Cardiovascular Disease & Risk Factors (4) Atherosclerosis and Lipid Lowering Drugs

Question 1

Dyslipidaemia

Answer 1

Abnormal lipid profile
- recognition that high blood cholesterol correlated with increased risk of IHD

• can lead to atherosclerosis, increased risk of MI, stroke
• Hypercholesterolaemia
  >high risk >7.5mmol/L total cholesterol, treatment target <4mmol/L
• hypertriglyceridaemia
• Mixed hyperlipidaemia

Question 2

Serum lipid levels

Answer 2

“Normal” total cholesterol levels not necessarily healthy

HDL cholesterol = “good” cholesterol
LDL cholesterol = “bad” cholesterol, leads to laying down of cholesterol in BV, atherosclerosis

Elevated LDL and low HDL gives you a “normal” total cholesterol = bad
>want to minimise LDL and maximise HDL

Question 3

Treatment for dyslipidaemia

Answer 3

Establish fasting plasma lipid profile for diagnosis
Consider cardiovascular status and risk factors

Treat secondary causes
(often, elevated lipid profile is causes by other conditions)
>obesity, diabetes, hypothyroidism

Manage modifiable risk factors
>Stop smoking
>avoid alcohol (increases triglyceride levels)
>weight reduction
>increase exercise
(these all reduce risk of cardiovascular events independently lowering lipid LDL)
>modify diet

Question 4

Targets for hypercholesterolaemia

Answer 4

Diet
>reduce saturated and trans fats (these increase LDL and triglycerides, want to avoid these fats)
>introduce
»mediterranean diet - reduces risk, not LDL (bad) cholesterol
»plant sterol esters - reduce LDL cholesterol
»fish oils - reduce triglycerides, increase HDL (good) cholesterols
>lifestyle/diet intervention for people at low risk

Pharmacological intervention
>for people at > moderate risk

Question 5

Sources of cholesterol

Answer 5

Cholesterol derived from
>diet (animal fat, eggs - absorbed via intestine)
>no recommended daily allowance set
>de novo synthesis (primarily in liver) adequate
(doesnt mean we should lower cholesterol intake, LDL is due to saturated and trans fat intake, not cholesterol intake)

Start synthesis with acetyl-CoA
>until we get to substrate HMG-CoA
>this product is enzymatically acted on to produce mevalonic acid

> Enzyme is HMG-CoA reductase
rate limited by the cholesterol that is circulating in our body

When cholesterol levels too high, it feeds back to the enzyme HMG-CoA reductase, and inhibits it
»reduction in synthesis of mevalonic acid and subsequently cholesterol

Question 6

Cholesterol transport

Answer 6

Transported in plasma lipoproteins
>chylomicrons = from small intestine through lymph cells
>very low density lipoproteins (VLDL)
>intermediate density lipoproteins (IDL)
>Low density lipoproteins (LDL = bad cholesterol)
>High density lipoproteins (HDL = good cholesterol)

Understand that there are several plasma lipoproteins and they have different roles in transporting cholesterol and triglycerides around the body

> lipoproteins that contain apolipoprotein (apo) B-100 can transport lipids into artery walls = ‘bad’
LDL, IDL, VLDL

> HDL can retrieve cholesterol from artery wall = “good”

Question 7

Cholesterol transport and metabolism

Answer 7

From intestine to capillary (mammary, muscle or adipose tissue)
>Chylomicrons
»responsible for transporting dietary cholesterol and dietary triglycerides around the body

In capillary
>Lipoprotein Lipase (LPL)
>hydrolyses the triglycerides and releases free fatty acids
>taken up by tissue (fat/muscle/brain) and used as an energy source or laid down as a stored source of energy as triglycerides

From capillary
1) Chylomicron remnants, VLDL remnants (IDL)
>transported to liver
>removed by hepatocytes from circulation, if hepatocytes require that cholesterol for synthesis of other things
>If not removed, is converted to LDLs&raquo_space;this is where the problem starts
»These LDLs can go on to circulate to extrahepatic tissues like blood vessels and lead to formation of bone cells and atherosclerosis if it occurs in chronic situation

2) HDL precursors (from liver and intestine)
>move to extrahepatic tissues

From Extrahepatic tissues
>HDL involved in reverse cholesterol transport
>when the liver requires cholesterol for synthesis of something, HDL removes the cholesterol and brings it back to the liver
>Understanding the balance between LDL and HDL is important if we want to tip it in the balance of having more HDL than LDL

From Liver
>Releases VLDL back into circulation
>contains triglycerides and cholesterols that are synthesised by the liver

Question 8

Treatment of hypercholesterolaemia with statins

Answer 8

Statins
>structural analogues of HMG-CoA (our substrate)
(competition for the HMG-CoA reductase enzyme, competitively inhibit HMG-CoA and reduce synthesis of mevalonic acid and therefore cholesterol)

