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Pharmacodynamics

Pharmacodynamics studies the biochemical and physiological effects of drugs on the human body, the mechanism of their action and the relationship between the concentration of the drug and its effect.

The activity of most cardiovascular drugs is mainly due to interaction with enzymes, structural or transport proteins, ion channels, hormone receptor ligands, neuromodulators and neurotransmitters, as well as cell membrane rupture (general anesthetics) or chemical reactions (cholestyramine, cholesterol-binding substances, active as chelate compounds). Enzyme binding alters the production or metabolism of key endogenous substances: acetylsalicylic acid irreversibly inhibits the enzyme prostaglandin synthase (cyclooxygenase), thereby preventing the development of an inflammatory response; ACE inhibitors prevent the production of angiotensin II and at the same time suppress the degradation of bradykinin, and therefore its concentration increases and the vasodilating effect increases; cardiac glycosides inhibit the activity of H+, K+-ATPase.

Agonism and antagonism

Most drugs act as ligands that bind to receptors responsible for cellular effects. Binding to the receptor can cause its normal activation (agonist, partial agonist), blockade (antagonist), or even reverse action (inverse or reverse agonist). The binding of a ligand (LG) to a receptor occurs according to the law of mass action, and the binding-dissociation ratio can be used to determine the equilibrium concentration of bound receptors. The response to the drug depends on the number of receptors bound (occupation). The relationship between the number of occupied receptors and the pharmacological effect is usually nonlinear.

The basic principles of drug-receptor interaction are based on the assumption that the agonist reversibly interacts with the receptor and, therefore, induces its effect. Antagonists bind to the same receptors as agonists, but usually have no effects other than interfering with the binding of agonist molecules to the receptor and, accordingly, suppressing the effects mediated by the latter. Competitive antagonists bind reversibly to receptors. If antagonists are able to weaken the maximum effects of agonists, then the antagonism is considered non-competitive or irreversible. Experimental pharmacology has shown that some angiotensin II type 1 receptor blockers (ARBs) exhibit irreversible effects, but the clinical significance of this finding is debatable because, within the dose range recommended for clinical use, the irreversible effects of ARBs are small or negligible. Concentrations of agonists and antagonists in humans are never as high as in the experiment, and the effects of all antagonists are mainly competitive in nature, i.e. reversible.

Specificity (selectivity) of cardiovascular drugs

The specificity of a molecule is determined by its activity at one receptor, receptor subtype, or enzyme. Depending on the therapeutic target, specificity of the drug's action within the cardiovascular system can be achieved. For example, since voltage-gated calcium channels have only a minor effect on the tone of venous smooth muscle cells, slow calcium channel blockers serve as selective arterial dilators.

Similarly, vasopressin agonists have a vasoconstrictor effect primarily on the vessels of the internal organs, so they are used in the treatment of portal hypertension. Sildenafil (phosphodiesterase type V inhibitor) has a dilating effect on the vascular bed of the penis and lungs, which may reflect the expression of this enzyme in these vascular beds. Along with their presence in target organs, receptors with similar structures are also found in other cells and tissues.

When activated, they lead to the development of known side effects: agonists of 5-HT1 receptors and vasopressin cause coronary spasm, phosphodiesterase type V inhibitors cause systemic hypotension. Moreover, as the dose is increased, a loss of specificity usually occurs. In Fig. Figure 1 shows a dose-response curve for a drug that acts on two receptors, but with different strengths. Under the influence of small doses of drugs, receptor A is specifically activated, but when high doses are used (the point where the curves converge), receptors A and B are activated equally. The selectivity of drugs is relative, not absolute.

Cardioselective β-adrenergic antagonists (β-blockers) are expected to act only on cardiac β1-adrenergic receptors, but in high doses they can also affect β2-adrenergic receptors in the bronchi and blood vessels, thereby stimulating broncho- and vasoconstriction. The selectivity of a drug can be expressed as the ratio of the relative binding strengths of different antagonists. It is obvious that targeted therapy requires drugs with a high degree of selectivity.

When drugs interact, the following conditions may develop: a) increased effects of a combination of drugs b) weakened effects of a combination of drugs c) drug incompatibility

Strengthening the effects of a drug combination is implemented in three options:

1) summation of effects or additive interaction– a type of drug interaction in which the effect of the combination is equal to the simple sum of the effects of each drug separately. Those. 1+1=2 . Characteristic of drugs from the same pharmacological group that have a common target of action (the acid-neutralizing activity of the combination of aluminum and magnesium hydroxide is equal to the sum of their acid-neutralizing abilities separately)

2) synergism - a type of interaction in which the effect of the combination exceeds the sum of the effects of each of the substances taken separately. Those. 1+1=3 . Synergism can relate to both the desired (therapeutic) and undesirable effects of drugs. The combined administration of the thiazide diuretic dichlorothiazide and the ACE inhibitor enalapril leads to an increase in the hypotensive effect of each drug, which is used in the treatment of hypertension. However, the simultaneous administration of aminoglycoside antibiotics (gentamicin) and the loop diuretic furosemide causes a sharp increase in the risk of ototoxicity and the development of deafness.

