Alpha Adrenergic Receptors

• Order of agonist potency

  • epinephrine > norepinephrine >> isoproterenol

  • Multiple alpha receptor subtypes have been identified.

  • Multiple forms were suggested when, after administration of an alpha-receptor antagonist, repetitive nerve stimulation resulted in increasing amount of norepinephrine release. This findings suggested a presynaptic alpha-receptor binding site.

  • Post-synaptic receptors alpha₁ .

  • Pre-synaptic receptors alpha₂ .

  • Alpha₂ receptors are also present post-synaptically. This site is involved in the action of some centrally-acting antihypertensive agents, e.g. clonidine.

  • Some drugs, such as clonidine are more active at alpha₂ receptors.

• Clonidine (Catapres)

  • Clonidine acts in the brain at post-synaptic alpha₂ receptors, inhibiting adrenergic outflow from the brainstem. Inhibition of sympathetic outflow results in a decrease in blood pressure.

  • Clonidine reduces cardiac output (by reducing both stroke volume and heart rate) and peripheral resistance. Reduction in stoke volume occurs due to increased venous pooling (decreased preload).

  • Clonidine does not interfere with cardiovascular responses to exercise.

  • Renal blood flow and function is maintained during clonidine treatment.

  • Clonidine has minimal or no effect on plasma lipids.

  • Adverse Effects

    • Dry Mouth (xerostomia)

    • Withdrawal syndrome upon abrupt discontinuation (increased blood pressure, headache, tachycardia, apprehension, tremors)

    • Bradycardia (in patients with SA nodal abnormality)

  • Some drugs such as methoxamine (Vasoxyl) or phenylephrine (Neo-Synephrine) are more active at alpha₁ receptors.

  • Multiple forms of both alpha₁ and alpha₂ receptors have been identified.

• Dopamine

  • D₁ receptor activation results in stimulation of adenylyl cyclase activity.

  • Smooth muscle relaxation (e.g. renal vasodilation) would result from increases in cAMP caused by activation of D₁ receptors

    • Increased cAMP levels may facilitate inactivation of myosin light chain kinase, MLK (activated by calcium-calmodulin complexes which means that increased Ca²⁺ promotes MLK activation).

    • Note that only phosphylated myosin can bind to actin and that phosphorylation state is controlled by the enzyme myosin light chain kinase.

  • D₂ receptor activation inhibits cAMP production (inhibits adenylyl cyclase activity), increases K⁺ conductance and decreases calcium influx.

• Catecholamine Refractoriness

  • Following exposure to catecholamines, there is a progressive loss of the ability of the target site to respond to catecholamines. This phenomenon is termed tachyphylaxis, desensitization or refractoriness.

  • Regulation of catecholamine responsiveness occurs at several levels:

    • Receptors

    • G proteins

    • Adenylyl cyclase

    • Cyclic nucleotide phosphodiesterase

  • Stimulation of ß-adrenergic receptors rapidly causes receptor phosphorylation and decreased responsiveness. The phosphorylated receptor exhibits:

    • decreased coupling to G_s and

    • decreased stimulation of adenylyl cyclase.

Lefkowitz, R.J, Hoffman, B.B and Taylor, P. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.112-137.Hoffman, B. B. Adrenoceptor-Activating & Other Sympathomimetic Drugs: Introduction to Antimicrobial Agents in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p.118-122

Category: Pharmacology Notes