Lipid lowering drugs

Question 1

Name all the classes of Lipid lowering drugs

Answer 1

1. Statins (HMG-coA reductase inhibitors)
2. Fibrates
3. PCSK9 inhibitors
4. Omega-3-acid ethyl esters
5. Bile acid binding resins/sequestrants
6. Ezetimibe

Question 2

Name the common statins

Answer 2

Atorvastatin
Simvastatin
Lovastatin
(suffix ends with -statin)

Question 3

What is the mechanism of statins?

Answer 3

• Competitively inhibits HMG-CoA reductase
• HMG-CoA reductase unable to convert HMG-CoA to mevalonate (the rate limiting step of cholesterol synthesis)
• Cholesterol is reduced and hence VLDL concentration and hence triglycerides
• Reduced intrahepatic cholesterol biosynthesis
• Decreases cholesterol intracellularly will induce synthesis of more LDL-Receptors to take in more LDL from the bloodstream
• Depletion of intracellular cholesterol causes
  the cell to increase the number of specific
  cell-surface LDL receptors that can bind and
  internalize circulation LDL-Cs.

Question 4

Statins are indicated for?

Answer 4

All types of hyperlipidemia

First line treatment for hypercholesterolemia

Significantly reduces the risk of mortality in patients suffering from CAD

Question 5

How does statins influence the lipid levels

Answer 5

Decreases LDL (MOST)

Decreases TGA

Increases HDL (Slightly)

Question 6

Pleotropic effects of statins

Answer 6

• NO synthesis ↑
• LDL cholesterol oxidation ↓
• Inflammatory processes ↓
• Coagulation processes ↓
• Endothelial and plaque stabilisation

Question 7

Route of administration of statins

Answer 7

Oral, given in evening

Reasons:
- Typically stop eating in the evening
- Body has lower cholesterol levels
- Evening will synthesise cholesterol thus HMG-CoA reductase more active
- Hence statins are used to increase efficacy

Question 8

Adverse effects of statins

Answer 8

General:
1. Headache
2. GI (Constipation, diarrhoea)

Hepatic
1. Increase in LFTs (involvement of cyp450 in breakdown of statins

Myopathy (decrease coenzyme Q synthesis and impair energy production)

Myalgia

Question 9

Statins contraindicated in?

Answer 9

• Hypersensitivity
• Active liver disease
• Muscle disorder
• Pregnancy, breastfeeding

Question 10

Name some common PCSK9 inhibitors

Answer 10

1. Alirocumab
2. Evolocumab
   -mab: Monoclonal antibodies

Question 11

Route of administration for PCSK9 inhibitors?

Answer 11

IV route

Cannot be oral as monoclonal antibodies will be digested

Question 12

Mechanism of actions of PCSK9 inhibitors?

Answer 12

• Inhibition of hepatic proprotein convertase subtilisin-kexin 9 (PCSK9) which targets LDL receptors for degradation in lysosomes
• Reduced LDL receptor degradation: more cell-surface LDL receptors that can bind and internalise circulation LDLs.
• Increasedremoval ofLDLfrom the blood stream
• ↓↓↓LDL,↑HDL,↓triglyceride

Question 13

What are the clinical indications for PCSK9 inhibitors?

Answer 13

1. Familial hypercholesterolemia (Typically an alternative for those intolerant to statins)
2. Patients with significant artherosclerotic CVD requiring more LDL-C lowering after being on diet control and statins

Question 14

PCSK9 inhibitors frequently combined with?

Answer 14

Statins to lower LDL-C levels 50%-60% above that achieved by statin therapy alone

Question 15

Adverse effects of PCSK9 inhibitors

Answer 15

1. Hypersensitivity
   
   • EG: hypersensitivity vasculitis or serious allergies requiring hospitalization
2. Injection site inflammatory reactions (erythema, itchiness, swelling, pain or tenderness)
3. Increased incidence of nasopharyngitis and sinusitis

Question 16

Name the common fibrates

Answer 16

1. Fenofoibrate
2. Gemfibrozil

Question 17

Route of administration of fibrates

Answer 17

Oral

Question 18

Mechanism of fibrates?

Answer 18

• Ligands for the peroxisome proliferators-activated receptor-alpha (PPAR-α) protein
• Results in increased activity of lipoprotein lipase (Interacts with Apo-C2)
• Stimulating lipoprotein lipase activity, which cleaves triglycerides to form glycerol and fatty acids

Question 19

How does fibrates influence the lipid levels

Answer 19

↓ LDL,↑HDL,↓↓↓triglyceride

lowers LDL through increasing Beta-oxidation of FAs, lower VLDL is produced and secreted by liver, LDL being derived from VLDL will decrease also

Question 20

Clinical uses of fibrates

Answer 20

Treatment of hypertriglyceridemias with VLDL elevations especially for dysbetalipoproteinemia

Typically only used for hypertriglyceridemias when TGA levels are too high

Question 21

Adverse effects of Fibrates?

