Session 3: Sex Steroids, Cholesterol and Lipid Metabolism Flashcards

Question

How can you prevent atherosclerosis?

Answer 1

Drug treatments apart, exercise change in dietary and other habits can reduce LDL and increase HDL. The main agents of clinical choice are: Statins, Cholesterol Lipase Inhibitors (e.g. Ezetimibe), Fibrates (Fenofibrate is most common), Bile Acid Sequestrants, Nicotinic acid/Niacin, Resins (Colestyramine), Omega-3 fatty acids – omacor, ? Plant sterols

Answer 2

Statins are the most common effective and best tolerated drug for lowering LDLs. Depending on the dose and type of statin used, the range of LDL reduction falls between 5-35%, whilst raising HDLs by about 5% and lowering triglycerides by 10-35%. The primary pharmacological action is by inhibiting the hepatic enzyme HMG-CoA reductase, which is involved in cholesterol synthesis. Decrease in hepatic cholesterol concentration stimulates production of LDL receptors, which then increase rate of LDL removal from plasma – increases clearance of IDL and LDL, and decreases production of VLDL and LDL Consequently statins are used to reduce CVD risk; they are especially important in cases of familial hypercholesterolaemia. Indications: CV risk prevention (CVD + diabetes mellitus), familial hypercholesterolaemia Animal and in vitro studies suggest statins may have secondary pleitropic anti-atheromatous actions, although the specific contribution they may have in humans is not clear. Some secondary benefits of Statin treatment include: anti-inflammatory, plaque reduction, improved endothelial cell function and reduced thrombotic risk. Statins may also provide additional benefit in slowing neurodegeneration and prostate cancer prevention.

Answer 3

There is considerable variation in PK and PD of this important drug group, which is partly related to molecular structure. Intestinal absorption varies between 30-85%. Hepatic first pass uptake is extensive, but may occur by diffusion or active transport by OATP2. Due to this and the requirement by some statins for activation, systemic availability may fall to 5-30% of administered dose. Hepatic elimination includes CYP 3A4 for some statins whilst others are only metabolised by Phase 2 pathways. In short acting statins e.g. Simvastatin, half life varies between 1-4 hours and these are usually given at night to coincide with peak cholesterol production in early morning. The structurally distinct atorvastatin and rosuvastatin have half lives ~20 hours. This is likely to contribute to their superior efficacy and can be given any time of day. Statins as a group also exhibit non-linear pharmacodynamics, where for any statin, a doubling of dose results in ~6% in LDL.

Answer 4

Statins appear to be well tolerated with the incidence of serious side effects, myopathy and rhabdomyolysis reported as ~0.01% at highest doses, also angioedema. In large-scale trials with low-intermediate doses, myalgia and myopathy rates were comparable to placebo. Significant elevation in plasma hepatic enzymes has been reported Increased transaminase levels * 0.1%-2.5% of treated patients develop increases of \>3x upper-normal limit, especially at higher doses. * Rapidly reversible, no evidence of chronic liver disease Myopathy * Diffuse muscle pain and CPK (creatine phosphokinase) \> 10x upper-normal limity * Primarily seen when higher doses of statins are used in combination with cyclosporine, gemfibrozil and occasionally erythromycin and niacin. Miscellaneous * Gastrointestinal complaints, arthralgias and headaches.

Answer 5

Statins as a group and individual agent interact with a wide range of other drugs. Predictably those metabolised via Phase I pathways are affected by CYP inducers/inhibitors. Notably, CYP inhibitors will increase the risk of myopathy due to increased statin levels e.g. grapefruit juice and verapamil. Conversely, rifampicin and St John’s Wort acting as inducers will decrease plasma levels in those statins metabolised by this route. OATP2 inhibitors can reduce the efficacy of those statins carried via this transporter. Interestingly, gemfibrizil is a fibrate that inhibits both OATP2 and statin glucorinidation. This increases statin plasma levels but co-administration also synergistically increases the risk of myopathy. Synergistic therapeutic interaction with other LDL lowering agents to augment this effect is sometimes employed e.g. Ezetimibe/Fibrate

Answer 6

Not withstanding the low ADR profile of statins, liver function tests at baseline may be obtained especially with higher doses. It is more important to monitor functional endpoints with LDL lowering in combination therapy with statins and with drugs from other groups that may affect statin PK and PD. Individuals placed on high doses of statins should have regular liver function tests, as well as constant LDL level monitoring.

