Pharmaceutical Chemistry PDF - Adrenergic Agents

Adrenergic Agents Lec :5+6 The three naturally occurring catecholamines DA, NE, and E are used as therapeutic agents. -DA stimulates the β1-receptors of the heart to increase cardiac output. -NE is a stimulant of α1-,α 2-, and β1-adrenoceptors (notice that lacking the N-methyl group resu...

Adrenergic Agents Lec :5+6 The three naturally occurring catecholamines DA, NE, and E are used as therapeutic agents. -DA stimulates the β1-receptors of the heart to increase cardiac output. -NE is a stimulant of α1-,α 2-, and β1-adrenoceptors (notice that lacking the N-methyl group results in lacking β2- and β3-activity. -E is a potent stimulant of all α1-, α2-, β1-, β2-, and β3- adrenoceptors,). It is much more widely used clinically than NE. -All are polar and rapidly metabolized by both COMT and MAO, resulting in poor oral bioavailability and short DOA.  Dipivefrin is a prodrug of Epinephrine that is formed by the esterification of the catechol OH groups of Epinephrine with pivalic acid. Most of the advantages of this prodrug over stem Epinephrine from improved bioavailability.  The greatly increased lipophilicity allows much greater penetrability in to the eye through the corneal epithelial and endothelial layer. Increased DOA is also achieved because the drug is resistant to the metabolism by COMT. After its absorption, it is converted to E by esterases slowly in the cornea and anterior chamber.  A second chemical class of α-agonists, the imidazolines, which give rise to α -agonists and are thus vasoconstrictors. These imidazolines can be nonselective, or they can be selective for either α1-or α2-receptors. Structurally, most imidazolines have their heterocyclic imidazoline nucleus linked to a substituted aromatic moiety via some type of bridging unit.The optimum bridging unit (X) is usually a single methylene group or amino group.  Agonist activity is enhanced when the aromatic ring is substituted with halogen substituents like chlorine (Cl) or small alkyl groups like methyl group, particularly when they are placed in the two ortho positions. All selective α1-agonists have therapeutic activity as vasoconstrictors. Structurally, they include: (a)Phenylethanolamine derivatives: such as phenylephrine, Metaraminol, and methoxamine. (b) 2-arylimidazolines derivatives: such as xylometazoline,oxymetazoline,tetrahydrozoline, and naphazoline.  (Neo- Synephrine), a prototypical selective direct-acting α1- 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-glucuronidation/ sulfation and metabolism by MAO. Lacking the p-OH group, it is less potent than E and NE but it is a selective α1-agonist and thus a potent vasoconstrictor. It is used for hypotension.  Metaraminol is just another example. Methoxamine (Vasoxyl) is another α1-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.  Naphazoline (Privine), tetrahydrozoline (Tyzine, Visine), xylometazoline (Otrivin), and oxymetazoline  (Afrin) These agents are used for their vasoconstrictive effects as nasal and ophthalmic decongestants.  All arylkylimidazoline α1-agonists contain a one-carbon bridge between C-2 of the imidazoline ring and a phenyl ring, and thus a phenylethylamine structure feature is there.  Ortho-lipophilic groups on the phenyl ring are important for - activity.  meta or Para-bulky lipophilic substituents on the phenyl ring may be important for the α1-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  Differs from 2-arylimidazoline α1-agonists mainly by the presence of o-chlorine groups and a NH bridge. The o-chlorine groups afford better activity than o- methyl groups at α2 sites. Importantly, clonidine contains a NH bridge (aminoimidazolines) instead of CH2 bridge in α2-arylimidazoline. The ability of clonidine and its analogs to exert an antihypertensive effect depends on the ability of these compounds not only to interact with the α2-receptor in the brain but also to gain entry into the CNS. Apraclonidine does not cross the BBB. However, brimonidine can cross the BBB and hence can produce hypotension and sedation, although these CNS effects are slight compared with those of clonidine. Brimonidine is a much more selective α2- agonist than clonidine or apraclonidine and is a firstline agent for treating glaucoma. Apraclonidine Brimonidine  Differs structurally from L-DOPA only in the presence of a α - methyl group. Methyldopa ultimately decreases the concentration of DA, NE, E, and serotonin in the CNS and periphery. However, its mechanism of action is not caused by its inhibition of AADC (L-Aromatic Amino acid Decarboxylase) but, rather, by its metabolism in the CNS to its active metabolite (α-methylnorepinephrine). This active metabolite is a selective α2-agonist because it has correct (1R,2S) configuration.  α- methyl norepinephrine acts on α2-receptors in the CNS in the same manner as clonidine, to decrease sympathetic outflow and lower blood pressure. Methyldopa is used only by oral administration because its zwitter ionic character limits its solubility. The ester hydrochloride salt of methyldopa, methyldopate (Aldomet ester), was developed as a highly water-soluble derivative that could be used to make parenteral preparations. It is converted to methyldopa in the body through the action of esterases Select this paragraph to edit Part one β-Adrenergic receptor agonists Isoproterenol Isoproterenol (Isuprel) is a nonselective and prototypical β -agonist (β2/β1 = 1). The principal reason for its poor absorption characteristics and relatively short DOA is its facile metabolism by sulfate and glucuronide conjugation of the phenolic OH groups and o-methylation by COMT.  