Lec 13- lipid lowering drugs

Question 1

Definition and important terms

NB ChE means cholesterol

Answer 1

• HYPERLIPIDAEMIA: inappropriate term, not all lipids are bad
• DYSLIPIDAEMIA: describes disorders of lipoprotein metabolism
• ESTERS: chemical compounds formed between oxoacid and hydroxyl group (MAG)

Question 2

Lipid structure: fatty acid

Answer 2

• Saturated = no double bonds
• Monounsaturated= 1 double bond
• Polyunsaturated= 2 or more double bonds
• Cholesterol- relatively polar (but non polar when esterification)
• 75% plasma ChE is esterified with ChE linoleate being the most common ester (43%)

Question 3

Lipid structure: triglycerides (TAGs)

Answer 3

• Glycerol molecule

- 3 fatty acids attached forming the ester

Question 4

Lipid structure: phospholipids

Answer 4

• Phospholipids usually contain a diglyceride and a polar phosphate head (plus a small molecule, choline)
• Phospholipid bilayer- this is used in all cell membranes

Question 5

Lipid structure: lipoproteins

Answer 5

• Lipoproteins are assembled molecules that contain both proteins (frequently apolipoproteins) and lipids
• 2 layers: hydrophobic core (non-polar lipids e.g. triglycerides; cholesteryl esters); more polar molecules (free ChE, phospholipids, proteins- apolipoprotein)
• How we carry lipids in the blood and lipids arent soluble enough to travel in the blood so have to be complexed with proteins

Question 6

Apolipoproteins

Answer 6

• Have helical amphipathic regions (hydrophobic and hydrophilic regions)
• Confer structural stability
• Severe as ligands for interaction with cellular receptors
• Act as a co-factor for enzymes involved in lipoprotein metabolism
• Apoproteins A-I, EC and B most important clinically

Question 7

Lipids: synthesis; transport and metabolism

Answer 7

• Clinically important lipids i.e. ChE (unesterified and esterified) and triacylglycerides (TAG) aren’t soluble
• Incorporate into lipoproteins
• Most ChE in tissue is synthesis rather than absorbed from the diet
• The main site of ChE synthesis is the liver

Question 8

Characteristics of lipoprotein classes

Answer 8

• Chylomicrons: carry TAG (fat) from the intestines to the liver skeletal muscle, and to adipose tissue
• V.low density lipoproteins (VLDL)- carry TAG from liver to adipose tissue
• Intermediate density lipoproteins (IDL)- between VLDL and LDL. Not usually detectable in blood
• Low-density lipoproteins (LDL)- formed from IDL and carry ChE to cells of the body referred to as bad ChE. They also return unused ChE to liver
• High-density Lipoprotein (HDL)- collects ChE from the body’s tissue and brings it back to the liver and is referred to good ChE

Question 9

Lipoprotein receptors

Answer 9

LDL RECEPTORS
-Binds lipoprotein containing Apo-B-100 and or Apo E
-Binds LDL and VLDL remnants (IDL)
-Provides ChE to cells throughout the body
-Delivers excess ChE to the liver (recycle or excrete as bile)
CHYLOMICRON REMNANT RECEPTOR (Apo E)
-Chylomicron remnants recognised by Apo E and are removed from the circulation NOT down-regulated by ChE
HDL receptors
-Up-regulated by ChE
-Bind Apo A-I

Question 10

Cholesterol synthesis

Answer 10

1) acetate –> 2) HMG CoA –(HMG CoA reductase)-> 3) mevalonic acid –> 4) ChE (Inhibits HMG CoA reductase; -ve feedback) –(ChE-7-a-hydroxylase)–> 5) 7-a-hydroxyChE –>6) Bile acids (inhibit ChE-7-a-hydroxylase; -ve feedback)

Question 11

ChE synthesis

Answer 11

• Rate limiting step in ChE synthesis= HMG CoA reductase
• ChE levels suppress HMG CoA reductase through feedback mechanism
• Bile acids are major metabolites of ChE and are synthesised in the liver
• The enzyme cholesterol 7-a-hydroxylase is rate limiting
• Bile acids suppress this enzyme through feedback