Decrease mevalonic acid and therefore cholesterol synthesis
>compensatory increase in hepatic LDL receptors (these remove circulating cholesterol)
>Increased clearance of LDL (with bound cholesterol) from blood
>decreased plasma total cholesterol and LDL (and TGs to lesser extent)
>Increased plasma HDL

Question 9

Statin Effect on LDL cholesterol

Answer 9

Diagram shows doses of various statins and their ability to reduce circulating LDL levels

1st initial dose that a patient might be put on is the most efficacious, best dose at lowering circulating LDL levels

Increasing the dose by doubling/tripling it has very little effect on lowering LDL level

You are increasing the statins and that has a dose dependent effect on increasing the adverse effects

If increase dose too much, will increase adverse effects

**Important that statin’s ability to lower LDL level is complemented by another drug so you dont elevate statin levels too much&raquo_space;toxic

Question 10

Statins - HMG-CoA reductase inhibitors (1)

Answer 10

Indications:
>Hypercholesterolaemia (high LDL)
>Mixed hypercholesterolaemia (High LDL, TGs)

Greater benefit after 1-2 years use
>poor compliance related to perceived lack of efficacy rather than side effects
(you dont feel the immediate effects, only indication that drug is working is when you do a subsequent fasting lipid profile at the GP)

Question 11

Statins - HMG-CoA reductase inhibitors (2)

Answer 11

Precautions
>avoid grapefruit juice (common metabolic pathway increases toxicity of statins)
(Metabolised by CYP-450 family of enzymes, anything that alters activity of that enzyme will modulate the level of circulating statins)
>drug-drug interactions due to cytochrome pathway

Statin levels are
>increased by some antibiotics, antifungals, fibrates (used to treat high TGs)
>decreased by phenytoin, barbiturates, glitazones
*important because you want to take a dose of statins that is meaningful and effective

Mild elevation of serum aminotransferase = transaminase
> less than 2% of patients
>measure of liver function, monitor at 2-4 month intervals, reduce dose if necessary
>main side effect = liver damage = level of serum aminotransferase has to be monitored closely

Minor increases in creatine kinase
>can cause release of myoglobulin in the bloodstream and cause liver failure
>can lead to muscle pain and tenderness

Question 12

Statins - HMG-CoA reductase inhibitors (3)

Answer 12

Common adverse effects
>mild GI symptoms, headache, insomnia

Rare but serious adverse effects
>myopathy (muscle weakness)
>rhabdomyolysis (breakdown of muscle resulting in myoglobin release into the bloodstream)
>Renal failure
>liver failure

Contraindicated in pregnancy
>impaired fetal myelination
(cholesterol is required for myelination of nerves)

Withhold during infection, pre-surgery, post-trauma
>increased risk in these 3 conditions that can cause acute renal damage

Statins are mainstay of dyslipidaemia
>might need to ad another drug to lower LDL even further
>some patients cannot stand statins, where they cannot stand the muscle pain or their liver/kidney damaged, need to use another drug

Question 13

Treatment of hypercholesterolaemia with bile acid binding resin

Answer 13

Oral route - granular preparations, taken with liquid

Non-absorbable macromolecules
- Polymeric cationinc exchange resins

Bind bile acid (cholesterol metabolites) preventing gut absorption
>up to 10-fold increase in bile excretion

Increased demand for cholesterol for bile acid synthesis causes upregulation of hepatic LDL receptors, removal of LDL from plasma and more cholesterol metabolism

Question 14

Bile acid binding resin

Answer 14

Quite non-specific, limited because of their unpleasant side effects

Indications:
>hypercholesterolaemia
>Mixed hyperlipidaemia

Common adverse effects:
>abdominal discomfort, bloating, constipation, flatulence

Rare adverse effects
>increased TGs, faecal impaction, decreased absorption of fat soluble vitamins, steatthorea
(Might need to supplement diet with fat soluble vitamins, bile acid binding resin can bind to everything in the gut, not just bile and not just cholesterol, can also bind to other drugs)

Decreases absorption of other drugs
>not just anions, also drugs with neutral or cationic charge (including glycosides, thiazides, statins, aspirin)
>give other drugs hours before or after resin to avoid this effect

Question 15

Treatment of hypercholesterolaemia with Ezetimibe

Answer 15

Ezetimibe
>specifically inhibits dietary cholesterol absorption in the intestine by binding to a specific sterol transporter (Niemann-Pick C1-like 1 protein)

