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Drugs for Hyperlipidemia

Ass.Prof. Naza M. Ali


Lec. 11-12
May 20 2018
Coronary heart disease (CHD) is the leading cause of death worldwide.

• CHD is correlated with elevated levels of LDL-C “bad” cholesterol


and TG and low levels of HDL-C good cholesterol.
• Other risk factors for CHD include
cigarette smoking, hypertension,
obesity, and diabetes.
• Hyperlipidemias can also result from an inherited defect in
lipoprotein metabolism or, more commonly, from a combination of
genetic and life- style factors.
• Appropriate lifestyle changes, along with drug therapy, can lead to a
30% to 40% reduction in CHD mortality.
TREATMENT GOALS

• Plasma lipids consist mostly of lipoproteins, which are spherical complexes of lipids
and specific proteins (apolipoproteins).
• Clinically important lipoproteins, listed in decreasing order of atherogenicity, are:
LDL, VLDL , chylomicrons, HDL.
• The occurrence of CHD is positively associated with high total cholesterol and with
elevated LDL-C.
• Total cholesterol is the sum of LDL-C, VLDL-C, and HDL-C.
• high levels of HDL-C have been associated with a decreased risk for heart disease.
Reduction of LDL-C is the primary goal of cholesterol-lowering therapy.
• Previously, cholesterol guidelines recommended treating to specific
targets for LDL- C.
• Recent cholesterol guidelines do not recommend targets but instead
emphasize high-intensity or moderate-intensity statin therapy in
defined populations with risk for atherosclerotic cardiovascular
disease (ASCVD).
• Higher-intensity therapy is recommended in those with established
ASCVD or in those with a higher overall risk of heart disease
• Chylomicrons carry triglycerides from the intestines to the liver,
to skeletal muscle, and to adipose tissue.
• VLDL carry (newly synthesised) triglycerides from the liver to adipose
tissue.
• IDL are intermediate between VLDL and LDL. They are not usually
detectable in the blood when fasting.
• LDL carry 3,000 to 6,000 fat molecules (phospholipids, cholesterol,
triglycerides, etc.) around the body. LDL particles are sometimes
referred to as "bad" lipoprotein because concentrations, dose related,
correlate with atherosclerosis progression.
• HDL collect fat molecules (phospholipids, cholesterol, triglycerides)
from the body's cells/tissues, and take it back to the liver. HDLs are
referred to as "good" lipoprotein because higher concentrations
correlate with low rates of atherosclerosis progression.
Metabolism of plasma lipoproteins
Treatment options for hypercholesterolemia

• Lifestyle changes ( diet, exercise, weight reduction)


can lead to modest decreases in LDL-C and increases in HDL-C.
• Most patients are unable to achieve significant LDL-C reductions
with lifestyle modifications alone, and drug therapy may be
required.
• Treatment with statins is the primary treatment option for
hypercholesterolemia.
• Statin therapy is recommended for four major groups as outlined
Treatment guidelines for hyperlipidemia.
ASCVD = atherosclerotic cardiovascular disease;
Treatment options for hypertriglyceridemia
• Elevated triglycerides are independently associated with increased
risk of CHD.
• Diet and exercise are the primary modes of treating
hypertriglyceridemia.
• If indicated, niacin and fibric acid derivatives are the most efficacious
in lowering triglycerides.
• Omega-3 fatty acids in adequate doses may also be beneficial.
• Triglyceride reduction is a secondary benefit of the statins, with the
primary benefit being reduction of LDL-C.
Effect of circulating LDL and HDL on the risk of coronary heart disease
Antihyperlipidemic drugs
1. Statins
2. Niacin
3. Fibrates
4. Bile acid– binding resins
5. Ezetimibe
6. Omega-3 fatty acids.
7. PSC9 inhibitor

Drug therapy should always be accompanied by lifestyle modifications,


such as exercise and a diet low in saturated fats.
1. Statins / HMG CoA reductase inhibitors
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ,
lower elevated LDL-C,
Lovastatin
Simvastatin,
Pravastatin,
Atorvastatin,
Fluvastatin,
Pitavastatin ,
Rosuvastatin
Mechanism of Action

• The rate limiting step in hepatic cholesterol


synthesis is conversion of hydroxy-methyl-glutaryl
coenzyme A to mevalonate by HMG-CoA reductase.

• The statins are structural analogs of HMG-CoA that


competitively inhibit the enzyme .
• they will fit into the enzyme's active site and
compete with the native substrate (HMG-CoA).
• By inhibiting de novo cholesterol synthesis, they deplete the
intracellular supply of cholesterol

• Depletion of intracellular cholesterol causes the cell to


increase the number of cell surface LDL receptors that can
bind and internalize circulating LDLs.

• plasma cholesterol is reduced, by both decreased cholesterol


synthesis and increased LDL catabolism.
• Pitavastatin, rosuvastatin, and atorvastatin are the most
potent LDL cholesterol–lowering statins,
• followed by simvastatin, pravastatin, and then lovastatin and
fluvastatin.

