A. Q.

Sangalang, MD, FPOGS, RMT

FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS
DRUGS USED IN THE TREATMENT OF
HYPERLIPIDEMIAS
METABOLISM
OF PLASMA
LIPOPROTEINS Loading...
 DRUGS USED IN THE TREATMENT OF
HYPERLIPIDEMIAS

METABOLISM
OF PLASMA
LIPOPROTEINS
 DRUGS USED IN THE TREATMENT OF
HYPERLIPIDEMIAS

HYPERLIPOPROTEINEMIA
PATHOGENESIS
Premature or accelerated development of atherosclerosis
Elevated levels of certain plasma lipoproteins

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Low-density lipoproteins (LDLs)
Participate in cholesterol transport
Depressed level of high-density lipoproteins
(HDLs)
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HYPERLIPIDEMIAS

Chylomicronemia
Occurrence of chylomicrons in the serum while fasting
Recessive trait that is correlated with a high incidence of acute
pancreatitis
Restriction of total fat intake
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HYPERLIPIDEMIAS

Regulation of plasma lipoprotein levels involves a balance

Dietary fat intake
Hepatic processing
Utilization in peripheral tissues
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HYPERLIPIDEMIAS

Diet
Alcohol raises levels of
Tricglycerides
Very-low-density liporoteins (VLDL)
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HYPERLIPIDEMIAS

Primary disturbances in regulation

Occur in various familial diseases
Secondary disturbances
Associated with
Western diet
Endocrine conditions
Diseases of the liver or kidneys
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TREATMENT STRATEGIES
Diet
First method of management
May be sufficient to reduce lipoprotein levels to a safe range
Cholesterol and saturated fats
Primary factors that contribute to elevated levels of plasma lipoproteins
Triglyceride and VLDL
Elevated by alcohol intake
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HYPERLIPIDEMIAS

TREATMENT STRATEGIES
Drugs
Drug therapy
All drugs given oral
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Can modify hepatic cholesterol synthesis
Hepatic hydroxymethylglutaryl coenzyme A
(HMG-CoA) reductase inhibitors
Reduce cholesterol
Ezetimibe
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HYPERLIPIDEMIAS

TREATMENT STRATEGIES
Drugs
Drug therapy
Reduce bile acid
Resins
Reduce absorption from the intestines and decrease secretion of
lipoproteins
Niacin
Increase peripheral clearance of lipoproteins
Fibrates
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HYPERLIPIDEMIAS

HMG-CoA REDUCTASE INHIBITORS

MECHANISM AND EFFECTS
Lovastatin and Simvastatin
Inactive lactone prodrugs
Pravastatin
Open active lactone ring
Atorvastatin, Fluvastatin, Rosuvastatin
Active fluorine-containing congeners
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HYPERLIPIDEMIAS

HMG-CoA REDUCTASE INHIBITORS

MECHANISM AND EFFECTS
Structural analogs that competitively inhibit
mevalonate synthesis by HMG-CoA reductase
First committed step in cholesterol biosynthesis in the liver
Most effective in reducing LDL
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HYPERLIPIDEMIAS

HMG-CoA REDUCTASE INHIBITORS

MECHANISM AND EFFECTS
Minimal total serum cholesterol-lowering effect
Greater effect in the reduction of the tightly
regulated hepatic pool of cholesterol
Liver compensates by increasing high affinity
LDL receptors that clear LDL from the blood
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HMG-CoA REDUCTASE INHIBITORS

MECHANISM AND EFFECTS
Have direct anti-atherosclerotic effects
It prevents bone loss
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DRUGS USED IN THE TREATMENT OF

HYPERLIPIDEMIAS
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HYPERLIPIDEMIAS

HMG-CoA REDUCTASE INHIBITORS

CLINICAL USE
Statins
Reduce LDL cholesterol levels dramatically
when used in combination with other drugs
Used commonly
Effective and well tolerated
Standard practice to initiate therapy after acute coronary syndrome
regardless of lipid levels
Reduces risk of coronary events, mortality among patients with IHD, risk
of ischemic stroke
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HYPERLIPIDEMIAS

