Eczema and psoriasis Flashcards

1
Q

Types of dermatitis (eczema)

A
• Primary irritant dermatitis
- Caused by Chemical irritants
• Allergic contact dermatitis
- Caused by topically applied antigen
• Atopic dermatitis
- Most common type of eczema, cause unknown ?Emotional triggers inheritable?
• Drug-related eczematous dermatitis
- Response to systemic drug
• Photoeczematous dermatitis
- Caused by uv light
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2
Q

Mechanism of contact dermatitis

A

• Langerhans cell functions as an antigen presenting cell
• Activates naïve T cells in lymph nodes, which differentiate into memory T cells and effector T cells
• Memory T cells in skin recognise antigen on re-exposure
• Cytokine release by memory cells triggers effector T cell
recruitment
• Vascular endothelium is “activated” allowing further T cells recruitment

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3
Q

Psoriasis

A
  • Red lesions, accompanied by skin forming as silver flakes (called scales, plaques or flakes)
  • Most commonly back of elbows, knees and scalp
  • Rapid turnover of the skin – 7 days instead of 56
  • Thickened skin plaques with scales
  • Dilation of capillaries
  • Lymphocytes infiltrating
  • Chronic condition, not curable
  • May have prolonged periods of remission (years)
  • Cause not well understood
  • Not contagious
  • Inflammation involved
  • May be heritable component
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4
Q

Overview of pharmacotherapy for

eczema and psoriasis

A

• Eczema
– Emollients
– Topical corticosteroids (mild or potent depending on disease)

• Psoriasis
– Phototherapy
– Emollients
– Coal tar
– Retinoid
» tazarotene topical
» Acitretin Systemic po
– Vitamin D analogs –calcipotriol, calcitriol tacalitol
• Immune modifiers
– Calcineurin inhibitors
» Pimecrolimus tacrolimus – topical for eczema
» Ciclosporin po for severe eczema or psoriasis
– Methotrexate – severe psoriasis
• Biologics - for severe unresponsive psoriasis
– Etanercept
– Adalimumab
– infliximab
– Ustekinumab
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5
Q

Coal tar

A
  • For treatment of psoriasis
  • Produced from distillation of coal
  • Very complex mixture – numerous chemicals
  • Mechanism unclear
  • relieves itching
  • “keratolytic” -breaks down keratin – helps reduce skin thickening
  • Cocois
  • Coconut oil containing coal tar, salicylic acid and sulfur
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6
Q

Tacrolimus & Pimecrolimus

A
  • Indicated when corticosteroids inadequate/inappropriate
  • Pimecrolimus – mild/moderate eczema
  • Tacrolimus – moderate/severe eczema

PK
• Topical administration
• Relatively little systemic exposure, but is metabolized by Cyp3A4

ADR
• Burning, pruritus – very common

Caution
• Relatively new drugs – safety still being assessed
• Increased risk of skin infection? (why?)
• Increased risk skin cancer, lymphoma ?
• Avoid exposure to UV light (stay in shade, avoid tanning) – potential
increased risk of cancer?

Contraindications
• Hypersensitivity – including other macrolides 14-16 membered lactone ring (eg erythromycin, sirolimus)
• Skin barrier defects
• avoid in immunodeficiency

Drug interactions
• Avoid with other immunosuppressants

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7
Q

Ciclosporin

A
  • “Older” calcineurin inhibitor for severe eczema or psoriasis
  • Similar mechanism of action but signficant ADR

PK
• P.o; F~ 30% and t½ ~18 hr but variable
• Cyp 3A4 substrate

ADR
• Can be severe! Esp. nephrotoxicity & hypertension
• Also neurotoxicity, hepatotoxicity, hyperlipidaemia, neoplasms, infection

Caution
• Avoid UV light
• Monitor renal function
• Existing infections

Contraindications
• Hypersensitivity
• Poor renal function, hypertension, uncontrolled Infection, cancer

Drug interactions
• Avoid with other immunosuppressants
• Cyp3A4 substrates, inducers, inhibitors

