CASE STUDY • Mr. RM takes these medications on a regular basis: Pravastatin 40mg nocte Gemfibrozil 600mg BD Captopril 25mg BD
CASE STUDY • Mr. RM was admitted to A&E with complaints of progressive muscle weakness, muscle pain and brown urine; all of which had developed over the last week. • He has a history of muscle weakness associated with trials of simvastatin and atorvastatin.
RHABDOMYOLYSIS • A rare but clinically significant ADR of statin monotherapy of combination therapy. • A clinical and biochemical syndrome resulting from skeletal muscle injury with the release of muscle contents into the plasma. • May result from either direct muscle injury, or from altered metabolic relationship between energy production and consumption in muscle.
CAUSES OF (NON-TRAUMATIC) RHABDOMYOLYSIS • Strenous physical exercise • Malignant hyperthermia • Muscle ischaemia, resulting from compression or cascular injury)infections • Myopathies • Toxins and drugs, including alcohol, which accounts for 20% of cases. This syndrome has been described with fibrates and statin lipid lowering drugs.
GEMFIBROZIL & STATINS STATINS: a class of HMG CoA reductase inhibitors that lower cholesterol and reduce the risk of coronary heart disease. Acetyl-CoA HMG-CoA Pravastatin Mevalonic Acid Cholesterol CoEnzyme Q10 • ALL statins have been associated with cases of rhabdomyolysis. • Rhabdomyolysis is linked to a deficiency in CoEnzyme Q10 levels (responsible for mitochondrial function myopathy; important for skeletal and cardiac muscle function). GEMFIBROZIL: afibric acid derivative, activates peroxisome proliferator-activated nuclear receptors and modulates lipoprotein synthesis and catabolism • Myalgia and muscle weakness, with elevated serum CK has been reported with fibrates. However, myopathy progressing to rhabdomyolysis is rare with fibrate therapy.
GEMFIBROZIL & STATINS The drug drug interaction! • Combination therapy of a statin and a fibrate is very effective treatment for combined hyperlipidemia (LDL, TG and HDL levels). • However, concomitant use leads to an increase risk of myopathy, rhabdomyolysis and renal failure. Fatal cases has involved the use of gemfibrozil. • In short term studies, the risk of myopathy is low, however the adverse effects may be delayed i.e. only seen in patients on long term therapy.
Role of Enzymes – Liver Function • ALT (Alanine Aminotransferase) and AST (Aspartate aminotransferase) • Indicator of liver cell damage • Leak into circulation when liver is damaged • ALT specific indicator of liver inflammation • AST indicator of other organs eg. Heart. • Range : ALT: 5-40 units/L AST: 10-45 units/L
AST and ALT • Alanine Aminotransferase (ALT) is found primarily in liver cells • ALT levels are greatly increased in Liver diseases, and to a lesser extent in other diseases • Aspartate Aminotransferase (AST) has same concentration in heart, skeletal muscle and liver • AST levels increase equally in liver and other diseases eg. MI, muscle diseases
Measurement of AST and ALT • Both measured by an enzyme-coupled system similar to Creatine Kinase analysis • The disappearance of NADH is continuously monitored at 340nm AST L-Aspartate + -Ketoglutarate < AST >Oxaloacetate + L-Glutamate Oxaloacetate + NADH < Malate dehydrogenase > Malate + NAD+ + H+ ALT L-Alanine + -Ketoglutarate < AST > Pyruvate + L-Glutamate Pyruvate + NADH < Lactate dehydrogenase > Lactate + NAD+ + H+
Elevation of AST and ALT ALT - Liver Specific • Hepatitis • Liver necrosis • Cholestasis • Crush injuries, trauma • Muscle disease • MI • Pancreatitis • AST • Hepatitis • Liver necrosis • Cholestasis • Crush injuries, trauma • Muscle disease • MI • Pancreatitis
AST and ALT in Rhabdomyolysis • AST levels are significantly elevated secondary to muscle ischemia and necrosis. • ALT levels are also increased in rhabdomyolysis • Hepatic dysfunction appears in approximately 25% of patients with rhabdomyolysis
Lactic DehydrogenaseRange: 110-230 units/L • detect tissue damage and aides in the diagnosis of liver disease. • Lactic dehydrogenase is a type of protein (an isoenzyme) that is involved in the body's metabolic processes • LDH is in many body tissues, especially the heart, liver, kidney, skeletal muscle, brain, blood cells, and lungs.