Answer 21

1. Dyspepsia

2 Myopathy
- When combined with statins particularly
- CYP-450 inibitor prevents breakdown of statins into metabolites, increasing co-enzyme Q

3. Cholelithiasis
   - Fibratesinhibitcholesterol 7α hydroxylase→ decreasedbile acidsynthesis→ supersaturation ofbilewithcholesterol(↑cholesterol:bile acidratio)

Question 22

Fibrates are contraindicated in

Answer 22

1. Renal insufficiencies (dose adjustments needed)
2. Liver failure
3. Gall bladder diseases (eg. cholelithiasis)

Question 23

Name the common Omega-3-acid ethyl ester

Answer 23

Omacor
Eicosapentaenoic acid (EPA) + Docosahexaenoic acid (DHA) ethyl esters

Question 24

Mechanism of Omega-3-acid ethyl ester

Answer 24

• Reduces hepatic triglycerides (TG) production and increases TG clearance from VLDL
• Functional inhibition of diglyceride acyltransferase (responsible for TG biosynthesis) as EPA and DHA are poor substrates for the enzyme.
  Diglyceride acyltransferase adds the 3d fatty acid to the chain, drug produces a 3rd fatty acid chain that has kinks in it thus enzyme take longer to synthesise new chain
• Increase fatty acids breakdown (via beta-oxidation)

Question 25

Clinical indications for Omega-3-acid ethyl ester

Answer 25

- Used (in conjunction with dietary measures) for Hypertriglycerideaemia (Type IV) monotherapy - Used for Familial Combined Hyperlipidaemia (Type IIb) in combination with statins (when control of TG is insufficient) - Not indicated for hyperchylamicronaemia because chylomicrons come from dietary origins not synthesised in liver hence no effect as this drug targets the synthesis of TAG

Question 26

Route of administration for Omega-3-acid ethyl ester

Answer 26

Oral (2-4g or more per day) Taken with food

Question 27

How is Omega-3-acid ethyl ester metabolised

Answer 27

In the liver

Question 28

How does Omega-3-acid ethyl ester influence the lipid levels

Answer 28

↓↓↓ triglyceride synthesis in the liver

Question 29

Adverse effects of Omega-3-acid ethyl ester

Answer 29

1. GI effects - Medication used as food source for bacteria may lead to abdominal distention, pain, flatulence, diarrhoea, constipation 2. DHA may lead to increase in LDL-C needs close monitoring eg. patients with familial hypercholesterolemias 3. Competes with Arachidonic Acid for COX enzymes By occupying the active sites on COX, omega-3 fatty acids decrease the production of thromboxane A2 from arachidonic acid. Reducing the production of TbA2 can lead to increased bleeding time (special monitoring for patients on anticoagulants like warfarin and aspirin)

Question 30

Name some common bile acid binding resins

Answer 30

Cholystyramine, Colestipol, Colesevelam

Question 31

Mechanism of bile acid binding resins

Answer 31

1. Positively charged bile resins bind negatively charged bile acids and bile salts in small intestines, increasing excretion in faeces 2. Lowering bile acid concentration causes hepatocytes to increase conversion of cholesterol to bile acids 3. Increase synthesis of LDL receptors 4. Activates an increased hepatic uptake of cholesterol containing LDL particles, reducing plasma LDL

Question 32

How does Bile acid binding resins influence the lipid levels

Answer 32

↓↓↓ LDL may lead to increase in VLDL - When bile acids are bound and excreted by cholestyramine, the liver compensates by increasing the synthesis of new bile acids from cholesterol. This increased cholesterol synthesis can result in increased production of VLDL particles by the liver to transport the excess cholesterol to peripheral tissues.

Question 33

Route of administration of Bile acid binding resins

Answer 33

Oral only

Question 34

Clinical indications of Bile acid binding resins

Answer 34

1. Primary hypercholesterolemia 2. +Niacin: Treat elevations in persons with combined hyperlipidemia

Question 35

Adverse effects of Biel acid binding resins

Answer 35

1. GI - constipation, nausea and flatulence 2. Impaired absorption of fat soluble vitamins A,D,E,K - Bile acids facilitate process of fats and vitamins 3. May slightly increase triglycerides levels, leading to hyper-triglyceridemia

Question 36

Name common intestinal cholesterol absorption inhibitors

Answer 36

Ezetimibe

Question 37

Mechanism of Ezetimibe

Answer 37

1. Reduces cholesterol absorption at the small intestine, brush border of enterocytes by inhibition of the sterol transporter Niemann-Pick C1-Like-1 (NPC1L1) 2. Decreases the chylomicrons formed from cholesterols 3. Lipoprotein lipase breaks down less chilomicrons into less chilomicrons remnants, which is transported to liver 4. Less chilomicron remnants thus lower chlesterol and hence less VLDL and triglyceride formations 5. Increases LDL receptors, increasing uptake of LDLs from bloodstream

Question 38

Combination therapy for ezetimibe?

Answer 38

Combination with simvastatin Ezetimibe + Simvastatin -> Vytorin

Question 39

Route of administration of ezetimibe?

Answer 39

Oral

Question 40

Adverse effects of ezetimibe?

Answer 40

1. Rhabdomyolysis breakdown of skeletal muscle tissues (More common when combined with statins) 2. Low incidence of reversible hepatotoxicity 3. Contraindicated to use with a statin during active liver disease 4. Angioedema 5. Myalgia