2 Lipid lowering drugs Flashcards
What is type I hyperlipoproteinaemia?
Familial hyperchylomicronemia
- due to deficiency of lipoprotein lipase
↑ chylomicrons
cholesterol: +
TG: +++
What is type IIa hyperlipoproteinaemia?
Familial hypercholesterolemia
- due to decreased number of normal LDL receptors
↑ LDL
cholesterol: +
TG: normal
risk of atherosclerosis: high
What is type IIb hyperlipoproteinaemia?
Familial combined (LDL + VLDL) hyperlipidemia
↑ LDL + VLDL
cholesterol: ++
TG: ++
risk of atherosclerosis: high
Name 5 classes of lipid lowering drugs + examples
Diet ↓ cholesterol & saturated fats ok
- Niacin aka Vitamin B3
- Fibrates - Gemfibrozil, Fenofibrate
- Resins - Cholestyramine
- HMG-CoA Reductase Inhibitors - Sim, Lo, Ator, Flu, Pra -vastatin
- Ezetimide
First line is statin
MoA of Niacin
- strongly inhibits lipolysis in adipose tissue
→ plasma TG (in VLDL) ↓ & plasma cholesterol (in VLDL and LDL) ↓ - ↑ HDL cholesterol levels 😊
- ↓ fibrinogen & ↑ t-PA → reverse thrombosis (atherosclerosis)
Niacin is used for which type of hyperlipoproteinaemia?
think TG!
Type IIb (high LDL + VLDL TG)
Type IV (high VLDL TG)
PK of niacin
a. route of administration
b. converted to what
a. oral administration
b. converted in the body to nicotinamide
Name 2 adverse effects of niacin
- an intense cutaneous flush and pruritus
- hyperuricemia and gout
Name 2 fibrates
gemfibrozil
fenofibrate
“fibr”
MoA of Fibrates
gemfibrozil, fenofibrate
- fibrates are ligands for PPAR-α → activates PPAR-α → increases activity of lipoprotein lipase → plasma TG levels decrease
VLDL levels decrease bc decreased secretion by liver
HDL levels rise moderately
PPAR-γ is pioglitazone (thiazolidinediones)
Fibrate is used for which type of hyperlipoproteinaemia?
hypertriglyceridemias with VLDL elevation
Type IIb, Type III
not useful for type IIa bc doesn’t target cholesterol
Name 4 adverse effects of fibrates
- GI effects: nausea
- skin rashes
- gallstones
- myositis
Name a bile acid binding resin
IMPT!!!
cholestyramine
MoA of cholestyramine
IMPT!!!
anion exchange resins bind negatively charged bile acids and bile salts in the small intestine
→ prevents reabsorption of bile acids at terminal ileum
lower bile acid concentration causes hepatocytes to increase conversion of cholesterol to bile acids → thus, intracellular cholesterol decreases
this activates increased hepatic uptake of cholesterol-containing LDL → plasma LDL ↓
may increase VLDL (bc less cholesterol) but have little effect on HDL
the only thing that increase HDL is niacin
Cholestyramine is used for which type of hyperlipoproteinaemia?
Type IIa (Familial hypercholesterolemia)
Cholestyramine + Niacin: Type IIb (mixed)
Cholestyramine → cholesterol
Niacin → TG
Route of administration for cholestyramine
Oral only
Bile salt binding resin mah. Inject for what…lol…
Name 2 adverse effects of cholestyramine
- GI effects: constipation, nausea and flatulence
- impaired absorption of vitamins A, D, E, K (fat-soluble)
if take cholestyramine long term, need vitamin supplement
Name 5 HMG-CoA reductase inhibitors
Sim
Lo
Ator
Flu
Pra
-vastatin
first-line lipid lowering drugs
MoA of statins
inhibits HMG-CoA reductase, rate-limiting step in cholesterol synthesis
depletes intracellular cholesterol → upregulates LDL receptors on cell surface → increase uptake of plasma LDL (bc LDL has cholesterol) → LDL levels ↓
Name 2 clinical uses of statins
- effective in lowering plasma cholesterol (LDL-C) levels in all types of hyperlipidemias 😍
- reduce the risk of coronary events and mortality in patients with ischaemic heart disease
PK of statins
a. route of administration
b. when to eat
a. oral administration with first pass extraction
b. given in the evening
cholesterol-making enzyme (HMG-CoA reductase) is most active at night
Why take statins in the evening?
Cholesterol synthesis rate is at its peak during fasting state (i.e. usually when sleeping)
If patient has Type IIa (hypercholesterolemia) but intolerant to statin, what do you give?
statin not enough how 🥵
PCSK9 inhibitors
Evolo
Aliro
-cumab
PCSK9 inhibitors + statin > statin only 😲😊
MoA of PCSK9 inhibitors
Inhibits PCSK9
→ reduced LDL receptor degradation
→ more LDL receptors to take in LDLs
→ plasma LDL ↓
PCSK9 targets LDL receptors for degradation in lysosomes
Route of administration
IM injection! bc monoclonal Ab
dose every 2 or 4 weeks
Name 1 contraindication and 2 adverse effects of PCSK9 inhibitors
Contraindicated in patients who develop hypersensitivity reactions
- Injection site inflammatory reactions (erythema, itch, swelling, pain or tenderness)
- Increased incidence of nasopharyngitis and sinusitis
MoA of Omega-3-acid ethyl esters
Omacor: EPA + DHA ethyl esters
- ↓ hepatic TG production & ↑ TG clearance from VLDL
- inhibits diglyceride acyltransferase (responsible for TG biosynthesis)
- ↑ FFA breakdown
- ↑ lipoprotein lipase activity
Omega-3-acid ethyl esters is used for which type of hyperlipoproteinaemia?
- drug + diet for Type IV (hypertriglyceridemia)
- drug + statins for Type IIb (when TG still high)
Route of administation for Omega-3-acid ethyl esters
Oral, take with food
Metabolised by liver (as with all lipids)
Name 1 contraindication and 3 adverse effects of Omega-3-acid ethyl esters
Contraindicated in patients who are allergic to fish lol (bc fish oil)
1. GI symptoms
2. In some patients, DHA lead to ↑ LDL-C
3. ↓ production of Thromboxane A2 → increase bleeding time
What is Ezetimibe?
Inhibitor of intestinal sterol absorption
MoA of ezetimibe
a selective inhibitor of cholesterol transport protein, NPC1L1
↓ absorption of both dietary cholesterol AND cholesterol in bile acids
Will ezetimibe still be effective in lowering LDL even in the absence of dietary cholesterol?
Yes
There is cholesterol from bile acids that can be reabsorbed
bile acid uses NPC1L1 too
Clinical use of ezetimibe
reduction of LDL
vytorin: ezetimibe + simvastatin is synergistic
PK of ezetimibe
Oral
readily absorbed, conjugated in the intestinal wall to an active glucuronide
Adverse effect of ezetimibe
Low incidence of reversible impaired hepatic function
