Pathogenesis of atherosclerosis and therapy goals
The development of an atherosclerotic plaque begins with endothelial damage and inflammation, accompanied by the production of reactive oxygen species. Under these conditions, low-density lipoproteins (LDL) undergo oxidation. Phagocytes engulf the modified LDL, transforming into foam cells that form the lipid core of the plaque.
Based on this pathogenesis, pharmacotherapy pursues four main strategic goals:
- Reduction of atherogenic fractions in plasma.
- Suppression of lipoprotein peroxidation.
- Reduction of free radical production using antioxidants.
- Protection of the vascular intima with endotheliotropic angioprotectors.
Universal cellular mechanism of action
Most hypolipidemic drugs work via a single principle at the liver level:
- The primary effect is a decrease in cholesterol reserves inside liver cells (hepatocytes).
- In response to this deficiency, hepatocytes increase the expression of lipoprotein receptors on their surface.
- Receptor-mediated endocytosis is activated: the liver begins to more intensively capture lipoproteins from the bloodstream to replenish its own reserves, effectively clearing the plasma.
Classification of hypolipidemic drugs
Pharmacological agents are divided into five key groups depending on their primary mechanism of action:
- HMG-CoA reductase inhibitors (statins): block the cholesterol synthesis enzyme (Simvastatin, Atorvastatin, Rosuvastatin).
- Cholesterol absorption inhibitors: suppress sterol transporters in the intestine (Ezetimibe).
- Bile acid sequestrants: bind acids in the gastrointestinal tract (Cholestyramine).
- Fibrates (fibric acid derivatives): activate lipoprotein lipase (Gemfibrozil).
- Nicotinic acid preparations: inhibit triglyceride lipase (Niacin).
Briefly: answers to topical questions
Which drugs belong to the group of HMG-CoA reductase inhibitors (statins)?
The group of HMG-CoA reductase inhibitors (statins) includes the following medications:
- Simvastatin — blocks the key enzyme of cholesterol synthesis in the liver;
- Atorvastatin — cholesterol synthesis inhibitor;
- Rosuvastatin — cholesterol synthesis inhibitor;
- Lovastatin — inhibits cholesterol synthesis inside hepatocytes;
- Pravastatin — inhibits cholesterol synthesis inside hepatocytes.
What is the mechanism of action of fibrates at the molecular level?
At the molecular level, the mechanism of action of fibrates consists in the activation of nuclear PPAR$\alpha$ receptors (peroxisome proliferator-activated receptors). This leads to the following effects:
- expression of endothelial lipoprotein lipase and stimulation of its activity;
- increase in the synthesis of apoproteins Apo A (apoA-I and apoA-II);
- inhibition of cholesterol synthesis in the liver;
- increase in the density of lipoprotein receptors on hepatocytes.
As a result, the catabolism of triglyceride-rich particles is accelerated.
What side effects are most characteristic of statins?
Statins are characterized by side effects affecting various body systems.
- General reactions — dyspeptic disorders, central nervous system disturbances (insomnia, headache), and skin manifestations (erythema, rash).
- Hepatotoxicity — a dose-dependent effect that may manifest as an increase in liver transaminase levels.
- Muscular tissue damage — occurs infrequently, but represents the greatest danger, manifesting as myopathy and rhabdomyolysis (destruction of muscle tissue).
Which drugs belong to bile acid sequestrants?
The group of bile acid sequestrants includes the following medicinal products, which are anion-exchange resins:
- Cholestyramine (also referred to as cholesterolamine or questran) — forms non-absorbable complexes with bile acids in the intestinal lumen;
- Colestipol (cholestid) — has approximately the same therapeutic efficacy as cholestyramine.
Both drugs disrupt enterohepatic circulation and enhance the excretion of bile acids from the body with feces.
Which specific enzyme is inhibited by nicotinic acid preparations in adipose tissue?
In adipose tissue (adipocytes), nicotinic acid preparations inhibit the enzyme triglyceride lipase (also referred to as TAG lipase or triacylglycerol lipase). Suppression of this enzyme's activity leads to the following effects:
- reduction of intracellular lipolysis in adipocytes;
- decrease in the formation of free fatty acids;
- decrease in the transport of free fatty acids from adipocytes to the liver.
Class and exam questions
What is the main ultimate goal of prescribing hypolipidemic agents?
Reduction of atherogenic lipoproteins in blood plasma, which is achieved by suppressing the synthesis of cholesterol and VLDL.
How do intestinal cholesterol absorption inhibitors work?
They inhibit a specific sterol transporter in the intestine, which reduces the incorporation of cholesterol into chylomicrons. The drug can be used as monotherapy or together with statins.
What happens to HDL levels during therapy?
As a concomitant effect, a compensatory increase in the level of high-density lipoproteins, which possess protective antiatherogenic properties, is often observed.
What else to study on this topic
- Differences in lipoproteins by lipid composition and apolipoproteins
- Pathways of VLDL metabolism to LDL in the bloodstream
- The role of laropiprant in reducing side effects of nicotinic acid
- Use of omega-3 fatty acid preparations (Eiconol) in therapy
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