Potassium Chloride vs Potassium Citrate

Today I encountered an interesting drug information question regarding the various potassium products that were available. I have summarized my findings in the table below. Additionally, the question arose as to whether or not potassium citrate and potassium chloride could be used interchangeably; if not, what is the difference in these two salts?

The answer is no, these are not equivalent products. Unlike potassium chloride, potassium citrate does not have an FDA-approved labeled indication for the treatment of  hypokalemia. Potassium citrate's three indications are as follows:

• Prevention of uric acid nephrolithiasis
• Prevention of calcium renal stones in patients with hypocitraturia 
• Urinary alkalinizer for situations in which sodium citrate is contraindicated

Mechanism of Action:

Oral administration of potassium citrate produces an alkaline load, as the citrate is converted hepatically to bicarbonate. This increases the urinary pH and further enhances the clearance of citrate, thus increasing urine citrate concentration. Also, the bicarbonate may reduce bone resorption (release of calcium from bone to blood via action of osteoclasts) and increased renal calcium reabsorption. These combined effects may lead to a transient decrease in urinary calcium, and makes the environment of the urine less conducive to the crystallization of stone-forming salts. Increased urinary PH also causes uric acid's more soluble urate ion to form, thus decreasing the risk of uric acid stones. 

GENERIC	DOSAGE FORM	BRAND NAMES	AVAILABLE STRENGTHS	INDICATIONS
Potassium Chloride	Extended-release capsules	Micro-K	8 mEq; 10 mEq	·         Treatment/prevention of hypokalemia ***K-TAB NOT BIOEQUIVALENT
	Oral Solution	K-Sol	20 mEq/15 mL ; 40 mEq/15mL
	Oral packet	K-Vescent	20 mEq
		Klor-Con	20 mEq; 25 mEq
	Extended-release tablets	K-Tab	8 mEq; 10 mEq; 20 mEq
		Klor-Con	8 mEq; 10 mEq; 15 mEq; 20 mEq
Potassium Citrate	Extended release tablets	Urocit-K 5	5 mEq	·         Prevention of uric acid nephrolithiasis ·         Prevention of calcium renal stones in patients with hypocitraturia ·         Urinary alkalinizer when Na-Citrate contraindicated
		Urocit-K 10	10 mEq
		Urocit-K 15	15 mEq
Potassium Gluconate (1gm = 4.3 mEq)	Capsules	K-99	595 mg	·         Dietary supplement
	Tablets	(generic)	2 mEq; 2.5 mEq; 8mg (base)
Potassium Acid Phosphate (500mg = 3.7 mEq)	Tablets	K-Phos	500mg	·         Acidify urine—lower urine calcium concentration ·         Reduce odor and rash from ammonia in urine ·         Synergistic effect with antibacterial activity of methenamine
Potassium Bicarbonate/Potassium Citrate	Tablets (for solution)	Effer-K	10 mEq; 20 mEq	·         Treatment/prevention of hypokalemia (if avoiding chloride or acid/base status requiring bicarb)
		Klor-Con/EF	25 mEq
Potassium Iodide	Oral Solution	SSKI	1 gm/mL	·         Expectorant; chronic pulmonary diseases complicated by mucus ·         Block uptake of radioactive isotopes
		ThyroShield	65 mg/mL
Potassium  P-aminobenzoate	Capsules	M2 Potassium	60 mg	·         Scleroderma ·         Dermatomyositis ·         Morphea ·         Pemphigus ·         Peyronie’s Disease
		Potaba	500 mg
	Packet	(generic)	2g
	Tablets	Potaba	500 mg

References:

1. Lexicomp. Accessed 7/31/2015. <www.online.lexi.com.proxy.lib.uiowa.edu>

2. Drugs.com. Accessed 7/31/2015 <http://www.drugs.com/pro/potassium-citrate.html>

3. Krieger NS, Asplin JR, Frick KK, et al. Effect of Potassium Citrate on Calcium Phosphate Stones       in a Model of Hypercalciuria. J Am Soc Nephrol. 2015.

Quick overview of Victoza (liraglutide)

Victoza (liraglutide) is an incretin mimetic (GLP-1 agonist) that is indicated for both blood glucose control in patients with type 2 diabetes mellitus and for chronic weight management.

Dosing
Weight management: 0.6 mg injected once daily for one week, then increase at weekly intervals to a target dose of 3 mg daily. Patients may delay the increase in dose by a week if the higher dose is not tolerated. Patients who cannot tolerate the 3mg daily dose, or those who have not lost 4%of their body weight within 16 weeks should discontinue this medication.

Diabetes, Type 2: 0.6 mg injected once daily for one week, then increase to 1.2 mg daily. If glycemic control is not achieved, you can increase to 1.8 mg once daily.

