Autonomic 1 PDF

Autonomic 1 Prepared by Abdallah Elsayed Abdallah, PhD Associate Professor of Pharmaceutical Chemistry Overview Autonomic nervous system innervates almost all organs of the body except skeletal muscles. It regulates the involuntary functions of the body such as hear...

Autonomic 1 Prepared by Abdallah Elsayed Abdallah, PhD Associate Professor of Pharmaceutical Chemistry Overview Autonomic nervous system innervates almost all organs of the body except skeletal muscles. It regulates the involuntary functions of the body such as heart rate, blood pressure, breathing, digestion, gland secretion, and urinary output. It is divided to major parts; sympathetic and parasympathetic.  Each involuntary organ usually receives both sympathetic and parasympathetic nerve supply except the body of the uterus, which innervated by sympathetic only. The functions of sympathetic and parasympathetic nerves are usually antagonistic. Give examples for these antagonistic effects.  The autonomic nervous system exerts its function through release of specific chemical substances from the stimulated nerve ending. These chemical molecules are called neuro transmitters, chemical transmitters, or chemical mediators. The neuro transmitters have their specific receptors to bind with in both ganglia and effector organs to give their effects. These neuro transmitters are acetyl choline and norepinephrine. Acetylcholine It is the neurotransmitter released from O all parasympathetic nerve fibers and O N+ acetylcholine from preganglionic sympathetic nerve fiber. It is the chemical mediator in autonomic ganglia. In addition, it is the neurotransmitter Norepinephrine (Noradrenaline) It is the main neurotransmitter released HO from the post ganglionic sympathetic nerve fibers. HO NH2 The nerves secrete NE are called OH adrenergic nerves as well as the receptors norepinephrine affected by NE are called adrenergic (R)-4-(2-amino-1-hydroxyethyl)benzene-1,2-diol receptors. What about cholinergic nerves and receptors  Adrenergic receptors Adrenergic receptorsα-adrenergic β-adrenergic α1 α2 β1 It is present at the end of postganglionic α1A α2A sympathetic nerves. β2 α1B α2B β3 α1C α2C Cholinergic receptors Are subdivided to muscarinic and nicotinic. The muscarinic receptors exist at the postganglionic parasympathetic nerve endings. The nicotinic ones present in the autonomic ganglia, motor end plate, and suprarenal medulla.  Drugs affecting autonomic nervous system 1- Adrenergic drugs Adrenergic drugs exert their principal pharmacological and therapeutic effects by either enhancing or reducing the activity of the various components of the sympathetic division of the autonomic nervous system. In general, substances that produce effects similar to stimulation of sympathetic nervous activity are known as sympathomimetics or adrenergic stimulants. Those that decrease sympathetic activity are referred to as sympatholytics, antiadrenergics, or adrenergic-blocking agents. Sympathomimetics According to their chemical structures, adrenergic stimulant drugs can be classified into three major categories 1- phenylethylamines 2- aliphatic amines 3- imidazolines Phenylethylamines This category can be subdivided to catecholamines and non catecholamines 1- Catecholamines: the chemical structure of this class contains a catechol ring and an amine; and it can be classified to natural and synthetic catecholamines. Natural catecholamines This subclass includes dopamine, epinephrine and norepinephrine. Dopamine. Epinephrine and nor epinephrine are nonselective α and β agonists. HO HO HO HO NH2 HO NH2 HO N H OH OH Dopamine Norepinephrine Epinephrine  O O Tyrosine Aromatic-L-amino HO HO OH hydroxylase OH acid decarboxylase NH2 NH2 Vit-B6 HO NH2 HO HO Tyrosine DOPA Dopamine Dopamine-- Vit-C hydroxylase HO HO Biosynthesis SAM HO N N-Methyl transferase HO NH2 H and OH OH Epinephrine Norepinephrine metabolism of COMT COMT catecholamine HO HO s O OH N H O OH NH2 HO O MAO MAO O H OH Aldehyde dehydrogenase 2-Hydroxy-2-(4-hydroxy-3-methoxyphenyl)acetic acid HO O 4-Hydroxy-3-methoxymandelic acid (HMMA) O OH Vanillylmandelic acid (VMA) OH A major end product Dopamine (DA) 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. DA increases blood flow to the kidney, brain, heart, as well as mesenteric blood flow in low doses that have no chronotropic effect on the heart or that cause no increase in blood pressure. The dilation of selective blood vessels produced by DA is the result of its agonist action on the D1-DA receptor. Dopamine DA in intermediate doses stimulates the β1-receptors of the heart to increase cardiac output (inotropic and chronotropic effects). Infusion at a rate greater than 10 g/kg per minute results in stimulation of α1- receptors, leading to vasoconstriction and an increase in arterial blood pressure. Norepinephrine (NE) Like DA, NE 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 α1, α2, and β1-adrenoceptors (notice that lacking the N-methyl group results in lacking β2- and β3-activity). It is used to counteract various hypotensive crises, and as an adjunct treatment in cardiac arrest. It has limited clinical application caused by the nonselective nature of its activities.  Epinephrine (E) Like the other CAs, E is light sensitive and easily oxidized on exposure to air O because of the catechol ring system is oxidized to quinone. The development of a pink-to-brown color indicates oxidative breakdown. R O 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. Epinephrine 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 α1-, α2-, β1-, β2-, and β3- adrenoceptors. E has, in general, greater β-activity caused by an additional N-methyl group. Therefore, E is used to  The ability of epinephrine to stimulate β2-receptors has led to its use by injection and by inhalation to relax bronchial smooth muscle in asthma and in anaphylactic reactions. Because of its α-activity, E is used to treat hypotensive crises and to enhance the activity of local anaesthetics, and as a constrictor in haemorrhage.  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 To overcome several of the pharmacokinetic and pharmaceutical shortcomings of E as an ophthalmic agent, the prodrug approach has been successfully applied. 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 O corneal epithelial and endothelial layer. HO O Esterase HO N O N H H OH OH O Dipivefrin Epinephrine  The stroma in between requires hydrophilicity 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 hydrophilic 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. In addition, it is less irritant to the eye.  Stereochemistry of E and NE R configuration is essential for maximum activity. Levo isomers are more potent than dextro ones. (-) epinephrine is 45 times more active than (+) epinephrine. OH OH H OH H H N OH N OH H H OH H ionic site X ionic site X flat area flat area heteroatom heteroatom (+)-Epinephrine binds via two sites of binding (-)-Epinephrine binds with three sites of binding as the -hydroxyl group is trans to ortho hydroxyl group as the -hydroxyl group is cis to ortho hydroxyl group  Synthetic catecholamines OH OH H HO N HO NH2 HO HO Isoproterenol -Methylnorepinephrine 4-(1-hydroxy-2-(isopropylamino)ethyl)benzene-1,2-diol 4-(2-amino-1-hydroxypropyl)benzene-1,2-diol OH OH H H HO N HO N HO HO Dobutamine Colterol 4-(2-(tert-butylamino)-1-hydroxyethyl)benzene- 4-(2-((4-(4-hydroxyphenyl)butan-2-yl)amino)ethyl)benzene-1,2-diol 1,2-diol Isoproterenol Cl O Cl O NH2 H HO HO Cl HO N O HO HO HO H2/Pt OH OH H H HO N HCl HO N HCl HO HO Isoproterenol hydrochloride Isoproterenol Chemical synthesis of isoproterenol  Isoproterenol Non selective β agonist Essential for optimum 2 activity OH H HO N Two hyfroxyl groups make it 1-sensetive to light and air; HO Isopropyl group results in aqueous solutions become Isoproterenol 1- almost lack of  activity pink on standing 2- increase  agonist activity 2-metabolized by COMT, 3- resistance to MAO sulfate and glucuronide conjugation leading to poor oral bioavailability and short DOA isoproterenol is 800 times more potent as bronchodilator than (+) isoproterenol. is reflects the importance of β-OH and its stereochemistry to β2 binding.  