Download Theme: Antiatherosclerotic drugs.

Theme: Antiatherosclerotic
drugs.
ANTIATHEROSCLEROTIC DRUGS
Antihyperlipidemic drugs (hypolipidemic drugs;
lipidlowering drugs) are used in patients with
hyperlipoproteinemia. They are the essential
components of the complex therapy used to prevent
and treat atherosclerosis and its complications
(ischemic disease of the heart, stroke, etc.). Their main
effect includes the reduction of elevated levels of
atherogenic lipoproteins in the plasma. Some of them
also increase the levels of antiatherogenic lipoproteins.
These principles of action are based on the fact that
atherogenic dislipoproteinemia is known to be one of
the main risk factors of atherosclerosis.
LDLs (low density lipoproteins), IDLs (intermediate
density lipoproteins), VLDLs (very low density
lipoproteins) and LPs(a) (lipoprotein (a)) possess
atherogenic properties. LDLs bind to lipoprotein tissue
receptors and, when metabolized, they release free
cholesterol and other compounds. Cholesterol in the
form of esters is deposited in the tissues.
Chylomicrons (CM) are not atherogenic. Nevertheless,
remnants of chylomicrons can penetrate through
thevascular endothelium and promote the
development of an atheromatous plaque. HDLs are
not atherogenic.
Moreover, elevated HDL concentration in
the plasma decreases the risk of
atheromatous damage to the vessels
(antiatherogenic action). Thus, in clinical
practice the prevention and management
of atherosclerosis and its complications
consists of lowering the excessive
concentrations of atherogenic lipoproteins
and increasing the level of antiatherogenic
HDLs in the blood plasma.
Antihyperlipidemic drugs (hypolipidemic drugs)
may be classified in the following way:
A). Drugs primarily decreasing the content of
cholesterol (LDL) in the blood
- Inhibitors of cholesterol synthesis (inhibitors of
3-hydroxi-3-methylglutaryl coenzyme Areductase; statins)
Lovastatin
Mevastatin
Pravastatin
Fluvastatin
Simvastatin
Inhibitors of cholesterol absorption from the gut
Ezetimib
Drugs increasing elimination of bile acids and
cholesterol from the body (sequestrants of bile
acids)
Cholestyramine
Cholestipol
Other drugs
Probucol
Treatment of lipid disorders begin with the appointment
of diet and, if the first fails and used lipid-lowering drug
or combination of drugs against the continuation of
diet. Choose a diet and lipid-lowering agent depends on
the identified type of hyperlipoproteinemia.
Distinguish 5 types of hyperlipoproteinemia:
Type I - giperhilomikronemii, i.e. an increase in the
blood content of XM.
Type II - hyper-β-lipoproteinemiya, Pa. subtype
characterized by an increase in blood levels of
cholesterol (LDL), a subtype of St Petersburg - additional
increase in triglycerides (VLDL).
Type III-dis-β-lipoproteinemiya, characterized by the
appearance of blood "pathological ¬ cal" lipoprotein (LPPP, βVLDL), an increase in the content of ¬ cholesterol and
triglycerides.
Type IV - hypersimple-β-lipoproteinemiya, i.e. an increase in
the blood content of trig ¬ litseridov (VLDL).
Type V - giperhilomikronemii and hypersimple-βlipoproteinemiya, characterized by an increase in the blood
content of the XM triglycerides (VLDL). These types of
hyperlipoproteinemia may be primary (hereditary nature or
effect of dietary disorders), and secondary, the associated
number of diseases (diabetes, hypothyroidism, liver, kidney,
etc.), as well as arising from prolonged ingestion of certain
drugs. It should be borne in mind that the successful
treatment of the underlying disease can lead to a significant
reduction of atherogenic hyperlipoproteinemia.
Lipid-lowering drugs can have the following courses:
• inhibition of the biosynthesis of lipids and lipoproteins
in the liver;
• activation of the capture (endocytosis) lipoprotein
liver by stimulating the synthesis of LDL receptors of the
liver;
• inhibition of cholesterol absorption and bile acids
from the intestine;
• activation of cholesterol catabolism, including its
conversion to bile acids;
• stimulation of lipoprotein lipase activity of vascular
endothelium;
• inhibition of fatty acid synthesis in the liver and their
release from adipose tissue (lipolysis inhibition);
• elevated levels of circulating antiatherogenic HDL.
