Anti-lipids Flashcards

1
Q

hyperlipidemia

A

Plasma lipids are transported in complexes called Lipoproteins.
Metabolic disorders that involve elevations in any lipoprotein species are termed hyperlipoproteinemias or hyperlipidemias.
Hyperlipidemia denotes increased levels of triglycerides (TG).
The two major clinical sequelae of hyperlipemias are
(1) acute pancreatitis
(2) atherosclerosis- must control TG’s
Atherosclerosis is the leading cause of death in both genders in the USA and other western countries.
Atherosclerosis has been shown to be correlated with the levels of plasma cholesterol- and/or triacylglycerol-containing lipoprotein particles.

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2
Q

lipoproteins

A

Lipoproteins that contain apolipoprotein (apo) B-100 convey lipids into the artery wall. These are low-density (LDL), intermediate-density (IDL), very-low-density (VLDL), and lipoprotein (a) (Lp[a].
Cellular components in atherosclerotic plaques include foam cells, which are transformed macrophages, and smooth muscle cells filled with cholesteryl esters. These cellular alternations result from endocytosis of modified lipoproteins by at least four species of scavenger receptors. Chemical modification of lipoproteins by free radicals creates ligands for these receptors.
The atheroma grows with the accumulations of foam cells, collagen, fibrin, and frequently calcium. These lesions can slowly occlude coronary vessels, but frequently a rupture of unstable plaques producing occlusive thrombi.
Although treatment of hyperlipidemia can cause slow physical regression of plaques, the reduction in acute coronary events that follows vigorous lipid-lowering treatment is attributable to mitigation of the inflammatory activity of macrophages.

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3
Q

HDLs

A

High-Density lipoproteins (HDL) – exert several antiatherogenic effects
(1) They participate in retrieval of cholesterol from the artery wall
(2) Inhibit the oxidation of atherogenic lipoproteins.
Low levels of HDL are an independent risk factor for atherosclerotic diseases

. Their levels can be altered by
(a) diet and exercise (life-style changes), and
(b) inherited genetic defects in their synthesis or degradation.
(c) pharmacologic intervention.

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4
Q

Lipoprotein lipase

A

Enz. that catalyzes the hydrolysis of TG in chylomicrons/VLDL. Anchored on endothelial cells proximal to muscle and adipose tissues. It is important to note that LPLipase synthesis is controlled by insulin. Diabetics are prone to hypertriglyceridemia because of an insulin-dependent decreased in LPLipase levels

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5
Q

SOME RISK FACTORS FOR CORONARY HEART DISEASE(CHD)

A
Increasing age
Family history of premature CHD
Current cigarette smoking
Hypertension
Marked obesity
Sedentary lifestyle
Diabetes mellitus
High serum LDL level
Low serum HDL level
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6
Q

Niacin Moa

A

At gram doses, niacin, a water soluble vitamin, strongly inhibits lipolysis in adipose tissue – the primary producer of circulating free fatty acids. The liver utilizes circulating free fatty acids as a major precursor for the synthesis of triacylglycerol (TG) and their subsequent packaging into newly synthesized VLDL particles. The net effect of niacin is therefore the reduction of TG synthesis and VLDL synthesis which translates into lower levels of VLDL, LDL and Cholesterol.
Niacin is effective in raising HDL’s (to a greater extent than the fibrates)

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7
Q

Niacin uses

A

Niacin lowers plasma levels of both cholesterol and triacylglycerol. Therefore, it is particularly useful in the treatment of Type IIb, III and IV hyperlipoproteinemia, in which both VLDL and LDL are elevated.

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8
Q

Niacin pharmokinetics

A

Niacin is administered orally. Niacin, its nicotinamide derivative and other metabolites are excreted in the urine.
4. Adverse effects: The most common side effects of niacin therapy are an intense cutaneous flush (accompanied by an uncomfortable feeling of warmth) and pruritus (itching), which limits its use. Administration of aspirin prior to taking niacin decreases the flush, which is prostaglandin-mediated. Nicotinic acid inhibits tubular secretion of uric acid and thus predisposes to hyperuricemia and gout.

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9
Q

the fibrates

A

gemfibrozil, fenofibrate, Fenofibric
These agents are derivatives of fibric acid and
have the same mechanism of action.

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10
Q

fibrates MOA

A

The fibrates function primarily as ligands for the nuclear transcription receptor peroxisome proliferator activated receptor –alpha (PPAR-alpha). They transcriptionally up-regulate lipoprotein lipase (LPL) and down regulate apoCIII, an inhibitor of lipolysis. The net effect is decreased levels of VLDL

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11
Q

fibrates uses & kinetics

A

The fibrates are used in the treatment of hypertriglyceridemias, causing a significant decrease in plasma triacylglycerol levels about 25-50%
The fibrates are completely absorbed after an oral dose

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12
Q

fibrates adverse

A

a. GI effects: Nausea (vomiting) which lessen as the therapy progresses.

b. Lithiasis/Malignancy: Gemfibrozil has the greatest incidence of gallstones and hepatobiliary neoplasms.

c. Muscle: Myositis (inflammation of a voluntary muscle) can occur with both drugs, thus muscle weakness or tenderness should be evaluated.
d. Drug interactions: fibrates compete with warfarin for binding sites on plasma protein which may potentiate the effects of warfarin (this should be evaluated by prothrombin times (PT).

