UMEM Educational Pearls - Pharmacology & Therapeutics

A recent, randomized study evaluated two approaches for treating acute pain in an inner-city ED.

  • Group 1 received hydromorphone 2 mg. Group 2 received hydromorphone 1 mg (with the option of a second 1 mg dose 15 minutes later).
  • 1 hour after the dose, patients were asked if they wanted more pain medication.
  • Both groups had an equal proportion of patients decline more pain medication at one hour (67%). 61% of patients in the 1 + 1 group only needed the initial dose of hydromorphone!
  • Secondary outcomes and safety measures were also similar between the groups.
  • Patients with chronic pain, age >64, weight <150 pounds, or opioid use within last 7 days were excluded. 

Application to clinical practice: For most patients with acute, severe pain in the ED, start with hydromorphone 1 mg. It may be all the patient needs and can potentially avoid giving them extra opioid they don't need.

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  • Hold metformin if the patient is at risk for dehydration (eg. vomiting, diarrhea) due to the risk of lactic acidosis
  • Medications that stimulate insulin secretion (eg. sulfonylureas, repaglinide, or nateglinide) should be held if the patient is at risk for hypoglycemia
  • Patients usually should continue their basal insulin, but may decrease or hold their bolus dosing.
  • Finger sticks should be checked every 2-4 hours for those on insulin, or 2-4 times per day for type II diabetics not on insulin.

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Category: Pharmacology & Therapeutics

Title: Add Strep Coverage to Outpatient Cellulitis Treatment Regimens

Keywords: cellulitis, cephalexin, sulfamethoxazole/trimethoprim, Bactrim, streptococcus (PubMed Search)

Posted: 5/20/2013 by Bryan Hayes, PharmD (Emailed: 6/1/2013) (Updated: 5/31/2013)
Click here to contact Bryan Hayes, PharmD

Background

In the current era of community-acquired MRSA (CA-MRSA), most of our outpatient treatment options for cellulitis aim to cover MRSA. Choices include sulfamethoxazole/trimethoprim (SMZ-TMP), doxycycline, linezolid, and clindamycin (depending on local susceptibility patterns).

A New Study

  • In a double-blind, placebo-controlled trial 146 patients with cellulitis were randomized to receive cephalexin alone or cephalexin + SMZ-TMP for 7-14 days
  • Lots of exclusion criteria basically narrowed the patient population to uncomplicated cellultits with no history of diabetes or other immunocompromising conditions
  • Cure rates up to 30 days post-treatment were the same between the two groups (>80%)

Take Home Clinical Points

  • Even in communities with high prevalence of MRSA, uncomplicated cellulitis cases without pus generally seem to be strep species.
  • Therefore, make sure to include an anti-streptococcal component (such as cephalexin) to the MRSA agent (doxycycline or SMZ-TMP). Clindamycin has sufficient strep coverage by itself (but may not adequately cover MRSA).
  • Given the potential for MRSA infections to deteriorate quickly and the inability to differentiate staph from strep without cultures, MRSA coverage should still be considered.

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Category: Pharmacology & Therapeutics

Title: Hyperphosphatemia from Fosphenytoin?

Keywords: phosphate, fosphenytoin, phenytoin, hyperphosphatemia (PubMed Search)

Posted: 4/29/2013 by Bryan Hayes, PharmD (Emailed: 5/4/2013) (Updated: 5/2/2013)
Click here to contact Bryan Hayes, PharmD

Introduction

Fosphenytoin is a prodrug and is metabolized quickly to phenytoin after administration. The conversion of fosphenytoin to phenytoin involves the release of phosphate. In fact, each mmol of fosphenytoin releases 1 mmol of phosphate.

Clinical Question

Are patients at risk for hyperphosphatemia after fosphenytoin loading?

Data

There are only two cases of reported hyperphosphatemia.

  • A 17-year old African-American male with end-stage renal disease developed acute hyperphosphatemia to 3.9 mmol/L (12.1 mg/dL) following the IV administration of 1000 mg of fosphenytoin for an idiopathic complex partial seizure
  • An infant in status epilepticus had marked hyperphosphatemia 8.4 mmol/L (25.9 mg/dL) after a 5-10 fold dosing error.

Bottom Line

Despite the phosphate load from fosphenytoin administration, hyperphosphatemia is very rare and probably associated with renal insufficiency and dosing errors.

