Antidyslipidemic Drugs (Geppetti)

Download as pptx, pdf, or txt
Download as pptx, pdf, or txt
You are on page 1of 32

AGENTS USED IN

DYSLIPIDEMIA
INTRODUCTION
Plasma lipids are transported in complexes called
lipoproteins.
Metabolic disorders that involve elevations in any
lipoprotein species are termed hyperlipoproteinemias or
hyperlipidemias.
Major clinical sequela of hyperlipidemias is
ATHEROSCLEROSIS, the leading cause of death for both
genders in the USA and other Western countries.
Deaths attributed to 19 leading risk factors, by country
income level (2004)
Structure of lipoproteins

Free cholesterol

Phospholipids Triglycerides

Apolipoproteins Cholesterol esthers


Classification of lipoproteins

according to their density

1. Chylomicrons

2. Very low density lipoproteins (VLDL)

3. Intermediate density lipoproteins (IDL)

4. Low density lipoproteins (LDL)

5. High density lipoproteins (HDL)


STRATEGY
High-density lipoproteins (HDL) exert several
antiatherogenic effects. They participate in retrieval of
cholesterol from the artery wall and inhibit the oxidation of
atherogenic lipoproteins. Low levels of HDL
(hypoalphalipoproteinemia) are an independent risk factor for
atherosclerotic disease and thus are a target for intervention.
Because atherogenesis is multifactorial, therapy should be
directed toward all modifiable risk factors.

Atherogenesis is a dynamic process. Quantitative angiographic trials have


demonstrated net regression of plaques during aggressive lipid-lowering
therapy. Primary and secondary prevention trials have shown significant
reduction in mortality from new coronary events and in all-cause mortality.
LIPOPROTEIN DISORDERS
Lipoprotein disorders are detected by measuring lipids in
serum after a 10-hour fast.
Risk of heart disease increases with concentrations of the
atherogenic lipoproteins, is inversely related to levels of
HDL, and is modified by other risk factors.
THE PRIMARY HYPERLIPOPROTEINEMIAS
SECONDARY CAUSES OF HYPERLIPOPROTEINEMIA
BASIC & CLINICAL PHARMACOLOGY OF
DRUGS USED IN HYPERLIPIDEMIA
The decision to use drug therapy for hyperlipidemia is based on the
specific metabolic defect:
1. COMPETITIVE INHIBITORS OF HMG-COA REDUCTASE:
REDUCTASE INHIBITORS STATINS
2. NIACIN (NICOTINIC ACID)
3. FIBRIC ACID DERIVATIVES (FIBRATES)
4. BILE ACID-BINDING RESINS
5. INHIBITORS OF INTESTINAL STEROL ABSORPTION
6. OMEGA-3 FATTY ACIDS (OMEGA-3 FAs)
7. CHOLESTERYL ESTER TRANSFER PROTEIN (CEPT) INHIBITORS
8. PROPROTREIN CONVERTASE SUBTILISIN/KEXIN-TYPE 9
(PPCSKT9) INHIBITORS
3-hydroxy-3-methylglutaryl-coenzyme A Reductase
STATINS
These compounds are structural analogs of HMG-CoA (3-hydroxy-
3-methylglutaryl-coenzyme A, fig.).
Lovastatin, atorvastatin, fluvastatin, pravastatin, simvastatin,
rosuvastatin, and pitavastatin belong to this class.
They are most effective in reducing LDL. Other effects include: decreased
oxidative stress and vascular inflammation with increased stability of
atherosclerotic lesions.
PHARMACOKINETICS
Lovastatin and simvastatin are inactive lactone prodrugs that are hydrolyzed
in the gastrointestinal tract to the active -hydroxyl derivatives, whereas
pravastatin has an open, active lactone ring.

Atorvastatin, fluvastatin, and rosuvastatin are fluorine-containing congeners


that are active as given.

Absorption of the ingested doses of the reductase inhibitors varies from 40%
to 75% with the exception of fluvastatin, which is almost completely absorbed.