**According to Facts & Comparisons, no maximum dose has been established**

Black Box Warning
Liraglutide was found to cause dose and duration-dependent thyroid C-cell tumors in rats; it has not yet been established whether or not it causes these tumors in humans. However, liraglutide is contraindicated in patients with a history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2.

Common Side Effects
Headache, negative GI effects (constipation or diarrhea, nausea, decreased appetite, dyspepsia), weakness/lack of energy, irritation at injection site.

Administration Pearls

• Victoza is only to be injected subcutaneously in the following sites: upper arm, thigh, abdomen
• May be administered without regard to meals or time of day
• Do not use if cloudy or containing particulate matter
• Change needle prior to each administration
• If also using insulin, do not inject Victoza directly adjacent to the site of insulin injection

Instructional Video

References
1. Lexicomp. Victoza. Accessed 7/30/2015.<http://online.lexi.com.proxy.lib.uiowa.edu/lco/action/doc/retrieve/docid/patch_f/2144379#thclist>
2. Facts & Comparisons. Victoza. Accessed 7/30/2015.
<http://online.factsandcomparisons.com.proxy.lib.uiowa.edu/MonoDisp.aspx?monoID=fandc-hcp15525&quick=880418%7c5&search=880418%7c5&isstemmed=True&NDCmapping=-1&fromTop=true#firstMatch>
3. Youtube. Victoza Pen Quick Guide. Accessed 7/30/2015. <https://youtu.be/BS39qXij-Jg>

Zylet vs Tobradex

Zylet (loteprednol/tobramycin) is a combination steroid/antibiotic eye drop like Tobradex. After difficulties with insurance reimbursement and an ultimate switch to tobramycin/dexamethasone, the question came up as to whether or not there was a substantial difference in efficacy/safety between these two products. I have summarized my findings from multiple trials below:

Title	Study Type	Results
Comparison of the safety and efficacy of loteprednol 0.5%/tobramycin 0.3% with dexamethasone 0.1%/tobramycin 0.3% in the treatment of blepharokeratoconjunctivitis2	Multicenter, randomized, investigator-masked, parallel group study	·  Loteprednol/tobramycin determined to be non-inferior to DM/T      ·   Pts treated with DM/T experienced a significant increase in intraocular pressure compared to those treated with LE/T
A randomized controlled trial comparing dexamethasone with loteprednol etabonate on postoperative photorefractive keractectomy3	Prospective, randomized, double-masked controlled study	·  Corneal epithelium healed one day sooner in patients treated with loteprednol       · 1/16 patients treated with lot. experienced significant increase in IOP (>5mmHg) whereas 3/16 patients treated with DM did.
Tolerability of loteprednol/tobramycin versus dexamethasone/tobramycin in healthy volunteers: results of a 4-week, randomized, double-masked, parallel-group study4	Multicenter, randomized, double-masked, parallel-group study	·  Loteprednol/tobramycin satisfied non-inferiority requirements       ·  Significant, but small, differences favored loteprednol for comfort/tolerability (tears, burning, itching, etc)
Effects of loteprednol/tobramycin versus dexamethasone/tobramycin on intraocular pressure in healthy volunteers.5	Randomized,       double-masked, multicenter, parallel-group trial	·  Significantly lower number of patients experienced IOP increase > 10mmHg when treated with loteprednol/tobramycin compared to tobramycin/dexamethasone (1.95% vs 7.48%)      · Both medications well tolerated

Conclusions

Zylet appears to be non-inferior to Tobradex. There may be a small difference in tolerability favoring Zylet, but both medications were well-tolerated overall.  However, tobramycin/dexamethasone was significantly more likely to cause significant increases in intraocular pressure in multiple studies, which may make Zylet a more favorable option for patients for whom intraocular pressure is a concern (glaucoma, etc).

References

1.   1.  White EM, Macy JI, Bateman KM, Comstock TL. Comparison of the safety and efficacy of loteprednol 0.5%/tobramycin 0.3% with dexamethasone 0.1%/tobramycin 0.3% in the treatment of blepharokeratoconjunctivitis. Curr Med Res Opin. 2008;24:(1)287-96. [pubmed]

3.   2. Thanathanee O, Sriphon P, Anutarapongpan O, et al. A randomized controlled trial comparing dexamethasone with loteprednol etabonate on postoperative photorefractive keratectomy. J Ocul Pharmacol Ther. 2015;31:(3)165-8. [pubmed]

