Statins - Induced Transaminitis

Introduction 

• The most commonly reported hepatic adverse effect is the phenomenon known as transaminitis, in which liver enzyme levels are elevated (transient) in the absence of proven hepatotoxicity and commonly occurs in the first 12 weeks of therapy.  
• This class effect is usually asymptomatic, reversible, and dose-related.
• There are changing data on the occurrence of these negative hepatic effects, recommendations on their actual risk, monitoring required, and safety of use in those with preexisting hepatic disorders.

Effects of Statins on The Liver

• Statins exert a potent inhibition of hepatic 3-hydroxyl-3-methylglutaryl coenzyme A reductase, which accounts for the reduction in LDL cholesterol observed with these drugs.
• Although the underlying mechanism remains unclear, hepatotoxicity may result from changes in the lipid components of the hepatocyte membrane, leading to an increase in its permeability with a subsequent “leakage” of liver enzymes.
• This is supported by the observation that elevations in aminotransferase levels.

Incidence of Elevation of Liver Enzymes During Statin Treatment

• The incidence of elevated aminotransferase levels with different types of statins generally did not exceed 3% of the studied patients' sample. 
• There seems to be a direct relationship between the statin dose and the incidence of transaminitis. 
• The reported average incidence of elevations in serum aminotransferase levels to >3x ULN was < 1% in patients receiving low to moderate doses.
• Similarly, the incidence of transaminitis increases up to 2% to 3% in those receiving high doses of statins.
• The incidence of transaminase elevations is similar among all statins, despite their different pharmacokinetic characteristics
• Most cases of transaminitis exhibit spontaneous improvement without the need for drug discontinuation, probably a result of the development of adaptation or tolerance.

Management and Monitoring

Algorithm for Management of Abnormal Liver Enzymes Before and During Statin Treatment

Statins in Preexisting Liver Dysfunction

• US FDA continues to recommend that statins be contraindicated in patients with chronic liver disease; however, several authors have recommended starting low-dose statin treatment (because of the possible greater incidence of liver enzyme elevations with higher doses) and having levels rechecked 2 weeks later.
• LFT monitoring should be performed every month for the first 3 to 4 months and 4 times a year thereafter.
•   If the levels of transaminases increase to > 3X baseline values, discontinuation of the drug should be considered.
• Clinical correlation with worsening of underlying disease, as well as exclusion of alcohol abuse and drug interactions, should be done before attempting permanent discontinuation of the drug. 
• Once levels return to baseline, rechallenge can be considered. 

Conclusion

• The latest reviewed data indicate or support the recommendation from US FDA that “all currently marketed statins appear to be associated with a very low risk of serious liver injury.”
• Clinicians should not withhold statin therapy for patients whose transaminase elevations have no clinical relevance or are attributable to known stable chronic conditions. Evaluating other causes for alteration in LFTs should be made before establishing a causal relationship with a statin agent.
• Statin use need not be avoided in patients with preexisting liver dysfunction if its use is clearly indicated.
• However, as reported in literature, potential of statins to cause significant and serious hepatic effects should not be overlooked in daily clinical practice

References 

1. Rossana M. Calderon, MD, Luigi X. Cubeddu, MD, Ronald B. Goldberg, MD, and Eugene R. Schiff, MD. Statins in the Treatment of Dyslipidemia in the Presence of Elevated Liver Aminotransferase Levels: A Therapeutic Dilemma. Mayo Clinic Proceedings 2010 Apr; 85(4): 349–356.
2. Jimmy Jose. Statins and its hepatic effects: Newer data, implications, and changing recommendations. J Pharm Bioallied Sci. 2016 Jan-Mar; 8(1): 23–28.
3. Edward Onusko MD. Statins and elevated liver tests: What’s the fuss?.J Fam Pract 2008 July;57(7):449-452.
4. US Food and Drug Administration (FDA) PhRMA/FDA/ASSLD drug induced hepatotoxicity white paper post marketing considerations: November 2000.
5. US Department of Health and Human Services. Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Guidance for industry: drug-induced liver injury: premarketing clinical evaluation Published July 2009

IVI Salbutamol Protocol

Availability in Hospital Keningau
Injection Salbutamol 0.5mg/ml

Indications:

• Severe bronchospasm and status asthamaticus

Dilution protocol:

• Reconstitution not required
• Dilute 5mg Salbutamol in 500mL of NS or D5. 
• Concentration of 10mcg/mL

Infusion rate:  

