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Adrenergic Drugs
LEARNING OBJECTIVES
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Define adrenergic receptors and the drugs acting on them
Describe the structural requirements of a sympathomimetics acting on α and β subtypes
Classify sympathomimetics and describe their preparation method
Describe the importance of specificity of the receptor environment based on optical isomers of
ephedrine
Define sympatholytics and their utility
Classify sympatholytics, their uses and actions
22.1 INTRODUCTION
Adrenergic drugs are those chemical agents that exert their principal pharmacologic and therapeutic
effects by acting at peripheral sites to either enhance or reduce the activity of components (adrenaline)
of the sympathetic division of the autonomic nervous system. In general, those substances that produce
effects similar to stimulation of sympathetic nervous activity are known as sympathomimetics,
adrenomimetics, or adrenergic stimulants. Those that decrease sympathetic activity are referred to as
sympatholytics, antiadrenergic, or adrenergic blocking agents.
Adrenergic receptors: In the adrenergic system there are two main types of receptors: α and β. There
are two types of α-adrenoreceptors, α1 and α2. The α1-adrenoreceptors subserve smooth muscle
stimulant functions, adrenergic sweating, and salivation. The α2-adrenoreceptors serve to inhibit the
pre-synaptic release of noradrenaline and the post-synaptic activation of adenylate cyclase (and, hence,
inhibit post-synaptic responses). The β-adrenoreceptors are subdivided into β1 and β2 adrenoreceptors,
and perhaps more. β1-adrenoreceptors effect cardiac stimulation and lipolysis; β2-adrenoreceptors
subserve adrenergic smooth muscle relaxation (vasodilatation, bronchodilatation, and intestinal and
uterine relaxation) and glycolysis.
22.2 SYMPATHOMIMETIC DRUGS
Peripheral actions and uses of sympathomimetics are discussed below.
22.2.1 α-Adrenoreceptor Agonists
α-Agonists cause arteriolar and venous constriction and, hence, have an action to increase blood
pressure. This vasopressor action is used to support blood pressure in hypotensive states, such as in
orthostatic hypotension, carotid sinus syndrome, shock, and during spinal anaesthesia.
The systemic vasoconstrictor effects are also employed in the management of a variety of serious
allergic conditions, such as giant urticaria, serum sickness, angioneurotic oedema, and anaphylaxis.
The α-agonists are applied topically to induce local vasoconstriction in nasopharyngeal,
scleroconjunctival, and otic blood vessels in acute conditions of rhinitis, coryza, nasopharyngitis,
sinusitis, conjunctivitis, and hay fever.
By inhalation, α-agonists may be used to suppress bronchial congestion in allergic and asthmatic
conditions.
Structural requirements: The structural requirements for α-agonist activity are a phenylethylamine
skeleton to which at least two hydroxyl groups are attached; the optimal positions are ring 3- and side
chain L-2, but ring 4- and L-2 and ring 3, 4-dihydroxy compounds are active.
22.2.2 β1-Adrenergic Agonists
The β1-receptors are located in the heart. The β1-agonists increase the heart rate, enhance
atrioventricular conduction, and increase the strength of the heartbeat. These effects are achieved in
part through the activation of the adenylyl cyclase system and intermediation of 3’,5’-cyclic adenosine
monophosphate (cAMP). They may be administered by intracardiac injection to restore the heartbeat
in cardiac arrest and heart block with syncopal seizures. Sometimes, β1-agonists also are used for their
positive inotropic actions in the treatment of acute heart failure and in cardiogenic or other types of
shock, in which contractility often is diminished.
22.2.3 β2-Selective Adrenergic Agonists
The β2-receptors are located in the lung and uterus. The β2-agonists relax smooth muscle and induce
hepatic and muscle glycogenolysis, also by activating the adenylyl cyclase system and increasing the
intracellular levels of cAMP. Thus, they dilate the bronchioles, arterioles in vascular beds which are
invested with β2-receptors and veins, and they relax the uterus and intestines.
Some β2-agonists are used as bronchodilators in the treatment of bronchial asthma, emphysema, and
bronchitis. They are also used to relax the uterus and delay delivery in premature labour, and to treat
dysmenorrhoeal problem.
