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

Hyponatremia : ACEi vs CCB

Symptoms

• presented with signs and symptoms of hyponatremia (eg, nausea, malaise, headache, lethargy, seizures, coma, respiratory depression) 
• decreased serum sodium levels (101-109 mEq/L)

ACE Inhibitors

• Frequency is unreported
• ACE inhibitors alone can precipitate hyponatremia without co-administration of thiazide diuretics
• hyponatremia induced by ACE inhibitors appears to be dilutional and is accompanied by features of SIADH
• discontinuing the ACE inhibitor leads to resolution of the hyponatremia
• Patients may show hypokalaemia if thiazide or loop diuretics are used concomitantly with ACE inhibitors
•  

Mechanism & Risk

• It is postulated that ACE inhibitors at low doses cannot block the conversion of angiotensin I to angiotensin II in the brain. Increased circulating angiotensin I is converted to angiotensin II in the brain causing thirst stimulation and consequently SIADH.
• risk for hyponatremia may be greater in patients on concomitant diuretic therapy or who have congestive heart failure.

Calcium Channel Blockers

• In theory, calcium channel antagonists with natriuretic properties could cause hyponatremia.
• A case of amlodipine-associated hyponatremia has been reported.
• calcium channel antagonist– related hyponatremia, if it exists, is extremely rare.

Management

• In mild to moderate cases with a normovolaemic fluid status clinically, ceasing the offending drug and gentle fluid restriction would improve serum sodium levels gradually within a week.
• In an acutely unwell patient due to severe drug induced hyponatraemia, severe fluid restriction or infusion of hypertonic saline may be require
• May consider changing therapy and monitoring patient for improvement

Alternatives

• Diuretics are not recommended as have higher likelihood of causing hyponatremia
• ARBs are also established to cause hyponatremia and no available data on comparison with ACEi
• Beta Blockers- Beta blockade, especially of the Beta 1 receptor at the macula densa, inhibits renin release, & the release of aldosterone. This causes hyponatermia and hyperkalemia

References:

1. http://www.gpnotebook.co.uk/simplepage.cfm?ID=x20120201092040500242
2. https://www.pjms.com.pk/issues/aprjun207/article/casereport3.html
3. Jenny A. Van Amburgh. Can Lisinopril Cause Hyponatremia? - Medscape - Jul 28, 2011
4. American Journal of Kidney Diseases, Vol 52, No 1 (July), 2008: pp 144-153

Improving Tolerability : Metformin

• Up to 30% of patients have gastrointestinal (GI) adverse effects when taking metformin
• Generally these adverse effects are mild and transient, but about 5% of patients are unable to tolerate metformin at all
• And almost half may not be able to tolerate the drug at a target dose of 2000 mg/day.

Initiating

• It is generally accepted that slow dose escalation increases GI tolerability but evidence for this is lacking.
• Start with either immediate-release (IR) or extended-release (ER) tablets.
• If using IR, give 500 mg once daily
• If a patient has a history of GI intolerance, consider starting with 250 mg once daily.
• If using ER, start with 500 mg once daily
• For even greater flexibility, metformin 100 mg/mL liquid can be used, allowing a patient to start at a lower dose and increase by smaller increments.
• Suggest starting with single-ingredient metformin for easier titration. Once dose is established, patient can be switched to a combination product with another glucose-lowering agent if that is indicated.

Dose Titration

• For IR or ER, increase by 500 mg per day every one to two weeks.
• Advise patients not to break, crush, or chew the ER tablets.
• If there is a history of GI intolerance increase more slowly, and maybe by only 250 mg at a time.
• If GI symptoms occur, decrease the dose back to the last tolerated dose and wait at least two weeks before further increases, in a smaller increment if possible
• It may take four to eight weeks, or longer to reach the target dose of 2000 mg/day.1 The benefit vs risk for adverse reactions does not support doses >2000 mg/day.

