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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 interactions with enzymes, structural or transport proteins, ion channels, hormone receptor ligands, neuromodulators and neurotransmitters, as well as rupture of the cell membrane (general anesthetics) or chemical reactions (colestyramine, cholesterol-binding substances, acting as chelates). The binding of enzymes changes 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, in connection with which 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 a receptor can cause its normal activation (agonist, partial agonist), blockade (antagonist) or even the opposite effect (inverse or reverse agonist). The binding of a ligand (LS) to a receptor occurs according to the law of mass action, and the ratio of binding and dissociation can be used to determine the equilibrium concentration of bound receptors. The response to the use of the drug depends on the number of bound receptors (occupation). The relationship between the number of occupied receptors and the pharmacological effect is usually non-linear.

The basic principles of drug-receptor interaction are based on the assumption that an agonist interacts reversibly with the receptor and therefore induces its effect. Antagonists bind to the same receptors as agonists, but usually do not have other effects than preventing agonist molecules from binding to the receptor and, accordingly, suppressing the effects mediated by the latter. Competitive antagonists bind reversibly to receptors. If the antagonists are able to attenuate the maximal effects of the agonists, then the antagonism is considered noncompetitive or irreversible. According to experimental pharmacology, some type 1 angiotensin II receptor blockers (ARBs) show irreversible effects, but the clinical significance of this finding is debatable, since in the range of doses recommended for clinical use, the irreversibility of the effects of ARBs is small or insignificant. The 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 for one receptor, receptor subtype, or enzyme. Depending on the therapeutic target, specificity of drug action within the cardiovascular system can be achieved. For example, because voltage-gated calcium channels only marginally affect venous smooth muscle tone, slow calcium channel blockers serve as selective arterial dilators.

Similarly, vasopressin agonists have a vasoconstrictor effect predominantly 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 the presence in target organs, receptors similar in structure have been 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 - systemic hypotension. Moreover, as the dose is increased, there is usually a loss of specificity. On fig. 1 shows the dose-response curve for a drug acting on two receptors, but with different strengths. Under the influence of low doses of drugs, the A receptor is specifically activated, but against the background of the use of high doses (the place where the curves converge), the A and B receptors are activated equally. The selectivity of drugs is relative, not absolute.

Cardioselective β-adrenergic antagonists (β-blockers) are thought to affect only β1-adrenergic receptors in the heart, but at high doses they can also affect β2-adrenergic receptors in the bronchi and blood vessels, thus stimulating bronchoconstriction and vasoconstriction. The selectivity of a drug can be represented as the ratio of the relative binding strength of various antagonists. It is obvious that drugs with a high degree of selectivity are needed for directed (targeted) therapy.

In the interaction of drugs, the following conditions may develop: a) strengthening the effects of a combination of drugs b) weakening the effects of a combination of drugs c) drug incompatibility

Strengthening the effects of a combination of drugs is implemented in three ways:

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 of the drugs taken separately. Those. 1+1=2 . It is typical for drugs from the same pharmacological group that have a common target of action (the acid-neutralizing activity of a 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 a combination exceeds the sum of the effects of each of the substances taken separately. Those. 1+1=3 . Synergism can relate to both desired (therapeutic) and undesirable effects of drugs. The combined administration of the thiazide diuretic dichlothiazide and the ACE inhibitor enalapril leads to an increase in the hypotensive effect of each of the drugs, 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 in itself does not have this effect, can lead to a sharp increase in the action of another drug. Those. 1+0=3 (clavulanic acid does not have an antimicrobial effect, but is able to enhance the effect of the -lactam antibiotic amoxicillin due to the fact that it blocks -lactamase; adrenaline does not have a local anesthetic effect, but when added to ultracaine solution, it sharply lengthens its anesthetic effect by slowing down absorption anesthetic from the injection site).

Weakening 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 (chemical antagonist of iron ions deferoxamine, which binds them into inactive complexes; protamine sulfate, the molecule of which has an excess positive charge - a 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) and non-competitive (irreversible):

a) competitive antagonism: a competitive antagonist binds reversibly 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 if the concentration of the agonist is increased. 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 is required for the agonist to interact with the receptor. Competitive antagonist shifts the dose-response curve for the agonist to the right of baseline and increases the EC 50 for an 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, it is necessary to keep the level sufficiently high at all times during treatment with competitive antagonists. In other words, the clinical effect of a competitive antagonist will depend on its elimination 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 interacts in general with its allosteric center. Therefore, no matter how the concentration of the agonist increases, it is not able to displace the antagonist from its connection with the receptor. Since, the part of the receptors that is associated with a non-competitive antagonist is no longer able to be activated , E value max decreases, while the affinity of the receptor for the agonist does not change, so the EC value 50 remains the same. On the dose-response curve, the action of a non-competitive antagonist appears as a compression of the curve about the vertical axis without shifting it to the right.

Scheme 9. Types of antagonism.

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 agonist 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 rarely used in medical practice. On the one hand, they have an undeniable advantage, because. their action 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 drug 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 to lower blood pressure. The effect of losartan can be overcome if a high dose of angiotensin II is administered. Valsartan is a non-competitive antagonist for the same AT 1 receptors. Its action cannot be overcome even with the introduction of high doses of angiotensin II.

Of interest is the interaction that takes place between full and partial receptor agonists. If the concentration of a full agonist exceeds the level of a partial agonist, then a maximum response is observed in the tissue. If the level of the partial agonist begins to rise, it displaces the full agonist from its 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 will occupy all the receptors).

3) physiological (indirect) antagonism- antagonism associated with the influence of 2 medicinal substances 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, which increases the transport of glucose into the cell and lowers the level of glycemia. Adrenaline activates  2 -adrenergic receptors of 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 the emergency care of patients with an insulin overdose that has led to hypoglycemic coma.