Lipid-Lowering Drugs Flashcards
Statins?
Statins
Atorvastatin, pravastatin, simvastatin, fluvastatin
MOA - Strong affinity for and therefore inhibition of HMG-CoA reductase, the rate-limiting step in cholesterol synthesis. Decreased endogenous cholesterol synthesis and liver cholesterol stores therefore upregulates LDL receptors on hepatocytes; Internalises circulating LDL-C.
Indications - Lowering LDL-C in all kinds of hyperlipidaemias. Reduces risk of coronary events and mortality in IHD pts!!!
PO, first-pass extraction; Given in the evening because we don’t eat much in the evening and the body starts to synthesise it’s own cholesterol in periods of starvation. This drops cholesterol!
ADR and C/I: Abnormal liver tests but stabilise after a while. Myopathy and rhabdomyolysis. This is serious and causes tea-coloured urine!
C/I in PREGNANCY, BREASTFEEDING, KIDS, TEENAGERS.
Cholesterol is essential for healthy neurodevelopment, statins interfere with that.
Statins may not be suitable for some patients. In addition to the C/I, some may be intolerant of statins. In some patients, statins don’t work no matter the dose. Some have severe hypercholesterolaemia that cannot be treated with statins. Other drugs can be used
PCSK9 inhibitors?
PCSK9 Inhibitors
Evolocumab, Alirocumab - These are human monoclonal antibodies!
MOA - Inhibit the enzyme that targets LDL receptors for degradation via lysosomes. The enzyme is proprotein convertase subtilisin-kexin 9 (PCSK9), so we inhibit that. Increased LDL receptor availability = Lowers blood LDL-C
Indications - Lower LDL-C in familial hypercholesterolaemia pts that can’t take statins. Also used in pts with significant atherosclerotic CVD that requires further lowering of LDL-C even after diet / lifestyle modifications and a maximal statin dose.
IV delivery through abdomen / upper arm / thigh. Cmax at >3 days with T1/2 of 10-20 days. Dosing is hence every 2-4 weeks!
PCSK9 inhibitors have great synergistic effects when taken with statins; reduce the LDL-C level by 50-60% more than if statins were taken alone.
ADR and C/I - Pts may develop hypersensitivity i.e. vasculitis or anaphylaxis. There is some inflammation at the site of infection (redness, itchiness, swelling, pain, tenderness). Increased incidence of nasopharyngitis and sinusitis but we don’t know why.
Fibrates / Fibric acid derivatives?
Fibrates / Fibric Acid Derivatives - For severe Type III dyslipid (dysbetalipoproteinaemia)
Gemfibrozil, fenofibrate
MOA - Activate the PPAR-alpha protein, which results in increased LPL activity (Peroxisome proliferators-activated receptor-alpha). This decreases the TG levels. How does this help LDL-C?
Because of decreased TG, the liver decreases secretion of VLDL so as to maintain it’s own stores. There is also a moderate rise in HDL
Indications - HyperTG with VLDL elevation (Dysbetalipoproteinaemia aka Type III dyslipidaemia). Statins are first-line drugs; Fibrates are used in severe cases
ADR and C/I - Nausea, Rashes, GALL STONES, Myositis
Omega-3 acid ethyl esters
Omacor (Eicosapentaenoic acid EPA and docosahexaenoic acid DHA ethyl esters)
MOA - The molecule itself has and ethyl ester group and double bonds in the omega-3 position that produces kinks in the fatty acid molecule. This slows down hepatic TG production and increases TG clearance from VLDL.
This is because there is functional inhibition of diglyceride acyltransferase that is responsible for TG biosynthesis (EPA and DHA are poor substrates for the enzyme).
In addition, there is more free FA breakdown via beta-oxidation.
Promotes LPL activity as well but we don’t know why
Indications - Used as mono-therapy in HyperTG (Type IV) but TO BE COMBINED WITH dietary measures. Also used for Type IIB (familial combined hyperlipid) when TG control is insufficient. Not indicated for hyperchlyomicronaemia (Type I) because it simply does not make sense
PO with food and metabolised by liver. Note that prescription Omega-3-acid ethyl esters are different from the OTC fish oil supplements because these have medical formulations!
ADR and C/I - Abdominal distension, pain, constipation, diarrhoea, dyspepsia, flatulence because gut bacteria digest fish oils well.
Some pts that take DHA may see increased LDL-C so we need to monitor especially in Type IIB pts.
Reduces TbxA2 production!!!, increasing bleeding tendency; Be careful with aspirin / warfarin / anticoagulant users.
C/I in pts with fish allergies obviously.
Resins?
Cholestyramine
MOA - Anion exchange resins bind negatively charged bile acids and bile sals in the small intestine, causing their elimination from the body via faeces as opposed to their reabsorption (supposed to be 95%!). This lowers the bile acid concentration and forces the hepatocytes to make more bile. This uses up intracellular cholesterol and in turn stimulates the hepatocytes to increase LDL receptor expression so that they have more cholesterol to make up their intracellular stores.
May increase VLDL because we are forced to make more endogenous TG.
Little effect on HDL
Indications - Used in Type IIA (primary hypercholesterolaemia). Given with Niacin to treat LDL elevations in pts that have combined hyperlipidaemia (Type IIB). Niacin is a water-soluble VitB3 supplement
PO!
ADR and C/I - Nausea, CONSTIPATION, flatulence. Impaired Vit. ADEK absorption! Good to supplement.
Ezetimibe?
Inhibit sterol absorption
MOA - Inhibits the action of sterol transporter Niemann-Pick C1-Like-1 (NPC1L1), thereby reducing cholesterol absorption at small intestine.
Note that ezetimibe is still effective in the absence of dietary cholesterol because it inhibits bile uptake. Similar to resins, drop in bile will then stimulate the liver to make more of it’s own and decrease LDL-C
Indicated for LDL reduction and cuts LDL by 18% Combined with something like simvastatin further lowers the LDL
PO and conjugated in the intestinal wall to an active glucuronide
ADR and C/I - Diarrhoea, flatulence. Rhabdomyolysis that is (obviously) more common when taken with statins. Low chance of reversible hepatotoxicity.
