Flashcards in Pharm - Lec#3 - Hyperlipidemia &TG drugs Deck (51):
What drugs are in the STATIN drug class?
A) Indicated for HIGH LDL
Inhibits HMG - Co A reductase & triggers SREBP transcription factor
1. increased LDL -R expression
2. increased LDL clearance from the plasma!
Statins affect on serum lipids (LDL, TG, HDL)
LDL decreased (20-60%)
TG decreased (10-20%)
HDL increased! (5-10%)
What is the MAJOR adverse reaction of Statins? (3 other adverse effects)
1. muscle myalgia/myopathy
3. Small risk of Type 2 diabetes
What is the major contraindication for statins?
SEVERE LIVER DISEASE
What are some drug interactions for statins? (4)
1. CYP3A4 inhibitors
(increase L, S, A )
increased risk of adverse effects!!!
- erythromycin, cyclosporine, ketaconazole, HIV pro inhibittors & GRAPEFRUIT juice
2. CYP3A4 inducers (decrease L, S , A)
- DECREASED CLINCIALY EFFICACY!
- pheynotin, phenobarbital, rifampin
3. CYP2C9 inhibitors
(increase E, R)
- ketoconazole, metronidazole
- decrease OATP2, decrease glucoronidation= increase all statins
What are the 3 bile acid binding resins?
Bile Acid Resins:
Indication: High LDL
MOA: binds bile acids and PREVENTS reabsorption--> increases 7a-hydroxylase --> decrease cholesterol --> increase LDL - R --> INCREASE LDL CLEARANCE!
when more 7a-hydroxlase = more bile acids made and less cholesterol!
Bile Acid Resins:
Effects on LDL?
DECREASE LDL (10-25%)
2. Adverse effect: can increase TG LEVELS IN HYPERTRIGLYCERIDEMIA
TG> 400 mg/dL
due to risk of further increasing VLDL levels!!!
What two bile acid resins interfere with the absorption of drugs like warfarin, phenobarbital, digoxin, and tetracycline?
At high concentrations Cholestyramine and Colestipol, but not Colesevelam,
impair the absorption of the fat soluble vitamins A, D E & K
& tetracyline, penicillin, vancomycin, phenobarbital, digoxin, warfarin,
propanalol, parvastatin, fluvastatin, aspirin, and thiazide diurectics
Indication high LDL
- primary hypercholesterolemia!!!
Ezetimibe: Therapeutic Uses
Reduces LDL-C in patients with primary hypercholesterolemia
- i.e. not completely dependent upon intact LDLR
2. Can induce a significant further LDL-C lowering effect when combined
with a STATIN
Ezetimibe: Effect on serum lipids
LDL decrease (18%)
NONE - flatulence& diarrhea
MOA: inhibits intestinal absorption of cholesterol (via NPCL1)
--> decrease hepatic cholesterol
--> increase LDL - R expression
--> INCREASE LDL CLEARANCE!
Inhibits the action of the Niemann-Pick C1-like 1 protein (NPC1L1) involved
in the absorption of dietary and biliary cholesterol in the small intestine
b) Reduced cholesterol absorption results in the decreased delivery of cholesterol
to the liver, thereby reducing VLDL and LDL production and increasing LDLR
1. High VLDL
2. High LDL
3. Low HDL
TG - 30-80% reduction in triglycerides
LDL - 10-20% reduction in LDLs
HDL - 10-30% increase in HDLs - most effective drug at raising HDLs!!
What is the most effective drug at raising HDLs?
MOA of Niacin
-decreased lipolysis in adipocytes--> decreased FFA --> decreased VLDL
2. - inhibits DGAT2 which results in decreased VLDL synthesis
3. inhibit ApoCIII --> which usually inhibits LPL --> thus increase in LPL-->
increased VLDL clearance
4. Increased apoAI expression --> increased HDL production
5. decreased Lp(a) --> decreased
(Lp(a) is homologous to plasminogen - Lp(a) blocks the formation of plasmin and prevents thrombolysis, thereby increasing the risk of a CLOT forming)
What are the 3 main adverse effects of Niacin?
1. SKIN FLUSHING (tx: NSAID - COX inhibitor to decrease prostaglandin production)
2. RISK OF GOUT
3. EXACERBATES PEPTIC ULCERS
4. Risk of hyperglycemia
What are the 2 fibrates?
What is the indication for fibrates: (Gemfibrozil, Fenofibrate)
Effect on serum lipids?
1. High VLDL
2. Low HDL
1. decrease TG (40-60%)
2. decrease LDL (10-20%)
3. Increase HDL (10-20%)
What is the MOA of fibrates
LIGANDS FOR PPAR alpha TF
1. decrease ApoC3 and increase LPL expression, increasing fatty acid oxidation
- decreased VLDL synthesis
- increased VLDL clearance
2. Increase APOI expression
- increased HDL production
What are the 2 main adverse effects of Fibrates?
1.Increased GALLSTONES! (test)
Contraindication in severe renal/hepatic disease
What are some drug interactions of Gemfibrozil & fenofibrate? (2- 2nd is especially true for gemfibrozil)
What type of drugs are these?
