09 Atherosclerosis and lipoprotein metabolism

Question 1

9.01 HMG-CoA REDUCTASE INHIBITORS

Statins: simvastatin, atorvastatin, pravastatin, lovastatin - actions

Answer 1

lowers LDL-C
also produces some lowering of plasma triglyceride and some increase in HDL-C

Question 2

9.01 HMG-CoA REDUCTASE INHIBITORS

Statins: simvastatin, atorvastatin, pravastatin, lovastatin - MOA

Answer 2

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

Question 3

9.01 HMG-CoA REDUCTASE INHIBITORS

Statins: simvastatin, atorvastatin, pravastatin, lovastatin - abs/distrib/elim

Answer 3

given orally
undergoes first-pass metabolism
inactive until biotransformation in the liver
plasma half-life 1-3h

Question 4

9.01 HMG-CoA REDUCTASE INHIBITORS

Statins: simvastatin, atorvastatin, pravastatin, lovastatin - clinical use

Answer 4

hypercholesterolaemia
used to prevent atherosclerosis in patients with high C serum levels and to prevent cardiac infarction in patients who already have atherosclerosis

Question 5

9.01 HMG-CoA REDUCTASE INHIBITORS

Statins: simvastatin, atorvastatin, pravastatin, lovastatin - adverse effects

Answer 5

usually mild: muscle pain, diabetes mellitus, sleep disturbance
rarer severe effects: severe myositis (risk increased if given with fibrates), angioedema

Question 6

9.02 FIBRATES

Gemfibrozil, bezafibrate, ciprofibrate, fenofibrate, clofibrate - actions

Answer 6

fibrates cause: a marked decrease in plasma VLDL and thus triglyceride, a modest decrease in LDL-C, a small increase in HDL-C

Question 7

9.02 FIBRATES

Gemfibrozil, bezafibrate, ciprofibrate, fenofibrate, clofibrate - MOA

Answer 7

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

Question 8

9.02 FIBRATES

Gemfibrozil, bezafibrate, ciprofibrate, fenofibrate, clofibrate - abs/distrib/elim

Answer 8

given orally, well absorbed
metabolised to glucuronide conjugates excreted via the kidney

Question 9

9.02 FIBRATES

Gemfibrozil, bezafibrate, ciprofibrate, fenofibrate, clofibrate - clinical use

Answer 9

mixed dyslipidaemia (i.e. ↑in both plasma triglycerides and cholesterol)
also in cases with low HDL and thus ↑risk of atheroma

Question 10

9.02 FIBRATES

Gemfibrozil, bezafibrate, ciprofibrate, fenofibrate, clofibrate - adverse effects

Answer 10

GIT upsets
rash
moderate increased risk of gallstones
myositis - which can be severe
rhabdomyolysis (particularly in patients with renal impairment)

Question 11

9.03 PCSK9 INHIBITORS

Evolocumab, alirocumab - actions

Answer 11

monoclonal antibody
reduces serum LDL-C

Question 12

9.03 PCSK9 INHIBITORS

Evolocumab, alirocumab - MOA

Answer 12

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

Question 13

9.03 PCSK9 INHIBITORS

Evolocumab, alirocumab - abs/distrib/elim

Answer 13

SC injection: evolocumab every 2-4 weeks, alirocumab every 2 weeks

Question 14

9.03 PCSK9 INHIBITORS

Evolocumab, alirocumab - clinical use

Answer 14

primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet

Question 15

9.03 PCSK9 INHIBITORS

Evolocumab, alirocumab - adverse effects

Answer 15

nasopharyngitis and influenza-like symptoms

Question 16

9.04 CHOLESTEROL-ABSORPTION INHIBITORS

Ezetimibe - actions

Answer 16

specifically inhibits the absorption of cholesterol from the intestine
main effect: decreased plasma LDL concentration

Question 17

9.04 CHOLESTEROL-ABSORPTION INHIBITORS

Ezetimibe - MOA

Answer 17

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

Question 18

9.04 CHOLESTEROL-ABSORPTION INHIBITORS

Ezetimibe - abs/distrib/elim

Answer 18

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

Question 19

9.04 CHOLESTEROL-ABSORPTION INHIBITORS

Ezetimibe - clinical use

Answer 19

hypercholesterolaemia, usually as adjunct to a statin

Question 20

9.04 CHOLESTEROL-ABSORPTION INHIBITORS

Ezetimibe - adverse effects

Answer 20

these are few
GIT upsets may occur, as may headache, rashes and myalgia

Question 21

9.05 CHOLESTEROL-ABSORPTION INHIBITORS

Colestyramine, colestipol, colesevelam - actions

Answer 21

these are bile acid sequestrants whose main action is to decrease LDL-C

Question 22

9.05 CHOLESTEROL-ABSORPTION INHIBITORS

Colestyramine, colestipol, colesevelam - MOA

Answer 22

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

Question 23

9.05 CHOLESTEROL-ABSORPTION INHIBITORS

Colestyramine, colestipol, colesevelam - abs/distrib/elim

Answer 23

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)

Question 24

9.05 CHOLESTEROL-ABSORPTION INHIBITORS

Colestyramine, colestipol, colesevelam - clinical use

Answer 24

hypercholesterolaemia, often used with a statin

Question 25

9.05 CHOLESTEROL-ABSORPTION INHIBITORS

Colestyramine, colestipol, colesevelam - adverse effects

Answer 25

GIT disturbances: constipation and bloating, sometimes diarrhoea