hyperlipidemia

Question 1

what is atherosclerosis and its risk factors?

Answer 1

• Cardiovascular disease is the number one killer in developed countries
• Atherosclerosis: Buildup of fats, cholesterol and other substances on artery walls, narrowing blood vessels and increasing risk of blood clots
• ~50% of people aged 45-84 have atherosclerosis to some degree
  Risk factors for atherosclerosis:
• High blood pressure
• High blood cholesterol and triglycerides
• Smoking
• Diabetes
• Obesity

Question 2

how does atherosclerosis begin and progress?

Answer 2

Higher atherosclerosis risk is associated with:
* ↑ LDL, IDL, and VLDL blood levels
* ↓ HDL blood levels
Lower atherosclerosis risk is associated with:
* ↓ lipoproteins (mainly LDL)

Question 3

what are lipoproteins and their exogenous pathway metabolism?

Answer 3

What are lipoproteins?
- Responsible for bulk lipid transport in the body
Lipoprotein Functions and Metabolism
- Exogenous pathway (hoe cholesteroil is taken up via the diet): Dietary fats are emulsified thanks to bile → enterocytes repackage lipids with apolipoproteins into chylomicrons (CMs)
- CMs encounter lipoprotein lipase on endothelial cells → cleaves free fatty acids that enter adipose tissue (for storage) and muscles (for energy)
- CM “remnants” move to liver where they are ↳ dissociated into cholesterol and triglycerides

Question 4

lipoproteins functions and endogenous pathway metabolism?

Answer 4

• Endogenous pathway: Liver packages triglycerides and cholesterol* with apolipoprotein to form VLDL particles that are released into the bloodstream
• VLDLs encounter lipoprotein lipase on endothelial cells → cleaves free fatty acids that enter adipose tissue and muscles
• VLDL remnants, or IDLs, can make their way back to the liver or be further processed into LDL, which has the highest cholesterol content
• Endogenous pathway: LDL can be taken up by the liver and its contents recycled, OR, if they are in a high enough quantity, may be taken up by
  macrophages an become “foam cells” → atherosclerosis
  *Synthesized from liver or from diet

Question 5

what is the role of HDL?

Answer 5

The role of HDL: Takes up excess cholesterol from tissues and redistributes them to other tissues or lipoproteins that need it, or returns cholesterol to the liver to be recycled

Question 6

what are the 5 steps of pathogenesis?

Answer 6

1. LDLs cross endothelium into intima of blood vessel
   ↳ too much LDL → supposed to be in the bloodtream but some enter intima :( →become oxidized which causes inflammation
2. Monocytes migrate into intima → become macrophages that engulf LDLs → foam cells
3. Lesion formed with foam cells, smooth muscle cells (“atherosclerotic plaque”)
4. Leads to localized inflammation → endothelial damage
5. Ruptured plaque thus leads to clot
   formation (bc of endothelial damage)

Question 7

what is the cause of atherosclerosis?

Answer 7

Cause: Hyperlipidemia
- Increased amount of lipids in blood (triglycerides,cholesterol)
- Increased risk of cardiovascular mortality is most closely linked to ↑ levels of LDL cholesterol and ↓ levels of HDL cholesterol

Question 8

drugs to treat atherosclerosis: statins mechanism of action

Answer 8

Statins - most common drug used, first line for ↑ LDL
- The most effective and best tolerated drugs for hyperlipidemias (high levels of lipoproteins in blood)
- Lovastatin (generic), Rosuvastatin (Crestor®)
- Mechanism of action: structural analog of HMG-CoA - the enzyme that mediates early steps of hepatic sterol synthesis
- partially inhibit HMG-CoA reductase: ↓ hepatic cholesterol
- statins also induce an increase in high affinity LDL receptors mainly in the liver
- ↑ LDL clearance and ↓ plasma LDLs (lowers LDL by ~60%)

Question 9

what are statins pleiotropic and adverse effects?

