Lipid Lowering Drugs Flashcards
1
Q
Exogenous pathway
A
- intestinal absorption of cholesterol & fatty acids
- in intestinal cell: free FAs combine w/ glycerol=TGs, cholesterol esterified to form cholesterol esters (acyl coenzyme A:cholesterol acyltransferase [ACAT])
- chylomicrons enter circulation, lipoprotein lipase removes TGs in extrahepatic tissues, & chylomicron remnants taken up by hepatocytes
2
Q
LOOK AT ENDOGENOUS & EXOGENOUS PATHWAY DIAGRAM IN NOTES
A
LOOK AT IT RIGHT NOW
3
Q
Endogenous pathway: VLDL
A
- synthesized & secreted by liver
- lipoprotein lipase hydrolyzes the TG core
- converted to LDL by further removal of TG by hepatic lipase
4
Q
Endogenous pathway: LDL
A
- can be internalized by hepatic & non hepatic tissues
- hepatic LDL: converted to bile acids & secreted into intestinal lumen
- nonhepatic LDL: used for hormone production, cell membranes, or stored in esterified form
- circulating LDL can enter macrophages & other tissues leading to foam cells contributing to atheromatous plaques
5
Q
Endogenous pathway: HDL
A
- hepatic & intestinal synthesis of particles containing phospholipids and apolipoproteins
- procurement of surface components from TG depleted chylomicron and VLDL remnants
- acquisition of free cholesterol from tissue sites and other lipoproteins
6
Q
Total cholesterol levels
A
240 - high
7
Q
LDL cholesterol levels
A
160 - high
8
Q
HDL cholesterol levels
A
> 60 high
9
Q
Triglyceride levels
A
desirable: 200
10
Q
Treatment of hypercholesterolemia: borderline high
A
- dietary lipoprotein analysis
- drug therapy if coronary heart disease (CHD) or 2 other risk factors
11
Q
Risk factors of hypercholsterolemia
A
male, family history of premature CHD, smoke cigs, HTN, low HDL (
12
Q
Treatment of hypercholesterolemia: high
A
- dietary if no CHD or less than 2 risk factors
2. dietary + drug if CHD or 2 or more risk factors
13
Q
Treatment of hypercholesterolemia: very high
A
dietary + drug even if no CHD or other risk factors
14
Q
Dietary changes
A
- major change should come from carbohydrates
- should be derived from foods rich in complex carbs including whole grains, fruits, & veggies
15
Q
Omega 3 fatty acids
A
- activate PPARalpha leading to decreased triglycerides (may increase LDL)
- only those in fish oils are active due to double bond organization
- over the counter: lovaza, mixed omega 3 acid ethyl ester, avoid in patients with fish/shellfish allergies
16
Q
Approaches to lowering lipids
A
- prevent intestinal absorption of cholesterol or of bile acids
- decrease cholesterol synthesis, increase LDL receptors, increase LDL uptake
- inhibit VLDL secretion, decrease LDL production
- upregulate lipoprotein lipase, decreasing TGs
17
Q
Classes of lipid lowering drugs
A
bile acid sequestrants, nicotinic acid, HMG-CoA reductase inhibitors (statins), fibric acids, ezetimibe
18
Q
Bile acid reabsorption
A
- very efficient
- amount excreted correlates to amount of cholesterol used to make them
- therefore if you inhibit their reabsorption then you will increase excretion of cholesterol
19
Q
Bile acid sequestrants
A
- cholestyramine, colestipol, colesevelam
- large polymeric cationic exchange resins insoluble in water
- safe and effective but not appetizing (4-5 grams, 3-4x/day)
- available in granular resins or tablets, resins must be taken w/ meals
- SECOND GENERATION SEQUESTRANTS BETTER DUE TO LESS SIDE EFFECT (COLESEVELAM)
20
Q
Cholestyramine & Colesevelam mechanism
A
- bind bile acids through ionic & hydrophobic interactions to prevent reabsorption
- increase uptake of LDL from upregulation of LDL receptors
- increase hepatic production of VLDL, increase TGs by 15-20%
- colesevelam also reduces hyperglycemia
21
Q
Side effects of cholestyramine & colesevelam
A
- dyspepsia, constipation, bloating, diarrhea
- malabsorption of vitamin K
- impaired absorption of other drugs
* *SIDE EFFECTS ARE REDUCED FOR COLESEVELAM
22
Q
Nicotinic acid (Niacin)
A
- water soluble vitamin incorporated into NAD
- inhibits VLDL secretion therefore decreases LDL (can increase HDL)
- decreases TG>cholesterol
- no effect on bile production
23
Q
Nicotinic acid (Niacin) toxicities
A
- prostaglandin mediated cutaneous vasodilation: BLUNTED WITH ASPIRIN/NSAID