• 0.3-2mL/min generally adequate. But in respiratory failure, higher dose has been used successfully
• Starting dose of 5mcg/min (0.5mL/min) is recommended with appropriate adjustment in dosage according to patient response.
• IV continuous infusion [Canadian product]: Initial: 5 mcg/minute; may increase up to 10 to 20 mcg/minute at 15- to 30-minute intervals if needed

References:

1. Sarawak Handbook of Medical Emergencies 3rd Edition
2. http://www.medicines.org.uk/EMC/medicine/105/SPC/Ventolin+Solution+for+IV+Infusion 
3. http://www.medsafe.govt.nz/profs/Datasheet/v/VentolininjIV.pdf 
4. www.uptodate.com

Methotrexate Treatment : Dose of Folic Acid

Availability in Hospital Keningau:

• T. Methotrexate 2.5mg 
• T. Folic Acid 5mg
• T. Obimin (Contain 1mg FA)
• T. Zincofer (Contain 1mg FA)

Need of Folate Supplementation

• Methotrexate is a first line disease-modifying-anti-rheumatic-drug (DMARD) for rheumatoid arthritis
• Administered in low doses, methotrexate inhibits a number of folate dependent metabolic steps, including a very potent inhibition of dihydrofolate reductase which reduces folic acid to dihydrofolic acid and to tetrahydrofolate thus causes a depleted pool of reduced folates and produces a state of effective folate deficiency.
• The British Society for Rheumatology states that regular folic acid supplements are thought to reduce toxicity of methotrexate
• But there has been much controversy regarding the dose of supplementation and whether it has benefit on toxicity without being detrimental to methotrexate efficacy

Dose Selection

• Meta-analysis shown that concurrently supplementation of low dose folic acid (<5mg/week) in low dose methotrexate (<20mg/week) achieved a 79% reduction of mucosal and gastrointestinal side-effects (p < 0.0001). 
• There were no major differences between low and high doses of folic acid (p = 0.17).
• Other studies have not found any significant difference in efficacy of methotrexate whether given with or without folate supplements.
• The potential of folic acid interfering with the gastro-intestinal absorption of methotrexate is a matter of controversy, but this possibility may be overcome by administration of folic acid 24 hours prior to the weekly methotrexate dose.
• The British Society for Rheumatology guidelines for disease modifying anti-rheumatic drug therapy recommends a typical folic acid dose of 5mg once weekly, preferably the day after the methotrexate.

Recommendation:

• Based on the evidence, 5mg of folic acid weekly is sufficient enough to benefit on reducing methotrexate toxicity.
• Preferably not to consume on methotrexate day which may reduce the effectiveness and efficacy of methotrexate.
• In other hand, prescribing with 5mg folic acid weekly may reduce the cost of medication and improve the compliancy.

References:

1. Ortiz Z, Shea B, Suarez-Almazor ME, Moher D, Wells GA, Tugwell P.  Folic Acid and Folinic Acid for Reducing Side-Effects in Patients Receiving Methotrexate for Rheumatoid Arthritis (Review).  Cochrane Review 2009
2. Ortiz Z, Shea B, Suarez-Almazor M E et al.  The Efficacy of Folic Acid and Folinic Acid in Reducing Methotrexate Gastrointestinal Toxicity in Rheumatoid Arthritis.  A Meta-analysis of Randomized Controlled Trials.  J Rheum 1998; 25 (1): 36 – 43
3. https://www.sps.nhs.uk/articles/what-is-the-dose-of-folic-acid-to-use-with-methotrexate-therapy-for-rheumatoid-arthritis/
4. https://academic.oup.com/rheumatology/article/43/3/267/1774685

ADR: Bullous on Acyclovir Infusion

Availability in Hospital Keningau:

• IV Acyclovir 250mg

Indication:

• Treatment and prophylaxis of herpes simplex in immunocompromised, severe initial genital herpes and Varicella -Zoster.

 Skin Reactions

• According to previous report, adverse cutaneous reactions have been reported with all routes of administration
• Local inflammation or phlebitis at the injection site are well-known dermatologic reactions of intravenous acyclovir therapy.
• Common dermatological reactions include alopecia, erythema multiforme, photosensitive rash, pruritus, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, and urticaria
•  Severe local inflammatory reactions, including tissue necrosis, have occurred following infusion of acyclovir into extravascular tissues
• There are rarely reported on acyclovir infusion induced the bullous.
• But recently, Yorulmaz et al., 2015, present a case of localized bullous eruption and phlebitis associated with intravenous acyclovir treatment in a patient with metastatic breast cancer
• Others case reported of acyclovir infusion induced bullous which mostly appeared after 10-15 days of infusion.

