Anti-hyperlipidemics Flashcards
What type of lipid disorder is often associated with metabolic syndrome or Type II DM?
atherogenic dyslipidemia - inc tri’s, dec HDL-C, small LDL particles (better at invading vessel wall)
What enzyme do statins inhibit?
HMG-CoA reductase in de novo cholesterol synthesis in liver = rate-limiting step (HMG CoA –> mevalonic acid)
How are statins administered? Elimination site?
- oral
- hepatic
Composition of LDL?
45% chol, 9% tri’s
Composition of VLDL?
22% chol, 50% tri’s
Composition of HDL?
30% chol, 8% tri’s
Which two statins are pro-drugs? Activation enzyme?
- simvastatin, lovastatin (lipophilic in pro-drug form)
- esterases
- these drugs are competitive inhibitors at HMG CoA reductase site
What drug class is the best at dropping total cholesterol and LDL?
Statins; also significantly decrease VLDL-TG, but minimal effects on HDL-C
What are the 3 statin prototypes and which can be used for high and medium intensity statin Tx?
- atorvastatin = M and H
- pravastatin = M
- rosuvastatin = M and H
Statins major site of action?
hepatocytes
What causes the biggest drop in LDL associated with statin Tx? How?
- increased hepatic uptake of LDL (cell always needs cholesterol - if it can’t make it anymore, it scavenges)
- dec chop activates SREBP which causes increased expression of LDL receptors
Three pleiotropic effects of statins? What may cause them?
- antioxidant (slow and stabilize plaques)
- improved endo function (vasodilation via NO)
- anti-inflam (slow and stabilize plaques)
- decreased isoprenoid production and therefore decreased protein anchoring on cell membranes (less communication, signaling pathways)
Contraindication of statin therapy?
Pregnancy or nursing - skeletal defects in fetal animals = CAT X
Three AE’s associated with statins?
- skeletal muscle toxicity
- hepatotox
- Type II DM: tends to elevate blood Glc a bit
- incidence of AE’s is fairly low
What liver enzyme do many statins inhibit?
CYP3A4
How do many statins enter hepatocytes?
- OATP1B1
- inhibition/dysfunction of transporter results in inc blood level of statin and the likelihood of myopathy
- OAT inhibitors have major effects on statins (gemfibrozil) = increased risk of muscle tox
How are the pharmacokinetics of pravastatin different? How is this useful?
- eliminated by multiple metabolic pathways and some renal excretion
- affected less than other statins by pharmacokinetic drug interactions
Name a bile acid sequestrant. Primary function?
- colesevelam
- decrease LDL-C modestly
- may actually increase VLDL-TG
How do bile acid sequestrants work?
- bind bile acids and decrease their enterohepatic recirculation – fecal elimination
- INC bile acid synthesis from cholesterol which results in INC LDLR expression to scavenge more LDL-C from blood
What type of patient are bile acid sequestrants indicated in?
patients with high cholesterol who cannot tolerate statins
How can colsevelam be used as adjunct Tx in IIDM?
- reduces HbA1C levels
- improves glycemic control
What are 3 GI adverse effects of BA sequestrants?
- bloating, constipation
- malabsorption of fat-soluble vitamins
- decreased absorption of some neg charged or lipid soluble drugs (warfarin, oral contraceptives, digoxin)
What drug type is ezetimibe?
selective cholesterol uptake inhibitor - acts in GI tract
What is ezetimibe target and where is it found?
- NPC1L1 (Niemann-pick) = transports chop into enterocytes from the lumen
In ezetimibe treatment, what are the consequences of decreased cholesterol absorption? Primary indication of the drug?
- up regulation of hepatic LDLR and hepatic LDL uptake
- DEC LDL-C = effective (can be combined with statins for an additive effect or can stand alone in patients who can’t take statins)
How is ezetimibe eliminated?
- glucuronidated and dumped in intestines
- undergoes enterohepatic cycling after being deconjugated by bacteria in gut = multiple plasma drug peaks and repeated exposure to its hepatic receptor
What two drug classes are better for triglyceride Tx?
fibrates and nicotinic acids
What are two fibrate drugs? Effects?
- fenofibrate
- gemfibrozil
- sig DEC in VLDL, mild INC in HDL-C (tri’s > chol)
What is a pharmacokinetic problem associated with fenofibrate?
- poor water solubility so decreased GI absorption
- take with meals + make particles smaller for increased bioavailability
- different formulations cannot be substituted for one another
What nuclear receptor regulates protein expression in liver and muscle?
PPAR-alpha - activated receptor translocates into the nucleus, heterodimzerizes with the retinoid X receptor before binding DNA and altering gene transcription
Two effects of fibrates on tri’s?
- dec tri syn in liver (inc ox of FA’s before inserted into tri’s)
- inc tri removal from VLDL (increased LPL in skeletal muscle, dec syn of apoCIII in liver = VLDL apolipoprotein that inhibits VLDL binding to LPL)
Function of endothelial LPL?
removal of FA’s from VLDL triglycerides
Major effects of nicotinic acid (form of niacin vitamin) on blood lipids?
- moderate dec in VLDL
- moderate inc in HDL-C
- small effect on LDL-C
Three sites of nicotinic acid effects?
altered lipoprotein levels through effects on liver, adipocytes, muscle
General MOA of nicotinic acid?
- dec tri syn in liver
- consequent inc metabolism of VLDL tri’s
Primary indication for nicotinic acid treatment?
one of the most useful drugs for Tx hypertriglyceridemia
What drug is the best available drug to treat low HDL levels?
nicotinic acid, but only a modest effect
Major AE associated with nicotinic acid?
hepatotoxicity
What two disorders can be aggravated by nicotinic acid?
- gout = dec uric acid secretion
- diabetes = dec insulin sensitivity
Two common AE’s that decrease patient tolerance with nicotinic acid regimen?
GI irritation, cutaneous flushing
How do fibrates decrease triglyceride synthesis in the liver?
increased ox of FA’s before they are inserted into triglycerides
How do fibrates increase removal of triglycerides from VLDL in the skeletal muscle? Liver?
- increased expression/activity of LPL
- decreased synthesis of apoCIII, which is a VLDL apolipoprotein that inhibits VLDL binding to LPL –> increased VLDL binding to LDL
Three significant AE’s associated with fibrates?
- cholelithiasis
- venous thrombosis and PE
- myopathy, esp w/ statins
What is a concern with co-administering gemofibrozil, a fibrate, with statins?
Gemfibrozil increases plasma levels of many statins
What are three lipid imbalances associated with Type II DM?
- high TG’s
- low HDL
- modestly elevated total chol
In which patient subgroup may fibrates be most useful?
Diabetics with retinopathy because fibrates were found to decrease nephropathy, retinopathy in the 2005 FIELD study
