Antihyperlipidemic Drugs Flashcards
What is Hyperlipidemia?
elevation of plasma cholesterol and/or TGs, or low HDL levels
** causes may be primary (genetic) or secondary
What is the link between plasma lipid concentrations and risk for CVD
as plasma cholesterol increases the risk for CVD increases as well.
Increased risk of cardiovascular mortality is most closely linked to elevated levels of LDL and decreased levels of HDL.
Log-Linear relationship between LDL levels and relative risk for CHD
For every 30-mg/dL reduction in LDL, the relative risk drops by 30%
Risk factors for CVD
Cigarette smoking
HTN
Obesity
Diabetes
Primary causes of hyperlipidemia include
Monogenic Diseases
Genetic Polymorphism
Gene-Environment interactions
Fredrickson class of Hyperlipidemias
- All five types
- Lipid profile
- Etiology
Type I (Hyperchylomicronemia)
- Lipid profile:
- increased chylomicrons
- Etiology:
- Deficiency in LPL or appCII
Type IIa (familial hypercholesterolemia)- (AD inheritance)
- Lipid profile:
- increased LDL
- Etiology:
- Decreased or no functional LDL receptor
Typer IIb (Familial combined hyperlipidemia) **
- Lipid profile:
- increased LDL and VLDL
- Etiology:
- Overproduction of VLDL by the liver
Type III (Dysbetalipoproteinemia)
- Lipid profile:
- increased IDL
- Etiology:
- abnormal apoE
Type IV (Hypertriglyceridemia)**
- Lipid profile:
- increased VLDL
- Etiology:
- Overproduction and/or impaired catabolism of VLDL
Type V (Familial mixed hypertriglyceridemia)
- Lipid profile:
- Increased in chylomicrons and VLDL
- Etiology:
- Increased production or decreased clearance of VLDL and chylomicrons
**most commonly found
Secondary Hyperlipidemia
Contribute to most cases of dyslipidemia in adults
Factors:
- sedentary lifestyle, excess dietary intake of saturated fats, cholesterol, and trans fatty acids
Hypertriglyceridemia vs Hypercholesterolemia Factors
Hypertriglyceridemia
- DM
- Chronic renal failure
- hypothyroidism
- Alcohol excess
- contraceptives
- beta blockers
- Glucocorticoids
Hypercholesterolemia
- hypothyroidism
- nephrotic syndrome
- Obstructive Liver disease
- glucocorticoids
Pharmacological management of hyperlipidemia
Statin are the lipid-lowering agent for first choice treatment for most patients with atherosclerotic CVD
In selected high-risk patients use of non-statins may be considered if statin therapy has not achieved >50% reduction in LDL.
Lipid-regulating drugs must be taken indefinitely.
When they are stopped, plasma lipoprotein levels return to pretreatment levels.
Antihyperlipidemic Drug (classes)
HMG-Coa Reductase inhibitors Niacin Bile acid binding resins Fibrates Cholesterol absorption inhibitors
HMG-Coa Reductase Inhibitors
- drugs
Atorvastatin Fluvastatin Lovastatin Pravastatin Rosuvastatin Simvastatin
** most effective drug in lowering LDL. Also decrease plasma TG and a small increase in HDL
Statins MOA
Analog of HMG (3-OH-3-methylglutarate)
Competitive inhibitors of HMG-Coa Reductase (inhibits the first committed step of cholesterol biosynthesis)
By inhibiting cholesterol biosynthesis the intracellular cholesterol levels are depleted which leads to an up regulation of LDL receptors and will subsequently decrease plasma LDL
Statins (potency levels for LDL and TG)
- they are the very similar
Rosuvastatin is the most potent Atorvastatin is the second most followed by simvastatin Lovastatin and pravastatin have similar potency Fluvastatin is the least potent
Statins Uses
DOC for LDL reduction
reduces Cardiovascular mortality
Lowers LDL in all types of hyperlipidemias
Hyperlipidemia Type IIa (homozygous) do not benefit much because of the lack functional LDL receptors
** contraindicated in pregnancy
Who should be treated with a statin? (4 groups)
- ASCVD
- LDL 190mg/dL or higher
- Patients age 40-75 with diabetes and LDL 70-189 mg/dL
- Patients w/o ASCVD or diabetes with LDL 70-189 mg/dL and an estimated 10 year risk of ASCVD of 7.5% or higher
Other effects of Statins
Improve endothelial function
decrease platelet aggregation
stabilizer atherosclerotic plaques
reduce inflammation
Statins AE and Monitoring
AE:
Elevation of aminotransferases
myopathy and rhabdomyolysis
Monitoring:
Aminotransferases should be measured at baseline and 1-2 months, and then every 6 months
CK should be measured at baseline and if pain or muscle weakness appears CK should be measured immediately and the drug should be D/C if activity is significantly elevated
Niacin (Nicotinic Acid)
- general
Favorably affects virtually all lipid parameters
Decreases VLDL, LDL, and Lp(a) (only drug to effect Lp(a))
increases HDL (most effective agent)
Many AE which limits its use
Niacin MOA
Inhibits Adenylyl cyclase in adipocytes. Leading to the inhibition of hormone sensitive lipase (prevents release of FFA)
Transport of FA to the liver is reduced and this reduces liver TG synthesis
In the liver niacin inhibits synthesis and esterification of FA. VLDL production is decreased
Increases LPL activity
the catabolism of HDL is decreased
Niacin Uses
Most efficacious drug to increase HDL
Particularly useful in patients with combined hyperlipidemia and low HDL levels
Effective combo with statins
Niacin AE
Intense cutaneous flushing (after each dose when drug is started or dose is increased)
- administration of aspirin prior to dose decreases flushing
Pruritus, rash, dry skin
Acanthosis nigricans
Nausea and abdominal discomfort
Hepatotoxicity and hyperglycemia
Niacin induced insulin resistance can cause severe hyperglycemia
Niacin elevates uric acid levels and precipitate as gout
Rare AE: Atrial arrhythmias, toxic amblyopia, toxic maculopathy
Fibrates
- drugs and General function
Gemfibrozil
Fenofibrate
- lower TAG and increase HDL
Fibrates MOA
Activate PRAR-alpha
PRAR-alpha are primarily expressed primarily in liver and brown adipose tissue
activation of PRAR-alpha leads to decrease in plasma TG levels (increase expression of LPL, decreased hepatic expression of apocalypse-III, and increased hepatic oxidation of FA) and increase in HDL levels
** Fibrates may increase LDL particularly if the TG level is greater than 400 mg/dL
Fibrates Uses
DOC in severe hypertriglyceridemia
As monotherapy, fibrates offer the highest TG reduction, followed by niacin, omega-3-fatty acids, statins, and ezetimibe.