Methods of measuring LDH Pyruvate to Lactate • Most frequently used method • Pyruvate + NADH pH 7.0 > Lactate + NAD+ • Rate of disapperance of absorption of NADH at 340nm measured
Elevations in LDH LDH is increased in; • Myocardial Infarction • hepatocellular damage • haemolytic and megaloblastic anaemia • skeletal muscle disease • kidney damage • various malignant diseases eg leukaemia
LDH in Rhabdomyolysis • LDH levels increases in rhabdomyolysis secondary to muscle ischemia and necrosis • Levels usually peak within 3 days
Creatine Kinase • CK catalyses the regeneration of ATP Creatine + ATP Creatine phosphate + ADP • Forward reaction occurs when muscles contract (pH 9.0) • Reverse reaction allows regeneration of ATP ( pH6.8) • Widely distributed in the skeletal muscle (highest activity), cardiac muscle and brain
Analysis of Creatine Kinase • Oliver and Rosalki Method • An enzyme-coupled system, using reverse reaction • The production of NADH is continuously monitored at 340nm • 1. Creatine phosphate + ADP pH 6.8 Mg++ > Creatine + ATP • 2. ATP + Glucose Hexokinase >Glucose-6-phosphate + ADP • 3. Glucose-6-phosphate + NAD+ < G6PD > 6-Phosphogluconate + NADH + H+
Elevated Levels of CK (>250U/L) Large Increase • MI • Shock, circulatory failure • Muscle disorders eg. Muscular dystrophy, Polymyositis • Rhabdomyolysis • Small Increase • muscle injury • surgery • physical exercise • muscle cramp • epileptic fit • Hypothyroidism
CK in Rhabdomyolysis • Elevated serum CK levels is one of the most important diagnostic criteria of Rhabdomyolysis • CK > 5 x normal level without evidence of cardiac or brain injury • Level of CK varies with injury • CK elevations tend to peak 24-48h after initial insult then gradually decrease in 5-7 days. (Micromedex)
Creatine Kinase Isoenzymes • CK is a dimer, composed of two subunits M(muscle) and B(brain) three isoenzymes formed • CK-MM: Predominate in skeletal muscle 95% of plasma CK activity • CK-MB: Highest amount in cardiac tissue < 5% of plasma CK activity. Used as a marker forMyocardial Infarction (MI) • CK-BB: Predominate in brain Normally undetectable in plasma
Analysis of CK Isoenzymes Method Usage Comments 1. Electrophoresis Still frequently Separates all 3 used Shows atypical bands 2. Ion-exchange Rarely used Carryover effect of CK-MM chromatography greatly CK-MB 3.Immunoinhibition Infreq. used CK-BB and macro-CK may CK-MB levels 4. Mass assay Most frequently Fast, specific for CK-MB used Drugs and hemolysis don’t interfere.
Mass Assay 1. Antibody attached to solid phase binds the B subunit of CK-MB [SOLID-Ab-(B)(M)] 2. The CK-MM in solution can’t bind, washed away. 3. Labelled Antibody binds to M subunit of CK-MBSOLID-Ab1-(B)(M)-Ab2-label 4. Remainder labelled antibody washed away, only CK-MB detected (label won’t bind to CK-BB undetectable) Label usually an enzyme eg Alkaline Phosphatase
Elevations of CK-isoenzymes • CK-MM:Increased in muscle disorders or injury, MI. Significantly raised in rhabdomyolysis • CK-MB: MI, Increased in certain muscle disorders, eg. Muscular dystrophy and polymyositis. Is increased in some forms of rhabdomyolysis, as it is present in small amounts in the skeletal muscle • CK-BB: Not usually detected in plasma even in brain damage, therefore it is not detected in rhabdomyolysis
Rhabdomyolysis and CK • Creatine Kinase (CK) is an indicator of muscle damage and acute MI. • Rhabdomyolysis is associated with CK >40x upper limit of the normal range. • Acute MI is associated with CK-MB is >9mg/mL and >2.5% total CK. (CK-MB is a CK isoenzyme and is compared with CK to diagnose acute MI.) • Mr. RM presents with rhabdomyolysis (>150x CK) but not acute MI (CK-MB <2.5% total CK).
