Atherosclerosis Flashcards
Cholestyramine
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
- Bind bile acids through ionic and hydrophobic interactions
to prevent reabsorption - Increase uptake of LDL from upregulation of LDL receptors
- Increase hepatic production of VLDL-increase triglycerides
by 15-20% - Colesevelam also reduces hyperglycemia
- 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.
colesevelam HCl
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
- Bind bile acids through ionic and hydrophobic interactions
to prevent reabsorption - Increase uptake of LDL from upregulation of LDL receptors
- Increase hepatic production of VLDL-increase triglycerides
by 15-20% - Colesevelam also reduces hyperglycemia
- 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.
atorvastatin
HMG CoA reductase inhibitor
- Competitively inhibit HMG CoA reductase
- Some prodrugs-some active drugs
- Decrease cholesterol synthesis and upregulate LDL
receptors and decrease LDL - 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. - Substrates of CYPs (metabolized by):
a. Lovastatin/simvastatin/atorvastatin – CYP3A4
b. Fluvastatin/rosuvastatin - CYP2C9 - Generally recommended to be taken in the evening
- Absorption enhanced by food
- 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
fluvastatin
HMG CoA reductase inhibitor
- Competitively inhibit HMG CoA reductase
- Some prodrugs-some active drugs
- Decrease cholesterol synthesis and upregulate LDL
receptors and decrease LDL - 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. - Substrates of CYPs (metabolized by):
a. Lovastatin/simvastatin/atorvastatin – CYP3A4
b. Fluvastatin/rosuvastatin - CYP2C9 - Generally recommended to be taken in the evening
- Absorption enhanced by food
- 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
lovastatin
HMG CoA reductase inhibitor
- Competitively inhibit HMG CoA reductase
- Some prodrugs-some active drugs
- Decrease cholesterol synthesis and upregulate LDL
receptors and decrease LDL - 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. - Substrates of CYPs (metabolized by):
a. Lovastatin/simvastatin/atorvastatin – CYP3A4
b. Fluvastatin/rosuvastatin - CYP2C9 - Generally recommended to be taken in the evening
- Absorption enhanced by food
- 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
simvastatin
HMG CoA reductase inhibitor
- Competitively inhibit HMG CoA reductase
- Some prodrugs-some active drugs
- Decrease cholesterol synthesis and upregulate LDL
receptors and decrease LDL - 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. - Substrates of CYPs (metabolized by):
a. Lovastatin/simvastatin/atorvastatin – CYP3A4
b. Fluvastatin/rosuvastatin - CYP2C9 - Generally recommended to be taken in the evening
- Absorption enhanced by food
- 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
pravastatin
HMG CoA reductase inhibitor
- Competitively inhibit HMG CoA reductase
- Some prodrugs-some active drugs
- Decrease cholesterol synthesis and upregulate LDL
receptors and decrease LDL - 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. - Substrates of CYPs (metabolized by):
a. Lovastatin/simvastatin/atorvastatin – CYP3A4
b. Fluvastatin/rosuvastatin - CYP2C9 - Generally recommended to be taken in the evening
- Absorption enhanced by food
- 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
clofibrate
fibric acids
- Serve as ligands for PPAR
fenofibrate
fibric acids
- Serve as ligands for PPAR
gemfibrozil
fibric acids
- Serve as ligands for PPAR
ezetimibe
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
nicotinic acid
misc. athersclerotic treatment
- Water soluble vitamin-incorporated into nicotinamide
adenine dinucleotide (NAD) - Inhibits VLDL secretion therefore ultimately decreases
production of LDL - Decreases triglycerides > cholesterol
- 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
