3. TREATMENT STRATEGIES
1. Diet:
Cholesterol and saturated fats are the primary dietary factors that contribute to
elevated levels of plasma lipoproteins.
Dietary measures designed to reduce the total intake of these substances
constitute the first method of management and may be sufficient to reduce
lipoprotein levels to a safe range.
Because alcohol raises triglyceride and very-low-density lipoprotein (VLDL)
levels, it should be avoided by patients with hypertriglyceridemia
4. OMEGA-3 FATTY ACIDS
They are essential fatty acids that are used for triglyceride lowering. Essential
fatty acids inhibit VLDL and triglyceride synthesis in the liver, which decreases
serum triglyceride concentrations with small increases in LDL-C and HDL-C.
Two forms: Omega-3 PUFAs eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA).
Icosapent ethyl is a prescription product that contains only EPA and, unlike
other fish oil supplements, does not significantly raise LDL-C.
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5. 2.Drugs:
The choice of drug treatment is based on the lipid abnormality.
The drugs that are most effective at lowering LDL cholesterol include the HMG-
CoA reductase inhibitors, resins, ezetimibe, and niacin.
The fibric acid derivatives (eg, gemfibrozil), and niacin are most effective at
lowering triglyceride and VLDL concentrations and raising HDL cholesterol
concentrations.
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7. HMG-COA REDUCTASE INHIBITORS ( STATINS)
Mechanism and Effects:
Mechanism: Inhibit Enzyme HMG-CoA reductase.
The rate-limiting step in hepatic cholesterol synthesis is conversion of
hydroxymethylglutaryl coenzyme A (HMG-CoA) to mevalonate by HMG-CoA
reductase. The statins are structural analogs of HMG-CoA that competitively inhibit the
enzyme.
Effect: Reduce cholesterol synthesis and upregulate low-density lipoprotein (LDL)
receptors on hepatocytes with modest reduction in triglycerides. Statins can reduce LDL
cholesterol levels dramatically.
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8. EFFECT CONT.
A greater effect of statins is from the response to a reduction in a tightly regulated
hepatic pool of cholesterol to which The liver compensates by increasing the number
of high-affinity LDL receptors, which clear LDL and VLDL remnants from the blood.
HMG-CoA reductase inhibitors also have direct anti-atherosclerotic effects and
anti-inflammatory effects and have been shown to prevent bone loss.
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9. CLINICAL USE
They Reduce the risk of coronary events and mortality in patients with ischemic heart
disease. And Reduce the risk of ischemic stroke. So they are used for treatment of:
Acute coronary syndrome.
Primary and secondary prevention of Atherosclerotic vascular disease.
Rosuvastatin, atorvastatin, and simvastatin have greater maximal efficacy than the
other HMG-CoA reductase inhibitors. These drugs also reduce triglycerides and
increase HDL cholesterol in patients with triglycerides levels that are higher than
250 mg/dL and with reduced HDL cholesterol levels.
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10. PHARMACOKINETICS AND TOXICITY
Pharmacokinetics: Oral administration with a duration of 12-24h.
Toxicity: Myopathy, Hepatic dysfunction.
CYP-dependent metabolism (34a, 2c9) interacts with CYP
inhibitors/competitors.
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11. BILE ACID SEQUESTRANTS (RESINS)
Mechanism and Effects:
Mechanism: Binds bile acids in gut which prevents its reabsorption, increases
cholesterol catabolism and upregulates LDL receptors.
Resins are large nonabsorbable polymers that bind bile acids and similar steroids in the
intestine and prevent their absorption.
By preventing the recycling of bile acids, bile acid-binding resins divert hepatic
cholesterol to synthesis of new bile acids, thereby reducing the amount of cholesterol
in a tightly regulated pool.
Effect: A compensatory increase in the synthesis of high-affinity LDL receptors
increases the removal of LDL lipoproteins from the blood. Resulting in a modest
reduction in LDL cholesterol.
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12. CLINICAL USE
They are used in patients with hypercholesterolemia ( elevated LDL
cholesterol).
They have also been used to reduce pruritus in patients with cholestasis and
bile salt accumulation.
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13. PHARMACOKINETICS AND TOXICITY
Pharmacokinetics: Taken with meals and it’s not absorbed.
Toxicity: Constipation, bloating, interferes with absorption of some drugs and
vitamins.
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14. STEROL ABSORBING INHIBITOR (EZETIMIBE)
Mechanism and Effects:
Mechanism: Blocks sterol transporter NPC1L1 in intestine brush border.
Ezetimibe is a prodrug that is converted in the liver to the active glucuronide form. This
active metabolite inhibits a transporter that mediates gastrointestinal uptake of
cholesterol and phytosterols.
Effect:
By preventing absorption of dietary cholesterol and cholesterol that is excreted in bile, it
reduces the cholesterol in the tightly regulated hepatic pool.
A compensatory increase in the synthesis of high-affinity LDL receptors of hepatocytes
increases the removal of LDL lipoproteins from the blood.
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15. CLINICAL USE
Ezetimibe is used for treatment of:
Hypercholesterolemia
Phytosterolemia.
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16. PHARMACOKINETICS AND TOXICITY
Pharmacokinetics: Oral Administration with a duration of 24H.
Toxicity: low incidence of hepatic dysfunction, myositis.
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17. NIACIN (NICOTINIC ACID)
Mechanism and Effects:
Mechanism: Decreases catabolism of apolipoprotein (apo) A-I • reduces VLDL
secretion from liver.
Decreased HDL–apo A-I catabolism by niacin explains the increases in HDL
half-life
In the liver, niacin reduces VLDL synthesis, which in turn reduces LDL levels.
In adipose tissue, activates a signaling pathway that reduces hormone-
sensitive lipase activity and thus decreases plasma fatty acid and triglyceride
levels
Effects: Reduces LDL cholesterol, triglycerides, and VLDL and also often
increases HDL cholesterol.
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18. CLINICAL USE
Treatment of :
Hypercholesterolemia.
Hypertriglyceridemia
low levels of HDL cholesterol.
Elevated LDL in statin-unresponsive or intolerant patients.
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19. PHARMACOKINETICS AND TOXICITY
Pharmacokinetics and Toxicity:
Oral administration.
Toxicity: Gastric irritation, flushing, low incidence of hepatic toxicity, may
reduce glucose tolerance.
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20. FIBRIC ACID DERIVATIVES (FIBRATES)
Mechanism and Effects:
Mechanism: Peroxisome proliferator-activated receptor-alpha (PPAR-α) agonists.
PPAR-α protein receptor, is a receptor that regulates transcription of genes involved in
lipid metabolism.
This interaction with PPAR-α results in increased synthesis by adipose tissue of
lipoprotein lipase, which associates with capillary endothelial cells and enhances
clearance of triglyceride-rich lipoproteins.
Effects: In the liver, fibrates stimulate fatty acid oxidation, which limits the supply of
triglycerides and decreases VLDL synthesis. They also increase lipoprotein lipase activity,
and increase high-density lipoproteins (HDL).
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