PHARM: Atherosclerosis + Lipid Lowering Agents

Question 1

atherosclerosis formation

Answer 1

• very slow process, Sx not evident until late stages
• LDL cholesterol taken up into vascular walls and oxidised
• macrophages phagocytose lipids to form foam cells
• release inflammatory cytokines = recruit immune cells inc B/T cells = amplified inflammation
• smooth muscle cells migrate to endothelium, forming a fibrous cap to stabilise underlying lipid core = angina

Question 2

how does atherosclerosis actually rupture?

Answer 2

• complete occlusion of the lumen puts pressure on tunica media and this keeps expanding until the vessel ruptures (no stenosis)

Question 3

familial hypercholesterolaemia pathophys

Answer 3

• apo B-100 receptor allows LDL/vLDL to bind to LDL receptor on hepatocytes = LDL clearance
• FH = apo B-100 mutation = non-functional

Question 4

lipoproteins

Answer 4

• chylomicron: transport dietary TAGs from intestine to tissues via LYMPH
• VLDL: transports TAGs and some cholesterol from liver to tissues - contain Apo B-100
• LDL: transports cholesterol from liver to tissues (bad) -contain Apo B-100
• HDL: transports cholesterol from tissue to liver to be excreted (good), contain apo-A-I to absorb cholesterol

Question 5

2 types of atherosclerosis

Answer 5

• stable: thick fibrous cap, thin lipid core, unlikely to rupture, causes stable angina or asymptomatic
• unstable: thin fibrous cap, large lipid core, prone to rupture, causes thrombus/ischaemia = unstable angina/AMI

Question 6

3 categories of drugs for atherosclerosis

Answer 6

• lipid-lowering drugs e.g. statins (1st line), fibrates, bile acid resins, ezetimibe, fish oils etc
• anti-platelets
• anti-coagulants

Question 7

purpose of LDL receptor + feedback inhibition

Answer 7

• receptor on hepatocytes causes liver uptake of LDL (decreased risk of atherosclerosis) = recycled and turned into cholesterol
• feedback inhibition: increased intracellular cholesterol decreases cholesterol synthesis and LDL receptor synthesis to prevent the cell up taking more LDL

Question 8

MOA and indications of statins

Answer 8

• HMG-coA reductase inhibitors = prevent formation of cholesterol from acetyl-coA to prevent atherosclerosis
• indications: primary prevention (high LDL, diabetes) or secondary prevention (past AMI or TIA/CVA, angina)

Question 9

side effects and contraindications of statins

Answer 9

• side effects: mild GIT issues, reversible memory loss, muscle weakness
• contraindications: w/ grapefruit juice or during pregnancy

Question 10

fibrates MOA, indications, e.g.

Answer 10

• PPAR-a activators = upregulation of lipoprotein lipase = more breakdown of triglycerides (also decreases LDL)
• indication: hypertriglyceridaemia
• e.g. gemfibrozil

Question 11

side effects and contraindications of fibrates

Answer 11

• side effects: GIT issues, gallstones, hepatitis
• contraindication: liver disease

Question 12

what are bile acids

Answer 12

• formed from liver cholesterol, help w/ absorption of dietary fat
• goes into duodenum, reabsorbed in terminal ileum for reuse

Question 13

bile acid resins MOA + indication

Answer 13

• bind to bile acids to decrease absorption of exogenous cholesterol and increase metabolism of endogenous cholesterol into bile acids
• indications: hypercholesterolaemia

Question 14

side effects and contraindications of bile acid resins

Answer 14

• side effects: GIT issues e.g. bloating, abdominal discomfort
• contraindications: pregnancy

Question 15

ezetimibe MOA + indication

Answer 15

• inhibits cholesterol absorption across intestinal wall
• always used in conjunction w statins
• indication: hypercholesterolaemia - better tolerated/higher potency than bile acid resins (therefore smaller dose)

Question 16

ezetimibe adverse effects + contraindications

Answer 16

• adverse effects: nausea, diarrhoea, fatigue, headache
• contraindicated in liver disease

Question 17

nicotinic acid/niacin/vit B3 MOA + indication

Answer 17

• inhibits vLDL secretion from liver
• mainly increased HDL but also decreased LDL and triglycerides
• indication: mixed dyslipidaemia

Question 18

adverse effects and contraindications of nicotinic acid/niacin/vit B3

Answer 18

• adverse effects: GIT issues, headache, flushing
• contraindicated in liver disease and w/ statins

Question 19

fish oils

Answer 19

• purified omega-3 fatty acids
• decrease CVD risk

Question 20

PCSK9 inhibitors MOA + indications

Answer 20

• inhibits PCSK9 (serine protease enzyme) = decreased degradation of LDL receptors = more clearance from circulation
• indicated if Pts w/ familial hypercholesterolaemia are already taking highest statin dose or are statin-intolerant