cardiovascular drugs (2023)

Sympathetic function inhibition

B- blockers

Because they were introduced in the 1960s.BAdrenergic blockers have become the most commonly used drugs in cardiovascular disease. The first was propranololB-blocker to come into wide clinical use and remains the most important of these compounds. It is a very potent non-selective adrenergic blocking agent that has no intrinsic sympathomimetic activity. However, due to its ability to blockBreceptors on bronchial smooth muscle and skeletal muscle, propranolol impairs epinephrine-induced bronchodilation and glycogenolysis that commonly occurs during hypoglycemia. Therefore, the drug is generally not used in people with asthma and should be used with caution in diabetics receiving insulin. Thus began the searchB-blockers that are cardioselective and many drugs have already been developed that show some degree of specificity forB1-adrenergic receptors. Metaprolol is the prototype of these more specific drugs.

a lot of pharmacologyB-blockers can be inferred from the knowledge of the functions supported by the receptors involved and the physiological conditions in which they are activated. Thus, β-receptor blockade has little effect on the normal heart of a patient at complete rest, but can have profound effects when sympathetic control of the heart is high, as during exercise.B- blockers reduce heart rate and cardiac output, prolong mechanical contraction and slightly lower blood pressure in people at rest. As a result of compensatory sympathetic reflexes, peripheral resistance increases and blood flow to all tissues except the brain is reduced. Some of these drugs also have direct effects on cell membranes, which are commonly described as membrane stabilizers and local anesthetics. The local anesthetic effect of propranolol is approximately the same as that of lidocaine.

B-blockers are effective antihypertensive drugs. Chronic treatment of hypertensive patients with beta-adrenergic blockers results in a slowly progressive decrease in blood pressure. Several mechanisms have been proposed for the effectiveness of β-blockers in the treatment of hypertension. Decreased cardiac output occurs rapidly after administration of beta-blockers. However, the hypotensive effectB-blockers don't spawn as fast. The release of renin from the perilingual apparatus is stimulated by adrenergic agonists and this action is blocked by drugs such as propranolol. Also, BBeta-adrenergic agonists are known to slightly increase the release of norepinephrine from adrenergic nerve endings, resulting in vasoconstriction.BBlockers block this effect, and this impairment of norepinephrine release following sympathetic nerve stimulation may contribute to the drugs' antihypertensive effect.

A- blockers

Alpha-adrenergic blocking agents are present in most blood vessels, especially resistance vessels. Since their stimulation leads to constriction and therefore an increase in blood pressure, it is understandable that blocking this stimulation leads to a decrease in blood pressure. Phenoxybenzamine binds covalently to the α receptor and forms an irreversible blockade. Phentolamine and tolazoline reversibly bind and competitively antagonize the action of sympathomimetic amines.

Rezerpina

serpentinowa rauwofiaIt is a climbing shrub native to India and neighboring countries. In 1954, it was reported that rauwolfia or reserpine was useful in the treatment of psychotic patients because it acts centrally, producing a characteristic sedation and a state of indifference to environmental stimuli; phenothiazine-like effects (discussed in Psychoactive Drugs). The subsequent discovery of the ability of rauwolfia alkaloids and related compounds to remove biogenic amines from storage sites in the body initiated many studies aimed at elucidating the interactions between these amines and reserpine. There are many rauwolfia alkaloids with a complex structure. The structure of reserpine is as follows:

It is clear that reserpine interferes with intracellular storage of catecholamines, but the amounts of reserpine in tissues are too small to assume a stoichiometric shift. Reserpine antagonizes norepinephrine uptake by isolated chromaffin granules by ATP-Mg inhibition²⁺Mechanism of uptake dependent on the granular membrane. The drug also binds to the alveolar membranes for several days, which is responsible for the irreversibility of the process.

Reserpine depletes catecholamine stores in many organs, including the brain and adrenal medulla, and most of its pharmacological effects are attributed to this action. As reuptake is inhibited, rather than catecholamine release, the existing pool must be completely depleted before antihypertensive effects become apparent. Even at relatively high doses, reserpine produces a transient sympathomimetic effect followed by a slowly progressive drop in blood pressure, often accompanied by bradycardia. At normal doses, reduced levels of catecholamines can be measured within one hour of reserpine administration, and depletion is maximal after 24 hours. Most catecholamines are deaminated within neurons, and the pharmacologic effects of the released mediator are minimal unless MAOIs have been inhibited.

The reserpine-induced decrease in norepinephrine synthesis is a blockade of dopamine uptake into storage granules containing the enzyme dopamine.B-hydroxylase (see norepinephrine synthesis). Furthermore, increasing the concentration of free catecholamines probably inhibits tyrosine hydroxylase, as norepinephrine competes with the cofactor pterin for the enzyme.

Hypersensitivity to catecholamines is observed after chronic use of reserpine. The site of change is presumably postjunctional and may be due to changes in adrenergic receptors. Such adaptive change is usually the result of chronic transmitter deprivation.

