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Questions and Answers
What is a characteristic of clonidine that allows it to enter the CNS?
What is a characteristic of clonidine that allows it to enter the CNS?
- Its vasoconstrictive activity
- Its basicity of the guanidine group
- Its ability to interact with α2-receptors in the brain
- Its nonionized form at physiological pH
What is the result of stimulation of α2-receptors in the brain?
What is the result of stimulation of α2-receptors in the brain?
- An increase in sympathetic outflow from the CNS
- A decrease in peripheral vascular resistance
- A decrease in sympathetic outflow from the CNS (correct)
- An increase in blood pressure
What is the effect of clonidine's ability to enter the CNS?
What is the effect of clonidine's ability to enter the CNS?
- An increase in vasoconstrictive activity
- A decrease in peripheral vascular resistance (correct)
- An increase in blood pressure
- An increase in sympathetic outflow from the CNS
What is the primary mechanism of action of indirect-acting sympathomimetics?
What is the primary mechanism of action of indirect-acting sympathomimetics?
What is the significance of the pKa of clonidine?
What is the significance of the pKa of clonidine?
What is the effect of clonidine's stimulation of peripheral α-receptors?
What is the effect of clonidine's stimulation of peripheral α-receptors?
What is the oral bioavailability of clonidine?
What is the oral bioavailability of clonidine?
What is the significance of the O-chlorine groups in clonidine?
What is the significance of the O-chlorine groups in clonidine?
What is the primary determinant of β-antagonistic activity?
What is the primary determinant of β-antagonistic activity?
What is the effect of a para-substituent of sufficient size on the aromatic ring?
What is the effect of a para-substituent of sufficient size on the aromatic ring?
What is the configuration of the β-OH-substituted carbon for maximal β-blocking activity?
What is the configuration of the β-OH-substituted carbon for maximal β-blocking activity?
What is propranolol?
What is propranolol?
What is a common feature of many cardioselective β1-blockers?
What is a common feature of many cardioselective β1-blockers?
What is the effect of propranolol on α-receptors?
What is the effect of propranolol on α-receptors?
What is the reason behind propranolol's ability to penetrate the CNS?
What is the reason behind propranolol's ability to penetrate the CNS?
What is one of the approved uses of propranolol in the United States?
What is one of the approved uses of propranolol in the United States?
What is the effect of the presence of catechol OH groups on indirect-acting phenylethylamines?
What is the effect of the presence of catechol OH groups on indirect-acting phenylethylamines?
Which of the following substituents decreases the effectiveness of indirect-acting agents?
Which of the following substituents decreases the effectiveness of indirect-acting agents?
What is the primary mechanism of action of L-(+)-pseudoephedrine?
What is the primary mechanism of action of L-(+)-pseudoephedrine?
What is the classic example of a sympathomimetic with a mixed mechanism of action?
What is the classic example of a sympathomimetic with a mixed mechanism of action?
What is the primary goal of developing β-blockers?
What is the primary goal of developing β-blockers?
Why is hydroxyamphetamine used in diagnostic eye examinations and surgical procedures on the eye?
Why is hydroxyamphetamine used in diagnostic eye examinations and surgical procedures on the eye?
What is the consequence of having a β-hydroxyl group on the effectiveness of indirect-acting agents?
What is the consequence of having a β-hydroxyl group on the effectiveness of indirect-acting agents?
Why was Isoprenaline chosen as the lead compound?
Why was Isoprenaline chosen as the lead compound?
What is the result of replacing the phenolic groups of Isoprenaline with chloro substituents?
What is the result of replacing the phenolic groups of Isoprenaline with chloro substituents?
What is the characteristic of phenylethylamines with a mixed mechanism of action?
What is the characteristic of phenylethylamines with a mixed mechanism of action?
What is the role of the phenolic groups in Isoprenaline?
What is the role of the phenolic groups in Isoprenaline?
What is the effect of an α-methyl group on the effectiveness of indirect-acting agents?
What is the effect of an α-methyl group on the effectiveness of indirect-acting agents?
What is the diastereoisomer of ephedrine?
What is the diastereoisomer of ephedrine?
What is the purpose of adding an extra aromatic ring to Isoprenaline?
What is the purpose of adding an extra aromatic ring to Isoprenaline?
What is used in folk medicine for many years?
What is used in folk medicine for many years?
What is D-(-)-Ephedrine often used to prevent?
What is D-(-)-Ephedrine often used to prevent?
What is the primary advantage of using cardioselective β1-blockers in patients with bronchitis or bronchial asthma?
What is the primary advantage of using cardioselective β1-blockers in patients with bronchitis or bronchial asthma?
What is the effect of nonselective β-blockers on peripheral resistance?
What is the effect of nonselective β-blockers on peripheral resistance?
What is the primary difference between tolazoline and phentolamine?
What is the primary difference between tolazoline and phentolamine?
Why are tolazoline and phentolamine not useful in treating essential hypertension?
Why are tolazoline and phentolamine not useful in treating essential hypertension?
What is the primary characteristic of prazosin, terazosin, and doxazosin?
What is the primary characteristic of prazosin, terazosin, and doxazosin?
What is the function of the 4-amino group on the quinazoline ring?
What is the function of the 4-amino group on the quinazoline ring?
What is the significance of the quinazoline ring in prazosin, terazosin, and doxazosin?
What is the significance of the quinazoline ring in prazosin, terazosin, and doxazosin?
What is the advantage of using quinazoline α-blockers over nonselective imidazoline α-blockers?
What is the advantage of using quinazoline α-blockers over nonselective imidazoline α-blockers?
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.