HMG-CoA REDUCTASE INHIBITORS

CLINICAL USE
Cholesterol synthesis occurs predominantly at night
Should be given in the evening
Except for Atorvastatin and Rosuvastatin
Absorption is enhanced by food
Except Pravastatin
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HYPERLIPIDEMIAS

HMG-CoA REDUCTASE INHIBITORS

CLINICAL USE
Rosuvastatin, Atorvastatin, Simvastatin
Higher efficacy than other reductase inhibitors
Reduce triglycerides and increase HDL levels in patients with trigly levels
of >250mg/dL
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HYPERLIPIDEMIAS

HMG-CoA REDUCTASE INHIBITORS

CLINICAL USE
Rosuvastatin
Most efficacious agent for severe hypercholesterolemia

Fluvastatin
Less maximal efficacy than the other drugs
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HMG-CoA REDUCTASE INHIBITORS

TOXICITY
Mild elevations of serum aminotransferase not often associated with hepatic
damage
More severe reactions in patients with
preexisting liver disease
Monitor at baseline, at 1-2 months then every 6-12 months
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HMG-CoA REDUCTASE INHIBITORS

TOXICITY
Increase in creatine kinase
Released from skeletal muscles
10% of patients
Severe muscle pain in few patients
Rhabdomyolysis and myoglobinuria may occur
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HMG-CoA REDUCTASE
INHIBITORS
TOXICITY
Metabolized by the cytochrome P450
Drugs or food (e.g., grapefruit
juice) that inhibit cytochrome P450
activity
Increase the risk of
hepatotoxicity and myopathy
Teratogenic
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RESINS
MECHANISMS AND EFFECTS
Cholestyramine, Colestipol, and Colesevelam
Bile acid-binding resins
Large nonabsorbable polymers that bind
bile acids and similar steroids in the intestine
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RESINS
MECHANISMS AND EFFECTS
Bile acids, metabolites of cholesterol are absorbed in the jejunum and ileum
Excretion is increased up to 10 fold when resins are given
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RESINS
MECHANISMS AND EFFECTS
Prevents absorption of dietary cholesterol
and reduces reabsorption of bile acids
secreted by the liver
Divert hepatic cholesterol to the synthesis
of new bile acids
Reduces the amount of cholesterol in a
tightly regulated pool
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RESINS
MECHANISMS AND EFFECTS
Liver compensates by increasing high affinity LDL receptors that clear LDL
from the blood
Modest reduction in LDL
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Useful only for isolated increases of LDL
Little effect on the HDL or triglycerides
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RESINS
CLINICAL USE
Patients with hypercholesterolemia
Reduce pruritus in patients with cholestasis
and bile salt accumulation
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RESINS
TOXICITY
Bloating
Constipation
Unpleasant gritty taste
Absorption of the following is impaired
Vitamins (Vitamin K, dietary folates)
Drugs (Pravastatin, Fluvastatin, Digitalis, Warfarin, Thiazides)
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EZETIMIBE
MECHANISM AND EFFECTS
Prodrug
Converted in the liver to active glucuronide
Prevents GI uptake of cholesterol and phytosterols
(plant sterols that normally enter GI epithelial cell
but are immediately transported back into the
intestinal lumen)
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EZETIMIBE
MECHANISM AND EFFECTS
Prevents absorption of dietary cholesterol and cholesterol excreted from
the bile
Reduces the cholesterol in the tightly regulated hepatic pool
Liver compensates by increasing high affinity LDL receptors that clear
LDL from the blood
LDL from the blood
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EZETIMIBE
MECHANISM AND EFFECTS
As monotherapy
Reduces LDL cholesterol by about 18%
More effective when combined with a reductase inhibitor
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EZETIMIBE
CLINICAL USE
Treatment of hypercholesterolemia
Phytosterolemia
Rare genetic disorder that results from impaired export of
phytosterols
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EZETIMIBE
TOXICITY
Well tolerated
When combined with reductase inhibitors
May increase the risk of hepatic toxicity
Serum concentrations of the glucuronide form
Increased by fibrates
Reduced by cholestyramine
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NIACIN (NICOTINIC ACID)