Answer 7

Clinical trial evidence of statin use. There is also consideration with the criteria be used to determine therapeutic targets as informed by optimal levels and ratios of plasma lipids. There is also consideration of which patient groups should receive statin therapy in primary or secondary prevention. Individuals placed on high doses of statin should have regular liver function tests, as well as constant LDL level monitoring. Individuals should be placed on statins if they have CHD (4S Study) or raised LDL levels (CARE study) as statins reduce morbidity and mortality rates; studies have even statins causing improved morbidity and mortality outcomes for those with normal cholesterol levels.

Answer 8

Cholesterol Absorption Inhibitors e.g. Ezetimibe: these inhibit intestinal cholesterol uptake by blocking the specific cholesterol transport protein NPC1L1 in the brush border. This reduction of dietary cholesterol reaching the liver secondarily induces LDL transporter expression (increases expression of hepatic LDL receptors) to further reduce circulating cholesterol levels (decreases cholesterol content of atherogenic particles). A single 10mg dose of Ezetimibe can reduce LDL levels by about 15-20%. Ezetimibe also undergoes repeated enterohepatic circulation Ezetimibe and its active glucuronide metabolite circulate enterohepatically. Delivers agent back to the site of action Limits systemic exposure. Ezetimibe is typically given as monotherapy in statin intolerant patients. It does however synergistically reduce LDL by a further 20% when given in combination with a statin. This is actually better than the reduction with a doubling of statin dose and also reduces the risk of statin ADRs. ADRs: headache, abdominal pain and diarrhoea.

Answer 9

: these ampipathic carboxylic acids act on the Peroxisome Proliferator-Activated Receptor-alpha (PPAR-alpha) (agonists) – increases production of lipoprotein lipase. A complex mechanism of action modestly lowers LDL (10-20% lower but variable, depending on specific drug) and raises HDL, but provides impressive lowering of triglycerides. Improved postprandial triglyceridemia? Can be used in conjunction with statins but are typically only used as first choice in specific types of hypertriglyceraemias. Indications * Adjunctive therapy to diet * Hypertriglyceridemia * Combined hyperlipidemia with low HDL who not respond to NA

Answer 10

Efficacy * Decreases TG 25-50% * LDL decreases but variable * Increases HDL 15-25% in hypertriglyceridemia Side Effects: GI upset (8%), cholelithiasis, myositis, abnormal LFTs Contraindications: hepatic or renal dysfunction, pre-existing gallbladder disease (due to risk of cholelithiasis) Intervention Trials: Helsinki Heart Study, LOCAT, BECAIT, VA-HIT, BIP

Answer 11

Reduces VLDL and increases HDL at high doses Best agent to raise HDL-c Lipid-lowering effect by inhibition of lipoprotein(a) synthesis Reduces coronary events (Coronary Drug Project) Adverse effects * Flushing, itching, headache (reduced by immediate-release, Niaspan or combination with low-dose aspirin) * Hepatotoxicity, GI (sustained-release) * Activation of peptic ulcer * Hyperglycemia and reduced insulin sensitivity Contraindications * Active liver disease or unexplained LFT elevations * Peptic ulcer disease

Answer 12

Statin plus: * Fibrate (not gemfibrozil) * Nicotinic acid * Ezetimibe * Omega-3 Fatty Acids * (Resins) Consider * Benefit (CV risk reduction) * Cost * ADRs

Answer 13

Combination fibrate and statin therapy may significantly improve triglyceride, LDL-c and HDL-c levels But…fibrates plus statins are associated with increased risk for myopathy and rhabdomyolysis Not thought due to cytochrome P450 drug interaction Gemfibrozil may impair glucuronidation of statins (with cerivastatin being more susceptible than other statins such as simvastatin and atorvastatin) Fenofibrate appears to have less potential for impairment of statin metabolism and thus this may account for the reduced reports Remember polypharmacy increases risk of ADR so close monitoring is required.

Answer 14

Consider plant sterols for those not willing to take tablets (sterols found in margarine, yogurt drinks etc compete with cholesterol for intestinal absorption). Other dietary factors Positive * Fish oils * Fibre * Vitamin C/E * Alcohol (HDL) Negative * Dietary cholesterol/fat * Alcohol (triacylglycerides)

Answer 15

Potential pharmacological cost of treating hyperlipidaemia in USA estimated at $3-17 billion per year…before the credit crunch The cost (per event prevented) increases as the baseline risk of the patient falls – cue the term NNT= numbers needed to treat Public Health or Public Harm OTC: Lipid Lowering Therapy Simvastatin available OTC…10mg daily Who is it for? Who buys it? Is it cost-effective? What are the implications? Or is it just to save the government (and us) some money?

Answer 16

Read over both Week 3 lectures!

Session 3: Sex Steroids, Cholesterol and Lipid Metabolism Flashcards

(40 cards)