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8
Q

Methotrexate

A
  • Inhibits dihyrofolate reductase
  • “antimetabolite” used to treat cancer
  • used for severe psoriasis
  • Mechanism in psoriasis unclear
  • Decreased nucleotide synthesis?
  • Increased apoptosis of T cells
  • Increase in adenosine is antiinflammatory

PK
• Low dose po once weekly!
• Elimination
• tubular secretion by OAT3

ADR
• Bone marrow suppression & Blood dyscrasia
• (abnormality in production of any blood cell type)
• Hepatoxicity (at high dose)
• Nephrotoxicity (at high dose)
• GI ulceration
• Risk of infection
• Blood counts, liver, renal function tests recommended

Caution
• Impaired liver function
• Blood disorder
• GI ulceration
• Impaired renal function
Drug interactions
• NSAIDS
» inhibit tubular secretion
» Both compete for OAT3
• Antifolate antibiotics
» risk of additive toxicity
» Both inhibit folate synthesis

Contraindications
• Severe renal or hepatic impairment
• Pregnancy & lactation- teratogenic

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9
Q

Steroids – a reminder

A
• Adrenal cortex steroids = “corticosteroids”
• Glucocorticoids (glucocorticosteroids)
» regulate protein and carbohydrate metabolism
» Anti-inflammatory
» Eg hydrocortisone and corticosterone
• Mineralocorticoids
» Regulate fluids/electrolytes
» Eg aldosterone. See diuretics lecture

• Sex steroids

  • Androgens eg testosterone
  • Estrogens eg estradiol

• Cholesterol
-Membrane fluidity

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10
Q

Glucocorticoid - mechanism of action

A

• Inhibition of inflammatory gene expression (COX2, NO synthase, TNFa, IL1)
• Induction on anti-inflammatory gene expression (annexin 1)
• Inhibition of leukocyte migration and activity
• Inhibition of prostanoid/leukotriene synthesis
• Inhibition of T lymphocyte proliferation (reduced IL2 etc.
production)

  • Topical glucocorticosteroids - first line therapy for atopic eczema
  • Anti-inflammatory, Vasoconstriction
  • Inhibit keratinocyte proliferation
  • 4 classes (others distinguish 7 classes)
  • Mild (e.g. hydrocortisone); Moderate (e.g. betamethasone valerate); Potent (e.g. budesonide); Very Potent (e.g. clobetasol propionate)
  • NB: different salts exhibit different potencies, some are systemically absorbed, others less so
  • Topical application preferred
  • Modest improvement in efficacy with systemic routes, but do get additional ADR
  • Systemic route only for v. severe/life threatening cases, e.g. allergic contact dermatitis with poison ivy
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11
Q

Glucocorticoids (3)

• ADR with systemic therapy

A

– Inhibition of hypothalamic/pituitary/adrenal axis
» Chronic use depresses ACTH which regulates cortisol production
by adrenal gland (adrenal insufficiency)
» Gradual withdrawal helps prevent disease flaring up during withdrawal
– weight gain and diabetes mellitus
» Stimulate gluconeogenesis and inhibit Glc uptake by liver/muscle
– Redistribution of fat
» Fat breakdown my some tissues, accumulation in others
– Broad anti-inflammatory effects
» Reduced production of inflammatory cytokines –reduced cellular response
» Impaired vascular response to damage (inhibit dilation &
permeability that leads to oedema) so reduced extravasation
– Hypertension
» Cortisol regulates bp
CRF
ACTH
Cortisol
-(when cortisol is used therapeutically, it’s called hydrocortisone)

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12
Q

Glucocorticoids (4)

• ADR with topical therapy

A

• The ADR associated with systemic use are less common with topical therapy unless large area treated with drug or potent steroid used
• However, may see:
» Thinning of skin and telangiectasia may be unsightly
» Acne

Caution
• Short term use
• Avoid potent glucocorticoids in psoriasis –possibility of rebound relapse

