Pharmacology Lecture 6 PDF

Naphazoline, tetrahydrozoline, xylometazoline, and oxymetazoline Are 2-arylimidazolines α1-agonists. These agents are used for their vasoconstrictive effects as nasal and ophthalmic decongestants. All 2-arylimidazoline α1-agonists contain a one-carbon bridge between C-2 of the imidazoline ring and...

Naphazoline, tetrahydrozoline, xylometazoline, and oxymetazoline Are 2-arylimidazolines α1-agonists. These agents are used for their vasoconstrictive effects as nasal and ophthalmic decongestants. All 2-arylimidazoline α1-agonists contain a one-carbon bridge between C-2 of the imidazoline ring and a phenyl ring. Xylometazoline and oxymetazoline have been used as topical nasal decongestants because of their ability to promote constriction of the nasal mucosa while the others used as topical ophthalmic decongestants. When taken in large doses, oxymetazoline may cause hypotension, presumably because of a central clonidine-like effect. Clonidine 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 2- arylimidazoline. The uncharged form of clonidine exists as a pair of tautomers. Clonidine is an example of a (phenylimino) imidazolidine derivative that possesses central α2-selectivity. Stimulation of α2-receptors located in the brain brings about a decrease in sympathetic outflow from the CNS, which in turn leads to decreases in peripheral vascular resistance and blood pressure. 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 and Brimonidine. Apraclonidine does not cross the BBB. However, Brimonidine can cross the BBB and can produce hypotension and sedation, although these CNS effects are slight compared with those of clonidine. CNS effects of these drugs are correlated well to their log P, pKa, and thus log D value. Brimonidine is a much more selective α2-agonist than clonidine or apraclonidine and is a first line agent for treating glaucoma. Apraclonidine is used specifically to control elevations in intraocular pressure that can occur during laser surgery on the eye. Guanabenz and Guanfacine (Open-Ring Imidazolidines). In these compounds, the 2,6-dichlorophenyl moiety found in clonidine is connected to a guanidino group by a two-atom bridge. In the case of guanabenz, this bridge is a —CH=N— group, whereas for guanfacine, it is a —CH2CO— moiety. Guanfacine is more selective for α2-receptors than is clonidine. Methyldopa (L-α-methyldopa) Differs structurally from L-DOPA only in the presence of a α- methyl group. Originally synthesized as an AADC inhibitor, methyldopa ultimately decreases the concentration of DA, NE and E in the CNS and periphery. However, its mechanism of action is not caused by its inhibition of AADC but, rather, by its metabolism in the CNS to its active metabolite (α-methyl norepinephrine). DUAL α- AND β-AGONISTS/ANTAGONISTS Dobutamine Is a positive inotropic agent administered intravenously for congestive heart failure. It resembles dopamine structurally but possesses a bulky 1-(methyl)-3-(4-hydroxyphenyl) propyl group on the amino group. The (- ) isomer of dobutamine is a potent α1-agonist, which is capable of causing marked pressor responses. In contrast, (+)-dobutamine is a potent α1-antagonist, which can block the effects of (-)-dobutamine. The therapeutic effects of these two isomers are mediated via β1-receptors. Both isomers appear to be full agonists, but the (+) isomer is a more potent β1-agonist than the (-) isomer. β-ADRENERGIC RECEPTOR AGONISTS Isoproterenol Is a nonselective and prototypical β-agonist (β2/β1 = 1). Unlike E and NE, ISO does not appear to undergo oxidative deamination by MAO. It 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. Metaproterenol and terbutaline Belong to the structural class of resorcinol bronchodilators that have 3ʹ,5ʹ-diOH groups of the phenyl ring (rather than 3ʹ,4ʹ-diOH groups as in catechols). 3ʹ,5ʹ-diOH groups confer β2-receptor selectivity on compounds with large amino substituents. Metaproterenol (a resorcinol analog of ISO), terbutaline (an N-t-butyl analog of metaproterenol). They relax the bronchial musculature in patients with asthma but cause less direct cardiac stimulation than do the nonselective β-agonists.  