Hyperlipidemia

Question 1

Classes of hypolipidemics

Answer 1

• For hypertriglyceridemias : nicotinic acid(Vit B3) and fibrates
• For elevated LDL-Cholesterol : Bile acid binding resins and Statins

Question 2

Nicotinic acid dose, therapeutic and adverse effects

Answer 2

• Recommended daily allowance: 20mg/day but dose for hyperlipidemias > 1 gram/day
• Therapeutic effects: decrease triglycerides( and LDL cholesterol) by decreasing fatty acid release from adipose tissue by action on GPCR and by decreasing hepatic VLDL synthesis and release.
• Adverse effects: liver damage, cutaneous flush, gastrointestinal discomfort

Question 3

Fibrates mechanism of action

Answer 3

• Activate the transcription factor PPARα
• Decrease serum triglycerides by increasing Lipoportein lipase activity and FA oxidation. Decrease VLDL secretion from liver
• Increase LDL receptor expression
• Increase serum HDL cholesterol by increasing Apo AI and II gene expression

Question 4

Bile acid binding resins action and side effects

Answer 4

• Bind bile acids in intestine and block reabsorption
• enhance hepatic conversion of cholesterol to bile acids
• increase heapic expression of LDL receptors
• *increase clearance of LDL cholesterol from plasma
• Side effects: increase serum TGs. GI: constipation, impaired absorption of fat, must not be taken with concomitantly with anionic drugs

Question 5

Ststins action

Answer 5

• Selective potent competitive inhibitors of hepatic HMG-coA reductase.
• reduce cholesterol production in the liver
• increase expression of LDL receptor
• increase haptic clearance of LDL cholesterol from plasma

Question 6

Mechanism of statin effect

Answer 6

Decrease in hepatic cholesterol increases protease activity

• protease releases sterol-regulatory-element binding protein(SREBP) from ER
• SREBP interacts with the promoter of LDL receptor gene
• More LDL receptor is synthesized and inserted into hepatic membrane
• LDL receptor binds LDL
• LDL internalized and metabolized in liver

Question 7

Effects of Statins on lipoproteins

Answer 7

• 25-60% decrease in LDL-cholesterol
• small increase of HDL
• small decrease of TGs

Question 8

effects of statins on LDL cholesterol

Answer 8

• Dose dependent with maximum effect within several weeks
• persistent upon chronic administration
• fully reversible on termination of drug

Question 9

Beneficial effects of statins

Answer 9

• regression of atherosclerotic plaque
• plaque stabilization
• reduced inflammation( lowering inflammatory markers)
• Decreased thrombogenicty
• reversal of endothelial dysfunction
• inhibition of leukocyte interaction with antigen-presentation or endothelium

Question 10

Adverse effects of statins

Answer 10

• Contraindicated in pregnancy
• increase serum hepatic enzymes(rare and reversible)
• Myopathy( rare but can be leathal). increase skeletal muscle inflammation and pain creatinine kinase
• risk increased by: specific SNP in genotype of an OATP that transports statin into hepatocyte