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What is a characteristic of clonidine that allows it to enter the CNS?
What is the result of stimulation of α2-receptors in the brain?
What is the effect of clonidine's ability to enter the CNS?
What is the primary mechanism of action of indirect-acting sympathomimetics?
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What is the significance of the pKa of clonidine?
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What is the effect of clonidine's stimulation of peripheral α-receptors?
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What is the oral bioavailability of clonidine?
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What is the significance of the O-chlorine groups in clonidine?
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What is the primary determinant of β-antagonistic activity?
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What is the effect of a para-substituent of sufficient size on the aromatic ring?
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What is the configuration of the β-OH-substituted carbon for maximal β-blocking activity?
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What is propranolol?
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What is a common feature of many cardioselective β1-blockers?
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What is the effect of propranolol on α-receptors?
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What is the reason behind propranolol's ability to penetrate the CNS?
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What is one of the approved uses of propranolol in the United States?
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What is the effect of the presence of catechol OH groups on indirect-acting phenylethylamines?
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Which of the following substituents decreases the effectiveness of indirect-acting agents?
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What is the primary mechanism of action of L-(+)-pseudoephedrine?
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What is the classic example of a sympathomimetic with a mixed mechanism of action?
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What is the primary goal of developing β-blockers?
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Why is hydroxyamphetamine used in diagnostic eye examinations and surgical procedures on the eye?
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What is the consequence of having a β-hydroxyl group on the effectiveness of indirect-acting agents?
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Why was Isoprenaline chosen as the lead compound?
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What is the result of replacing the phenolic groups of Isoprenaline with chloro substituents?
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What is the characteristic of phenylethylamines with a mixed mechanism of action?
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What is the role of the phenolic groups in Isoprenaline?
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What is the effect of an α-methyl group on the effectiveness of indirect-acting agents?
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What is the diastereoisomer of ephedrine?
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What is the purpose of adding an extra aromatic ring to Isoprenaline?
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What is used in folk medicine for many years?
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What is D-(-)-Ephedrine often used to prevent?
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What is the primary advantage of using cardioselective β1-blockers in patients with bronchitis or bronchial asthma?
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What is the effect of nonselective β-blockers on peripheral resistance?
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What is the primary difference between tolazoline and phentolamine?
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Why are tolazoline and phentolamine not useful in treating essential hypertension?
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What is the primary characteristic of prazosin, terazosin, and doxazosin?
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What is the function of the 4-amino group on the quinazoline ring?
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What is the significance of the quinazoline ring in prazosin, terazosin, and doxazosin?
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What is the advantage of using quinazoline α-blockers over nonselective imidazoline α-blockers?
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Study Notes
Clonidine and Imidazolidine Derivatives
- Clonidine is an imidazolidine derivative that possesses central α2-selectivity.
- The O-chlorine groups in clonidine afford better activity than O-methyl groups at α2 sites.
- Clonidine's uncharged form exists as a pair of tautomers.
- Clonidine can briefly exhibit vasoconstrictive activity due to stimulation of peripheral α-receptors, but this is followed by a longer-lasting hypotensive effect due to stimulation of α2-receptors in the brain.
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.
- Structure-activity relationship:
- Catechol OH groups enhance the potency of indirect-acting phenylethylamines.
- The presence of a β-hydroxyl group decreases, and an α-methyl group increases, the effectiveness of indirect-acting agents.
- Nitrogen substituents decrease indirect activity, with substituents larger than methyl groups rendering the compound virtually inactive.
Hydroxyamphetamine and L-(+)-Pseudoephedrine
- Hydroxyamphetamine is an effective indirect-acting sympathomimetic drug.
- It differs from amphetamine in the presence of a p-OH group and 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.
- L-(+)-Pseudoephedrine is the (1S,2S) diastereoisomer of ephedrine and acts mostly by an indirect mechanism, with virtually no direct activity.
Sympathomimetics with a Mixed Mechanism of Action
- D-(-)-Ephedrine is a natural product that acts on both α- and β-receptors.
- It is often used to prevent low blood pressure during spinal anesthesia.
Adrenergic Receptor Antagonists (Blockers)
- β-Blockers:
- The most useful adrenergic antagonists used in medicine today.
- Originally designed to act as antagonists at the β1-receptors of the heart.
- Isoprenaline was chosen as the lead compound, and its phenolic groups were replaced with other substituents to produce dichloroisoprenaline.
- Dichloroisoprenaline was a partial agonist, and adding an extra aromatic ring converted it into an antagonist.
- β-Blockers structure-activity relationship:
- The nature of the aromatic ring and its substituents is the primary determinant of β-antagonistic activity.
- The aryl group affects the absorption, excretion, and metabolism of the β-blockers.
- The presence of a para-substituent of sufficient size on the aromatic ring along with the absence of meta-substituents is a common feature of many cardioselective β1-blockers.
β-Blockers Classification
- Nonselective β-Blockers:
- Propranolol (Inderal) is a nonselective β-blocker that blocks the β1- and β2-receptors with equal affinity.
- It is approved for use in various conditions, including hypertension, cardiac arrhythmias, angina pectoris, and migraine prophylaxis.
- Selective β1-Blockers:
- Cardioselective β1-blockers are drugs that have a greater affinity for the β1-receptors of the heart than for β2-receptors in other tissues.
- They theoretically provide two important therapeutic advantages: lack of a blocking effect on β2-receptors in the bronchi and absence of blockade of vascular β2-receptors.
α-Blockers
- Nonselective α-Blockers:
- Tolazoline (Priscoline) and phentolamine (Regitine) are imidazoline competitive α-blockers.
- They are primarily of historical interest and are not useful in treating essential hypertension.
- Selective α-Blockers:
- Prazosin (Minipress), terazosin (Hytrin), and doxazosin are quinazoline α1-blockers.
- They exhibit greater clinical utility and have largely replaced the nonselective imidazoline α-blockers.
- The 4-amino group on the quinazoline ring is very important for α1-receptor affinity.
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Description
This quiz covers the structure and activity of clonidine, a central α2-selective imidazolidine derivative, including its tautomers and effects on vasoconstriction.
