Potential cardiovascular adverse events when phenylephrine is combined with paracetamol: simulation and narrative review

Potential cardiovascular adverse events when phenylephrine is combined with paracetamol: simulation and narrative review Hartley C. Atkinson 0 1 Amanda L. Potts 0 1 Brian J. Anderson 0 1 0 Department of Anaesthesiology, University of Auckland , Private Bag 92019, Auckland 1142 , New Zealand 1 Clinical Solutions NZ Ltd , PO Box 10574Te Rapa Hamilton 3241 , New Zealand Background Increased bioavailability of phenylephrine is reported when combined with paracetamol in over-the-counter formulations for the symptomatic treatment of the common cold and influenza. Such formulations could increase phenylephrine-related cardiovascular adverse events particularly in susceptible individuals. Quantification of the effect of phenylephrine concentration on blood pressure allows simulation of potential adverse combination therapy effects. Methods MEDLINE and EMBASE databases were searched for papers discussing or describing any adverse effect, hypersensitivity or safety concerns related to phenylephrine alone or in combination with other drugs. The pharmacodynamic relationship between plasma phenylephrine concentration and mean arterial blood pressure was characterized using published observations of blood pressure changes after ophthalmic eye drops. The resulting pharmacokinetic and pharmacodynamic parameters were then used to predict mean arterial blood pressure (MAP) changes in that population if given an oral combination of phenylephrine and paracetamol. Paracetamol; Phenylephrine; Interaction; Pharmacodynamics; Blood pressure - * Brian J. Anderson Phenylephrine is a selective alpha-1 adrenoceptor agonist with powerful vasoconstrictive properties. Historically, its use had been restricted to the perioperative period and intensive care medicine for preparation of the surgical field and control of haemorrhage during ear nose and throat procedures, pupillary dilation and maintenance of blood pressure. Phenylephrine is commonly used now as a nasal decongestant in many overthe-counter (OTC) cold and influenza preparations. When phenylephrine was combined with another commonly administered cold and flu medication, paracetamol, the plasma concentration of phenylephrine was, on average, twice that obtained when phenylephrine was given alone and the peak concentration approximately four times higher [1]. It is suggested that the increase in phenylephrine bioavailability is due to a reduction in the amount of phenylephrine undergoing first-pass metabolism due to saturation of the sulfation pathways by paracetamol [1]. Formulation may also have impact. Phenylephrine bioavailability was reduced when administered as a paracetamol-guaifenesin-phenylephrine syrup compared to the same combination in tablet form [2]. These findings raise the concern that phenylephrine administered as a combination with paracetamol may increase the incidence of adverse effects attributable to phenylephrine, most notably cardiovascular adverse effects particularly those with preexisting cardiovascular conditions. Here, we provide a systematic narrative review of cardiovascular adverse effects associated with phenylephrine. We quantify the effect of phenylephrine concentration on blood pressure using published data and simulate the potential impact paracetamol phenylephrine combination oral therapy may have on cardiovascular endpoints. Literature review of phenylephrine adverse events A b r o a d s e a r c h ( s e a r c h t e r m s a r e d e t a i l e d i n t h e Supplementary Appendix) of both MEDLINE and EMBASE databases was undertaken followed by manual selection of relevant reports based on the inclusion and exclusion criteria described below. No specific time limits were applied to the search. The time frame of the search was limited only by the coverage of the database (MEDLINE: 1946 to April 2014; EMBASE: 1947 to April 2014). Papers discussing or describing any adverse effect, hypersensitivity or safety concern related to phenylephrine alone or in combination were included. Papers were excluded if they (1) did not describe an adverse effect for phenylephrine; (2) related to children under 12 years of age; (3) were not written in English or a full-text version was not available for purchase; (4) was not a clinical trial [either prospective or retrospective], case report or series, or a meta-analysis; and (5) did not relate to the cardiovascular system. References of identified papers were reviewed for additional relevant reports. Phenylephrine PKPD relationship analysis The relationship between plasma phenylephrine concentration and mean arterial blood pressure was characterized using those published data from Kumar and colleagues [3], who related the systemic absorption of phenylephrine eye drops to cardiovascular effects. Individual plasma concentrations and corresponding blood pressure changes at 0, 10, 20 and 60 min after 2.5 % (n=10) and 10 % (n=10) eye drops (two 32-L drops at 5-min intervals) are contained in Tables 1 and 2 of that publication(n=20). Further pharmacokinetic (PK) data were available from healthy volunteers given oral phenylephrine 10 mg alone, with blood for concentration assay taken at 5, 15, 30, and 45 min and 1, 2, 3, and 6 h (n=28, data from [1, 4]). Intravenous time-concentration data were available from a study by Hengstmann and colleagues [5]. Four healthy volunteers were given phenylephrine 1 mg, and blood was taken for assay on 17 occasions over the subsequent 4 h. Pooled data for that study are presented in Table 2 of that publication(n=1). Technical methods for population parameter estimates using nonlinear mixed effects models (NONMEM) can be found in the Supplementary Appendix. A total of 1172 papers were identified for examination. Fortyseven reports fulfilled the inclusion criteria. The majority of literature concerning phenylephrine and cardiovascular effects related to its use as a hypertensive agent for the management of hypotension associated with shock and spinal anaesthesia. These effects are therapeutic in these scenarios, and as they are not adverse effects, they are not discussed. Case reports and studies that described unexpected or unwanted cardiovascular effects following the use of phenylephrine are listed in Table 1. The standard OTC 10-mg dose of phenylephrine appears to be well tolerated by the majority of people; however, increases in blood pressure and decreases in heart rate are reported with doses over 15 mg [6, 7]. It has been estimated that a 20-mmHg increase in systolic blood pressure would occur with an oral dose of 45 mg phenylephrine in normotensive healthy people [8]. This situation changes considerably in people taking medications such as monoamine oxidase inhibitors where interaction with phenylephrine caused increases in systolic blood pressure of greater than 60 mmHg and required intervention [9, 10]. Blood pressure and heart rate changes also appear to be potentiated in patients with underlying hypertension. One study reports (...truncated)