2005A08 Outline the pathology of acute anaphylactic reactions with reference
to the mediators released and their effects. Outline the role of adrenaline
and its mechanism of action in treating anaphylaxis.

Definition

·  Type 1 hypersensitivity reaction

Problem

·  ↑↑ mortality if untreated

Common triggers

·  Antibiotics: penicillins

·  Muscle relaxants: suxamethonium, rocuronium

·  Food: peanuts

·  Environment: latex

First exposure

(sensitization)

·  Antigen-presenting cell + antigen -> activate specific T cell -> activate specific B cell -> produce specific IgE

·  IgE fixes to basophils (blood), mast cells (tissues)

Second exposure

(showtime)

·  Antigen binds IgE

·  Systemic degranulation (early phase)

·  ↑Mediator production (late phase)

Mucocutaneous

·  Vasodilation (VD), capillary leak (CL) -> urticaria, angioedema

Cardiovascular

·  VD,CL-> ↓blood volume -> ↓preload -> ↓cardiac output -> ↓mAP -> +/- arrest

Respiratory

·  Bronchoconstriction (BC)-> +/- arrest

GIT

·  Vomiting, abdo pain, diarrhea

Histamine

·  Basic amine derived from histidine

·  Mechanism of action (MoA):

o H1: G_q G protein coupled receptor (G_q-GPCR)

o H2: G_s-GPCR

·  CVS effects:

o Heart: H1: ↑AV delay, coronary vasoconstriction

o Heart H2A: ↑inotropy, coronary vasodilatation

o Vasculature: H1: VD,CL (↑nitric oxide synthesis)

·  Resp:

o H1: BC

o H2: bronchodilation (BD)

·  CNS: H1: ↑wakefulness, (↓PONV)

·  GIT: H2: ↑gastric acid secretion

Serotonin

·  MoA: binds 5HT receptor, usually GPCR

·  CVS: VD

·  Resp: BC

·  CNS: nausea (5-HT₃)

Tryptase

·  MoA: serine protease

·  Activates complement cascade, coagulation cascade

·  Useful in retrospective Dx anaphylaxis

·  CVS: VD, CL

·  Resp: BC

Prostaglandins

·  e.g. PGE₂

·  Produced from arachidonic acid (AA) by COX-2

·  MoA: binds various GPCR

·  CVS: VD, CL

·  (exception: PGI₂)

Leukotrienes

·  a.k.a. slowly releasing substance of anaphylaxis A

·  Produced from AA by lipo-oxygenase

·  MoA: via GPCR and PPAR receptors

·  CVS: VD, CL

·  Resp: BC

Bradykinin

·  MoA: via β₁ and β₂ GPCR

·  Inactivated by ACE

·  CVS: VD, CL

·  Resp: BC

Platelet activating factor

·  Effects via PAF receptor

·  Role unknown

Class of drug

·  Catecholamine

Dose

·  50mcg IV bolus +/- repeat

·  0.5mg IM once

·  +/- infusion required

Dose-dependent effects

·  Low dose: β₁>β₂>α₁

·  High dose: α₁>β₁>β₂

Receptor effects

·  α₁ effect:

o G_q GPCR -> ↑IP₃, DAG

o Vasoconstriction, ↑SVR, ↑coronary and cerebral perfusion

·  β₁ effect:

o G_s GPCR -> ↑cAMP

o ↑heart rate and contractility -> ↑mAP

·  β₂ effect:

o G_s GPCR->↑cAMP

o Bronchodilatation

o ↓Mast cell mediator release

o (Also vasodilation, offset by α₁ effect at high dose)