• Because these agents undergo a marked first-pass extraction by


the liver, their dominant effect is on that organ.

• The HMG CoA reductase inhibitors also decrease triglyceride


levels and may increase HDL cholesterol levels in some patients.
Therapeutic uses:
• are effective in lowering plasma cholesterol
levels in all types of hyperlipidemias.

• patients who are homozygous for familial


hypercholesterolemia lack LDL receptors and,
therefore, benefit much less from treatment
with these drugs.
Pharmacokinetics:
• Lovastatin and simvastatin are lactones that are hydrolyzed to
the active drug.
• The remaining statins are all administered in their active form.
Absorption of the statins is variable (30% to 85%) following oral
administration.
• All statins are metabolized in the liver, with some metabolites
retaining activity.
• Excretion takes place principally through bile and feces, but
some urinary elimination also occurs.
Adverse effects:
1. Elevated liver enzymes may
occur with statin therapy.

 liver function should be


evaluated prior to starting therapy
and if a patient has symptoms
consistent with liver dysfunction.

2.Myopathy and rhabdomyolysis


have been reported.
Simvastatin is metabolized by cytochrome P450 3A4, and
inhibitors of this enzyme may increase the risk of
rhabdomyolysis.
Plasma creatine kinase levels should be determined in
patients with muscle complaints.
 These drugs increase the effect of warfarin.

• These drugs are contraindicated during pregnancy and


lactation.
2. Niacin (nicotinic acid)
• can reduce LDL-C by 10% - 20%
• is the most effective agent for increasing HDL-C.
• also lowers TG by 20% - 35% at typical doses of 1.5 - 3 grams/day.
• Niacin can be used in combination with statins.
Mechanism of action:
• At gram doses, niacin strongly inhibits lipolysis in adipose tissue,
thereby reducing production of free fatty acids ( FFA )
• The liver normally uses circulating FFA as a major precursor for TG
synthesis.
• Reduced liver TG levels decrease hepatic VLDL production, which in
turn reduces LDL-C plasma concentrations.
Therapeutic uses:
• Since niacin lowers plasma levels of both cholesterol
and triglycerides,
it is useful in the treatment of familial hyperlipidemias.
• also used in combination with other agents.
Niacin inhibits lipolysis in adipose tissue
Pharmacokinetics
• Administered orally.
• It is converted in the body to nicotinamide, which is
incorporated into the cofactor NAD+

Adverse effects:
• an intense cutaneous flush and pruritus.
• Administration of aspirin prior to taking niacin decreases
the flush,
• Slow titration of the dosage
3. Fibrates
• Fenofibrate
• gemfibrozil,
• benzafibrate
are derivatives of fibric acid that lower serum TG and
increase HDL levels.
Mechanism of action:
• The peroxisome proliferator–activated receptors (PPARs) are
members of the nuclear receptor family that regulates lipid
metabolism.
• Upon binding to their natural ligands (fatty acids or
eicosanoids) or antihyperlipidemic drugs, PPARs are activated.

• They then bind to peroxisome proliferator response elements,


which ultimately leads to decreased TG concentrations
through increased expression of lipoprotein lipase
Activation of lipoprotein lipase by gemfibrozil.
Therapeutic uses:
• in the treatment of hypertriglyceridemias.

Pharmacokinetics:
• Gemfibrozil and fenofibrate are completely absorbed after
oral administration and distribute widely, bound to albumin.
• Fenofibrate is a prodrug, which is converted to the active
moiety fenofibric acid.
Adverse effects:
• mild gastrointestinal disturbances. These lessen as the therapy
progresses. Because these drugs increase biliary cholesterol excretion,
there is a predisposition to form gallstones.
• Myositis (inflammation of a voluntary muscle) can occur, and muscle
weakness or tenderness should be evaluated.
• may increase the effects of warfarin.
• Fibrates should not be used in patients with severe hepatic or renal
dysfunction or in patients with preexisting gallbladder disease.
4. Bile acid–binding resins

• Bile acid sequestrants (resins) have significant LDL


cholesterol– lowering effects,
• Cholestyramine,
Colestipol
Colesevelam
Mechanism of action:
• are anion-exchange resins that bind negatively charged bile
acids and bile salts in the small intestine.
• The resin/bile acid complex is excreted in the feces, thus
lowering the bile acid concentration.
• This causes hepatocytes to increase conversion of cholesterol
to bile acids, which are essential components of the bile.
• Consequently, intracellular cholesterol concentrations
decrease, which activates an increased hepatic uptake of
cholesterol- containing LDL particles, leading to a fall in plasma
LDL-C.
• Note: This increased uptake is mediated by an up-regulation of
cell surface LDL receptors.
Therapeutic uses:
• The bile acid–binding resins are useful (often in combination with diet
or niacin) for treating type IIA and type IIB hyperlipidemias.

