Hyperlipidemia Drugs Flashcards
(48 cards)
1
Q
Antihyperlipidemics - Extrahepatic Drugs
A
- Lipid absorption inhibitors
- Bile acid binders
- Niacin
- Fibrates
2
Q
Cholesterol/Fat Absorption Inhibitors (2)
A
- Ezetimibe (Zetia)
2. Orlistat (Xenical)
3
Q
Bile Acid Binding Resins (3)
A
- Colesevelam (Welchol)
- Colestipol (Colestid)
- Cholestyramine (Quetran)
4
Q
Niacin (3)
A
- Niacor - IR
- Niacin - SR
- Niaspan - ER
5
Q
Fibrates (2)
A
- Gemfibrozil (Lopid)
2. Fenofibrate (Tricor)
6
Q
HMG-CoA Reductase Inhibitors (7)
A
- STATINS
1. Atorvastatin (Lipitor)
2. Lovastatin (Mevocor)
3. Pravastatin (Pravachol)
4. Simvastatin (Zocor)
5. Fluvastatin (Lescol)
6. Rosuvastatin (Crestor)
7. Pitavastatin (Livalo)
7
Q
MTTP Inhibitors
A
Lopitamide (Juxtapid)
8
Q
PCSK-9 Inhibition (2)
A
- Alirocumab (Praluent)
2. Evolocumab (Repatha)
9
Q
Antihyperlipidemics - Hepatic Action Drugs
A
- Statins
- MTTP Inhibitors
- PCSK9 Inhibitors
- Mipomersen
10
Q
Ezetimibe (MOA)
A
- Zetia
- Cholesterol Absorption Inhibitor
- MOA: selective inhibition of cholesterol absorption at the brush border of the small intestine
- Blocks Niemann-Pick C1 Like 1 (NPCL1) receptor (transporter of cholesterol to found mixed micelles)
11
Q
Ezetimibe Therapeutic/Adverse Effects
A
- Decreases LDLs
- No effect on absorption of fat-soluble vitamins, TGs, or bile acids
- Can use alone with dieting or in combination with statins
- Main adverse effect = flatulence. May also produce diarrhea and myalgia
12
Q
Orlistat (MOA)
A
- Xenical (Rx) or Alli (OTC)
- Fat absorption inhibitor
- MOA - inhibitor of pancreatic lipase, decreases the absorption of dietary fat by about 25%
- Pancreatic lipase is released into the duodenum to break down larger dietary fat globules into FFAs
13
Q
Orlistat Therapeutic Effects
A
- Primarily used to treat obesity
- Studies indicate that it also has additional effect to decrease LDL levels obese individuals
14
Q
Zetia ADME
A
A: Zetia is absorbed, glucuronidated and reexcreted into the gut (Plasma peak concentration is 4-12h post dosing)
D: Zetia is systemically distributed to a limited degree, ~90% is protein bound
M: Zetia is glucuronidated.
E: >80% are eliminated in feces, Zetia systemic half life = 22h
15
Q
Orlistat ADME
A
A: Orlistat is poorly absorbed systemically.
