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PH2501- pharmacology > Lec 13- lipid lowering drugs > Flashcards

Lec 13- lipid lowering drugs Flashcards

1
Q

Definition and important terms

NB ChE means cholesterol

A
  • HYPERLIPIDAEMIA: inappropriate term, not all lipids are bad
  • DYSLIPIDAEMIA: describes disorders of lipoprotein metabolism
  • ESTERS: chemical compounds formed between oxoacid and hydroxyl group (MAG)
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2
Q

Lipid structure: fatty acid

A
  • 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%)
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3
Q

Lipid structure: triglycerides (TAGs)

A
  • Glycerol molecule

- 3 fatty acids attached forming the ester

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4
Q

Lipid structure: phospholipids

A
  • Phospholipids usually contain a diglyceride and a polar phosphate head (plus a small molecule, choline)
  • Phospholipid bilayer- this is used in all cell membranes
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5
Q

Lipid structure: lipoproteins

A
  • 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
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6
Q

Apolipoproteins

A
  • 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
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7
Q

Lipids: synthesis; transport and metabolism

A
  • 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
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8
Q

Characteristics of lipoprotein classes

A
  • 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
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9
Q

Lipoprotein receptors

A

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

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10
Q

Cholesterol synthesis

A

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)

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11
Q

ChE synthesis

A
  • 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
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12
Q

Cholesterol in the intestine

A

-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

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13
Q

Regulation of cellular cholesterol

A

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
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14
Q

Lipoprotein metabolism

A
  • Lipoprotein metabolism can be separated into 2 pathways
  • EXOGENOUS- lipid absorbed from diet
  • ENDOGENOUS- lipids produced in the liver
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15
Q

Disorders of lipid biology

A
  • 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
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16
Q

Where do we start in terms of diagnosis

A
  • 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
17
Q

Examples and signs to look out for

A
  • 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
18
Q

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

A
  • 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
19
Q

Measurements of blood lipids

A
  • 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
20
Q

Therapeutic approaches to dyslipidaemia

A

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

21
Q

Diet

A
  • 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
22
Q

Diet continued

A
  • 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
23
Q

Absorption inhibition

A
  • Ezetimibe (Ezetrol MSD)= ChE absorption inhibitor in small intestine
  • Does not affect triglyceride absorption
  • Bile acid resins e.g.Cholestyramine
24
Q

Statins

A
  • 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
25
Q

Examples of statins

A
  • 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)
26
Q

Myopathy and statins

A

-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)

27
Q

Fibrates

A
  • 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
28
Q

Nicotinic acids

A
  • 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
29
Q

Novel therapies

A

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

30
Q

Lipoprotein metabolism

A
  • 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

PH2501- pharmacology (47 decks)

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