References:

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271519/
2. https://www.ncbi.nlm.nih.gov/pubmed/26911608
3. https://aidsinfo.nih.gov/drugs/8/acyclovir/39/professional
4. http://www.jacionline.org/article/S0091-6749(16)31818-8/fulltext
5. Formulary Ubat KKM August, 2017

Vitamin C in reducing uric acid level

Availability in Hospital Keningau:

• Tablet Ascorbic Acid 100mg

Vitamin C as serum uric acid lowering:

• According to older research, consuming of vitamin C results serum uric acid reduction

• Research by Juraschek et al., 2010 state that, meta-analysis suggest that oral vitamin C supplementation results in modest SUA reduction.

• While, another research on 2012 conclude that, dietary vitamin C was shown to be more effective than vitamin C tablets in reduction of serum acid concentration 

Vitamin C NOT as serum acid lowering:

• Recent study on 2013 shown that supplemental vitamin C at a dosage of 500 mg/day does not lead to a clinically significant reduction in the SU level in patients with gout.

• The study shown that vitamin C may reduce the production of serum uric acid and risk of developing gout.

• No data that support the use of vitamin C supplementation as a urate-lowering therapy in patients with established gout.

Recommendation:

• Prescribing of vitamin C to gout patient for serum uric acid lowering were not indicated as recent study shown not significantly reduce in SUA level.

• Besides, according to latest FUKKM, vitamin C only indicated for vitamin C deficiency.

• May suggest to patient taking more dietary vitamin C instead of prescribing vitamin C tablet.

References:

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169708/pdf/nihms-300040.pdf
2. https://www.researchgate.net/publication/230562792_Implementing_High_Vitamin_C_Treatments_to_Decrease_Blood_Uric_Acid_Levels_in_Hyperuricemic_Saudi_Patients
3. http://onlinelibrary.wiley.com/doi/10.1002/art.37925/full
4. Formulary Ubat KKM August, 2017

Interaction : Calcium and Food

• Due to its dependence on stomach acid for absorption, calcium carbonate is absorbed most efficiently when taken with food
• calcium citrate is absorbed equally well when taken with or without food.
• Calcium citrate is also useful for people with achlorhydria, inflammatory bowel disease, or absorption disorders
• Other calcium forms in supplements or fortified foods include gluconate, lactate, and phosphate.

Absorption

• Not all calcium consumed is actually absorbed in the gut. Humans absorb about 30% of the calcium in foods, but this varies depending upon the type of food consumed
• Amount consumed: 
• the efficiency of absorption decreases as calcium intake increases
• Age:
• Absorption decreases to 15%–20% in adulthood (though it is increased during pregnancy) and continues to decrease as people age; compared with younger adults, recommended calcium intakes are higher for females older than 50 years and for both males and females older than 70 years
• Other components in food:
• phytic acid and oxalic acid, found naturally in some plants, bind to calcium and can inhibit its absorption. 
• Foods with high levels of oxalic acid include spinach, collard greens, sweet potatoes, rhubarb, and beans. 
• Among the foods high in phytic acid are fiber-containing whole-grain products and wheat bran, beans, seeds, nuts, and soy isolates
• The extent to which these compounds affect calcium absorption varies. Research shows, for example, that eating spinach and milk at the same time reduces absorption of the calcium in milk.
• In contrast, wheat products (with the exception of wheat bran) do not appear to lower calcium absorption
• For people who eat a variety of foods, these interactions probably have little or no nutritional consequence and, furthermore, are accounted for in the overall calcium DRIs, which factor in differences in absorption of calcium in mixed diets

Elimination

• Sodium and protein intakes:
• high sodium intake increases urinary calcium excretion. 
• High protein intake also increases calcium excretion and was therefore thought to negatively affect calcium status 
• However, more recent research suggests that high protein intake also increases intestinal calcium absorption, effectively offsetting its effect on calcium excretion, so whole body calcium retention remains unchanged
• Caffeine intake: 
• this stimulant in coffee and tea can modestly increase calcium excretion and reduce absorption. 
• One cup of regular brewed coffee, for example, causes a loss of only 2–3 mg of calcium
• Alcohol intake: 
• alcohol intake can affect calcium status by reducing its absorption and by inhibiting enzymes in the liver that help convert vitamin D to its active form. 
• However, the amount of alcohol required to affect calcium status and whether moderate alcohol consumption is helpful or harmful to bone is unknown
• Fruit and vegetable intakes: 
• metabolic acids produced by diets high in protein and cereal grains increase calcium excretion. 
• Fruits and vegetables, when metabolized, shift the acid/base balance of the body towards the alkaline by producing bicarbonate, which reduces calcium excretion. 
• However, it is unclear if consuming more fruits and vegetables affects bone mineral density. These foods, in addition to reducing calcium excretion, could possibly reduce calcium absorption from the gut and therefore have no net effect on calcium balance

