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MOHDIII - Unit 2 > Lipid Lowering Drugs > Flashcards

Lipid Lowering Drugs Flashcards

1
Q

Exogenous pathway

A
  • intestinal absorption of cholesterol & fatty acids
  • in intestinal cell: free FAs combine w/ glycerol=TGs, cholesterol esterified to form cholesterol esters (acyl coenzyme A:cholesterol acyltransferase [ACAT])
  • chylomicrons enter circulation, lipoprotein lipase removes TGs in extrahepatic tissues, & chylomicron remnants taken up by hepatocytes
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2
Q

LOOK AT ENDOGENOUS & EXOGENOUS PATHWAY DIAGRAM IN NOTES

A

LOOK AT IT RIGHT NOW

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3
Q

Endogenous pathway: VLDL

A
  • synthesized & secreted by liver
  • lipoprotein lipase hydrolyzes the TG core
  • converted to LDL by further removal of TG by hepatic lipase
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4
Q

Endogenous pathway: LDL

A
  • can be internalized by hepatic & non hepatic tissues
  • hepatic LDL: converted to bile acids & secreted into intestinal lumen
  • nonhepatic LDL: used for hormone production, cell membranes, or stored in esterified form
  • circulating LDL can enter macrophages & other tissues leading to foam cells contributing to atheromatous plaques
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5
Q

Endogenous pathway: HDL

A
  • hepatic & intestinal synthesis of particles containing phospholipids and apolipoproteins
  • procurement of surface components from TG depleted chylomicron and VLDL remnants
  • acquisition of free cholesterol from tissue sites and other lipoproteins
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6
Q

Total cholesterol levels

A

240 - high

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7
Q

LDL cholesterol levels

A

160 - high

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8
Q

HDL cholesterol levels

A

> 60 high

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9
Q

Triglyceride levels

A

desirable: 200

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10
Q

Treatment of hypercholesterolemia: borderline high

A
  • dietary lipoprotein analysis

- drug therapy if coronary heart disease (CHD) or 2 other risk factors

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11
Q

Risk factors of hypercholsterolemia

A

male, family history of premature CHD, smoke cigs, HTN, low HDL (

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12
Q

Treatment of hypercholesterolemia: high

A
  1. dietary if no CHD or less than 2 risk factors

2. dietary + drug if CHD or 2 or more risk factors

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13
Q

Treatment of hypercholesterolemia: very high

A

dietary + drug even if no CHD or other risk factors

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14
Q

Dietary changes

A
  • major change should come from carbohydrates

- should be derived from foods rich in complex carbs including whole grains, fruits, & veggies

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15
Q

Omega 3 fatty acids

A
  • activate PPARalpha leading to decreased triglycerides (may increase LDL)
  • only those in fish oils are active due to double bond organization
  • over the counter: lovaza, mixed omega 3 acid ethyl ester, avoid in patients with fish/shellfish allergies
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16
Q

Approaches to lowering lipids

A
  • prevent intestinal absorption of cholesterol or of bile acids
  • decrease cholesterol synthesis, increase LDL receptors, increase LDL uptake
  • inhibit VLDL secretion, decrease LDL production
  • upregulate lipoprotein lipase, decreasing TGs
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17
Q

Classes of lipid lowering drugs

A

bile acid sequestrants, nicotinic acid, HMG-CoA reductase inhibitors (statins), fibric acids, ezetimibe

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18
Q

Bile acid reabsorption

A
  • very efficient
  • amount excreted correlates to amount of cholesterol used to make them
  • therefore if you inhibit their reabsorption then you will increase excretion of cholesterol
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19
Q

Bile acid sequestrants

A
  • cholestyramine, colestipol, colesevelam
  • large polymeric cationic exchange resins insoluble in water
  • safe and effective but not appetizing (4-5 grams, 3-4x/day)
  • available in granular resins or tablets, resins must be taken w/ meals
  • SECOND GENERATION SEQUESTRANTS BETTER DUE TO LESS SIDE EFFECT (COLESEVELAM)
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20
Q

Cholestyramine & Colesevelam mechanism

A
  • bind bile acids through ionic & hydrophobic interactions to prevent reabsorption
  • increase uptake of LDL from upregulation of LDL receptors
  • increase hepatic production of VLDL, increase TGs by 15-20%
  • colesevelam also reduces hyperglycemia
21
Q

Side effects of cholestyramine & colesevelam

A
  1. dyspepsia, constipation, bloating, diarrhea
  2. malabsorption of vitamin K
  3. impaired absorption of other drugs
    * *SIDE EFFECTS ARE REDUCED FOR COLESEVELAM
22
Q

Nicotinic acid (Niacin)

A
  • water soluble vitamin incorporated into NAD
  • inhibits VLDL secretion therefore decreases LDL (can increase HDL)
  • decreases TG>cholesterol
  • no effect on bile production
23
Q

Nicotinic acid (Niacin) toxicities

A
  1. prostaglandin mediated cutaneous vasodilation: BLUNTED WITH ASPIRIN/NSAID
  2. Liver: elevation of liver function tests, dysfunction with use of OTC sustained release, not reported w/ extended release Niaspan
  3. long term niacin treatment may cause insulin resistance
  4. hyperuricemia: niacin competes w/ uric acid excretion by kidneys
24
Q