Reserpine is used as an effective antihypertensive, especially when combined with other agents such as diuretics. Its low cost, once-daily administration, and minimal change in effect when adherence is inconsistent make it useful as a long-term treatment for patients with uncomplicated mild hypertension. However, reserpine causes mental depression in 25% of patients.

diuretics

A diuretic is a substance that increases the rate of urine excretion, as the name suggests. Most diuretics also increase urinary excretion of solutes, especially sodium and chloride. In fact, most clinically used diuretics work by reducing the rate of sodium reabsorption from the nephron tubules, which in turn causes nature, and this, in turn, causes diuresis. The most common clinical use of diuretics is to reduce the volume of extracellular fluids, mainly in diseases associated with edema and hypertension.

carbonic anhydrase inhibitors

Shortly after the introduction of sulfonamides as antibacterial agents in the 1930s, changes in patients' electrolyte balance and systemic acidosis with urine alkalinization due to increased HCO₃^-excretion. Proposals by several scientists have established that inhibition of the enzyme carbonic anhydrase (CA) is responsible for the electrolyte imbalances produced. Since the antibacterial sulfonamides were relatively weak inhibitors, a successful search for a more potent CA inhibition was initiated. Acetazolamide became the first effective drug introduced into clinical use.

Of the large number of sulfonamides that have been synthesized and tested, acetazolamide has been studied most extensively as a carbonic anhydrase inhibitor. Other drugs in this class available in the US include dichlorphenamide and methazolamide. There, the structural formulas are as follows:

Mechanism of action.The kidneys control the body's acid-base balance by excreting acidic or alkaline urine. The general mechanism by which the kidneys achieve this is as follows: Large numbers of bicarbonate ions are continually filtered into the renal tubules, and if they are excreted in the urine, this removes alkali from the blood. On the other hand, large amounts of hydrogen ions are also secreted into the lumen of the tubules by the tubular epithelial cells, thus removing acids from the blood.

Bicarbonate ions enter the lumen of the renal nephron tubules along with the glomerular filtrate. Bicarbonate ions do not easily penetrate the luminal membranes of renal tubular cells; therefore, the bicarbonate ions that are filtered by the glomeruli cannot be directly reabsorbed. Instead, bicarbonate is reabsorbed in a special process where it first combines with hydrogen ions to form H₂SWINDLER₃, which eventually becomes CO₂I H₂O.

\[\ce{ H^{+} + HCO3 <=> H2CO3 <=> CO2 + H2O}\]

This reabsorption of bicarbonate ions is initiated by a reaction in the tubules between bicarbonate ions filtered in the glomeruli and hydrogen ions secreted by the tubular cells. H₂SWINDLER₃is formed and then dissociates into CO₂I H₂CO₂can move easily through the tubular membrane; therefore, it immediately diffuses into the tube cell where it recombines with the H₂O, under the influence of carbonic anhydrase, to produce a new H₂SWINDLER₃molecule. este H₂SWINDLER₃in turn dissociates to form a bicarbonate ion and a hydrogen ion. Hydrogen ions are secreted from the cell into the lumen of the tube by the sodium-hydrogen pump in exchange for sodium. Bicarbonate ions along with said Na+ then enter the peritubular blood supply. The hydrogen ion now in the lumen of the tube combines with another bicarbonate ion to form H₂SWINDLER₃, which is then dehydrated again in CO₂, which re-enters the tube cell. The net result is reabsorption of most of the bicarbonate. Some of these concepts can be seen here in an animated nephron (you need the Shockwave plugin to see this).cheered up

The mechanism of hydrogen bonds, which act competitively, explains the effects of carbonic anhydrase inhibitors similar to acetazolamide, which have diuretic properties. Carbonic acid is a normal substrate that fits into the cavity and forms complexes with the enzyme carbonic anhydrase. This complex is strongly stabilized by four hydrogen bonds (see figure below).

Acetazolamide-like drugs that fit into the enzyme cavity also bind efficiently, presumably to the same four regions via hydrogen bonds (see figure below).

Thus, these sulfonamides competitively prevent the binding of carbonic acid at this site, which inhibits NaHCO reabsorption.₃I H₂0. More than 99% of enzyme activity in the kidneys must be inhibited before physiological effects become apparent.

Urinary volume increases rapidly after administration of acetazolamide. Urinary excretion of bicarbonate and related cations, primarily sodium (also potassium) and the normally acidic pH becomes alkaline. As a result, the concentration of bicarbonate in the extracellular fluid is reduced and metabolic acidosis occurs. The concentration of chloride in the urine decreases.

The presence of carbonic anhydrase in many intraocular structures, including the ciliary processes, and the high concentration of bicarbonate in aqueous humor have drawn attention to the role that this enzyme may play in aqueous humor secretion. acetazolamide reduces the rate of aqueous humor formation; intraocular pressure in patients with glaucoma is correspondingly reduced.

Benzotiadiazinas

Thiazines and related compounds are the most commonly used antihypertensive drugs in the United States. They were synthesized as an extension of research on carbonic anhydrase inhibitors. Thiazides act directly on the kidneys to increase excretion of sodium chloride and its associated water volume. In addition, many of these drugs act as carbonic anhydrase inhibitors. At the molecular level, it is not known how benzothiadiazines inhibit sodium chloride reuptake.

