Anaphylaxis

Week 1

Hypersensitivity
Summary of Hypersensitivity
Immediate (Type I) Hypersensitivity
Allergy
Anaphylaxis
Antibody-Mediated (Type II) Hypersensitivity
Immune Complex-Mediated (Type III) Hypersensitivity
Cell-Mediated (Type IV) Hypersensitivity

Shock

Dermatology
Clinical Dermatology
Bullous (Blistering) Diseases
Acute Inflammatory Dermatoses
Chronic Inflammatory Dermatoses
Eczema
Psoriasis

Drugs
Corticosteroids
Antihistamines
Catecholamines

Collapse
Sudden Collapse
Unconsciousness
Summary of Hypersensitivity

Examples Mechanism Effects

Vasodilation, oedema,
Anaphylaxis; IgE → mast cell release of
Immediate (type SM contraction, mucus
Allergies; mediators → recruitment of
I) hypersensitivity production,
Bronchial asthma inflammatory cells
inflammation

Transfusion reactions,
IgG, IgM → antigen binding →
Antibody- Autoimmune
phagocytosis/ lysis of target cell Phagocytosis, cell lysis,
mediated (type II) haemolytic anaemia;
by complement or Fc receptors; inflammation
hypersensitivity Goodpasture
leukocyte recruitment
syndrome

Immune Ag:Ab complexes →

complex- SLE; complement activation →
Inflammation,
mediated (type Some forms of leukocyte recruitment → release
nectrotizing vasculitis
III) Glomerulonephritis of enzymes & other toxic
hypersensitivity molecules

Contact dermatitis;
Activated T cells → release of Perivascular cellular
Cell-mediated Multiple sclerosis;
cytokines → inflammation and infiltrates, oedema, cell
(type IV) DM1; Rheumatoid
macrophage activation; T cell- destruction, granuloma
hypersensitivity arthritis;
mediated cytotoxicity formation
IBD; Tuberculosis
Immediate (Type I) Hypersensitivity
• IgE-mediated triggering of mast cells - allergy
• Allergens are large molecules (usually proteins) or haptens – small molecules (e.g. penicillin) that bind to
proteins to induce a type I hypersensitivity response

Atopy
• Predisposition to type 1 hypersensitivity
o Excessive Th-2 function
o Excessive IgE production
o Increased eosinophil numbers
• 50% of atopic individuals have a positive family history

Pathogenesis
Sensitisation - exposure to allergen
1. Activation of TH2 call
2. IgE class-switching in B cells
3. Production of IgE
4. Binding of IgE to Fc RI on mast cells

Elicitation - repeat exposure to allergen

1. Activation of mast cells
2. Release of IL-4 to stimulate IgE production
3. Release of other mediators

Chemical Mediators
1. Preformed mediators (within mast cell
Histamine
granules) Vasodilation + Platelet-activating factor
o Vasoacitve amines – histamine ↑ vascular Leukotrienes C4, D4, E4
o Enzymes permeability Neutral proteases
o Proteoglycans - heparin Prostaglandin D2
2. Lipid mediators (mast cells → phospholipase A2
activation → arachidonic acid & PAF) Leukotrienes C4, D4, E4
o Leukotrienes Histamine
Smooth muscle spasm
Prostaglandins
o Prostaglandin D2
Platelet-activating factor
o Platelet activating factor (PAF)
3. Cytokines - TNF, IL-1, IL-3, IL-4, IL-5, IL-6, IL-9, IL- Cytokines
13, chemokines, GM-CSF Cellular infiltration Leukotriene B4
Platelet-activating factor

Phases
1. Immediate phase reaction – mast cell degranulation → preformed mediators, lipid mediators
o Within 5-30 minutes; subsides within an hour
o Vasodilation, vascular leakage, SM spasm
2. Late phase reaction - cytokines
o 2-24 hours after exposure
o Eosinophils, neutrophils, basophils, T cells
o Tissue destruction – mostly mucosal epithelial cell damage
Allergy
• A type I hypersensitivity reaction to an allergen
Allergic
• 6-8% of children and 1-2% of adults have food allergies rhinitis

Asthma

Incidence
Atopic
dermatitis
Allergic/Atopic March Food
allergy
• Typical progression of allergies in the first decades of life →

