Endogenous Catecholamines

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The three naturally occurring catecholamines DA, NE, and E are used as therapeutic agents.

Dopamine. (DA, 3' ,4' -dihydroxyphenylethylamine) differs from NE in lacking of i-OH group. It is the immediate precursor of NE and is a central NT particularly important in the regulation of movement (see Chapter 13). As a catechol and primary amine, DA is rapidly metabolized by COMT and MAO and has a short DOA with no oral activity. It is used intravenously in treatment of shock. In contrast with the NE and E, DA increases blood flow to the kidney in doses that have no chronotropic effect on the heart or that cause no increase in blood pressure. The increased blood flow to the kidneys enhances glomerular filtration rate, Na+ excretion, and, in turn, urinary output. The dilation of renal blood vessels produced by DA is the result of its agonist action on the d1-DA receptor.

Dopamine (DA, Log P = 0.12) NE (Log P = -0.63) E (Log P = 0.28)

All are polar and metabolized by both MAO and COMT orally inactive and short duration of action

In doses slightly higher than those required to increase renal blood flow, DA stimulates the ^-receptors of the heart to increase cardiac output. Some of the effects of DA on the heart are also caused by NE release. Infusion at a rate greater than 10 fg/kg per minute results in stimulation of a1-receptors, leading to vasoconstriction and an increase in arterial blood pressure. DA should be avoided or used at a much reduced dosage (one tenth or less) if the patient has received an MAO inhibitor. Careful adjustment of dosage also is necessary in patients who are taking tricyclic antidepressants.

Norepinephrine (NE, Levophed) differs from DA only by addition of a 1-OH substituent (S-OH-DA) and from E only by lacking the n-methyl group. Like DA, it is polar and rapidly metabolized by both COMT and MAO, resulting in poor oral bioavailability and short DOA (1 or 2 minutes even when given intravenously). It is a stimulant of a1-, a2-, and ^-adrenoceptors (notice that lacking the n-methyl group results in lacking fS2- and jS3-activity). It is used to counteract various hypotensive crises, because its a--activity raises blood pressure and as an adjunct treatment in cardiac arrest because its j-activity stimulates the heart. It has limited clinical application caused by the nonselective nature of its activities.

Epinephrine (E, Adrenalin) differs from NE only by the addition of an n-methyl group. Like the other CAs, E is light sensitive and easily oxidized on exposure to air because of the catechol ring system. The development of a pink-to-brown color indicates oxidative breakdown. To minimize oxidation, solutions of the drug are stabilized by the addition of reducing agents such as sodium bisulfite. E is also destroyed readily in alkaline solutions and by metals (e.g., Cu, Fe, Zn) and weak oxidizing agents. It is used in aqueous solution for inhalation as the free amine. Like other amines, it forms salts with acids, hydrochloride, and the bitartrate being the most common.

Like NE, it lacks oral activity and has short DOA. However, it is much more widely used clinically than NE. E is a potent stimulant of all a1-, a2-, j1-, j2-, and fS3-adrenoceptors, and thus it switches on all possible adrener-gic receptors, leading to a whole range of desired and side effects. Particularly prominent are the actions on the heart and on vascular and other smooth muscle. It is a very potent vasoconstrictor and cardiac stimulant. NE has, in general, greater S-activity caused by an additional n-methyl group. Therefore, E is used to stimulate the heart in cardiac arrest. Although intravenous infusion of E has pronounced effects on the cardiovascular system, its use in the treatment of heart block or circulatory collapse is limited because of its tendency to induce cardiac arrhythmias.

The ability of epinephrine to stimulate jS2-receptors has led to its use by injection and by inhalation to relax bronchial smooth muscle in asthma and in anaphylactic reactions. Several OTC preparations (e.g., Primatene, Bron-kaid) used for treating bronchial asthma use E. It is also used in inhibiting uterine contraction. Because of its a-activity, E is used to treat hypotensive crises and nasal congestion, to enhance the activity of local anesthetics, and as a constrictor in hemorrhage.

In addition, E is used in the treatment of open-angle glaucoma, where it apparently reduces intraocular pressure by increasing the rate of outflow of aqueous humor from the anterior chamber of the eye. The irritation often experienced on instillation of E into the eye has led to the development of other preparations of the drug that potentially are not as irritating. One such example is dipivefrin.

Dipivefrin (Propine, Dipivalyl Epinephrine). To overcome several of the pharmacokinetic and pharmaceutical shortcomings of E as an ophthalmic agent, the prodrug approach has been successfully applied. Dipivefrin is a prodrug of E that is formed by the esterification of the catechol OH groups of E with pivalic acid. Most of the advantages of this prodrug over E stem from improved bioavailability. The greatly increased lipophilicity allows much greater penetrability into the eye through the corneal epithelial and endothelial layer. The stroma in between requires hy-drophilicity for penetration. Dipivefrin has that, too, due to the 1-OH group and cationic nitrogen (the eyedrops contain the hydrochloride [HCl] salt). This dual solubility permits much greater penetrability into the eye than the very hy-drophilic E hydrochloride. Increased DOA is also achieved because the drug is resistant to the metabolism by COMT. In addition to its increased in vivo stability, it is also less easily oxidized by air due to the protection of the catechol OH groups. This high bioavailability and in vivo and in vitro stability translate into increased potency such that the 0.1% ophthalmic solution is approximately equivalent to a 2% E solution. After its absorption, it is converted to E by esterases slowly in the cornea and anterior chamber. Dipivefrin also offers the advantage of being less irritating to the eye than E.


