Paracetamol: a review with specific focus on the haemodynamic effects of intravenous administration

Paracetamol is one of the most commonly used drugs worldwide with non-prescription sales exceeding 25 thousand million doses per year in the United States of America. The haemodynamic effects of the intravenous paracetamol formulations are largely understudied. There is an emerging body of evidence suggesting that intravenous paracetamol may cause iatrogenic hypotension. Little is known as to the mechanisms of this phenomenon or if intravenous paracetamol indeed does cause hypotension. As paracetamol has negligible solubility in aqueous solutions, many of the commercially available intravenous formulations contain mannitol (up to 3.91 g/100 mL paracetamol) as a stabilising ingredient. It is unknown if mannitol is a contributing factor in the observed hypotension. In this review, we outline the development of paracetamol’s current intravenous formulations, describe the composition of these formulations, and overview the literature pertaining to the proposed phenomenon of paracetamol-induced altered hypotension. Understanding the pharmacokinetic and pharmacodymanic properties of intravenous paracetamol may have important clinical implications for vulnerable patients in subgroups where haemodynamic stability is at risk such as those undergoing elective and emergency surgery.

[1]  F. Servadei,et al.  Intravenous paracetamol for fever control in acute brain injury patients: cerebral and hemodynamic effects , 2014, Acta Neurochirurgica.

[2]  M. Galinski,et al.  Detection and Follow-Up, after Partial Liver Resection, of the Urinary Paracetamol Metabolites by Proton NMR Spectroscopy , 2014, Pharmacology.

[3]  A. Krajčová,et al.  Mechanism of paracetamol-induced hypotension in critically ill patients: a prospective observational cross-over study. , 2013, Australian critical care : official journal of the Confederation of Australian Critical Care Nurses.

[4]  S. Needleman Safety of Rapid Intravenous Infusion of Acetaminophen , 2013, Proceedings.

[5]  I. Gich,et al.  [Hemodynamic and antipyretic effects of paracetamol, metamizol and dexketoprofen in critical patients]. , 2012, Medicina intensiva.

[6]  M. Royal,et al.  Plasma and Cerebrospinal Fluid Pharmacokinetic Parameters After Single‐Dose Administration of Intravenous, Oral, or Rectal Acetaminophen , 2012, Pain practice : the official journal of World Institute of Pain.

[7]  S. Ricksten,et al.  Mannitol increases renal blood flow and maintains filtration fraction and oxygenation in postoperative acute kidney injury: a prospective interventional study , 2012, Critical Care.

[8]  M. Morais‐Almeida,et al.  Selective anaphylaxis to paracetamol in a child. , 2012, European annals of allergy and clinical immunology.

[9]  S. Baker,et al.  Centrally administered parenteral paracetamol: A potentially under-reported cause of haemodynamic instability within the adult intensive care unit , 2012 .

[10]  S. Jefferies,et al.  Paracetamol in critical illness: a review. , 2012, Critical care and resuscitation : journal of the Australasian Academy of Critical Care Medicine.

[11]  J. Pearson,et al.  Postoperative Plasma Paracetamol Levels following Oral or Intravenous Paracetamol Administration: A Double-Blind Randomised Controlled Trial , 2012, Anaesthesia and intensive care.

[12]  G. Tzovaras,et al.  Impact of intraoperative hypotension on hospital stay in major abdominal surgery , 2011, Journal of Anesthesia.

[13]  M. Boyle,et al.  Paracetamol induced skin blood flow and blood pressure changes in febrile intensive care patients: An observational study. , 2010, Australian critical care : official journal of the Confederation of Australian Critical Care Nurses.

[14]  H. Ponssen,et al.  Paracetamol for intravenous use in medium- and intensive care patients: pharmacokinetics and tolerance , 2010, European Journal of Clinical Pharmacology.

[15]  F. Coluzzi,et al.  What anesthesiologists should know about paracetamol (acetaminophen). , 2009, Minerva anestesiologica.

[16]  Y. Liu,et al.  Pulmonary edema in the transurethral resection syndrome induced with mannitol 5% , 2009, Acta anaesthesiologica Scandinavica.

[17]  A. Úbeda,et al.  Blood pressure reduction in hypertensive patients after withdrawal of effervescent medication , 2009, Pharmacoepidemiology and drug safety.

[18]  S. Arıcı,et al.  Preemptive analgesic effects of intravenous paracetamol in total abdominal hysterectomy. , 2009, Agri : Agri (Algoloji) Dernegi'nin Yayin organidir = The journal of the Turkish Society of Algology.

[19]  S. Montefort,et al.  Association between paracetamol use in infancy and childhood, and risk of asthma, rhinoconjunctivitis, and eczema in children aged 6–7 years: analysis from Phase Three of the ISAAC programme , 2008, The Lancet.

[20]  E. Le Gall,et al.  Antipyretic efficacy and safety of a single intravenous administration of 15 mg/kg paracetamol versus 30 mg/kg propacetamol in children with acute fever due to infection. , 2007, International journal of clinical pharmacology and therapeutics.