Allergic Reactions 0 ½ 1 3 7 15
Age (years)
Depend on site of mast cell activation

1. Mast cells associated with the circulation

o Occurs with intravenous or rapid gastrointestinal absorption – drugs, insect bites, peanuts
o Leads to anaphyactic shock - ↓ blood pressure, airway constriction, suffocation

2. Mast cells associated with the respiratory system

o Occurs with inhalation or airborne allergens
o Allergic rhinitis
o Allergic conjunctivitis – similar to allergic rhinitis but in the conjunctiva
o Allergic asthma – lower respiratory tract effects

3. Mast cells associated with the skin

o Occurs with local injection of small amounts of allergen (e.g. by insects)
o Wheal-and-flare reaction
‐ Wheal – local ↑ in vascular permeability → swelling
‐ Flare – chemical mediators → vasodilation → redness of surrounding skin

Common Allergens
Most Common Food Allergies Most Common Aeroallergens
1. Cow’s milk Inside
2. Egg (usually egg white) 1. Dust mites
3. Peanuts 2. Pet fur
4. Fish 3. Mould
5. Soy 4. Cockroaches
6. Wheat Outside
7. Tree nuts 5. Trees
8. Shellfish 6. Grass
7. Weeds

Atopic Eczema
• Affects ~20% of children in early childhood
• 80% of cases → develop rhinitis or asthma

Triggers Management
• Food • Moisturise skin
• Aeroallergens • Cut and file fingernails
• Sand, temperature, humidity • Antihistamines to decrease itch
• Infection • Removal/avoidance of triggers
• Emotional triggers • Wet wraps/bandaging
Allergic Rhinitis
• Hayfever – IgE-mediated inflammation of the nose
• Affects 10-25% of the population
• Mean onset 9.1 years

Classification
• Intermittent - <4 days/week or <4 weeks • Mild – normal sleep, no impairment of lifestyle
• Persistent - >4 days/week or >4 weeks • Moderate/severe – abnormal sleep,
impairment

Symptoms Signs
From Inflammation From Obstruction • Allergic salute
• Itch • Congestion • Swollen mucosa inside eye
• Sneeze • Dry lips/mouth • Dark circles around eyes
• Rhinorrhoea • Sleep disturbance • Mouth breathers
• Conjuctivitis • Sinusitis • May have overbite
• Post-nasal drip • Apnoea

Differential Diagnosis
• Infectious rhinitis – acute, chronic (CF)
• Nonallergic rhinitis
• Hormonal (pregnancy, menstrual cycle, hypothyroidism)
• Mechanical obstruction

Diagnosis
• History
o Relationship/timing with exposure (e.g. with food intake)
o Previous reactions
o Family History

• Consultation with patient – oral challenges, food diaries, elimination diets

• Skin prick testing

o Pricking with a small amount of allergen on the skin and comparing to a saline control
o Quick, sensitive, relatively specific, cheap

• RAST testing - needle test identifying levels of allergen-specific IgE antibodies

Treatment
Avoidance of the Allergen
• House cleaning
• Mattress and pillow covers
• Air conditioning and filters
• Food education
• Reading food labels
• Asking about ingredients

Pharmacological
1. Long-acting antihistamines – sedating or non-sedating
o Sedating (CNS-depressant) antihistamines should be attempted first because they are cheaper
and most of the population is not sedated by them

2. Corticosteroid sprays – no systemic side-effects, very effective

3. Cytokine/enzyme inhibitors – IL-4, IL-5, IL-13, lipooxygenase inhibitors

Anaphylaxis
• Type I hypersensitivity reaction to an allergen – severity reflects level of sensitisation
• The reaction begins within seconds or minutes of exposure
• Death may occur from hypoxaemia or shock

Aetiology
• Food – peanuts/tree nuts, eggs, strawberries
o Peanuts 30.5%, cashew nuts 74.1%, other tree nuts 66.7%
o Most common in children
o Can occur without ingestion of food

• Drugs – penicillin, sulphonamides, local anaesthetic, salicylates

• Stinging insects – bees, wasps, ants

• Blood products

• Latex – healthcare workers, occupational

• Radiocontrast media

• Idiopathic

Clinical Features

Circulatory Skin (minutes) Central Nervous System

• Low blood pressure • Pruritis (itch) • Agitation
• Low pulse pressure • Urticaria (bumps) • Confusion
• Compensatory tachycardia • Erythema (redness) • Coma