D: Orlistat stays in gut
M: Minimal metabolism in gut epithelium and microflora
E: >80% eliminated in feces
16
Q
Bile Acid Binding Resins MOA
A
- Bind negatively charged bile acids in the small intestine that are made from cholesterol
- Resin/bile acid complex is excreted in the feces
- Hepatocytes must increase conversion of cholesterol to bile acids to compensate for loss
- Upregulates LDL receptors in liver to increase hepatic intake of cholesterol to convert to bile to replace what is lost, decreases plasma LDL
17
Q
Bile Acid Binders Therapeutic Effects
A
Therapeutic Uses
- Moderate decrease in LDL levels, increases HDL
- Large molecules, insoluble in water, not absorbed or metabolized, totally excreted in feces
18
Q
Bile Acid Binders Adverse Effects
A
- GI effects: most common (constipation, nausea, flatulence), fiber supplements may help
- Impaired absorption at high doses of fat-soluble vitamins
- Decreases absorption of tetracycline, phenobarbital, digoxin, warfarin, pravastatin, fluvastatin, aspirin, and thiazide diuretics (take 1-2 hours before or 4-6 hours after)
- *Colesevelam is better tolerated and does not decrease the absorption of other drugs**
19
Q
Bile Acid Binder Cautions/CIs
A
- Good safety record for long periods
- Pregnancy - preferred drug therapy during pregnancy (monitor fat soluble vitamins)
- Cholelithiasis (biliary stores) or complete biliary obstruction, so CI if bile acid secretion is impaired
20
Q
Bile Acid Binder ADME
A
A: Not systemically absorbed
D: Stays in the gut
M: Not metabolized
E: 99.95% excreted in feces
21
Q
Niacin (MOA)
A
- Nicotinic Acid
- Broad lipid-lowering ability but clinical use is limited due to unpleasant side effects
MOA
-Niacin strongly inhibits lipolysis in adipose tissue to lower circulating FFAs which is used for TG synthesis and then VLDL/LDL ultimately
22
Q
Niacin Therapeutic Effects
A
- Lowers plasmalevels of cholesterol (LDL by 5-25% and TG (20-50%)
- Most effective antihyperlipidemic agent for raising plasma HDL levels (15-35%)
23
Q
Preparation of Niacin
A
- Immediate-release - Niacor - truncal and facial flushing (52-100%)
- Sustained-release - (Slo-Niacin) absorbed over 12-24 hours, dietary supplement NOT APPROVED for dyslipidemia, some linked to hepatotoxicity and liver failure
- Extended-release - Niaspan (absorbed ober 8 hr), FDA-approved, lower incidence of flushing and reduced risk of hepatotoxicity
24
Q
Niacin ADME
A
A: Peak plasma concentrations: Niacor = ~30-60minutes; Niaspan = ~5h, highly variable
D: Broad systemic distribution
M: Rapid 1st pass metabolism - handled by numerous enzymes to become nicotinamide adenine dinucleoide, nicotinuric acid, etc.
E: 60-76% in urine, only 12% as a parent compound
25
Prevention of Cutaneous Flush
Take aspirin or ibuprofen 30 minutes prior to taking niacin to decrease flush.
26
Niacin Adverse Effects
- Cutaneous flush = main symptom
- Nausea, vomiting, abdominal pain, flushing and tachycardia
- Inhibits tubular secretion of uric acid
- May impair glucose tolerance (caution with diabetes)
- Hepatotoxicity
27
Fibrates (MOA)
- Gemfibrozil or Fenofibrate
- MOA: increases LPL activity by activating PPARs which is a transcription factor for LPL. LPLs then decrease TG levels by hydrolyzing triglycerols in CMs and VLDLs. Also increase HDL
28
Fibrates Therapeutic Uses
- Decrease triglyceride levels (25-50%)
| - Increase HDL cholesterol levels (10-30%) - first line to reduce risk of pancreatitis in patients with high plasma TGs
29
Fibrates Adverse Effects
- Mild GI disturbances
- Predisposition to form gallstones
- Increased hepatotoxicity from increased transaminases
- Clofibrate - significant number of malignancy-related deaths
- Myositis - more common with Gemfibrozil since it inhibits metabolism of statins, fenofibrate doesn't do this
30
Fibrate DI/CI
DI: competes with coumadin thus potentiating anticoagulant activity (monitor prothrombin)
CI: patients with severe hepatic and renal dysfunction or pre-existing gall bladder disease
31
Fibrate ADME
A: Peak plasma concentrations: Lopid = ~1-2 hours
D: Broad systemic distribution, plasma bound
M: rapid 1st pass metabolism
E: 60-70% eliminated as glucuronidated compound in urine, less than 2% is parent compound, half life ~20-22h
32
MTTP Inhibition
- Lomitapide (Juxtapid)
- MTTP is essential fortransferring TG to ApoB48 in enterocytes and ApoB100 in hepatocytes
- Inhibiting this inhibits the production of chylomicrons and VLDL
- CYP3A4 metabolizes it