High lipid-lowering efficacy have means selectively ¬
relatively inhibits the synthesis of cholesterol in the
liver, collectively referred to "statins." K. These include
nutrients - lovastatin (Mevacor), in ¬ obtained was from
cultures Monascus ruber and Aspergillus terreus, and
mevastatin (compactin), which is a metabolite of
Penicillium and Penicillium citricum brevicompactum.So
semi ¬ Buildings (simvastatin, pravastatin) and synthetic
(fluvastatin ) Substances with such type of action. These
drugs inhibit the syn ¬ mes cholesterol in the liver by
inhibiting the enzyme N-hydroxy-3-methylglutaryl
coenzyme A reductase inhibitors.
Compensatory increases the number ¬ lo LDL receptors
in the liver, which is accompanied by a decrease in the
content LPPP and LDL cholesterol in the blood plasma,
because of their increased endocytosis and catabolism ¬
ism. Drugs in this group also reduce the absorption of
dietary cholesterol ¬ Rina. Furthermore, inhibited
synthesis of VLDL in the liver, a small degree ¬ ceeding
content in plasma HDL.
Lipid-lowering effect of substances shows quickly and
expressed all the ma ¬ substantially. An even greater
effect was observed with a combination of these agents
¬ Ratov with cholestyramine.
In recent years suggests that the effect of statins
antiatherosclerotic connected not only with their
hypolipidemic action, but also to a direct effect on the blood
vessels. This leads to improvement in endothelial function ¬
NIJ, the suppression of the inflammatory process, increased a
hundred ¬ bility of atherosclerotic plaques, and perhaps some
of its regression, to reduce the likelihood of blood clots. The
basis of these changes on the experimental data, many of the
processes involved: inhibition of proliferation and migration of
arterial myocytes, inhibition of the growth of monocyte /
macrophage accumulation and a decrease in their cholesterol
lowering metalloproteinase production by macrophages,
enhancing formation in endothelial NO synthase, inhibition of
endothelin-1 production , decreased platelet adhesion and
aggregation, etc.
The most significant clinical experience with lovastatin. It is a
prodrug. Its active metabolite is formed in the liver. Assign
lovastatin orally 1 time a day at bedtime. Bioavailability is low.
Much of the drug and its metabolites bind to plasma proteins.
Biotransformation of lovastatin in the liver. Allocated lovastatin
and its metabolites in the intestine and primarily to a lesser
extent by the kidneys.
The drug is well tolerated. Side effects are relatively rare
(dyspepsia, headache, skin rash, myopathy). In 2% of patients
experienced higher levels of hepatic transaminases, which
swarm, however, is not accompanied by any pathological
phenomena. According ¬ ceeding the level of muscle creatine
kinase (in 10-11% of patients), which may be accompanied by
muscle aches, rarely - myopathy and possible damage to the
muscle tissue (if you do not stop taking the drug).
Indications for use of the same for the whole
group of fibrates.
Nicotinic acid (niacin) reduces the content of
VLDL in blood plasma, to a lesser extent and LDL
LPPP. Triglycerides begins to decline before (1-4
days) than cholesterol (5-7th day). Nicotinic acid
inhibits lipolysis in adipose tissue (due to the
activation of cAMP phosphodiesterase content
decreases, which reduces the activity of
intracellular ¬ accurate lipase). The content of
fatty acids in the blood and their delivery to the
liver are reduced.
Naturally, this affects the biosynthesis of
triglycerides and VLDL. The content of VLDL and
LDL in plasma decreases. With prolonged use of
nom ¬ nicotinic acid increases the level of HDL.
She is well and rapidly absorbed from the
gastrointestinal tract. ¬ is to stand out in the
urine, mainly as unchanged substance and in
part - its meta ¬ hurts.
As hypolipidemic agents effective at II-V
hyperlipoproteinemia type (especially III and V).
Taken in high doses (at approximately ¬ 100 times
above designated as vitamin).
The use of nicotinic acid to limit its side effects: hy ¬ of
change of the skin, itching, vomiting, diarrhea, and
possible formation of peptic ulcers as ¬ gastric, hepatic
dysfunction, hyperglycemia, hyperuricemia, etc.