1. Strong protein binders:
- increase warfarin & risk of bleeding
-- increased sulfonylureas and hypoglycemia
- inhibit OATP2 / glucoronidation
- increased STATINS and rhabdomyolysis
What two drugs are PCSK9 inhibitors?
- hetero Familial Hypercholesterolemia
- High LDL not controlled with maximum STATIN or STATIN intolerant!
- bind to PCSK9 and prevent its binding to the LDLR
- thereby prevent the targeting of LDLR to the lysosome
- result in increased expression of LDLR at the cell surface
- approved for treatment of heterozygous FH & patients that
have not achieved goals with maximally tolerated STATINs
MOA of Alirocumab
Inhibits PCSK9 --> blocks normal targeting of LDLR to lysosome
- increased LDL-R expression and increased LDL clearance
Effect of PCSK9 inhibitors on serum lipids ( alirocumab, Evolocumab)
decreased LDL (>50%)
What drug (s) is indicated for homozygous familiar hypercholesterolemia?
MOA of Lopitapide
inhibits MTP in both enterocytes and liver
- decreased production of chylomicrons, VLDL, and LDL
Inhibitor of microsomal triglyceride transfer protein (MTP)
MTP is required for the assembly of both chylomicrons & VLDLs
Since chylomicrons and VLDLs give rise to LDLs LOMITAPIDE can reduce LDL levels in FH patients
Lopitapide: effect on serum lipids
chylomicrons, VLDL, LDL
Adverse effects/ contraindication
- contraindicated in PREGNANCY!!
2. CYP3A4 and P-gp inhibitor
- many drug interactions
Indication: Homozygous FH (like lopitamide)
- antisense oligonucleotide specific for apoB100
- Reduces expression of ApoB (100 & 48) resulting in reduced production of VLDLs and hence lower levels of LDLs
Mipomersen: effect on serum lipids
Contrindicated: mild/moderate HEPATIC impairment
Which 3 drugs are contraindicated in SEVERE liver disease?
(lipotamide & mipomersen can both use severe LIVER toxicity)
What are the accepted values for desirable, borderline, and high
high: 240 mg/dL
high 190 mg/Dl
What are the accepted values for desirable and high
M> 40 mg/dl
W> 50 mg/dl
very high: 500 mg /dL
Severe hypercholesterolemia drug therapy indicated for:
what LDL levels?
1. LDL >190 md/dl
2. or >70 md/dl in diabetes
the initial goal is to reduce LDL - risk of atherosclerosis
- the initial drug of choice is typically a STATIN
What drugs would be used to treat hypercholesterolemia?
Bile Acid Binding Resins
Cholesterol Absorption Ihbitiors (ezetimibe)
What drugs would be used to treat hypertrygliceridemia?
Homozygous Familial Hypercholosterolemia is treated with which drugs?
Lomitapide & Mipomersen
What is the DOC for hyperlipidemia?
Which statin is NOT metabolized by the CYP450 mechanism and is the DOC to use with verapamil, ketoconazole, and macrolide antibiotics (erythromycin)?
- thus drugs that inhibit CYP450 (cyclosporin, erythromycin, verapamil, warfarin, ketoconazole) will NOT affect pravastatin
GRAPEFRUIT JUICE also inhibits CYP450
HOWEVER this will affect Lovastatin, SImvastatin & Atorvastatin and result in increased levels of these drugs and RHABDOMYOLYSIS risk!
Phenytoin, griseofulvin, barbiturates, rifampin, thiazolidnediones INCREASE CYP3A4 expression and reduce plasma statins
What fibrate inhibits the metabolism of ALL statin drugs by inhibiting statin glucoronidation & statin transporter?
What vibrate is the DOC to be used with statins?
- also inhibit OATP2 (statin uptake transporter)
- increase statin drugs results in rhabdomyolysis
- does not affect statin metabolism
What are the 3 contraindications of patients taking statins?
1. Pregnant/nursing moms
2. pts. taking Gemfibrozil
3. Patients with liver disease
Without bile acids, there is no suppression of _____ synthesis
so the Bile Acid resin drugs ( Cholestyramine, colestipol, colesevelam) which are cationic polymers binding to negatively charged bile acids thus preventing in their reabsorption result in HIGHER TG levels
What drug is contraindicated in type II dyslipoproteinemia?
BILE ACID RESINS
-increased TG's --> increased VLDLs --> increased serum TG's which lead to PANCREATITIS
(cholestyramine, colestipol, colesevelam)
___ and ____ inhibit fat soluble vitamins D, A, K,E absorption
Cholestyramine & colestipol
- also interferes with the intestinal absorption of many drugs (tetracycline, digoxin, warfarin etc)
- NOT colesevelam!
What drug when combined with a statin results in an increased LDL lowering?
- bile acids interfere with its absorption
- cyclosporinincreases its concentration
What drugs should not be taken during pregnancy
3. Lomitapide ( drug to treat homozygous familial hypercholesterolemia)
4. Fibrates (also predispose to gallbladder formation due to increased cholesterol excretion in bile)
What is the most affective drug for increasing HDL levels?
What is the therapy of choice for patients with Familial dysbetalipoproteinemia (type III hyperlipoproteinemia)
( Fenofibrate, Gemfibrozil)