Contraindications
• Uncontrolled infections

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13
Q

Retinoids

A
  • normalize abnormal growth and differentiation in keratinocytes
  • Alitretinoin
  • for eczema
  • Tazoretene
  • for psoriasis
  • Topical
  • Acitretin
  • For severe psoriasis
  • p.o

ADR/ Cautions/ Contraindications
• Topical
• burning, erthymea
• Retinoids are teratogenic
• Systemic retinoids are contraindicated in pregnancy
• Topical retinoids should be avoided.
• Acitretin contraindicated in hyperlipidaemia and should be avoided in hepatic and renal impairment

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14
Q

Vitamin D analogues examples

A
  • Calcipotriol, Calcitriol, Tacalcitol
  • For psoriasis – mostly commonly prescribed drugs for psoriasis
  • Calcitriol is active metabolite of vitamin D
  • Vitamin D production is catalysed by uv light (also used as a psoriasis treatment)
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15
Q

Vitamin D analogues

• ADR + Contraindications

A

ADR
• Skin reactions common: burning, erythema, pruritus, paraesthesia
• Hypercalcaemia
• (vitamin D stimulates Ca2+ absorption from small intestine)
• Risk increased if exposed to uv light too

Contraindications
• Ca2+ metabolism disorders

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16
Q

TNF α inhibitors (1):

Role of TNFα

A

draw slide 31
TNFα produce

  • APC -> IL1, 6,12 -> TH1
  • Macrophage -> Activation (phagocytosis)
  • NK (natural killer cells) cytotoxicity
  • T -> Effector T cell proliferation
  • Endothelial cell -upregulate adhesion molecules
  • Mast cells -> Histamine, LT release
  • TH -> IL13,17 IFNγ
17
Q

TNFα inhibitors examples

A

• For severe plaque psoriasis which hasn’t responded to conventional systemic therapy

  • Etanercept
  • Fully human, recombinant fusion protein
  • TNF receptor ligand binding domain fused to Fc domain of IgG
  • Infliximab
  • Mouse-human chimeric antibody
  • Binds TNFα
  • Complement mediated cytolysis
  • Adalimumab
  • Human IgG
  • Complement-mediated cytolysis
18
Q

TNFα inhibitors (3)

• PK, ADR, caution, contraindication, interactions

A
• PK
• It’s a large protein -> parenteral:
» Etanercept s.c.
» Infliximab i.v.
» Adalimumab s.c.
  • ADR
  • increase risk of infection
  • Antibodies to infliximab may limit its action (mouse!) – less likely with human antibodies
  • Caution
  • Predisposition to infection
  • Contraindications
  • Uncontrolled infection
  • Drug interactions
  • Avoid with live vaccines
19
Q

IL12/IL23 inhibitors: Ustekinumab

A
  • IL12, IL23 involved in NK activation, T cell activation (see diagram)
  • Share a common “p40” subunit
  • Ustekinumab human IgG recognising p40
  • Sequesters free ligand, so doesn’t induce complement mediated cytolysis
20
Q

Ustekinumab: indications, PK, ADR, Caution, contraindications, interaction

A
  • Indications - For severe plaque psoriasis which hasn’t responded to conventional systemic therapy
  • PK - S.c. injection
  • ADR - increase risk of infection
  • Caution -Predisposition to infection
  • Contraindications - Uncontrolled infection
  • Drug interactions - Avoid with live vaccines
21
Q

RAR

A

genes regulating differentation/proliferation

22
Q

RXR

A

genes regulating apoptosis

23
Q

TNFα produced by

A

TH1
Macrophage
Cells other than leukocytes

24
Q

Vitamin D analogues Mechanism

A
  • Not fully understood
  • Vitamin D analogues bind vitamin D receptor, part of retinoic receptor acid family
  • Inhibit epidermal cell proliferation
  • Induce keratinocyte differentiation
  • Anti-inflammatory
  • Inhibit Tcell proliferation
  • Inhibit cytokine production