Structural requirements: The structural requirements include an L-β-OH group, which is essential to
both β1 and β2 activity. N-Alkyl substitution enhances both the activities, while isopropyl and t-butyl
confer optimal activity. A ring hydroxyl group at the 3- or 4-position is required; the 3-OH appears to
be more favourable for β2- and the 4-OH for β1-activity.
22.2.4 Classification of Sympathomimetics
1. Phenylethanolamine derivatives
2. Imidazoline derivatives
R
Xylometazoline
Oxymetazoline
Naphazoline
22.2.5 Phenylethanolamine Derivatives
Adrenaline (-)-3,4-Dihydroxy-α-[(methylamino)methyl] benzyl alcohol
It possesses all of strong α1-, α2-, β1-, and β2-agonist activities. It is the drug of choice in the
management of allergic emergencies such as anaphylaxis, angioneurotic oedema, urticaria, and serum
sickness.
Synthesis
Adrenaline (epinephrine) is obtained from the adrenal glands tissue of livestock as well as in a
synthetic manner. Epinephrine is synthesised by reaction between catechol and chloroacetyl chloride
to give ester, which undergoes Fries rearrangement to form ω-chloro-3,4-dihydroxyacetophenone.
Reaction of this with excess of methylamine gives ω-methylamino-3,4-dihydroxyacetophenone.
Reduction of this gives D,L-epinephrine, which is separated into isomers using (-) tartaric acid.
Epinephrine was isolated and identified in 1895 by Napoleon Cybulski, a Polish physiologist. In May
1896, William Bates reported the discovery of a substance produced by the adrenal gland in the New
York Medical Journal.
Isoprenaline: 3, 4-Dihydroxy-α-[(isopropylamino)methyl]benzyl alcohol
Preparation: By the synthetic procedure given for adrenaline using isopropylamine in place of
methylamine
It has strong β1- and β2-agonist activity but lacks α-activity. Its primary use is in the treatment of
bronchial asthma.
Salbutamol: 4-Hydroxy-3-hydroxymethyl-α-[(tert-butylamino)methyl] benzyl alcohol.
Synthesis
Acylation of methyl ester of salicylic acid using chloroacetyl chloride afford acetophenone derivative.
This on reaction with N-benzyl-tert-butylamine, and the resulting product is completely reduced by
lithium aluminium hydride into the N-benzyl-substituted salbutamol, the benzyl group of which is
removed by hydrogen over a palladium catalyst to give the desired salbutamol.
The therapeutic action and uses of salbutamol are similar to those of isoprenaline.
Metarminol (-)-α-1-Aminoethyl-3-hydroxy benzyl alcohol
Reaction of 4-hydroxy propiophenone with benzyl chloride gives O-benzyl derivative, which on
treatment with butyl nitrite undergoes nitrosation reaction at the α-position. Stepwise reduction of the
nitrosoketone leads to amino alcohol metarminol.
Phenylephrine (-)-3-Hydroxy-α-[(methylamino)methyl] benzyl alcohol
It is synthesised by an analogous scheme of making epinephrine; however, instead of using ω-chloro3,4-dihydroxyacetophenone, ω-chloro-3-dihydroxyacetophenone is used.
It has a strong α-agonist and negligible β-agonist activity. It is used in the treatment of paroxysmal
supraventricular tachycardia and to support blood pressure.
Ephedrine (-)-Erythro-α-[1-(methylamino)ethyl] benzyl alcohol
The method consists of the fermentation of glucose by yeast carboligase in the presence of
benzaldehyde, which during the process turns into (-)-1-phenyl-2-ketopropanol. This is reduced by
hydrogen in the presence of methylamine, to give the desired ephedrine.
Ephedrine, although 100 times less potent than epinephrine, has prolonged bronchodilatory effects
after oral administration. Pseudoephedrine is the (-) optical isomer of (+) ephedrine. The activities of
the optical isomers of ephedrine show the rather precise nature of the receptor–drug interactions.
Pseudoephedrine is much less potent than ephedrine. The following figure depicts the importance of
hydrogen bonding for activity.
FIGURE 22.1 Binding site of ephedrine at the receptor.
Imidazoline Derivatives
Xylometazoline 2-(4-tert-Butyl-2, 6-dimethylbenzyl)-2-imidazoline
Synthesis
Xylometazoline is synthesised by chloromethylation of mesitylene derivative and the further
transformation of the resulting chloromethyl derivative into a nitrile. The reaction of this with
ethylenediamine gives xylometazoline.
