L8.1 Atherosclerosis and Lipid lowering drugs

Question 1

What is dyslipidaemia and what are its indications

Answer 1

• dyslipidaemia = abnormal lipid profile
  
  • Elevated cholesterol
  • Elevated trigly
  • Or both
• can lead to atherosclerosis, increased risk of MI, stroke

Question 2

What level of cholesterol is considered igh risk and what is the treatment target?

Answer 2

• high risk > 7.5 mmol/L total cholesterol,
• treatment target < 4 mmol/L

Question 3

Considerations for the treatment for dyslipidaemia?

Answer 3

• Consider cardiovascular status and risk factors
• Consider secondary causes
  
  • obesity, diabetes, hypothyroidism
  • Treat the secondary causes
• manage modifiable risk factors
  
  • stop smoking - increase probability of stroke and infarct
  • avoid alcohol - able to increase trigly levels
  • weight reduction - increase exercise (able to restore lipid balance and improves CV health)
  • modify diet

Question 4

Target for hypercholesterolaemia - Diet

Answer 4

• Reduce saturated and trans fats
• Introduce
  
  • Mediterranean diet – reduces CV risk, not LDL cholesterol
  • Plant sterol esters (from margarine) – reduce LDL cholesterol
  • fish oils – reduce triglycerides, increase HDL cholesterol
• lifestyle/diet intervention for people at low risk (for those with CV risk, need therapeutic intervention)

Question 5

Sources of cholesterol

Answer 5

• cholesterol derived from:
  
  • diet (in animal fat, eggs - absorbed via intestine)
  • de novo synthesis (primarily in liver) (adequate)Acetyle Coa → 3-hydroxy-3-methylglutaryl-CoA (by HMG-CoA) (RATE LIMITING STEP) → mevalonic acid → cholesterol
    
    • Too much cholesterol inhibits rate limiting step to limit amount of cholesterol syn

Question 6

Fate of cholesterol

Answer 6

• stored in liver for export in VLDL (very low density lipoproteins)
• converted to bile acids, stored in gall bladder to emulsify fat
• used for membrane synthesis

Question 7

How are cholesterol transported around?

Answer 7

• Trigly and cholesterol do not circulate freely
• transported in plasma lipoprotein
  
  • – chylomicrons - from small intestine through lymph cells
  • – Very low density lipoproteins (VLDL)
  • – Intermediate density lipoproteins (IDL)
  • – Low density lipoproteins (LDL = “bad” cholesterol)
  • – High lipoproteins (HDL = “good” cholesterol) - takes bad cholesterol from bad deposits

Question 8

Transport and metabolism of Cholesterol

Answer 8

• In capillaries, fat, muscles have enz called lipoprotein liapose
• Trgiylcerides Hydrolysed into free fatty acids → Taken up by chylomicrons and vLDLs
  
  • Chylomicrons takes free fatty acids to liver
  • vLDL remnants:
    
    • takes FFA into liver
    • converted into LDL → laid down in extrahepatic tissues
  • HDL takes deposit of cholestorol and brings it back to the liver

Question 9

Significance of the HDL/LDL ratio

Answer 9

• Normal cholesterol levels does not mean you have a healthy lipid profile - it’s the ratio of HDL/LDL that shows whether you have a good lipid prolife

Question 10

Statins

Answer 10

• HMG-CoA reducatase inhibitor (hypercholesterolaemia)
• Inhibit cholesterol synthesis
• decrease mevalonic acid (precursor for cholestorol) and therefore cholesterol synthesis
• compensatory increase in hepatic LDL receptors (take back cholesterol that is circulating)
  
  • increased clearance of LDL (with bound cholesterol) from blood
• decreased plasma total cholesterol and LDL (and TGs to lesser extent)
• increased plasma HDL

Question 11

Uses of statin

Answer 11

• high LDL or high trigyl levels
• Needs to be used for number of years before seeing benefits but good at lowering cholesterol
  
  • Poor compliance due to not perceiving any benefits from taking drug (not due to SE)

Question 12

Precaution with statins

Answer 12

• avoid grapefruit juice (common metabolic pathway increases toxicity of statins - the cP450 pathways)
  
  • Higher levels of circulating statin leading to higher toxic effects
  • drug-drug interactions also due to cP450 pathways
• statin levels are
  
  • increased by some antibiotics, antifungals and fibrates
  • decreased by phenytoin, barbiturates, glitazones (which treat diabetes)

Question 13

Monitoring of statin administration

Answer 13

• measure of liver function, monitor (by looking at serum aminotransferase) at 2-4 month intervals, reduce dose if necessary
  
  • May have liver toxicity
• minor increases in creatine kinase
  
  • can lead to muscle pain and tenderness

Question 14

Statin SE

Answer 14

• mild GI symptoms, headache, insomnia, dizziness
• rare but serious adverse effects
  
  • – myopathy (minimised by UQ10 treatment)
  • – rhabdomyolysis (breakdown of muscle resulting in myoglobin release into the bloodstream)
  • – renal failure
  • – hepatitis, liver failure