Question 12

Cholesterol in the intestine

Answer 12

-Cholesterol and bile acids are secreted into bile acids are secreted into bile and on to the intestine
=50% cholesterol; 97% bile salts are reabsorbed
-Continuous cyclin between liver and intestine with some net loss in the faeces
-Bile acids= emulsifier

Question 13

Regulation of cellular cholesterol

Answer 13

INCREASED INTRACELLULAR CHOLESTEROL

• Decreases HMG-CoA reductase activity in hepatocytes so decreases ChE synthesis
• Increases acyl CoA cholesterol acyl transferase- esterifies cholesterol
• The lower rate of synthesis of LDL receptors so decreases uptake of ChE
• This allows peripheral cells to regulate ChE uptake in line with cellular requirements

Question 14

Lipoprotein metabolism

Answer 14

• Lipoprotein metabolism can be separated into 2 pathways
• EXOGENOUS- lipid absorbed from diet
• ENDOGENOUS- lipids produced in the liver

Question 15

Disorders of lipid biology

Answer 15

• Primary Disorders (mostly genetic 60%)- 2 main divisions hypercholesterolaemia and hypertriglyceridaemia- may have both
• Secondary disorders: as a consequence of another disorder e.g. diabetes, uraemia, drug action (thiazide, beta-antagonists)
• Cholesterolaemia –> deposition of fats: main risk is atherosclerosis, also peripheral deposition of cholesterol

Question 16

Where do we start in terms of diagnosis

Answer 16

• Clinicians are advised not to do opportunistic screening of unselected people
• The key issue here is to identify people who are at high risk of CVD
• There is a QRISK2 risk assessment tool- that gives a % risk of developing CVS over 10 years
• Patients who have or whose family history suggest that they may have primary hypercholesterolaemia- e.g. history of early cardiac morbidity or mortality in the family

Question 17

Examples and signs to look out for

Answer 17

• Arcus cornea- Deposits of cholesterol at the edge of the cornea
• Xanthelasma- Deposits of cholesterol around the eyes
• Xanthoma- cutaneous or tendonous eruptions containing cholesterol
• Apart from these, patients with dyslipidaemia generally don’t report symptoms and may be at early stages asymptomatic- unless the disorder has led to more serious disease (angina)- due to atherosclerosis; acute MI; stroke
• The key as a clinician is to help patient reduce their risk and prevent this once this is detected

Question 18

Raised serum ChE- demographics and clinical importance of treatment and prevention

Answer 18

• About 46% of deaths due to CHD attributable to raised serum cholesterol
• CHD major caused of death in the UK- accounting for 1/3 of deaths
• In 2010- approx 180,000 people died from CVD
• British population has highest average serum ChE in the world 66% >5.2 mmol/L
• Lipid-lowering therapy has proven to reduce deaths. Overall about 30% reduction in CHD events, 20% death
• LDL most important fraction

Question 19

Measurements of blood lipids

Answer 19

• Risk is based on lipid level and CHD risk- alone serum ChE relatively poor indicator
• 1st priority is established CHD, stroke etc.
• 2nd is those with 10 years CHD risk >30% but without CHD disease
• Unselected screening of the whole population is not to be recommended. Screening should be targeted at hypertensives and diabetics
• Screening should be coupled with counselling

Question 20

Therapeutic approaches to dyslipidaemia

Answer 20

1) Diet
2) Reduction of GI absorption: bile acid-binding resins; ChE absorption inhibitors
3) Hyperlipidaemic agents: HMG CoA reductase inhibitors (statins); fibrates; nicotinic acid
4) Novel agents

Question 21

Diet

Answer 21

• Reduce intake of cholesterol and fat-containing foods
• Encourage fibre intake (35g dd)
• Achieve ideal body weight. increase exercise
• Benefit: reduced fat absorption; reduced ChE and saturated fats increase hepatic LDL receptor synthesis so increasing hepatic uptake and reducing plasma concentrations
• Reduce drinking; stop smoking

Question 22

Diet continued

Answer 22

• From 2014- NICE introduced further advice on the lifestyle modifications for the primary and secondary prevention of CVD
• NICE has also recommended taking account of a person’s individual circumstances- e.g. drug therapy; other conditions and other lifestyle modifications when giving dietary advice
• Advise and support people at high risk of CVD to achieve a healthy diet in line with behaviour change- NICE public health guideline