- Liver: elevation of liver function tests, dysfunction with use of OTC sustained release, not reported w/ extended release Niaspan
- long term niacin treatment may cause insulin resistance
- hyperuricemia: niacin competes w/ uric acid excretion by kidneys
24
Q
HMG CoA reductase inhibitors
A
- lovastatin, simvastatin, pravastatin, fluvastatin
- COMPETITIVELY inhibit HMG CoA reductase
25
Prodrug HMG Co A reductase inhibitors
- mevastatin, lovastatin, simvastatin
| - closed ring
26
Active HMG CoA reductase inhibitor drugs
- pravastatin, fluvastatin
| - opened ring
27
HMG CoA reductase inhibitors process
- decrease cholesterol synthesis & upregulate LDL receptors, decreasing LDL
- marked first pass metabolism: b/c liver is target organ of statins, an efficient first pass uptake may be more important than high bioavailability to achieve statin effect
28
HMG CoA reductase inhibitor metabolism
- substrates of CYPs (metabolized by)
- LOVASTATIN/SIMVASTATIN/ATORVASTATIN -- CYP3A4
- FLUVASTATIN/ROSUVASTATIN -- CYP2C9
* ********ON TEST*********
29
HMG CoA reductase recommendations
- recommended to be taken in evening due to half life of drugs
- absorption enhance by food
30
HMG CoA reductase inhibitors toxicities
- increases liver function tests
- increases creatine kinase(CK), myopathy, rarely rhabdomyolysis
- worse w/ concurrent cyclosporin, clofibrate, niacin, erythromycin
31
HMG CoA reductase inhibitors drug-drug interactions
- Statins that are CYP3A4 substrates have: increased drug levels in presence of CYP3A4 inhibitors, decreased drug levels in presence of CYP3A4 inducers (BARBITURATES***ON TEST)
- Statins that are CYP2C9 substates have: increased drug levels in presence of CYP2C9 inhibitors (ketoconazole, metronidazole, amiodarone) **all statins under glycosylation--interaction w/ gemfibrozil
32
Grapefruit juice consumption effects
- lovastatin, simvastatin, atorvastatin can be elevated in patients drinking more than 1L/day (inhibits CYP3A4)
33
Fibric acids
- gemfibrozil, clofibrate, fenofibrate
- serve as ligands for PPARalpha (transcription factor)
- upregulate lipoprotein lipase, apo A-I, apo A-II
- apo A-I/II are major components of HDL promoting cholesterol efflux
34
Fibric acids: gemfibrozil, clofibrate, fenofibrate
- clears chylomicrons & VLDL quickly
- lowers TGs (VLDLs) &a raises HDL cholesterol
- generally modest decrease in LDL
* **PRIMARILY USEFUL FOR TEATING HYPERTRGLYCERIDEMIAS (VLDL)***
35
Fibric acid toxicities
1. rashes, GI symptoms, arrhythmias, low potassium, elevated LFTs
2. risk of myopathy increased when used w/ statins -- gemfibrozil increases concentration by inhibiting metabolism of statin byproduct, fenofibrate does not do this
3. increased risk of cholesterol gallstones
36
Ezetimibe
- inhibitor of intestinal sterol absorption (inhibits NPC1L1-transport protein)
- absorbed & glucuronidated
- excreted into bile & feces
- NOT A CYP450 substrate
37
Bile acid sequestrants LDL,HDL,TG effects
- decrease LDL
38
Nicotinic acid LDL, HDL, TG effects
- decrease LDL, TGs
| - increase HDL
39
HMG CoA reductase LDL, HDL, TG effects
- decrease LDL, TG
| - small increase in HDL
40
Fibrate LDL, HDL, TG effects
- decrease TGs -- largest out of all lipid lowering drugs
41
Ezetimibe HDL, LDL, TG effects
- decreased TGs largest effect
42
Therapy for high cholesterol and TGs
always with dietary therapy
43
Drug therapy: high LDL
1. bile acid sequestrants
2. nicotinic acid or HMG CoA reductase inhibitor
3. combination of 1 & 2
44
Drug therapy: high HDL & TGs
1. weight loss, alcohol restriction
2. nicotinic acid or gemfibrozil
3. bile acid sequestrants or HMG CoA reductase inhibitors in combination with 2 above
45
Drug therapy: high TGs (>500mg/dL), normal LDL
1. weight loss, alcohol restriction
| 2. gemfibrozil or nicotinic acid
46
Drug therapy: low HDL (
1. diet, exercise, stop smoking
| 2. nicotinic acid or gemfibrozil
47
Effect of combining statin and bile acid sequestrant
combination is more effective than either alone
| ***ON TEST***
48
Cholesterol facts
- essential component of animal cell membranes
- sources: animal fats (cheese, eggs, meat, poultry, fish)
- cholesterol biosynthetic pathway: 25% of total cholesterol production occurs in the LIVER
