Cafedrine/Theodrenaline (20:1) Is an Established Alternative for the Management of Arterial Hypotension in Germany-a Review Based on a Systematic Literature Search

Abstract

A 20:1 combination of cafedrine:theodrenaline (Akrinor®) is widely used in Germany for the treatment of hypotensive states during anesthesia and in emergency medicine. Although this drug formulation has been available since 1963, there are few studies relating to its use and many of the data are only available in German. In this article, we summarize the available data and propose mechanisms for the effects of cafedrine/theodrenaline on cardiac muscle cells and vascular smooth muscle cells. Cafedrine/theodrenaline leads to a rapid increase in mean arterial pressure that is characterized by increased cardiac preload, stroke volume, and cardiac output. Systemic vascular resistance and heart rate remain mostly unchanged. Factors which impact the effects of cafedrine/theodrenaline are gender, high arterial pressure at baseline, use of β-blockers, and heart failure. Importantly, the drug is frequently used in obstetric anesthesia without detrimental effects on umbilical cord pH or APGAR score.

Keywords: arterial hypotension: treatment; cafedrine/theodrenaline drug combination; heart frequency; inotropy; obstetric anesthesia; spinal hypotension: treatment.

Figure 1

(A) Proposed mechanism of action of cafedrine/theodrenaline in cardiomyocytes: increased inotropy. Cafedrine/theodrenaline is a combination of norephedrine and theophylline (cafedrine) and noradrenaline and theophylline (theodrenaline). The norephedrine component releases noradrenaline from endogenous stores (nerve endings). The endogenously released noradrenaline and the noradrenaline component of theodrenaline activate the β₁-adrenoceptor (β₁-AR) in the heart muscle cell, which leads—via G_s-proteins—to activation of adenylyl cyclase (AC). Adenylyl cyclase catalyzes the conversion of ATP to cAMP which increases inotropy. The theophylline component of cafedrine and theodrenaline is expected to inhibit the phosphodiesterases (PDEs) in an unselective manner. PDE3 is the most relevant PDE in human cardiac tissue. Inhibition of PDE slows degradation of cAMP and increases cAMP concentration, thereby reinforcing the β₁-adrenoceptor stimulation. (B) Proposed mechanism of action of cafedrine/theodrenaline in vascular smooth muscle cells: contradictory effects. The noradrenaline component of theodrenaline activates the α₁-adrenoceptor of the vascular smooth muscle cell. This leads—via G_q-proteins—to activation of phospholipase C (PLC) which ultimately leads to release of Ca²⁺ from the endoplasmic reticulum (ER) into the cytosol, thereby initiating muscle contraction. The norephedrine component of cafedrine stimulates the release of endogenous noradrenaline but may also act as a partial agonist at the α₁-adrenoceptor, thereby mediating vasoconstriction by itself but possibly reducing the effects of endogenous noradrenaline and of the noradrenaline component of theodrenaline. The positive effect on muscle contraction may be counteracted further by a vasodilatory effect of theophylline, which is thought to inhibit PDE3 and therefore the degradation of cGMP to 5′-GMP. This would result in accumulation of cGMP. cGMP inhibits release of Ca²⁺ into the cytosol, leading to relaxation of the muscle, thus counteracting α₁-mediated vasoconstriction. The net effect of α₁-mediated vasoconstriction and cGMP-mediated vasodilatation on the vascular muscle cell has not been described yet and may vary depending on the specific vessel and local distribution of α₁-adrenoceptors.