Respiratory Systemic (min-hours) Metabolic

• Increased respiratory rate • Hypotensive shock • Increased potassium
• Bronchoconstriction • Death • Increased lactate
• Laryngeal oedema/obstruction • Metabolic acidosis
• Cyanosis

Management of an Anaphylactic Reaction

Oxygen → Adrenaline → Fluids

1. Secure the airway; give 100% oxygen (±intubate)

2. Place the patient in the supine position ± raise feet to help restore circulation

3. IM adrenaline (into vastus lateralus)

o 0.01mg/kg adrenaline up to a maximum of 0.5mg Many patients with allergies have
(i.e. 0.5mL of 1:1000) epipens, which they should use to
o Repeat every 5 minutes if needed until BP, pulse and inject adrenaline into their thigh in
respiratory function improve the case of an anaphylactic
reaction.
4. IV saline – 20mL/kg

5. If still hypotensive, IV adrenaline may be needed

Antibody-Mediated (Type II) Hypersensitivity
• Antibodies bind to self or foreign antigens

Aetiology
• Antigens in blood cells/platelets – drug reactions, transfusion reactions, haemolytic disease of the
newborn
• Hyperacute graft rejection (<48 hours after transplantation)
• Tissue antigens – myasthenia gravis

Pathogenesis
1. Opsonisation and phagocytosis - depletion of cells coated with antibodies
o Cells opsonised by IgG or C3b/C4b (IgG/IgM activate classical complement pathway)
o Direct lysis by MAC (C5-C9)
o Antibody-dependent cellular cytotoxicity – cells coated with IgG are killed by effector cells

2. Inflammation – recruitment & activation of non-specific inflammatory cells (neutrophils and

macrophages)
o Mediated by complement and Fc receptors
o Activated inflammatory cells release proteases and ROS that cause tissue damage

3. Cellular dysfunction – antibodies inappropriately activate/block normal cellular or hormonal function

Immune Complex-Mediated (Type III) Hypersensitivity
• Antigen:antibody complexes elicit inflammation at the sites of deposition
• Antigens can be exogenous (foreign protein, bacterium, virus) or endogenous (autoimmune)
• Immune complexes accumulate when
o Antibody production is continuous (chronic inflammation)
o Complement is deficient

Types of Type III Reactions

Route of Antigen delivery → Site of Immune complex deposition → Disease
Blood vessel walls Vasculitis
Intravenous Renal glomeruli Nephritis
Joint spaces Arthritis
Inhaled Alveolar-capillary interface Pneumonitis
Subcutaneous Perivascular area Arthus reaction

Serum Sickness
• Foreign serum proteins are introduced into circulation
• Immune complexes deposited in kidneys, blood vessels and joints cause nephritis, vasculitis and
arthritis

Clinical Features
Occur 7-10 days after exposure and disappear once the immune complexes are cleared
• Rashes, intching, joint pain
• Fever, swollen lymph nodes
• Hypotension
• Shock
• Splenomegaly
Cell-Mediated (Type IV) Hypersensitivity
• Initiated by specifically sensitised T cells
• Reactions develop hours to days after antigen contact

Pathogenesis

Examples
• Type 1 Diabetes Mellitus
• Contact dermatitis
• Inflammatory bowel disease
• Rheumatoid arthritis
• Multiple sclerosis

Contact Dermatitis
• Also known as contact hypersensitivity
• Antigens are haptens – simple chemicals e.g. nickel, plant material, topical drugs, soaps/cosmetics
• Initial contact causes sensitisation, second contact leads to erythema, itching, eczema or skin necrosis

Tuberculin
• Injection of tuberculin intradermally to sensitive individuals causes redness/itching within 12-18 hours
• Forms the basis for todays tuberculosis skin tests – Mantoux and Heaf tests
Shock
• Acute circulatory crisis – hypotension and inadequate blood flow that can lead to severe hypoperfusion
• Alghevar scheme for clinical detection: systolic blood pressure < heart rate
• Classical signs of shock: rapid weak pulse, pallor, sweating

