Transcript core area 3: cardiovascular & ischaemic heart disease

CORE AREA 3:
CARDIOVASCULAR
& ISCHAEMIC
HEART DISEASE
CASE STUDY
Mr. RM takes these medications on a
regular basis:
Pravastatin 40mg nocte
Gemfibrozil 600mg BD
Captopril 25mg BD
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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.
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RHABDOMYOLYSIS
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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 (NONTRAUMATIC)
RHABDOMYOLYSIS
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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
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HMG-CoA
Pravastatin 
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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: a fibric acid derivative, activates peroxisome proliferatoractivated 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.
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GEMFIBROZIL & STATINS
The drug drug interaction!
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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
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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
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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
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Both measured by an enzyme-coupled
system similar to Creatine Kinase analysis
The disappearance of NADH is
continuously monitored at 340nm
AST
+ -Ketoglutarate < AST >Oxaloacetate + LGlutamate
Oxaloacetate + NADH < Malate dehydrogenase > Malate + NAD+ +
H+
L-Aspartate
ALT
+ -Ketoglutarate < AST > Pyruvate + LGlutamate
Pyruvate + NADH < Lactate dehydrogenase > Lactate + NAD+ + H+
L-Alanine
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
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Lactic Dehydrogenase
Range: 110-230 units/L
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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
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Creatine Kinase
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CK catalyses the regeneration of ATP
Creatine + ATP  Creatine phosphate +
ADP
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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
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Oliver and Rosalki Method
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An enzyme-coupled system, using reverse
reaction
The production of NADH is continuously
monitored at 340nm
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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.
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(Micromedex)
Creatine Kinase Isoenzymes
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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 for Myocardial Infarction (MI)
CK-BB: Predominate in brain
Normally undetectable in plasma
Analysis of CK Isoenzymes
Method
Usage
1. Electrophoresis
Still frequently
used
Rarely used
2. Ion-exchange
3. Immunoinhibition
4. Mass assay
Comments
Separates all 3
Shows atypical bands
Carryover effect of CK-MM
chromatography
greatly CK-MB
Infreq. used
CK-BB and macro-CK may
CK-MB levels
Most frequently
used
Fast, specific for CK-MB
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-MB
SOLID-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 CKisoenzymes
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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
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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
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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.
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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.
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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.
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Treatment of
Rhabdomyolysis
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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:
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Saline 0.45%, with
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Sodium bicarbonate 40meq (1-2 ampoules)
and
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Mannitol 10 grams per litre
2. Contraindications:
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Persistent oliguria despite hydration as
listed above
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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
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Anticipate serum calcium increase in the
recovery phase
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Calcium re-mobilized from injured tissues
Monitoring of elderly with
co-morbid conditions
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2.
3.
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
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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
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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.