Hyperlipidemia Tx Flashcards
Mechanism of HDL return to the liver?
HDL returns cholesterol to the liver by one of two ways: 1. HDL is delivered directly to the liver through interaction with the scavenger receptor, class B, type I (SR-BI). 2. cholesteryl esters in HDL are transferred by the cholesteryl ester transfer protein (CETP) to very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) and are then returned to the liver through the LDL receptor.
What makes LDL “bad” cholesterol?
What disease increase negative effects of LDL?
Plasma lipoproteins that contain Apo B100 including LDL, VLDL, IDL have been identified as vehicles that (1)transport cholesterol to the artery wall. Once at the artery wall, it is thought that (2)oxidation of the lipoproteins creates ligands for the scavenger receptors SR-A or CD36 present on macrophages resulting in the formation of foam cells. These (3)macrophages adhere to vessel walls and migrate underneath the endothelial cells continually endocytose the oxidized lipoproteins forming the atherosclerotic plaque.
Glycation of lipoproteins in poorly controlled diabetes also contributes to foam cell formation. Arterial hypertension also accelerates atherogenesis.
What makes HDL “good”?
- HDL cholesterol can be taken directly back to the liver, thus it is removing cholesterol from the plasma.
- In addition, HDL also decreases atherosclerosis by protecting LDL from oxidation. If LDL is not oxidized it is not readily taken up by the macrophage scavenger receptors.
- HDL may also slow the progression of lesions by selectively decreasing the production of endothelial cell-adhesion molecules that facilitate the uptake of inflammatory cells into the vessel wall.
How is cholesterol regulated?
The mechanisms of cholesterol regulation are poorly understood. The liver has a central role in the production and regulation of serum cholesterol. When the liver or extrahepatic tissues require extra cholesterol for synthesis of new membranes, bile acids, or hormones, the liver can increase the synthesis of either cholesterol itself or increase the number of LDL receptors, thereby capturing LDL from the plasma.
Bile Resins
List Drugs in Category
Pharmokinetics
MOA
Adverse Effects
Drugs- Cholestyramine and colestipol and colesevelam (FA)
Pharmacokinetics
- Anion exchange resins that bind negatively charged bile acids in the small intestines Insoluble in water
- Complex is excreted in the feces
MOA
- Loss of bile acids leads to compensatory increase in the number of hepatic LDL receptors reduce plasma cholesterol 15-30% decrease in LDL, HMG CoA reductase activity is increased reduces cholesterol loss
- Triglyceride synthesis is enhanced temporarily then no effect on TG (this is counter intuitive– used in patients with well controlled TAGs but high LDL)
HDL Adverse effects:
- Increase in Plasma TG levels first few weeks
- Bad taste (texture- like drinking sand) inconvenient to swallow
- GI irriation- Abdominal bloating Constipation/ steatorrhea, anal leakage, anal fissures
- Impairment of other drug absorption: take 1 to 2 hrs before or 3 hr after resin Fat soluble vitamin absorption
- Poor compliance due to inconvenience and abdominal bloating and steatorrhea
Ezetimibe
Pharmokinetics
MOA
Adverse Effects
Effects on long term imporvement of mortality?
Alternative to what LLD? Why?
Zetia (Ezetimibe)
Pharmacokinetics a.
- Ezetimibe is absorbed and conjugated to glucuronide in the liver and small intestine. Both Ezetimibe and ezetimibe-glucurinide are pharmacologically active with plasma levels containing 80- 90% of the conjugated form. B
- oth Ezetimibe and ezetimibe-glucurinide are highly bound to plasma proteins,
- T1/2= 22 hrs b. Eliminated by liver and kidneys
MOA
- Ezetimibe is thought to act as a transport inhibitor, blocking the absorption of cholesterol by the brush border cells of the intestine.
- LDL 18% TG 8% HDL 1% Uses Used to reduce LDL.
- Unlike the statins, there are no long-term studies demonstrating the effect of ezetimibe on reducing plaque, coronary events or improving mortality. Statins remain the preferred treatment
- Effects on LDL are additive when used with statin drugs. (see drug combinations)
- No myopathy effects- a possible alternative to for those that can’t tolerate statins.
Adverse effects
- Not recommended for patients with moderate or severe hepatic insufficiency.
- Drug interaction with cyclosporine
- Appears safe to use in combination with statin drugs, but may cause an elevation of transanimase liver enzymes when used with statins
Statins
Pharmokinetics
MOA (2)
Adverse Effects
CI?
Statins- pravastatin, simvastain, atrovastatin, rosuvastatin
PK
- Some are pro drugs (lovastatin and simvastatin) others are active or have an additional active metabolite (atorvastatin)
- T 1/2 varies generally 1-3 hrs, atorvastatin = 14 hrs
- Excretion predominantly via liver.
