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Clinical Pharmacology & Therapeutics Phase III lecture Treatment of Anaphylaxis PowerPoint Presentation
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Clinical Pharmacology & Therapeutics Phase III lecture Treatment of Anaphylaxis. Aims & Objectives To describe the presentation and cellular basis for anaphylaxis Highlight important differentials that can mimic it Discuss in detail its drug management

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Clinical Pharmacology & Therapeutics Phase III lecture Treatment of Anaphylaxis

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    1. Clinical Pharmacology & Therapeutics Phase III lecture Treatment of Anaphylaxis Aims & Objectives • 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

    2. 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)

    3. Anaphylactic vs. Anaphylactoid reactions • Anaphylactoidreactions 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.

    4. 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 ‘late-phase’ 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

    5. 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

    6. Anaphylactic Reactions: Differential Diagnosis • Anxiety (Panic Disorder) • Asthma • Epiglottitis • Foreign body Inhalation • AMI • PE • Vasovagal Attack* Wheeze/Stridor/SOB Syncope/Collapse * but bradycardic NOT tachycardic

    7. A real allergic response? Non-allergens and hidden allergens ‘Allergy’ to fish could be due any one of the following: • Histamine intoxication (Scombroidism) • Dinoflagellate poisoning (algal blooms) • Cod worm (Anisarkis) allergy • Latex allergy (latex gloves used in food preparation)

    8. Histamine & the Mast cell • Intradermalhistamine 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

    9. 2002 Guidelines of the UK Resuscitation Council

    10. 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

    11. 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.

    12. 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).

    13. 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.

    14. 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.

    15. 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)

    16. 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.

    17. 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).

    18. 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.

    19. 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 - • 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. Frequency

    20. Further Information • Treatment algorithms in pdf format (Clin Pharm Website) • Allergy section of E-medicine ( • Resuscitation council - full text of 2002 report (