Oxymetazoline 6-tert-butyl-3-(2-imidazolin-2-ilmethyl)-2,4-dimethylphenol
Synthesis
It is synthesised by chloromethylation of 6-tert-butyl-2,4-dimethylphenol and the further
transformation of the resulting chloromethyl derivative into a nitrile. The reaction of this with
ethylenediamine gives oxymetazoline.
Naphazoline 2-(1-Naphthylmethyl)-2-imidazoline
Synthesis
Naphazoline is synthesised by reaction with naphthyl methyl chloride and potassium cyanide to give
(1-naphthyl)acetonitrile, which upon reaction with ethanol transforms into iminoester, and undergoes
further heterocyclization into the desired imidozoline derivative upon reaction with ethylenediamine.
22.3 SYMPATHETIC (ADRENERGIC) BLOCKING AGENTS (SYMPATHOLYTICS)
Adrenergic blocking agents are drugs that produce their pharmacologic effects primarily by preventing
the release of noradrenaline from sympathetic nerve terminals.
These drugs produce their effects by stabilization of the neuronal membrane or the membranes of the
storage vesicles. This stabilization makes the membranes less responsive to nerve impulses, thereby
inhibiting the release of noradrenaline into the synaptic cleft.
22.3.1 Classification, Action, and Uses
α-Adrenergic Antagonists
1. Non-selective α-antagonists: Examples: Phenoxybenzamine, Phentolamine, Tolazoline
This class produces α1 and α2 blockade. Antagonism of α1-adrenergic impulses to the arterioles
decreases vascular resistance, thus tending to lower the blood pressure, and causes a pink warm
skin and nasal and scleroconjunctival congestion. α-Antagonism causes tachycardia,
palpitations, and increased secretion of renin. They are used in the treatment of peripheral
vascular disorders such as Raynaud’s disease, acrocyanosis, frostbite, acute arteriolar
occlusion, causalgia, and pheochromocytoma.
2. Selective α-antagonists: Theoretically, α1-blockers (prazosin and terazosin) should be useful
for the same disorders as are the non-selective α-blockers, but they are approved only for the
treatment of hypertension.
Selective α2-antagonists include yohimbine and rauwolscine, but there are presently no
therapeutic application of α2-blockade.
β-Adrenergic Antagonists
1. Non-selective β-antagonists: Drugs such as Propranolol, Nadolol, Pindolol, and Timolol
suppress both β1- and β2-adrenoreceptor-mediated responses almost equally. Blockade of
myocardial β1-receptors causes sinoatrial bradycardia, decreased force of myocardial
contraction, slowing of atrioventricular conduction, and increased atrioventricular
refractoriness.
Uses
β-Blockers are of prophylactic value in the treatment of stable angina pectoris
The effect to decrease sinoatrial rate is also used to suppress tachycardia in
thyrotoxicosis and pheochromocytoma
o The effect to decrease atrioventricular nodal conduction is employed in the chronic
management of paroxysmal supraventricular tachycardia
o All available β-antagonists are used in the treatment of hypertension
o β-Antagonists have usefulness in the prophylaxis of migraine headache
2. Selective β1-antagonists: Examples: Acebutolol, Atenolol, Metoprolol, Practolol, and Tolamol
o
o
Selective β1-antagonists can be used for all the purposes listed under the non-selective
blockers. Advantages to selective β1-blockade are lesser effect on bronchiolar airway resistance
and diminished effect to increase insulin-induced hypoglycaemia.
3. Partial agonist β-antagonist: Examples: Oxprenolol, Acebutolol, and Pindolol
It also causes some stimulation of β-adrenoreceptors. This partial agonism acts as buffer to
lessen the seriousness of the various adverse effects attributable to β-blockade.
22.3.2 Synthesis of α-adrenergic Blockers
Phenoxybenzamine N-(2-Chloroethyl)-N-(1-methyl-2-phenoxyethyl)benzylamine
Phenoxybenzamine is synthesised by reacting phenol with propylene chlorohydrin, which forms 1phenoxy-2-propanol, the chlorination of which with thionyl chloride gives 1-phenoxy-2propylchloride. Reacting this with 2-aminoethanol leads to formation of 1-phenoxy-2-(2hydroxyethyl)aminopropane. Alkylation of the secondary amino group gives N-(2-hydroxyethyl)-N(1-methyl-2-phenoxyethyl)benzylamine, the hydroxyl group of which is chlorinated using thionyl
chloride, giving phenoxybenzamine.
