Hypotension occurs frequently after induction of anesthesia or in emergency medicine. Some organs are especially susceptible to hypotension (Weyland and Grüne, 2013): the brain, which has a high oxygen demand and a variable autoregulatory threshold. The kidney and the heart need adequate perfusion pressure for ultrafiltration (Walsh et al., 2013; Weyland and Grüne, 2013) and to maintain coronary blood flow (Walsh et al., 2013; Weyland and Grüne, 2013). In hypotensive patients, timely restoration of blood pressure is important to avoid end-organ damage (Walsh et al., 2013).

In Germany, a combination of cafedrine (covalently linked norephedrine and theophylline) and theodrenaline (covalently linked noradrenaline and theophylline) called Akrinor® is used for the treatment of hypotension in adults that occurs during emergency situations, general anesthesia, and regional anesthesia, especially during cesarean sections (Koch and Knoth, 2006). Hypotensive states during general anesthesia or following spinal or epidural anesthesia are the most common situations in which this drug is administered (Koch and Knoth, 2006). Cafedrine/theodrenaline has been widely used in Germany since 1963. In 2005, AWD.pharma GmbH & Co. KG (the company which owned the rights to the drug at the time) decided to take cafedrine/theodrenaline off the market because the requirements for subsequent approval could not be met within the required timeframe (Radke, 2005; Koch and Wenzel, 2006). However, because there was no alternative product with comparable pharmacodynamic characteristics on the German market at that time, the federal authority granted provisional approval after consultation with the German Society of Anesthesiology and Intensive Care (Deutsche Gesellschaft für Anästhesiologie und Intensivmedizin; DGAI; Koch and Wenzel, 2006; Radke, 2006). In 2012, cafedrine/theodrenaline received regular approval by German federal authorities after meeting the approval requirements (ratiopharm GmbH, 2013).

While hypotensive states in other countries are often treated with ephedrine and phenylephrine (Lonjaret et al., 2014), German anesthesiologists often use cafedrine/theodrenaline and have gained a lot of practical experience with the substance. 86.2% of German hospitals use cafedrine/theodrenaline for the treatment of hypotension during regional anesthesia for cesarean section (Marcus et al., 2011).

However, few data relating to its use have been published so far and the majority of existing publications are only available in German. Thus, to give the entire scientific community access to these data, we aim to summarize the current state of knowledge by providing a comprehensive English-language overview. We consider this of particular importance for on-going studies in non-German-speaking countries.

Cafedrine/theodrenaline may have advantages over other vasopressor drugs. For example, it can be administered via bolus while catecholamines normally need to be diluted and administered via syringe pumps. Bolus injection is faster, which may be beneficial in emergency situations, plus it is more cost efficient with respect to the disposables.

The combination of cafedrine and theodrenaline is unique and the substances complement one another. Sole administration of theodrenaline increases vascular resistance, while cafedrine exhibits an inotropic effect (Sternitzke et al., 1984). By administering the two substances in combination the optimal ratio of cafedrine and theodrenaline can be used. Sakai et al. tested different ratios in dogs and rats and concluded that 20:1 is the ideal ratio for both a rapid onset and a long-lasting hypertensive effect (Sakai et al., 1972a).

MEDLINE®, BIOSIS Previews®, Embase®, and SciSearch® were systematically searched using the following terms: akrinor OR acrinor OR praxinor OR H-835 OR H835 OR “cafedrine—theodrenaline” OR (cafedrine AND theodrenaline). The German and English results were screened manually for relevance. Reference lists of internal reports provided by the manufacturer of the drug were screened for additional publications.

The pharmacokinetics of cafedrine/theodrenaline have not been the subject of extensive research. Theodrenaline's pharmacokinetic properties have not been characterized due to this agent's lack of stability and the low doses administered. There are few data available for cafedrine. The initial plasma level of cafedrine after intravenous administration of 200 mg is 6 μg.ml⁻¹. Cafedrine is metabolized to norephedrine and several minor metabolites, as summarized by Koch and Knoth (2006). However, nearly 90% of the administered norephedrine is excreted via the kidneys, mostly unchanged, within 24 h (Sinsheimer et al., 1973). Cafedrine has a half-life of 60 min following both oral and intravenous administration (summarized in Koch and Knoth, 2006). Data are hard to interpret since it is not known whether cleavage products are active or even more active than cafedrine itself; exact metabolites and their potency are unknown.