It is one of the most potent bronchodilators available and is available for use by inhalation and injection. The drug has DOA of 1 to 3 hours after inhalation. Cardiac stimulation is an occasionally dangerous adverse effect. This effect of Isoproterenol on the heart is sometimes used in the treatment of heart block. The cardiac stimulation caused by its β1-activity and its lack of oral activity have led to its diminished use in favor of more selective β2-agonists. Assay of isoproterenol As a catecholamine it can be assayed spectrophotometrically As a weak base it can be assayed by non aqueous titration with perchloric acid  Dobutamine It resembles DA structurally but possesses a bulky 1-(methyl)- 3-(4- hydroxyphenyl)propyl group on the amino group. It is a sympathomimetic drug that is a β1-adrenergic agonist with α1- activity. It is primarily used in cases of cardiogenic shock as a positive inotropic agent (β1-adrenergic agonist) administered intravenously for congestive heart failure. The drug is dispensed and administered as a racemic mixture consisting of both (+) and (-) isomers. Dobutamine No -OH, so no significant 2 activity OH H HO N  Catechol is highly important for 1 agonist HO activity The (-) isomer of dobutamine is a potent 1-agonist, which is capable of causing marked pressor responses. In contrast, (+)- dobutamine is a potent 1-antagonist, which can block the effects of (-)-dobutamine. Importantly, the effects of these two isomers are mediated via 1- receptors. Both isomers appear to be full agonists, but the (+) isomer is a more potent 1-agonist than the (-) isomer (approximately tenfold) Non-catecholamines a subclass of phenylethylamines. OH OH H H OH OH HO N HO N H N HO OH OH Terbutaline Metaproterenol Albuterol (Sulbutamol) 4-(2-(tert-butylamino)-1-hydroxyethyl)-2- 5-(2-(tert-butylamino)-1- 5-(1-hydroxy-2- (hydroxymethyl)phenol hydroxyethyl)benzene-1,3-diol (isopropylamino)ethyl)benzene-1,3-diol OH OH OH H H H HO N N N HO OH Phenylephrine Ephedrine Ritodrine 3-(1-hydroxy-2- 4-(1-hydroxy-2-((4- 2-(methylamino)-1-phenylpropan-1-ol (methylamino)ethyl)phenol hydroxyphenethyl)amino)ethyl)phenol  Albuterol O O O O O HO AlCl3 NBS Br HO HO CH3OH or Br2/ gl. AcOH O HO HO O NH2 O OH O O OH OH H H H LiAlH4 N N H2/Pd N HO HO HO HO HO Albuterol (Sulbutamol) Chemical synthesis of Albuterol 2-selectivity results from OH OH H ter. butyl group results in replacement of the meta-OH N 1- almost lack of  activity group of the aromatic ring 2- increase  agonist activity with a hydroxymethyl moiety. HO 3- resistance to MAO 2- It is not metabolized by (R)-Albuterol (Sulbutamol) COMT. 3- It can be used orally (S)-Albuterol enhances bronchial muscle contraction, and this undesirable effect is completely avoided by using the pure (R)- albuterol, levalbuterol. Therefore, the efficacy is achieved at one-fourth dose of racemic albuterol with markedly reduced adverse effects. Pirbuterol Pirbuterol is closely related structurally to albuterol (β2/β1 = 60); the only difference between the two is that pirbuterol contains a OH OH H ring. pyridine ring instead of aNbenzene N HO Pirbuterol Ring equivalent bioisosteric replacement retains the activity on 2 receptors Salmeterol N-phenylbutoxyhexyl substituent -OH group A salicyl phenyl ring OH H N HO O HO This combination is for optimal direct-acting 2- receptor selectivity and potency. It has a potency similar to that of Isoproterenol. Salmeterol It 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 phenylalkyl substituent on the nitrogen atom, which is believed to interact with a site  Terbutaline, Metaproterenol and Fenoterol 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). 3,5-diOH groups confer β2-receptor selectivity on compounds with large OH amino OH substituents. OH H H H HO N HO N HO N OH OH OH OH Terbutaline Metaproterenol Fenoterol  -OH group Formoterol OH Lipophilic N-isopropyl-p- H methoxyphenyl group  N  HO O HN O 3-Formylamino and H 4-OH groups Long-acting selective 2-agonist log P = 1.6, DOA is about 12 h comparable to salmeterol. Resistant to COMT and MAO. Formoterol has a much faster onset of action than does salmeterol as result of its lower lipophilicity.  