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ISCHEMIC HEART DISEASE

ISCHEMIC HEART DISEASE. GROUP B. 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. Recent blood test.

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ISCHEMIC HEART DISEASE

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  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 JB’s 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 <3.5mmol/L) • This formula is not valid if chylomicrons, IDL or serum triglyceride concentration >4.6 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

  9. 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)

  10. β-blockers and  TG Cholesterol ↓ ↑ Triglycerides cytoplasm LIVER Fatty acid Malonyl-Co A β-blockers – Acetyl Co-A ATP AC - Citrate cAMP + β2-agonist 5’-AMP Lijnen P. Am Heart J 1992(124) p549-56

  11. β-blockers and  HDL β-blockers LIVER VLDL - LPL + β2-agonist HDL3 FFA L-CAT IDL HDL2 Apo B,E receptors in liver and other tissues HDL1 LDL Peripheralcell From Lijnen P. Am. Heart J 1992;124:549-56

  12. β-blocker and HDL Liver cells (excretion) HDL - β-blockers LCAT + β2-agonist Tissue cell Unesterified cholesterol

  13. Cardioselectivity or intrinsic sympathomimetic activity of beta blockers on lipid profiles • ↑TG and ↓ HDL levels: Non-selective > Selective > with ISA

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

  15. Efficacy of statins Based on LDL lowering potency on a mg per mg basic: atorvastatin > simvastatin > pravastatin > fluvastatin

  16. 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

  17. Advantages and the Rationale for the use of Friedewald’s 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.

  18. 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 TG>2000mg but acceptable and completely unacceptable at TG>4000mg. • Since TGs are measured the patient should be fasting for 12 hours prior to the test.

  19. 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.

  20. 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

  21. Lipid levels Total cholesterol Triglycerides HDL Liver function AST ALT Electrolytes Sodium Calcium Phosphate Blood pressure Further clinical chemistry examinations

  22. Monitoring lipid levels • Continue monitoring total cholesterol, triglycerides and HDL • To ensure condition is controlled

  23. 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 >3 times normal range • CK is >10 times normal range • Unexplained muscle pain and CK >4 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,

  24. 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

  25. 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

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