All selective a1-agonists have therapeutic activity as vasoconstrictors. Structurally, they include (a) phenylethanolamines

Midodrine And DesglymidodrinePharmaceutical Chemistry Images

such as phenylephrine, metaraminol, and methoxamine and (b) 2-arylimidazolines such as xylometazoline, oxymetazo-line, tetrahydrozoline, and naphazoline.

Phenylephrine. (Neo-Synephrine, a prototypical selective direct-acting ^-agonist) differs from E only in lacking a p-OH group. It is orally active, and its DOA is about twice that of E because it lacks the catechol moiety and thus is not metabolized by COMT. However, its oral bioavailability is less than 10% because of its hydrophilic properties (log P = —0.3), intestinal 3'-O-glucuronida-tion/sulfation and metabolism by MAO. Lacking the p-OH group, it is less potent than E and NE but it is a selective ^-agonist and thus a potent vasoconstrictor. It is used similarly to metaraminol and methoxamine for hypotension. Another use is in the treatment of severe hypotension resulting from either shock or drug administration. It also has widespread use as a nonprescription nasal decongestant in both oral and topical preparations. When applied to mucous membranes, it reduces congestion and swelling by constricting the blood vessels of the membranes. In the eye, it is used to dilate the pupil and to treat open-angle glaucoma. In addition, it is used in spinal anesthesia to prolong the anesthesia and to prevent a drop in blood pressure during the procedure. It is relatively nontoxic and produces little CNS stimulation. Metaraminol is just another example.

Methoxamine (Vasoxyl) is another a1-agonist and parenteral vasopressor used therapeutically and so have few cardiac stimulatory properties. It is bioactivated by O-demethylation to an active m-phenolic metabolite. In fact, it tends to slow the ventricular rate because of activation of the carotid sinus reflex. It is less potent than phenylephrine as a vasoconstrictor. Methoxamine is used primarily during surgery to maintain adequate arterial blood pressure, especially in conjunction with spinal anesthesia. It does not stimulate the CNS. Because it is not a substrate for COMT, its DOA is significantly longer than NE.

Midodrine (ProAmatine) is the N-glycyl prodrug of the selective ^-agonist desglymidodrine. Removal of the N-glycyl moiety from midodrine occurs readily in the liver as well as throughout the body, presumably by amidases. Midodrine is orally active and represents another example of a dimethoxy-j-phenylethylamine derivative that is used therapeutically for its vasoconstrictor properties. Specifically, it is used in the treatment of symptomatic orthostatic hypotension.

Midodrine And DesglymidodrineWhat Pharmaceutical Chemistry

Naphazoline (Privine), tetrahydrozoline (Tyzine, Visine), xylometazoline (Otrivin), and oxymetazoline (Afrin) are 2-aralkylimidazolines aragonists. These agents are used for their vasoconstrictive effects as nasal and ophthalmic decongestants. Although nearly all [-agonists are phenylethanolamine derivatives, a--receptors accommodate more diverse chemical structures. All 2-aralkylimidazoline a1-agonists contain a one-carbon bridge between C-2 of the imidazoline ring and a phenyl ring, and thus a phenylethyl-amine structure feature is there. Ortho--lipophilic groups on the phenyl ring are important for a-activity. However, meta-or para-bulky lipophilic substituents on the phenyl ring may be important for the a1-selectivity. They have limited access to the CNS, because they essentially exist in an ionized form at physiological pH caused by the very basic nature of the imidazoline ring (pKa = 10-11). Xylometazoline and oxymetazoline have been used as topical nasal deconges-tants because of their ability to promote constriction of the nasal mucosa. When taken in large doses, oxymetazoline may cause hypotension, presumably because of a central clonidine-like effect. Oxymetazoline also has significant affinity for œ2A-receptors.

Clonidine (Catapres) differs from 2-arylimidazoline ^-agonists mainly by the presence of ^-chlorine groups and a NH bridge. The ^-chlorine groups afford better activity than tf-methyl groups at a2 sites. Importantly, clonidine contains a NH bridge (aminoimidazolines) instead of CH2 bridge in 2-arylimidazoline. The uncharged form of clonidine exists as a pair of tautomers as shown next. Clonidine is an example of a (phenylimino) imidazolidine derivative that possesses central ^-selectivity. The a1:a2 ratio is 300:1. Under certain conditions, such as intravenous infusion, clonidine can briefly exhibit vasoconstrictive activity as a result of stimulation of peripheral œ-receptors. However, this hypertensive effect, if it occurs, is followed by a much longer-lasting hypotensive effect as a result of the ability of clonidine to enter into the CNS and stimulate

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