ddrery

1. Drugs for
Hyperlipidemia
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2. Overview: Hyperlipidemia
• Elevated cholesterol levels (hyperlipidemia) may be due to
lifestyle factors (E.g. lack of exercise or diet containing excess
saturated fats).
• Hyperlipidemia can also result from an inherited defect in
lipoprotein metabolism or, more commonly, from a combination
of genetic and lifestyle factors.
• Coronary heart disease (CHD), the leading cause of death
worldwide, is correlated with elevated levels of LDL-C and
triglycerides, and low levels of HDL-C. 2

3. Drugs for Hyperlipidemia
• Antihyperlipidemic drugs include
Statins, Niacin, fibrates
Bile acid sequestrants, cholesterol absorption inhibitor,
Proprotein convertase subtilisin kexin type 9 (PCSK9)
inhibitors
Omega-3 fatty acids.
• These agents may be used alone or in combination.
• However, drug therapy should always be accompanied by
lifestyle modifications, such as exercise and a diet low in 3

4. Drugs for Hyperlipidemia ….
HMG CoA reductase inhibitors (statins)
• lower LDL-C, resulting in a substantial reduction in coronary
events and death from CHD.
• Therapeutic benefits include atherosclerotic plaque stabilization,
improvement of coronary endothelial function, inhibition of
platelet thrombus formation, and vascular anti-inflammatory
activity.
• They are first-line treatment for patients with elevated risk of
ASCVD to reduce the occurrence of ASCVD events
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5. HMG CoA reductase inhibitors (statins): MOA
• Lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin,
pitavastatin, and rosuvastatin are competitive inhibitors of HMG
CoA reductase, the rate-limiting step in cholesterol synthesis.
• deplete the intracellular supply of cholesterol w/c causes the cell
to increase the number of cell surface LDL receptors that can
bind and internalize circulating LDL-C.
• The HMG CoA reductase inhibitors also decrease triglyceride
levels and may increase HDL-C in some patients.
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6. HMG CoA reductase inhibitors : Pharmacokinetics
• Lovastatin and simvastatin are lactones that are hydrolyzed to
the active drug.
• The remaining statins are all administered in their active form.
• Absorption of the statins is variable (30% to 85%) following oral
administration.
• All statins are metabolized by CYP450 isoenzymes in the liver,
except pravastatin.
• Excretion takes place principally through bile and feces, but
some urinary elimination also occurs 7

7. HMG CoA reductase inhibitors : Adverse effects
• Elevated liver enzymes may occur with statin therapy
liver function should be evaluated prior to starting therapy
• Myopathy and rhabdomyolysis (disintegration of skeletal muscle;
rare)
• increase the effect of warfarin
Evaluate INR when initiating a statin or changing the dosage.
• are contraindicated during pregnancy, lactation, and active liver
disease.
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8. Niacin (nicotinic acid): Mechanism of action
• Niacin strongly inhibits lipolysis in adipose tissue, thereby
reducing production of free fatty acids w/c are major precursor
for triglyceride synthesis in the liver
• Reduced liver triglyceride levels decrease hepatic VLDL
production, which in turn reduces LDL-C plasma concentrations.
• reduces LDL-C by 10% to 20% and is the most effective agent for
increasing HDL-C.
• lowers triglycerides by 20% to 35% at typical doses of 1.5 to 3
g/day.
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9. Niacin (nicotinic acid): Mechanism of action
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10. Niacin (nicotinic acid): PK & Therapeutic uses
• Niacin is administered orally.
• It is converted in the body to nicotinamide, which is
incorporated into the cofactor nicotinamide adenine
dinucleotide (NAD+).
• Niacin, its nicotinamide derivative, and other metabolites are
excreted in the urine
• Because niacin lowers plasma levels of both cholesterol and
triglycerides, it is useful in the treatment of familial
hyperlipidemias.
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11. Fibrates: Mechanism of action
• Fenofibrate and gemfibrozil are derivatives of fibric acid that
lower serum triglycerides and increase HDL-C.
• They decreased triglyceride concentrations through increased
expression of lipoprotein lipase and decreased apolipoprotein
(apo) CII concentration.
• Fibrates also increase HDL-C by increasing the expression of apo
AI and apo AII.
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12. Bile acid sequestrants (Resins)
• Cholestyramine, colestipol and colesevelam are anion-exchange
resins that bind -vely charged bile acids and bile salts in the
small intestine
• The resin/bile acid complex is excreted in the feces, thus
lowering the bile acid concentration.
• hepatocytes increase conversion of cholesterol to bile acids,
• intracellular cholesterol concentrations decrease, which
activates an increased hepatic uptake of LDL-C particles,
leading to a decrease in plasma LDL-C. 13

13. Cholesterol absorption inhibitor
• Ezetimibe selectively inhibits absorption of cholesterol in the
small intestine (SI), leading to a decrease in the delivery of
intestinal cholesterol to the liver.
• This causes a reduction of hepatic cholesterol stores and an
increase in clearance of cholesterol from the blood.
• ezetimibe is often used as an adjunct to maximally tolerated
statin therapy in patients with high ASCVD risk, or in statin-
intolerant pts
• it is metabolized in the SI & liver with subsequent biliary and
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14. Protein convertase subtilisin kexin type 9 inhibitors
• PCSK9 binds to the LDL receptor on the surface of hepatocytes,
leading to the degradation of LDL receptors.
• By inhibiting the PCSK9 enzyme, more LDL receptors are
available to clear LDL-C from the serum.
• Alirocumab and evolocumab are PCSK9 inhibitors
• are only available as Sc and are administered every two to four
weeks.
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15. Protein convertase subtilisin kexin type 9 inhibitors
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16. Characteristics of antihyperlipidemic drug families
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