UMEM Educational Pearls - Pharmacology & Therapeutics

Alteplase may be considered in some patients with a presumed or confirmed pulmonary embolism.  Below is a list of the different patient populations and the associated alteplase dosing.

-Hemodynamically Stable/Submassive: Alteplase usually not indicated.

-Hemodynamically Unstable/Massive: Alteplase IV 100 mg as an infusion over 2 hours.

-Cardiac Arrest: Alteplase IV/IO 50 mg bolus over 2 minutes.  Can repeat a second 50 mg bolus 15 minutes later if unable to achieve return of spontaneous circulation.

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Continuous home infusion therapies of medications such as insulin, milrinone, dobutamine, and pulmonary hypertension medication such as treprostinil are becoming more common.  As a result, you may see these patients present to the emergency room and need to know the basics for checking the pump.

• Is the pump working correctly?
  • Check the infusion lines for leaks or holes
  • Is the screen on, and does it show the correct dose information
• How long will the current battery last?
• How long will the current infusion bag last or expire?
  • Also consider the half-life of the medication. Infusions for pulmonary hypertension have a very short half-life and cannot be stopped abruptly.
• Is the medication carried by the hospital or will the patient need to provide their own medication for pump refills?
• What is the current dose?
  • Look for doses in weight based increments (i.e. mcg/kg/min, or ng/kg/min)
  • Insulin may have a basal rate and a bolus dose.
• What is the patient's "dosing weight"?
  • Ensure that the weight used to program the pump is the same weight used to enter a continuation order in the electronic medical record. This may be different from their current weight and can lead to dose changes if not done properly.
• What is the current bag concentration?

These questions are very important to determine if you will need to order a replacement infusion bag and run it on a hospital infusion pump, or if the patient can safely remain on their pump during the initial medical evaluation. 

Identifying serotonin syndrome in the emergency department can be difficult without an accurate patient history. Furthermore, the physical symptoms may look similar to many other disorders such as neuroleptic malignant syndrome and anticholinergic toxicity. If you remember the acronym SHIVERS, you can easily recognize the signs and symptoms of serotonin syndrome.

Shivering: Neuromuscular symptom that is unique to serotonin syndrome

Hyperreflexia and Myoclonus: Seen in mild to moderate cases. Most prominent in the lower extremities. This can help differentiate from neuroleptic malignant syndrome which would present with lead-pipe rigidity.

Increased Temperature: Not always present, but usually observed in more severe cases

Vital Sign Abnormalities: Tachycardia, tachypnea, and labile blood pressure

Encephalopathy: Mental status changes such as agitation, delirium, and confusion

Restlessness: Common due to excess serotonin activity

Sweating: Autonomic response to excess serotonin. This symptom can help differentiate from anticholinergic toxicity in which the patients would present with increased temperature but dry to the touch

Once serotonin syndrome is identified, it is important to discontinue all serotonergic agents, provide supportive care with fluids, and sedate with benzodiazepines. Sedation with benzodiazepines helps to decrease myoclonic jerks which also helps with temperature control. If patients are hyperthermic, they will require intensive cooling. Cyproheptadine, a potent antihistamine and serotonin antagonist, should also be administered. The initial dose of cyproheptadine in serotonin syndrome is 12mg which can be followed by 2 mg every 2 hours as needed for symptom control.

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---Early antiviral treatment can shorten the duration of fever and illness symptoms, and may reduce the risk of some complications from influenza.

---Early treatment of hospitalized adult influenza patients with oseltamivir has been reported to reduce death in some observational studies.

---Clinical benefit is greatest when antiviral treatment is administered within 48 hours of influenza illness onset.

Antiviral treatment is recommended for patients with confirmed or suspected influenza who:

---are hospitalized;

---have severe, complicated, or progressive illness; or

---are at higher risk for influenza complications. (See below for in-depth information)

Oral oseltamivir is the recommended antiviral for patients with severe, complicated, or progressive illness who are not hospitalized, and for hospitalized influenza patients.

Treatment:

Doses: Oseltamivir 75 mg twice daily

Renal Impairment Dosing

CrCl >60 mL/minute: No dosage adjustment necessary

CrCl >30 to 60 mL/minute: 30 mg twice daily

CrCl >10 to 30 mL/minute: 30 mg once daily

ESRD undergoing dialysis: 30 mg immediately and then 30 mg after every hemodialysis session

Duration of Treatment:

Recommended duration for antiviral treatment is 5 days for oral oseltamivir. Longer daily dosing can be considered for patients who remain severely ill after 5 days of treatment.

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Providing naloxone to patients at risk for opioid overdose is now standard of care. A retrospective study evaluated the rate of naloxone obtainment after standardizing the process for prescribing naloxone in the emergency department and dispensing from the hospital outpatient pharmacy. 

