UMEM Educational Pearls - Pharmacology & Therapeutics

• Angioedema is induced by elevated levels of bradykinin.

• Bradykinin is noramlly degraded by angiotensin-1 converting enzyme and several other enzymes (including aminipeptidase–P)

• A deficiency in aminopeptidase-P likely leads to ACE induced angioedema.

• Treatment typically starts with discontinuing ACE inhibitors, administering H1 and H2 antagonists, and corticosteroids (all Class indeterminate). 

• Another consideration may be FFP 10-15 ml/kg IV or the off label use of icatibant (both Class II recommendations).

• Icatibant inhibits the bradykin B2 receptor. It is a sythetic decapeptide structurally similar to bradykin.

• Icatibant has been effective in case reports and case series in ACE induced angioedema. There is a prospective, double blind randomized placebo controlled trial underway.

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Patients frequently report having a sulfa allergy. In most cases, the allergic reaction was secondary to a sulfonamide antimicrobial agent, such as sulfamethoxazole-trimethoprim.

The question is: Can I use furosemide (or other non-antimicrobial agents containing a sulfa component)?

• There is minimal evidence of cross-reactivity between sulfonamide antimicrobials and non-antimicrobials.

• Despite this, the U.S. FDA-approved product information for many non-antimicrobial sulfonamide drugs contains warnings concerning possible cross-reactions.

Bottom line: If a patient had a true IgE-mediated anaphylatic reaction to a sulfonamide antimicrobial, it may be best to avoid other sulfa-related medications (use ethacrynic acid if a loop diuretic is needed). Otherwise, the available literature does not support cross-reactivity between sulfonamide antimicrobials and non-antimicrobials.

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Carbapenems (meropenem, ertapenem, doripenem, imipenem/cilastatin) are broad-spectrum antibiotics that have good gram-negative and anaerobic coverage and are used to treat resistant bacterial infections.

• Early retrospective studies showed ~10% cross-reactivity in penicillin-allergic patients.

• More recent prospective studies verified penicillin allergy by the accepted standard (ie, skin test to the major and minor penicillin determinants) and tested for carbapenem allergy by administering a full therapeutic dose to carbapenem skin test-negative patients.

• The cross-reactivity between skin tests appears to be around 1%, with all carbapenem skin test-negative patients tolerating the challenge.

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A recent paper reviewed 53 articles to assess the utility of vasopressors in cardiac arrest. The authors aimed to determine if vasopressors improved ouctomes in this patient population. Here are their conclusions:

1. Epinephrine is associated with improvement in short term survival outcomes as compared to placebo, but no long-term survival benefit has been demonstrated.
2. Vasopressin is equivalent for use as an initial vasopressor when compared to epinephrine during resuscitation from cardiac arrest.
3. There is a short-term, but no long-term, survival benefit when using high dose vs. standard dose epinephrine during resuscitation from cardiac arrest.
4. There are no alternative vasopressors that provide a long-term survival benefit when compared to epinephrine.

Although these conclusions don't support the use of vasopressors in cardiac arrest, we should not abandon these therapies. Most of the trials were completed before wide-spread recognition of the post-cardiac arrest syndrome, implementation of therapeutic hypothermia protocols, and early cardiac catheterization.

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Acute, uncomplicated cystitis (in the non-pregnant female):

·      The drug of choice is SMX/TMP (provided the resistance rate is <20%) X 3 days.

·      An alternative is nitrofurantoin X 5 days.

Acute, uncomplicated pyleonephritis (in the non-pregnanct female) may be treated with:

·      Levofloxacin X 5 days, or ciprofloxacin X 7 days (provided resistance rate is <10%).

·      Alternatively, SMX/TMP may be used X 14 days.

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• IV alteplase (tPA) has many contraindications when administered for acute ischemic stroke. Among them is a history of warfarin use with INR > 1.7 (0-3 hours) or any history of warfarin use regardless of INR (3-4.5 hours).
• A recent retrospective analysis of a major stroke registry compared the risk of symptomatic intracerebral hemorrhage (ICH) following tPA in patients on warfarin with an INR < 1.7 (n - 1,802) with patients not on warfarin therapy (n = 21,635).
• After adjusting for differences in the two populations, the authors found no increased symptomatic ICH risk in patients with preadmission warfarin use (5.7% vs. 4.6%, p = 0.94).

Issue 1: Mean INR in study patients was only 1.22 (median 1.2). An INR of 1.2 represents very little actual anticoagulation.