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Category: Pharmacology & Therapeutics

Title: Prothrombin Complex Concentrate Approved by FDA

Keywords: Prothrombin Complex Concentrate, warfarin, coumadin, vitamin K antagonist, anticoagulant, PCC (PubMed Search)

Posted: 5/2/2013 by Ellen Lemkin, MD, PharmD
Click here to contact Ellen Lemkin, MD, PharmD

 

  • Prothrombin Complex Concentrate (PCC) Kcentra™ has been approved for urgent reversal of major bleeding in patients taking vitamin K antagonists (e.g. warfarin).
  • It contains factors 2,7,9 and 10, and antithrombotic Proteins C and S.
  • Both fatal and non-fatal arterial and venous thromboembolic complications have occurred with Kcentra™. Thrombotic events occurred more frequently in the PCC group compared to plasma, although the differences were not statistically significant.
  • Volume overload occurred less frequently in the PCC group, as there is a smaller volume  administered with PCC compared to that of plasma.
  • Percentage of INR ≤ 1.3 at 30 minutes was 62% in the PCC group and 9.6% in the plasma group.

Approval of Kcentra™ may open the door for studying treatment of the bleeding patient on newer oral anticoagulants.


Category: Pharmacology & Therapeutics

Title: tPA Use in Patients on New Oral Anticoagulants: Recommendations from the 2013 Ischemic Stroke Guidelines

Keywords: alteplase, tPA, dabigatran, anticoagulant, apixaban, rivaroxaban (PubMed Search)

Posted: 4/3/2013 by Bryan Hayes, PharmD (Emailed: 4/6/2013) (Updated: 4/5/2013)
Click here to contact Bryan Hayes, PharmD

A new recommendation in the 2013 Ischemic Stroke Guidelines provides guidance on what to do in patients taking new oral anticoagulants who are deemed eligible for IV fibrinolysis. Here is what the guidelines say:

"The use of IV rtPA in patients taking direct thrombin inhibitors (dabigatran) or direct factor Xa inhibitors (rivaroxaban, apixaban) may be harmful and is not recommended unless sensitive laboratory tests such as aPTT, INR, platelet count, and ECT, TT, or appropriate direct factor Xa activity assays are normal, or the patient has not received a dose of these agents for >2 days (assuming normal renal metabolizing function)." (Class III; Level of Evidence C)
 
Additional points:
  • The most helpful lab tests are not widely available.
  • A detailed history is important, but not always obtainable.

Until further data are available, a history consistent with recent use of new oral anticoagulants generally precludes use of IV tPA.

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Category: Pharmacology & Therapeutics

Title: Levetiracetam (Keppra) for Status Epileptics

Keywords: Status epilepticus, Keppra, seizures, valproic acid, levetiracetam (PubMed Search)

Posted: 4/4/2013 by Ellen Lemkin, MD, PharmD (Updated: 8/17/2022)
Click here to contact Ellen Lemkin, MD, PharmD

 

  • Although Keppra has been used more frequently in clinical practice, there is little evidence for its use in status epilepticus.
  • It has a wide spectrum of action and few drug interactions.
  • Initially, case series appeared to be highly successful in terminating seizures as an add-on agent.
  • A review of 2 prospective studies found efficacies of 44% as an add- on agent, and 75% as a primary agent. The studies had markedly different populations.
  • In a retrospective study, the treatment failure rates were 3X higher than that of intravenous valproic acid as an add-on agent in terminating status epilepticus.
  • Therefore, although it is used frequently, the evidence for use is limited and inconclusive in terminating status epilepticus.

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Category: Pharmacology & Therapeutics

Title: Statins in Acute Coronary Syndrome

Keywords: Statins, Acute Coronary Syndrome, Myocardial Infarction (PubMed Search)

Posted: 3/7/2013 by Ellen Lemkin, MD, PharmD
Click here to contact Ellen Lemkin, MD, PharmD

 

  • A recent Cochrane review examined the use of early statin therapy in patients with ACS.
  • They evaluated 18 studies (14,303 patients), which compared early statin therapy (within 14 days) to placebo or usual care.
  • The conclusion was that initiation of early statin therapy does not reduce death, myocardial infarction of stroke up to four months, but reduces the occurrence of unstable angina by 24% at 4 months following ACS.
  • Many smaller studies previously noted benefits with early statin initiation prior to this meta-analysis.