Reference:

https://ods.od.nih.gov/factsheets/Calcium-HealthProfessional/

Conversion : Novomix to Mixtard

• A more rapid onset-of-action means that the newer analogue premixed insulins are more effective at lowering post-prandial rises in glucose. 
• Rapid-acting analogues have a shorter duration of action than human insulin, there is a much lower risk of hypoglycaemia, especially in the hours prior to the next meal. 
• In a meta-analysis, Davidson et al (2009) found that premixed insulin containing the analogue aspart was associated with 50% reduced rates of nocturnal hypoglycaemia and 65% less major hypoglycaemia than human premixed insulin.

Dose Equivalence

• Unit to unit equivalent
• However, Novomix (analgoues) have a faster onset of reactions  
• Ensure patients are counselled, especially on the importance of initial blood glucose monitoring following the switch and monitored for compliance and adverse events.

 

 
Premixed-Insulin as TDS Dosing

• not recommended by manufacturer or guides
• however a study on thrice daily biphasic human insulin regimen showed it is non-inferior to the basal bolus insulin analogue regimen in terms efficacy and safety in patients with poorly controlled T2DM (dose split by 40:20:40) 

References:

1. Wu T (2016) Premixed insulin analogues: A new look at an established option. Diabetes & Primary Care Australia 1: 129–33
2. Clinical Resource, Initiation and Adjustment of Insulin Regimens for Type 2 Diabetes. Pharmacist’s Letter/Prescriber’s Letter. March 2017 
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3307189/
4. http://www.gpnotebook.co.uk/simplepage.cfm?ID=x20160214160507771435

Interaction: Warfarin and Liver

• Liver is often seen suggested as a source of vitamin K2 and beef liver in particular has been recommended as a good dietary source. 
• From the tables below it seems that while the beef liver tested contains mk-4, it is not a particularly good source 
• However, most studies have not tested for long-chain menaquinones, mk-6 to mk-13, which are produced by the bacterial fermentation in the stomachs of cattle and provide them with a readily absorbable source of vitamin K2. 
• When absorbed from the gut these reach the liver first where they appear to remain. 
• This can be seen as very little long chain menaquinones were detected in any of the other meat or organs of cattle. 
• The only small study that has tested for these found quite high levels of menaquinones 11, 12, and 13

as a comparison, a 100g of cabbage/brocoli has 100mcg of vitamin K, while that of spinach contains 200mcg.

References:

1. Vitamin K. Academic Press, 3 Mar 2008
2.  https://honey-guide.com/2014/03/10/menaquinones-k2-and-phylloquinone-k1-content-of-animal-products-and-fermented-foods/ 
3. http://apjcn.nhri.org.tw/server/info/books-phds/books/foodfacts/html/data/data3e.html

Mannitol

Availability:

• Mannitol 10% (INFUSOL®M10)
• Mannitol 20% (INFUSOL®M20)

Composition:

                                             10%                                     20%

Mannitol                                10g                                       20g

Water for Injection to          100mL                                  100mL

Osmolarity                        550mOsm/L                       1100mOsm/L

Dosing and Administration for Diuretic:

Adult	Paediatric
Dose: 50-100 gram of Mannitol   Administration: rate adjusted to maintain urine flow of at least 30-50mL per hour.	Dose: 0.25-2g/kg  Administration: 2-6 hours

Dosing and Administration for Cerebral Oedema or Elevated Intracranial Bleeding or Glaucoma:

Adult	Paediatric
Dose: 0.25-2g/kg Administration: 30 to 60 minutes	Dose: 1-2g/kg  Administration: 30 to 60 minutes

 

References:

1. INFUSOL®M10 and M20 product Information

2. http://www.rxlist.com/mannitol-iv-drug.htm

3. Micromedex

4. Lexicomp

5. Formulari Ubat KKM, March 2016.