4.   3. Bartlett JD, Holland EJ, Usner DW, Paterno MR, Comstock TL. Tolerability of loteprednol/tobramycin versus dexamethasone/tobramycin in healthy volunteers: results of a 4-week, randomized, double-masked, parallel-group study. Curr Med Res Opin. 2008;24:(8)2219-27. [pubmed]

5.   4. Holland EJ, Bartlett JD, Paterno MR, Usner DW, Comstock TL. Effects of loteprednol/tobramycin versus dexamethasone/tobramycin on intraocular pressure in healthy volunteers. Cornea. 2008;27:(1)50-5. [pubmed]

Inhaled Insulin is Back

Today I was able to use Afrezza's new demo inhaler. As some may be aware, this is not the first time that inhaled insulin has hit the market. In 2006 the FDA approved an inhaled insulin called Exubera which Pfizer later pulled off the market in 2007. Patients complained about its large size (see image below) and its difficulty of use. In addition to its increased cost without additional proven efficacy, some had concerns about the risk of damage to the lung, and even lung cancer.

Afrezza was approved on June 27, 2014 for the treatment of type I and type II diabetes and is starting to roll out to pharmacies. I had not personally seen it in any pharmacy until today, but it's certainly has some vast improvements over its predecessor. It's a substantially smaller and more discrete device; one patients will feel much more comfortable bringing out in social settings. This may be beneficial for adherence in patients with strong needle phobias. It works similarly to a dry powder inhaler, with 4 and 8 unit delivery devices. Unfortunately, this means many patients will end up having to use multiple cartridges. Per Lexicomp, a unit with 90 4 Unit cartridges will run for approximately $270, with 8 unit and mixed unit packages increasing in price from there. In comparison, Novolog solution runs at about $268. I am not familiar with insurance coverage for Afrezza at this point, so I can't comment on the cost-effectiveness for the patient.

It is important to note that Afrezza cannot be used in patients with asthma or COPD, and has a boxed warning for bronchospasm. I will be interested to see the outcomes of this product over the years, particularly regarding if the same safety concerns that Exubera faced will arise once again.

Afrezza

EXUBERA

Types of Insulin

Types of Insulin

v  Rapid-acting: Taken before a meal. Covers glucose elevations related to meals

o    Works in about 15 minutes and peaks at about 1 hour

o    Duration: 2 to 4 hours

o    Examples: Apidra (glulisine), Humalog (lispro), NovoLog (aspart)

o    Inhaled insulin: works in 15 minutes and peaks in 30 minutes. Out of system in 180 minutes

§  Afrezza

v  Short-acting: Taken before a meal. Covers glucose elevated related to meals

o    Works in 30 minutes and peaks in 2 to 3 hours

o    Duration: 3 to 6 hours

o    Examples: Humulin R and Novolin R

v  Intermediate-acting: Taken two times daily. Covers both meal and basal insulin needs

o    Works in 2 to 4 hours and peaks in 4 to 12 hours

o    Duration: 12 to 18 hours

o    Example: NPH (Humulin N, Novolin N)

v  Long-acting: Typically taking once daily (can be done twice daily). Meets basal insulin needs

o    Works in a few hours and covers insulin needs for 24 hours

o    Duration: 24 hours

o    Examples: Levemir (detemir) and Lantus (glargine)

v  Pre-mixed insulin: NPH with short or rapid-acting insulin

o    NPH/regular

§  70/30 (Humulin/Novolin) and 50/50 (Humulin)

o    Other pre-mixed insulin            

§  Novolog 70/30, Humalog 75/25, and Humalog 50/50

o    Ideal for patients with a consistent schedule

§  Same meal composition and activity level each day

§  Increase risk for hypoglycemia

§  Hard to adjust for changes in routine

New meningitis vaccine

The FDA approved a new vaccine called Trumenba which is licensed in the US to prevent meningococcal disease caused by N. meningitides serogroup B. It is approved in individuals ages 10 to 25. According to the CDC, of the 500 total cases of meningococcal disease in 2012, 160 of the cases were caused by serogroup B. Before this approval the current vaccine on the market was the meningococcal conjugate vaccine or MCV4. The serogroups covered with the current vaccine include: A, C, W, and Y. The new recombinant vaccine covers serogroup B which was not covered in the past vaccines. It is given on a 0, 2, and 6 month schedule. This vaccine comes at a time after there have been outbreaks of serogroup B meningococcal disease at various college campuses. The most common side effects of the vaccine are: pain/swelling at the injection site, headache, diarrhea, muscle pain, joint pain, fatigue, and chills. 

Should antihypertensives be dosed at night?

