Lipid Metabolism & Pharmacology Flashcards
Familial Hyperchylomicronemia
Caused by defect in removing Chylomicrons (apoCII and/or LPL defects)
*Manifests as elevated Triglycerides w/ resulting Pancreatitis
Familial Hypertriglyceridemia
Caused by less severe defects in LPL and ApoCII, or by from elevated ApoCIII (which inhibits LPL)
- Manifests as:
- Moderately elevated triglycerides, usually just VLDL
Familial Dysbetalipoproteinemia
Caused by defective removal of remnant particles (IDL) due to loss of function mutations in ApoE alleles (E2/E2)
(I.e. ApoE can’t bind LDL receptors on liver cells)
- Manifests as:
- elevated VLDL and IDL
- Cholesterol and TG elevated at a 1:1 ratio
- premature athersclerosis
- poor response to statins
Familial combined Hyperlipodemia (FCH)
Due to overproduction of apoB100 (the primary structural protein of VLDL)
- Variable phenotype: Elevated VLDL, LDL, or both
- Autosomal Dominant
- Associated with Premature Atherosclerosis
Familial Hypercholesterolemia
Cause by inherited (AD) defects in LDL receptor and ApoB
*LDL increased w/ premature athersclerosis (lipid profile stable otherwise)
- Xanthelasma may appear in 3rd decade
- Coronary Disease occurs prematurely
- Tendon Xanthomas often present
Secondary causes of Hyperlipidemia
- Excess caloric intake
- Hypothyroidism
- Kidney & Liver disease
- Medications
- excess in take of simple sugars (Pop & Alcohol)
- Genetic
Current recommendations for dietary management of hyperlipoproteinemia?
- limit cholesterol, Saturated fats, and trans-fats (Red meat, diary, backed goods)
- Limit excess simple sugars, carbohydrates, alcohol. (these lead to increased synth and secretion of VLDL
- use poly or mono-unsaturated fats
MOA for Statin drugs
Competitively Inhibit the rate limiting step of cholesterol biosynthesis (HMG-CoA reductase enzyme) resulting in increased expression of LDL-receptors and therefore lower LDL plasma
MOA for Bile Acid Resins
Bind to bile acids and prevent their reabsorption and re-use of bile cholesterol
- Modest effect on HDL
- Does NOT decrease TGs
- GI side effects can limit use
What are the intermediately potent and efficient Statin drugs?
Lovastatin and Simvastatin
- CYP3A4 metabolized
What are the potent and highly efficient Statin drugs?
Atrovastatin and Rosuvastatin
- Synthetic versions with longer plasma half-lives
What is the advantage of using Pravastatin?
It does NOT have any CYP interactions
CYP drugs that commonly cause drug interactions with statins
- Macrolide Antibiotics (Erythromycin, Clarithromycin)
- Azole antifungals
- Calcium channel blockers (verapamil, diltiazem)
- Grapefruit juice
- HIV PIs (“Navirs”)
- Immunosuppresants (Cyclosporine)
Drugs, other than CYP and P-gp drugs, that inhibit statin metabolism?
Gemfibrozil
- glucuronyltransferase-1
Name 3 Bile Acid Sequesters
- Colestipol (powder or tab)
- Cholestyramine (powder)
- Colesevelam (tab)
Adverse affects and contraindications of Bile Acid Sequestrants
GI: Bloating, Nausea, flatulence, constipation
*Take w/ water!
- Drug-interactions: Beta-Blockers, coumadin
- take hours before or after bile acid seq.
- Contraindications: Hypertriglyceridemia, complex drug regimens, and hx of constipation
- May increase TGs
Ezetimibe
Cholesterol absorption Inhibitor
- prevents the direct uptake of cholesterol itself from the the intestines (lowers intake and also upregulates LDL-receptors)
- normally given in conjunction with statins or when they cannot be used
Gemfibrozil
Fibric acid derivative
- MOA: competitive inhibitors of PPAR-alpha nuclear receptor (lipid metabolism receptor)
- > reduces TGs (~50%) and Increases HDL
- drug-drug interaction with STATINS
- *can be safely given to those w/ renal disease
Fenofibrate
Fibric acid derivative
- MOA: competitive inhibitors of PPAR-alpha nuclear receptor (lipid metabolism receptor)
- > reduces TGs (~50%) and Increases HDL
- *does NOT interact w/ statins
- not recomended for advance renal disease due to accumulations
Fenofibric Acid
Fibric acid derivative
- MOA: competitive inhibitors of PPAR-alpha nuclear receptor (lipid metabolism receptor)
- > reduces TGs (~50%) and Increases HDL
Niacin (MOA
MOA: Inhibits mobilization of free FA from adiopocytes resulting in:
- reduced hepatic TG synthesis
- reduced VLDL syn and secretion (ApoB)
- Enhances reverse cholesterol transport via HDL
- Enhances LPL conversion of VLDL to LDL
Adverse affects of Niacin
Cutaneous Flushing
- give asprin and start w/ low dose then increase slowly
When are high efficacy statins recommended to be used?
for patients with atherosclerotic vascular disease and/or a previous MI