 18 October 2016.