Lipid Lowering Drugs Flashcards
Classes of lipid lowering drugs
- HMG-CoA reductase inhibitors (statins)
- PCSK9 inhibitors (alirocumab, evolocumab)
- Fibrates/ Fibric acid derivatives (fenofibrate, gemfibrozil)
- Omega-3-acid ethyl esters (omacor)
- Bile acid binding resins (cholestyramine)
- Inhibitors of intestinal sterol absorption (ezetimibe)
MOA of HMG-CoA reductase inhibitors + name
Inhibits HMG-CoA reductase, the late-limiting enzyme of cholesterol synthesis
-> Reduces cholesterol synthesis
Clinical uses of HMG-CoA inhibitors
- Reducing plasma cholesterol (LDL-C) levels in all types of hyperlipidemias
- Reduce the risk of coronary events and mortality in patients with ischaemic heart disease
Which time of the day is it best to take statins?
Evening, when the body’s main source of cholesterol is from synthesis
Adverse effects of statins
Liver: biomedical abnormalities in liver function
Muscle: myopathy and rhabdomyolysis (protein in muscle is broken down and metabolised)
Examples of HMG-CoA reductase inhibitors
Atorvastatin, Simvastatin, Pravastatin
MOA of PCSK9 inhibitors + name
Inhibits PCSK9 which targets and degrades LDL receptors in lysosomes
Inhibits PCSK9 → more cell-surface LDL receptors that can bind and internalise circulation LDL → lower plasma LDL
Alirocumab, Evolocumab
Administration of PCSK9 inhibitors?
Monoclonal antibodies: administration only via injection
Clinical uses of PCSK9 inhibitors
- Lowering plasma cholesterol (LDL-C) levels in familial hypercholesterolaemia, especially those intolerant to statins
- In patients with clinically significant atherosclerotic CVD, requiring additional LDL-C lowering after being on diet control and maximally tolerated statin therapy (additive effect on top of statin)
Adverse effects of PCSK9 inhibitors
- Contraindicated in patients who develop hypersensitivity reactions (since it is an antibody)
- Injection site inflammatory reactions
Increase incidence of nasopharyngitis and sinusitis
Examples of PCSK9 inhibitors
Evolocumab, Alirocumab
MOA of Fibrates/Fibric acid derivatives + name
They are ligands for peroxisome proliferators-activated receptor alpha proteins (PPAR-a)
- Interaction with PPAR-a results in increased activity of lipoprotein lipase (LDL)
Increased breakdown of plasma triglycerides → lower levels of VLDL → LDL in plasma decreases
2.Interaction with PPAR-a also results in increased activity of enzymes e.g. CPT1 involved in beta oxidation of FA –> increase beta oxidation –> less FA in the liver –> Less hepatic VLDL produced –> Less LDL
- Increases synthesis of Apolipoproteins on HDL
- Increase synthesis of HDL
Gemfibrozil, Fenofibrate
Clinical uses of Fibrates/Fibric acid derivatives
Treatment of hypertriglyceridemia with VLDL elevation, especially for dysbetalipoproteinemia
Examples of Fibrates/Fibric acid derivatives
Gemfibrozil, Fenofibrate
Adverse effects of Fibrates/Fibric acid derivatives
GI effects
Skin rashes
Gallstones
Myositis
MOA of Omega-3-acid ethyl esters + name
Omega 2 fatty acids that are unsaturated = they have a kink
Unsaturated fatty acids are bad substrates for enzymes that form TG
- Functional inhibition of diglyceride acyltransferase (responsible for TG biosynthesis) as EPA and DHA are poor substrates for the enzyme → Reduces hepatic TG production → increases TG clearance from VLDL
- Increase free fatty acid breakdown (via beta oxidation)
- Increase lipoprotein lipase activity
Omacor - EPA + DHA ethylesters
Example of Omega-3-acid ethyl esters
Omacor: eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) ethyl esters
Clinical uses of Omega-3-acid ethyl esters
- Used (in conjunction with dietary measures) for hypertriglyceridemia monotherapy (Type IV)
- Used for familial combined hyperlipidaemia (Type IIb) in combination with statins
Adverse effects of Omacor
- Contraindicated in patients who are allergic to fish
- GI symptoms: abdominal distension, pain, constipation, diarrhoea, dyspepsia, flatulence
- In some patients, DHA may lead to increased LDL-C
- Reduce production of Thromboxane A2 → increase bleeding (esp with patients on anticoagulants!)
MOA of Bile acid binding resins
Cholesterol is made into bile acids, which are usually recycled back to the liver via the portal vein
- Binds to bile acids → prevents bile from being recycled (excreted instead) → liver has to constantly use cholesterol to make bile acids → decrease hepatic cholesterol levels
- As adaptation, the liver expresses more LDL –> more circulating cholesterol taken up
Clinical uses of Cholestyramine
Patients with primary hypercholesterolaemia (Type IIa)
Treat LDL elevations in patients with combined hyperlipidaemia (Type IIb)
Adverse effects of Cholestyramine
- GI effects: constipation, nausea, flatulence
- Impaired absorption of vitamins A,D,E,K
MOA of Ezetimibe (zetia)
Inhibitor of sterol transporter Niemann-Pick C1-Like-1 (NPC1L1) → blocks cholesterol absorption at the small intestine (dietary cholesterol and cholesterol that is reabsorbed from bile)
Clinical uses of Ezetimibe
Reduction of LDL
Vytorin: ezetimibe + simvastatin
Adverse effects of Ezetimibe
- GI: diarrhoea, flatulence
- Rhabdomyolysis (more common when
combined with statins) - Low incidence of reversible hepatotoxicity
Is ezetimibe still effective even in the absence of dietary cholestrol?
Yes, as it also prevents absorption of cholesterol from bile at the small intestine
Name the lipid lowering drugs and which type of lipid they target
- Statins (HMG-CoA Reductase Inhibitors):
Target: Low-density lipoprotein cholesterol (LDL-C)
- Ezetimibe (Cholesterol Absorption Inhibitor):
Target: LDL-C, Total cholesterol (TC)
- Fibrates (Fibric Acid Derivatives):
Target: Triglycerides (TG), increase High-density lipoprotein cholesterol (HDL-C)
Examples: Fenofibrate, Gemfibrozil
- Niacin (Nicotinic Acid):
Target: LDL-C, Triglycerides (TG), increase High-density lipoprotein cholesterol (HDL-C)
- Bile Acid Sequestrants (Resins):
Target: Low-density lipoprotein cholesterol (LDL-C)
- PCSK9 Inhibitors:
Target: Low-density lipoprotein cholesterol (LDL-C)
- Omacor
Target: TG and increasing HDL
