Transcript No Slide Title

Clinical Pharmacology & Therapeutics
Phase III lecture
Treatment of Anaphylaxis
Aims & Objectives
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To describe the presentation and cellular basis for anaphylaxis
Highlight important differentials that can mimic it
Discuss in detail its drug management
Introduce other hypersensitivity-based drug reactions
Treatment of Anaphylaxis
• No accepted definition
• ‘A life threatening activation of mast cells and basophils’
• Not necessarily type I hypersensitivity/IgE mediated
• Death from asphyxiation or cardiovascular collapse
• Incidence uncertain (probably underreported)
• ? 1:2,300 A&E admissions (=1:15,000 general pop/year)
Anaphylactic vs. Anaphylactoid reactions
Anaphylactoid reactions mimic the features of an
anaphylactic reaction but mast cell/basophil
activation is not IgE-dependent.
Certain drugs (and venoms) are able to directly
activate mast cells including:
• Succinylcholine
• Morphine
• Tubocurarine
• Vancomycin (‘Red-man Syndrome’)
• N-acetyl-cysteine
Treatment is the same as for Anaphylaxis.
Clinical Features of Anaphylaxis
- Is there a predisposition? Latex and food allergies usually
occur against a background of atopy and other allergic
disorders e.g. asthma and eczema.
- Onset is rapid (5-10 minutes of exposure) peaking in 30
minutes. Duration can be long especially if allergen persists
(e.g. swallowed) or the response is biphasic (classical ‘latephase’ allergic response in the airways)
- May be heralded by impending sense of doom. Subsequent
features reflect to some extent route of allergen exposure:
• Systemic (IV drugs) - cardiovascular (hypotension/syncope)
• Ingested (food allergens) - respiratory (laryngeal
oedema/bronchoconstriction)
• Percutaneous (insect stings) - respiratory or cardiovascular
problems equally likely
All may be accompanied by cutaneous features
e.g. urticarial rash.
Urticarial Rash
Features Suggesting Severe Anaphylactic Reaction
•Wheeze
•Stridor
•Cyanosis
•Skin Pallor*
•Prominent Tachycardia**
* 80% of fatal food-related anaphylactic reactions have no skin signs
** Compared to bradycardia in vasovagal attack
Anaphylactic Reactions: Differential Diagnosis
•Anxiety (Panic Disorder)
•Asthma
Wheeze/Stridor/SOB
•Epiglottitis
•Foreign body Inhalation
•AMI
•PE
Syncope/Collapse
•Vasovagal Attack*
* but bradycardic NOT tachycardic
A real allergic response?
Non-allergens and hidden allergens
‘Allergy’ to fish could be due any one of the following:
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Histamine intoxication (Scombroidism)
Dinoflagellate poisoning (algal blooms)
Cod worm (Anisarkis) allergy
Latex allergy (latex gloves used in food preparation)
Histamine & the Mast cell
Intradermal histamine produces the classical Triple
response: central red spot (vasodilatation) ; flare;
wheal (oedema overlying initial red spot).
Intravenous histamine causes: (1) marked
vasodilatation (largely from endothelial derived NO);
(2) increased capillary leak. These H1-mediated
effects contract effective blood volume.
Importance of mast cell-derived histamine in
anaphylaxis depends on species & tissue.
In humans, protection offered by H1 blockade is
variable:
• oedema/itch - good
• hypotension - modest
• bronchoconstriction - negligible
2002 Guidelines of the UK
Resuscitation Council
Effects of Adrenaline (Epinephrine)
Comparison of its cardiovascular
effects (at 10g/min IVI) with
noradrenaline (-dominant) and
isoprenaline (2-dominant).
Other important (if not crucial) 2 effects:
• Mast-cell stabilisation (against IgE activation)
• Bronchodilatation
The Use of Adrenaline in Anaphylaxis
The problems with its use:
•Variable Absorption - give I.m. AVOID s.c.
•Arrhythmogenic in high dose - NEVER give 1:1000 ADRENALINE I.v.
If using ADRENALINE as an IVI, it must be diluted and do not delay
administration of ADRENALINE to set up IVI and gain IV access.
Therefore:
1. Give ADRENALINE I.m promptly (can repeat at 5-10 min intervals)
2. Gain IV access
3. If patient remains shocked resort to IVI thus ….
Dilute 0.5ml of 1:1000 ADRENALINE in 50ml of N/saline (1:100,000)
4. Infuse at 0.1-2ml/min (1-20ug/min) until haemodynamically stable
5. If using prolonged IVI, add renal-dose of DOPAMINE IVI.
Drugs that Interact with Adrenaline
• The effects of adrenaline are markedly potentiated in patients
taking concurrent tricyclic antidepressants, MAOIs or cocaine.
• The -effects of adrenaline may also be antagonised (and the
manifestations of anaphylaxis more severe) if the patient is taking
concurrent -blockers (especially non-selective agents).
• Phenothiazines (especially chlorpromazine) are potent -blockers
hence adrenaline may cause unexpected hypotension (unrestrained
2-mediated vasodilatation).
