Pharmacology of Clonidine

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.