Skin pharmacology; Drug Eruptions; Topical Skin Therapeutics Flashcards

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1
Q

What is the outermost barrier of the skin?

A

The stratum corneal

Water tight barrier

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2
Q

What does this barrier place a restriction on?

A

Diffusion of topical drugs

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3
Q

Major drug routes on the skin

A

> Topical (local effect)

> Subcut/ depot (systemic, prolonged effects)

> Epithelial routes

  • airways
  • bladder
  • conjunctival sac
  • nasal mucosa
  • rectum
  • vagina
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4
Q

What are topical medications used to achieve?

A

Used to achieve a local effect.

Can be used to deliver drugs to underlying tissues (joints, muscles).

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5
Q

Transdermal and subcut

A

SYSTEMIC effect

Drug action is prolonged

Relatively steady plasma concentration of drugs

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6
Q

Epithelial routes

A

High LOCAL concentration

BUT a minimum systemic absorption to avoid adverse side effects

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7
Q

What is the most important barrier to drug penetration?

A

The stratum corneum

(keratin layer)

Drug must cross this layer in order to have an effect

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8
Q

What does the stratum corner consist of?

A

Keratinocytes that have reached the end of their biological life.

Hard, flattened cells.

Dead keratinocytes –> CORNEOCYTES

Surrounded by intercellular lipids forming 10-30 sheets of tissue.

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9
Q

Adjacent corneocytes are held together by

A

Corneodesmosomes

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10
Q

Intercellular lipids

A

Ceramides, cholesterol, free fatty acids

Highly hydrophobic

Intercellular route.

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11
Q

Topical route

A

Local effects

  • superficial skin disorders (psoriasis, eczema)
  • skin infections (viral, bacterial, fungal & parasitic)
  • itching
  • dry skin
  • warts
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12
Q

Topical route - VEHICLES (i.e. formulations)

A

Ointments, creams, gels, lotions, pastes, powders

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13
Q

The vehicle is usually pharmacologically….

A

INACTIVE

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14
Q

Rate of absorption (or flux J) is described by…

A

Fick’s law

J = KpCv

Kp - permeability coefficient

Cv - conc. of drug in the vehicle.

Kp embodies Km (partition coefficient); D (diffusion coefficient) and L (length of diffusion pathway)

Km - the equilibrium solubility of drug in stratum corneum relative to its solubility in the vehicle.

J = (DKm/L)Cv

Cv and Km are highly dependent upon the vehicle

Length of diffusion pathway –> tortuous pathway in the intercellular spaces between the stratum corneum.

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15
Q

Role of the Vehicle

A

> Vehicle can profoundly influence the rate and extent of absorption of a topically applied drug

Important factors are:

  • solubility of the drug in vehicle
  • maximising the movement (or partitioning) of the drug
    from vehicle to stratum corneum

Drug must “escape” from the vehicle and enter the outmost layer of the stratum corneum.

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16
Q

Km is the…

A

“pushing force”

Partition coefficient

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17
Q

When drugs are applied topically only…

A

The soluble fraction provides the driving force for absorption

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18
Q

Excipients

A

Enhance solubility and absorption

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19
Q

Propylene glycol

A

Excipient for glucocorticoids

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20
Q

Dimethylsulphoxide

A

Excipient for lidocaine

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21
Q

When excess, non-dissolved drug included in transdermal patches

A

Increases duration of effectiveness

Provides a constant rate of delivery

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22
Q

By increasing the free conc of the drug in the vehicle it…

A

Increases absorption

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23
Q

Topically applied drugs are generally poorly…

A

Absorbed because only a small fraction partitions into the stratum corneum

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24
Q

Topically applied drugs are generally poorly…

A

Absorbed because only a small fraction partitions into the stratum corneum

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25
Q

Physical and chemical factors can improve partitioning

A

> Hydration of the skin by occlusion (prevention of water loss)

  • may be achieve by choice of vehicle
  • cling film

> Inclusion of excipients which also increase the solubility of hydrophobic drugs

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26
Q

Using a vehicle that limits perspiration..