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Category: Pharmacology & Therapeutics

Title: Blood Pressure Management Updates from the 2013 Acute Ischemic Stroke Guideline

Keywords: ischemic stroke, hypertension, blood pressure (PubMed Search)

Posted: 2/25/2013 by Bryan Hayes, PharmD (Emailed: 3/2/2013) (Updated: 3/2/2013)
Click here to contact Bryan Hayes, PharmD

The newest iteration of 'Guidelines for the Early Management of Patients with Acute Ischemic Stroke' was recently published. Here are the key revisions specific to blood pressure management:

  • In patients with markedly elevated blood pressure who do not receive fibrinolysis, a reasonable goal is to lower blood pressure by 15% during the first 24 hours after onset of stroke. The level of blood pressure that would mandate such treatment is not known, but consensus exists that medications should be withheld unless the systolic blood pressure is >220 mmHg or the diastolic blood pressure is >120 mmHg (Class I; Level of Evidence C).
  • No data are available to guide selection of medications for the lowering of blood pressure in the setting of acute ischemic stroke. Labetalol and/or nicardipine are listed as preferred, but other options can be used (Class IIa; Level of Evidence C).
  • Restarting antihypertensive medications is reasonable after the first 24 hours for patients who have preexisting hypertension and are neurologically stable (Class IIa; Level of Evidence B).

If administering rtPA, blood pressure needs to be <185/110 mm Hg. That recommendation didn't change.

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Category: Pharmacology & Therapeutics

Title: Lidocaine after IO Line Placement

Keywords: lidocaine, intraosseus, IO (PubMed Search)

Posted: 1/2/2013 by Bryan Hayes, PharmD (Emailed: 2/2/2013) (Updated: 2/2/2013)
Click here to contact Bryan Hayes, PharmD

Intraosseus (IO) access has become quite popular in critically ill patients requiring immediate resuscitation. In a patient responsive to pain, however, pain and discomfort is associated with the force of high-volume infusion through the established line.

  • Before flushing the line, consider administering preservative-free 2% lidocaine (without epinephrine) for patients responsive to pain prior to flush.

  • The suggested dose is 20-40 mg (1-2 mL) of the 2% lidocaine, followed by the 10 mL saline flush.

If preservative-free 2% lidocaine is not stocked in your ED, now is the time to consider adding it.

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Category: Pharmacology & Therapeutics

Title: Tdap Recommended for all Patients 65 Years and Older

Keywords: Tdap, tetanus, immunization, vaccine, pertussis (PubMed Search)

Posted: 1/3/2013 by Bryan Hayes, PharmD (Emailed: 1/5/2013) (Updated: 1/5/2013)
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The two available Tetanus/reduced diphtheria toxoid/acellular pertussis (Tdap) vaccine products in the U.S. are Boostrix and Adacel. Neither were originally approved in older adults age 65 and older. Boostrix received FDA-approval for use in this age group in July 2011, but Adacel never has.

However, in June 2012 ACIP issued new guidance recommending Tdap for all adults age 65 years and older. 

"When feasible, Boostrix should be used for adults aged 65 years and older; however, ACIP concluded that either vaccine administered to a person 65 years or older is immunogenic and would provide protection. A dose of either vaccine may be considered valid."

Bottom line: Regardless of which Tdap product is stocked at your institution, both are considered safe to use in adults 65 years and older.

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Category: Pharmacology & Therapeutics

Title: Treating PID in a Doxycycline-Allergic Patient

Keywords: doxycycline, PID, pelvic inflammatory disease, STD, azithromycin (PubMed Search)

Posted: 11/28/2012 by Bryan Hayes, PharmD (Emailed: 12/1/2012) (Updated: 12/1/2012)
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In the rare circumstance you need to treat a patient with suspected PID and an allergy to doxycycline, what is the alternative?

For oral regimens, azithromycin is an option in place of doxycycline.

  • In one randomized trial, azithromycin demonstrated short-term effectiveness when given 500 mg X 1, followed by 250 mg/day for 6 days.
  • In another randomized study, the combination of ceftriaxone 250 mg IM single dose and azithromycin 1 g orally once a week for 2 weeks was effective.