MOA
- The statin drugs inhibit the enzyme HMG CoA reductase. This enzyme catalyzes the conversion of Acetyl CoA to melvonic acid a key step in the synthesis of cholesterol. There is some up-regulation of HMG CoA reductase levels but not enough to reduce the effect on cholesterol synthesis Because of low hepatic cholesterol, the liver increases LDL receptors resulting in decreases serum LDL May also be anti inflammatory (reduce c reactive protein)
- Most potent and preferred for reduction in LDL
- 18%-55% HDL 5%-15% TG 7%-30% Reduction in LDL is dose dependent
Adverse effects: Generally safe and well tolerated, side effects increase with dosage.
- Check liver enzymes before starting treatment and immediately after starting treatment can cause heptatoxicity (increase LFT)
- Myopathy may be life threatening Rhabdomyolysis
- Transanimase hepatitis
Contraindications:
- Renal Failure
- Cyclosporine
- macrolide antibiotics
- various antifungal agents, and cytochrome P-450 inhibitors
Which statins have the bet evidence for preventing Heart attack and stroke?
simvastatin (Zocor), atorvastatin (Lipitor), and Rosuvastatin (Crestor).
What cholesterol is the best determinant of heart attack?
HDL- inverse coorelation!
LDL marginal risk factor
Total Nor predicitive
According to 1977 framington heart study
Niacin- Other names?
Pharmokinetics
MOA (2)
What is the most effective agent for?
Adverse Effects
CI?
Nicotinic acid (Niacin b3)
Pharmacokinetics
- Much higher dosage, 1-3g, is used for hypolipidemic effect. Vitamin dose is only 20 mg. Niacin is rapidly absorbed and eliminated by renal clearance. Note: The acid form of the drug, Niacin or nicotinic acid, is active. The basic form of the drug, niacinamide or nicotinamide does not have hypolipidemic action.
MOA
- Inhibition of VLDL secretion LDL 5-25%
- clearance of VLDL via lipoprotein lipase pathway leads to triglycerides 20-50%
- Enhanced HDL levels
Uses: Most effective agent for HDL 15%-35%– think of the healthy (HDL) effect of vitamins
Adverse Effects -Just because it is over the counter do not assume that it is safe at these dosages
- Intense Flushing, and associated Pruritis– One aspirin can relieve the symptoms
- Nausea, abdominal pain o dosage,+ antacid (not Al3+), AL3+ antacids are contraindicated -peptic ulcer
- Hyperuricemia
- Hyperglycemia may decrease glucose tolerance in patients with sub clinical diabetes –Acanthosis nigricans (patches of dark skin) associated with insulin resistance-discontinue
- Hepatotoxicity transaminase, & ALT, flu-like fatigue
Firbic acid derivatives- list drugs in this group?
Pharmokinetics
MOA (2)
Most effect at effecting which type of choleterol?
Adverse Effects
Fibric acid derivative- Gemfibrozil, clofibrate, bezofibrate, fenofibrate
Pharmacokinetics
- Well absorbed 95% protein bound may displace warfarin 60-90%
- excreted in urine
MOA
- Upregulated LPL to increase TG clearance and activate PPAR-alpha to induce HDL synthesis
- Uses - Reduce TG 20%-50% HDL 10-30% , LDL 5-20 %
- Most effective for high triglycerides
Adverse Effects
- Dyspepsia Gallstones Myopathy–When used in combination with HMG CoA reductase inhibitors it may increase severe side effects of these drugs- enhanced risk of rhabdomyolysis.
Method of excretion of each Lipid lowering drug?
Niacin- renal
Fibrates- renal/urine
Statins- liver
Bile resins- feces
Ezetimibe- liver and kidney
Most effective at decreasing TAGs?
Decreasing LDL?
INcreasing HDL?
Tags- Fibrates
LDL- statins
HDL- niacin
Statin with Bile
Benefits?
Downfall?
mevacor with cholestyramine.
Benefit-
- A good combination as both have different mechanisms of action with Statins targeting cholesterol synthesis and the bile acid resins targeting dietary cholesterol absorption.
- Likewise, there is little overlap in side effects.
Downfall-
- There are issues with timing. You must take the statin 1 to 2 hr before the cholestyramine or three hrs after to avoid problems with statin drug absorption caused by cholestyramine.
- As with cholestyramine alone there are compliance issues. (remember resins decrease absorption of fat soluble vitamins and some drugs and taste gross)
Statin with Eztimibe- trade name?
Benefits?
Downfall?
TradenameVytorin.
benefits
- Vytorin is available as single pill containing both drugs
- he effect of the two drugs is additive.
- There are minimal side effects with Zetia and there is little evidence that combining zetia with statins exacerbates the side effects of the statins. Rather, the combination may be used to reduce potential side effects of the statins by allowing for a lower dose of the statin drug to be used to obtain a specific reduction in cholesterol.
Downfall
- combination of simvastatin and ezetimibe (Vytorin) was no more effective than simvastatin alone. While the combination reduced cholesterol better than simvastatin alone, there was no significant improvement in intima media thickness (IMT) of carotid artery measured using ultra sound imaging patients heterozygous familial hypercholesterolemia;
- Other studies found postiive effects of Vytorin.