Question 23

Absorption inhibition

Answer 23

• Ezetimibe (Ezetrol MSD)= ChE absorption inhibitor in small intestine
• Does not affect triglyceride absorption
• Bile acid resins e.g.Cholestyramine

Question 24

Statins

Answer 24

• All block liver HMG CoA reductase and so hepatic ChE Biosynthesis. little effect on other cells
• Compensatory increase in hepatic LDL receptors and so in clearance of plasma LDL
• Modified VLDL formed- reduced biosynthesis of Apo-B-100, also increased clearance
• Maximal effect in 4 weeks
• Generally well tolerated- some GI side effects, raised Cr phosphokinase, sometimes myositis
• 22-30% decrease in mortality

Question 25

Examples of statins

Answer 25

- Atorvastatin; fluvastatin; pravastatin; simvastatin - Improve clinical outcomes- all reduce blood lipids - Simvastatin metabolised by cP450- avoid inhibitors of this enzyme (azole antifungals; grapefruit juice) - Can have several side effects: muscle myopathy (toxicity); hepatotoxicity (affecting the liver and shown by deranged LFT- this is rare, but a reason why LFT are performed)

Question 26

Myopathy and statins

Answer 26

-Proven benefits outweigh risk of myopathy -Most common symptoms are non-serious and usually transient (a headache, sleep disorders, GI disturbance) -Peripheral neuropathy and myopathy including rhabdomyolysis(breakdown of skeletal muscle) are serious RISKS INCREASED: -Underlying muscle disorders or family history -Concomitant use of other lipid-lowering agents -Concomitant use of other cP450 inhibitors e.g.cyclosporins, macrolides and ketoconazole -Patients with high alcohol intake in their diet, renal impairment or hyperthyroidism- (cautions and further information about these groups in the BNF)

Question 27

Fibrates

Answer 27

- Mechanism still not fully understood- increase activation of LPL (increased hydrolysis of VLDL) - Overall, lower VLDL, modest rise in HDL and variable effects of LDL - Largest effect is fall in triglycerides (max 35%) - 1st line for those with TG> 10mmol/L - Well tolerated- side effects- 5-10% - Main problem GI issues, rash, less likely myositis

Question 28

Nicotinic acids

Answer 28

- Water-soluble vitamin - Reduces VLDL production through effect upon apolipoprotein biosynthesis - Secondary effect is to decrease LDL production - Normal doses, reduce triglycerides (5-10%) and LDL (10%); HDL effects are variable - Numerous adverse effects: Intense flushing; GI including peptic ulcers; hyperpigmentation; hepatic dysfunction; dry skin

Question 29

Novel therapies

Answer 29

1) Microsomal transfer protein inhibitors- reduces ChE in endoplasmic reticulum e.g. lomitapide. The UK approved in 2013 with low-fat diet and lipid-lowering drugs 2) Evolocumab- antibody inhibitor against proprotein convertase (PCSK9). The enzyme degrades the LDL-receptors, so inhibiting it reduces plasma ChE 3) Thyroid memetics- Research has shown thyroxine receptor agonists can reduce LDL without causing arrhythmias e.g.eprotirome causes 30% reduction in LDL 4) Gene silencing treatment- e.g. mipomersen reduces Apo-B and LDL-c dose-dependently. FDA approved for the treatment of homozygous familial hypercholesterolaemia

Question 30

Lipoprotein metabolism

Answer 30

- We absorb fat from the intestines and this enters the chylomicrons - Chylomicrons enter the tissue through the capillaries - Chylomicrons then get used by peripheral cells and there is an enzyme called lipoproteinliapse which breaks down them into glycerol (returned to liver) , fatty acids (resynthesis and storage in adipose tissue) - We then get left with remnant chylomicrons and ChE, these then enter the liver where biosynthesis of fats, ChE and triglycerides occurs - VLDL's then leave the liver - VLDL then enters the tissue and get attacked by lipoprotein lipase (LPL) - We are then left with IDL (some go back to the liver) but many are further attacked by LPL to for LDL's - LDL's prodominantly deliver there ChE to the peripheral tissues (but can go back to the liver), Once they have delivered there ChE LDL's turn into HDL's which pick up excess ChE and transport it to the liver