Dyslipidemia Flashcards
what is the lipoprotein particle structure?
Plasma lipids exist and circulate in the form of lipoproteins
Hydrophobic core –
Cholesteryl esters
&
triglycerides
Apoprotein – acts as a ligand for receptors
Outer layer -Phospholipids & free cholesterol
what are the 2 lipoprotein metabolic pathways? how is most of LDL cleared?
Lipoprotein metabolic pathways
The exogenous pathway transports dietary lipids to the periphery and the liver.
The endogenous pathway transports hepatic lipids to the periphery.
75% of plasma LDL is cleared by the liver – through the LDL receptor
what are the lipoprotein classes based on their relative density?
HDL is A1/II/E protein and it is 20% cholesterol and 5% triglycerides
LDL is B100 protein, 60% cholesterol, 5% triglycerides
there is also intermediate density lipoproteins, verly low density lipoproteins, and chylomicrons.
what is hyperlipidemia?
Major cardiovascular (CV) risk factor affecting 25% of the population
Reducing LDL with diet (~10%) or drugs (~20-60%) prevents CV disease, saves lives and money
Generally safe but expensive (use in high risk pts.)
Drug classes: Statins, fibrates, niacin, bile acid binding resins, ezetimibe
all of the following are proatherogenic risk factors for developing CV disease… LDL? total cholersterol? total cholesterol/HDL? 1/HDL?
↑ LDL
↑ Total Cholesterol
↑ Total Cholesterol / HDL
↑ 1 / HDL
how does high cholesterol form blood vessel damage?
small dense LDL moves out of the blood vessel and gets phagocytosed and the monocyte then turns into what is known as a foam cell and forms then a swelling just on the outside of the wall known as an atheroma
what is hyperlipidemia and vessel damage?
Scavenger receptors (SR-AI/II and CD36) on macrophages take up oxidized LDL – form foam cells and atherosclerotic lesions
Pre-β1 HDL (made up of mainly apoAI and phospholipids) picks up cholesterol from cells (arterial wall) and transports it to the liver (reverse cholesterol transport)
High HDL is protective and low HDL is atherogenic
Estrogen enhances LDL receptor gene expression (females are better protected against atherosclerosis)
Estrogen also up-regulates endothelial nitric oxide synthase – improves endothelial function
what does HDL do?
HDL transports cholesterol from periphery (artery wall) back to the liver – Reverse cholesterol transport
what is the biosynthesis and metabolism of cholesterol?
Acetyl CoA –> 3-hydroxy-3-methyl-glutaryl-CoA (HMG CoA) —> mevalonate (HMG CoA reductase reduces HMG CoA into mevalonate) –> cholesterol (it then either goes to various tissues or to be bile acids.
Bile acids go to the intestine and then are either enterohepaticly recycled for 95% of it to be reabsorbed into cholesterol or it goes from the intestine to feces (5%).
what are statins?
Most effective and best-tolerated agents for treating hyperlipidemia
Effective in most cases except when LDL receptor is dysfunctional
Inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme that catalyzes cholesterol biosynthesis
Reduce cholesterol and VLDL synthesis in the liver
how do statins work?
Statins inhibit
cholesterol
synthesis in the liver
Liver needs cholesterol Increases LDL receptor number on hepatocytes Picks up more cholesterol from blood Plasma cholesterol levels decrease by 20-55%
Some statins may ↑ HDL levels
what are the kinetics of statins?
Given at bedtime – cholesterol synthesis – midnight to 2 a.m., not at the same time of the day as bile-acid binding resin
Contraindicated during pregnancy or while breast feeding
May work better in combination with bile-acid binding resins (cholestyramine & colestipol), niacin or fibrates
what are the adverse effects of statins?
Hepatotoxicity [serum alanine aminotransferase (ALT) should be checked regularly]
Myopathy (can progress to myoglobinuria and renal failure), esp. when other drugs metabolized by CYP3A4 are given together – erythromycin, azole antifungals, cyclosporine, antidepressants, nefazodone, protease inhibitors
what are fibrates?
Least used of all 4 groups - increased mortality?
Drugs of choice to treat severe hypertriglyceridemia (>1000 mg/dl) to prevent pancreatitis
Mechanism of action: Activate a nuclear transcription factor receptor - peroxisomal proliferation activated receptor α (PPAR-α) – causes metabolic changes
↑ Fatty acid oxidation, ↑ clearance of triglycerides, ↑ HDL
Primarily in the liver and adipose tissue
Better absorbed with meals
Side effects are uncommon - GI distress
what is the drug-drug interaction to consider with fibrates?
Drug-Drug Interactions:
Fibrates plus statins – increased risk of myopathy
Renal failure and hepatic dysfunction are relative contraindications for the use of fibrates
Not used in children, during pregnancy and breast-feeding
what is niacin (nicotinic acid)?
