ISCHEMIC HEART DISEASE

1
ISCHEMIC HEART DISEASE
GROUP B
2
Medication history

• Mr JB, aged 45 years, has been taking the
  following medications on a regular basis for at
  least 2 years.
• Atorvostatin 10mg mane
• Metoprolol 100mg BD
• Prednisolone 5mg 1.5 D

3
Recent blood test
4
Explanation of these results

• Poor lifestyle factors
• (high fat diet and/or lack of exercise)
• Poor compliance with statin therapy
• Administration of drugs which cause disturbances
  in lipid metabolism as a side effect

5
Action Of Statin

• Competitively inhibit HMG CoA reductase
• (rate limiting enzyme in cholesterol synthesis)
• ? cholesterol levels
• Specific Effect
• ? hepatic cholesterol uptake from blood, HDL
• (small extent)
• ? total cholesterol, LDL, triglycerides
• (modest extent)

6
Calculation of Mr JBs LDL

• Using Friedewald formula
• LDL tot cholesterol HDL Triglycerides
  (mmol/L)
  2.19
• 7.8 0.7 2.9/2.19
• 5.8mmol/L (reference lt3.5mmol/L)
• This formula is not valid if chylomicrons, IDL or
  serum triglyceride concentration gt4.6 mmol/L!!!

7
Potential Drug Causes-Prednisolone Prednisolone
5mg 1.5 D

• Exogenous glucocorticoid that facilitates
  synthesis of cAMP dependent protein kinase
• Catecholamines and various hormones activate
  adenylate cyclase
• ? cAMP, which activates the protein kinase
• Activation of protein kinase leads to
  phosphorylation and activation of lipase
• ? triglycerides, LDL and possibly HDL

8
Potential effects of metoprolol on lipid
profile.

• ?1 selective ? blocker (Metoprolol)
• Effects
• ? TG levels
• ? HDL levels

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CLASSES OF ?-BLOCKERS

• Non-selective ?-blockers
• ?1 selective ? blockers
• ?-blockers with ISA
• Actions of ?- blockers
• ? TG inhibit adenylate cyclase (AC)
• ? HDL inhibit lipoprotein lipase (LPL)
• inhibit lecithin cholesterol
  acyltransferase(LCAT)

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ß-blockers and ? TG
Cholesterol
?
Triglycerides
?
cytoplasm
LIVER
Fatty acid
Malonyl-Co A
ß-blockers

Acetyl Co-A
ATP
AC
-
Citrate
cAMP

ß2-agonist
5-AMP
Lijnen P. Am Heart J 1992(124) p549-56
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ß-blockers and ? HDL
ß-blockers
LIVER
VLDL
-
LPL

ß2-agonist
HDL3
FFA
L-CAT
IDL
HDL2
Apo B,E receptors in liver and other tissues
LDL
HDL1
Peripheral cell
From Lijnen P. Am. Heart J 1992124549-56
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ß-blocker and ?HDL
Liver cells (excretion)
HDL
ß-blockers
-
LCAT

ß2-agonist
Tissue cell
Unesterified cholesterol
13
Cardioselectivity or intrinsic sympathomimetic
activity of beta blockers on lipid profiles

• ?TG and ? HDL levels
• Non-selective gt Selective gt with ISA

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Comparisons of Statins
Fluvastatin
Atorvastatin
Simvastatin
Pravastatin
Characteristics
40
80
80
40
Maximal dose (mg/day)
24
60
47
34
Maximal serum LDL-C reduction produced ()
24
50
41
34
Serum LDL-C reduction produced ()?
10
29
18
24
Serum TG reduction produced ()?
8
6
12
12
Serum HDL-C increase produced ()?
15
Efficacy of statins

• Based on LDL lowering potency on a mg per mg
  basic
• atorvastatin gt simvastatin gt pravastatin gt
  fluvastatin

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Equation used to estimate LDL levels

• The Friedewald Study and Equation
• By using the principle that total cholesterol is
  made up of a percentage of various lipoproteins
  and that VLDL carry most of the circulating TGs
  (and thus can be estimated as TG/5 mg/L or TG/2.2
  mmol/L), the following equation was derived
• LDL total cholesterol HDL triglycerides
• 2.19

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Advantages and the Rationale for the use of
Friedewalds formula.

• Since LDL levels are difficult to measure, an
  empirical calculation is quick and simple,
  compared to direct measurements.
• It is universal used and thus more convenient
  when comparing LDL levels.
• Is thus the benchmark in terms of the routine
  measuring of LDL.

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Disadvantages and Limitations of Friedewald

• There is a large variability when using the
  Friedewald calculation due to the additive errors
  of using three variables in one equation.
• As TGs increases the proportion of VLDL decreases
  and LDL increases where the calculations become
  less relevant at TGgt2000mg but acceptable and
  completely unacceptable at TGgt4000mg.
• Since TGs are measured the patient should be
  fasting for 12 hours prior to the test.

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Other Methods of Measuring LDL

• Ultracentrifugation
• By exploiting the different densities of each
  lipoprotein, ultracentrifugation separates the
  lipoproteins where the lightest lipoprotein
  floats to the top and is precipitated. Thus, VLDL
  is precipitated first and then LDL afterwards.
  The process of ultracentrifugation and then
  precipitation is called Beta-quantification.
• Ultracentrifugation is very tedious and time
  consuming. The lipoproteins are very labile and
  can be altered by the high salt concentrations or
  centrifugal forces. Furthermore, various
  equipment is used making conditions and results
  difficult to reproduce.

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Gradient gel electrophoresis

• Method for measuring particle size of LDL
• Gel prepared with different concentrations of
  acrylamide
• Form a mesh like matrix
• Higher gel-solution concentration form a tighter
  mesh so larger molecules cannot pass through.
• Distance of migration depends on the size of
  molecule and concentration gradient of the gel
• Slow technique, expensive due to gel cost,
  variable due to gel characteristics

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Further clinical chemistry examinations

• Lipid levels
• Total cholesterol
• Triglycerides
• HDL
• Liver function
• AST
• ALT

• Electrolytes
• Sodium
• Calcium
• Phosphate
• Blood pressure

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Monitoring lipid levels

• Continue monitoring total cholesterol,
  triglycerides and HDL
• To ensure condition is controlled

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Monitoring liver function

• Atorvastatin could increase transaminase (AST,
  ALT) and creatinine kinase (CK)
• Monitor AST, ALT and CK levels
• Cease Atorvastatin if
• AST/ALT are persistently elevated to gt3 times
  normal range
• CK is gt10 times normal range
• Unexplained muscle pain and CK gt4 times normal
  range
• If mild myopathy/myositis resume treatment after
  4 weeks when levels returned to normal
• Permanently ceased if problem recurs
• Use alternatives such as fibrates,

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Monitoring elctrolytes

• Monitor electrolytes
• In particular Na, K, Ca, PO4
• Prednisolone may cause
• Na and fluid retention
• Increase blood pressure
• Lead to heart failure
• Inhibit absorption from GI and kidney
• Cause PTH released
• Inhibit PO4 reabsorption from renal tubules
• Causing bone resorption

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Monitoring blood pressure

• Na and fluid retention caused by Prednisolone
  result in increase blood pressure.
• Blood pressure could also be affected by
  Metoprolol
• Decreased in blood pressure