55 patients were prescribed naloxone.  Demographics: mean age 48 years old, 75% male, 40% primary diagnosis of heroin diagnosis, 45.5% were prescribed other prescriptions.

Outcomes:

• 25.5% brought the prescription to the pharmacy
• 18.2% completed education and obtained naloxone
• 10% higher rate of success if patient had multiple prescriptions to fill

Barriers identified included lack of ED dispensing program, cost of medication, even though cost is minimal and can be waived, and likely multifactorial reasons why patients did not present to pharmacy as instructed.

Take Home Points:

• In this complex and challenging patient population, naloxone should be provided
• Utilize UMMC ED Meds to Beds technicians 1130-1900 M-F to prevent patients from having to travel to pharmacy post-ED visit as this can be a barrier.  The pharmacy technician
• Prescribe AED To-Go naloxone after hours to improve access to naloxone

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The most common methods of medication administration in the emergency department are oral, intravenous (IV), and intramuscular (IM).  If the oral route is not available, if IV/IM are not necessary, or if obtaining IV access is challenging, intranasal (IN) medication delivery is a reasonable alternative.  More concentrated products are preferred and a volume of 1 mL or less per nostril should be utilized.  Below is a table of the commonly used medications used via the IN route. 

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Clonidine is an alpha-2 agonist commonly used to treat hypertension. Clonidine can also be used to mitigate symptoms of opioid withdrawal as it easily crosses the blood brain barrier and reduces sympathetic effects.

When using clonidine for acute withdrawal or blood pressure control, oral tablets are the preferred route.  Clonidine transdermal patches have slow absorption and take 2-3 days for the effect to be seen.  Once removed, clonidine patches can provide therapeutic levels for up to 20 hours.

Bottom Line: If clonidine is needed acutely for your patient, select oral tablets and titrate to effect.

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Steroids induce leukocytosis through the release of cells from bone marrow and the inhibition of neutrophil apoptosis.   This effect typically occurs within the first two weeks of steroid treatment. 

Leukocyte elevation is commonly used in the diagnosis of septic patients; however, this can be hard to discern in patients on concomitant steroid therapy.

A retrospective cohort study of adult patients presenting with fevers and a diagnosis of pneumonia, urinary tract infection, bacteremia, cellulitis, or COPD exacerbation was conducted to determine the maximal level of WBC within the first 24h of admission between patients on acute, chronic, or no steroid treatment.

Results: maximal WBC levels (p< 0.001)

·        Acute steroid therapy: 15.4 ± 8.3 x 10 ⁹/L

·        Chronic steroid therapy: 14.9 ± 7.4 x 10 ⁹/L

·        No steroid therapy: 12.9 ± 6.4 x 10 ⁹/L

An increase in WBC of 5 x 10 ⁹/L can be found in acute and chronic steroid use when presenting with an acute infection and fever.

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Fosfomycin is an antibiotic infrequently used for the treatment of urinary tract infections (UTIs). It has a broad spectrum of activity that covers both gram-positive (MRSA, VRE) and gram-negative bacteria (Pseudomonas, ESBL, and carbapenem-resistant Enterobacteriaceae), which is useful in the treatment of multidrug-resistant bacteria. 

Fosfomycin is FDA approved for the treatment of uncomplicated UTIs in women due to susceptible strains of Escherichia coli and Enterococcus faecalis (3g oral as a single dose). Data has also demonstrated that it can be used for complicated UTIs; however, dosing is different in this population (3 g oral every 2-3 days for 3 doses).  Fosfomycin is not recommended for pyelonephritis.

The broad spectrum of activity, in addition to only needing a single dose in most cases, makes fosfomycin an attractive option; however, it should be reserved for use in certain circumstances.  Fosfomycin should not be considered as a first-line option.  It is also more expensive than other medications (~$100/dose) and in countries with high rates of utilization bacteria are developing resistance to fosfomycin.  In addition, most outpatient pharmacies do not keep this medication in stock.

Take-Home Point:

Fosfomycin should be reserved for multidrug-resistant UTIs in which other first-line options have been exhausted.

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Patients with severe asthma exacerbations that are unresponsive to inhaled beta-agonists may require the use of epinephrine to control their symptoms.  When patients get to this point what route of administration should be used for the administration of epinephrine?

The most recent asthma guidelines (published in 2007) recommend the use of SubQ epinephrine 0.3-0.5 mg every 20 minutes for 3 doses.  Drug references typically list SubQ or IM epinephrine 0.01 mg/kg (~0.3-0.5 mg) every 20 minutes as appropriate routes of administration.  There is currently no data demonstrating that one route of administration is better than the other in patients with asthma; however, in other disease states, such as anaphylaxis, IM epinephrine is preferred due to the more rapid and reliable absorption over SubQ administration.