Types
1. Hypovolaemic
o Blood loss - external/internal (traumatic/nontraumatic)
o Fluid loss - burns, diarrhoea, vomiting, sweating

2. Cardiogenic (Pump Failure)

o Massive MI
o Heart rupture
o Arrhythmias
o Myocarditis
o Tamponade
o Embolism

3. Distributive – massive vasodilation → ↓ total peripheral resistance

o Septic (infection → massive inflammation)
o Anaphylactic (allergic reaction)
o Neurogenic (trauma to spinal cord → ↓SNS activation)

4. Obstructive
o Pulmonary embolism
o Cardiac tamponade
o Tension pneumothorax

Pathogenesis

Cardiogenic Shock Hypovolemic Shock Distributive Shock

Tamponade Arrythmia blood volume Anaphylactic Septic Neurogenic

Pump Failure
venous return Ag exposure Brain/Spinal
Microbial Damage
end diastolic Mast Cell Products
volume Degranulation SNS activity

stroke volume heart rate vasodilation

cardiac output total peripheral

resistance

Blood Pressure
Stages
Blood
Stage Class Characteristics
Loss
Non-
Class I <15% ~Asymptomatic – completely compensated
progressive
Compensated shock – tachycardia, cool skin, confusion, thirst,
Class II 15-30%
weakness, lactic acidosis
Progressive
Class III 30-40% Failure of compensation - hypotension, tachycardia, oliguria
Irreversible and immediately life-threatening: cardiac arrest,
Irreversible ClassIV >40%
organ failure, anuria

Management
1. Oxygen

2. Insert IV and take a blood sample

3. IV fluids – saline 20mL/kg

4. Identify and treat the cause

o ECG, chest X-ray, mid-stream urine
o Blood replacement ± surgery
o Antibiotics
o Adrenaline for anaphylaxis
Clinical Dermatology
History Examination
Presenting Complaint 1. Distribution
• SOCRATES o Symmetry
• Distribution o Location
• Changes over time o Focal or generalised
• Exposure to chemicals/animals 2. Secondary Involvement
• Response to heat, cold, sun
• Pruritis (itching) 3. Individual lesions
• Pain o Size
o Colour
Past history o Arrangement
• Atopic conditions o Morphology
o Consistency
• Diabetes, IBD, other autoimmune disease
o Mobility
• Medications

Definitions
Macroscopically
• Blister: fluid-filled lesion
o Bulla: fluid-filled lesion ≥5mm
o Vesicle: fluid-filled lesion ≤5mm
• Exanthem: acute generalised eruption of the skin - rash
• Excoriation: deep scratch: a traumatic lesion resulting in epidermal breakage
• Lichenification: thick, rough skin with prominent markings, often due to repeated rubbing
• Macule: flat lesion ≤5mm
• Nodule: raised spherical lesion ≥5mm
• Onycholysis: loss of nail substance
• Papule: raised spherical/flat-topped lesion ≤5mm
• Patch: flat lesion ≥5mm
• Plaque: raised flat-topped lesion ≥5mm
• Pustule: discrete, pus-filled, raised lesion
• Scale: dry, horny, plate-like lesion
• Wheal: pruritic, erythematous elevated lesion formed as a result of dermal oedema

Microscopically
• Acantholysis: loss of intercellular connections between keratinocytes
• Acanthosis: epidermal hyperplasia
• Dyskeratosis: abnormal keratinisation below stratum corneum
• Erosion: focal, incomplete loss of epidermis
• Exocytosis: infiltration of inflammatory cells into the epidermis
• Hyperkeratosis: thickening of the stratum corneum
• Papillomatosis: elongation or widening of dermal papillae
• Parakeratosis: retention of nuclei in the stratum corneum
• Spongioisis: intercellular epidermal oedema
• Ulceration: focal, complete loss of epidermis ± dermis and subcutaneous fat
• Vacuolization: vacuoles within or adjacent to cells
Exanthems
• Acute generalised eruptions (rashes) of the skin

• Morbilliform – erythematous macules and papules, caused by

o Drugs
o Viruses – measles, rubella, HIV
o Bacteria – typhoid fever, syphilis, rickettsia
o Graft vs. host disease

