Adrenoblockers

Drugs that exhibit reversible competitive blocking action on ¡-adrenoreceptive receptor system and that counteract effects of catecholamines are called ¡-adrenoblockers.

These drugs selectively reduce cardiostimulatory, vasodilating, broncholytic, and metabolic (glycogenolytic and lipolytic) action of catecholamines released from adrenergic nerve endings and adrenal glands.

¡j-Receptors are present in heart tissues, and cause an increased heart rate by acting on the cardiac pacemaker cells. Many ¡-blockers used for treatment of angina will mainly affect these receptors and the ¡2-receptors to a lesser extent. These are referred to as 'cardio-selective' ¡-blockers.

¡2-Receptors are in the vessels of skeletal muscle, and cause vasodilation, which allows more blood to flow to the muscles, and reduces total peripheral resistance. These tend to work with epinephrine (adrenaline), but not norepinephrine (noradrenaline).

¡2-Receptors are also in bronchial smooth muscle, and cause bronchodilation when activated. Some antiasthma drugs, such as the bronchodilator salbutamol work by binding to and stimulating the ¡2-receptors.

Nonselective ¡-blocking drugs, such as propranolol, can represent a risk to people with asthma by blocking the ¡2-receptors, causing bronchoconstriction.

Introduction of ¡-adrenoblockers into medicine was one of the main advancements of pharmacology of the cardiovascular system. Initially these drugs were used only in treating essential hypertension. Currently, they are used in treating angina, arrhythmia, migraines, myocardial infarctions, and glaucoma.

Their efficacy in many illnesses is explained by the competitive binding of ¡-adrenore-ceptors in the autonomic nervous system by basically any of the employed drugs of the 1-aryloxy-3-aminopropanol-2 class, which result in reduction of heart rate and strength of cardiac beats, slowing of atrioventricular conductivity, reduction of the level of renin in the plasma, and reduction of blood pressure. The main effects of ¡-adrenoblockers are expressed at the level of the vasomotor center in the hypothalamus, which result in a slowing of the release of sympathetic, tonic impulses. Included in the main group of

¡¡-adrenoblockers are the drugs propranolol, metoprolol, nadolol, atenolol, timolol, acebu-tol, pindolol, esmolol, and a combinded a- and ¡¡-adrenoblocker, labetalol.

In terms of chemical structure, ¡-adrenoblockers have much in common. Practically, all of them are derivatives of 1-aryloxy-3-aminopropanol-2, the Q position of which always possesses a substituted or nonsubstituted aromatic or heteroaromatic group connected by an ether bond to a three-carbon chain. An R group at the nitrogen atom of the propanoic region must be represented as either a tertiary butyl group (nadolol, timolol), or an iso-propyl group (the remainder of the drugs).

It should be mentioned that the substituted ethanolamine group in the structure of ¡¡-adrenoblockers is similar to that of many compounds with agonistic adrenergic activity (isoproterenol (11.1.9), albuterol (11.1.21), and others), and therefore it is possible that it may be responsible for high affinity of the examined adrenoblockers with ¡-adrenergic receptors.

Levorotatory isomers of these drugs are much more powerful adrenoblockers than dextrorotatory isomers; however, all of these drugs are made and used as racemic mixtures.

The examined drugs reversibly bind with ¡-adrenergic receptive regions and competitively prevent activation of these receptors by catecholamines released by the sympathetic nervous system, or externally introduced sympathomimetics.

As was already noted, ¡-adrenoreceptors are subdivided into ¡1-adrenoreceptors, which are predominantly found in cardiac muscle, and ¡2-adrenoreceptors, which are predominantly found in bronchial and vascular muscles. Thus, ¡-adrenoblocking substances are classified by their selectivity in relation to these receptors.

Compounds that exhibit roughly the same affinity to ¡1- and ¡2-receptors independent of dosage such as nadolol, propranolol, pindolol, timolol, and labetalol (combined a- and ¡-adrenoblocker) are classified as nonselective blockers. Drugs which in therapeutic doses have higher affinity to ¡1-receptors than to ¡2-receptors such as acebutol, atenolol, meto-prolol, and esmolol, are called selective or cardioselective ¡-adrenoblockers.