Water soluble B-complex vitamin
Multiple actions – e.g. Reduces hepatic triglyceride (VLDL) synthesis, increases HDL-C levels by reducing their clearance in the liver
Reduces plasma LDL by 20 to 30% (4.5-6 g/d)
Best agent to increase HDL (30-40%)
Reduces triglycerides by 35-45% (2-6 g/d)
Side effects limit use
what are adverse reactions with niacin?
Common and reduce patient compliance:
Flushing (with drop in blood pressure - syncope in some patients) (give aspirin)
Dyspepsia (take after meals)
Pruritis, skin rashes.
Hepatotoxicity (the most serious side effect)
Avoid in peptic ulcer patients & gout
Worsens diabetes
Avoid in pregnancy – can cause birth defects
Niacin + statins – watch out for myopathy
what are resins?
bile-acid sequestrants
Oldest lipid-lowering drug – second line drugs to add to statins – can reduce LDL-C by upto 25%
Positively-charged anion-exchange resins
Binds negatively charged bile acids (95% of which are normally reabsorbed)
Liver has to synthesize new bile acid and uses cholesterol – adaptive increase in LDL receptors removes cholesterol from plasma
what is the advantage of resins and what are the side effects?
Advantage: Probably the safest - not absorbed into systemic circulation
Not used in patients with hypertriglyceridemia (increase triglyceride synthesis)
Side Effects: Gastrointestinal (bloating, dyspepsia etc), reduce absorption of fat soluble vitamins (ADEK), folic and ascorbic acids and fat-soluble drugs
what is ezetimibe?
Approved in October 2002
Prevents the absorption of dietary cholesterol from the intestines
It is not a bile-acid binding resin
Reduces serum LDL (by ~ 18%), Total cholesterol, and triglycerides and increases HDL
what do you do for low HDL-C level individuals?
Clinical trials data support drug treatment for patients whose major risk factor is low plasma levels of HDL-C, even if their LDL-C is normal.
Drug therapy in the above group of patients reduced coronary heart disease (CHD) events by 20-35%
2/3rd of patients with CHD in the US have low HDL-C levels (<40 mg/dl)
For a given level of LDL-c, the risk of CHD increases 10-fold as the HDL-c varies from high to low
Conversely, for a fixed level of HDL-c, the risk increases three-fold as LDL-c varies from low to high
how can you increase HDL levels?
Life style changes can raise HDL levels
Daily exercise of moderate intensity for more than 12 weeks – can increase HDL by 4.6%
Weight loss of 1 kg increases HDL by 1%
Moderate consumption of alcohol (30 grams per day) increases HDL by 8.3%
Smoking cessation
how is obesity calculated?
BMI = weight (kg)/(height m) squared
BMI 20-25 normal
BMI 25-27 borderline
BMI 27-30 overweight
BMI > 30 obese
waist male>100cm (40 inches)
waist female > 90cm (36 inches)
Obesity is a risk factor for type 2 diabetes, hypertension, myocardial infarction, stroke, sleep apnea and certain types of cancer
what does leptin do?
Leptin is released mainly from adipocytes in response to fat storage
Acts on leptin receptors in hypothalamus
Reduces secretion of neuropeptide Y
Reduces hunger and food intake
Increases energy expenditure
Reduced size and number of adipocytes – wt loss
Increases gondotropin releasing hormone secretion from the hypothalamus, which in turn increases leutinizing hormone and follicle stimulating hormone secretion
Affects reproductive function
Abnormally thin females have reduced leptin secretion and develop infertility
what is orlistat (Xenical)?
Approved by the FDA for over-the-counter sale in Feb. 2007
Inhibits pancreatic and intestinal lipases – inhibits breakdown of dietary fat
Not absorbed (<1%) (no systemic adverse effects)
Prevents absorption of dietary fatty acids by 30%
Adverse effects: Mainly related to the GI tract and unabsorbed fat - bloating, oily spotting, fecal urgency in one third of the patients
Prevents absorption of vit A,D,E,K. Give vitamin supplements
Can reduce absorption of some drugs taken simultaneously
Contraindicated during pregnancy
What is phentermine?
One of the more widely used antiobesity drugs
Releases norepinehrine in the appetite centre in the hypothalamus in the brain
Anorectic – reduces appetite
Adverse effects: dry mouth, headache, constipation, increased HR and BP (dose related)
what is phentermine - topiramate combination?
Topiramate is an antiepiletic drug
It reduces voltage-gated Na+ currents
It also activates a hyperpolarizing K+ current
Mild to moderate weight loss in clinical trials
Combination is contraindicated during pregnancy
Topiramate may cause suicidal thoughts or behaviour
what is locraserin (belviq)?
Approved by the FDA in June 2012 to treat adult obesity
Activates serotonin 2C receptors in the brain to increase satiety and decrease hunger
Lorcaserin is contraindicated during pregnancy
what is pramlintide (symlin)?
Pramlintide (Symlin®) is a synthetic analogue of the hormone amylin secreted by the pancreas in response to eating
Delays gastric emptying and causes satiety
Pramlintide is given to diabetic patients.
A combination with leptin showed promise in reducing body wt. in a small trial (Ravussin et al., 2009).