• Scarlatiniform – confluent blanching erythema

o Scarlet fever Morbilliform
o Toxic shock syndrome
o Kawasaki’s Disease

• Papular – warts, caused by HPV Scarletiniform

Ichthyosis
• A collection of genetically hereditary conditions
• Characterised by hyperkeratosis with lesions
resembling fish scales
• Microscopically, characterised by build-up of
compacted stratum corneum with minimal
inflammation

Ichthyosis
Bullous (Blistering) Diseases
Pathogenesis Morphology

Antibodies to a component of
keratinocyte desmosomes
Pemphigus
→ release of plasminogen activator
~Patients 30-60
→ acantholytic breakdown of
desmosomes
Macroscopically
• Pemphigus vulgaris (80%) – superficial, easily ruptured blisters
• Pemphigus vegetans – large, moist plaques studded with pustules
• Pemphigus foliaceus – superficial bullae leaving slight erythema
• Pemphigus erythematosus – localised, milder variant
Microscopically
Acantholysis, intraepithelial blisters

Macroscopically
Bullous Antibodies to hemidesmosomes Tense bullae containing clear fluid 4-8cm in diameter
Pemphigoid responsible for attaching basal cells Typically on inner thigh, forearm flexors, lower abdomen
~Elderly individuals to basal membrane Microscopically
Subepidermal nonacantholytic blister

Associated with specific HLA types Macroscopically

Dermatitis and celiac disease Intensely pruritic, urticarial plaques and grouped vesicles
Herpetiformis Thought to be mediated by gliadin
~Men aged 20-40 (gluten) antibodies cross-reacting Microscopically
with junction-anchoring Accumulation of neutrophils and fibrin in dermal papillae
components Basal vacuolisation

Epidermolysis bullosa – neonatal blistering at pressure sites or trauma

• Junctional type – blistering at lamina lucida
Noninflammatory • Dystrophic type – blistering beneath lamina densa
Blistering • Simplex type – epidermal basal cell degeneration
Diseases
Porphyria – disturbances of porphyrin metabolism leading to urticaria and vesicular lesions exacerbated by
sun exposure
Acute Inflammatory Dermatoses
Pathogenesis Morphology

• Contact Dermatitis - topical antigens

Acute
Eczematous • Atopic Dermatitis - unknown (?heritable)
Macroscopically
Dermatitis • Drug-related eczema - systemic antigens/ haptens All types of lesions are pruritic, red, blistered
(Eczema) and subsequently crusted
• Eczematous insect bite reaction - locally injected
Five types of antigen/toxin Microscopically
conditions with Initial spongiosis sith progressive fluid
• Photoeczematous eruption - UV light
similar histological accumulation
features • Primary irritant dermatitis - repeated trauma/
chemical irritation

Urticaria Macroscopically
(Hives) Mostly mediated by IgE Variation from small, pruritic papules to large
Focal mast cell degranulation oedematous plaques
Individual lesions
that develop and Histamine-mediated dermal pruritis, oedema and wheal Microscopically
regress within formation Sparse mononuclear infiltrate with oedema and
hours occasional dermal eosinophils

Macroscopically
Erythema Multiform - including macules, papules, bullae
CD8+ mediated cytotoxicity
Multiforme Central blister/necrosis + surrounding erythema
Stevens-Johnson syndrome Microscopically
An uncommon,
• Severe, febrile form typically occurring in children Early infiltration into dermal-epidermal junction
self-limited
• Erosions and haemorrhagic crusting Dermal oedema
hypersensitivity
• Affects the lips, oral mucosa, conjunctiva, urethra and Basal keratinocyte degeneration & necrosis
response to drugs
anogenital regions Later epidermal necrosis, blistering and
or infections
erosions
Chronic Inflammatory Dermatoses
Description Pathogenesis Morphology
1. Psoriasis vulgaris – acute, Accumulation of
chronic plaque, inverse forms Macroscopic
CD4+ and CD8+ T
Pustules (early), erythema, scales (late)
2. Pustular psoriasis – chronic cells in the
erythematous, scaly plaques epidermis Microscopic
Psoriasis Epidermal thickening
3. Psoriatic Arthritis – psoriasis Keratinocyte
Thinned/absent stratum granulosum
of skin/nails with arthropathy proliferation,
Overlying parakeratotic scale Early Late
inflammation
4. Erythrodermic psoriasis –
and angiogenesis
severe