Question 15

Contra-indication of statins

Answer 15

• in pregnancy
  
  • impaired fetal myelination
• contra-indication with AB - may elevate statin levels and leads to toxicity
  
  • Withheld during infection/post-surgery/post-trauma

Question 16

Dosage of statin administered

Answer 16

• Starting does of statin is very variable
• Initial does causes the most significant effect in lowering LDL levels in the plasma
  
  • Subsequent increase dose does not show significant increase in effect, but has significant increase adverse effects

Question 17

Bile acid sequestrants/resins

Answer 17

• (hypercholesterolaemia)
• Cholestyramine, colestipol
• Binds to bile acids in intestine, acid cannot be taken up and reused
  
  • Increase demand for cholesterol for bile acid synthesis → upregulate hepatic LDL → increase removal of LDL and increased cholesterol metabolism
• oral route - granular preparations, taken with liquid
• non-absorbable macromolecules

Question 18

Resins SE

Answer 18

• mainly GIT where it works
• abdominal discomfort, bloating, constipation, flatulence
• rare adverse effects
  
  • increased TGs, faecal impaction
  • Need to drink a lot of water with these drugs
• decreases absorption of other drugs
  
  • give other drugs hours before or after resin

Question 19

Ezetimibe

Answer 19

• (Hypercholesterolaemia)
• specifically inhibits cholesterol absorption in the intestine by binding to a sterol transporter
• does not affect absorption of bile acids, fat soluble vitamins
• lowers LDL

Question 20

Ezetimibe SE

Answer 20

• diarrhea, headache, tiredness
• allergic reactions, severe joint or stomach pain
• can be used alone in statin-intolerant patients, or in combination with all other lipid-lowering agents including statins (to reduce statin dose)

Question 21

Nicotinic acid/niacin

Answer 21

• (hypercholesterolaemia)
• Nicotinic acid = niacin = vitamin B3
• mechanism unclear - but shows less cholesterol circulating
  
  • – decrease secretion of VLDL particles from liver
  • – reduces plasma LDL and triglycerides (so also for mixed hyperlipidaemia)
  • – increases HDL
  • – lowers potentially atherogenic lipoprotein - formed from LDL found in plaques which inhibits thrombolysis
    
    • By lowering, niacin inhibits thrombus formation

Question 22

Niacin SE

Answer 22

• common adverse effects
  
  • – vasosodilation, flushing, hypotension
  • – nausea, vomiting
  • – tolerance develops to flushing as gastric upsets (positive effects of taking drugs still persists)
• rare adverse effects – itching
  
  • – glucose intolerance
  • – uric acid retention
  • – may increase hepatic impairment

Question 23

Are niacins widely used?

Answer 23

• not widely used except in combination (drug of last resort)

Question 24

Fibrates

Answer 24

• (for hypertriglyceridaemia)
• Gemfibrozil, fenofibrate
• agonists at nuclear receptors, so regulate gene expression
  
  • – peroxisome proliferator activated receptor a
  • – increased synthesis of lipoprotein lipase (LPL)
• increase lipolysis of lipoprotein triglyceride
• moderate reduction in plasma triglycerides
• moderate increase in HDL
• variable effects on LDL (won’t use fibrates in patients with high cholesterol levels)
• generally used as adjunct to dietary changes for high TGs, mixed hyperipidaemia, and second line therapy for hypercholesterolaemia

Question 25

Fibrate SE and precautions

Answer 25

* mild elevation of serum aminotransferase (may have liver toxicity) * Need to monitor * Common adverse effects * – nausea, dry mouth, headache, rash * Rare adverse effects – arrhythmias * – gallstones * – photosensitivity – impotence * – depression

Question 26

Fish oils

Answer 26

* (for hypretriglyceridaemia) * Omega 3 fatty acids e.g. eicoapentanoic acid (EPA) docosahexanoic acid (DHA) * reduce triglycerides and VLDL also increase HDL * Plant sources contain a-linolenic acid (ALA) which can be converted to EPA/DHA, * but conversion is variable (fatty fish is more reliable)

Question 27

Possible side effects:

Answer 27

* aftertaste, fishy burps * diarrhea, abdominal discomfort * blood thinning effect

Question 28

What is required for severe hypertriglyceridemia

Answer 28

* Severe hypertriglyceridemia requires polytherapy * low fat diet, fibrates, fish oils, statins, niacin, orlistat (used for obesity inhibits fat absorption from gut)

Question 29

Summary of the drugs

Answer 29

* Statin = first line therapy * Still need to lower other crap, use other drugs

Question 30

Summary of sites of drug action

Answer 30

* Dietary trigly abs in SI, packaged into chylomicrons * Ezetimibde * Bile acid resins * Fibrates acting on lipoprotein lipase in capillaries * Increase hydrolysis of triglycerides * Increase release of FFA and taken up in adjacent tissues * Statins * Altering cholesterol syn within liver * Reduction in the conversion (the RATE LIMITING STEP)