Hyperlipidemia Drugs Flashcards
List the Optimal, borderline and high serum LDL levels
Optimal less than 100, borderline 130-159, high 160-189, very high greater than 190mg/dL
List the optimal and low serum HDL
M >40mg/dL
W >50mg/dL
List the optimal, borderline and high TG level
optimal less than 150, borderline 150-199, high 200-499, very high greater than 500
MOA of the statins
- Analog of HMG-CoA, and competitively inhibits the HMG-CoA Reductase (rate limiting enzyme in cholesterol synthesis)
- Reduce hepatic cholesterol synthesis and triggers induction of SREBP transcription factor
- SREBP increase the expression of the LDL-R and increases clearance of serum LDL
MOA of the Bile Acid Binding Resins
- Bind to bile acid and prevent their reabsorption in the small intestines
- Increased bile acid production (upreg. cholesterol 7a hydroxylase) - decreasing hepatic cholesterol conc
- Triggers up regulation of the LDL-R and increased LDL clearance
What are the 2 drugs in the PCSK9
Evolocumab, Alirocumab
What drugs can be used for familial hyercholestolemia
heterozygous FH (PSCK9 inhibitors), Ezetimibe (Cholesterol Absorption Inhbitor)
Indications for the Statins
drug of choice for treating patients with increased LDL-C, drug of choice for both primary and secondary prevention of CHD
What statin would be not contraindicated in a patient liver disease or taking other medications metabolized by the CYP450 system
Pravastatin
For a patient with cardiovascular risk what are the preferred lipoprotein goals
LDL > 190mg/dL (or >70mg/dL with Diabetes)
Contraindications of the Stains
Pregnancy and Severe liver disease (except pravastatin - hepatic/elimination)
Clinical effects of Niacin
leads to a significant decrease in TGs (30-80%), mild decrease in LDLs (10-20%) and mild increase in HDLs (10-30%)* most effective at raising HDLs
Indications for Bile Acid Binding Resins
2nd line agent due to efficacy of STATIN, can be used in combo with statin, can be used in patients for whom statin are either not effective or contraindicated, drug of choice for treating hypercholesterolemia in children & women who are lactating or pregnant
List the statin drugs
Atorvastatin, Fluvastatin, Lovastatin, Simavastatin, Pravastatin, Rosuvastatin
MOA of Ezetimide
Inhibitor of NPCIL1
What 3 drugs are the Bile Acid binding resins
Cholestryamine, Colestipoli, Colesevelan
Contraindications of the Bile Acid Binding Resins
type III dysbetalipoproteinemia and raised TGs (>400mg/dL) due to risk of further increasing VLDL levels
What are the 2 fibrate drug
Gemfibrozil and Fenofibrate
Adverse Effects of the statin
RHABDOMYOLYSIS, muscle myalgia/myopathy, GI disturbance, increase liver enzymes, small increase in risk of T2DM
Adverse Effects of the bile acid-binding resins
Not absorbed or metabolized and therefore very safe and few side effects, GI disturbances, at high con, Cholestyramine and Colestipol impair the absorption of Vit. A, D, E, and K
Drug interactions with the BAB Resins
Cholestyramine and Colestipol (not Colesevelam) interfere with the absorption of MANY drugs (tetracyline, penicillin, vancomycin, phenobarbital, digoxin, warfarin, propanalol, parvastatin, fluvastatin, aspirin, and thiazide diurectics)
Effect of Statins on cholesterol
Significant reduction in LDL (20-60%), modest reduction in TGs (10-20%) and modest increase in HDL (5-10%)
Other activities of statins that contribute to anti-atherogenic effects
Inhibits adhesion molecule expression on endothelium, inhibts adhesion of monocytes to the endothelium, inhibits monocyte prolix and migration, inhibits oxidation of LDLs (foam cell formation), inhibits SMC prolif., Inhibits inflammatory responses, and stabilizes the endothelium (reduced plaque rupture risk)
What drugs interaction with the statins increase the incidence of rhadomyolysis
inhibitors of CYP3A4 (cyclosporin, macrolide abx, ketaconazole)
How do the therapeutic benefits increase when the dose of Statins is increased
Double or quadrupling the statin dose usually results in ONLT a modest (5-6%) further decease in LDL and significantly increases the potential for AEs
How are Statins take up into the liver
OATP2
How are most statins metabolized
Glucoronidated by glucurornyl transferase enzymes and the
CYP450 system
Which statin are metabolized by CYP3A4
Lovastatin, Simvastatin, Atorvastatin (grapefruit juice interaction)
Which statin are metabolized by CYP2C9
Fluvastatin and Rosuvastatin
Which statin is metabolized by CYP2C19
Rosuvastatin
Which statin is NOT metabolized by the CYP450 system
Pravastatin
CYP3A4 inhibitors (Cyclosporin, Ritonavir, Intraconazole, and Erythromycin) will increase levels of which statins
Lovastatin, Simvastatin and Atorvastatin
CYP2C9 inhibitors will increase levels of which statin
Fluvastatin and Rosuvastatin