A

You can increase the diffusion of the drug

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27
Q

Factors that influence absorption of topically applied drugs

A

> Nature of the skin

  • site of application
  • hydration of the skin
  • integrity of the epidermis

> Drug/pharmaceutical preparation

  • drug concentration
  • the drug salt (hydrocortisone butyrate far more potent than hydrocortisone acetate)
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28
Q

What’s more potent - hydrocortisone butyrate or acetate

A

Butyrate (more lipophilic)

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29
Q

Dry and flaky skin requires…

A

Ointment; or cream that allows hydration

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30
Q

Features of the Glucocorticoids

A

Topically - atopic eczema, psoriasis, pruritus

Possess anti inflammatory, immunosuppressant and vasoconstriction effects and anti-proliferating action upon keratinocytes and fibroblasts

Categorised as mild, moderate, potent and very potent

Choice depends upon severity of disease and its anatomical site

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31
Q

Glucocorticoid penetration, potency and clinical effect varies with…

A

> Body site
- thickness of stratum corneum

> State of the skin
- lower potency in children/certain body sites

> Occlusion

> Vehicle

  • affects potency
  • affects compliance

> Concentration of drug

> Form of drug

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32
Q

Short term treatment with LOW potency steroids is generally…

A

SAFE

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33
Q

Long term use of HIGHER POTENCY STEROIDS may produce serious…

A

ADVERSE EFFECTS

  • steroid rebound
  • skin atrophy
  • systemic effects
  • spread of infection
  • steroid rosacea
  • production of stretch marks and telangiectasia
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34
Q

Glucocorticoids are immuno…

A

SUPPRESSIVE

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35
Q

Mechanism of glucocorticoids

A

> Glucocorticoids signal via nuclear receptors (class 1) specifically

> Glucocorticoids are lipophilic molecules - enter cells by diffusion across the plasma membrane

> Within the cytoplasm, they combine with GRα producing dissociation of inhibitory heat shock proteins. The activated receptor translocates to the nucleus aided by “importins”

> Within the nucleus activated receptor monomers assemble into homodimers and bind to glucocorticoid response elements (GRE) in the promoter region of specific genes.

> The transcription of specific genes is either “switched on” (transactivated) or “switched off” (trans repressed) to alter mRNA levels and the rate of synthesis of mediator proteins.

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36
Q

Subcut Route

Systemic or local?

How does drug reach the circulation?

A

Drug delivered by needle

Drug reaches systemic circulation by diffusion into either i) capillaries
ii) lymphatic vessels (particularly high molecular weight compounds)

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37
Q

Subcut route

  • Advantages
  • Disadvantages
A

Advantages//

  • absorption is relatively slow due to poor vascular supply (can be disadvantageous too)
  • route of administration for many protein drugs (insulin)
  • suitable for administration of oil-based drugs (steroids)
  • Can be used to introduce a depot of drug under the skin that is very slowly released into the circulation.
  • simple and painless

Disadvantages//

  • injection volume limited
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38
Q

Why skin is a good drug route for a systemic effect?

A

> Simple application and non-sterile
Potentnially allows for a steady state plasma conc. of drug to be achieved over a prolonged period of time
AVOIDS first pass metabolism

> drug absorption can be terminated rapidly (however some drug may have accumulated in the skin)

HOWEVER

Completely intact skin is water tight so only a limited number of drugs can diffuse across the epidermis to reach the superficial capillaries

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39
Q

What does drug administration via the skin do?

