Drugs for Hyperlipidemia Flashcards
Statins
HMG-CoA reductase inhibitos
Atorvastatin Fluvastatin Lovastatin Pitavastatin Pravastatin Rosuvastatin Simvastatin
Statins - MoA
HMG-CoA reductase converts HMG-CoA to mevalonic acid and is the rate-limiting enzyme in cholesterol biosynthesis. By competitively inhibiting this enzyme, statins reduce hepatic cholesterol biosynthesis and the amount of cholesterol available for incorporation into VLDL. This leads to compensatory increase in the number of hepatic LDL receptors, which increases hepatic uptake of LDL-C. Together, these actions cause a substantial reduction in LDL-C.
In patients with hypercholesterolemia, statins typically decrease LDL-C levels by 20% to 60%, whereas HDL-C levels are increased by up to 10%
The statins also reduce serum triglycerides but are usually not a sufficient treatment for hypertriglyceridemia
Statins - Clinical use
Reduce blood cholesterol levels in persons with Hypercholesterolemia.
Slow the progression of atherosclerosis, reduce the risk of CHD and other atherosclerotic vascular diseases, and reduce cardiac mortality rate.
May protect against osteoporosis and certain forms of cancer.
Statins - Adverse effects
GI problems; abdominal cramps, constipation, diarrhea, heartburn.
Hepatitis and elevated liver enzymes Rhabdomyolysis Muscle myopathy(earliest stage is myalgia, which consists of muscle ache or weakness without creatine kinase levels)
Myalgia can be followed by myositis or muscle inflammation accompanied by muscle pain, leakage of muscle creatine kinase into the plasma, and elevated creatine kinase levels
Myositis can eventually lead to rhabdomyolysis in which muscle cells disintegrate, thereby releasing myoglobin into the circulation
Myoglobin then accumulates in the kidneys and cause acute kidney failure
10-25% risk in incidence of diabetes
Statins - Interactions
Atrovastatin, lovastatin and simvastatin are metabolized by CYP3A4, plasma levels increases strong by inhibitors of this isozyme; erythromycin, itraconazole, ritonavir
Fluvastatin is metabolized by CYP2C9, and its plasma levels may be increased by inhibitors of this CYP, including some NSAIDs
They increase warfarin levels slightly by inhibiting warfarin metabolism.
Statins - Contraindications
Because statins , fibric acid derivatives, and niacin may cause myopathies, the combined use of drugs should be undertaken with greater caution using lower doses of each agent employed
Which statins are used for mixed hyperlipidemia?
Atorvastation and Rosuvastatin
Most potent statin
Second most potent satin
Rosuvastatin
Atorvastatin
Which statins crosses the blood brain barrier and can cause sleep disturbances?
Lovastatin and Simvastatin
Lovastatin - Interactions
Should be taken with evening meal to facilitate its absorption
Bile Acid-Bindings Resins
Cholestyramine
Colestipol
Colesevelam
Bile Acid-Bindings Resins - MoA
After resins bind to bile acids, the bile acid-resin complex is excreted. This action prevents the enterohepatic cycling of bile acid and obligates the liver to synthesize replacement bile acid from cholesterol. To obtain more cholesterol for this purpose, the liver increases the number of LDL receptors. Then the levels of LDL-C in the blood are reduced as more cholesterol is delivered to the liver
Bile Acid-Bindings Resins - Clinical use
Hypercholesterolemia in pat who cannot tolerate other drugs and in patients who are young.
Chronic diarrhea due to bile acid malabsorption
Bile Acid-Bindings Resins - Adverse effects
Constipation Fecal impaction GI side effect, nausea, vomiting. Irritation of the perianal area Skin rash
Bile Acid-Bindings Resins - Interactions
Decrease absorption of digoxin, thyroxin and warfarin.
Decreases absorption of fat soluble vitamins; A, D, E
Cholestyramine and Colestipol - Interactions
Bind to digoxin, thyroxin, warfarin and other drugs. For this reason, it is best to take the resins 2 hours before or after taking other medications
Ezetimibe - MoA
Absorbed from the intestines after oral adm, and mostly is converted to active ezetimibe-glucuronide. This metabolite is distributed by the circulation to the small intestines, where it localizes in the brush border and inhibits absorption of both biliary and dietary cholesterol. Acts by disrupting two protein, annexin-2 and caveolin-1, which mediates cholesterol transport in intestinal brush border cells.
Ezetimibe - Clinical use
Hypercholesterolemia
Ezetimibe - Adverse effects
Increases serum hepatic transaminase levels
Headache
Myalgia
Niacin - Classification
Vitamine B3
Niacin - MoA
Inhibiting the formation and secretion of hepatic VLDL, the major carrier of plasma triglycerides and the precursor of LDL. The effect on VLDL secretion is caused by inhibition of lipolysis in adipose tissue. This action reduces the supply of circulating free fatty acids that the liver uses to synthesize triglycerides for incorporation into VLDL. The inhibition of lipolysis has been attributed to the binding of niacin to a G-protein coupled receptor in adipose tissue. Niacin decreases LDL-C levels and LDL associated with atherosclerosis, at the same time it increases HDL-C levels. Decreases lipoprotein (a)
Niacin - Clinical use
Hypertriglycerdemia
Increase HDL-C levels in persons with abnormally low levels of this lipoprotein.
