Pharmacology of Clonidine
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Questions and Answers

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?

  • 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?

  • 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?

    <p>Releasing endogenous NE</p> Signup and view all the answers

    What is the significance of the pKa of clonidine?

    <p>It affects the ability of clonidine to enter the CNS</p> Signup and view all the answers

    What is the effect of clonidine's stimulation of peripheral α-receptors?

    <p>A vasoconstrictive effect</p> Signup and view all the answers

    What is the oral bioavailability of clonidine?

    <p>More than 90%</p> Signup and view all the answers

    What is the significance of the O-chlorine groups in clonidine?

    <p>They afford better activity than O-methyl groups at α2 sites</p> Signup and view all the answers

    What is the primary determinant of β-antagonistic activity?

    <p>The nature of the aromatic ring and its substituents</p> Signup and view all the answers

    What is the effect of a para-substituent of sufficient size on the aromatic ring?

    <p>It increases β1-selectivity</p> Signup and view all the answers

    What is the configuration of the β-OH-substituted carbon for maximal β-blocking activity?

    <p>S absolute configuration</p> Signup and view all the answers

    What is propranolol?

    <p>A nonselective β-blocker</p> Signup and view all the answers

    What is a common feature of many cardioselective β1-blockers?

    <p>The presence of a para-substituent of sufficient size on the aromatic ring</p> Signup and view all the answers

    What is the effect of propranolol on α-receptors?

    <p>It has no effect on α-receptors</p> Signup and view all the answers

    What is the reason behind propranolol's ability to penetrate the CNS?

    <p>Its high lipophilicity</p> Signup and view all the answers

    What is one of the approved uses of propranolol in the United States?

    <p>Treatment of hypertension</p> Signup and view all the answers

    What is the effect of the presence of catechol OH groups on indirect-acting phenylethylamines?

    <p>It enhances their potency</p> Signup and view all the answers

    Which of the following substituents decreases the effectiveness of indirect-acting agents?

    <p>Nitrogen substituents larger than methyl groups</p> Signup and view all the answers

    What is the primary mechanism of action of L-(+)-pseudoephedrine?

    <p>Indirect mechanism</p> Signup and view all the answers

    What is the classic example of a sympathomimetic with a mixed mechanism of action?

    <p>D-(-)-Ephedrine</p> Signup and view all the answers

    What is the primary goal of developing β-blockers?

    <p>To achieve selectivity for β-receptors over α-receptors</p> Signup and view all the answers

    Why is hydroxyamphetamine used in diagnostic eye examinations and surgical procedures on the eye?

    <p>It has little or no CNS-stimulating action</p> Signup and view all the answers

    What is the consequence of having a β-hydroxyl group on the effectiveness of indirect-acting agents?

    <p>It decreases their effectiveness</p> Signup and view all the answers

    Why was Isoprenaline chosen as the lead compound?

    <p>Because it is active at β-receptors and not α-receptors</p> Signup and view all the answers

    What is the result of replacing the phenolic groups of Isoprenaline with chloro substituents?

    <p>A partial agonist</p> Signup and view all the answers

    What is the characteristic of phenylethylamines with a mixed mechanism of action?

    <p>They have no hydroxyls on the aromatic ring but do have a β-hydroxyl group</p> Signup and view all the answers

    What is the role of the phenolic groups in Isoprenaline?

    <p>They are essential for agonist activity</p> Signup and view all the answers

    What is the effect of an α-methyl group on the effectiveness of indirect-acting agents?

    <p>It increases their effectiveness</p> Signup and view all the answers

    What is the diastereoisomer of ephedrine?

    <p>L-(+)-Pseudoephedrine</p> Signup and view all the answers

    What is the purpose of adding an extra aromatic ring to Isoprenaline?

    <p>To remove the partial agonist activity</p> Signup and view all the answers

    What is used in folk medicine for many years?

    <p>D-(-)-Ephedrine</p> Signup and view all the answers

    What is D-(-)-Ephedrine often used to prevent?

    <p>Low blood pressure during spinal anesthesia</p> Signup and view all the answers

    What is the primary advantage of using cardioselective β1-blockers in patients with bronchitis or bronchial asthma?

    <p>They are safe for use in patients with bronchitis or bronchial asthma</p> Signup and view all the answers

    What is the effect of nonselective β-blockers on peripheral resistance?

    <p>They increase peripheral resistance</p> Signup and view all the answers

    What is the primary difference between tolazoline and phentolamine?

    <p>Their lipophilic substituents</p> Signup and view all the answers

    Why are tolazoline and phentolamine not useful in treating essential hypertension?

    <p>They are not effective in reducing blood pressure</p> Signup and view all the answers

    What is the primary characteristic of prazosin, terazosin, and doxazosin?

    <p>They are selective α-blockers</p> Signup and view all the answers

    What is the function of the 4-amino group on the quinazoline ring?

    <p>It enhances the molecule's affinity for α1-receptors</p> Signup and view all the answers

    What is the significance of the quinazoline ring in prazosin, terazosin, and doxazosin?

    <p>It enhances the molecule's affinity for α1-receptors</p> Signup and view all the answers

    What is the advantage of using quinazoline α-blockers over nonselective imidazoline α-blockers?

    <p>They exhibit greater clinical utility</p> Signup and view all the answers

    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.

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