Suggested regimen for PID with doxycycline allergy:

  • Ceftriaxone 250 mg IM X 1
  • Azithromcyin 500 mg IV/PO X 1, then 250 mg PO daily for 6 days
  • plus/minus Metronidazole 500 mg PO twice daily for 14 days

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Category: Pharmacology & Therapeutics

Title: Tolerability of penicillins in cephalosporin-allergic patients

Keywords: penicillin, cross-reactivity, cephalosporin, IgE, allergy (PubMed Search)

Posted: 10/29/2012 by Bryan Hayes, PharmD (Emailed: 11/3/2012) (Updated: 11/3/2012)
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It seems we've finally put to bed the myth that 10% of penicillin-allergic patients will also react to cephalosporins. Dr. Campagna, et al. recently published a review article concluding that the true cross-reactivity is negligible except when side-chains are similar [PMID 21742459]. 

This topic was also the subject of a recent post on the Academic Life in EM blog (http://academiclifeinem.blogspot.com/2012/08/busting-myth-10-cephalosporin.html).

But what about the reverse question? Can I give a penicillin to a cephalosporin-allergic patient?

Dr. Romano's group tested 98 patients with skin-test postitive cepahlosprin allergy (mostly IgE -mediated anaphylaxis). Patients were then skin tested for penicillin allergy. Those testing negative were challenged with a penicillin.

  • 25% of patients reacted to the penicillin

  • Similar side-chain was a strong predictor of cross-reactivity

​A Letter to the Editor response to this study pointed out that the authors used a smaller-than-standard size threshold for a positive response to the penicllin AND used a higher-than-standard dose of amoxicillin for testing. In light of this, the rate of subjects with cephalosporin allergy who do not have a history of penicillin allergy but with true IgE-mediated allergy to penicillin might be much closer to 5%.

Bottom line: The cross-reactivity of penicillins in cephalosporin-allergic patients is somewhere between 5-25%.

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A slight correction: The correct AUTHOR in the referenced article is:

Wilkerson, R. Gentry, MD. Angioedema in tthe Emergency Department: An Evidence-Based Review. Emergency Medicine Practice, Nov 2012;14(11).

 


 

  • 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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Category: Pharmacology & Therapeutics

Title: Cross-reactivity Between Sulfonamide Antimicrobials and Non-Antimicrobials

Keywords: sulfa, allergy, cross-reactivity, antimicrobial, sulfonamide (PubMed Search)

Posted: 9/24/2012 by Bryan Hayes, PharmD (Emailed: 10/6/2012) (Updated: 10/6/2012)
Click here to contact Bryan Hayes, PharmD

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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Category: Pharmacology & Therapeutics

Title: Carbapenem Cross-Reactivity in Penicillin-Allergic Patients

Keywords: carbapenem, penicillin, allergy, skin test, cross-reactivity (PubMed Search)

Posted: 8/26/2012 by Bryan Hayes, PharmD (Emailed: 9/1/2012) (Updated: 9/4/2013)
Click here to contact Bryan Hayes, PharmD

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.

 
Key point: Remember that only 10% of patients reporting penicillin allergy actually have a true IgE allergy. It's like a built-in, 10-fold safety factor.
 
Bottom line: In a patient reporting a penicillin allergy, the incidence of cross-reactivity to a carbapenem is probably around 0.01%. With cross-reactivity this low, it is likely that if a patient does have a reaction to the carbapenem, they are independently allergic to that drug too.

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Category: Pharmacology & Therapeutics

Title: Vasopressors in Cardiac Arrest: Where Do We Stand in 2012?

Keywords: vasopressor, cardiac arrest, epinephrine, vasopression (PubMed Search)

Posted: 7/30/2012 by Bryan Hayes, PharmD (Emailed: 8/4/2012) (Updated: 8/4/2012)
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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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Category: Pharmacology & Therapeutics

Title: Drugs for UTIs

Keywords: Uti,bactrim,smx/tmp,ciprofloxacin,levofloxacin (PubMed Search)

Posted: 8/2/2012 by Ellen Lemkin, MD, PharmD
Click here to contact Ellen Lemkin, MD, PharmD

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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Category: Pharmacology & Therapeutics

Title: tPA for Acute Ischemic Stroke Patients on Warfarin

Keywords: alteplase, tPA, warfarin, INR, ischemic stroke (PubMed Search)

Posted: 7/2/2012 by Bryan Hayes, PharmD (Emailed: 7/7/2012) (Updated: 7/7/2012)
Click here to contact Bryan Hayes, PharmD

  • 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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