To reduce the severity of the side effects of nicotinic
acid synthesized ¬ Wana its poorly soluble salts, esters,
amides, slowly hydrolyzed to the acid, but the long-term
to maintain a certain level in her blood. The most
effective ¬ GOVERNMENTAL of them were
pyridylcarbinol (ronikol) holeksamin. In addition, the
use of such derivatives have found nicotinic acid as
ksantinola nicotinate and inozitolnikotinat.
Among the substances that promote catabolism and
excretion of cholesterol, polyunsaturated relation ¬
syatsya (polyene) fatty acids (linoleic, linolenic and
arachidonic). They increase cholesterol bile eksk ¬
rementah and the intensity of its catabolism in the
liver. In clinical practice using drugs linetol and
arachidonic (containing a mixture of ethyl ¬ ethers
of unsaturated fatty acids). Linetol derived from flax
w ¬ la and arachidonic - from lipids of the pancreas
and adrenal glands of cattle. Both drugs are used as
one component of the complex ¬ therapy
hyperlipoproteinemia type II-V. Enter them
enterally.
Lipid-lowering effect has also dextrothyroxine (Dthyroxine). It is a synthetic dextrorotatory isomer of
thyroid hormone thyroxine ¬ zy. Dextrothyroxine
activate the catabolism of cholesterol in the liver. ¬ tion
under the influence of microsomal liver enzymes
cholesterol more rapidly transformed into bile acids. In
plasma, the blood is reduced LDL content. In adipose
tissue pre ¬ Parat can stimulate lipolysis, which
increases the synthesis of VLDL. At the same time, the
level of triglycerides, as well as the basal metabolic rate
changed little.
It is recommended for the treatment of
hyperlipoproteinemia of type II and III. The effect of ¬
veins with enteral administration.
Dextrothyroxine similar endogenous L-thyroxine sensitize the
myocardium to the action of catecholamines, which
contributes to the development or enhancement of angina
and ser ¬ dechnyh arrhythmias. This can lead to increased
mortality from coronary heart bo ¬'s disease. Therefore, in
some countries, the use dextrothyroxine terminated or
knowledge ¬ considerably limited, although the negative effect
of the drug on the heart and may be offset by β-blockers.
Dextrothyroxine mainly administered young people, especially
thyroid hypofunction.
Once again it should be emphasized that in many cases the
treatment of hyperlipoproteinemia most pronounced effect is
the combined use of drugs with different mechanisms of
action (statins + cholestyramine; gemfibrozil + cholestyramine,
colestipol + nicotinic acid, nicotinic acid statins + +
sequestering bile acids).
The complex antiatherosclerotic means used and
the so-called mye ¬ endoteliotropnye drugs
(angioprotektory), reducing the permeability of the
endothelium to atherogenic lipoproteins. These
drugs include Parmidin (piridinolkarbamat, anginin,
prodektin). Possessing antibradikininovym effect, it
inhibits the swelling and reduces the permeability of
the vascular walls ¬ ki. Furthermore, Parmidin
improves microcirculation vascular wall reduces
platelet aggregation. Promotes regeneration of
elastic and of muscle fibers in the ground
cholesterol deposits. Reduces blood clotting ¬ ve.
Enter it inside for a few months. Tolerated drug ho ¬
Rosho. Sometimes causes nausea, allergic reactions.
A certain importance in the prevention of
atherosclerosis and its complications ¬ tions is
also given to antioxidants (tocopherol acetate,
ascorbyl acid ¬ bins, etc.) affecting the peroxide
mechanisms of atherosclerosis. The basic
principle of action is the inhibition of free radical
oxidation of lipids by molecular oxygen.
Please be aware that the efficacy and safety of
anti ¬ atherosclerotic drugs, or combinations
thereof can only be judged on the basis of longterm clinical studies on a large cohort of
patients.
Triglycerides and cholesterol are essential constituents of the organism.
