Lipid Disorder

Front 1

List the lipid lowering drugs

Back 1

1. Statins
2. Ezetimibe
3. Resins
4. Niacin
5. Fibrates
6. Omega-3 FA

Front 2

1. Statins - mechanism of action

Back 2

1. HMG CoA reductase inhibitors
(inhibit cholesterol synthesis from acetyl CoA)

2. less cholesterol biosyntheses -> hepatocyte cholesterol depletion

3. more LDL receptors via SREBP upregulation (sterol regulatory element binding protein)

4. Increased clearance of plasma LDL-C (also other atherogenic particles)

5. statins lower LDL-C, lower LDL-C = lower risk of coronary events

Front 3

1. Statins - list, and special info

Back 3

Atorva, Rosuva, Fluva, Lova (not in Aus), Prava, Simva

Rosuvastatin and Pravistatin have low lipophilicity (less absorption into tissue, but less side effects)

Atorvastatin and Simvastatin (and Lova) - CYP3A4 large ADRs

Fluvastatin and Rosuvastatin - CYP2C9

Efficacy: R>A>S>P

First dose is most cost effective
(law of diminishing returns - double dose only incr efficacy by 7%)

Front 4

1. Statins - side effects

Back 4

due to HMG-CoA reductase inhibition & more likely in lipophilic drugs

1) MUSCLE-RELATED (less cholestrol in muscle membrane, and less Coenzyme Q10 - electron transport chain and AOX)

can be overcome by 1) switching to water soluble or 2) adding Coenzyme Q10

(insignificant):
2) Liver: increase in ALT+AST, hepatic necrosis rare
3) Kidneys: dose dependent incro. in protein in proximal tubule

Front 5

Factors that increase the risk of Statin-induced myopathy

Back 5

Patient
age, female, kidney/liver/thyroid dysfunction, grapefruit, polypharmacy

Statin
high systemic exposure, lipophilicity, incr. bioavailability, protein binding, CYP3A4

Front 6

2. Ezetimibe

Back 6

Cholesterol Absorption Inhibitor
blocks NPC1L1 transporter on enterocyte brush border
(blocks absorption of cholesterol in gut)
reduces LDL-C by 18% in hypercholesterolaemics

therefore, also reduces LDL in liver

Enterohepatic circulation - taken once daily

Ezetimibe & Statins (low dose) often used together - Dual Inhibition: cholesterol absorption AND syntheses

Front 7

3. Bile Acid Resins - moa

Back 7

inhibit bile acid resorption by binding to it (since bile acid is made from cholesterol in the liver)
increased bile acid secretion

less cholesterol in intracellular hepatocytes (incr. SREBP) incr. LDL receptors

~15-20% reduction in LDL-C

Front 8

3. Bile Acid Resins - side effects & interactions

Back 8

headache
GIT: constipation, abdominal discomfort, intestinal gas, indigestion, diarrhea
musculoskeletal pain
impairment of fat soluble vitamins

Can bind with other drugs (decreasing their absorption) - cholestipol and cholestyramine (should be given 1h before or 4h after)
interaction risk less problematic with colesevelam

Front 9

4. Niacin - basics: what does it do?

Back 9

Nicotinic Acid (in low doses it is Vit B3), in high doses - oldest known lipid lowering agent

1) decreases mobilization of FFA, leading to reduced production of VLDL
2) decreases hepatic output of ApoB, resulting in less VLDL
3) increases HDL-C levels due to a reduced clearance of HDL (not by increase production of HDL)

Front 10

4. Niacin - moa on LDLs/VLDLs

Back 10

1. blocks 'hormone sensitive lipase' - so FFAs can't be hydrolysed from TGs in peripheral adipocytes
2. hence, less FFAs reaching hepatocytes
3. less FFAs means less TG re-synthesized in liver (2nd point of action - direct inhibitor of this step also by inhibiting DGAT2 in liver)
4. This decr VLDL production from liver -> lower serum VLDL
5. Since VLDL is the precursor of LDL, less LDL is produced
(also TG poor VLDLs are less atherogenic and do not form reminants & small LDL)

(by inhibiting fatty acid mobilization, you decrease the production of LDL - as compared to the first 3 drugs which increase catabolism)

Front 11

4. Niacin - HDL

Back 11

Inhibits hepatic lipase

hepatic lipase takes up cholesterol from HDL returning to the liver, reducing lypolysis of large HDL

(only drug which inhibits Lipoprotein (a) - atherogenic lipotprotein)

Front 12

4. Niacin - adverse effects

Back 12

Flushing (as many as 88%)
nicotinic acid receptor also activated in dermal macrophages (releasing PGE2 - vasodilator)

hence, combine with PGE2 inhibitor (Niacin + Laropriprant)

others:
hepatotoxicity, insulin resistance, blurry vision, gout

Front 13

5. Fibrates

Back 13

PPAR-alpha Agonism (peroxisome proliferator-activated receptor a)

agonist for the PPAR-a receptor that increases lipid metabolism (by dimerising with RXR to form a TF)

reduces TG & LDL and increases HDL

Front 14

5. Fibrates - adverse efects

Back 14

Fenofibrate lowers fibrinogen whist Gemfibrozil increases fibrinogen

Often combine Fibrate with a Statin
Gemfibrozil inhibits CYP2C8/9 therefore increases effects of all statins - ADRS :(
Fenofibrate does not use any of these pathways and therefore less likely to cause any muscle side effects


Typically well tolerated
hepatic/renal dysfunction, pre-existing gallbladder disease
.................................

Front 15

6. Essential Fatty Acids (Omega-3)

Back 15

EPA and DHA
needs to be in HIGH doses >1gm per day
1) inhibits TG synthesis
2) stimulates FA oxidation
3) stimulates VLDL clearance

Omacor (AUS, UK)
Lovaza (US)

natural products, no ADRs

includes other cardioprotective mechanisms

Front 16

Look through table of lipid lowering drugs
1. LDL-C lowering
2. HDL-C raising
3. TG loweing

Back 16

Go through table.....

Front 17

Lowering LDL-C

Back 17

1) Use a Statin
2) Then combine with Bile Acid Sequestrant or Ezetimibe

THE FIRST THREE IN SERNFO LOWER LDL-C

Front 18

Lowering TG

Back 18

Fibrates, Omega-3, Niacin

THE LAST 3 IN SERNFO LOWER TGs

Front 19

Raising HDL-C

Back 19

Niacin and Fibrates

(the same as the ones lowering TGs but without fish oil)

Front 20

Which ones do not produce muscle side effects when coupled with statins

Back 20

the HDL-C raising ones (Niacin and Fibrates)