Rhabdomyolysis and other LFT • Bilirubin: myoglobin is cleared by renal excretion and metabolsim to bilirubin. An elevation of myoglobin present in rhabdomyolysis results in increased clearance, thus increasing bilirubin. • Alkaline Phosphatase (ALP): indicates extrahepatic obstruction and severe liver damage. Values may increase with age, impaired bile formation and bone growth. It is not affected by muscle breakdown. • Gamma-glutamyl transpeptidase (GGT): A liver microsomal enzyme involved in amino acid and peptide transport and glutathione metabolism. It may be elevated in severe tissue damage, thus may be elevated in rhabdomyolysis. • Total Protein: Total protein is unaffected by rhabdomyolysis. It is decreased with kidney disease.
Rhabdomyolysis and renal function. • Damaged muscles release myoglobin. • Myoglobin enters the kidneys and may cause direct nephrotoxicity, causing cell damage and a reduction in blood flow in the outer medulla. • There is therefore a possibility of rhabdomyolysis causing acute renal failureThis occurs in 20% patients with rhabdomyolysis.
Factors predisposing to rhabdomyolysis • Concurrent use of statins with drugs that inhibit CYP 450. This causes an inhibition on statin metabolism via glucoronidation (eg fibrates). An increase in statin concentration results. • Factors increasing the risk of muscle damage include hypertension, age, ischaemia, hypothyroidism, infections, direct muscle injury and sustained muscular activity.
Treatment of Rhabdomyolysis • Initial: Forced diuresis to prevent all episodes of acute renal failure • 1.Start immediately (especially in the first 6hrs) • 2.Protocol: • Normal saline 1.5litres per hour • Urine output should approach 300ml/hour • 3.End point: • No myoglobinuria • Creatine kinase less than 1000units per litre
Maintenance: Alkalinise Urine pH>6.5 1.Protocol: • Saline 0.45%, with • Sodium bicarbonate 40meq (1-2 ampoules) and • Mannitol 10 grams per litre 2. Contraindications: • Persistent oliguria despite hydration as listed above • Hypocalcemia (provoked by sodium bicarbonate)
Precautions 1.Aggressive hydration is critical 2.Avoid diuretics (loop or other types), as they don’t improve and may actually comprise the final renal outcome 3.Do not correct hypocalcaemia unless symptomatic • Anticipate serum calcium increase in the recovery phase • Calcium re-mobilized from injured tissues
Monitoring of elderly with co-morbid conditions • Intensive care unit admission • Hourly vital signs closely monitored including input and output • Consider invasive monitoring
Rhabdomyolysis: Symptoms and Signs 1. Muscular symptoms: • Muscle pain, weakness, tenderness and stiffness 2. Urinary findings: • Dark urine typically brown in colour 3. Constitutional symptoms: • Malaise, fever, tachycardia, nausea
Significance of Dark Urine • Dark urine is often the first clue to the diagnosis of rhabdomyolysis, and the colour change is the consequence of myoglobinuria • Myoglobin is released from a disrupted muscle cell into the blood stream, it travels to the kidney and it is filtered out • Myoglobin doesn’t directly damage the kidney, but in great enough concentration it will cause damage indirectly. • It clogs up the kidney, restricting the blood supply to the kidney tissue creating myoglobinuric nephrosis & possibly renal failure • It is also the myoglobin being filtered out that shows up as very dark urine.
References • Walker R and Edwards C, Clinical Pharmacy and Therapeutics. 2003 • Hamilton-Craig I, Australian Prescriber 26: p74-5, 2003 • The Merck Manual 17th edition 1999 • Casteels K, Beckers D, Wouters C, Van Geet C. Rhabdomyolysis in diabetic ketoacidosis. Pediatric Diabetes 2003: 4: 29—31 • APF 18 • Harrison’s Principles of Internal Medicine, 15th ed. 2001, Braunwald E., Fauci A., Isselbacher K., Kasper D., Hauser S., Longo D., Jameson J.