Phenylephrine OH H A prototypical selective direct-acting α1- HO N agonist) differs from E only in lacking a p-OH group. Phenylephrine Its oral bioavailability is less than 10% because It is orally active, and its DOA is of its hydrophilicity (log P = -0.3), intestinal 3- about twice that of E because it lacks the catechol moiety and thus O-glucuronidation/sulfation and metabolism by is not metabolized by COMT. MAO. In addition it lacks 1 activity Oral, nasal drops, and eye drops.  The drug is not metabolized by either COMT or MAO so it is active orally Ephedrine OH H  N Enantiomers OH   H N  Ephedrine = Erythro (1R,2S) -D-(-) Ephedrine (1S,2R)-L-(+) Ephedrine The most active of the This stereochemistry (1R) Mixed direct and indirect racemate four isomer as a pressor is the correct activity, but mainly indirect amine. (cis) Direct activity on  and  configuration Mixed mechanism of Some indirect activity for direct activity action 1-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. It causes more pronounced stimulation of the CNS than E. 2- Phenolic groups are not essential for  activity.  Pseudoephedrine The drug is not metabolized by either COMT or MAO so it is active orally Pseudoephedrin e = Threo OH H OH H racemate   N Enantiomers  N ( trans) Mainly indirect (1S,2S)-L-(+)Pseudophedrine Mainly indirect activity (1R,2R) -D-(-) Pseudoephedrine it is a diasteriomer of ephedrine acting Lacking H-bonding phenolic OH groups, pseudoephedrine is less polar (log P = 1.05, pKa = 9.38) and, thus, crosses the BBB. Although it crosses the BBB L-(+)- pseudoephedrine’s lack of direct activity affords fewer CNS effects than does ephedrine Pseudoephedrine This agent is found in many OTC nasal decongestant and cold medications. Although it is less prone to increase blood pressure than ephedrine, it should be used with caution in hypertensive individuals, and it should not be used in combination with MAO inhibitors.  Midodrine O O Free amino gp. H N Amidase NH2 gives  agonist NH2 activity with potent O O vasopressor effect O Midodrine Desglymidodrine N-Glycyl prodrug No phenolic groups No -OH group it is used in the treatment of symptomatic orthostatic hypotension Ritodrine is a selective β2-agonist that was developed specifically for use as a uterine relaxant. Its uterine inhibitory effects are more sustained than its effects on the cardiovascular system, which are minimal compared with those caused by nonselective β-agonists. The cardiovascular effects usually associated with its administration are mild tachycardia and slight diastolic pressure decrease. Usually, it is administered initially by intravenous infusion to stop OH premature labor and subsequently it may be given orally. H N HO OH Ritodrine 2-Aliphatic amines These agents are mainly non selective α agonists. For example cyclopentamine. N H Cyclopentamine It was used as nasal decongestant. 1-Cyclopentyl-N-methylpropan-2-amine  O O O Base 1- Hydrolysis Br + O O 2- HCl O O O HO ethyl acetoacetate Decarboxylation H2/Pt CH3NH2 NH N O Cyclopentamine Illustration for chemical synthesis of cyclopentamide Assay : Non aqueous titration with perchloric acid  3- Imidazoline derivatives (α agonists) 3-One carbon bridge between C2 of imidazoline and aryl group R N 4-Bulky group at ortho position HN 1- Imidazoline 2- Aryl group Essential structural features of imidazoline derivatives for binding to  receptors  HN HN N N H HO H N N N N Naphazoline Ttrahydrozoline Xylometazoline Oxymetazoline 1- Presence of bulky lipophilc groups at ortho and/or para positions gives selectivity to 1 receptors and diminshes the affinity to 2 receptors. 2- pKa of imidazoline ring is about 10, so that it is almost completely ionized at the physiological pH, giving limitted CNS penetration.  