Histamine (H1) receptor antagonists
FIRST-GENERATION e.g Chlorpheniramine and Diphenhydramine
• sedating (although paradoxical excitation in overdose)
• anticholinergic effects
SECOND- GENERATION e.g. Terfenadine and Cetirizine
• Non-sedating (poor CNS penetration)
• No anticholinergic effects
• Risk of VT (Torsade de Pointes) with Terfenadine and Astemizole *
* This is a PK problem due to their clearance through CYP 3A4/5. Drugs (e.g. erythromycin,
ketoconazole, or grapefruit juice) block conversion of parent drug to the active H1 antagonist - the
parent drugs block delayed rectifier (K-current) in the heart prolonging QTc I.e. behave like class III
agents.
Other drugs used in Anaphylaxis
Nebulised or IV 2 agonist (e.g. salbutamol) - useful where
bronchospasm is the major sign and fails to respond promptly to IM
adrenaline.
IV Glucocorticoid (e.g. hydrocortisone 200-500mg) - probably of limited
efficacy (onset of action delayed 3-6 hrs) except where the response is
biphasic or asthmatic features predominate.
IV Glucagon (1mg in 1L, infused at 5-15ml/min) - anecdotal reports of efficacy in
refractory hypotension. Releases catecholamines and +ve inotrope (raising cAMP
independent of cardiac -adrenoceptors).
H2 Antagonists - isolated reports of increased efficacy of combined blockade NB
histamine relaxes VSM directly by H2 effect - this is slower in onset but much more
sustained than H1 effect on endothelial cells. Efficacy in systemic mastocytosis clearer.
Further Ix and Management
Collect (preferably within 1hr and NOT >6hr) 10ml of clotted blood for:
• Mast Cell Tryptase assay (if diagnostic doubt exists)
• Assay of Allergen-Specific IgE levels (RAST).
Refer to Allergist for:
• Identification of allergen (RAST, skin-prick testing etc)
• Desensitisation (especially Bee/Wasp venoms)
• Assessment of need for Px of Epipen (Adrenaline autoinjector)
Drug-Induced Allergic Reactions
Type I - IgE dependent. Needs previous exposure to allergize.
Type II - Cytolytic IgG/M antibodies causing C activation. Usually fade with drug
withdrawal. Form basis of :
• Methyl-DOPA induced haemolysis
• Quinidine-induced thrombocytopenia
• Sulphonamide-induced granulocytopenia
• Drug-induced lupus (hydralazine & procainamide)
Type III - Serum sickness (Arthus reaction). Deposition of C fixing IgG-Ag complexes in
vessel wall produces urticaria, arthritis, lymphadenopathy and fever. Offenders
include:
• Antibiotics (sulphonamides* and penicillin)
• Anticonvulsants (phenytoin and carbamazepine)
• Iodides.
*Also cause Steven-Johnson syndrome as a rare & severe form of type III immune vasculitis.
Allergic reactions: Angioedema
Usually localised (to head & neck) but may be
more generalised (especially GI) +/- urticaria.
Presents as swelling of the face, neck and
oropharynx. Represents mast cell degranulation
in skin deep to dermis vs. superficial dermis in
urticaria.
• Inherited - C1 esterase inhibitor deficiency due
to mutation (autosomal dominant) of the C1-INH
gene.
• Acquired - usually autoantibodies to C1-INH in
the context of autoimmune disease or
lymphoproliferative disorders. Rarer reports of
hypercatabolism of C1-INH in infection.
• Drug-induced - commonest culprit ACE
inhibitors (and OMAPATRILAT).
ACE inhibitors & Angioedema
• Mechanism probably related to massive elevation of BK but unclear
why it can appear days to years after 1st dosing.
• Incidence probably <0.1% - Afro-Caribbean and renal/cardiac
transplant patients may be at increased risk.
• Treatment is usually with standard therapy for an anaphylactic reaction
+/- inhaled Epi but not mast cell dependent! If airway threatened,
intubation or tracheostomy needed.
• Under recognised especially in milder forms. ACE inhibitors should be
stopped and an AT1 receptor antagonist substituted if necessary (e.g.
Losartan) BUT isolated reports have appeared of angioedema with these
agents!
• New combined ACE/NEP inhibitors suffer same problem.
Allergic Reactions to Penicillins
• Allergization often occult (food containing pen. or the pen. mould itself)
• Anti-pen abs are detectable in almost everyone
• Patients reports of previous ‘allergy’ are frequently inaccurate
• A class problem manifesting as -
Frequency
Rash (MP > urticarial)
Fever
Bronchospasm
Vasculitis
Serum sickness/Stevens-Johnson
Anaphylaxis
• Rashes most frequent with ampicillin (10%); essentially 100% in IM infection.
• Rashes more likely if allopurinol co-administered
• Cross-sensitisation with cephalosporins now thought to be <1% and reactions usually mild
• If pen drug-of-choice consider either ‘controlled’ challenge or desensitisation
* VERY uncommon <1/10,000 prescriptions; 2/3 have previously received it and of these only 1/3
report previous reaction.
Further Information
• Treatment algorithms in pdf format (Clin Pharm Website)
• Allergy section of E-medicine (www.emedicine.com/emerg)
• Resuscitation council - full text of 2002 report (www.resus.org.uk)