L 6/7 Anti-Hyperlipidemics Flashcards
What is Hyperlipidemia?
Excess lipids in the blood
Cholesterol plaque formation is the underlying cause of which conditions?
Angina, MI, Atherosclerosis, Hypertension, Heart Failure
Cholesterol Synthesis occurs through which pathway?
Mevalonate Pathway
Which enzyme catalyzes the rate limiting step of the Cholesterol Synthesis Pathway?
HMG-CoA Reductase (HMGCR)
Statin drugs all end with ______?
-statin
Statin MOA (Primary):
-Inhibits HMGCR enzyme in Mevalonate Pathway. (Selective competitive inhibition)
-Blocks cholesterol synthesis
-Reduces Cholesterol
Statin MOA (Secondary):
SREBP, in ER and Golgi, senses decreased cholesterol and gets cleaved and translocated into nucleus. LDL Receptor gene turned on to increase LDL receptors on every cell to breakdown LDL and make new cholesterol.
-Decrease LDL
Which two statins are inactive precursors?
Simvastatin and Lovastatin.
Converted to Beta-hydroxy acid derivatives.
-Simvastatin Hydroxy Acid (SVA)
-Lovastatin Hydroxy Acid (LVA)
Statin First Pass Metabolism is regulated by:
Organic Anion Transporter (OAT1B1)
Statin Adverse Effects:
- Hepatotoxicity ( increased AST, ALT)
- Myopathy: Should supplement with Co-Enzyme Q10
- Rhabdomyolysis (rapid muscle damage, rare): risk increases with Grapefruit drug-food interaction (furanocoumarins inhibit CYP enzymes, increases hepatotoxicity).
Bile Acid Sequestrant Drug names all start with ______.
Cole-/Chole-
Bile Acid Sequestrants MOA:
Are resins (positively charged) that bind bile acids (negatively charged). The complex is easily excreted from body.
- Decreases Bile Acids
- Induces production of more bile acids, using cholesterol.
-Decreases Hepatic Cholesterol
-Increased LDL receptor expression
Bile Acid Sequestrants Adverse Effects
Hypertriglyceremia
-must monitor triglycerides
GI issues:
-Bloating
-Dyspepsia
-Constipation
Bile Acid Sequestrant Contraindications:
High Triglycerides
Also, resins bind to other drugs and prevents absorption. Take this drug at least a few hours before or after other drugs.
Niacin MOA:
( Acts on Niacin receptor 1/2 (GPCR Family) )
-Inhibits HSL (Hormone Sensitive Lipase) in Adipose tissue. Prevents TG breakdown into FFAs.
-Decreased FFAs prevents liver from making TG to form VLDLs
-Results in Decreased TG and LDL, and increased HDL
-Niacin also increases LPL activity: Increases clearance of VLDLs and Chylomicrons
-Increases Apo A (HDL)
-Enhances Efflux of cholesterol from monocytes and macrophages (good)
Niacin Adverse Effects
-Flushing: increased by caffeine or ethanol
-Hepatotoxicity (important)
-Hyperglycemia (from liver)
Niacin Contraindications
History of GI complications
-Diabetes (b/c hyperglycemia), need to switch to diabetes meds immediately. Stop Niacin
Niacin Metabolism
-Peak Plasma levels 1 hr
-t1/2=1hr
-in liver
-metabolite: nicotinuric acid
Fibrate drugs have ____ in their names.
-fibr-
Fibrated MOA:
-Act on PPARs in Liver and Adipose (also kidney, heart, skeletal muscle.)
-Upregulate LPL, LDL receptor, Apo CII, Apo A1 (good genes)
-Downregulate Apo CIII, IL6 (bad genes)
Ultimately increase HDL
Decrease TG
Fibrated DDIs:
Warfarin: increased blood thinning (bleeding) need monitoring
-Statins (Genofibrozil only) Interfere with OAT1B1 for liver uptake. And competes for metabolism. both drug plasma levels increase. Statin can cause myopathy.
Fibrates Contraindications
-Renal failure
-Hepatic disorders
-Children, or pregnant
Fibrates Adverse Effects
-GI (rare)
- Minor hepatotoxicity
- lithogenic (galstones)
PCSK9 Inhibitor drug names end in ________.
-ocumab
PCSK9 Inhibitor MOA:
Antibody binds and inhibits PCSK9.
- LDL receptors are not cleaved for degradation by PCSK9
- LDL receptor levels are maintained
- LDL decreases
PCSK9 Inhibitor Adverse Effects and Contraindications
AE: Mild/severe allergic reactions
Contraindication: Pregnant/breastfeeding. Prior autoimmune or allergic diseases
Inclisiran MOA:
SiRNA targets PCSK9 mRNA for degradation.
-increase LDL receptor
-increased clearance of LDL
-Decreased LDL
Ezetimibe MOA:
Dietary cholesterol uptake inhibitor: Blocks NPC1L1 cholesterol transport protein.
- decreased chylomicron synthesisE
Ezetimibe Adverse Efects, Contraindications, DDIs:
AE: Rare allergic rxns
Contraindications: pregnant
DDI: No statins
Lomitapide MOA:
MTTP Inhibitor in ER
-prevents Apo B lipoproteins (chylomicrons and VLDLs)
Lomitapide Adverse Effects
-GI
-Headaches
-Hepatotoxicity (Important)
Lomitapide DDIs
-Warfarin
-Strong CYP3A4 inhibitors
What are the Omega 3 Derivative Drug names
- Eicosapentaenoic Acid (EPA)
- Docosahexaenoic Acid (DHA)
Omega 3 Derivative MOA:
Multiple:
-Anti-inflammatory
-Upregulates PPAR activity
-Upregulates Endothelial NOS protein, increased NO release
Omega 3 Derivative Adverse Effects
DHA component can increase LDL levels
- VASCEPA is a drug with only EPA, so no DHA side effects. Also inhibits platelet aggregation.
What are the names of the newest Anti-Hyperlipidemics
-Bempedoic Acid
-Evinacumab
Bempedoic Acid MOA:
Inhibits ACL (ATP Citrate Lyase)
- Prevents the formation of Acetyl-CoA, a precursor of HMG-CoA
-decreased cholesterol synthesis
-very similar to statins
Bempedoic Acid Adverse Effects
Increased Uric Acid Levels in blood
Contraindications: Gout and pregnancy
What drugs can Bempedoic Acid sometimes be taken with?
-Ezetimibe
-Statins, but lower statin dose to decrease side effects
Evinacumab MOA, Effects, and Adverse Effects.
MOA: Antibody targets ANGPTL3.
-Increases LPL activity and Endothelial Lipase (EL) activity. This increases TG breakdown
- Reduces LDL
AE: Hypersensitivity Rxn
- No pregnant