Blood pressure is determined by cardiac output and systemic vascular resistance. The cardiac effect of cafedrine/theodrenaline is mediated by β-adrenoceptors, while the resistance of the blood vessels is largely controlled by α-receptors (Ahlquist, 1967). Possible mechanisms of action of cafedrine/theodrenaline on cardiac muscle cells and vascular smooth muscle cells are summarized in Figure 1.

The effects of cafedrine/theodrenaline on cardiac output are believed to be mediated via β-receptors. Cafedrine/theodrenaline has a positive inotropic effect in humans, and this can be abolished by administration of the non-selective β-adrenoceptor antagonist propranolol (Sternitzke et al., 1976, 1984). In anesthetized patients on β-blocker therapy, onset of theodrenaline/cafedrine's effect on blood pressure is delayed and the effect size is decreased (Heller et al., 2008, 2015).

The effect of cafedrine/theodrenaline on α-receptors is still under debate (Sakai et al., 1969; Sternitzke et al., 1984; Usichenko et al., 2006) and may differ with respect to vessel region and species. In porcine coronary arteries, cafedrine/theodrenaline induces vasoconstriction only when β-adrenoceptors are blocked. This vasoconstriction by cafedrine/theodrenaline can be abolished by the α₁-adrenoceptor blocker prazosin (Usichenko et al., 2006). Theodrenaline alone shows an α-adrenergic peripheral vasoconstrictor effect in healthy subjects (Sternitzke et al., 1984). However, this effect is counteracted by the vasodilatory component of cafedrine, as shown in a study with healthy subjects (Sternitzke et al., 1984) and dogs (Sakai et al., 1969). Norephedrine, which is a part of cafedrine, has been shown to act as a partial agonist at α₁-adrenoceptors in rats (Minneman et al., 1983). Partial agonists can activate receptors. However, maximum effects are clearly smaller than with the full, natural agonist. Therefore, partial agonists behave as competitive antagonists in the presence of the full agonist. At present it is unclear if norephedrine bound to theophylline shares partial agonistic activity of norephedrine. Therefore, partial agonistic activity on α₁-adrenoceptors by norephedrine could mediate vasoconstriction by itself but may reduce vasoconstriction evoked from noradrenaline.

Another expected effect of cafedrine/theodrenaline is the inhibition of phosphodiesterase (PDE), since both drugs contain the non-selective PDE inhibitor theophylline (Sternitzke et al., 1984). PDE degrades second messengers such as cAMP and cGMP which mediate inotropy and vascular muscle relaxation, respectively (Maurice et al., 2014). Because cafedrine/theodrenaline is a 20:1 mixture of the two drugs, it is believed that the PDE-inhibiting effect of cafedrine/theodrenaline is primarily mediated by cafedrine. PDE inhibition is thought to affect both the heart and the blood vessels (Maurice et al., 2003), even though it has not yet been proven that cafedrine's and theodrenaline's theophylline component exhibit this effect when administered in combination with norephedrine (from cafedrine) and noradrenaline (from theodrenaline). PDE3 inhibition alone can increase inotropy, independently of catecholamines (Christ et al., 2006; Molenaar et al., 2013). On the other hand, inhibition of PDE blunts α₁-adrenoceptor-mediated vasoconstriction, as demonstrated by experiments on internal mammary artery segments (He and Yang, 1996). It is unclear to what extent PDE inhibition accounts for the effects of cafedrine/theodrenaline.

In summary we hypothesize that cafedrine/theodrenaline acts predominantly via β-adrenoceptors in the heart, directly activating β₁-adrenoceptors, and probably reinforcing the effects of β₁-adrenoceptor stimulation via PDE inhibition. Effects on isolated vessels are difficult to predict due to the different pharmacodynamics of the individual constitutes of cafedrine/theodrenaline.

If theodrenaline is intravenously administered as a single drug to healthy subjects, this leads to an immediate, rapid increase in mean arterial blood pressure (MAP) by 28%; this effect decreases gradually up to 20 min after administration (Sternitzke et al., 1984).

