B.9

Question 1

Drugs affecting lipid metabolism

Answer 1

Simvastatin,
Atorvastatin,
Rosuvastatin,
Ezetimib,
Fenofibrate,
Colesevelam

Question 2

Atherosclerotic plaque development

Answer 2

PGI2 & NO production ↓ → Endothelial dysfunction → Activation of monocytes and other WBCs→ LDL oxidation → Macrophages uptake of oxLDL via scavanger receptors → subendothelial migration→ Fatty streak lesion → SMC proliferation + fibrosis initiation → PLAQUE development

Question 3

Increased LDL-C dominant

Answer 3

Primarily statins, second choice ezetimibe/bile acid sequestrants, third choice niacin

Question 4

Increased LDL-C and decreased HDL-C

Answer 4

Primarily statins, second line niacin

Question 5

Increased LDL-C, decreased HDL-C, increased TAG

Answer 5

Niacin and statin, second choice fibrates

Question 6

Increased TAG

Answer 6

Primarily fibrates, second choice Niacin

Question 7

Low HDL-C

Answer 7

Niacin, second choice Fibrates OR NOTHING

Question 8

Simvastatin, Atorvastatin, Rosuvastatin

Answer 8

MOA: Inhibit HMG-CoA reductase, the rate-limiting step of cholesterol synthesis
(→HMG-CoA→ mevalonate conversion) in the liver (Cholesterol synthesis↓, LDL-R upregulation→increased hepatic LDL uptake from circulation, inhibition of the farnesol synthesis);
Clinical effects: better endothelial function, plaque stabilization, ↓LDL-oxidation, inhibition of SMC proliferation, fibrinolytic & antithrombic effect, anti-inflammatory effects;
Kinetics: good abs. p.o, very lipophilic, extensive hepatic 1st pass metabolism, CYP3A4 metabolism, excreted with bile;
SEs: mild GI symptoms (diarrhea, constipation), sleep disturbances, skin rash, mild transient proteinuria, muscle related SEs - are dose dependent (Rhabdomyolysis, myopathy), ↑serum CK;
Contra-IND: pregnancy, severe liver failure;
IND: treatment of hyperlipidemia (to reduce total Cholesterol, LDL cholesterol, ApoB and TAG, and increase HDL cholesterol), to reduce risk of cardiovascular morbidity and mortality (incl. MI, stroke)

Question 9

Colesevelam

Answer 9

MOA: Bile acid sequestrants (→ after oral adm. they bind to bile acids in the intestines→ Interfere with the enterohepatic recirculation→ decreased cholesterol absorption + increased bile acid synthesis for which the liver use up cholesterol);
SEs: GI symptoms (nausea, flatulence, constipation), inhibits absorption of other drugs (avoid concomittant drug for 4 hours);
IND: Isolated LDL-C↑ (even during pregnancy), children may also tak

Question 10

Fenofibrate

Answer 10

MOA: PPARα agonist, increase β-oxidation, activates LPL (→VLDL & TAG levels↓), promotes urate excretion (→can be used in diabetic patients as well);
Kinetics: 90% abs from intestine, ↑Plasma protein binding, hepatic glucoronidation, renal excretion;
SEs: Rhabdomyolysis (especially if combined with statins), acute kidney failure, gallstone production, hypoglycemia;
Dose:45-145mg/day;
IND: adjuvant therapy to diet to reduce elevated LDL-C, Total-C, TAG, ApoB, and to increase HDL-C in adults with hypercholeterolemia/mixed dyslipidemia. Also indicated to treat severe hypertriglyceridamia

Question 11

Ezetimibe

Answer 11

MOA: selective inhibition of intestinal cholesterol absorption
(→1. NPC1L1 sterol transporter is inhibited,
2. Cholesterol content is decreased in chylomicron,
3. Hepatic LDL-R expression increases);
Kinetics: glucoronidation is needed for its activation, enterohepatic recirculation is characteristic;
SEs: concomittant statin use increases liver enzyme levels, increased cancer risk;
Dose: 5-20mg/day (recommended 10mg/day);
Contra-IND: liver diseases, pregnancy;
IND: reduce elevated total-C, LDL-C, ApoB, and non-HDL-C in patients with primary hyperlipidemia/mixed hyperlipidemia

Question 12

PPARα effect

Answer 12

Expressed: Liver, kidney, heart, skeletal muscle
Ligands: fatty acids, fibrates
Effects: increased production of Apo-AI and LPL, FFA uptake and breakdown is increased, VLDL synthesis is decreased,

Question 13

Prevention of atherosclerosis

Answer 13

1. Physical exercise (increase HDL production)
2. Healthy diet
3. Estrogen
4. Drugs (antihypertensive and antihyperlipidemic)