Tips to Improve Tolerance

• Take with food, during or right after meals.
• Recommend taking with the evening meal, typically the largest meal of the day
• Dividing the daily dose may improve tolerability. Consider giving the IR product three times per day or the ER product twice daily. Some reports indicate splitting the dose has no effect on the rate of adverse effects

Patient Education

• Let the patient know what to expect. It can be easier to tolerate some of these adverse effects if they know they’ll likely subside.
• Persistent diarrhea will subside quickly if metformin is stopped.
• Metformin can have an undesirable odor. Patients might even complain the odor makes them nauseous. Try a different brand or generic tablet if patients complain.
• Let patients know that they should be patient during the titration as it will take weeks and maybe a month or two to reach the target dose.

Managing Complaints

• Symptoms are generally transient, resolve over several months of treatment, and are reduced by slow dose titration and administration with food.
• It is unusual for GI symptoms from metformin to begin after prolonged therapy.
• Recommend a trial off metformin to see if symptoms resolve. You should see a resolution of symptoms within two to three days if the cause was metformin.
• Be aware that GI symptoms that developed later in therapy may need further investigation as they could be symptoms of lactic acidosis or other serious conditions
•  If patients cannot tolerate IR metformin at optimal doses, consider switching to a trial of ER.    
• There have been some retrospective and observational studies that report improved GI tolerability with ER over IR tablets.  However, large, direct comparative studies are lacking.

If Can't Achieve Target Dose?

• In most patients, there is some efficacy at a minimum dose of 500 mg/day, with a maximal effect at 2000 mg/day
• There may be some patients who see more benefit with doses up to 2500 mg/day but there is likely to be a higher incidence of GI adverse effects.21
• Up to 85% of the maximal effect is seen at a dose of 1500 mg/day.
• If a patient cannot tolerate metformin IR or ER at target dose, consider adding a second agent to the maximum metformin dose they can tolerate

Adapted from

• Improving Tolerability to Metformin. (PL Detail-Document #311202). PHARMACIST’S LETTER / PRESCRIBER’S LETTER. December 2015

Tramadol : Cardiovascular Side Effects

Hypotension

• There have been several reported cases of patient who are receiving Tramadol and develop hypotension. 
• Several references did mention the development of hypotension as side effect of administration of tramadol but it categories as rarely occurrence.
• Overdose of Tramadol also may cause patient to develop hypotension such as in underweight patient or error in administration. This factor need to be rule out first.

Insert leaflet of Tramal Injection

• Uncommon effects include disorders of cardiovascular regulation (e.g. palpitation, tachycardia, postural hypotension up to cardiovascular collapse), further, retching and gastrointestinal irritation, or dermal reactions (e.g. pruritus, rash or urticaria).

Insert Leaflet of ULTRAM

Drugs.com

Insert Leaflet Trama Injection

Comparison : Amisulpride vs Sulpiride

Suggested Antipsychotic Treatment

Based on up to date evidence, first line recommended antipsychotic options are:

• Amisulpride (greater comparative cost may outweigh first line choice).
• Aripiprazole
• Olanzapine (significant risk of metabolic adverse effects may outweigh first line choice).
• Quetiapine
• Risperidone
• Sulpiride (greater comparative cost may outweigh first line choice).

Licensed ages (BNF for Children)

• Amisulpiride : > 15 years
• Sulpiride: > 14 years

Cost

Side effects

QT prolongation

Effect on Prolactin Levels

Breast feeding

Elderly

Conclusion

• Amisulpride and Sulpiride are listed as the first line recommended antipsychotic.
• There is not much different in the side effects of both drugs.
• In terms of cost, sulpiride is cheaper than amisulpride.

