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Questions and Answers
What is the effect of DA on the heart?
Which catecholamine is a potent stimulant of all α1-, α2-, β1-, β2-, and β3-adrenoceptors?
What is the reason for the poor oral bioavailability of naturally occurring catecholamines?
What is the advantage of Dipivefrin over Epinephrine?
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What type of substituents on the aromatic ring can enhance agonist activity in imidazolines?
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What is the optimum bridging unit in imidazolines?
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Which of the following is a selective α1-agonist with therapeutic activity as a vasoconstrictor?
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What is the location where Dipivefrin is converted to Epinephrine?
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Which of the following arylimidazoline derivatives is used for hypotension?
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What is the main reason for the low oral bioavailability of naphazoline?
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What is the structural feature common to all arylkylimidazoline α1-agonists?
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Why do arylkylimidazoline α1-agonists have limited access to the CNS?
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What is the importance of ortho-lipophilic groups on the phenyl ring of arylkylimidazoline α1-agonists?
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Which of the following is a characteristic of clonidine?
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Why are o-chlorine groups on the phenyl ring more effective than o-methyl groups at α2 sites?
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What is the effect of methoxamine on the body?
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What is a characteristic of brimonidine in comparison to apraclonidine?
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What is the mechanism of action of methyldopa?
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Why is methyldopa used only by oral administration?
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What is the purpose of developing methyldopate (Aldomet ester)?
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Why does isoproterenol have poor absorption characteristics and a relatively short duration of action?
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What is a characteristic of apraclonidine?
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What is the configuration of α-methylnorepinephrine that makes it a selective α2-agonist?
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What is the difference between apraclonidine and L-DOPA?
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What is a characteristic of the β3-receptor?
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What is the effect of an α-methyl group on indirect-acting sympathomimetics?
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What is a characteristic of indirect-acting sympathomimetics that are used therapeutically?
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What is the effect of a β-hydroxyl group on indirect-acting sympathomimetics?
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What is a characteristic of phenylethylamines that contain a tertiary amino group?
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What is the primary effect of amphetamine-type drugs?
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What is a characteristic of hydroxy amphetamine (Paredrine)?
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What is propylhexedrine (Benzedrex)?
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What is the primary mechanism of action of ephedrine on nasal membranes?
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What is the effect of the β-hydroxyl group on the phenylethylamines?
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Why does ephedrine have a higher CNS stimulant effect compared to other CAs?
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What is the difference between ephedrine and phenylpropanolamine?
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What is the effect of N-desmethylation on ephedrine?
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Why does phenylpropanolamine have a more prolonged action as a nasal decongestant compared to ephedrine?
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Study Notes
Adrenergic Agents
- The three naturally occurring catecholamines are Dopamine (DA), Norepinephrine (NE), and Epinephrine (E), which are used as therapeutic agents.
- DA stimulates the β1-receptors of the heart to increase cardiac output.
- NE is a stimulant of α1-, α2-, and β1-adrenoceptors, lacking the β2- and β3-activity due to the absence of the N-methyl group.
- E is a potent stimulant of all α1-, α2-, β1-, β2-, and β3-adrenoceptors.
- All three catecholamines are polar and rapidly metabolized by both COMT and MAO, resulting in poor oral bioavailability and short duration of action.
Dipivefrin
- Dipivefrin is a prodrug of Epinephrine, formed by the esterification of the catechol OH groups of Epinephrine with pivalic acid.
- It has improved bioavailability due to its increased lipophilicity, allowing for greater penetration into the eye through the corneal epithelial and endothelial layers.
- It is resistant to metabolism by COMT and has a longer duration of action.
Imidazolines
- Imidazolines are a second chemical class of α-agonists, which are vasoconstrictors.
- They can be non-selective or selective for either α1- or α2-receptors.
- Structurally, most imidazolines have a heterocyclic imidazoline nucleus linked to a substituted aromatic moiety via a bridging unit.
- The optimum bridging unit is usually a single methylene group or amino group.
- Agonist activity is enhanced when the aromatic ring is substituted with halogen substituents like chlorine or small alkyl groups like methyl, particularly when they are placed in the two ortho positions.
Selective α1-Agonists
- All selective α1-agonists have therapeutic activity as vasoconstrictors.
- Structurally, they include:
- Phenylethanolamine derivatives: such as phenylephrine, Metaraminol, and methoxamine.
- 2-arylimidazolines derivatives: such as xylometazoline, oxymetazoline, tetrahydrozoline, and naphazoline.
Phenylephrine
- Phenylephrine is a prototypical selective direct-acting α1-agonist.
- It differs from Epinephrine only in lacking a p-OH group.
- It is orally active, and its duration of action is about twice that of E because it lacks the catechol moiety and is not metabolized by COMT.
- However, its oral bioavailability is less than 10% due to its hydrophilic properties, intestinal 3-O-glucuronidation/sulfation, and metabolism by MAO.
Other Selective α1-Agonists
- Metaraminol is another example of a selective α1-agonist.
- Methoxamine is a selective α1-agonist and parenteral vasopressor used therapeutically.
- Naphazoline, tetrahydrozoline, xylometazoline, and oxymetazoline are used for their vasoconstrictive effects as nasal and ophthalmic decongestants.
α2-Agonists
- Clonidine is a prototypical α2-agonist.
- It 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.
- Clonidine's ability to exert an antihypertensive effect depends on its ability to interact with the α2-receptor in the brain and gain entry into the CNS.
- Brimonidine is a more selective α2-agonist than clonidine or apraclonidine and is a first-line agent for treating glaucoma.
- Apraclonidine does not cross the blood-brain barrier.
Methyldopa
- Methyldopa differs structurally from L-DOPA only in the presence of a α-methyl group.
- It ultimately decreases the concentration of DA, NE, E, and serotonin in the CNS and periphery.
- 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-methylnorepinephrine).
- The active metabolite is a selective α2-agonist because it has the correct (1R,2S) configuration.
β-Adrenergic Receptor Agonists
- Isoproterenol is a non-selective and prototypical β-agonist (β2/β1 = 1).
- It has a poor absorption characteristic and a relatively short duration of action due to its facile metabolism by sulfate and glucuronide conjugation of the phenolic OH groups and o-methylation by COMT.
Indirect-Acting Sympathomimetics
- They 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.
- 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
- Hydroxy amphetamine is an effective, indirect-acting sympathomimetic drug.
- It differs from amphetamine in the presence of a 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
- Propylhexedrine is 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.
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 is a classic example of a sympathomimetic with a mixed mechanism of action.
- It acts on both α- and β-receptors.
- Lacking H-bonding phenolic OH groups, ephedrine is less polar 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 duration of action than E.
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Description
Learn about the three naturally occurring catecholamines, Dopamine, Norepinephrine, and Epinephrine, and their effects on adrenoceptors and the body.