A

Avoids first pass metabolism

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40
Q

Transdermal Drug Delivery (TDD)

A

> rug incorporated into an adhesive patch applied to epidermis

> Drug absorption is controlled by a drug release membrane - occurs by diffusion across cutaneous barrier

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41
Q

Most suitable drugs for TDD

A

i) Low molecular weight
ii) Moderately lipophilic
iii) potent
iv) relatively brief half life

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42
Q

Advantages of TDD

A

> Steady rate of drug delivery, decreased dosing frequency, avoidance of first-pass metabolism, rapid termination of action (if t½ is short)

> User friendly –> increased patient compliance

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43
Q

Disadvantages of TDD

A

Relatively few drugs are suitable for TDD allergies,

Cost

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44
Q

TDD examples

A

Nicotine
GTN
Fentanyl
Estradiol

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45
Q

Enhancing Transdermal Drug Delivery

How it works
Advantages
Disadvantages

Examples of agents used

A

Chemical enhancement

  • interact with lipid matrix of statum corneum to increase permeability

Low cost
can be incorporated into vehicles

However can cause//

skin irritation
not effective for highly water soluble drugs or macromolecules

Agents used//

  • WATER - prolonged occlusion causing increased hydration of the stratum corneum and formation of a “PORE” pathway
  • Solvents like ETHANOL and surfactants like SODIUM DODECYLSULPHATE
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46
Q

Skin is a common target for what kind of drug reaction/eruption?

A

Idiosyncratic

Distinctive reaction

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47
Q

How common are cutaneous drug reactions?

A

30% of adverse drug reactions

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48
Q

Types of drug reaction

A

> Immunologically mediated (allergic)

> Non immunologically mediated (non allergic)

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49
Q

Are allergic reactions dose dependent?

A

NO

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50
Q

Examples of each type of allergic reaction?

A

> Type 1 (anaphylactic)
- Urticaria

> Type II (Cytotoxic)
- Pemphigus & pemphigoid

> Type III (Immune complex mediated reactions
- purpura/rash

> Type IV (cell mediated delayed hypersensitivity)
- T cell mediated. Erythema/rash

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51
Q

Are non-allergic drug reactions dose dependent?

A

Yes, they can be.

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52
Q

Examples of non allergic drug reactions?

A
Eczema
drug induced alopecia
Phototoxicity
Skin erosion or atrophy
Psoriasis
Pigmentation
Cheilitis, xerosis
53
Q

What side effect can DOXYCYCLINE have?

A

Can make the patient sensitive to sunlight

Higher does - more likely to have photosensitivity

54
Q

Morphology of drug eruptions

A

> Commonly Exanthematous/Morbilliform (measle-like)/ Maculopapullar

> Urticarial (5-10%)
Papulosquamous/ pustular/ bullous

> Pigmentation
Itch/pain
Photosensitivity

55
Q

Who to consider for a cutaneous drug eruption

A

Any patietn who is taking medication and develops a SYMMETRIC skin eruption

56
Q

Are drug eruptions often symmetrical or unsymmetrical?

A

Symmetrical

57
Q

Drug eruption risk factors

A

> Age (young adults more likely than infants/elderly)

> Gender (more females than males)

> Genetics

> Concomitant disease/ comorbidities

> Immune status

> Polypharmacy

58
Q

What is the most common type of drug eruption?

Features

Onset

A

Exanthematous drug eruption

Itch, mild fever

Widespread symmetrically distributed rash

Mild and self limiting

Onset 4-21 days after taking drug

59
Q

What type of hypersensitivity reactions are Exanthematous eruptions?

A

T cell mediated delayed type hypersensitivity

Type IV

60
Q

What are usually spared in Exanthematous reactions?

A

Mucous membranes

61
Q

Indicators of potential severe exanthematous reaction

A

> Involvement of mucous membrane and face

> Facial oedema & erythema

> Widespread confluent erythema

> Fever

> Blisters, purpura, necrosis

> Lymphadenopathy, arthralgia

> SoB, wheezing

> Puffy face

62
Q

Drugs associated with EXANTHEMATOUS drug eruptions

A
  • Penicillins
  • Sulphonamide antibiotics
  • Erythromycin
  • Streptomycin
  • Allopurinol
  • Anti-epileptics: carbamazepine
  • NSAIDs
  • Phenytoin
  • Chloramphenicol
63
Q

