Session 3 - Lipid metabolism Flashcards Preview

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Flashcards in Session 3 - Lipid metabolism Deck (40)

Outline line the pathophysiology of athersclerosis

1. Endothelial injury due to
o Raised LDL
o ‘Toxins’ e.g. cigarette smoke
o Hypertension
o Haemodynamic stress
2. Endothelial injury causes
o Platelet adhesion, PDGF release, smooth muscle cell proliferation and migration
o Insudation of lipid, LDL oxidation, uptake of lipid by smooth muscle cells and macrophages
o Migration of monocytes into intima
3. Stimulated SMC produce matrix material
4. Foam cells secrete cytokines causing
o Further SMC stimulation
o Recruitment of other inflammatory cells


Give four pro-atherogenic effects of oxidate LDL

o Inhibits macrophage motility
o Induces T-cell activation and vascular smooth muscle cell division/differentiation
o Toxic to endothelial cells
o Enhances platelet aggregation


What correlates with increased risk of atherosclerosis?

Total and LDL cholesterol concentrations correlate
HDL levels have inverse correlation


What are the transport functions of chylomicrons?

Transport dietary triacylglycerols from the intestine to tissues such as adipose tissue.


What are the transport functions of VLDL?

Transport of triacylglycerols synthesised in the liver to adipose tissue for storage.


What are the transport functions of LDL?

Transport of cholesterol synthesised in the liver to tissues.


What are the transport functions HDL?

Transport of excess tissue cholesterol to the liver for disposal as bile salts


What is the role of cholesterol in preventing cardiovascular/coronary events

A 10% reduction in total cholesterol results in:
o 15% reduction in Coronary Heart Disease mortality
o 11% reduction in total mortality.
LDL is main target


What are the effects of statins (3)

o LDL reduction of between 5-35%,
o HDL raised by ~5%
o Triglycerides reduction of 10-35%


What are the mechanisms of action?

The primary pharmacological action of statins is by inhibiting the hepatic enzyme HMG-CoA Reductase, which is involved in cholesterol synthesis. Decrease in hepatic cholesterol concentration stimulates the production of LDL receptors, which increases rate of LDL removal from plasma.


What are the three main side effects of statins?

Myalgia, myopathy and rhabdomyolysis


Give four types of statins

 Simvastatin
 Atorvastatin
 Rostuvastatin
 Pravastatin


What is the route of admin for statins?



What are the indications for statins?

 Hyperlipidaemia resistant to dietary control
 Secondary prevention in patients with serum cholesterol greater than 5.5mmol/L (value varies depending on local policy)


What are the contraindications for statins?

 Pregnancy, breastfeeding, liver disease


What are some adverse drug reactions for statins?

 Increased transaminase levels (Rapidly reversible, no evidence of chronic liver disease)
 Myopathy (diffuse muscle pain, primarily seen when used in combination with cyclosporine and occasionally erythromycin & niacin)
 GI Disturbances
 Arthralgia
 Headaches


What induces breakdown of statins?

 CYP450 inducers/inhibitors. Inhibitors significantly increase the risk of myopathies


Give a three alternatives to statins?

Fibric Acid Derivatives (Fibrates)
Cholesterol Absorption Inhibitors
Bile Acid Sequestrants


What do fibrates do?

Fibrates act as agonists on the Peroxisome Proliferator-Activated Receptor-α (PPAR-α).


What do fibrates result in?

o LDL lowering (variable amount)
o HDL increases of 15-25% in hypertriglyceridemia
o Decreases Triglycerides 25-50%


Give three examples of fibrates?

 Bezafibrate
 Ciprofibrate
 Gemfibrozil


When are fibrates used?

Fibrates can be used in conjunction with statins, but typically are only used as first line choices in hypertriglyceridemias. Usually used in  Hyperlipidaemia unresponsive to dietary control


What are some contraindications of fibrates?

 Pregnancy, breast feeding, gall bladder disease, severe renal or hepatic impairment, Hypoalbuminaemia


Give four adverse reactions to fibrates?

 Gastrointestinal disturbances
 Dermatitis, pruritus, rash
 Impotence
 Headache, dizziness, blurred vision


Give some drug drug interactions fibrates?

 Increased change of myalgia and myopathies when taken with statins


What are cholesterol absorption inhibitors?

Cholesterol absorption inhibitors inhibit intestinal cholesterol uptake, by blocking the specific cholesterol transport protein NPC1L1 in the brush border. This reduction of dietary cholesterol reaching the liver increases LDL receptor expression, further reducing circulating cholesterol.


To what extent do cholesterol absorption inhibitors reduce LDL

A single 10mg dose of a cholesterol absorption inhibitor, Ezetimibe, is enough to reduce LDL levels by 15-20%. It is normally given as monotherapy in statin intolerant patients, however it will reduce LDL by a further 20% when given in combination with a statin. This is a better reduction than is gained by doubling statin dose and also reduces the risk of statin ADRs.


What increases half life of cholesterol absorption inhibitors?

Ezetimibe also undergoes enterohepatic circulation, increasing its half-life.


Give an indication for a cholesterol absorption inhibitor

 Hyperlipidaemia resistant to dietary control, in statin intolerant patients
 Given in combination with a statin


Give a contraindication for route cholesterol absorption inhibitor



What is mech of action of cholesterol absorption inhibitor

 Hyperlipidaemia resistant to dietary control, in statin intolerant patients
 Given in combination with a statin


Give two adverse drug reactions of ezetimibe

 Gastrointestinal disturbances (Diarrhoea, pain)
 Headache


Give two bile acid sequsterants

 Colestyramine
 Colestipol


What is an indication for bile acid sequesterants

o Elevated cholesterol resulting from a high LDL concentration


What is a contraindiction for bile acid sequestration

Billiary obstruction


Give a mechanism of action for bile acid sequesterants

o Bind to bile acids in the intestine. This prevents their reabsorption and subsequent conversion of hepatic cholesterol into bile acids. Lower levels of hepatic cholesterol leads to increased LDL receptor expression and lowered plasma cholesterol concentration.


Give an adverse drug reaction of bile acid sequesterants

o GI disturbances – Nausea, vomiting, constipation, abdominal pain, flatulence, heart burn
o Very few systemic side effects as they are not absorbed


Give a couple of physiological processes which effect ADME of statins

o Intestinal absorption varies between 30 – 85%
o Hepatic first pass uptake is extensive
 May occur either by diffusion or active transport by OATP2
 Systemic availability may fall to 5 – 30% of administered dose
o Hepatic elimination includes CYP3A4 for some statins, whilst others are only metabolised by Phase 2 pathways
o Exhibit Non-Linear Pharmacokinetics
 Doubling of dose results in ~6% reduction in LDL


Give a short acting statin



Give a long acting statin

 Atorvastatin
 Rostuvastatin
 Half-life ~20 hours. Given any time of day.