It is important to note that selectivity is not absolute, and it depends on the administered dose. In large doses, selectivity is even and both subtypes of ¡-adrenoreceptors are inhibited equally. In addition to blocking ¡-adrenoreceptors, these drugs affect the cardiovascular system in a different manner.

So, drugs that block ¡^-receptors lower the heart rate and blood pressure and hence are used in conditions when the heart itself is deprived of oxygen. They are routinely prescribed in patients with ischemic heart disease. In addition, ¡-blockers prevent the release of renin, which is a hormone produced by the kidneys which leads to constriction of blood vessels.

Drugs that block ¡2-receptors generally have a calming effect and are prescribed for anxiety, migraine, esophageal varices, and alcohol withdrawal syndrome, among others.

Propranolol: Propranolol, 1-(iso-propylamino)-3-(1-naphthyloxy)-2-propanol (12.1.2), is synthesized in two ways from the same initial substance. The first way consists of reacting

1-naphthol with epichlorohydrin. Opening of the epoxide ring gives 1-chloro-3-(1-naphthyloxy)-2-propanol (12.1.1), which is reacted further with iso--propylamine, giving propranolol (12.1.2).

The second method uses the same reagents in the presence of a base and consists of initially making 3-(1-naphthyloxy)propylenoxide (12.1.3), the subsequent reaction with iso-propylamine which results in epoxide ring opening leading to the formation of propranolol (12.1.2) [1-6].

O CH3

The second method uses the same reagents in the presence of a base and consists of initially making 3-(1-naphthyloxy)propylenoxide (12.1.3), the subsequent reaction with iso-propylamine which results in epoxide ring opening leading to the formation of propranolol (12.1.2) [1-6].

O CH3

Propranolol is a prototype of this series of drugs and is the oldest and most widely used nonselective /¡-adrenoblocker. It possesses antianginal, hypotensive, and antiarrhythmic action. Propranolol is a cardiac depressant that acts on the mechanic and electrophysio-logical properties of the myocardium. It can block atrioventricular conductivity and potential automatism of sinus nodes as well as adrenergic stimulation caused by catecholamines; nevertheless, it lowers myocardial contractility, heart rate, blood pressure, and the myocar-dial requirement of oxygen.

All of these properties make propranolol and other ¡-adrenoblockers useful antiarrhythmic and antianginal drugs.

Propranolol lowers blood pressure in the majority of patients with essential hypertension. These effects can be caused by a number of possible mechanisms, including lowering cardiac output, inhibiting the release of renin, lowering sympathetic release from the central nervous system, inhibiting the release of norepinephrine from sympathetic postganglionic nerves, and others.

However, not one of the suggested mechanisms adequately describes the antihypertensive activity of propranolol and other ¡-blockers.

Propranolol is used in treating arterial hypertonicity, angina, extrasystole, superventric-ular arrhythmia, ventricular tachycardia, migraines, hypertrophic subaortic stenosis, and pheochromocytoma. It also is used in the postanginal phase of myocardial infarctions. Universally accepted synonyms of this drug are anaprilin, inderal, and many others.

Metoprolol: Metoprolol, 1-(iio-propylamino)-3-[4'(2-methoxyethyl)phenoxy]-2-propanol (12.1.5), is synthesized by reacting 4-(2-methoxyethyl)phenol with epichlorhy-dride in the presence of a base, isolating 1,2-epoxy-3-[4'(2-methoxyethyl)phenoxy] propane (12.1.4), the subsequent reaction of which, analogous to that described before, with «o-propylamine, gives an opening of the epoxide ring and leads to the formation of metoprolol (12.1.5) [7,8].

O NaOH / \ ^ „,, A / ^ , -w ch_o-ch__ch—u a-O-CH2— —^

CH3O-CH2-CH2^^ j)—OH + CH2CI '» CH3O-CH2~CH2^^ /J ^"CH2" "

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