Circadian rhythm of blood pressure

·         Typically blood pressure is highest early to mid-morning and falls throughout the day

·         Blood pressure was usually lowest at night, called nighttime dipping

o   Drop in systolic pressure by >10%

o   Normal nighttime blood pressure <120/70mmHg

·         Average 24-hour range should be <130/80mmHg

·         The typical rhythm is influenced by both intrinsic and extrinsic factors such as: neurohormonal regulation, physical activity, and dietary sodium

·         Behavioral influences include: mental activity, emotional state, smoking, and alcohol

·         Platelet aggregation, catecholamines, coronary resistance, and vascular resistance increase in the early morning hours, which along with the blood pressure surge can increase the cardiovascular risk in the morning

·         Cardiovascular events and organ damage is better predicted by the 24-hour measurement than a single point measurement due to the consideration of the nighttime blood pressure

·         “Non-dippers”

o   Occurs in 35 to 40% of patients with hypertension

o   Blood pressure reduction of <10% while sleeping (normal reduction- 15-25%)

o   Occurs with increase in adrenergic and decrease in vagal activity during sleep

o   Stronger predictor of cardiovascular events versus daytime blood pressure

·         In a study by Verdecchia et. al., that compared patients with ambulatory hypertension versus those with white coat hypertension, patients who had daytime hypertension with a nighttime dipping pattern had a relative risk of 3.70 (95% CI 1.13-12.5) and those with a non-dipping pattern had a relative risk of 6.26 (95% CI 1.92-20.32) when compared to those with just white coat hypertension

·         A non-dipping pattern of blood pressure may be one of the best predictors of risk of increased cardiovascular events

·         Patients with resistant hypertension, diabetes, or chronic kidney disease are more likely to be non-dippers than patients without these conditions

o     Administration of bedtime anti-hypertensives has been shown to convert patients to dippers

Bedtime versus morning dosing

·         Historically blood pressure was given twice daily (1980’s) but changed due to the attempt to increase medication adherence

·         Bedtime dosing of at least one medication is thought to decrease both the nighttime blood pressure and cardiovascular disease

·         When blood pressure medication is administered in the morning (usually dose about 6-7am) it takes about 60 to 90 minutes to achieve peak concentrations

o   Measurements in the clinic are usually done when this medication is at its maximum concentration

o   This misses the early morning spike of blood pressure

·         Medications such as: HCTZ, atenolol, enalapril, labetalol, nadolol, pindolol, propranolol ER, nifedipine, and others have a short half-life don’t reduce morning blood pressure spikes

·         American Diabetes Association gives nighttime dosing of at least one hypertension agent a level A recommendation

o   Recommendation based on the following study:

§  661 patients  with CKD and taking at least blood pressure medication

§  332 randomized to take all anti-hypertensives in the morning and 329 were supposed to take at least one at bedtime

§  Patients with at least one blood pressure medication at bedtime at a statistically significant lower hazard ratio of events

·         HR= 0.31; CI 0.21-0.46; P<0.001

§  The decline of blood pressure was greater among those having a bedtime dose of medication with a non-dipper profile (P<0.001)

§  The proportion of patients with controlled blood pressure was significantly higher in those patients with a bedtime blood pressure medication

·         56.5% (bedtime dosing) v. 45.2% (morning dosing) (p=0.003)

·         By dosing the medication at bedtime it helps protect the patients during the nighttime period as well as the early morning surge

o   Not found to be a predictable effect

o   Quinapril dosed in the morning or evening had similar effects on the blood pressure during the day, but there was a greater reduction of blood pressure during sleep and a greater rise in morning blood pressure

·         A Cochrane review found 21 studies with 1993 patients compared morning and evening dosing

o   Significantly lower 24-hour blood pressure by 1.71mmHg

o   Morning mean systolic blood pressure was 1.62mmHg lower with evening dosing but not statistically significant

o   No difference in adverse effects with morning and evening doses

·         Risks related to evening dosing of medications

o   It is possible for blood pressures during the nadir of dippers to reach 90/60 mmHg with the medications peaking in 1 to 2 hours it could cause lows during the midnight to 4am period

§  No difference in adverse effects were found between the different dosing time

o   In one study by Hayreh et. al., there was evidence of ocular vascular disorders with nocturnal hypotension

§  166 patients with ocular disorders (anterior ischemic optic neuropathy, glaucoma, and other optic nerve head disorders) patients with visual deterioration had a significantly lower systolic blood pressure (114 +/- 2.5mmHg) than those without deterioration

§  Patients with visual field deterioration had significantly greater mean decreases in systolic blood pressures from daytime readings (46.8+/- 2.5mmHg) v. (35+/-3.1mmHg) without deterioration

§  Some patients with nocturnal hypotension had been taking their antihypertensives at  bedtime

·         The nocturnal hypotension was decreased when the nighttime dosing was discontinued