Cl Clonidine H N H N N Cl It is an example of a (phenylimino) imidazoline Clonidine derivative that possesses central α2-selectivity. the basicity of the guanidine group (typically pKa Chlorine atoms at ortho 13.6) is decreased to 8.0 (the pKa of clonidine) positions result in better because of the inductive and resonance effects of affinity for 2 receptors the dichlorophenyl ring. Cl Cl H Thus, at physiological pH, clonidine will exist to a H N H N N N HN significant extent in the nonionized form required Cl N Cl for passage into the CNS. It exists as a pair of tautomers It has an oral bioavailability of more than 90%. Antiadrenergic drugs They can be classified according to mechanism of action to 1- Adrenergic receptor blockers 2- Adrenergic neuron blockers 3- Catecholamine biosynthesis inhibitors 4- Catecholamine depleting agent 5- Ganglion blockers 1- Adrenergic receptor blockers Non selective alpha blockers Selective alpha Alpha blockers Non selective 1 blockers Adrenergic receptor Selective blockers Selective adrenergic alpha2 blockers blockers Non selective beta blockers Beta blockers Selective beta1 blockers  Non selective HO OH  H N  adrenergic receptor O blockers NH2 Labetalol It exists as a mixture of four isomers, Labetalol is a producing 1, and 2 blocking effects with partial 2 agonist activity. phenylethanolamine The -blocking activity resides solely in derivative. the (R,R) isomer, which has partial 2 It is mainly used orally for agonist activity. Whereas the 1-blocking activity is seen treatment of chronic in the (S,R) and (S,S) diasteriomers. hypertension and On the other hand, the (R,S) isomer devoids both  and  blocking activity. parenterally for  Carvedilol It has an antioxidant activity and It is a -blocker that possesses 1-blocking activity. an antiproliferative effect on Only the (S) enantiomer possesses the -blocking vascular smooth muscle cells. activity, although both enantiomers are blockers of the 1-receptor. It thus has a neuroprotective O Four-carbon distance  O effect and the ability to provide between the aliphatic O N H OH for activity major cardiovascular organ amine and the aromatic ring (carbazole). N H protection. Carvedilol It is used in treating hypertension 1-((9H-carbazol-4-yl)oxy)-3-((2-(2-methoxyphenoxy)ethyl)amino)propan-2-ol. Overall, its β-blocking activity is 10- to 100-fold of its α-blocking activity. Non selective alpha blockers H Phentolamine is a competitive α N N N blocker, acts on both α1- and α2- HO receptors. Phentolamine Imidazoline derivative but lacks It is mainly used for symptomatic the requirements of agonist ctivity treatment of pheochromocytoma. Its clinical use is limited due to non selectivity.  Non competitive or irreversible α blocker receptor receptor Nu Nu Cl N N N irreversible O O covalent bond O Phenoxybenzamine Irreversible binding of phenoxybenzamine to alpha adrenergic receptors Selective α1 blockers This class includes 1-quinazoline derivatives 2- phenoxyethylamine derivatives 3- indolethylamine derivatives 4- uracil derivatives 1- Quinazoline derivatives O O O O N N O N N O N N N N O O NH2 NH2 Prazosin Terazosin 5,000-fold greater affinity for 1-receptors Terazosin hydrochloride has a halflife of approximately 12 than for some 2-adrenergic receptors. hours, which is much longer than that of prazosin (2-3 hours), so that once daily for hypertension, not for BPH for hypertension and BPH O O N O N N O H O N N N N O O N O NH2 O Doxazosin NH2 (4-(4-Amino-6,7-dimethoxyquinazolin-2-yl)piperazin- Alfuzosin 1-yl)(2,3-dihydrobenzo[ b][1,4]dioxin-2-yl)methanone for benign prostatic hyperplasia (BPH), not for for hypertension and BPH hypertension  O O O Cl O O OH H2N NH2 NH POCl3 O N O NH2 fusion O N O Et3N H O N Cl NH3 O NH2 Cl NH2 HN NH O O NH2 N furoylchloride O O N Piperazine N O N N O N N O N Cl N O NH Prazosin O Synthesis of prazosin  Phenoxyethylamine derivatives OH O NH2 O N O O N S O H NH2 N O H O O F Silodosin Tamsulosin F F N-substituted catecholamine-related sulfonamide) substituted indole carboxamide Tamsulosin, alfuzosin, and silodosin are uroseletive alpha1-adrenergic antagonists developed specifically to treat BPH. 2- Indolethylamine derivative 3- Uracil derivative N N H O N N N O N N H H O N Indoramine O Urapidil Indolethylamine derivative Uracil derivative  Selective α2 blocker Yohimbine is a competitive and selective α2- blocker. The compound is an indolealkylamine alkaloid N H and is found in the bark of the tree Pausinystalia N H H H yohimbe and in Rauwolfia root. OH O Yohimbine increases heart rate and blood O Yohimbine pressure as a result of its blockade of α2- receptors in the CNS. It has been used experimentally to treat male erectile