[21]  E. Rimm,et al.  Frequency of analgesic use and risk of hypertension among men. , 2007, Archives of internal medicine.

[22]  A. Ottani,et al.  Paracetamol: new vistas of an old drug. , 2006, CNS drug reviews.

[23]  M. Galinski,et al.  Reduction of Paracetamol Metabolism after Hepatic Resection , 2006, Pharmacology.

[24]  S. Nørholt,et al.  Analgesic efficacy and safety of intravenous paracetamol (acetaminophen) administered as a 2 g starting dose following third molar surgery , 2006, European journal of pain.

[25]  M. Stampfer,et al.  Non-Narcotic Analgesic Dose and Risk of Incident Hypertension in US Women , 2005, Hypertension.

[26]  L. A. Skoglund,et al.  Intravenous Acetaminophen (Paracetamol): Comparable Analgesic Efficacy, but Better Local Safety than Its Prodrug, Propacetamol, for Postoperative Pain After Third Molar Surgery , 2005, Anesthesia and analgesia.

[27]  D. Benhamou,et al.  Effects of single-dose injectable paracetamolversus propacetamol in pain management after minor gynecologic surgery: A multicenter, randomized, double-blind, active-controlled, two-parallel-group study. , 2005, Current therapeutic research, clinical and experimental.

[28]  E. Viscusi,et al.  Efficacy and Safety of Single and Repeated Administration of 1 Gram Intravenous Acetaminophen Injection (Paracetamol) for Pain Management after Major Orthopedic Surgery , 2005, Anesthesiology.

[29]  Mary Ellen Mortensen Acetaminophen toxicity in children. , 2002, American family physician.

[30]  R. Aster,et al.  Immune thrombocytopenia resulting from sensitivity to metabolites of naproxen and acetaminophen. , 2001, Blood.

[31]  S. Henneberg,et al.  Pharmacokinetics of rectal paracetamol after repeated dosing in children. , 2000, British journal of anaesthesia.

[32]  S. Nørholt,et al.  Time to Onset of Analgesia and Analgesic Efficacy of Effervescent Acetaminophen 1000 mg Compared to Tablet Acetaminophen 1000 mg in Postoperative Dental Pain: A Single‐Dose, Double‐Blind, Randomized, Placebo‐Controlled Study , 2000, Journal of clinical pharmacology.

[33]  Barney Ward,et al.  Paracetamol revisited: A review of the pharmacokinetics and pharmacodynamics , 1999 .

[34]  A. Morgan,et al.  Effects of acetaminophen and ibuprofen on renal function in the stressed kidney. , 1999, Journal of applied physiology.

[35]  J. Lepoittevin,et al.  Mechanism of allergic contact dermatitis from propacetamol: sensitization to activated N,N‐diethylglycine , 1998, Contact dermatitis.

[36]  C. Coté,et al.  Twenty‐four‐Hour Pharmacokinetics of Rectal Acetaminophen in Children: An Old Drug with New Recommendations , 1997, Anesthesiology.

[37]  H. Quiding,et al.  Analgesic Efficacy of Acetaminophen Sustained Release , 1990, Journal of clinical pharmacology.

[38]  A. Lam,et al.  The effect of high-dose mannitol on serum and urine electrolytes and osmolality in neurosurgical patients , 1987, Canadian journal of anaesthesia = Journal canadien d'anesthesie.

[39]  J. D. Boyle,et al.  HYPERNATREMIA COMPLICATING PROLONGED MANNITOL DIURESIS. , 1965, The New England journal of medicine.

[40]  D. Lester,et al.  The metabolic fate of acetanilid and other aniline derivatives; major metabolites of acetanilid appearing in the blood. , 1947, The Journal of pharmacology and experimental therapeutics.

[41]  J. Smith,et al.  Studies in Detoxication , 2005 .

[42]  S. Fitoussi,et al.  Bioequivalence study comparing a new paracetamol solution for injection and propacetamol after single intravenous infusion in healthy subjects. , 2004, International journal of clinical pharmacology and therapeutics.

[43]  Committee on Drugs Acetaminophen Toxicity in Children , 2001 .

[44]  G. Eknoyan,et al.  Analgesics and the kidney: summary and recommendations to the Scientific Advisory Board of the National Kidney Foundation from an Ad Hoc Committee of the National Kidney Foundation. , 1996, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[45]  L. Allgén,et al.  Mannitol concentrations in blood plasma in connection with transurethral resection of the prostate using mannitol solution as an irrigating fluid. , 1986, Scandinavian journal of urology and nephrology.

[46]  J. Gabrilove,et al.  Glucose-induced hyperkalemia in diabetic subjects. , 1981, Archives of internal medicine.

[47]  R. T. Williams,et al.  Studies in detoxication. 22. The metabolism of phenacetin (p-ethoxyacetanilide) in the rabbit and a further observation on acetanilide metabolism. , 1949, The Biochemical journal.

[48]  R. T. Williams,et al.  Studies in detoxication: 16. The metabolism of acetanilide in the rabbit. , 1948, The Biochemical journal.

[49]  R. T. Williams,et al.  Studies in detoxication , 1941 .