Fibrates AE
Mild GI disturbances.
Myositis. Patients with renal insufficiency may be at risk. Rhabdomyolysis has occurred rarely.
Lithiasis. Fibrates increase biliary cholesterol excretion, therefore they may cause gallstones.
Fibrates Drug Interactions
Gemfibrozil inhibits hepatic uptake of statins, thus increasing plasma concentration of statins.
Gemfibrozil competes for the glucuronosyl transferases that metabolize most statins.
As a consequence, levels of both drugs may be increased when they are co-administered. This increases the risk of rhabdomyolysis.
Fenofibrate does not inhibit statin metabolism, and is much less likely to increase risk of rhabdomyolysis.
Bile Acid-Binding Resin drugs
- some PK
Cholestyramine
Colestipol
Colesevelam
Insoluble in water
Larger molecular weight (neither metabolized nor absorbed)
Totally excreted in the feces
Bile Acid-Binding Resin MOA
Bind to anionic bile acids in the intestinal lumen and prevent their reabsorption.
The resin-bile acid complex is excreted in the feces, thus preventing bile acids from returning to the liver by the enterohepatic circulation.
The reduction in bile acid concentration causes hepatocytes to increase conversion of cholesterol to bile acids
Consequently, intracellular cholesterol decreases
This leads to up-regulation of LDL receptors in the liver
Liver uptake of LDL increases, leading to a decrease in plasma LDL levels.
This effect is partially offset by increased cholesterol synthesis due to upregulationof HMG-CoA reductase.
HDL rises modestly.
Bile Acid-Binding Resin Uses
Useful in hyperlipidemia involving isolated increases in LDL
Used with statins or niacin to increase LDL reduction.
Drugs of choice for pregnant women and for children.
Little effect in individuals who completely lack functional LDL receptors.
Bile Acid-Binding Resin AE
GI adverse effects: bloating, nausea, cramping and constipation.
Colesevelam produces fewer GI adverse effects than cholestyramine or colestipol.
They may increase TG: contraindicated in hypertryglyceridemia.
Bile Acid-Binding Resin Drug interactions
Cholestyramine and colestipol reduce absorption of several drugs and liposoluble vitamins.
Cholesterol Absorption inhibitor
Drug and function
Ezetimibe
inhibits intestinal absorption of cholesterol and phytosterols
Primary clinical effect is to lower LDL
Ezetimibe MOA
Ezetimibe inhibits an intestinal transport protein (NPC1L1), which takes up cholesterol from the lumen
Cholesterol absorption is reduced by 54%.
This triggers a compensatory increase in cholesterol synthesis (which can be inhibited with a statin).
Reduced delivery of intestinal cholesterol to the liver leads to upregulation of LDL receptors, which enhances LDL clearance from plasma.
The maximal efficacy of ezetimibe for lowering LDL is about 15-20%.
Ezetimibe Uses
Useful in combination with a statin in patients unable to reach their LDL goal on statin monotherapy.
First non-statin drug that should be considered as an adjunct to a statin.
Ezetimibe is only used as monotherapy in patients who do not tolerate statins.
Ezetimibe AE
Low incidence of reversible impaired hepatic function.
Small increase in incidence when ezetimibe is given with a statin.
Myositis has been reported rarely.
Ezetimibe Drug Interactions
Bile-acid sequestrants inhibit absorption of ezetimibe.
The two agents should not be administered together.
Omega-3 FA
General function and drugs
EPA and DHA reduce TG synthesis and increase fatty acid oxidation in the liver
HDL levels may modestly increase
indicated as an adjunct to to diet to reduce TG
Suggested Drug Therapy for elevated LDL
Initial:
Statin
Additions:
Niacin, Resin, Ezetimibe
Suggested Drug Therapy for elevated LDL and TG
Initial:
statins
Additions:
Niacin, Fibrate, omega-3 FA
Suggested Drug Therapy isolated low HDL
Initial:
Statin
Addition:
Niacin
Suggested Drug Therapy isolated sever hypertriglyceridemia
Initial:
Fibrate (or Niacin or omega-3 FA)
Addition:
Statin