All have high first-pass extraction by the liver. Most of the absorbed dose is
excreted in the bile; 520% is excreted in the urine. Plasma halflives of these
drugs range from 1 to 3 hours except for atorvastatin (14 hours), pitavastatin
(12 hours), and rosuvastatin (19 hours).
MECHANISM OF ACTION
HMG-CoA reductase mediates the first committed
step in sterol biosynthesis. The active forms of the
reductase inhibitors are structural analogs of the
HMG-CoA intermediate that is formed by HMG-CoA
reductase in the synthesis of mevalonate.

These analogs cause partial inhibition of the


enzyme and thus may impair the synthesis of
isoprenoids such as ubiquinone and dolichol and
the prenylation of proteins. It is not known whether
this has biologic significance.

This effect increases both the fractional catabolic


rate of LDL and the livers extraction of LDL
precursors (VLDL remnants) from the blood, thus
reducing LDL. Because of marked firstpass hepatic
extraction, the major effect is on the liver.
THERAPEUTIC USES & DOSAGE
Reductase inhibitors are useful alone or with resins, niacin, or ezetimibe in reducing levels of LDL.
Women with hyperlipidemia who are pregnant, lactating, or likely to become pregnant should not be
given these agents. Use in children is restricted to selected patients with familial
hypercholesterolemia or familial combined hyperlipidemia.

Because cholesterol synthesis occurs predominantly at night, reductase inhibitors - except


atorvastatin and rosuvastatin - should be given in the evening if a single daily dose is used.

Absorption generally (with the exception of pravastatin) is enhanced by food.

Daily doses:
Lovastatin vary from 10 to 80 mg.
Pravastatin has a maximum recommended daily dose of 80 mg.
Simvastatin is given in doses of 580 mg daily. Because of increased risk of myopathy with the 80 mg/day
dose, the FDA issued labelling for scaled dosing of simvastatin and Vytorin in June 2011.
Fluvastatin is given in doses of 1080 mg daily.
Atorvastatin is given in doses of 1080 mg/d.
Rosuvastatin, the most efficacious agent for severe hypercholesterolemia, at 540 mg/d.

The dose-response curves of pravastatin and especially of fluvastatin tend to level off in the upper part of the dosage
range in patients with moderate to severe hypercholesterolemia.
TOXICITY
Elevations of serum aminotransferase activity (up to three times normal) occur in
some patients. This is often intermittent and usually not associated with other evidence
of hepatic toxicity. Therapy may be continued in such patients in the absence of
symptoms if aminotransferase levels are monitored and stable.

Minor increases in creatine kinase (CK) activity in plasma are observed in some
patients receiving reductase inhibitors, frequently associated with heavy physical
activity. Rarely, patients may have marked elevations in CK activity, often accompanied
by generalized discomfort or weakness in skeletal muscles. If the drug is not
discontinued, myoglobinuria can occur, leading to renal injury.

Myopathy may occur with monotherapy, but there is an increased incidence in patients
also receiving certain other drugs. Genetic variation in an anion transporter (OATP1B1)
is associated with severe myopathy and rhabdomyolysis induced by statins.
MYOPATHY, CK AND NON CK ASSOCIATED
Statin-induced myalgia is a very frequent phenomenon encountered in daily
practice.

The true nature of muscle pain remains often unclear, and the vast majority of
patients with statin-induced myalgia have normal CK levels, thus a novel
sensitive biomarker would be greatly appreciated both by patients and
physicians.

However, CK activity should be measured in patients receiving potentially


interacting drug combinations and, in all patients, CK should be measured at
baseline. If muscle pain, tenderness, or weakness appears, CK should be
measured immediately and the drug discontinued if activity is elevated
significantly* over baseline. The myopathy usually reverses promptly upon
cessation of therapy.

*Usually, if the CK level is five times the upper limit of normal or more.
INTERACTIONS
Catabolism of lovastatin, simvastatin, and atorvastatin proceeds chiefly through
CYP3A4.

The 3A4-dependent reductase inhibitors tend to accumulate in plasma in the presence of drugs that
inhibit or compete for the 3A4 cytochrome (macrolide, antibiotics, cyclosporine, ketoconazole and
its congeners, some HIV protease inhibitors, tacrolimus, nefazodone, fibrates, paroxetine,
venlafaxine, and others). Concomitant use of reductase inhibitors with amiodarone or verapamil
also causes an increased risk of myopathy. Conversely, drugs such as phenytoin, griseofulvin,
barbiturates, rifampin, and thiazolidinediones increase expression of CYP3A4 and can reduce the
plasma concentrations of the 3A4-dependent reductase inhibitors.