Issue 2: In the small subgroup of patients with INR 1.5 to 1.7 (n = 269) there was a higher risk of ICH (7.8%), but did not reach statistical significance (it was significant in the unadjusted risk population).

Bottom line: Patients with INRs < 1.5 may be ok to receive tPA. Patients with INRs 1.5 or greater need further study.

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Naltrexone and methylnaltrexone are both mu-receptor antagonists that look similar and have similar names. But, they have very different uses.

• Naltrexone (ReVia, Vivitrol)
  • Used to treat opioid/alcohol dependence or to prevent relapse following opioid detoxifcation
  • Dose: 25 to 100 mg PO daily or 380 IM every 4 weeks
  • Crosses blood-brain-barrier and can precipitate withdrawal

• Methylnaltrexone (Relistor)
  • Used to treat opioid-induced constipation
  • Dose (weight-based): 8 to 12 mg (or 0.15 mg/kg) subcutaneously once daily
  • Peripherally acting, does not cross blood brain barrier

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The American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults is now available. 

The update differs in several ways from the 2003 edition. Medications that are no longer available have been removed, and drugs introduced since 2003 have been added. Research on drugs included in earlier versions has been updated and new information is provided about appropriate prescribing of medications for an expanded list of common geriatric conditions. 

Here is an abbreviated list of medications/classes on the list that we may use in the ED. Use caution.

• Anticholinergics
• Nitrofurantoin
• Clonidine
• Antidysrhythmics
• Digoxin
• Antipsychotics
• Benzodiazepines
• Insulin
• Metoclopromide
• NSAIDs

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If vancomycin resistance is suspected with MRSA infections, there are several other antibiotic choices. They are all extremely expensive.

Skin and soft tissue infection (SSTI); ventilator acquired pneumonia (VAP)

In a recent  multicenter, double-blind, randomized, non-inferiority trial, vancomycin was compared to fidaxomixin for Clostridium difficile infection.

• Location: 45 sites in Europe and 41 sites in the USA and Canada

• Patients: Age 16 years or older with acute toxin-positive C difficile infection.

• Treatment: Oral fidaxomicin (200 mg every 12 h) or oral vancomycin (125 mg every 6 h) for 10 days.

• Endpoint: Clinical cure, defined as resolution of diarrhea and no further need for treatment. 

• Results: 198 (91.7%) of 216 patients in the per-protocol population given fidaxomicin achieved clinical cure, compared with 213 (90.6%) of 235 given vancomycin (one-sided 97·5% CI -4·3%). Occurrence of treatment-emergent adverse events did not differ between groups. 

• Author conclusions: Fidaxomicin could be an alternative treatment for infection with C difficile, with similar efficacy and safety to vancomycin.

• Funding: Optimer Pharmaceuticals.

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The seasonal influenza vaccine is produced in chicken eggs. Ovalbumin, an egg protein, is often listed as a component of the purified vaccine on most drug-package inserts. The concentration of ovalbumin indicates the potential egg-allergen content of a vaccine.

Earlier ACIP guidelines recommended against giving the influenza vaccine to people with egg allergy, including those with a history of mild symptoms. However, several studies showed that influenza vaccine containing inactivated, or killed, virus is safe to give to people with egg allergy, especially those with a history of mild allergic reactions.

Influenza vaccines are now made with much lower ovalbumin concentrations than in the past; therefore, the level of potential egg protein allergens in a single dose of vaccine is extremely low.

The following are ACIP recommendations for the 2011 to 2012 influenza season:

• Inactivated influenza vaccine (seasonal flu shot) is safe to give to people whose history of allergic reactions to egg has been limited to hives.
• People with more severe allergic reactions to egg may receive the seasonal flu shot, but the vaccine must be given by a healthcare professional familiar with the signs and symptoms of an allergic reaction to egg and who has the ability to treat a severe reaction if one occurs.

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In the setting of critical drug shortages of ondansetron, prochlorperazine, and metoclopramide, consider droperidol as a viable option for the treatment of nausea and vomiting.

Although it is similar to haloperidol, it is actually FDA-approved for “prevention and/or treatment of nausea and vomiting from surgical and diagnostic procedures” (unlike haloperidol). Ironically, it is not approved for agitation, although it can be used for that indication.

Dosing for antiemesis is 1.25 to 2.5 mg IV/IM. Additional doses of 0.625 to 1.25 mg can be administered to achieve desired effect. Onset is 3-5 minutes and duration of effect is 2-4 hours. It should be administered via slow IV push over 2 minutes.

Why is it not commonly used? Black Box Warning for QTc prolongation. An ECG is a must prior to administration. Also be cautious in patients who are on other medications that can prolong the QT interval (www.qtdrugs.org).