3) potentiation - a type of drug interaction in which one of the drugs, which by itself does not have this effect, can lead to a sharp increase in the effect of another drug. Those. 1+0=3 (clavulanic acid does not have an antimicrobial effect, but can enhance the effect of the β-lactam antibiotic amoxicillin due to the fact that it blocks β-lactamase; adrenaline does not have a local anesthetic effect, but when added to the ultracaine solution, it sharply prolongs its anesthetic effect by slowing down absorption anesthetic from the injection site).

Reducing Effects Drugs when used together are called antagonism:

1) chemical antagonism or antidotism– chemical interaction of substances with each other with the formation of inactive products (the chemical antagonist of iron ions deferoxamine, which binds them into inactive complexes; protamine sulfate, the molecule of which has an excess positive charge - the chemical antagonist of heparin, the molecule of which has an excess negative charge). Chemical antagonism underlies the action of antidotes (antidotes).

2) pharmacological (direct) antagonism- antagonism caused by the multidirectional action of 2 drugs on the same receptors in tissues. Pharmacological antagonism can be competitive (reversible) or non-competitive (irreversible):

a) competitive antagonism: a competitive antagonist reversibly binds to the active site of the receptor, i.e. shields it from the action of the agonist. Because the degree of binding of a substance to the receptor is proportional to the concentration of this substance, then the effect of a competitive antagonist can be overcome by increasing the concentration of the agonist. It will displace the antagonist from the active center of the receptor and cause a full tissue response. That. a competitive antagonist does not change the maximum effect of the agonist, but a higher concentration of the agonist is required for the interaction of the agonist with the receptor. Competitive antagonist shifts the dose-response curve for the agonist to the right relative to the initial values ​​and increases the EC 50 for the agonist, without affecting the value of E max .

In medical practice, competitive antagonism is often used. Since the effect of a competitive antagonist can be overcome if its concentration falls below the level of the agonist, during treatment with competitive antagonists it is necessary to constantly maintain its level sufficiently high. In other words, the clinical effect of a competitive antagonist will depend on its half-life and the concentration of the full agonist.

b) non-competitive antagonism: a non-competitive antagonist binds almost irreversibly to the active center of the receptor or generally interacts with its allosteric center. Therefore, no matter how much the concentration of the agonist increases, it is not able to displace the antagonist from its connection with the receptor. Since some of the receptors that are associated with a non-competitive antagonist are no longer able to activate , E value max decreases, but the affinity of the receptor for the agonist does not change, so the EC value 50 remains the same. On a dose-response curve, the effect of a non-competitive antagonist appears as a compression of the curve relative to the vertical axis without shifting it to the right.

Scheme 9. Types of antagonism.

A – a competitive antagonist shifts the dose-effect curve to the right, i.e. reduces the sensitivity of the tissue to the agonist without changing its effect. B - a non-competitive antagonist reduces the magnitude of the tissue response (effect), but does not affect its sensitivity to the agonist. C – option of using a partial agonist against the background of a full agonist. As the concentration increases, the partial agonist displaces the full one from the receptors and, as a result, the tissue response decreases from the maximum response to the full agonist to the maximum response to the partial agonist.

Non-competitive antagonists are used less frequently in medical practice. On the one hand, they have an undoubted advantage, because their effect cannot be overcome after binding to the receptor, and therefore does not depend either on the half-life of the antagonist or on the level of the agonist in the body. The effect of a non-competitive antagonist will be determined only by the rate of synthesis of new receptors. But on the other hand, if an overdose of this medicine occurs, it will be extremely difficult to eliminate its effect.

Losartan is a competitive antagonist for angiotensin AT 1 receptors; it disrupts the interaction of angiotensin II with receptors and helps lower blood pressure. The effect of losartan can be overcome by administering a high dose of angiotensin II. Valsartan is a non-competitive antagonist for these same AT 1 receptors. Its effect cannot be overcome even with the administration of high doses of angiotensin II.

Of interest is the interaction that takes place between full and partial receptor agonists. If the concentration of the full agonist exceeds the level of the partial agonist, then a maximum response is observed in the tissue. If the level of a partial agonist begins to increase, it displaces the full agonist from binding to the receptor and the tissue response begins to decrease from the maximum for the full agonist to the maximum for the partial agonist (i.e., the level at which it occupies all receptors).

3) physiological (indirect) antagonism– antagonism associated with the influence of 2 drugs on various receptors (targets) in tissues, which leads to a mutual weakening of their effect. For example, physiological antagonism is observed between insulin and adrenaline. Insulin activates insulin receptors, as a result of which the transport of glucose into the cell increases and the glycemic level decreases. Adrenaline activates  2 -adrenergic receptors in the liver and skeletal muscles and stimulates the breakdown of glycogen, which ultimately leads to an increase in glucose levels. This type of antagonism is often used in emergency care of patients with an insulin overdose that has led to hypoglycemic coma.