Unlike E and NE, ISO does not appear to undergo oxidative deamination by MAO. Because of an isopropyl substitution on the nitrogen atom, isoproterenol has virtually no α -activity. However, it does act on both β1- and β2-receptors. It thus can produce an increase in cardiac output by stimulating cardiac β1-receptors and can bring about bronchodilation through stimulation of β2-receptors in the respiratory tract.  They belong to the structural class of resorcinol, bronchodilators that have 3,5-diOH groups of the phenyl ring (rather than 3,4-diOH groups as in catechols).they are β2-selective agonists. They relax the bronchial musculature in patients with asthma but cause less direct cardiac stimulation than do the nonselective -agonists. Metaproterenol is less β2 selective than either terbutaline or albuterol (both have t-butyl groups), Although these agents are more selective for β2-receptors, they have a lower affinity for β2-receptors than ISO. However, they are much more effective when given orally, and they have a longer DOA.This is because they are resistant to the metabolism by either COMT or MAO.  These drugs are selective β2-agonists whose selectivity results from replacement of the meta-OH group of the aromatic ring with a hydroxymethyl moiety. Pirbuterol is closely related structurally to albuterol (β2/β1 60); the only difference between the two is that pirbuterol contains a pyridine ring instead of a benzene ring. As in the case of metaproterenol and terbutaline, these drugs are not metabolized by either COMT or MAO. Instead, they are conjugated with sulfate. They are thus orally active, and exhibit a longer DOA than ISO.  Salmeterol This drug associates with the β2 -receptor slowly resulting in slow onset of action and dissociates from the receptor at an even slower rate. It is resistant to both MAO and COMT and highly lipophilic (log P 3.88). It is thus very long acting (12 hours), an effect also attributed to the highly lipophilic phenyl alkyl substituent on the nitrogen atom, which is believed to interact with a site outside but adjacent to the active site.  The β3-receptor has been shown to mediate various pharmacological effects such as lipolysis, thermogenesis, and relaxation of the urinary bladder. Activation of the β3-receptor is thought to be a possible approach for the treatment of obesity, type 2 diabetes mellitus, and frequent urination.  Indirect-acting sympathomimetics act by releasing endogenous NE. They also enter the nerve ending by way of the active-uptake process and displace NE from its storage granules. The indirect-acting drugs that are used therapeutically are not catechol derivatives and, in most cases, do not even contain an OH moiety. In contrast with the direct-acting agents, the presence of a β –hydroxyl group decreases, and an α-methyl group increases, the effectiveness of indirect-acting agents..  The presence of nitrogen substituents decreases indirect activity, with substituents larger than methyl groups rendering the compound virtually inactive. Phenylethylamines that contain a tertiary amino group are also ineffective as NE-releasing agents. Amphetamine and p-tyramine are often cited as prototypical indirect-acting sympathomimetics. Because amphetamine- type drugs exert their primary effects on the CNS.  Hydroxy amphetamine (Paredrine) Is an effective, Indirect-acting sympathomimetic drug. It differs from amphetamine in the presence of p-OH group and so it has little or no CNS-stimulating action. It is used to dilate the pupil for diagnostic eye examinations and for surgical procedures on the eye. Propylhexedrine (Benzedrex) Another analog of amphetamine in which the aromatic ring has been replaced with a cyclohexane ring. This drug produces vasoconstriction and a decongestant effect on the nasal membranes, but it has only about one half the pressor effect of amphetamine.  Those phenylethylamines considered to have a mixed mechanism of action usually have no hydroxyls on the aromatic ring but do have a β -hydroxyl group. D-(-)-Ephedrine. The pharmacological activity of (1R,2S)- D-(-)-They are thus orally active resembles that of E. The drug acts on both α – and β -receptors. It is the classic example of a sympathomimetic with a mixed mechanism of action. Lacking H-bonding phenolic OH groups, ephedrine is less polar (log P 1.05, pKa 9.6) and, thus, crosses the BBB far better than do other CAs. Therefore, ephedrine has been used as a CNS stimulant and exhibits side effects related to its action in the brain. The drug is not metabolized by either MAO or COMT and therefore has more oral activity and longer DOA than E.  Is the N-desmethyl analog of ephedrine and thus has many similar properties. Lacking the N-methyl group, phenylpropanolamine is slightly more polar, and therefore does not enter the CNS as well as ephedrine. This modification gives an agent that has slightly higher vasopressive action and lower central stimulatory action than ephedrine. Its action as a nasal decongestant is more prolonged than that of ephedrine. It is orally active. Select this paragraph to edit The End