> does not affect absorption of bile acids, fat soluble vitamins

> Lowers LDL

Question 16

Ezetimibe

Answer 16

Possible side effects
>diarrhea, headache

Well tolerated when used in combination with other lipid lowering agents especially statins
>this drug is used as an adjunct, rarely used by itself
>PTs who are already on statins and could use a bit of a boost to lower their LDL even more

Question 17

Proprotein convertase subtilisin/kexin type 9 (PCSK9)

Answer 17

Hepatocyte expressing LDL receptors
>PCSK9 is synthesised and secreted by hepatocytes, main purpose is to bind to LDL receptors

> Once LDL particle binds to LDL receptor, PCSK9 also binds to LDL receptor
»basically targets that LDL receptor to degradation by the lysosome and endosomal compartments within that hepatocyte rather than being recycled back to the surface
means more LDL receptors need to be synthesised

For really elevated LDL levels, can use monoclonal antibodies to the PCSK9 protein
>binds to it at a site close to where the PCSK9 binds to LDL receptor
>PCSK9 can no longer bind to the LDL receptors
>When LDL binds to receptors and the receptors get internalised, they can be recycled

> > we get an increase in number of LDL receptors on hepatocyte surface
means more LDL can be cleaved and removed from circulation

Question 18

Humanised PCSK9 monoclonal antibody

Answer 18

Indications
>Familial hypercholesterolaemia (genetic mutation)

S.C. injection once every 2 weeks or once a month
(humanised antibody cannot be taken orally - peptide gets degraded in stomach)

Common adverse effects
>Injection site reactions, nasopharyngitis, upper respiratory tract infections

Can reduce circulating LDL levels by 45-70% (massive ability to reduce)
>a reduction in LDL translates to a reduction in MI and stroke (would expect that here)
>but not necessarily what’s been observed in the initial clinical trials

> > Long-term safety and efficacy has not been clearly demonstrated (long term trials have not been conducted yet)
not sure what are the implications of reducing LDL levels by that much
Expensive to produce because its a monoclonal antibody

Question 19

Hypertriglyceridaemia

Answer 19

Elevated triglyceride levels
>elevate risk of acute pancreatitis
>associated with increased risk of atherosclerosis

Question 20

Treatment of hypertriglyceriadaemia with Fibrates (1)

Answer 20

Fibrates
>nuclear receptor agonists
>acts or binds to a receptor within the cytoplasm (PPARalpha)

> Has to have the property of being lipid soluble (lipophilic), has to be able to cross cell membrane

> Heterodimerisation of PPARalpha results in altering of protein synthesis
change in protein translation
Affect lipoprotein lipase (enzyme that hydrolyses triglycerides into FFA)

Question 21

Treatment of hypertriglyceriadaemia with Fibrates (2)

Answer 21

Agonists at nuclear receptors, so regulate gene expression
>peroxisome proliferatior activated receptor alpha (PPAR 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
>in some individuals, will increase LDLs, in others will decrease
»because of the risk that they might increase LDLs, they are not used in PTs with high LDLs
»used only in PTs with high triglyceride levels

**Generally used as an adjunct to dietary changes for high TGs, mixed hyperlipidaemia, and second line therapy for hypercholesterolaemia

Question 22

Fibrates - PPARa agonists

Answer 22

Precautions (can cause liver damage like statins)

Mild elevation of serum aminotransferase
>monitor at 3 month intervals, reduce dose or discontinue if necessary

Common adverse effects
>GI disturbances

Rare adverse effects
>Arrythmias
(PPARa receptor is located in numerous places - activation in heart can cause arrythmias)
>Gallstones
(because of long term increased cholesterol in bile acids, chronically lead to gallstones)

Question 23

Summary of lipid lowering drugs

Answer 23

1) Statins
>lower LDL
>increase LDL receptor numbers
>Increase HDL
>Lower TGs
**Mainstay for treatment of elevated cholesterol because they reduce LDL levels quite dramatically and do it in a number of ways

2) Bile acid resins
>Lower LDL
>Increase LDL receptor numbers
>GI side effects arent so pleasant
>Increase production of bile acids, so we need to bring LDL back to the liver to accomplish that

3) Ezetimibe
>Lowers LDL
>very specific, used as an adjunct to other drugs to be fully effective

4) PCSK9 inhibitors
>Lower LDL (more than statins)
>Increase LDL receptor numbers
>monoclonal antibodies, really good at lowering LDLs
>Some limitations mean they’re usually only used in people with familial hypercholesterolaemia (genetic)

5) Fibrates
>Increase HDL
>used to treat hypertriglyceriadaemia
>Lower TGs
>might increase or decrease LDL so contraindicated in PTs with high LDL

Question 24

Where do the drugs work?

Answer 24

Statins and PCSK9 inhibitors
>work in liver

Ezetimibe and Bile acid resins
>work in small intestine

Fibrates
>work in circulation (systemic)