Whereas that of fluvastatin and rosuvastatin, and to a lesser extent pitavastatin,


is mediated by CYP2C9.

Inhibitors of CYP2C9 such as ketoconazole and its congeners, metronidazole, sulfinpyrazone,


amiodarone, and cimetidine may increase plasma levels of fluvastatin and rosuvastatin. Pravastatin
and rosuvastatin appear to be the statins of choice for use with verapamil, the ketoconazole group
of antifungal agents, macrolides, and cyclosporine. Doses should be kept low and the patient
monitored frequently.
Pravastatin is catabolized through other pathways, including sulfation.
NIACIN
Niacin (vitamin B3) decreases VLDL and LDL levels, and Lp(a) in most
patients. It often increases HDL levels significantly.

Is converted in the body to the amide, which is incorporated into niacinamide


adenine dinucleotide (NAD). It is excreted in the urine unmodified and as
several metabolites.

Niacin inhibits VLDL secretion, in turn decreasing production of LDL.


Increased clearance of VLDL via the LPL pathway contributes to reduction of
triglycerides. Niacin has no effect on bile acid production. Excretion of neutral
sterols in the stool is increased acutely as cholesterol is mobilized from tissue
pools and a new steady state is reached. The catabolic rate for HDL is
decreased. Niacin inhibits the intracellular lipase of adipose tissue via
receptor-mediated signaling, possibly reducing VLDL production by
decreasing the flux of free fatty acids to the liver.
THERAPEUTIC USES & DOSAGE
In combination with a resin or reductase inhibitor, niacin normalizes LDL in
most patients with heterozygous familial hypercholesterolemia and other
forms of hypercholesterolemia.
In severe mixed lipemia that is incompletely responsive to diet, niacin often
produces marked reduction of triglycerides, an effect enhanced by marine
omega-3 fatty acids.
It is clearly the most effective agent for increasing HDL and the only agent
that may reduce Lp(a).

For treatment of heterozygous familial hypercholesterolemia, most patients


require 26 g of niacin daily.
For other types of hypercholesterolemia and for hypertriglyceridemia,1.53.5 g
daily is often sufficient.
Crystalline niacin should be given in divided doses with meals, starting with 100
mg two or three times daily and increasing gradually.
TOXICITY
Most persons experience a harmless cutaneous vasodilation and sensation of warmth after each
dose when niacin is started or the dose increased. Taking aspirin or ibuprofen one half hour before
blunts this prostaglandin-mediated effect.

Some patients experience nausea and abdominal discomfort. Niacin should be avoided in most
patients with severe peptic disease.

Reversible elevations in aminotransferases up to twice normal may occur, usually not associated
with liver toxicity. However, liver function should be monitored at baseline and at appropriate
intervals. Rarely, true hepatotoxicity may occur.

Carbohydrate tolerance may be moderately impaired, especially in obese patients, but this is
usually reversible except in some patients with latent diabetes. Niacin may be given to diabetics
who are receiving insulin and to some receiving oral agents. Niacin may increase insulin resistance
in some patients. This can often be addressed by increasing the dose of insulin or the oral agents.
Other:
Hyperuricemia
Red cell macrocytosis
Significant platelet deficiency
Arrhythmias, mostly atrial
Macular edema
May potentiate the action of antihypertensive agents
FIBRIC ACID DERIVATIVES
Fibrates decrease levels of VLDL and, in some patients, LDL as well.

Gemfibrozil is absorbed quantitatively from the intestine and is tightly


bound to plasma proteins. It undergoes enterohepatic circulation and
readily passes the placenta. The plasma half-life is 1.5 hours.
Seventy percent is eliminated through the kidneys, mostly
unmodified. The liver modifies some of the drug to hydroxymethyl,
carboxyl, or quinol derivatives.