Primary hyperlipidemia
Mixed dyslipidemia
Reduce the risk of pancreatitis in pat with high triglyceride levels.
Reduces risk of myocardial infaction among men with hypercholesterolemia and atherosclerosis, and is decreased total mortality
Niacin - Adverse effects and Interactions
Vasodilation and flushing of the skin accompanied by pruritus and a feeling of warmth and tingling.
Elevate serum transaminase levels and cause hepatitis
Gastric distress Trigger peptic ulcers Increase glucose levels, but well tolerated in diabetes. Hyperuricemia and gout Myopathy
Interactions:
Fibrates or statins increase risk of myopathy
Avoid in pt w: PUD, acute liver disease, Pregnancy, Arterial bleeding
Fibric acid derivatives
Gemfibrozil
Fenofibrate
Fibric acid derivatives - MoA
Reduce serum levels of triglycerides and LDL-C while rasing levels of HDL-C. They activate a receptor in cell nuclei that regulates gene transcription and is called peroxisome proliferator activated receptor-a. In the liver and elsewhere, PPAR-a increases the transcription of certain genes while inhibition transcription of others. The effect of fibrate on serum triglyceride levels is attributed to PPAR-a mediated expression of lipoprotein lipase. This enzyme is in the vascular endothelium and catalyzes the hydrolysis and removal of triglycerides from VLDL, thereby lowering triglyceride levels. PPAR-a activation also reduces the expression of an inhibitor of lipoprotein lipase, apolipoprotein C-III. The effects of fibrates on HDL-C are attributed to PPAR-a mediated expression of apoproteins A-I and A-II for HDL. PPAR-a also increases the expression of cholesterol transport proteins (ATP-binding cassette transporters A1 and G1) involved in reverse cholesterol transport.
Fibric acid derivatives - Clinical use
Very high serum triglyceride levels (higher then 1500mg/dL) in order to prevent pancreatitis
Reduce the risk of developing Coronary Heart Disease in patients who have a triad of elevated LDL-C, low HDL-C, and elevated triglycerides, and whose lipidemia has not responded to lifestyle changes or other pharmacologic agents
Antiretroviral therapy
Fibric acid derivatives - Adverse effects
GI side effects Blood cell deficiency Hypersensitivity reactions Myopathy Rhabdomyolysis
Fibric acid derivatives - Contraindications
Given with statins
Hepatic/Renal disease
increased risk of gallstones
Fibric acid derivatives - Interactions
Cholestyramine and colestipol must be separated by two hours because the resins reduce fibrate absorption
Fenofibrate - MoA
Reduces serum LDL-C levels by increasing expression of hepatic LDL receptors and by increasing LDL receptor affinity, both via activation of PPAR-a. These actions increase the uptake of LDL-C by the liver and reduce serum LDL-C levels.
Drugs for Familial Hypercholesterolemia
Lomitapide
Mipomersen
Evolocumab
Alirocumab
Lomitapide - MoA
Act to reduce the production of VLDL in the liver
Inhibits the microsomal triglyceride transfer protein (MTTP), which is essential for VLDL assembly and secretion in the liver
Lomitapide - Clinical use
Homozygous familial hypercholesterolemia
Lomitapide - Adverse effects
GI side effects
Hepatic toxicity
Embryotoxicity
Lomitapide - Contraindications
Pregnancy because it is embryotoxic
Lomitapide - Interactions
Lomitapide decreases the absorption of fat-soluble vitamins A, D, and E, and omega-3 fatty acids. These nutrient should be supplemented in patients taking this drug
Inhibitors of CYP3A4 increases levels of Lomitapide
Lomitapide increases Warfarin levels
Mipomersen - MoA
Act to reduce the production of VLDL in the liver
Binds to the messenger RNA for apo-B, preventing synthesis of apo B required for VLDL production in the liver.
Mipomersen - Clinical use
Reduce LDL-C and apo B in persons with Homozygous familial hypercholesterolemia
Mipomersen - Adverse effects
Elevate serum transaminase levels Injection site reactions Flu-like symptoms Nausea Headache
Evolocumab and Alirocumab - MoA
Monoclonal antibody to a protease enzyme that destroys LDL receptors in the liver. This enzyme is known as proproteins convertase subtilisin/kexin type 9 (PCSK9). By this mechanism, the hepatic uptake of LDL cholesterol is increased, and the serum cholesterol level falls.
Evolocumab and Alirocumab - Clinical use
Homozygous or heterozygous familial hypercholesterolemia and for patients with demonstrated atherosclerotic cardiovascular disease who are not adequately treated with statins
Evolocumab and Alirocumab - Adverse effects
Injection site reactions
Allergic reactions
Elevated levels of hepatic enzymes
Drugs for Leptin Deficiency
Metreleptin
Metreleptin - MoA
Binds to and activates the leptin receptor, leading to increase in insulin sensitivity and reduced food intake
Metreleptin - Clinical use
Lipodystrophy
Indicated as replacement therapy (in addition to diet) for the complications of leptin deficiency in patients with congenital generalized or acquired generalized lipodystrophy
Metreleptin - Adverse effects
Neutralizing antibodies and a risk of lymphoma