References

1. BNF, March –September 2016
2. BNF for Children, September 2015-2016
3. http://www.sussexpartnership.nhs.uk/
4. http://www.malaysianpharma.com/index.php/articles22/

Antituberculosis & Joint Pain

	Arthalgia Type 1	Arthalgia Type 2 (Gouty Arthritis)
Possible Causative Agent	pyrazinamide>>ethambutol> isoniazid	pyrazinamide>>ethambutol
Clinical Presentation	Pain and tenderness of joints: fingers, shoulders, knees, etc. (usually mild)	Symptoms : pain, tenderness and swelling of joints (fingers, shoulders, knees, etc) Symptoms are usually severe  Signs: elevated serum uric acid concentrations
Management	TB medications do not require discontinuation Symptomatic relief:  NSAIDS	TB medications usually do not require discontinuation If acute swelling is present examined for urate crystals to confirm the diagnosis of acute gouty arthritis. Symptomatic relief:  NSAIDS or colchicine (as alternative to NSAIDS) If recurrent episodes occur, may consider using prophylactic colchicine

Proposed Mechanism

• A metabolite of pyrizinamide, pyrinazoic acid, inhibits the renal tubular secretion of uric acid and ethambutol reduces its renal clearance.

• The resulting hyperuricaemia can give rise to arthralgias and very rarely an arthritis.

Reference; 

1. http://rheumatology.oxfordjournals.org/content/45/9/1173.full
2.  http://www.uphs.upenn.edu/TBPA/treatment/managingsideeffects.pdf

Statins & Myopathy

• Statins are considered very effective in reducing cardiovascular morbidity and mortality in high-risk patients. However, although adherence to statins improves morbidity and mortality , it remains suboptimal. 
• One of the most important causes of nonadherence is the so-called statin intolerance, mainly because of muscle-related symptoms.

Myopathy

• Myopathy is defined in various ways.
•  The National Lipid Association (NLA) defines myopathy as symptoms of myalgia in addition to an elevation in serum creatine kinase (CK) greater than 10 times the upper limit of normal (CK >10 × ULN).
• The American College of Cardiology (ACC), American Heart Association (AHA), and National Heart, Lung, and Blood Institute (NHLBI) use myopathy as a general term referring to any disease of the muscles, which is the most common definition.

Mechanism

• Precise mechanisms underlying statin-associated myopathy are not well understood; however, theories do exist. Proposed mechanism  includes: 

1. Alterations in myocyte membrane cholesterol.
2. Depletion of isoprenoids that control myofiber apoptosis
3. Depletion of ubiquinone or coenzyme Q10 (CoQ₁₀)  

Clinical Feature

• Typically present as proximal, symmetric muscle weakness and/or soreness
•  Muscle tenderness and there may be functional impairments such as difficulty raising the arms above the head, arising from a seated position, or climbing stairs; these symptoms are often described as fatigue or tiredness by the patient
• Less often the discomfort is asymmetric.
• Other symptoms may include unintentional weight loss, tachycardia, nausea, and brown urine from myoglobin breakdown.

Time to Onset of Symptoms

• Within weeks to months after the initiation of statin therapy but may occur at any time during treatment
• Some other reference claimed , generally  patients may tolerate statin therapy for up to 1 year before statin myopathies occur. Nevertheless, statin therapy in combination with fibrates, particularly gemfibrozil, may induce reactions in a little over 30 days.
• Normally myalgias and weakness resolve and serum creatine kinase concentrations return to normal over days to weeks after discontinuation of the drug. 

 Evaluation of Patient that Develops Myalgia

• CK level should be measured to rule out rhabdomyolysis (CK levels >10 times the upper limit of normal values or elevation of serum creatinine levels), which mandates immediate stopping of the statin and prompt hydration.
• Assess the presence of contributing factors, such as lifestyle modification, concomitant medication, hypothyroidism and vitamin D deficiency) .