Albuterol, pirbuterol, and salmeterol Are examples of 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; the only difference between the two is that pirbuterol contains a pyridine ring instead of a benzene ring. Salmeterol has an N-phenylbutoxyhexyl substituent in combination with a β-OH group and a salicyl phenyl ring for optimal direct-acting β2-receptor selectivity and potency similar to that of ISO. Formoterol. Formoterol is a lipophilic and long-acting β2-agonist. It has 3ʹ- formylamino and 4ʹ-OH group on one phenyl ring and a lipophilic N-isopropyl-p-methoxyphenyl group on the nitrogen atom. Formoterol and salmeterol are long-acting drugs used by inhalation and are recommended for maintenance treatment of asthma, usually in conjunction with an inhaled corticosteroid. Indirect-Acting Sympathomimetics Indirect-acting sympathomimetics act by releasing endogenous NE. They enter the nerve ending by way of the active-uptake process and displace NE from its storage granules. Amphetamine and p-tyramine are prototypical indirect-acting sympathomimetics. Hydroxyamphetamine 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. It is sometimes used with cholinergic blocking drugs like atropine to produce a mydriatic effect, which is more pronounced than that produced by either drug alone. L-(+)-Pseudoephedrine. Is the (S,S) diastereoisomer of ephedrine. Whereas ephedrine has a mixed mechanism of action, L-(+)-pseudoephedrine acts mostly by an indirect mechanism and has no direct activity. This agent is found in many OTC nasal decongestant and cold medications. Sympathomimetics with a Mixed Mechanism of Action 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-(-)-ephedrine resembles that of E. The drug acts on both α- and β-receptors. Its ability to activate β- receptors accounted for its earlier use in asthma. It is the classic example of a sympathomimetic with a mixed mechanism of action. Ephedrine has been used as a CNS stimulant and exhibits side effects related to its action in the brain. Ephedrine and its salts are used orally, intravenously, intramuscularly, and topically for various conditions, such as allergic disorders, colds and hypotensive conditions. ADRENERGIC RECEPTOR ANTAGONISTS (BLOCKERS) α-Blockers α-blockers used therapeutically as antihypertensive agents. Unlike the β- blockers, which have structural similarities to the adrenergic agonists NE, E, and ISO, the α-blockers consist of several compounds of different chemical structure that have little similarities to the α-agonists. NONSELECTIVE α-BLOCKERS Phentolamine Is imidazoline competitive α-blocker. Phentolamine is not useful in treating essential hypertension due to its α1- and α2-blocking activity and produce tachycardia. Phentolamine is used to prevent or control hypertensive episodes that occur in patients with pheochromocytoma. It also has been used in combination with papaverine to treat impotence. IRREVERSIBLE α-BLOCKERS Agents in this class, when given in adequate doses, produce a slowly developing, prolonged adrenergic blockade that is not overcome by E. They are irreversible α-blockers, because β-haloalkylamines in the molecules alkylate α-receptors producing a long- lasting, irreversible α-receptor blockade. The initial step involves the formation of an intermediate aziridinium ion (ethylene iminium ion). The positively charged aziridinium ion electrophile then reacts with a nucleophilic group on the α-receptor, resulting in the formation of a covalent bond between the drug and the receptor. These nonselective drugs alkylate not only α- receptors but also other biomolecules, leading to their toxicity. It is thus used only to relieve the sympathetic effects of pheochromocytoma. Phenoxybenzamine Oral phenoxybenzamine is used for the preoperative management of patients with pheochromocytoma and in the chronic management of patients whose tumors could not be removed by surgery. SELECTIVE α1-BLOCKERS Prazosin, terazosin, and doxazosin Are quinazoline α1-blockers. Structurally, these agents consist of three components: the quinazoline ring, the piperazine ring, and the acyl moiety. The 4-amino group on the quinazoline ring is very important for α1-receptor affinity. Although they possess a piperazine moiety attached to the quinazoline ring, this group can be replaced with other heterocyclic moieties (e.g., piperidine moiety) without loss of affinity. The nature of the acyl group has a significant effect on the pharmacokinetic properties. These drugs are used in the treatment of hypertension. Contraction of the smooth muscle of prostate gland, prostatic urethra and bladder neck is also mediated by α1A- adrenoceptors and blockade of these receptors relaxes the tissue. For this reason, these agents are used in the treatment of Benign prostatic hyperplasia (BPH), where they improve urination flow rates.  