Among other things, triglycerides represent a form of energy store and
cholesterol is a basic building block of biological membranes. Both lipids are
water insoluble and require appropriate "packaging” for transport in the
aqueous media of lymph and blood. To this end, small amounts of lipid are
coated with a layer of phospholipids, embedded in which are additional
proteins—the apolipoproteins (A). According to the amount and the
composition of stored lipids, as well as the type of apoli- poprotein, one
distinguishes four transport forms (see table).
other tissues with fatty acids. Left behind are LDL particles that either return
into the liver or supply extrahepatic tissues with cholesterol.
LDL particles carry the apolipoprotein B- 100, by which they are bound to
receptors that mediate uptake of LDL into the cells, including the hepatocytes
(receptor-mediated endocytosis, p. 26).
HDL particles are able to transfer cholesterol from tissue cells to LDL particles.
In this way, cholesterol is transported from tissues to the liver.
Drugs.
As nonabsorbable anion-exchange resins, colestyramine and
colestipol can bind bile acids in the gut lumen, which are thus
removed from cholesterol metabolism. The required dosage is
rather high (15-30 g/day) and liable to produce gastrointestinal
disturbances. Consequently, patient compliance is low. Moreover,
the resins trap needed drugs and vitamins. A more promising
approach to lowering absorption of cholesterol derives from a
novel mechanism of action probably based on the specific
inhibition of intestinal cholesterol transporters that are required
for absorption of cholesterol. An inhibitor of this type is
ezetimibe.
p-Sitosterin is a plant steroid that is not absorbed after oral administration; in suf ciently high dosage it impedes enteral absorption of cholesterol. Treatment with sitosterin has become obsolete. The drug is no longer on the market.
The statins lovastatin and fluvastatin inhibit HMG-CoA reductase. They contain a
molecular moiety that chemically resembles the physiological substrate of the enzyme
(A). Lovastatin is a lactone that is rapidly absorbed by the enteral route, subjected to
extensive first-pass extraction in the liver, and there hydrolyzed to active metabolites.
Fluvastatin represents the active form and, as an acid, is actively transported by a specific anion carrier that moves bile acids from blood into liver and also mediates the
selective uptake of the mycotoxin amanitin (A). Normally viewed as presystemic
elimination, ef cient hepatic extraction serves to confine the action of statins to the
liver. Despite the inhibition of HMG-CoA reductase, hepatic cholesterol content does
not fall because hepatocytes compensate any drop in cholesterol levels by increasing
the synthesis of LDL receptor protein (along with the reductase). Since, in the presence
of statins, the newly-formed reductase is inhibited as well, the hepatocyte must meet
its cholesterol demand entirely by uptake of LDL from the blood (B). Accordingly, the
concentration of circulating LDL falls. As LDL remains in blood for a shorter time, the
likelihood of LDL being oxidized to its proatherogenic degradation product decreases
pari passu.
Other statins include simvastatin (also a lactone prodrug),
pravastatin, atorvastatin, and cerivastatin (active form with open
ring). The statins are the most important therapeutics for
lowering cholesterol levels. Their notable cardiovascular
protective effect, however, appears to involve additional actions.
The combination of a statin with an inhibitor of cholesterol
absorption (e.g., ezetimibe) can lower LDL levels even further.
A rare but dangerous adverse effect of statins is damage to
skeletal muscle (rhab- domyolysis). This risk is increased by combined use of fibric acid agents (see below). Cerivastatin has
proved particularly toxic. Besides muscle damage associated with
myoglobinuria and renal failure, severe hepatotoxicity has also
been noted, prompting withdrawal of the drug.
Nicotinic acid and its derivatives (pyridyl- carbinol, xanthinol
nicotinate, and acipimox) activate endothelial lipoprotein lipase
and thereby mainly lower triglyceride levels. At the start of
therapy, a prostaglandin-mediated vasodilation occurs (flushing,
hypotension) that can be prevented by low doses of
acetylsalicylic acid.
Clofibrate and derivatives (bezafibrate, fe- nofibrate, and
gemfibrozil) lower concentrations of VLDL (triglycerides) along
with LDL (cholesterol). They may cause damage to liver and
skeletal muscle (myalgia, myopathy, rhabdomyolysis with
myoglobinemia and renal failure). The mechanism of action of
fibrates is not completely understood. They bind to a peroxisome
proliferator-activated receptor (PPARa) and thereby influence
genes regulating lipid metabolism.
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