Fenofibrate is an isopropyl ester that is hydrolyzed completely in the


intestine. Its plasma half-life is 20 hours. Sixty percent is excreted in
the urine as the glucuronide, and about 25% in feces.
MECHANISM OF ACTION
Fibrates function primarily as ligands for
the nuclear transcription receptor, PPAR-
. They transcriptionally up-regulate LPL,
apo A-I and apo A-II, and down-regulate
apo C-III, an inhibitor of lipolysis. A major
effect is an increase in oxidation of fatty
acids in liver and striated muscle.

They increase lipolysis of lipoprotein


triglyceride via LPL. Intracellular lipolysis
in adipose tissue is decreased. Levels of
VLDL decrease, in part as a result of
decreased secretion by the liver. Only
modest reductions of LDL
occur in most patients.
THERAPEUTIC USES & DOSAGE
Fibrates are useful drugs in hypertriglyceridemias in which VLDL
predominate and in dysbetalipoproteinemia.

They also may be of benefit in treating the hypertriglyceridemia that


results from treatment with viral protease inhibitors.

The usual dose of gemfibrozil is 600 mg orally once or twice daily.


Absorption of the drug is better when it is taken with food.

The dosage of fenofibrate is one to three 48 mg tablets (or a single


145 mg tablet) daily.
TOXICITY
Rare adverse effects of fibrates include: rashes, gastrointestinal
symptoms, myopathy (risk of myopathy increases when fibrates are
given with reductase inhibitors), arrhythmias, hypokalemia, and high
blood levels of aminotransferases or alkaline phosphatase. A few
patients show decreases in white blood count or hematocrit.

Both agents potentiate the action of coumarin and indanedione


anticoagulants.

There appears to be a modest increase in the risk of cholesterol


gallstones, reflecting an increase in the cholesterol content of bile.
Sterol Absorption Inhibitor
Ezetimibe is the first member of a group of drugs that inhibit
intestinal absorption of phytosterols and cholesterol.

Its primary clinical effect is reduction of LDL levels.

A transport protein, NPC1L1, appears to be the target of the


drug. It is effective even in the absence of dietary cholesterol
because it inhibits reabsorption of cholesterol excreted in the
bile.

The effect of ezetimibe on cholesterol absorption is constant


over the dosage range of 520 mg/d.

Therefore, a single daily dose of 10 mg is used. Average


reduction in LDL cholesterol with ezetimibe alone in patients
with primary hypercholesterolemia is about 18%, with minimal
increases in HDL cholesterol.

Ezetimibe is synergistic with reductase inhibitors, producing


decrements as great as 25% in LDL cholesterol beyond that
achieved with the reductase inhibitor alone.
OMEGA-3 FAs
Omega-3 FAs include eicosapentaenoic
acid (EPA) and docosahexaenoic acid
(DHA) from marine sources, and their
metabolic precursor, -linolenic acid
(ALA), is from vegetable sources.

The mechanism of action of omega-3


FAs likely involves hepatic inhibition of
triglycerides synthesis, decreased LDL-
C (VLDL-C) production and secretion,
and increased VLDL-C metabolism.

Omega-3 FAs are generally well-


tolerated, with the most commonly
reported adverse effects being
gastrointestinal complaints.
CETP INHIBITORS
CET (cholesterylester transfer protein) is a protein produced by the
liver and macrophages that facilitates transfer of cholesterol esters
from HDL-C to larger lipoproteins. This shift CE mass from HDL-C to
apolipoprotein B-containing proteins, thereby reducing HDL-C, which
in turn may increase atherogenicity. Therefore, inhibition of CEPT
raises HDL-C levels.

Currently, 4 CEPT inhibitors have been studied in clinical trials:


1. Torcetrapib
2. Dalcetrapib
3. Anacetrapib
4. Evacetrapib.

but have failed to reduce cardiovascular events.


PCSKT9 INHIBITORS
PCSK9 (Proprotein convertase subtilisin/kexin type 9) is a novel human
proteinase expressed in the liver, kidney, intestine and central nervous
system.

PCSK9 is a regulator of serum LDL-C by post-translational reduction of the


LDL-receptor.

Several therapeutic approaches to the direct inhibition of PCSK9 have been


proposed, with monoclonal antibodies being the most advanced approach for
clinical development.

Current PCSK9 inhibitors include:

Alirocumab
FDA-approved
Evolocumab
Bococizumab (phase III)

You might also like