Alfuzosin Is a quinazoline α1-blocker but differs from terazosin in replacing the piperazine ring in terazosin with an open piperazine ring. Alfuzosin is more selective for the subtype of α1A-receptor in the prostate gland than those in vascular tissue. Tamsulosin A nonquinazoline benzensulfonamide. It is many folds more selective for α1A-receptors than for the other α1-receptors. This selectivity may favour blockade of α1A-receptors found in the prostate gland over those found in vascular tissue. Tamsulosin is efficacious in the treatment of BPH with little effect on blood pressure. Orthostatic hypotension is not as great with this agent as with the nonselective quinazolines. β-Blockers STRUCTURE–ACTIVITY RELATIONSHIPS β-Blockers are among the most widely used antihypertensives and are also considered the first-line treatment for glaucoma. Most of β-blockers are in the chemical class of aryloxypropanolamines. The nature of the aromatic ring and its substituents is the primary determinant of β-antagonistic activity. The amino function of the aryloxypropanolamine β-blockers must be a secondary amine for optimal activity. However, for β-blockers, the β-OH-substituted carbon must be in the S absolute configuration for maximal β- blocking activity.  NONSELECTIVE β-BLOCKERS (FIRST GENERATION) Propranolol Is the prototypical and nonselective β-blocker. It blocks the β1- and β2- receptors with equal affinity, lacks ISA (intrinsic sympathomimetic activity), and does not block α-receptors. Propranolol, like the other β-blockers, is a competitive blocker whose receptor-blocking actions can be reversed with sufficient concentrations of β-agonists. Propranolol is used for hypertension, cardiac arrhythmias, angina pectoris, postmyocardial infarction, hypertrophic cardiomyopathy, pheochromocytoma, migraine prophylaxis, and essential tremor. Because of its high lipophilicity it penetrates the CNS so that has been used in treating anxiety. Other Nonselective β-Blockers. Several other clinically used nonselective β-blockers include Nadolol, carteolol, timolol and sotalol. The first three of these blockers are used to treat hypertension. Sotalol is used as an antiarrhythmic in treating ventricular arrhythmias and atrial fibrillation. Carteolol and timolol are used topically to treat open-angle glaucoma. β1-SELECTIVE BLOCKERS (SECOND GENERATION) Cardioselective β1-blockers are drugs that have a greater affinity for the β1-receptors of the heart than for β2-receptors in other tissues. Such cardioselective agents should provide two important therapeutic advantages. The first advantage should be the lack of a blocking effect on the β2-receptors in the bronchi. Theoretically, this would make β1-blockers safe for use in patients who have bronchitis or bronchial asthma. The second advantage should be the absence of blockade of the vascular β2-receptors, which mediate vasodilation. This would be expected to reduce or eliminate the increase in peripheral resistance that sometimes occurs after the administration of nonselective β-blockers. Unfortunately, cardioselectivity is usually observed with β1- blockers at only relatively low doses. At normal therapeutic doses, much of the selectivity is lost. The following β1-selective blockers are used therapeutically: acebutolol, atenolol, bisoprolol, and metoprolol. All of them are indicated for the treatment of hypertension. Atenolol and metoprolol are also approved for use in treating angina pectoris and in therapy following myocardial infarction. Acebutolol is indicated for treating certain cardiac arrhythmias. Acebutolol is one of the very few β-blockers whose metabolite plays a significant role in its pharmacological actions. After oral administration, plasma levels of diacetolol are higher than those of acebutolol. Diacetolol is also a selective β1-blocker with partial agonistic activity. β-BLOCKERS WITH α1-ANTAGONIST ACTIVITY (THIRD GENERATION) As in the case of dobutamine, the arylalkyl group with nearby methyl group in these molecules is responsible for its α1-blocking activity. The bulky N-substituents and substituted aromatic ring are responsible for its β-blocking activity. Labetolol A phenylethanolamine derivative, is representative of a class of drugs that act as competitive blockers at α1-, β1-, and β2-receptors. It is a more potent β-blocker than α-blocker. Labetalol is a clinically useful antihypertensive agent.  Carvedilol Like labetalol, it is a β-blocker that possesses α1-blocking activity. Only the (S) enantiomer possesses the β-blocking activity, although both enantiomers are blockers of the α1-receptor. Overall, its β-blocking activity is 10- to 100-fold of its α-blocking activity. It has a neuroprotective effect and the ability to provide major cardiovascular organ protection. It is used in treating hypertension and congestive heart failure.