 Proposed evaluation for statin associated myopathy

References: 

1. (Bitzur et al., 2013)Bitzur, R., Cohen, H., Kamari, Y., Harats, D., Shalev, V., Chodick, G., … Spezzi, A. (2013). Intolerance to statins: mechanisms and management. Diabetes Care, 36 Suppl 2(Supplement 2), S325–30. http://doi.org/10.2337/dcS13-2038
2. http://www.medscape.com/viewarticle/759844_5                                   
3. www.uptodate.com.
   

Drugs and Tinnitus

Drugs and Tinnitus

• According to British Tinnitus Association, number of people who report tinnitus while taking drug is tiny, usually less than 1 people in 1000 people for most drugs for cholesterol lowering drugs, high blood pressure drugs, and most antidepressant.
• Despite that, there are small number of drugs that do cause tinnitus. In general, the dose would correlate to the worsening of symptoms.  

• Aspirin – taken in high doses
• Quinine & some other anti-malarial drugs
• Aminoglycoside antibiotics – eg Gentamicin, Amikacin
• Cytotoxic drugs – eg Cisplatin, Vincristine
• Diuretics – eg Frusemide
• Antibiotics – eg Polymixin B , Erythromycin, Vancomycin

Statin and Tinnitus

• Statin is a drug class used extensively for hyperlipidaemia.
• While some patients cite tinnitus as a statin adverse effect, but trends to tinnitus benefit have also been reported.

Can Statin Cause Tinnitus?

• In an article by (Cianfrone, 2011), out of all statins, only Atorvastatin has been linked to both tinnitus while other statins has been linked to vertigo.
• A case report by (Liu et al, 2012) reported a case of tinnitus in a 32-year old. In the case report, the man which develops tinnitus after six months of taking atorvastatin which resolves spontaneously. By 18 months however, tinnitus becomes continuous.
• By self reporting, number of reports of tinnitus following use of simvastatin is as in figure below.

*Despite many reports of drugs causing tinnitus, only few scientifically confirmed cases as tinnitus might coincide while patient is taking the medicine.  
Can Statin Cure Tinnitus?

• There are currently no FDA approved drugs to treat tinnitus. Based on article by (Salvi et al, 2009) Atorvastatin is amongst drug that is studied for treatment of tinnitus.
• Based on study by (Olzowy et al, 2007), Atorvastatin resulted in a trend toward a beneficial effect of relieving tinnitus although it was not statistically significant when compared with placebo.

 Pharmacological Justification

• Based on study by (Golomb & Meskimen, 2012), statins have both antioxidant and prooxidant effects, tinnitus effects might depend on which predominate.
• Bidirectional effects of statins on oxidative stress/energetics may contribute to variable and perhaps bidirectional effects on tinnitus.

References: 

1. Olzowy, B., Canis, M., Hempel, J.-M., Mazurek, B., & Suckfüll, M. (2007). Effect of atorvastatin on progression of sensorineural hearing loss and tinnitus in the elderly: results of a prospective, randomized, double-blind clinical trial. Otology & Neurotology : Official Publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology, 28(4), 455–8. http://doi.org/10.1097/01.mao.0000271673.33683.7b
2. Liu, M., Alafris, A., Longo, A. J., & Cohen, H. (2012). Irreversible atorvastatin-associated hearing loss. Pharmacotherapy, 32(2), e27–34. http://doi.org/10.1002/PHAR.104)
3. Salvi, R., Lobarinas, E., & Sun, W. (2009). Pharmacological Treatments for Tinnitus: New and Old . Drugs of the Future, 34(5), 381–400. http://doi.org/10.1358/dof.2009.034.05.1362442
4. Cianfrone, G., Pentangelo, D., Cianfrone, F., Mazzei, F., Turchetta, R., Orlando, M. P., … Cianfrone, G. (2011). Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus: a reasoned and updated guide.
5. http://vestibular.org/tinnitus
6. http://vestibular.org/sites/default/files/page_files/Tinnitus%20Ringing%20in%20the%20Ears.pdf
7. http://www.tinnitus.org.uk/drugs-food-and-drink