Urticarial drug reactions

A

> Immediate IgE mediated hypersensitivity reaction (type 1) after rechallenge with drug

or

> Direct release of inflammatory mediators from mast cells on first exposure

64
Q

Drugs causing URTICARIAL drug reactions

A

Beta-lactam abx; carbazepine

Aspirin, opiates, NSAIDs, muscle relaxants, vancomycin quinolones

65
Q

Pustular/Bullous drug eruptions

A

> Acne

    • glucocorticoids
    • Androgens, lithium, isoniazid, phenytoin

> Acute generalised exanthematous pustulosis

> Reactions can range from mild –> severe

66
Q

Acute generalised exanthematous pustulosis (AGEP)

A
  • Rare
  • Antibiotics
  • Calcium channel blockers
  • Antimalarials
67
Q

Drug induced bullous pemphigoid

A
  • ACE inhibitors
  • Penicillin
  • Furosemide
68
Q

Linear IgA disease

A

Can be triggered by Vancomycin

69
Q

Fixed drug eruptions - features

A
  • Well demarcated round/ovoid plaques.
  • Red, painful.
  • Hands, genitalia, lips, occasionally oral mucosa.
  • Resolves with persistent pigmentation when the drug is stopped.
  • Can re-occur on the same site on re-exposure to the drug.
  • Usually mild when restricted to a single lesion.
  • Can present as eczematous lesions, papules, vesicles or urticaria.
70
Q

Drugs associated with fixed drug eruptions

A

> Tetracycline, doxycycline
Paracetamol
NSAIDs
Carbamazepine

71
Q

Severe Cutaneous Adverse reactions

A

> Combine cutaneous and systemic symptoms

> Stevens-Johnson syndrome
Toxic epidermal necrolysis

> Drug reaction with eosinophilia and systemic symptoms (DRESS)

> Acute generalised exanthematous pustulosis (AGEP)

72
Q

Toxic epidermal necrolysis (TEN)

drugs causing this
also causing Stevens Johnson Syndrome

A

Skin completely sloughs off.

Treated like burns.

Life threatening.

Drug reaction caused by//

Sulfonamide abx, cephalosporins, carbamazepine, phenytoin, NSAIDs, nevi rapine, lamotrigine, sertraline, pantoprazole, tramadol

73
Q

Drug reaction w/ eosinophilia and systemic symptoms (DRESS)

A

Sulfonamides, anticonvulsants, allopurinol, minocycline, dapsone, NSAIDs, abacavir, nevirapine, vancomycin

74
Q

Phototoxic Drug Reactions

A

Acute//

  • Skin toxicity
  • systemic toxicity
  • photo degradation

Chronic//

  • pigmentation
  • photo ageing
  • photocarcinogenesis
75
Q

What type of UV light can get through windows?

A

UVA

76
Q

Phototoxic cutaneous drug reactions

A

> Non immunological mediated skin reaction
- requires enough photo reactive drug and the appropriate wavelength of light

> Idiosyncratic reactions can occur

> Photosensitivity can occur via immunosuppression and other mechanisms

77
Q

Patterns of Cutaneous Phototoxicity

A

> Immediate prickling with delayed erythema and pigmentation
– chlorpromazine, amiodarone

> Exaggerated sunburn
– quinine, thiazides, DCMT

> Exposed telangiectasia
– calcium channel antagonists

> Delayed 3-5 days erythema and pigmentation
– psoralen

> Increased skin fragility
- naladixic acid, tetracycline naproxen, amiodarone

78
Q

Drugs associated with phototoxicity

A
> Abx
> Thiazide diuretics
> Chlorpromazine
> NSAIDs
> Psoralens
> Amiodarone
> Porphyrins/tetrapyrroles
> BRAF inhibitors
> Antifungals
> Immunosuppressants
79
Q