dysfunction Stereochemistry is critical N H N H N H  N H  H H H H OH O OH O O O Yohimbine Corynanthrine Selective 2-blocker. Selective 1-blocker. Beta blocker It is classified to two major groups 1- Phenylethanolamines 2- Aryloxypropanolamines, which is further divided to A- non selective beta blockers B- selective beta blockers  1- Phenylethanolamine derivative OH H N  Sotalol is used as an HN O S O antiarrhythmic in treating Sotalol ventricular arrhythmias and atrial It contains a chiral center and is marketed as fibrillation because in addition to them racemic mixture. Because of its its β-adrenergic blocking activity, enantiomers, its mechanism of action spans two of the antiarrhythmic drug classes. this agent blocks the inward The l(-) enantiomer has both -blocking (class potassium current that delays II) and potassium channel-blocking (class III) activities. The d(+) enantiomer has class III cardiac repolarization. properties similar to those of the (-) isomer, but its affinity for the -adrenergic receptor is 30 to 60 times lower. 2- Aryloxypropanolamines OH OH HN O N O N H O N H OH H OH OH Propranolol Pindolol Nadolol O O N N S O N N O N H O N OH H H OH OH Alprenolol Oxprenolol Timolol Non-selective -blocker  Propranolol Aliphatic amine Aryl moiety It blocks the β1- and β2-receptors with equal affinity. It does not block α receptors. O N H OH Propranolol is approved for use in the United States Propranolol Distance 4-carbon Log P = 3.1 for hypertension, cardiac arrhythmias, angina pKa = 9.14 beta OH pectoris, postmyocardial infarction, hypertrophic Log D = 0.99 pass BB cardiomyopathy, pheochromocytoma, migraine CNS activity (anti-anxiety) with CNS side effects, such prophylaxis, and essential tremors. as dizziness, confusion, or depression. Contraindicated in asthma and bronchitis.  OH HN O 1- NaOH O H2N O OH O 2- Cl Naphthalen-1-ol Epichlorohydrine Propranolol Representative illustration for propranolol synthesis Timolol O HO Cl O Cl OH Cl O S2Cl2 1- NaOH O H2N N + N N N N N S O S S Cl 2- N carbamoyl cyanide Cl H2N O N O NH O N O H H N OH Cl OH N N N S N S Timolol Synthesis of timolol Selective β1 blockers O H2N O O O N O H O OH O N N H H Atenolol OH OH Betaxolol Bisoprolol O H N O O O N H O N OH H O N OH O H OH O Esmolol Metoprolol Diacetolol All of these agents except esmolol 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. Betaxolol is the only 1-selective blocker indicated for the treatment of glaucoma. Esmolol Esmolol was designed as a soft drug to give ultra short selective β 1 inhibition. T1/2 is about 9 minutes. Its effect disappears after about half an hour of discontinuation of the infusion. The methyl ester is rapidly hydrolyzed to give the carboxylic acid metabolite (very weak β blocker). Esterase O O O N H HO O O N OH H OH Esmolol Inactive metabolite  Nebivolol (selective beta 1 blocker) Chromen nucleus as a result of cyclization F F O N O H OH OH Nebivolol 2,2'-iminobis[1-(6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethanol] In addition to selective beta blocker properties, it has NO potentiating effect so it causes vasodilatation in contrast to non selective beta blocker. Used for treatment of hypertension Catecholamines biosynthesis inhibitors Rate limiting step, so inhibition of tyrosine It is not the rate limiting step, so inhibition of it is not significant in lowering blood pressure. hydroxylase is the most significant. O O O HO HO OH OH OH NH2 NHNH2 NH2 HO HO HO Example: -Methyldopa Carbidopa Example: Metyrosine O O Tyrosine Aromatic-L-amino HO HO OH hydroxylase OH acid decarboxylase NH2 NH2 Vit-B6 HO NH2 HO HO Tyrosine DOPA Dopamine HO Dopamine--hydroxylase HO NH2 Vit.C OH Norepinephrine  α-Methyldopa O HO Aromatic-L-amino HO Dopamine-- HO OH acid decarboxylase hydroxylase HO NH2 NH2 HO NH2 HO OH -Methyldopa -Methyldopamine -Methylnorepinephrine It is suitable for oral use, is a zwitterion and is not soluble enough Acts on 2-adrenergic receptors to inhibit for parenteral use. the release of norepinephrine, resulting in decreased sympathetic outflow from the CNS and activation of parasympathetic outflow. Assay : Non aqueous titration with 0.1 M perchloric acid