Phentolamine 3-[[(4,5-Dihydro-1H-imidazol-2-yl)methyl](4-methyl-phenyl)amino]phenol
Chlormethylation of diphenylamine is followed by further transformation of the resulting
chloromethyl derivative into a nitrile. The reaction of this with ethylenediamine gives phentolamine.
Tolazoline 2-Benzyl-2-imidazoline
Tolazoline is synthesised by the heterocyclation of the ethyl ester of iminophenzylacetic acid with
ethylenediamine, which forms the desired tolazoline.
(Synthesis of prazosin and terazosin was discussed in Chapter 16 on ‘Antihypertensive Agents’.)
(For synthesis of β-Adrenergic blockers, refer to Chapter 16 on ‘Antihypertensive Agents’.)
22.4 NEWER DRUGS
Clenbuterol 1-(4-Amino-3,5-dichlorophenyl)-2-(tert-butylamino)ethanol
It is a drug prescribed to sufferers of breathing disorders as a decongestant and bronchodilator.
Clenbuterol is a β2-adrenergic agonist with some similarities to ephedrine, but its effects are more
potent and longer lasting as a stimulant and thermogenic drug.
Salmeterol 2-(Hydroxymethyl)-4-{1-hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl}phenol
It is a long-acting β2-adrenergic receptor agonist drug that is currently prescribed for the treatment of
asthma and chronic obstructive pulmonary disease (COPD).
Formoterol N-[2-Hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl) propan-2-ylamino]ethyl]
phenyl]formamide
It is a long-acting β2-agonist, which has an extended duration of action (up to 12 hours) compared to
short-acting β2 -agonists such as salbutamol, which are effective for 4–6 hours. It is used in the
management of asthma and/or COPD.
FURTHER READINGS
1. Choudhary, M. Iqbal, 1996. Progress in Medicinal Chemistry, Taylor & Francis (UK).
2. Silverman, Richard B., 2004. The Organic Chemistry of Drug Design and Drug Action, Elsevier.
MULTIPLE-CHOICE QUESTIONS
1. β-Adrenergic blockers are not used for
1. Migraine headache
2. Hypertension
3. Angina pectoris
4. Supra-ventricular bradycardia
2. Pindolol is a (an)
1. α1-Agonist
2. β1-Agonist
3. β1-Partial agonist antagonist
4. α1-Partial agonist antagonist
3. Propanolol is useful for
1. Asthma
2. Ventricular tachycardia
3. Anaesthesia
4. Atropine poison
4. The β1-receptors are located in
1. Heart
2. Lungs
3. Kidney
4. Adrenal gland
5. Orthostatic hypotension is treated with
1. β-Blockers
2. β-Agonists
3. α-Blockers
4. α-Agonists
6. Drug of the following class is useful in the treatment of asthma:
1. β1-Blockers
2. β1-Agonists
3. α1-Blockers
4. α1-Agonists
7. The adrenergic agent obtained by fermentation procedure is
1. Propanolol
2. Adrenaline
3. Ephedrine
4. Phenylephrine
8. 3, 4-Dihydroxy-α-[(isopropylamino)methyl]benzyl alcohol is
1. Adrenaline
2. Propanolol
3. Phenylephrine
4. Isoprenaline
9. 3-[[(4,5-Dihydro-1H-imidazol-2-yl)methyl](4-methyl-phenyl)amino]phenol is
1. Phentolamine
2. Tolazoline
3. Naphazoline
4. Phenoxybenzamine
10. Salbutamol is synthesised starting from
1. Phenyl acetonitrile
2. Methyl salicylate
3. 4-Hydroxy propiophenone
4. Mesitylene derivative
QUESTIONS
1. Classify sympathomimetics and discuss their therapeutic uses.
2. With the structure of epinephrine, discuss the design of agonists and antagonists based on the
structural modification.
3. Write the synthetic scheme for salbutamol, isoprenaline, phentolamine, and ephedrine.
4. Classify antiadrenergic drugs with structural examples.
5. Write a short note on the therapeutic uses of β-blockers.
SOLUTION TO MULTIPLE-CHOICE QUESTIONS
1. d;
2. c;
3. b;
4. b;
5. d;
6. b;
7. c;
8. d;
9. a;
10. b.