Antihyperlipidemic Drugs Flashcards
increased risk of cardiovascular mortality is closely linked to what
elevated level of LDL cholesterol
decreased level of HDL cholesterol
hypertriglyceridemia (esp with low HDLs)
other risk factors of cardiovascular diseases
smoking
obesity
diabetes
hypertension
primary causes of hyperlipidemia
monogenic diseases
genetic polymorphisms
gene environment interactions
how does excessive alcohol intake cause VLDL production
alcohol increases the synthesis of FA which are esterified to form triglycerides
how does type II DM cause hyperlipidemia
- insulin suppresses VLDL production by the liver but with insulin resistance in type II DM, there is lack of suppression and increased VLDL production
- also apoCIII levels are increased with insulin resistance leading to reduced breakdown of chylomicrons and VLDL
common secondary causes of hyperlipidemia
- hypertrigylcerides: DM, renal failure, hypothyroidism, alcohol excess, contraceptives, beta blockers, glucocorticoids
- hypercholesterolemia: hypothyroidism, nephrotic syndrome, obstructive liver disease, glucocorticoids
what can dyslipidemia cause
symptomatic vascular disease such as CAD and peripheral artery disease
high TGs can cause acute pancreatitis
how to diagnose hyperlipidemia
- measure serum lipids after 10 hour fast: gives you tot cholesterol, TGs, and HDL
- if TGs is less than 400mg/dL and patient has been fasting, LDL = TC - [HDL + (TG/5)]
5 main classes of drugs available for the treatment of hyperlipidemia
- HMG-CoA reductase inhibitors
- Niacin
- Bile acid binding resins
- Cholesterol absorption inhibitors
- fibrate derivatives
what are the HMG-CoA reductase inhibitors
FiRe SLAP
Fluvastatin Rosuvastatin Simvastatin Lovastatin Atorvastatin Pravastatin
mechanism of statins
- competitive inhibitor of HMG-CoA reductase the enzyme that catalyzes the first committed step of cholesterol synthesis
- therefore deplete intracellular cholesterol
- upregulation of LDL receptors
- increased clearance of LDL from the blood
- improve endothelial functions
- decrease platelet aggregation
- stabilize atherosclerotic plaque
- reduce inflammation
statin in order of decreased potency in lowering TGs and LDL
Rosuvastatin, Atorvastatin, Simvastatin, Lovastatin = Pravastatin, then last is Fluvastatin
RAS LP F
which statins are prodrugs and how are they activated
Lovastatin and Simvastatin which are inactive lactones that are hydrolyzed in the GI to yield the active beta hydroxyl derivatives
clinical uses of statins
- drug of choice for LDL reduction
- reduce cardiovascular mortality
- useful also when combined with bile acid binding resins, niacins, or ezetimbe
who does statins not benefit
those who are homozygous for familial hypercholesterolemia IIA because they have non functional LDL receptors
what types of people should not take statins
women who are pregnant, lactating, or likely to become pregnant
four major statin benefit groups
- pts with clinical atherosclerotic cardiovascular disease (ASCVD)
- pts with LDL 190mg/dL or higher
- pts 40-75 with diabetes and LDL 70-189mg/dL
- pts without ASCVD or diabetes with LDL 70-189mg/dL and an estimated 10 year risk of ASCVD or higher
adverse effects of statins
- elevation of aminotransferases
- myopathy and rhabdomyolysis
most effective drug for increasing HDL and most may reduce lipoprotein a
niacin
mechanism of niacin
- inhibits adenylyl cyclase in adipocytes (via Gi) –> inhibition of hormone sensitive lipase –> reduces transport of fatty acids to liver and decreases hepatic TG synthesis
- decreased TG –> decreased VLDL production –> reduced LDL levels
- increases LPL –> increases clearance of chylomicrons and VLDL TGs
- catabolic rate of HDL decreased –> increased HDL
uses of niacin
- raise HDL levels
- pts with combined hyperlipidemia with low HDL
- effective with statins
adverse effects of niacin
- red flushed face with first dose or increased dose but can be decreased with NSAIDs prior to intake of drug
- Hyperglycemia and Hyperuricemia
- Hepatotoxicity (increased serum transaminases)
4Hs
what are the fibrate derivatives
Fenofibrate
Gemfibrozil
mechanism of fibrates (name them again)
fenofibrate and gemfibrozil
- activate the nuclear receptor PPAR-α (peroxisome proliferator activated receptor)
- decreased in TGs due to increased expression of lipoprotein lipase, decreased apoCIII (liver), and increased hepatic oxidation of FA
uses of fibrates
severe hypertrigylceridemia
adverse effects of fibrates
- myositis (inflammation and degeneration of muscle tissues)
- rhabdomyolysis (destruction of striated muscle cell
- lithiasis (gallstones)
- mild GI disturbances
types of pts that should avoid fibrates
those with hepatic or renal dysfuncton
drug interaction with gemfibrozil
- inhibits hepatic uptake of statins by OATP1B1 hence increasing plasma conc of statins
- also competes for same glucuronosyl transferase that metabolizes most statins hence both drugs will be increased in plasma
- hence higher chance of rhabdomyolysis is more likely
what are the bile acid binding resins
cholestyramine
colestipol
colesevelam
mechanism of action for bile acid binding resins (name them again)
cholestyramine, colestipol, colesevelam
polymeric anionic exchange resins that are insoluble in water that bind to anionic bile acids in intestinal lumen and preventing their absorption and excrete them in feces –> leads to more conversion of cholesterol to bile acids hence depleting amount of intracellular cholesterol –> upregulation of LDL receptors –> decreased LDL in plasma
partially offset by increased cholesterol synthesis due to upregulation of HMG-CoA reductase
uses of bile acid binding resins
- used with statins and niacins to reduce LDL
- drug of choice for children and women planning to become pregnant
type of pts that bile acid binding resins are not effective on
those with defective LDL receptors
adverse effects of bile acid binding resins (name the drugs again)
cholestyramine, colestipol, colesevelam
GI symptoms: bloating, nausea, cramping, constipation
contraindications of bile acid binding resins
those with hypertriglyceridemia because it increase TGs
drug interactions of bile acid binding resins
cholestyramine and colestipol impair the absorption of fat soluble vitamins A, D, E, and k