Involves areas with high densities

Aetiology Macroscopically
of sebaceous glands –scalp,
unknown, but Macules and papules, often with scaling and crusting
Seborrhoeic forehead, nasolabial folds and
presternal area thought to be due Microscopically
Dermatitis
to lipophilic yeasts Spongiosis (early), acanthosis (late), parakeratosis
Dandruff is seborrhoeic e.g. Malassezia Accumulation of inflammatory cells around hair follicles
dermatitis affecting the scalp

Macroscopically
Self-limited disease that lasts 1-2 Unknown; T-cell Pruritic papules that may coalesce into plaques
years and leaves only post- infiltrates and Symmetrically distributed - wrists, elbows, glans penis
Lichen Planus inflammatory hyperpigmentation Langerhans cell
hyperplasia are Microscopically
Affects skin and mucus
seen Dense, dermal-epidermal junction infiltration
membranes
Basal cell degeneration and necrosis

Macroscopically
The localised cutaneous form of Immune-complex Ill-defined erythema or sharply defined discoid plaques
lupus erythematous, without mediated and cell- Zones of irregular pigmentation
systemic manifestations mediated injury to Exacerbation with sun exposure
Discoid Lupus
pigment-
Erythematosus Patients with DLE rarely progress Microscopically
containing basal
to SLE, but ~1/3 of patients with cells Dermal-epidermal junction and perivascular infiltration
SLE develop DLE Basal cell vacuolisation and epidermal atrophy
Hyperkeratosis
Eczema
• Acute Eczematous Dermatitis - five types of conditions with similar histological features
• Pathogenesis - cytokine release and non-specific recruitment of inflammatory cells

Aetiology/Pathogenesis Histology Clinical Features

Contact Itching, burning with
Topical antigens Spongiotic dermatitis
Dermatitis exposure
Atopic Erythematous plaques
Unknown (?heritable) Spongiotic dermatitis
Dermatitis Family Hx of eczema/asthma

Temporal relationship to
Drug-related Systemic antigens/ Spongiotic dermatitis
drug administration
eczema haptens Abundant eosinophils
Remits with cessation of drug

Eczematous Spongiotic dermatitis

Locally injected
insect bite Wedge-shaped infiltrate Papules, nodules, plaques
antigen/toxin
reaction Many eosinophils

Photoeczematou Spongiotic dermatitis Occurs at sites of sun

UV light
s eruption Infiltrate ↓ with depth exposure

Primary irritant Repeated trauma or

Spongiotic dermatitis Localised irritants
dermatitis chemical irritation

Morphology
• Macroscopically – all types of lesions are pruritic, red, blistered and subsequently crusted
• Microscopically – initial spongiosis sith progressive fluid accumulation

Stages of Eczema Development

A B C D E
A. Initial dermal oedema and
perivascular infiltration by
inflammatory cells

B. Spongiosis and microvesicle

formation

C. Parakeratosis

D. Progressive acanthosis

E. Hyperkeratosis

Assessment

Management

Complications
Psoriasis
• Systemic inflammatory disease affecting the scalp, nails and sometimes joints
• Triggers
o Social/emotional stress o Nutrition
o Drugs o Alcohol
o Infection o Climate and sun

Distribution
• Typical distribution: armpits, hands, intergluteal cleft, glans penis
• Inverse distribution: scalp, lumbosacral area, elbows, knees

Pathogenesis
• Genetic disposition
o Correlation with HLA-Cw6 - 10 times higher risk
o 20% with one affected parent; 75% with two affected parents
• Accumulation of sensitised CD4+ TH1 and CD8+ T cells in epidermis
• ‘Cytokine soup’ induced by CD4+/CD8+ T cells, dendritic cells and
keratinocytes

Forms
1. Psoriasis vulgaris - eruptive (acute) , chronic plaque and inverse forms
o Peak incidence at 22 years; M = F
o Stimulated by scratching/rubbing

2. Pustular psoriasis - pustules on normal or inflamed skin

o Palmoplantar – chronic; palms and soles Psoriasis vulgaris
o Generalised acute – life-threatening with
Systemic involvement (fever, weakness)

