lipid-lowering drugs

Question 1

Classification of hyperlipoproteinemias

Answer 1

Type 1, familial hyperchylomicronemia
= Deficiency in lipoprotein lipase
= Chylomicrons high

Type 2A, familial hypercholesterolemia
= Decreased number of normal LDL receptors
= LDL high

Type 2B, familial combined hyperlipidemia
= Overproduction of VLDL by the liver
= LDL + VLDL high

Type 3, familial dysbetalipoproteinemia
= Overproduction or underutilization of IDL
= Beta VLDL high

Type 4, familial hypertriglyceridemia
= Overproduction and/or decreased removal of VLDL triacylglycerol
= VLDL high

Type 5, familial mixed hypertriglyceridemia
= Either increased production or decreased clearance of VLDL and chylomicrons
= Chylomicrons + VLDL high

Question 2

HMG-CoA reductase inhibitors

Answer 2

Atorvastatin, Pravastatin, Simvastatin, Fluvastatin

MOA: inhibit HMG-CoA reductase, the rate-limiting step in cholesterol synthesis = decrease intracellular cholesterol = increase LDL receptors to bind to and internalise circulating LDLs

Clinical uses = decrease plasma cholesterol LDL levels in all types of hyperlipidemias, reduce risk of MI/death in patients with ischemic heart disease

adverse effects = initial biomedical abnormalities in liver function, myopathy and rhabdomyolysis

contraindicated in pregnancy, nursing mothers, children and teenagers as it affects neurodevelopment of fetus and child

note: better to give in evening - no more dietary cholesterol means body endogenously synthesises more cholesterol, making HMG-CoA reductase more active

Question 3

PCSK9 inhibitors

Answer 3

Monoclonal antibodies - Evolocumab, Alirocumab

MOA: Since PCSK9 naturally degrades LDL receptors, its inhibition increases LDL receptors = can bind to and absorb more circulating LDLs

Clinical uses = further lowering LDL levels, esp to those intolerant to statins/ clinically significant atherosclerotic CVD requiring additional LDL lowering (when combined with statins can lower LDL by additional 50-60%)

adverse effects = hypersensitivity, injection site inflammatory reactions, increased incidence of nasopharyngitis and sinusitis

Question 4

Fibrates/ fibric acid derivatives

Answer 4

Gemfibrozil, fenofibrate

MOA: ligands for peroxisome proliferators-activated receptor-alpha (PPAR-alpha) protein = interaction with PPAR-alpha = up-regulation of many genes (inclu. LPL) = increase activity of LPL = decrease TG, VLDL also decreases due to reduce secretion by liver

Clinical uses = hypertriglyceridemias with VLDL elevation (esp for dysbetalipoproteinemia)

adverse effects = nausea, skin rashes, gall-stones, myositis

Question 5

Omega-3-acid ethyl esters

Answer 5

Omacor: eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) ethyl esters

MOA:
a. EPA and DHA are poor substrates for diglyceride acyltransferase = inhibition of diglyceride acyltransferase (that is responsible for TG synthesis)
b. reduce hepatic TG production and increase TG clearance from VLDL
c. increase free fatty acid breakdown via beta-oxidation

Clinical uses
a. Type IV with dietary measures
b. Type IIB with statins - altho monitoring required as DHA may lead to increased LDL-C
note: NOT used for type I (as chylomicrons do not decrease), patients allergic to fish (derived from fish oil)

adverse effects = reduces production of thromboxane A2, leading to increased bleeding time

Question 6

Bile acid binding resins

Answer 6

Cholestyramine

MOA: resins bind to bile acid and salts that lowers bile acid concentration = hepatocytes increases conversion of cholesterol to bile acids = increased hepatic uptake of cholesterol-containing LDL particles = fall in plasma LDL

Clinical uses
a. Type IIa primary hypercholesterolemia
b. Type IIb combined hyperlipidemia - administered together with niacin

adverse effects = GIT effects (constipation, nausea, flatulence), impaired absorption, esp vit ADEK

Question 7

Inhibitors of intestinal sterol absorption

Answer 7

Ezetimibe (Zetia)

MOA: decrease cholesterol absorption at small intestine by inhibition of sterol transporter Niemann-PIck Cl-Like-1 (NPC1L-1)

Clinical uses = decrease LDL
note: ezetimibe + simvastatin (vytorin) together decreases LDL a lot more

adverse effects = diarrhoea, flatulence (bacteria metabolises cholesterol in gut), rhabdomyolysis, reversible hepatotoxicity