Which statin is the drug of choice for a transplant patient treated with cyclosporin
Pravastatin is NOT metabolized by P450 enzymes
How does gemfibrozil interact with statin metabolism
- inhibits OATP2 tranporter mediated uptake of statins in to the liver
- inhibits the glucoronidation of statin (which is involved in the metabolism and ultimate excretion of ALL statin drugs)
MOA of cholesterol absorption inhibitors (Ezetimibe)
- inhibits action of NPC1L1 involved in the absorption of dietary and biliary cholesterol in the small intestines
- reduced cholesterol results in decreased delivery to the liver reducing VLDL and LDL production and LDLR
Clinical Effect of Ezetimibe
Reduces LDL-C, minimal effect on HDL and TGs (does not raise TGs)
What effect does Ezetimibe have when administered with a statin
further 25% reduction in LDL than with Statin alone (allows the use of a lower statin dose to avoid adverse effects)
Indication for Ezetimibe
Primary hypercholesterolemia (esp with Statin) and FH
Adverse effects of Ezetimibe
GI disturbance
MOA of alirocumab and evolocumab
Inhibitor of PCSK9 (binds to PCSK9 and prevents its binding to the LDLR there by preventing the LDLR from degradation and) and increases LDLR on the cell surface
Indications for alirocumab and evolocumab
heterozygous FH and patients that have not achieved goals with maximally tolerated statins
MOA of Lomitapide
Inhibitor of MTP (micosomal triglyceride transfer protein), which is required for the assembly of chylomicrons and VLDLs
Indication for Lomitapide
homozygous FH
MOA of Mipomersen
Antisense oligonucleotide for apoB (48,100), reduced expression of apoB resulting in reduced production of VLDLs and lower levels of LDLs
What is a major risk of TGs >500mg/dL
pancreatitis
MOA of Niacin
Very complex: 1. decreases lipolysis in adipocytes leads to a decrease in FFA and a decrease in VLDL. 2. inhibits DGAT2 leading to decreases VLDL synth. 3. decreases apoCIII (LPL inhibitor) and thus enhances LPL leading to VLDL. 4. increases apoA1 expression leading to increased HDL production. 5. decreases Lp(a) leading to decrease in thrombosis
What is the best treatment option for a patient with TG level of 175mg/dL
when TGs are borderline high (150-199mg/dL) a lifestyle change is indicated, low fat diet, exercise & cessation of smoking/alcohol
Adverse effects of Niacin
SKIN FLUSHING, inhibits tubular secretion of URIC ACID (predispose to GOUT), exacerbate PEPTIC ULCER DISEASE, GI disturbance, modest hyperglycemia in T2DM, rare hepatic toxicity
Contraindications of Niacin
Peptic ulcer disease, pt. with history of gout, caution with diabetics and pts with impaired liver function
What is the clinical effects of the fibrates (Fenofibrate and Gemfibrozil)
Significant reduction in TGs (40-60%), mild reduction in LDLs (10-20%), and mild increase in HDL (10-20%)
MOA of Fenofibrate and Gemfibrozil
activate PPARa to promote the expression of genes involved in lipoprotein, function and metabolism (increase apoA1, apoAII (increasing HDL), decreases ApoCIII increasing LPL (decreases TGs)
Indications for Fenofibrate and Gemfibrozil
hypertriglyceridemia associated with low HDL and therapy of choice for patients with familial dysbetalipoproteinemia/Type III hyperlipoproteinemia, TG levels greater than 500mg/dL
Adverse effects of the fenofibrate and gemfibrozil
Increased predisposition to GALLSTONES, myopathy/rhadomyolysis leading to acute renal failure (v. rare - a lot more common with gemfibrozil vs fenofibrate, esp with given with high dose of statin), hepatitis, GI disturbance
Drug interaction with the fenofibrate and gemfibrozil
STONG PROTEIN BINDERS and can displace other prot. bound drugs from albumin resulting in increase conc (warfarin, sulfonyureas)
why in fenofibrate preferred over gemfibrozil when given in combination with a statin
genfibrozil inhibits OATP2 and glucoronidation (fenofibrate does not), and can increase serum contents of statins and increased risk of myopathy and rhabdmyolysis
Contraindication for fenofibrate and gemibrozil
- pregnant/lactating women, 2. pt with severe hepatic dysfunction, 3. Pt with severe renal dysfunction, 4. pts with preexisting gall bladder disease
What are eicosapentaenoic acid and docosahexaenoic acid
Fish oils: omega-3 long chain polyunsaturated fatty acids
clinical effect of fish oils (eicosapentaenoic acid and docosahexaenoic acid)
lowers serum TGs (30-50%), minor HDL increase, can increase LDL in some patients
Indication for fish oils (eicosapentaenoic acid and docosahexaenoic acid)
ONLY as an adjunct to diet in the treatment of high TGs in pt with TG level >500mg/dL
MOA of fish oils (eicosapentaenoic acid and docosahexaenoic acid)
unclear: inhibiting expression of genes involved in hepatic TG synthesis, and anti-inflammatory activity via GPCR on macrophages