3. Psoriatic arthritis - psoriasis of skin/nails with arthropathy

o Asymmetric peripheral involvement of upper extremities

Pustular psoriasis
4. Erythrodermic psoriasis - serious condition involving nearly entire skin
o Leads to constitutional symptoms

Treatment
• Topical drugs – glucocorticoids, vitamin D analogues, hydrocolloid dressing
• Light Therapy – UVA, UVB
• Systemic – Methotrexate, cyclosporine, acitretin
• ‘Biologicals’
Corticosteroids
• Endogenous corticosteroids are synthesised by the adrenal cortex

Adrenal Cortex
Synthesizes Example
Structure
Zona glomerulosa Mineralocorticoids Aldosterone
Zona fasciculate Glucocorticoids Cortisol
Zona reticularis Androgens DHEA, androstenedione

Biosynthesis
• Steroids are derived from cholesterol
• Rate-limited by the conversion of cholesterol to pregnenalone – regulated by ACTH
• Different enzymes stimulate or inhibit the synthesis of different steroids

Mineralocorticoids
• Regulate salt and water balance in the kidneys
• Aldosterone is the main endogenous mineralocorticoid - increases sodium reabsorption
• Release depends on electrolyte composition in the plasma, as well as the renin-angiotensin system

Mineralocorticoid Drugs
• Fludrocortisone is an exogenous mineralocorticoid
• Spiranolactone is a competitive aldosterone antagonist

Adverse Effects
• Gynaecomastia
• Impotence
Glucocorticoids
• Regulate inflammation and metabolic processes
• Secretion is controlled in a circadian rhythm
• Cortisol (hydrocortisone) is the most potent endogenous glucocorticoid
• Common glucocorticoid drugs are hydrocortisone, prednisolone and dexamethasone

Actions
• Carbohydrates - ↓ glucose uptake and use; ↑ gluconeogenesis (→ hyperglycaemia)
• Proteins - ↑breakdown, ↓ formation
• Lipids – redistribution of fat (as observed in Cushing’s syndrome
• HPA axis – negative feedback → ↓ glucocorticoids
• Cardiovascular - ↓ vasodilation, ↓ fluid exudation
• Musculoskeletal - ↓osteoblast and ↑ osteoclast activity (bone breakdown)
• Inflammation - overall decreased
o ↓leukocyte influx/activity
o ↓angiogenesis
o ↓ fibrosis (modified transcription of collagenase)
o ↓ clonal expansion of T and B cells
o ↓ IgG production
o ↓ cytokine production (inhibition of transcription)
o ↓ prostanoid production (inhibition of cyclooxygenase 2)
o ↓ other chemical mediators (histamine, nitric oxide)
o ↓ complement components in blood

Glucocorticoid Drugs
• Anti-inflammatory agents
• Used to treat asthma, eczema, hypersensitivity, autoimmune disease, graft-versus-host disease etc.
• Given orally, intravenously, intramuscularly, by aerosol, through eye/nose drops or as topical creams

Adverse Effects Cushing’s Syndrome

• Suppression of the body’s response to infection or injury
• Adrenal insufficiency (with sudden withdrawal)
• Iatrogenic cushing’s Syndrome
• Osteoporosis
• Avascular necrosis of the head of femur
• Tendency to hyperglycaemia → Diabetes
• Muscle wasting
• Growth retardation in children
Antihistamines
• Anti-inflammatories used to treat allergies, motion sickness, itching, nausea
• Sedating or non-sedating
• Cannot be used for the common cold – histamine is not a mediator

Histamine
• A mediator released primarily from mast cells
• Acts on histamine receptors:

Receptor Sites Inhibited by

H1 Lungs, skin, GI tract Antihistamines
H2 GI tract H2 antagonists
H3 Central nervous system No clinical antagonists
• H1 activation causes
o Smooth muscle activation
o Vasodilation
o Increased vascular permeability
o Activation of sensory nerve endings (pruritis)

Types of Antihistamines
• Old antihistamines are sedating – used to treat allergies, motion sickness, itching, nausea
• New antihistamines are non-sedating (poor CNS penetration) – used to treat allergies

