09 Atherosclerosis and lipoprotein metabolism Flashcards
9.01 HMG-CoA REDUCTASE INHIBITORS
Statins: simvastatin, atorvastatin, pravastatin, lovastatin - actions
lowers LDL-C
also produces some lowering of plasma triglyceride and some increase in HDL-C
9.01 HMG-CoA REDUCTASE INHIBITORS
Statins: simvastatin, atorvastatin, pravastatin, lovastatin - MOA
specific reversible competitive inhibition of the rate-limiting enzyme HMG-CoA reductase, which decreases hepatic C synthesis
this up-regulates LDL receptor synthesis and causes increased clearance of LDL-C from plasma into liver cells
9.01 HMG-CoA REDUCTASE INHIBITORS
Statins: simvastatin, atorvastatin, pravastatin, lovastatin - abs/distrib/elim
given orally
undergoes first-pass metabolism
inactive until biotransformation in the liver
plasma half-life 1-3h
9.01 HMG-CoA REDUCTASE INHIBITORS
Statins: simvastatin, atorvastatin, pravastatin, lovastatin - clinical use
hypercholesterolaemia
used to prevent atherosclerosis in patients with high C serum levels and to prevent cardiac infarction in patients who already have atherosclerosis
9.01 HMG-CoA REDUCTASE INHIBITORS
Statins: simvastatin, atorvastatin, pravastatin, lovastatin - adverse effects
usually mild: muscle pain, diabetes mellitus, sleep disturbance
rarer severe effects: severe myositis (risk increased if given with fibrates), angioedema
9.02 FIBRATES
Gemfibrozil, bezafibrate, ciprofibrate, fenofibrate, clofibrate - actions
fibrates cause: a marked decrease in plasma VLDL and thus triglyceride, a modest decrease in LDL-C, a small increase in HDL-C
9.02 FIBRATES
Gemfibrozil, bezafibrate, ciprofibrate, fenofibrate, clofibrate - MOA
fibrates ↑transcription of the genes for lipoprotein lipase and for the apoproteins apoA1 and apoA5, which are ligands for specific receptors
fibrates ↑LDL-C uptake by the LDL-C receptors
9.02 FIBRATES
Gemfibrozil, bezafibrate, ciprofibrate, fenofibrate, clofibrate - abs/distrib/elim
given orally, well absorbed
metabolised to glucuronide conjugates excreted via the kidney
9.02 FIBRATES
Gemfibrozil, bezafibrate, ciprofibrate, fenofibrate, clofibrate - clinical use
mixed dyslipidaemia (i.e. ↑in both plasma triglycerides and cholesterol)
also in cases with low HDL and thus ↑risk of atheroma
9.02 FIBRATES
Gemfibrozil, bezafibrate, ciprofibrate, fenofibrate, clofibrate - adverse effects
GIT upsets
rash
moderate increased risk of gallstones
myositis - which can be severe
rhabdomyolysis (particularly in patients with renal impairment)
9.03 PCSK9 INHIBITORS
Evolocumab, alirocumab - actions
monoclonal antibody
reduces serum LDL-C
9.03 PCSK9 INHIBITORS
Evolocumab, alirocumab - MOA
evolocumab binds selectively to proprotein convertase subtilisin/kexin type 9 (PCSK9) and prevents circulating PCSK9 from binding to the low density lipoprotein receptor (LDLR) on the liver cell surface, thus preventing PCSK9-mediated LDLR degradation
increased liver LDLR levels results in associated reductions in serum LDL-C
9.03 PCSK9 INHIBITORS
Evolocumab, alirocumab - abs/distrib/elim
SC injection: evolocumab every 2-4 weeks, alirocumab every 2 weeks
9.03 PCSK9 INHIBITORS
Evolocumab, alirocumab - clinical use
primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet
9.03 PCSK9 INHIBITORS
Evolocumab, alirocumab - adverse effects
nasopharyngitis and influenza-like symptoms
9.04 CHOLESTEROL-ABSORPTION INHIBITORS
Ezetimibe - actions
specifically inhibits the absorption of cholesterol from the intestine
main effect: decreased plasma LDL concentration
9.04 CHOLESTEROL-ABSORPTION INHIBITORS
Ezetimibe - MOA
blocks a sterol carrier protein in the brush border of enterocytes and thus reduces the amount of biliary and dietary C delivered to the liver via chylomicrons
this results in a ↓in the liver’s C store, ↑in hepatic LDL absorption and ↑clearance of LDL-C from plasma into liver cells
9.04 CHOLESTEROL-ABSORPTION INHIBITORS
Ezetimibe - abs/distrib/elim
given orally, activated in the liver, reaches maximum concentration in 2h after which it undergoes enterohepatic cycling and is gradually excreted in the faeces
plasma half-life 22h
9.04 CHOLESTEROL-ABSORPTION INHIBITORS
Ezetimibe - clinical use
hypercholesterolaemia, usually as adjunct to a statin
9.04 CHOLESTEROL-ABSORPTION INHIBITORS
Ezetimibe - adverse effects
these are few
GIT upsets, headache, rashes, myalgia
9.05 CHOLESTEROL-ABSORPTION INHIBITORS
Colestyramine, colestipol, colesevelam - actions
these are bile acid sequestrants whose main action is to decrease LDL-C
9.05 CHOLESTEROL-ABSORPTION INHIBITORS
Colestyramine, colestipol, colesevelam - MOA
bind the negatively charged bile acids to inhibit their absorption
this reduces the pool of bile acids in the liver, which decreases the hepatic store of C
this stimulates LDL receptor synthesis and causes increased uptake of LDL into liver cells
also decreases absorption of C from the GIT
9.05 CHOLESTEROL-ABSORPTION INHIBITORS
Colestyramine, colestipol, colesevelam - abs/distrib/elim
given orally and is not absorbed so there are no adverse systemic effects
but can cause drug interactions by preventing absorption of fat-soluble vitamins, statins, gemfibrozil and other drugs (e.g. digoxin, thiazides, thyroxine, steroids, iron salts, folic acid)
9.05 CHOLESTEROL-ABSORPTION INHIBITORS
Colestyramine, colestipol, colesevelam - clinical use
hypercholesterolaemia, often used with a statin
9.05 CHOLESTEROL-ABSORPTION INHIBITORS
Colestyramine, colestipol, colesevelam - adverse effects
GIT disturbances: constipation and bloating, sometimes diarrhoea