On the other hand, if cafedrine is intravenously administered as a single drug to healthy subjects without arterial hypotension, the increase in blood pressure is delayed, but lasts longer (Sternitzke et al., 1984). The maximum effect of 200 mg cafedrine was noted after 20 min (Sternitzke et al., 1984). However, one in vitro study suggests that the pressor effect of cafedrine may exhibit tachyphylaxis (Daweke and Oberdorf, 1958), while an animal study showed that repeated oral administration is not associated with a reduction in the pressor effect of this agent (Sakai et al., 1972b).

Many of the data cited in this review were published in the 1960s and scientific standards have changed substantially since then. However, data relating to the use of cafedrine/theodrenaline in the management of hypotension treatment are scarce, and these studies have been included to give a comprehensive summary of the current state of knowledge.

Future areas of research on cafedrine/theodrenaline could include: (a) a more comprehensive description of the pharmacokinetics (e.g., determination of how long the individual components stay in the body); (b) further elucidation of the mechanism of action of each of the components and their cleavage products; (c) characterization of the inotropic, bathmotropic, and chronotropic effects of cafedrine/theodrenaline (possibly involving the use of isolated Langendorff preparations); (d) characterization of the temporal relationship between cafedrine/theodrenaline administration and vasoconstriction or vasodilatation in isolated venous and arterial vessel preparations; and (e) comparison of the effects of cafedrine/theodrenaline and alternative drugs on blood pressure, heart rate, and cardiac output in a clinical context (e.g., head-to-head comparisons with internationally used substances, such as ephedrine and phenylephrine). A multicenter, non-interventional study of cafedrine/theodrenaline vs. ephedrine for the treatment of perioperative hypotensive states is currently ongoing, and is registered in ClinicalTrials.gov (NCT02893241) and in the German Clinical Trials Register (DRKS-ID: DRKS00010740).

In this review article we focus on cafedrine/theodrenaline, but there are other antihypotensive agents available. Phenylephrine stimulates predominantly the α-receptors and is a strong vasopressor which leads to an increase in blood pressure and a reflex bradycardia. The vascular resistance is increased, which in turn leads to a decrease of the cardiac output (Sintetica, 2015). Ephedrine stimulates both, α- and β-receptors, has an inotropic and chronotropic effect and therefore increases the cardiac output (Sintetica, 2014). In addition, ephedrine stimulates the heart rate (Loubert, 2012).

Unfortunately, there is a lack of high quality head-to-head studies between cafedrine/theodrenaline and other pressor agents. However, one study from 1985 compared equipotent doses of cafedrine/theodrenaline, etilefrine, ephedrine, norfenefrin, and amezinium in 50 anesthetized patients (Muller et al., 1985). The authors concluded that vasopressors that stimulate predominantly the α-receptors, such as norfenefrin, may lead to an unwanted high increase of the systemic vascular resistance and a subsequent decrease of cardiac output. Predominantly betamimetic substances may display a delayed increase of blood pressure. The authors recommended the use of α- and β-receptor-stimulating substances, such as ephedrine and cafedrine/theodrenaline, which successively provide both venoconstriction and cardiac stimulation.

Cafedrine/theodrenaline leads to a rapid increase in blood pressure and the pharmacologic properties exhibit many of the characteristics of an ideal antihypotensive agent. As outlined in section “Effects of Cafedrine and Theodrenaline in Combination,” the increase in blood pressure is mainly due to increased inotropy, cardiac preload, stroke volume, and cardiac output, while the systemic vascular resistance remains largely unchanged. This is an advantage compared to drugs which act predominantly via activation of α₁-adrenoceptors. In addition, the heart rate remains mostly unchanged. This may be advantageous compared with drugs that exhibit a pronounced activation of β₁-receptors, since tachycardia is an unwanted side effect with respect to myocardial oxygen consumption. The duration of the effect is long-lasting possibly due to the proposed combination of direct and indirect sympathomimetic properties and simultaneous PDE-inhibition (Figure 1). The long-lasting effect enables comfortable drug handling, because repeated bolus administrations or the use of syringe pumps can be avoided.

Also, this drug combination has a very good safety record, as it has been used widely in Germany since the 1960s. However, it should be noted that there are only few safety data from controlled trials available.

BB, TC, and LE have all substantially contributed to the conception of the manuscript, revised it critically, approved it before submission and agree to be accountable for all aspects of the work.