Nursing Pharmacology:  Autonomic Pharmacology Adrenergic Drugs

Therapeutic uses of indirect-acting adrenoceptor agonists

• Ephedrine

  • Ephedrine is classified as an indirect-acting synthetic non-catecholamine

    • This drug is resistant to MAO metabolism in the gastrointestinal tract.

    • Routes of administration include oral, IV, and intramuscular.

  • Pharmacological actions due to both direct and indirect components:

    • Direct action is mediated by activation of adrenergic receptors.

    • Indirect action is based on drug-induced endogenous norepinephrine release.

  • Pharmacokinetics:

    • 40% of ephedrine does excreted unchanged in urine

    • Hepatic deamination (hepatic MAO) and conjugation reactions are important drug metabolizing pathways for ephedrine.

    • Ephedrine's prolonged duration of action results from slow inactivation.

  • Pharmacodynamics:

    • Cardiovascular Effects:

      • Ephedrine's cardiovascular activity is similar to epinephrine but shows a reduced pressor effect and is longer lasting.

      • IV ephedrine:

        • IV ephedrine administration results in increased systolic & diastolic blood pressure, heart rate, cardiac output, coronary blood flow, skeletal muscle blood flow.

        • IV ephedrine, by contrast, causes a reduction in both renal and splanchnic blood flow.

      • Primary mechanism for cardiovascular effects is activation of cardiac ß₁ receptors.

      • A second ephedrine dose causes a lesser blood-pressure response, which is an example of "tachyphylaxis."

        • The reduced response following a second dose is due to, in part, depletion of norepinephrine storage sites.

  • Clinical Use

    • Ephedrine by IV administration may be used to increase systemic blood pressure following sympathetic blockade during regional anesthesia or to reverse a hypotensive response due to injected or inhaled anesthetics.

    • Chronic, oral ephedrine administration may be helpful in bronchial asthma management.

• Mephentermine (Wyamine)

  • This drug is classified as an indirect-acting synthetic, non-catecholamine sympathomimetic agent.

  • Mephentermine is similar in chemical structure to methylamphetamine, but with reduced CNS-stimulation.

  • Mephentermine activates α and β-adrenergic receptors and following IV administration results in  ephedrine-like cardiovascular effects.

• Metaraminol (Aramine)

  • Overview:

    •  Metaraminol is classified as a direct and indirect acting, synthetic, non-catecholamine sympathomimetic

    •  This agent activates α and β-adrenergic receptors

    •  Upon uptake into post-ganglionic sympathetic nerve terminals, metaraminol displaces norepinephrine and acts as a weak, false transmitter (i.e. not the normal norepinephrine neurotransmitter).

    •  Metaraminol is not a. substrate for MAO or COMT enzymatic degradation.

  • Pharmacodynamics:

    •  Cardiovascular Effects:

      •  Metaraminol administration causes significant, peripheral vasoconstriction but exhibits less positive inotropic action compared to ephedrine. (A positive inotropic effect is an increase in force of cardiac contraction; a positive chronotropic effect is an increase in heart rate.)

      •  Following IV administration, metaraminol increases both systolic and diastolic blood pressure as a result of α-adrenergic receptor activation which in turn causes peripheral vasoconstriction.

      •  The increase in blood pressure after metaraminol then activates an autonomic nervous system reflex which compensates for the increase in blood pressure by slowing the heart rate, i.e. , reflex bradycardia

        •  Bradycardia is associated with a reduction in cardiac output.

    • Renal effects of metaraminol include a decrease in blood flow; moreover, reduction is cerebral blood flow is also noted.

  

   

   

   

  • Adverse Effects: β-Adrenoceptor Antagonists

    • Rebound hypertension and tachycardia upon abrupt drug discontinuation (receptor "up-regulation" with chronic use).

    • Hypoglycemic episodes in insulin-dependent diabetics.

    • Increased plasma triglycerides (VLDL); Decreased plasma high-density lipoproteins (HDL)

    • Non-selective adrenergic antagonists (blockers) adverse effects:

      • Bronchoconstriction, due to ß₂-antagonism therefore use should be limited to non-asthmatics.

      • Decreased myocardial contractility.

      • Decreased heart rate (cardiac output).

    •  ß₁-selective Adrenergic Antagonists (blockers) adverse effects:

      • Careful use in asthmatics because selectivity for ß₁- vs. ß₂- is limited.

      • Decreased myocardial contractility.

      • Decreased heart rate (cardiac output).

   

Stoelting, R.K., "Sympathomimetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp. 271-272