Atherosclerosis

Question 1

Cholestyramine

Answer 1

bile acid sequestrants

Large polymeric cationic exchange resins-insoluble in water
2. Safe and effective, but not appetizing
(4-5 grams 3-4x/day)
a. Available as granular resins or tablets
b. Resins have to be taken with meals

1. Bind bile acids through ionic and hydrophobic interactions
   to prevent reabsorption
2. Increase uptake of LDL from upregulation of LDL receptors
3. Increase hepatic production of VLDL-increase triglycerides
   by 15-20%
4. Colesevelam also reduces hyperglycemia
5. Side effects:
   a. Dyspepsia, constipation, bloating, diarrhea (reduced for
   colesevelam)
   b. Malabsorption of vitamin K (reduced for colesevelam)
   c. Impaired absorption of other drugs: digoxin, thyroxine,
   Coumadin®, thiazides, iron salts, pravastatin, fluvastatin,
   ezetimide, folic acid, aspirin, ascorbic acid. Colesevelam does not
   bind digoxin, warfarin, or reductase inhibitors.

Question 2

colesevelam HCl

Answer 2

bile acid sequestrants

Large polymeric cationic exchange resins-insoluble in water
2. Safe and effective, but not appetizing
(4-5 grams 3-4x/day)
a. Available as granular resins or tablets
b. Resins have to be taken with meals

1. Bind bile acids through ionic and hydrophobic interactions
   to prevent reabsorption
2. Increase uptake of LDL from upregulation of LDL receptors
3. Increase hepatic production of VLDL-increase triglycerides
   by 15-20%
4. Colesevelam also reduces hyperglycemia
5. Side effects:
   a. Dyspepsia, constipation, bloating, diarrhea (reduced for
   colesevelam)
   b. Malabsorption of vitamin K (reduced for colesevelam)
   c. Impaired absorption of other drugs: digoxin, thyroxine,
   Coumadin®, thiazides, iron salts, pravastatin, fluvastatin,
   ezetimide, folic acid, aspirin, ascorbic acid. Colesevelam does not
   bind digoxin, warfarin, or reductase inhibitors.

Question 3

atorvastatin

Answer 3

HMG CoA reductase inhibitor

1. Competitively inhibit HMG CoA reductase
2. Some prodrugs-some active drugs
3. Decrease cholesterol synthesis and upregulate LDL
   receptors and decrease LDL
4. Marked first pass metabolism: because the liver is the
   target organ of statins, an efficient first-pass uptake
   may be more important than high bioavailability to
   achieve the statin effect.
5. Substrates of CYPs (metabolized by):
   a. Lovastatin/simvastatin/atorvastatin – CYP3A4
   b. Fluvastatin/rosuvastatin - CYP2C9
6. Generally recommended to be taken in the evening
7. Absorption enhanced by food
8. Toxicities:
   – Increases in liver function tests
   – Increases in creatine kinase (CK), myopathy, rarely
   rhabdomyolysis
   – Worse with concurrent cyclosporin, clofibrate, niacin,
   erythromycin

Drug-drug interactions:
– Statins which are CYP3A4 substrates have:
– increased drug levels in the presence of CYP3A4 inhibitors (e.g.,
macrolides, cyclosporine, ketoconazole, fibrates, tacrolimus,
paroxetine)
– decreased drug levels in the presence of CYP3A4 inducers (e.g.,
phenytoin, barbiturates, rifampin)
– Statins which are CYP2C9 substrates have:
– increased drug levels in the presence of CYP2C9 inhibitors (e.g.,
ketoconazole, metronidazole, amiodarone)
– all statins undergo glycosylation

Question 4

fluvastatin

Answer 4

HMG CoA reductase inhibitor

1. Competitively inhibit HMG CoA reductase
2. Some prodrugs-some active drugs
3. Decrease cholesterol synthesis and upregulate LDL
   receptors and decrease LDL
4. Marked first pass metabolism: because the liver is the
   target organ of statins, an efficient first-pass uptake
   may be more important than high bioavailability to
   achieve the statin effect.
5. Substrates of CYPs (metabolized by):
   a. Lovastatin/simvastatin/atorvastatin – CYP3A4
   b. Fluvastatin/rosuvastatin - CYP2C9
6. Generally recommended to be taken in the evening
7. Absorption enhanced by food
8. Toxicities:
   – Increases in liver function tests
   – Increases in creatine kinase (CK), myopathy, rarely
   rhabdomyolysis
   – Worse with concurrent cyclosporin, clofibrate, niacin,
   erythromycin

Drug-drug interactions:
– Statins which are CYP3A4 substrates have:
– increased drug levels in the presence of CYP3A4 inhibitors (e.g.,
macrolides, cyclosporine, ketoconazole, fibrates, tacrolimus,
paroxetine)
– decreased drug levels in the presence of CYP3A4 inducers (e.g.,
phenytoin, barbiturates, rifampin)
– Statins which are CYP2C9 substrates have:
– increased drug levels in the presence of CYP2C9 inhibitors (e.g.,
ketoconazole, metronidazole, amiodarone)
– all statins undergo glycosylation