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In 2011, updated treatment guidelines were published for acute uncomplicated cystitis and pyelonephritis in women. The recommendations differ from the previous iteration due to increased E. Coli resistance. The good news is we have been ahead of the curve in changing our prescribing habits.

Cystitis (recommendations in order of preference)

1. Nitrofurantoin 100 mg BID X 5 days
2. Bactrim DS 1 tab BID X 3 days (not recommended when resistance rate is > 20% - UMMC is 32%)
3. Fosfomycin (not currently available at UMMC)
4. Fluoroquinolones not recommended as first-line therapy due to “propensity for collateral damage”
5. Beta-lactam agents, including amoxicillin-clavulanate, cefdinir, cefaclor, and cefpodoxime-proxetil, in 3–7-day regimens are appropriate choices for therapy when other recommended agents cannot be used. Other beta-lactams, such as cephalexin, are less well studied but may also be appropriate in certain settings.

Take home points:

• Be familiar with your institution’s antibiogram
• Use nitrofurantoin first-line for uncomplicated cystitis in women (it is contraindicated with CrCl < 60 mL/min)
• Consider beta-lactams such as Augmentin or Vantin (cefpodoxime) in patient’s with kidney injury

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• Approved for CAP and Skin/Skin structure infections

• “Fifth generation” cephalosporin- implies activity against MRSA, although has broad spectrum

• Resistance is expected to be limited, with the exception of VRE, and VSE (vanco resistant or sensitive enterococcus faecalis)

• Renally excreted

• Common side effects: diarrhea, nausea, headache

• Serious side effects: anaphylaxis, renal failure, hepatitis, seizure

• Low incidence of C. difficile

• Dose : 600 mg IV (over 1 hour) q12 hours X 5-7 days

A recent article estimated 100,000 emergency hospitalizations for adverse drug events in U.S. adults 65 years of age or older each year. Nearly half of these hospitalizations were among adults ≥80 years old and two-thirds were due to unintentional overdoses.

Four medications or medication classes were implicated alone or in combination in 67% of hospitalizations:

• Warfarin (33.3%)
• Insulins (13.9%)
• Oral antiplatelet agents (13.3%)
• Oral hypoglycemic agents (10.7%)

Opioids were #5. Digoxin was #7 and resulted in the highest percentage of hospitalizations per ED visit at 80%.

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A recent randomized trial compared nicardipine as a continuous infusion to labetalol boluses to determine which one was more effective at lowering blood pressure to a target range within 30 minutes.

Median initial SBP for the 226 patients was 212 mm Hg. Within 30 minutes, nicardipine patients more often reached target range than labetalol (91.7 vs. 82.5%, P = 0.039). Of 6 BP measures (taken every 5 minutes) during the study period, nicardipine patients had higher rates of five and six instances within target range than labetalol (47.3% vs. 32.8%, P = 0.026).

What this means: Nicardipine is a reasonable choice for patients needing acute lowering of blood pressure (e.g., ischemic stroke with tPa).  Nicardipine seems to achieve faster and smoother lowering of blood pressure than labetalol therapy with less blood pressure readings outside the target range.

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There are an increasing number of intranasal medications commercially available for use, which is opportune as more and more intravenous medications become scarce.

These now include:

*******In addition, you can administer glucagon, midazolam and narcan intranasally as well.

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An acute increase in the INR over 3 in patients with chronic kidney disease (CKD) is often associated with an unexplained acute increase in serum creatinine and an accelerated progression of CKD.

Kidney biopsy in a subset of these patients showed obstruction of the renal tubule by red blood cell casts, and this appears to be the dominant mechanism of the acute kidney injury. This has been termed warfarin-related nephropathy (WRN).

In 15,258 patients who initiated warfarin therapy during a 5-year period, 4006 had an INR over 3 and creatinine measured at the same time. A presumptive diagnosis of WRN was made if the creatinine increased by over 0.3 mg/dl within 1 week after the INR exceeded 3 with no record of hemorrhage. WRN occurred in 20.5% of the entire cohort, 33.0% of the CKD cohort, and 16.5% of the no-CKD cohort. Other risk factors included age, diabetes mellitus, hypertension, and cardiovascular disease. The 1-year mortality was 31.1% in patients with WRN compared with 18.9% in those without WRN, an increased risk of 65%.

Take home message: Although the mechanisms are not clear, be very wary of even a small creatinine bump in patients presenting with an INR > 3 on warfarin therapy.  Yet another reason to fear warfarin...

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