Hyperlipidemia Drugs Flashcards
Antihyperlipidemics - Extrahepatic Drugs
- Lipid absorption inhibitors
- Bile acid binders
- Niacin
- Fibrates
Cholesterol/Fat Absorption Inhibitors (2)
- Ezetimibe (Zetia)
2. Orlistat (Xenical)
Bile Acid Binding Resins (3)
- Colesevelam (Welchol)
- Colestipol (Colestid)
- Cholestyramine (Quetran)
Niacin (3)
- Niacor - IR
- Niacin - SR
- Niaspan - ER
Fibrates (2)
- Gemfibrozil (Lopid)
2. Fenofibrate (Tricor)
HMG-CoA Reductase Inhibitors (7)
- STATINS
1. Atorvastatin (Lipitor)
2. Lovastatin (Mevocor)
3. Pravastatin (Pravachol)
4. Simvastatin (Zocor)
5. Fluvastatin (Lescol)
6. Rosuvastatin (Crestor)
7. Pitavastatin (Livalo)
MTTP Inhibitors
Lopitamide (Juxtapid)
PCSK-9 Inhibition (2)
- Alirocumab (Praluent)
2. Evolocumab (Repatha)
Antihyperlipidemics - Hepatic Action Drugs
- Statins
- MTTP Inhibitors
- PCSK9 Inhibitors
- Mipomersen
Ezetimibe (MOA)
- 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)
Ezetimibe Therapeutic/Adverse Effects
- 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
Orlistat (MOA)
- 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
Orlistat Therapeutic Effects
- Primarily used to treat obesity
- Studies indicate that it also has additional effect to decrease LDL levels obese individuals
Zetia ADME
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
Orlistat ADME
A: Orlistat is poorly absorbed systemically.
D: Orlistat stays in gut
M: Minimal metabolism in gut epithelium and microflora
E: >80% eliminated in feces
Bile Acid Binding Resins MOA
- 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
Bile Acid Binders Therapeutic Effects
Therapeutic Uses
- Moderate decrease in LDL levels, increases HDL
- Large molecules, insoluble in water, not absorbed or metabolized, totally excreted in feces
Bile Acid Binders Adverse Effects
- 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**
Bile Acid Binder Cautions/CIs
- 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
Bile Acid Binder ADME
A: Not systemically absorbed
D: Stays in the gut
M: Not metabolized
E: 99.95% excreted in feces
Niacin (MOA)
- 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
Niacin Therapeutic Effects
- Lowers plasmalevels of cholesterol (LDL by 5-25% and TG (20-50%)
- Most effective antihyperlipidemic agent for raising plasma HDL levels (15-35%)
Preparation of Niacin
- 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
Niacin ADME
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
Prevention of Cutaneous Flush
Take aspirin or ibuprofen 30 minutes prior to taking niacin to decrease flush.
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
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
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
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
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
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
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)
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
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)
Statin’s Pleiotropic Effects
- Regression of plaque size
- Increased endothelial function
- Stabilizes platelets
- Decreases plasma fibrinogen
- Decreases inflammatory markers
Statin Toxicity
- Hepatotoxicity - rare, reversible
- Increases serum aminotransferase
- Not severe unless already has a liver disorder (CI)
- Check liver function before prescribing - 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
Cerivastatin
- Removed from market
- Caused death from rhabdomyolysis
- Especially when used with gemfibrozil
Inhibitors of CYP3A4
- Erythromycin
- Clarithromycin
- Ketoconazole
- Itraconazole
- Gemfibrozil
- Many HIV drugs
- Grapefruit juice
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)
Bempedoic Acid
- New drug that inhibits cholesterol synthesis
- Inhibits ACL, protein further up the pipeline than statins
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
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
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
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
HDL Beneficial Effects
- Increase reverse cholesterol transport
- Increased NO and prostaglandin effects on smooth muscle/platelets
- Inhibits platelet and monocyte binding to damaged endothelium cells
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
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
Drugs that Alter Serum Lipoprotein Levels
All of the ones in this chapter excluding MTTP inhibitors and PCSK9 Inhibitors