Anticholinergic
Antihistamine (dryness of mouth, blurred Sedation Uses
vision, constipation, urine
retention)
Allergic reactions,
contact dermatitis,
Promethazine +++ +++ +++ pruritis, nausea,
motion sickness,
sedation
Allergic reactions,
Cyproheptadine ++ ++ +
pruritis
Allergic reactions,
Dexochlopheniramine +++ ++ + contact dermatitis,
pruritis
Allergic rhinitis,
Cetirizine ++ - - conjunctivitis, chronic
urticaria
Sudden Collapse
Causes
• Can have syncopal or non-syncopal causes
• Syncope (fainting): transient loss of consciousness due to reduced cerebral blood flow

Mechanism Causes
Syncopal Causes

Vasovagal syncope – ↑vagal tone + ↓ sympathetic tone

• Preceded by presyncope - nausea, pallor, sweating
Postural (orthostatic) hypotension
Neurally ↑PSNS (bradycardia) and
Carotid sinus hypersensitivity
Mediated ↓SNS (vasodilation)
Situational reflex-mediated syncope
• On coughing, exercise, micturition
Autonomic dysfunction

Bradyarrythmias
• abnormal impulse generation (e.g. sinoatrial
arrest)
Cardiac ↓ cardiac output • abnormal conduction (e.g. AV block)
Tachyarrythmias
Obstructive – aortic stenosis, mitral stenosis

Cerebro- Transient ischaemic attack

Cerebral ischaemia
vascular Subarachnoid haemorrhage

Non-Syncopal Causes

• Epilepsy – grand mal (LOC) or complex partial (impairment of consciousness) preceded by aura
• Hypoglycaemia – tremor, hunger and perspiration; rare in non-diabetics
• Drop attacks – sudden weakness of the legs, especially in older women (no LOC)
• Anxiety – ↑RR, tremor, sweating, ↑HR, light-headedness, no LOC → panic attack
• Choking – patient may collapse, turn blue and be unable to speak

Assessment
• History
1. Before the attack – any warning (e.g. epileptic aura, presyncope), circumstances (watching TV)
2. During the attack – ask a witness
o Loss of consciousness o Change in complexion (white/red → arrythmia)
o Injury following collapse o Duration
o Incontinence o Patient movement – floppy or stiff
3. After the attack – patient’s memory, patient confused/sleepy; muscle pain afterwards
(→tonic/clonic seizure)

• Examination – cardiovascular and neurological exams; BP lying & standing

• Investigations – ECG, FBC, Hb, electrolytes, LFTs, echocardiogram, CT/MRI, PaCO2 (hyperventilation)
Unconsciousness
• Consciousness requires the cerebral cortex and brain stem (reticular activating system)
• Drowsiness → stupor → coma → vegetative state (‘awake coma’)
• Primary care: same as first aid – DR ABCD

Causes of Unconciousness
COMA
CO2 Narcosis - respiratory failure (uncommon)
Overdose – tranquilisers, alcohol, salicylates, CO, anti-deppresants etc.
Metabolic – hypoglycaemia, diabetic ketoacidosis, uraemia, hypothyroidism, hepatic coma,
hypercalcaemia
Apoplexy - head injury, stroke, cerebral haemorrhage, sub-dural/extradural haematoma, meningitis,
encephalitis, epilepsy

AEIOU TIPS
Alcohol/drugs
Endocrine/electrolytes
Insulin
Oxygen
Uraemia
Trauma
Infection/intercranial pressure
Poison/porphyrins
Seizure/stroke/space-occupying lesion/ sub-arachnoid haemorrhage

The Glasgow Coma Scale

• Three components
o Eye opening (4 options)
o Best verbal response (5 options)
o Best motor response (6 options)
• The lower the mark the more severe the brain injury
o Lowest mark possible is 3/15
o Highest mark possible is 15/15

1 2 3 4 5 6
Opens eyes in Opens eyes
Does not Opens eyes
Eyes response to in response
open eyes spontaneously
painful stimuli to voice

Utters Oriented,
Makes no Incomprehensible Confused,
Verbal inappropriate converses
sounds sounds disoriented
words normally

Abnormal
Extension to flexion to
Localizes
Makes no painful stimuli painful Flexion/withdrawal Obeys
Motor painful
movements (decerebrate stimuli to painful stimuli commands
stimuli
response) (decorticate
response)