HMG CoA reductase inhibitors

A
  • lovastatin, simvastatin, pravastatin, fluvastatin

- COMPETITIVELY inhibit HMG CoA reductase

25
Q

Prodrug HMG Co A reductase inhibitors

A
  • mevastatin, lovastatin, simvastatin

- closed ring

26
Q

Active HMG CoA reductase inhibitor drugs

A
  • pravastatin, fluvastatin

- opened ring

27
Q

HMG CoA reductase inhibitors process

A
  • decrease cholesterol synthesis & upregulate LDL receptors, decreasing LDL
  • marked first pass metabolism: b/c liver is target organ of statins, an efficient first pass uptake may be more important than high bioavailability to achieve statin effect
28
Q

HMG CoA reductase inhibitor metabolism

A
  • substrates of CYPs (metabolized by)
  • LOVASTATIN/SIMVASTATIN/ATORVASTATIN – CYP3A4
  • FLUVASTATIN/ROSUVASTATIN – CYP2C9
  • **ON TEST***
29
Q

HMG CoA reductase recommendations

A
  • recommended to be taken in evening due to half life of drugs
  • absorption enhance by food
30
Q

HMG CoA reductase inhibitors toxicities

A
  • increases liver function tests
  • increases creatine kinase(CK), myopathy, rarely rhabdomyolysis
  • worse w/ concurrent cyclosporin, clofibrate, niacin, erythromycin
31
Q

HMG CoA reductase inhibitors drug-drug interactions

A
  • Statins that are CYP3A4 substrates have: increased drug levels in presence of CYP3A4 inhibitors, decreased drug levels in presence of CYP3A4 inducers (BARBITURATES***ON TEST)
  • Statins that are CYP2C9 substates have: increased drug levels in presence of CYP2C9 inhibitors (ketoconazole, metronidazole, amiodarone) **all statins under glycosylation–interaction w/ gemfibrozil
32
Q

Grapefruit juice consumption effects

A
  • lovastatin, simvastatin, atorvastatin can be elevated in patients drinking more than 1L/day (inhibits CYP3A4)
33
Q

Fibric acids

A
  • gemfibrozil, clofibrate, fenofibrate
  • serve as ligands for PPARalpha (transcription factor)
  • upregulate lipoprotein lipase, apo A-I, apo A-II
  • apo A-I/II are major components of HDL promoting cholesterol efflux
34
Q

Fibric acids: gemfibrozil, clofibrate, fenofibrate

A
  • clears chylomicrons & VLDL quickly
  • lowers TGs (VLDLs) &a raises HDL cholesterol
  • generally modest decrease in LDL
  • PRIMARILY USEFUL FOR TEATING HYPERTRGLYCERIDEMIAS (VLDL)*
35
Q

Fibric acid toxicities

A
  1. rashes, GI symptoms, arrhythmias, low potassium, elevated LFTs
  2. risk of myopathy increased when used w/ statins – gemfibrozil increases concentration by inhibiting metabolism of statin byproduct, fenofibrate does not do this
  3. increased risk of cholesterol gallstones
36
Q

Ezetimibe

A
  • inhibitor of intestinal sterol absorption (inhibits NPC1L1-transport protein)
  • absorbed & glucuronidated
  • excreted into bile & feces
  • NOT A CYP450 substrate
37
Q

Bile acid sequestrants LDL,HDL,TG effects

A
  • decrease LDL
38
Q

Nicotinic acid LDL, HDL, TG effects

A
  • decrease LDL, TGs

- increase HDL

39
Q

HMG CoA reductase LDL, HDL, TG effects

A
  • decrease LDL, TG

- small increase in HDL

40
Q

Fibrate LDL, HDL, TG effects

A
  • decrease TGs – largest out of all lipid lowering drugs
41
Q

Ezetimibe HDL, LDL, TG effects

A
  • decreased TGs largest effect
42
Q

Therapy for high cholesterol and TGs

A

always with dietary therapy

43
Q

Drug therapy: high LDL

A
  1. bile acid sequestrants
  2. nicotinic acid or HMG CoA reductase inhibitor
  3. combination of 1 & 2
44
Q

Drug therapy: high HDL & TGs

A
  1. weight loss, alcohol restriction
  2. nicotinic acid or gemfibrozil
  3. bile acid sequestrants or HMG CoA reductase inhibitors in combination with 2 above
45
Q

Drug therapy: high TGs (>500mg/dL), normal LDL

A
  1. weight loss, alcohol restriction

2. gemfibrozil or nicotinic acid

46
Q

Drug therapy: low HDL (

A
  1. diet, exercise, stop smoking

2. nicotinic acid or gemfibrozil

47
Q

Effect of combining statin and bile acid sequestrant

A

combination is more effective than either alone

ON TEST

48
Q

Cholesterol facts

A
  • essential component of animal cell membranes
  • sources: animal fats (cheese, eggs, meat, poultry, fish)
  • cholesterol biosynthetic pathway: 25% of total cholesterol production occurs in the LIVER

MOHDIII - Unit 2 (23 decks)

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