Mechanisms of N-acetylcysteine Mediated Vascular Adverse Effects

Summary

Paracetamol overdose is the leading cause of acute liver failure in the Western World. N-acetylcysteine (NAC) has been the antidote of choice for over 30 years but its use is associated with adverse effects in 40% of cases. Patients characteristically experience nausea, vomiting and an anaphylactoid ('pseudo-allergic') syndrome. This reaction is clinically similar to true anaphylaxis (allergic reaction) including flushing, rash, constriction of airways, and a fall in blood pressure, but occurs via a different mechanism. Although treatable, these reactions lead to patient distress, commonly cause confusion among treating physicians, and lead to significant delays in antidote administration. The aetiology of these adverse reactions to NAC remains unclear. We hypothesise: i) these reactions result from a dose-dependent release of the chemical histamine, causing dilatation of blood vessels (vasodilatation) and the anaphylactoid syndrome; ii) paracetamol conversely exerts a protective effect on the reaction, with a less severe reaction observed in the presence of higher paracetamol concentrations. We will investigate the mechanisms underlying adverse reactions to NAC in the human forearm model, examining the role of histamine and other markers involved in the inflammatory process. The wider significance is an improved understanding of this poorly delineated phenomenon, with implications for other medications associated with similar reactions, such as non-steroidal anti-inflammatory drugs and opioids such as morphine.

Conditions

• Poisoning

Interventions

DRUG

Chlorphenamine and Ranitidine

We intend to use chlorphenamine (H1 antagonist) and ranitidine (H2 antagonist).Assuming NAC causes vasodilatation with an increase in forearm blood flow, we propose to administer 5 mcg/min to ensure maximal H1 blockade. In the presence of increased forearm blood flow, we propose to administer 37.5 mcg/min.

DRUG

Paracetamol

Therapeutic IV administration of 1g paracetamol results in a plasma concentration of \~12 mg/l. To achieve a desired concentration of \~25 mg/l, in the presence of a forearm blood blow of 50 ml/min, we would intend to administer an IA infusion of 1.25 mg/min. To account for the presence of increased forearm blood flow, we propose to administer 4 mg/min IA paracetamol.

DRUG

Paracetamol

To achieve a local paracetamol concentration of \~200 mg/l, a concentration comparable to potentially hepatotoxic concentrations following paracetamol overdose, we propose to administer 30 mg/min paracetamol.

Sponsors & Collaborators

• NHS Lothian

  collaborator OTHER_GOV

• University of Edinburgh

  lead OTHER

Principal Investigators

• Euan A Sandilands, MRCP BSc · NHS Lothian

Study Design

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

DOUBLE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Max Age

64 Years

Sex

MALE

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2011-01-03

Primary Completion

2011-07-15

Completion

2011-07-15

Countries

• United Kingdom

Study Locations