Lipid-lowering drugs

Question 1

_____ are the mainstay of treatment of hyperlipidemia

Answer 1

Statin

Question 2

_____ and to a lesser extent Lovastatin and Simvastatin may need adjustments in renal pts.

Answer 2

Pravastatin

Question 3

Side effects of Niacin

Answer 3

Most common: intense prostaglandin-induced cutaneous flushing in ~ 10% of pts ASA 30 min before ingestion of niacin decreases flushing Abd pain, N/V/D Malaise Large doses: Hepatic dysfunction; jaundice Do not give to pts with hx of liver disease Hyperglycemia and abnormal glucose tolerance may occur in non diabetic pts on niacin Increased uric acid concentrations in plasma Increase in incidence of gouty arthritis May exaggerate orthostatic hypotension associated with antihypertensive drugs and myopathy associated statins PUD can be reactivated by niacin

Question 4

Metabolized by CYP2C9 and have lowest rate of events.

Answer 4

Fluvastatin and rosuvastatin

Question 5

Statin side effect

Answer 5

Most Common Complaints: GI, Fatigue, Headache. Clinical trial = < 5% experience adverse side effects (vs. placebo). Incidence in general population is thought to be higher. Most Common Adverse Side Effects: Range from simple myalgias to myositis with mild creatine kinase (CK) elevation to life-threatening rhabdomyolysis (>10-fold elevation of CK) Myositis and rhabdomyolysis are rare. Myalgias are reported in as many as 1/3 of statin users: See table 23-4 p545 Risk factors Myotoxicity Possibly caused by inhibiting HMG-CoA reductase. Statins decrease cholesterol synthesis and the formation of ubiquinone (coenzyme Q10) which is important for mitochondrial function and cell membrane integrity

Question 6

Hepatic cholesterol synthesis and its distribution to the peripheral tissues

Answer 6

Endogenous

Question 7

_________ can decrease absorption of statins

Answer 7

Bile acid-binding resins

Question 8

Statin drugs

Answer 8

Atorvastatin Fluvastatin Lovastatin Pravastatin Simvastatin Rosuvastatin

Question 9

Bile and Resin drugs

Answer 9

Colesevelam Cholestyramine Colestipol

Question 10

Statin moa Inhibits __________(the enzyme that catalyzes the rate-limiting step of cholesterol biosynthesis) Structurally related to HMG-CoA and competitive inhibition of the enzyme causes increase in hepatic LDL-R.

Answer 10

HMG-CoA reductase

Question 11

EXOGENOUS PATHWAY

Answer 11

Small Intestines: Bile emulsifies dietary fat and cholesterol Pancreas: Hydrolyzes triglycerides Intestinal endothelium takes up these products by endocytosis and packages lipids into large chylomicrons, which then enter the lymphatic system Chylomicrons → travel through thoracic duct enter blood stream interaction with lipoprotein lipase (LPL) in vascular endothelial cells yields glycerol and free fatty acids these can be utilized by peripheral tissues for fuel or storage. During this process chylomicrons shrink and become chylomicron remnants. Remnants transport to liver taken up by hepatocytes via endocytosis then hydrolyzed

Question 12

Prodrugs. Require metabolism to the open β-hydroxyl acid form to be pharmacologically active

Answer 12

Lovastatin, Simvastatin

Question 13

↑ LDL associated with ↑ risk of _____

Answer 13

CV disease

Question 14

naturally occurring. Isolated from a strain of Aspergillus terreus.

Answer 14

Lovastatin

Question 15

Niacin Primary Route of Metabolism is __________

Answer 15

Methylation to N-methyl-nicotinamide

Question 16

Hyperlipidemia may also arise from secondary causes:

Answer 16

Obesity Diabetes Alcohol abuse Hypothyroidism Glucocorticoid excess Hepatic or renal dysfunction

Question 17

Homozygotes more rare: total LDL cholesterol levels 4 x normal and have extreme propensity for ________

Answer 17

atherosclerosis

Question 18

Relatively new. Selective inhibitor of cholesterol absorption leading to a secondary upregulation of LDL-R Cholesterol absorption is inhibited due to the disruption of a complex between annexin-2 and cavolin-1 proteins in the small intestines Monotherapy

Answer 18

Ezetimibe

Question 19

↓ plasma concentrations of TOTAL and LDL with medications ↓ risk of CV events in pts with and without ______

Answer 19

CAD

Question 20

Synthetically derived from a fermentation of the same fungus (Aspergillus terreus)

Answer 20

Simvastatin and Pravastatin

Question 21

Hypertriglyceridemia causes ______: less of causal relationship with atherosclerosis

Answer 21

pancreatitis

Question 22

increase in noncardiovascular mortality: due to low plasma cholesterol concentrations, which predispose pts to hemorrhagic stroke, particularly when system hypertension is present.