Drug reaction information

A
  • Detailed description of reaction
  • Timing of onset of symptoms in relation to drug administration
    previous exposure to drug?
  • When did the drug start (in relation to symptoms)
    When was the drug stopped?
  • Did stopping the drug affect the symptoms?
    Photograph of reaction?
    Why was the drug being taken?
  • Underlying illness
  • Comprehensive drug history including prescribed/non prescribed and herbal/alternative remedies
  • Previous history of drug reaction, allergy or other illnesses?
80
Q

Drug eruption Investigations

A

History & physical examination

In less clear situations:

> Phototesting
Biopsies
Patch and photo patch tests
Skin prick/ intradermal tests for specific drugs

81
Q

When is skin testing not indicated?

A

Skin testing is not indicated for serum sickness reactions (Type III) or for T-cell mediated reactions (Type IV) and can potentially trigger SJS, TEN & DRESS, or for those with severe cutaneous adverse drug reactions

82
Q

Drug eruptions - Management

A

Discontinue the drug (if possible). Use an alternative.

Topical steroids may be useful.

Antihistamines may be useful.

Allergy bracelets are useful for some drugs.

Drug eruptions should be reported via the Yellow Card scheme (Medicines and Healthcare products Regulatory Agency).

83
Q

Are immunocompromised patients more likely to suffer from a severe cutaneous reaction?

A

Yes

84
Q

What can furosemide cause?

A

A blistering rash

85
Q

Advantages and disadvantages of topical treatments

A

Advantages//

  • direct application
  • reduced systemic effects

Disadvantages//

  • time consuming
  • correct dosage can be difficult
  • messy to use
86
Q

What should you consider when prescribing topical treatments?

A

Consider what they do for a living.

Are they working a full day? Will they be able to apply this cream?

working with paperwork - can their hands be oily?

87
Q

Bases/Vehicles

A
Gels
Creams
Ointments
Pastes
Lotions
88
Q

Creams - topical therapeutics

A

> Semisolid emulsion of OIL in WATER

> Contains emulsifier and preservative

> High water content

> Cool and moisturises

> Non greasy

> Easy to apply

> Cosmetically acceptable

89
Q

Ointments - topical therapeutics

A

> Semisolid grease/oil (soft paraffin)

> no preservative

> Occlusive and emollient

> Restrict transepidermal water loss

> Greasy - less cosmetically attractive

90
Q

When do you need to prescribe an ointment?

A

If skin is very dry or cracked

91
Q

Lotions - topical therapeutics

A

> Liquid formulation
Suspension or solution of medication in water, alcohol or other liquids
If contain alcohol, may sting
Treat scalp, hair bearing areas

92
Q

Gels - topical therapeutics

A

> Thickened aqueous lotions
Semi-solids, containing HMW polymers (methyl cellulose)

> Treat scalp, hair bearing areas, face

93
Q

Pastes - topical therapeutics

A
> Semisolids
> Contain finely powdered material (ZnO)
> Stiff, greasy, difficult to apply
> Protective, occlusive, hydrating
> Often used in cooling, drying, soothing bandages
94
Q

Types of topical therapies

A
> Emollients
> Topical steroids
> Antiinfective agents 
-- antiseptics, abx, antivirals, antifungals
> Antipruritics
>Keratolytics
> Psoriasis therapies
95
Q

Emollients - topical therapeutcs

A

> Enhance rehydration of epidermis
For all dry/scaly conditions esp eczema
Need to be effective and cosmetically acceptable
Prescribe 300-500g weekly
Frequent application

96
Q

Emollient prescribing tips

A

> Apply immediately after bathing
Apply in direction of hair growth
dont slip over.
Use clean spoon or spatial to remove from tub (risk of bacterial contamination)

> FIRE risk if paraffin based

97
Q

Why should you use a clean spoon or spatula to remove emollient from tub?

A

Reduce risk of bacterial contamination

98
Q

Why shouldn’t you smoke when you have applied emollient?