• Cholestyramine can also relieve pruritus caused by accumulation of


bile acids in patients with biliary stasis.
• Colesevelam is also indicated for type 2 diabetes due to its glucose-
lowering effects.
Mechanism of action:
• are anion-exchange resins that bind negatively
charged bile acids and bile salts in the small
intestine.
• The resin/bile acid complex is excreted in the feces,
thus lowering the bile acid concentration.

• This causes hepatocytes to increase conversion of


cholesterol to bile acids, which are essential
components of the bile.
• Consequently, intracellular cholesterol concentrations
decrease, which activates an increased hepatic uptake of
cholesterol- containing LDL particles, leading to a fall in
plasma LDL-C.

• Note: This increased uptake is mediated by an up-


regulation of cell surface LDL receptors.
Pharmacokinetics:
• Bile acid sequestrants are insoluble in water and have large
molecular weights.
• After oral administration, they are neither absorbed nor metabolically
altered by the intestine.
• they are totally excreted in feces.
Adverse effects:
• are GI disturbances( constipation, nausea, and flatulence).
• These agents may impair the absorption of the fat-soluble vitamins
(A, D, E, and K), and they interfere with the absorption of many drugs
( digoxin, warfarin, and thyroid hormone).
• Therefore, other drugs should be taken at least 1 to 2 hours before, or
4 to 6 hours after, the bile acid–binding resins.
Mechanism of bile acid–binding resins.
5. Cholesterol absorption inhibitor
Ezetimibe
• Selectively inhibits absorption of dietary and biliary cholesterol in the
small intestine, leading to a decrease in the delivery of intestinal
cholesterol to the liver.
• This causes a reduction of hepatic cholesterol stores and an increase
in clearance of cholesterol from the blood.

• Ezetimibe lowers LDL cholesterol by approximately 17%.

• Is metabolized in the small intestine and liver via glucuronide


conjugation, with subsequent biliary and renal excretion.
6. Omega-3 fatty acids
Eicosapentaenoic acid EPA
Docosahexaenoic acid DHA

• found in tuna and salmon


• Omega-3 PUFA are essential fatty acids used for TG lowering.
• Essential fatty acids inhibit VLDL and TG synthesis in the liver.
• Omega-3 can be used as an adjunct to other lipid-lowering therapies
for individuals with significantly elevated TG (≥500 mg/dL).
• Omega-3 has not been shown to reduce CV morbidity & mortality.
Combination drug therapy
• It is often necessary to use two antihyperlipidemic drugs to achieve
treatment goals in plasma lipid levels.

• The combination of an HMG CoA reductase inhibitor with a bile acid–


binding agent has been shown to be very useful in lowering LDL-C
levels

• Simvastatin and ezetimibe, as well as simvastatin and niacin, are


available combined in one pill to treat elevated LDL cholesterol.

• Liver and muscle toxicity occurs more frequently with drug


combinations.
Drug M.O.A Side effects

Statins HMG-CoA reductase inhibitor / In liver Elevated liver enzymes,


Myopathy

Niacin strongly inhibits lipolysis / in adipose tissue intense cutaneous flush,


pruritus

Fibrate Bind to peroxisome proliferator activator response GIT disturbance,


elements, increased expression of lipoprotein lipase Myositis

Bile acid–binding The resin/bile acid complex lowering the bile acid GIT disturbance
resins concentration.
increase conversion of cholesterol to bile acids

Ezetimibe Ezetimibe selectively inhibits absorption of dietary and GIT disturbance,


biliary cholesterol in the small intestine tiredness or weakness

PCSK9 inhibitors/ SC Monoclonal antibodies. Hypersensitivity reactions


inactivate a specific protein in the liver
Alirocumab
• Which one of the following is the most common side effect of
antihyperlipidemic drug therapy?
A.Elevated blood pressure.
B. Gastrointestinal disturbance.
C. Neurologic problems.
D. Heart palpitations.
E. Migraine headaches.

• Which one of the following hyperlipidemias is characterized by elevated


plasma levels of chylomicrons and has no drug therapy available to lower the
plasma lipoprotein levels?
A. Type I. B. Type II. C. Type III. D. Type IV. E. Type V.

• Which one of the following drugs decreases cholesterol synthesis by inhibiting


the enzyme 3-hydroxy-3- methylglutaryl coenzyme A reductase?
A.Fenofibrate.
B. Niacin.
C. Cholestyramine.
D. Lovastatin.
E. Gemfibrozil.
• Which one of the following drugs causes a decrease in liver triglyceride
synthesis by limiting available free fatty acids needed as building blocks
for this pathway?
A. Niacin.
B. Fenofibrate.
C. Cholestyramine.
D. Gemfibrozil.
E. Lovastatin.
• Which one of the following drugs binds bile acids in the intestine, thus
preventing their return to the liver via the enterohepatic circulation?
A. Niacin.
B. Fenofibrate.
C. Cholestyramine.
D. Fluvastatin.
E. Lovastatin.
• Correct answer = B.
• Correct answer = A.
• Correct answer = D.
• Correct answer = A.
• Correct answer = C.

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