Answer 9

• Used as monotherapy due to its high efficacy, may be used with other drug classes
  Pleiotropic effects
• May contribute to reduction in cardiovascular morbidity and mortality in addition to lowering of LDLs!
• Decreased inflammation
• Reversal of endothelial dysfunction, improved vasodilation
• Stabilization of existing plaques
• Decreased thrombosis
  adverse effects: (not many, considered safe)
• main adverse effect: Myopathy (muscle damage), rhabdomyolysis can occur in rare cases
• Statins have a high hepatic first-pass effect, and thus can impact liver enzymes like CYP450 (drug-drug interactions possible)
• Contraindicated in pregnancy
• Incidence of adverse effects with statins is lower than any other lipid-lowering drug

Question 10

drugs to treat atherosclerosis: niacin (generic) mechanism of action

Answer 10

• One of the oldest drugs used to treat hyperlipidemias (↑ LDL)
• Mechanism of action: At physiological concentrations, niacin (nicotinic acid) acts as a vitamin (B3) when converted to NAD (nicotinamide adenine dinucleotide)
• At pharmacological doses (1.3-3 grams/day), niacin acts independently of NAD:
• inhibits VLDL production and secretion by ↓ triglyceride (TG) synthesis therefore ↓ LDL levels
• increases the half life of apoA1, a protein on HDL → best agent for rasing HDLs
• responsible for helping HDL proteins live longer, maintains ↑ activity

Question 11

what are niacin adverse effects?

Answer 11

• One of the oldest drugs used to treat hyperlipidemias
  Adverse Effects
• Cutaneous flushing and itching can occur (mediated by prostaglandins) which can be alleviated with NSAIDs
• GI distress and ulcers possible
• Niacin is indicated for patients with elevations of triglycerides AND cholesterol, usually in combination with a statin

Question 12

drugs to treat atherosclerosis: Cholestryamine mechanism of action and side effects

Answer 12

• Cholestryamine (generic), Colestipol (Colestid®)
• One of the other oldest drugs used to treat hyperlipidemias * Mechanism of action: Bile acid sequestrant
• Highly positively charged resins bind negatively charged bile acids in the GI tract lumen; prevents reuptake in intestine
• this ↑ bile acid synthesis which, when there is ↓ liver cholesterol, ↑ hepatic LDL receptors and ↑ LDL uptake and clearance from plasma (stops recycling of bile and tells body to make more, ↑ LDL reuptake to get back to the liver therefore cleared from plasma → pulls cholesterol out of the bloodstream where it can make plaques)
• usually used as seconds agents if statins alone are effective
• take with meals when bile secretion is highest

side and adverse effects: constipation/bloating, drug interactions are possible due to positive charges on resins

Question 13

drugs to treat atherosclerosis: Ezetimibe (Zetia®) mechanism of action and side effects

Answer 13

Ezetimibe (Zetia®): helps to ↓ absorption of cholesterol from intestine
- Mechanism of Action: Inhibits cholesterol absorption
- Reduced absorption of dietary cholesterol and biliary cholesterol, which comprises the majority of intestinal cholesterol (reduces it by 50%)
- Ezetimibe ↓ cholesterol transport from micelles to enterocytes by inhibiting cholesterol uptake through NPC1L1 → increases the excretion of cholesterol in stool
- End result = Decreased VLDL production therefore * decreasing plasma LDL (also increasing LDL re- uptake in liver)
- When used with statins, lowers LDL an additional 15% - good for people with very high LDL levels
- very safe, few side effects

Question 14

drugs to treat atherosclerosis: Fibrates: Gemfibrozil mechanism of action and side effects

Answer 14

most confusing drug :(
- Mechanism of action: Unclear, but outcome is decreased VLDLs, modest LDL decrease, moderate HDL increase
- Activates PPAR- gene receptor, which increases extrahepatic lipoprotein lipase expression, which increases fatty acid uptake in muscle (↓ ↓ ↓ triglycerides) leading to lowered LDL concentrations (modest)
- increases HDL synthesis through PPAR-mediated activation of apo proteins associated with HDL = ↑ reverse cholesterol transport (taking in back to liver or redistributing among tissues)
- Used to treat hypertriglyceridemia, but also used for regular hyperlipidemia in combination with statins to increase HDL
- side effects include GI discomfort, but otherwise very safe