Session 3 - Lipid metabolism Flashcards
Outline line the pathophysiology of athersclerosis
- Endothelial injury due to
o Raised LDL
o ‘Toxins’ e.g. cigarette smoke
o Hypertension
o Haemodynamic stress - 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 - Stimulated SMC produce matrix material
- 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?
oral
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
Breastfeeding
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
Simvastatin
Give a long acting statin
Atorvastatin
Rostuvastatin
Half-life ~20 hours. Given any time of day.