A

Could set fire to yourself as some emollients are paraffin based

99
Q

More cosmetically acceptable means the patient is more likely to be

A

Compliant with the treatment

100
Q

Wet wrap therapy

A

Used for very dry (xerotic) skin

Difficult and time consuming to apply

101
Q

Topical corticosteroids

A

Mode of action - vasoconstrictive, anti inflame, anti proliferative

MILD, MODERATE, POTENT, VERY POTENT

Used for eczema, psoriasis, lichen plans, keloid scars

102
Q

Steroid rebound in psoriasis can lead to

A

Pustular psoriasis

103
Q

Steroid quantities

A

> 1 application to whole body (adult): 20-30g ointment

> 1 fingertip unit = 1/2g

> Covers 2 hand areas

> Patient education essential for correct use

104
Q

Topical steroids - side effects

A

> Thinning of skin, purport and stretch marks

> Steroid rosacea

> Perioral dermatitis

> Fixed telangiectasia

> May worsen or mask infections

> Systemic absorption (can cause adrenal suppression, Cushings syndrome)

> Tachyphylaxis

> Rebound flare of disease

105
Q

Antiseptics - therapeutics

A

Bacteriostatic or bactericidal

106
Q

Povidone iodine

A

Antiseptic

skin cleanser

107
Q

Chlorhexidine

A

Antiseptic

Hibitane, savlon

108
Q

Triclosan

A

Antiseptic

aquasept, sterzac

109
Q

Hydrogen peroxide

A

Antiseptic

Crystacide

110
Q

Herpes simplex

A

Cold sore

Topical antiviral

111
Q

Eczema herpeticum

A

Oral antiviral

112
Q

Herpes Zoster

A

Shingles

Oral antiviral

113
Q

Treatment for Candida

A

Anti yeast

Nystatin
Clotrimazole

114
Q

Treatment for dermaphytes

A

Antifungal
Clotrimazole
Terbinafine cream

115
Q

Pityriasis versicolor treatment

A

Ketoconazole

116
Q

Menthol

A

Antipruritic

Added to calamine & other lotions and creams to impart cooling sensation

117
Q

Capsaicin

A

Antipruritic

Shingles

Chili peppers
Depletes substance P at nerve endings and reduces neurotransmission

118
Q

Camphor/ phenol

A

For pruritis

119
Q

Crotamiton

A

Antipruritic

Eurax cream

120
Q

Keratolytics

A

Used to soften keratin

121
Q

When are keratolytics used?

A

> Viral warts
Hyperkeratotic eczema & psoriasis
Corns and calluses
Keratin plaques in scalp

122
Q

Warts - treatment

A

Mechanical paring

+

Keratolytics  e.g.Salicylic acid
Formaldehyde
Glutaraldehyde
Silver nitrate
Cryotherapy (usually                            liquid nitrogen)
Podophyllin (genital warts)
123
Q

Psoriasis - topical treatments

A

Emollients and choice of:

  • coal tar
  • vitamin D analogue
  • keratolytic
  • topical steroid
  • Dithranol

Based on sites affected, extent, severity, side effects, compliance.

124
Q

Stable Chronic Plaque psoriasis treatment

A

> Coal tar
- mild –>strong (messy and smelly)

> Vitamin D analogues
- clean, no smell, easy to apply, can be irritant. 100g/weekly max

> Dithranol

  • effective, but difficult to use
  • irritant and stains normal skin
125
Q

Calcipotriol

A

Vitamin D analogue

Used to treat stable chronic plaque psoriasis

126
Q

Scalp psoriasis - treatment

A

Greasy ointments to soften scale

Tar shampoo

Steroids in alcohol base or shampoo

Vitamin D analogues

127
Q

Psoriasis in axilla

A

Topical steroids for face, flexures and groin/ genitals.

Consider combo antibacterial, antifungal, calcineurin inhibitors.

128
Q

Overall side effects of topical therapies

A

> Burning or irritation
Contact allergic dermatitis
Local toxicity
Systemic toxicity

129
Q

Can people be sensitive to sunscreen?

A

Yes