- GI effects are most common SE
- Comparable results to Zetia with slightly more adverse events (considered mild and safe)
33
Statins MoA
- Analogs of HMG-CoA, a precursor to cholesterol, inhibits HMG-CoA reductase competitively
- Depletion of intracellular cholesterol leads to elevated levels of cellular LDL receptors to increase cholesterol uptake from circulation
- Decreases cholesterol synthesis, increases catabolism of LDLs, and smaller increases of HDL and decreases of TGs
34
Statins Therapeutic Uses
- Decreases total and LDL cholesterol (1st line for LDL reduction)
- May be useful for those with or without CVD
- Pleiotropic effects (non-lipid)
35
Statin's Pleiotropic Effects
- Regression of plaque size
- Increased endothelial function
- Stabilizes platelets
- Decreases plasma fibrinogen
- Decreases inflammatory markers
36
Statin Toxicity
1. Hepatotoxicity - rare, reversible
- Increases serum aminotransferase
- Not severe unless already has a liver disorder (CI)
- Check liver function before prescribing
2. Myopathy - rare, dose-related
- Myalgia, muscle weakness, skeletal muscle pain
- Encourage patient to report unexplained muscle pain
- Monitor CPK periodically
- Increased risk when used with fibrates (gemfibrozil), niacin, inhibitors of CYP3A4/statins metabolized by CYP3A4
37
Cerivastatin
- Removed from market
- Caused death from rhabdomyolysis
- Especially when used with gemfibrozil
38
Inhibitors of CYP3A4
- Erythromycin
- Clarithromycin
- Ketoconazole
- Itraconazole
- Gemfibrozil
- Many HIV drugs
- Grapefruit juice
39
Statins + When to Take Them
* *Depends on half life**
- Atorvastatin, rosuvastatin, pravastatin all have long half lives and can be taken at any time of day
- Simvastatin, lovastatin, fluvastatin have short half lives and have to be taken in the evening (most cholesterol synthesized while sleeping)
40
Bempedoic Acid
- New drug that inhibits cholesterol synthesis
| - Inhibits ACL, protein further up the pipeline than statins
41
PCSK9 Inhibitors
- Antibodies being tested as therapeutics
- Binds to LDLR and induces endosomal uptake and degradation
- Decreases LDLR and increases circulating LDL
- Approved for heterozygous familial hypercholesterolemia and clinical ASCVD who need additional reduction of LDL-C
- DRAMATICALLY lowers LDL, found to be a very safe drug
42
Drug Combinations
-If single drug with diet/exercise/life change doesn't control lipidemia, THEN combine 2+ drugs
Examples
1. Statin + BAB: increases LDL receptors which decreases LDL by 42%
2. Statin + Fibrates: increases myopathies potential
3. ER Niacin/Lovastatin (Advicor, Simcor): decreases LDL, TG, and increases HDL with less flushing and low myopathy/liver damage compared to each alone
4. Ezetimibe + Simvastatin/Ator/Prav/Lova: significantly decreases LDL below that obtained with a statin alone
43
Preggo + Lipid-Lowering Drugs
- Lipid-lowering drugs tend to be completely or relatively contraindicated during pregnancy because of the essential role of cholesterol in fetal development
- DON'T use statins. BAB are the safest
- Stop statins ~6 months before conception ideally
44
HDLs
- Protective lipoproteins that decrease risk of CHD
- Participates in reverse cholesterol transport (excess from cells is taken up to the liver for excretion)
- HDL = anti-inflammatory, antioxidative, platelet antiaggregatory, anticoagulant, and profibrinolytic activities
- Antioxidant enzymes in HDL = paraoxonase, PAF acetylhydrolase, glutathione peroxidase
45
HDL Beneficial Effects
1. Increase reverse cholesterol transport
2. Increased NO and prostaglandin effects on smooth muscle/platelets
3. Inhibits platelet and monocyte binding to damaged endothelium cells
46
Illuminate Study
-15K+ enrolled with coronary artery disease
-Gave some Torcetrapib (HDL promoter) + Atorvastatin and some Atorvastatin alone
Increased HDL (71.1%), decreased LDL (24.9%), decreased TG (9%)
-HOWEVER, the combination also increased BP significantly and increased mortality of patients
47
Hoffman LaRoche
- Dalcetrapib
- Increases HDL, but no clinical benefits
- HDL not a simple molecule, complex subcellular particle. Can become pro-inflammatory in oxidative environments
- Proteomic, lipidemic studies are ongoing to better understand the link to CVD
- Overall, cholesterol efflux is the best functional marker between CVD and HDL
48
Drugs that Alter Serum Lipoprotein Levels
All of the ones in this chapter excluding MTTP inhibitors and PCSK9 Inhibitors