MECHANISM AND EFFECTS
Niacin (but not Nicotinamide)
Directly reduces the secretion of triglycerides, VLDL and LDL
Increases HDL level
Reduced catabolic rate for HDL
Inhibits hepatic synthesis of apolipoproteins or cholesterol
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HYPERLIPIDEMIAS
DRUGS USED IN THE TREATMENT OF
HYPERLIPIDEMIAS
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NIACIN (NICOTINIC ACID)

TOXICITY
Cutaneous flushing
Common
Pretreatment with aspirin or other NSAIDs
Reduces the intensity of cutaneous flushing
Mediated by prostaglandin release
Tolerance to the flushing reaction develops
within a few days
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NIACIN (NICOTINIC ACID)

TOXICITY
Dose-dependent nausea
Abdominal discomfort
Pruritus
Other skin problems
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NIACIN (NICOTINIC ACID)

TOXICITY
Moderate elevations of liver enzymes
Severe hepatotoxicity
Hyperuricemia
20% of patients
Carbohydrate tolerance may be moderately impaired
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SITES OF ACTION OF
HMG-COA REDUCTASE
INHIBITORS, NIACIN,
EZETIMIBE, AND RESINS
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HYPERLIPIDEMIAS

FIBRIC ACID DERIVATIVES

MECHANISM AND EFFECTS
Gemfibrozil, Fenofibrate, Clofibrate, Bezafibrate
Ligands for the peroxisome proliferator
-activated receptor-alpha (PPAR-) protein
Receptor that regulates transcription of genes involved
in lipid metabolism
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FIBRIC ACID DERIVATIVES

MECHANISM AND EFFECTS
Increases activity of lipoprotein lipase
Enhances clearance of triglyceride-rich lipoproteins
Cholesterol biosynthesis in the liver is secondarily reduced
Stimulate fatty acid oxidation limits supply of triglycerides
decreases VLDL synthesis
Decreases expression of apoC-III impedes clearance
of VLDL
Increases expression of apoA-I and apoA-II increases HDL levels
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HYPERLIPIDEMIAS

HEPATIC AND
PERIPHERAL EFFECTS
OF FIBRATES
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HYPERLIPIDEMIAS

FIBRIC ACID DERIVATIVES

MECHANISM AND EFFECTS
Reduce serum triglyceride concentrations
Small reduction in LDL
Small increase in HDL levels
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HYPERLIPIDEMIAS

FIBRIC ACID DERIVATIVES

CLINICAL USE
Treatment of hypertriglyceridemia
Modest effects on LDL cholesterol
Combined with other cholesterol-lowering drugs
Patients with elevated concentrations of both LDL and VLDL
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HYPERLIPIDEMIAS

FIBRIC ACID DERIVATIVES

TOXICITY
Nausea is most common with all the drugs
Skin rashes
Common with Gemfibrozil
Decreases in white blood count or hematocrit
Can potentiate the action of anticoagulants

Can potentiate the action of anticoagulants

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HYPERLIPIDEMIAS

FIBRIC ACID DERIVATIVES

TOXICITY
Increased risk of cholesterol gallstones
Caution in patients with a history of cholelithiasis
When combined with reductase inhibitors

Increase risk of myopathy

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COMBINATION THERAPY
Dietary modification
First treatment for all patients with hyperlipidemia
Often insufficient and drugs must be added
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HYPERLIPIDEMIAS

COMBINATION THERAPY
Drug combinations
Often required to achieve the maximum lowering
possible
Minimum toxicity
Achieve the desired effect on the various lipoproteins (LDL, VLDL,
HDL)
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HYPERLIPIDEMIAS

COMBINATION THERAPY
Presents as a challenge
Resins
Interfere with the absorption of certain reductase inhibitors
Pravastatin, Cerivastatin, Atorvastatin, and Fluvastatin
Given at least 1 hour before or 4 hours
after the resins
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HYPERLIPIDEMIAS

COMBINATION THERAPY
Presents as a challenge
Combination of reductase inhibitors with either fibrates or niacin
Increases the risk of myopathy
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HYPERLIPIDEMIAS
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HYPERLIPIDEMIAS
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HYPERLIPIDEMIAS