Question 5

lovastatin

Answer 5

HMG CoA reductase inhibitor

1. Competitively inhibit HMG CoA reductase
2. Some prodrugs-some active drugs
3. Decrease cholesterol synthesis and upregulate LDL
   receptors and decrease LDL
4. Marked first pass metabolism: because the liver is the
   target organ of statins, an efficient first-pass uptake
   may be more important than high bioavailability to
   achieve the statin effect.
5. Substrates of CYPs (metabolized by):
   a. Lovastatin/simvastatin/atorvastatin – CYP3A4
   b. Fluvastatin/rosuvastatin - CYP2C9
6. Generally recommended to be taken in the evening
7. Absorption enhanced by food
8. Toxicities:
   – Increases in liver function tests
   – Increases in creatine kinase (CK), myopathy, rarely
   rhabdomyolysis
   – Worse with concurrent cyclosporin, clofibrate, niacin,
   erythromycin

Drug-drug interactions:
– Statins which are CYP3A4 substrates have:
– increased drug levels in the presence of CYP3A4 inhibitors (e.g.,
macrolides, cyclosporine, ketoconazole, fibrates, tacrolimus,
paroxetine)
– decreased drug levels in the presence of CYP3A4 inducers (e.g.,
phenytoin, barbiturates, rifampin)
– Statins which are CYP2C9 substrates have:
– increased drug levels in the presence of CYP2C9 inhibitors (e.g.,
ketoconazole, metronidazole, amiodarone)
– all statins undergo glycosylation

Question 6

simvastatin

Answer 6

HMG CoA reductase inhibitor

1. Competitively inhibit HMG CoA reductase
2. Some prodrugs-some active drugs
3. Decrease cholesterol synthesis and upregulate LDL
   receptors and decrease LDL
4. Marked first pass metabolism: because the liver is the
   target organ of statins, an efficient first-pass uptake
   may be more important than high bioavailability to
   achieve the statin effect.
5. Substrates of CYPs (metabolized by):
   a. Lovastatin/simvastatin/atorvastatin – CYP3A4
   b. Fluvastatin/rosuvastatin - CYP2C9
6. Generally recommended to be taken in the evening
7. Absorption enhanced by food
8. Toxicities:
   – Increases in liver function tests
   – Increases in creatine kinase (CK), myopathy, rarely
   rhabdomyolysis
   – Worse with concurrent cyclosporin, clofibrate, niacin,
   erythromycin

Drug-drug interactions:
– Statins which are CYP3A4 substrates have:
– increased drug levels in the presence of CYP3A4 inhibitors (e.g.,
macrolides, cyclosporine, ketoconazole, fibrates, tacrolimus,
paroxetine)
– decreased drug levels in the presence of CYP3A4 inducers (e.g.,
phenytoin, barbiturates, rifampin)
– Statins which are CYP2C9 substrates have:
– increased drug levels in the presence of CYP2C9 inhibitors (e.g.,
ketoconazole, metronidazole, amiodarone)
– all statins undergo glycosylation

Question 7

pravastatin

Answer 7

HMG CoA reductase inhibitor

1. Competitively inhibit HMG CoA reductase
2. Some prodrugs-some active drugs
3. Decrease cholesterol synthesis and upregulate LDL
   receptors and decrease LDL
4. Marked first pass metabolism: because the liver is the
   target organ of statins, an efficient first-pass uptake
   may be more important than high bioavailability to
   achieve the statin effect.
5. Substrates of CYPs (metabolized by):
   a. Lovastatin/simvastatin/atorvastatin – CYP3A4
   b. Fluvastatin/rosuvastatin - CYP2C9
6. Generally recommended to be taken in the evening
7. Absorption enhanced by food
8. Toxicities:
   – Increases in liver function tests
   – Increases in creatine kinase (CK), myopathy, rarely
   rhabdomyolysis
   – Worse with concurrent cyclosporin, clofibrate, niacin,
   erythromycin

Drug-drug interactions:
– Statins which are CYP3A4 substrates have:
– increased drug levels in the presence of CYP3A4 inhibitors (e.g.,
macrolides, cyclosporine, ketoconazole, fibrates, tacrolimus,
paroxetine)
– decreased drug levels in the presence of CYP3A4 inducers (e.g.,
phenytoin, barbiturates, rifampin)
– Statins which are CYP2C9 substrates have:
– increased drug levels in the presence of CYP2C9 inhibitors (e.g.,
ketoconazole, metronidazole, amiodarone)
– all statins undergo glycosylation

Question 8

clofibrate

Answer 8

fibric acids

1. Serve as ligands for PPAR

Question 9

fenofibrate

Answer 9

fibric acids

1. Serve as ligands for PPAR

Question 10

gemfibrozil

Answer 10

fibric acids

1. Serve as ligands for PPAR

Question 11

ezetimibe

Answer 11

misc. atherosclerotic treatment

inhibitor of intestinal sterol absorption
1. Impairs intestinal absorption of cholesterol
(inhibits NPC1L1)
2. Absorbed and glucuronidated
3. Excreted into bile and feces
4. Is not a CYP450 substrate

Question 12

nicotinic acid

Answer 12

misc. athersclerotic treatment

1. Water soluble vitamin-incorporated into nicotinamide
   adenine dinucleotide (NAD)
2. Inhibits VLDL secretion therefore ultimately decreases
   production of LDL
3. Decreases triglycerides > cholesterol
4. No effect on bile production

Toxicities:
1. Prostaglandin mediated cutaneous vasodilation: blunted
with aspirin/NSAID
2. Liver:
a. Reversible elevations in liver function tests
b. Severe dysfunction (acute hepatic necrosis) reported with the
use of OTC sustained-release preparations. This has not been
reported with the extended-release preparation Niaspan®
3. Long-term niacin treatment may increase insulin resistance
4. Hyperuricemia:
a. Nicotinic acid competes with uric acid for excretion by the
kidneys