Dikumarol

The first orally active anticoagulant, dicumerol, which is a molecule composed of two 4-hydroxy coumarin moieties connected at position 3 by a CH2 bridge, was isolated from decomposed yellow sweet clover. It was discovered and identified due to the hemorrhagic death of cattle consuming this improperly stored feed in the early 1920s (sweet clover disease). This followed the demonstration that oral administration of the compound prolonged clotting time and reduced the incidence of postoperative intravascular thrombus formation.

Oral anticoagulants are vitamin K antagonists. Their administration to humans or other animals leads to the appearance of precursors of four vitamin K-dependent clotting factors in plasma and liver. These precursor proteins are biologically inactive in clotting assays. The prothrombin precursor protein can be non-physiologically activated to thrombin by snake venom, demonstrating that the part of the molecule required for this activity is intact. However, prothrombin and other precursor proteins cannot bind divalent cations such as calcium and therefore cannot interact with membranes containing phospholipids, which are their normal activation sites. This was puzzling for a while because abnormal prothrombin has the same number of amino acid residues and gives the same amino acid analysis after acid hydrolysis as normal prothrombin. NMR studies have shown that normal prothrombin containsG-carboxyglutamate (see figure below), a previously unknown residue. The vitamin K-sensitive step in the synthesis of clotting factors is the carboxylation of ten or more glutamic acid residues at the amino terminus of the precursor protein to formG-carboxyglutamate. These amino acid residues are much more potent calcium chelators than glutamate. Binding of Ca2+ by prothrombin anchors it to platelet-derived phospholipid membranes after damage. The functional significance of prothrombin binding to phospholipid surfaces is that it brings prothrombin closer to the two proteins that mediate its conversion to thrombin, factor Xa and factor V. The amino-terminal fragment of prothrombin, which contains Ca2+ binding sites, is released in this step of activation. The thrombin thus released from the surface of the phospholipids can then activate plasma fibrinogen.

In liver microsomes, the reduction of vitamin K to the form of hydroquinone (vitamin KH₂) precedes the bicarbonate-dependent carboxylation of the precursor prothrombin, decarboxyprothrombin, to prothrombin (see figure below). This carboxylase activity for prothrombin synthesis is related to the epoxidase activity for vitamin KH₂, which oxidizes the vitamin to vitamin K epoxide (KO). Epoxide reductase, which requires NADH, converts vitamin K epoxide back to vitamin KH₂. This reaction is the site of action for coumarins and the site of genetic resistance to coumarins, which is also characterized by an increased requirement for vitamin K. Therefore, it is the recycling of the vitamin into its reduced active cofactor that ultimately leads to decreased thrombin levels. The vitamin K analogue chloro-K1 (in which the 2-methyl group of vitamin K1 is replaced by a chloro group) directly inhibits the reaction of carboxylase and epoxidase, which are not sensitive to coumarins.

Vitamin K is reduced to the form of hydroquinone (KH₂). Gradual oxidation to vitamin K epoxide (KO) is coupled to protein carboxylation, where decarboxyprothrombin is converted to prothrombin by carboxylation of glutamate residues to g-carboxyglutamate. Enzymatic reduction of epoxide with NADH as a cofactor regenerates vitamin KH₂. Vitamin KH Oxidation₂. Vitamin K oxidation is inhibited by the chlorine analogue of vitamin K epoxide, which is a coumarin-sensitive step.

Dicoumerol, the prototype coumarin drug, is relatively low potency, with a slow onset of up to 5 days for maximum activity and hypoprothrombinemia. The anticoagulant effect may persist for more than 1 week after discontinuing the drug. Although excessive doses can be treated with vitamin K1, clinical correction of anticoagulation, especially downwards, is difficult. Warfarin has become the most widely used coumarin drug. It is the strongest, and many patients stick to just 5 mg a day.

Warfarin was initially introduced as a rodenticide because it was thought to be too dangerous for humans. It is still used for pest control. The drug, in the form of sugared pills, causes the death of rats by internal bleeding. Warfarin resistant rats were reported in London in the early 1960's. They were called "super rats". A few years later, this phenomenon appeared in humans. It has been shown to be an autosomal dominant trait. A person with this trait requires a 20-fold increase in drug dose to achieve anticoagulation - easily fatal for healthy patients. Explanations for this unusual phenomenon have been proposed. One is that a tissue protein that regulates the synthesis of one or more clotting factors has been genetically altered. Another is a mutation in the daphorase enzyme that makes it less susceptible to inhibition by coumarin drugs.

questions

1. What factors affect the heart's supply and demand for O2?
2. What are the symptoms and etiology of angina pectoris?
3. Both nitrates and beta-blockers have antianginal properties. Compare and compare the pharmacological effects of these two classes of compounds.
4. What are the sites of action of nitrates?
5. When prescribing nitrates, what would you advise the patient about side effects?
6. What are the benefits of calcium channel blockers in the treatment of angina pectoris? What is its mechanism of action? What are the contraindications for its use?
7. What are the two main goals of pharmacotherapy for angina pectoris?
8. What is the mechanism of action of nitroglycerin?