Hyperlipidemia

Question 1

What are the steps in the pathogenesis of atherosclerosis?

Answer 1

1. endothelial injury
2. LDL accumulation and oxidation
3. monocytes adhere –> become macrophages that phagocytose oxidized LDL –>
4. foam cells
5. platelets adhere
6. smooth muscle cell migration deposits collagen
7. necrosis, plaque lysis

Question 2

What is the 1st step in treatment of all forms of primary hyperlipidemia?

Answer 2

diet modification

Question 3

What are 3 ways in which HDL is anti-atherogenic?

Answer 3

1. reverse cholesterol transport
2. protections against endothelial dysfunction
3. inhibits oxidative stress

Question 4

Which drug is the best agent to increase HDL? What 2 other effects does this drug have and how does it achieve them?

Answer 4

Niacin–>

1. increased HDL: reduced hepatic clearance of ApoAI (important HDL lipoprotein);
2. decreases triglycerides: decreases lipolysis in adipose tissue, leading to lowered FFA transport to liver;
3. decreaess LDL: Reduction of liver triglyceride synthesis, leading to less hepatic VLDL (thus, LDL) production

Question 5

Name 4 less serious side effects and 3 medically serious side effects of Niacin that limits its use to only 50% of eligible patients

Answer 5

Less Serious:
flushing/pruritis face & upper trunk; rash; acanthosis nigricans; dyspepsia
More Serious:
hepatotoxicity, hyperglycemia, hyperuricemia

Question 6

In which patients is Niacin contraindicated?

Answer 6

patients with diabetes mellitus and/or gout

may cause hyperglycemia and hyperuricemia

Question 7

Name 3 Fibric Acid derivatives (fibrates). Which of these is no longer used due to increased bile lithogenicity?

Answer 7

Clofibrate (not used anymore - causes gallstone formation)
Gemfibrozil
Fenofibrate

Question 8

In what subtype of hyperlipidemic patients is Gemfibrozil and those in its class used? Possible mechanism of action?

Answer 8

(fibrates)
used mostly in patients with severe hypertriglyceridemias
–> may interact w/peroxisome proliferator-activated receptor (esp. PPARα) to stimulate LPL synthesis (enhance TG-rich lipoprotein clearance)

Question 9

What are 2 adverse effects of Fenofibrate and those in its class?

Answer 9

(Fibrates)

1. Potentiates oral anticoagulants (displace from albumin)
2. myositis flu-like syndrome in 5% [Combination w/statin inadvisable due to higher myositis risk]

Question 10

What is the only hypolipidemic class indicated for use in children? Why?

Answer 10

Bile Acid Sequestrants –>

VERY safe- not absorbed from intestine

Question 11

Name 3 Bile Acid Sequestrants. What other drug may they be combined with for standard treatment of hyperlipidemia?

Answer 11

Cholestyramine
Colestipol
Colesevelam
[last 2 are combined with statins in standard treatment]

Question 12

What is the mechanism of action of Colestipol and others in its class?

Answer 12

(bile acid sequestrants)
Very positively charged resins binds negative charged bile acids–> The large size inhibits reabsorption and increasing bile/cholesterol excretion–> depletion in liver stores of bile acid leads to increase in LDL receptors in liver (to make more cholesterol/bile), decreasing LDL in blood by ~25%

Question 13

What are 4 adverse effects of Colesevelam and those in its class?

Answer 13

(bile acid sequestrants)

1. impairs fat soluble vitamin absorption
2. binds other drugs (e.g., cardiac glycosides, coumarins) and interferes with their absorption
3. GI effects: bloating, dyspepsia, constipation
4. causes slight increase in TGs [contraindicated in hypertriglyceridemia]

Question 14

Name 7 statins. Which 2 are prodrugs that must be modified in the liver to active form?

Answer 14

Mevastatin (Compactin)
Lovastatin (Mevacor) - prodrug
Simvastatin (Zocor) - prodrug
Pravastatin (Pravachol)
Fluvastatin (Lescol)
Atorvastatin (Lipitor)
Rosuvastatin (Crestor)

Question 15

What is the mechanism of action of Mevastatin and others in its class?

Answer 15

HMG-CoA Reductase competitive inhibitors:
Inhibits cholesterogenesis in liver–> less free cholesterol leads to activation of SREBP, a membrane-bound transcription factor that increases LDL-R synthesis and lessens degradation–> increased removal of LDL from blood (25-60%)
reduced cholesterol synthesis decreases VLDL synthesis–> lowers TG (25%)

Question 16

Since hepatic cholesterol synthesis is maximal between 12am and 2am, statins should be taken in the evening. What are the 2 exceptions that can be taken at any time?

Answer 16

Atorvastatin
Rosuvastatin
(Longer half-lives than older statins which are 1-4hrs)

Question 17

What are the adverse effects of Lovastatin and others in its class?

Answer 17

(statin)
Very few;
-hepatic dysfunction in 1% (serious hepatotoxicity rare);
-myopathy/rhabdomyolysis (reduced risk if no factors inhibiting statin catabolism or use of fibrates/niacin)

Question 18

What drug inhibits BOTH bilary and dietary cholesterol absorption in the gut? What is the result and combination with what drug enhances its results?

Answer 18

Ezetimibe –>
reduced cholesterol content of chylomicrons remnants (direct reduction atherogenesis) –> decreased cholesterol delivery to liver –> increased cholesterol synthesis [combo with statin inhibits this result leading to increased effect]

Question 19

What is Vytorin?

Answer 19

combination tablet containing ezetimibe and various doses of simvastatin (average LDL-C reduction of 60%)