Auto-injectors that administer IM epinephrine 0.3 mg are available.  These auto-injectors may decrease the risk of medications error; however, they can be expensive.  SubQ administration requires the use of a syringe and a vial/ampule of 1 mg/mL epinephrine.

Bottom Line: Either SubQ or IM epinephrine administration is appropriate for patients with severe asthma exacerbations.  The preferred method at a given institution will be dictated by historical practice, risk of medication dosing errors, and drug cost.

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Insulin mechanism of action for hyperkalemia:

· Binds to skeletal muscle receptors

· Increased activity of the sodium-potassium adenosine triphosphatase and glucose transporter GLUT4

· Glycemic response occurs at lower levels of insulin

· Potassium transport activity increases as insulin levels increase

Patients with insulin resistance due to type-2 diabetes do not become resistant to the kalemic effects of insulin.

Hypoglycemia following insulin administration for hyperkalemia:

· Occurs 1-3 hours post dose, even with initial bolus of dextrose

· The amount of glucose is insufficient to replace the glucose utilized in response to the administered dose of insulin

· Insulin’s half-life is increased in ESRD leading to longer duration of action

A systematic review of 11 studies regarding insulin dosing for hyperkalemia:

· 22 patients (18%) experienced hypoglycemia

· Studies that only gave 25 grams (1 amp) of dextrose had the highest incidence of hypoglycemia (30%)

Tips:

· Consider insulin dose reduction in patients with renal failure

· Use an order set to ensure patients receive appropriate POC glucose monitoring to detect delayed onset of hypoglycemia

· Dextrose 50% (25 grams) should be given to all patients with pre-insulin BG <350 mg/dL

Subsequent PRN dextrose 50% (25 grams) should be used to maintain BG >100 mg/dL after insulin administration

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Fever occurs in 40% of patients with sepsis.  Historically, there has been conflicting evidence of whether patient outcomes improve with antipyretic therapy.

A recent large meta-analysis assessed the effect of antipyretic therapy on mortality of critically ill septic patients.  The analysis included 8 randomized studies (1,531 patients) and 8 observational studies (17,432 patients) that assessed mortality of septic patients with and without antipyretic therapy.

The authors found no difference in mortality at 28 days or during hospital admission.  There was also no difference in shock reversal, heart rate, or minute ventilation.

As expected, they found a statistically significant reduction in posttreatment body temperature (-0.38°C, 95% IC -0.63 to -0.13) in patients who received antipyretic therapy.  NSAIDs and cooling therapies were more effective than acetaminophen, however no agent or dosing information was provided and only one study included physical cooling therapies.

Bottom Line: Antipyretic therapies do not reduce mortality in patients with sepsis, but they may improve patient comfort by reducing body temperature.

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Alpha-blockers (tamsulosin, alfuzosin, doxazosin, and terazosin) are antagonists of alpha1A-adrenoreceptors, which results in the relaxation of ureteral smooth muscle.    Current evidence suggests alpha-blockers may be useful when ureteral stones are 5-10 mm; however, there is no evidence to support the use of alpha-blockers with stones <5 mm.  Patients with ureteral stones >10 mm were excluded from studies utilizing these medications.

The size of most ureteral stones will be unknown due to the lack of need for imaging able to measure stone size. Given that the median ureteral stone size is <5 mm, most patients will not benefit from the use of an alpha-blocker.

Also, keep in mind that the data for adverse events with alpha-blockers used for ureteral stones is limited and that these medications have a risk of hypotension.

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When you look up dosing for levofloxacin for community acquired pneumonia (CAP), you will find that both of the following options are approved:

• Levofloxacin 500 mg IV/PO daily x 7-14 days
• Levofloxacin 750 mg IV/PO daily x 5 days

This is based on a multicenter, randomized, double-blind, active treatment trial comparing these two regimens in CAP (mild to severe). This non-inferiority trial shows that the 750 mg dose of levofloxacin for 5 days is "at least as effective and well tolerated" as the 500 mg dose of levofloxacin for 10 days.

So why should you choose the 750 mg daily x 5 day regimen?

• Higher doses maximize the concentration-dependent pharmacokinetic profile of the drug
• Higher doses and shorter duration may be associated with less drug resistance
• Patients subjectively report feeling better at day 3 with the higher dose regimen

As alway with levofloxacin, don't forget to renally dose adjust subsequent doses when writting a script or scheduled inpatient order for patients with reduced creatinine clearance! 

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• The incidence of Staphylococcus aurea as a urinary pathogen is increasing, however, this finding may represent more than a simple urinary tract infection.
• One review found an 8-21%rate of association between S. aureus in the urine with bacteremia.
• Additional work up, including blood cultures, may be warranted in patients with systemic symptoms, lack of access to follow up, and no urinary tract pathology or instrumentation.

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