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13
Q

Bile acid binding resins

A

Cholestryramine, Colestipol and Colesevelam

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14
Q

Bile acid binding resins MOA

A

Each drug is a cationic resin that bind negatively charged bile salts (bile salts are derived from cholesterol). Thus, these drugs interrupt the entero-hepatic cycle and allow more bile salts to be excreted in the feces. Lowering bile salt concentration results in diverting more liver cholesterol to the synthesis of bile salts. This lowers hepatocyte cholesterol concentration which upregulates (increases the synthesis of) the LDL receptor. Increasing hepatic LDL receptors effectively decrease plasma levels of LDL.

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15
Q

Bile acid binding resins uses & kinetics

A

These resins are the drugs of choice (often in combination with diet and statins) in treating Type IIa and IIb hyperlipidemias.
Bile acid resins are taken orally. They are non-digestable and are excreted in the feces together with bile salts.

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16
Q

Bile acid binding resins adverse

A

a. GI effects: Some constipation, nausea and flatulence, diminishing with time.
b. Impaired absorption: Possible impairment of fat soluble vitamins and ascorbate and folate,
c. Drug interactions: All these bile acid sequestrants interfere with the intestinal absorption of many drugs, for example, tetracycline, phenobarbital, digoxin, warfarin, statins, aspirin, and thiazide diuretics. Therefore, drugs should be taken either before (1-2 hr) or after (~4 hr) other oral drugs.
d. Hyperchloremic metabolic acidosis- chloride salts

17
Q

HMG-CoA reductase inhibitors

A

statins

18
Q

HMG-CoA reductase inhibitors MOA

A

This group of antihyperlipidemic agents inhibits the first committed enzymatic step of sterol synthesis. As structural analogs of the natural substrate, 3-hydroxy-3-methylglutaric acid (HMG), all members of this group. compete to block hydroxymethylglutaryl-Coenzyme A reductase (HMG-CoA reductase).
Inhibition of HMG-CoA reductase
Decrease in LDL via increase of LDL receptors
Statins undergo a marked first-pass extraction by the liver

19
Q

Inhibition of HMG-CoA reductase

A

All statins are analogs of 3-hydroxy-3-methylglutarate, the precursor of cholesterol. Because of their strong affinity for the enzyme, all compete effectively to inhibit HMG-CoA reductase, the rate-limiting step in cholesterol synthesis and therefore deplete the intracellular supply of cholesterol.

20
Q

Decrease in LDL via increase of LDL receptors

A

Depletion of intracellular cholesterol causes the hepatocyte to increase the number of specific cell-surface LDL receptors that can bind and internalize circulating LDLs i.e., upregulation of LDL.. Thus the end result is a reduction in plasma cholesterol both by lowered cholesterol synthesis and by increased catabolism of LDL.

21
Q

Statins undergo a marked first-pass extraction by the liver

A

their dominant effect is on that organ. The HMG-CoA reductase inhibitors can also increase plasma HDL levels in some patients, resulting in an additional lowering of risk for coronary artery disease. This is especially true for atorvastatin.

22
Q

HMG-CoA reductase inhibitors kinetics

A

Atorvastatin and simvastatin are absorbed by about 50%. Due to first-pass extraction, the primary action of these drugs is on the liver. All are biotransformed, with some of the products retaining activity. Excretion takes place principally through the bile and feces.

23
Q

HMG-CoA reductase inhibitors kinetics adverse

A

It is noteworthy that during the 5-year trials of simvastatin, atorvastatin and lovastatin, only a few adverse effects, related to liver and muscle function, were reported.

a. Liver: Biochemical abnormalities in liver function have occurred with the HMG-CoA reductase inhibitors. Therefore it is prudent to evaluate liver function and measure serum transaminase levels periodically (ALT and/or AST every 6 mo). These return to normal on suspension of the drug.

24
Q

HMG-CoA reductase inhibitors drug effects

A

The HMG-CoA reductase inhibitors also increase warfarin levels. Thus, it is important to evaluate prothrombin times frequently.

25
Q

HMG-CoA reductase inhibitors contraindications

A

These drugs are contraindicated in pregnancy and nursing mothers. They should not be used in children or teen-agers.

26
Q

HMG-CoA reductase inhibitors other affects

A

As more information becomes available on long-term side effects of the statins, it appears that they diminish visual acuity (lens of eye is 50% cholesterol) and for some unknown reason, patients taking statins appear to be less inclined toward osteoporosis?
“super statin”—rosuvastatin (Crestor). Rosuvastatin lowers LDL about 50%, (more potent than atorvastatin), raises HDL 10-14% when compared to 3 to10% for the other statins
High intensity statins-Atorvastatin & Rosuvastatin

27
Q

EZETIMIBE MOA

A

blocks the absorption of cholesterol from the small intestine
Most patients decrease total cholesterol by 15% in combination with statins, total cholesterol decreases by about 50%
Low side-effect profile