Answer 22

Clofibrate

Question 23

Statins have been shown to have benefit on ______ ______ in native vessels or grafts in pts treated with statins as well as in pts experiencing acute coronary syndromes.

Answer 23

coronary stenosis

Question 24

Fenofibrate is a ___drug

Answer 24

Prodrug

Question 25

Food intake increases plasma concentrations. Has minimal effects on other statins.

Answer 25

Lovastatin

Question 26

Water soluble B complex vitamin inhibits synthesis of VLDLs in liver by unknown MOA

Answer 26

Niacin

Question 27

increases cholesterol content of bile (lithogenicity) and may increase formation of gallstones; Increase risk of myopathy and rhabdomyolysis when given with statins especially lovastatin. Anticoagulant effect of warfarin is potentiated. Prudent to avoid in renal and hepatic disease.

Answer 27

Gemfibrozil

Question 28

Processing of dietary fats, cholesterol, and lipid-soluble vitamins

Answer 28

Exogenous

Question 29

myopathy is frequent. Metabolized by CYP3A4 thus their concentrations are increased by CYP3A4 inhibitors: Coumadin, Protease Inhibitors (HIV), Macrolide Abx, and Azole Antifungals.

Answer 29

Simvastatin and Lovastatin

Question 30

Elimination of statins is ____ hours except ________(Elimination half times = 14 hours)

Answer 30

1-4, Atorvastatin

Question 31

minimal renal excretion and may not require renal dose adjustments

Answer 31

Atorvastatin and Fluvastatin

Question 32

Gemfibrozil protein binding

Answer 32

99%

Question 33

ENDOGENOUS PATHWAY

Answer 33

In liver: hepatocytes synthesize cholesterol, lipids, and proteins, which are assembled into VLDL and excreted into the blood stream. Endothelial cell LPL hydrolyzes the fats in VLDL particles, which then shrink from IDL and LDL. LDL particles contain most of the cholesterol in the plasma and are cleared from the blood by binding to LDL receptors (LDL-R) on hepatocytes. Apoproteins C and E are essential cofactors of the hydrolysis of VLDL. These apoproteins are contributed by HDL particles HDL also transfers ApoC-II to chylomicrons in the exogenous pathway and is responsible for reverse cholesterol transport, in which excess cholesterol is delivered from the peripheral tissues to the liver for excretion in the bile.

Question 34

Clofibrate: original fibric acid drug. No longer drug of choice d/t concerns of___________

Answer 34

increased noncardiovascular adverse events

Question 35

the most effective drugs for decreasing plasma concentrations of triglycerides

Answer 35

Fibrates: -Gemfibrozil -Fenofibrate -Bezafibrate: In -addition thought to improve insulin sensitivity

Question 36

Statins are teratogenic in animals: What pts would you not expect to be on statins??

Answer 36

Pregnant pts

Question 37

Bile and Resin drugs side _

Answer 37

Palatability and Constipation are common complaints Need high fluid intake Colesevelam: fewer gastric side effects; approved for adolescents with familial hypercholesterolemia. Cholestyramine: a chloride form of an ion exchange resin thus hyperchloremic acidosis can occur especially in younger and smaller pts (where relative doses are larger); Impairs absorption of fat-soluble vitamins and other meds may be impaired; Cholestyramine: Drugs should be given at least 1 hours before or 4 hours after administration of cholestyramine

Question 38

only statin not highly protein bound and is only statin that does not undergo extensive metabolism by Hepatic P450 enzymes

Answer 38

Pravastatin

Question 39

Administered as active β-hydroxyl acid form

Answer 39

Atorvastatin, Fluvastatin, Pravastatin

Question 40

Randomized Clinical Trials (RCTs): show statins lower cardiac events (total mortality, death from MI, revascularization procedures, stroke, PVD) in pts with or without ___________

Answer 40

atherosclerosis

Question 41

Effective for tx of lipid disorders that have a primarily abnormal increase in plasma LDL cholesterol concentration with a normal or near normal triglyceride level.

Answer 41

BILE ACID RESINS

Question 42

↑ HDL ↓risk of _____________and ___ events due to critical role of HDL in reverse cholesterol transport

Answer 42

atherosclerosis and CV

Question 43

Completely synthetic compounds

Answer 43

Atorvastatin, Fluvastatin, Rosuvastatin