Skin pharmacology; Drug Eruptions; Topical Skin Therapeutics Flashcards
What is the outermost barrier of the skin?
The stratum corneal
Water tight barrier
What does this barrier place a restriction on?
Diffusion of topical drugs
Major drug routes on the skin
> Topical (local effect)
> Subcut/ depot (systemic, prolonged effects)
> Epithelial routes
- airways
- bladder
- conjunctival sac
- nasal mucosa
- rectum
- vagina
What are topical medications used to achieve?
Used to achieve a local effect.
Can be used to deliver drugs to underlying tissues (joints, muscles).
Transdermal and subcut
SYSTEMIC effect
Drug action is prolonged
Relatively steady plasma concentration of drugs
Epithelial routes
High LOCAL concentration
BUT a minimum systemic absorption to avoid adverse side effects
What is the most important barrier to drug penetration?
The stratum corneum
(keratin layer)
Drug must cross this layer in order to have an effect
What does the stratum corner consist of?
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.
Adjacent corneocytes are held together by
Corneodesmosomes
Intercellular lipids
Ceramides, cholesterol, free fatty acids
Highly hydrophobic
Intercellular route.
Topical route
Local effects
- superficial skin disorders (psoriasis, eczema)
- skin infections (viral, bacterial, fungal & parasitic)
- itching
- dry skin
- warts
Topical route - VEHICLES (i.e. formulations)
Ointments, creams, gels, lotions, pastes, powders
The vehicle is usually pharmacologically….
INACTIVE
Rate of absorption (or flux J) is described by…
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.
Role of the Vehicle
> 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.
Km is the…
“pushing force”
Partition coefficient
When drugs are applied topically only…
The soluble fraction provides the driving force for absorption
Excipients
Enhance solubility and absorption
Propylene glycol
Excipient for glucocorticoids
Dimethylsulphoxide
Excipient for lidocaine
When excess, non-dissolved drug included in transdermal patches
Increases duration of effectiveness
Provides a constant rate of delivery
By increasing the free conc of the drug in the vehicle it…
Increases absorption
Topically applied drugs are generally poorly…
Absorbed because only a small fraction partitions into the stratum corneum
Topically applied drugs are generally poorly…
Absorbed because only a small fraction partitions into the stratum corneum
Physical and chemical factors can improve partitioning
> 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
Using a vehicle that limits perspiration..
You can increase the diffusion of the drug
Factors that influence absorption of topically applied drugs
> 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)
What’s more potent - hydrocortisone butyrate or acetate
Butyrate (more lipophilic)
Dry and flaky skin requires…
Ointment; or cream that allows hydration
Features of the Glucocorticoids
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
Glucocorticoid penetration, potency and clinical effect varies with…
> 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
Short term treatment with LOW potency steroids is generally…
SAFE
Long term use of HIGHER POTENCY STEROIDS may produce serious…
ADVERSE EFFECTS
- steroid rebound
- skin atrophy
- systemic effects
- spread of infection
- steroid rosacea
- production of stretch marks and telangiectasia
Glucocorticoids are immuno…
SUPPRESSIVE
Mechanism of glucocorticoids
> 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.
Subcut Route
Systemic or local?
How does drug reach the circulation?
Drug delivered by needle
Drug reaches systemic circulation by diffusion into either i) capillaries
ii) lymphatic vessels (particularly high molecular weight compounds)
Subcut route
- Advantages
- Disadvantages
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
Why skin is a good drug route for a systemic effect?
> 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
What does drug administration via the skin do?
Avoids first pass metabolism
Transdermal Drug Delivery (TDD)
> rug incorporated into an adhesive patch applied to epidermis
> Drug absorption is controlled by a drug release membrane - occurs by diffusion across cutaneous barrier
Most suitable drugs for TDD
i) Low molecular weight
ii) Moderately lipophilic
iii) potent
iv) relatively brief half life
Advantages of TDD
> 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
Disadvantages of TDD
Relatively few drugs are suitable for TDD allergies,
Cost
TDD examples
Nicotine
GTN
Fentanyl
Estradiol
Enhancing Transdermal Drug Delivery
How it works
Advantages
Disadvantages
Examples of agents used
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
Skin is a common target for what kind of drug reaction/eruption?
Idiosyncratic
Distinctive reaction
How common are cutaneous drug reactions?
30% of adverse drug reactions
Types of drug reaction
> Immunologically mediated (allergic)
> Non immunologically mediated (non allergic)
Are allergic reactions dose dependent?
NO
Examples of each type of allergic reaction?
> 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
Are non-allergic drug reactions dose dependent?
Yes, they can be.
Examples of non allergic drug reactions?
Eczema drug induced alopecia Phototoxicity Skin erosion or atrophy Psoriasis Pigmentation Cheilitis, xerosis
What side effect can DOXYCYCLINE have?
Can make the patient sensitive to sunlight
Higher does - more likely to have photosensitivity
Morphology of drug eruptions
> Commonly Exanthematous/Morbilliform (measle-like)/ Maculopapullar
> Urticarial (5-10%)
Papulosquamous/ pustular/ bullous
> Pigmentation
Itch/pain
Photosensitivity
Who to consider for a cutaneous drug eruption
Any patietn who is taking medication and develops a SYMMETRIC skin eruption
Are drug eruptions often symmetrical or unsymmetrical?
Symmetrical
Drug eruption risk factors
> Age (young adults more likely than infants/elderly)
> Gender (more females than males)
> Genetics
> Concomitant disease/ comorbidities
> Immune status
> Polypharmacy
What is the most common type of drug eruption?
Features
Onset
Exanthematous drug eruption
Itch, mild fever
Widespread symmetrically distributed rash
Mild and self limiting
Onset 4-21 days after taking drug
What type of hypersensitivity reactions are Exanthematous eruptions?
T cell mediated delayed type hypersensitivity
Type IV
What are usually spared in Exanthematous reactions?
Mucous membranes
Indicators of potential severe exanthematous reaction
> Involvement of mucous membrane and face
> Facial oedema & erythema
> Widespread confluent erythema
> Fever
> Blisters, purpura, necrosis
> Lymphadenopathy, arthralgia
> SoB, wheezing
> Puffy face
Drugs associated with EXANTHEMATOUS drug eruptions
- Penicillins
- Sulphonamide antibiotics
- Erythromycin
- Streptomycin
- Allopurinol
- Anti-epileptics: carbamazepine
- NSAIDs
- Phenytoin
- Chloramphenicol
Urticarial drug reactions
> Immediate IgE mediated hypersensitivity reaction (type 1) after rechallenge with drug
or
> Direct release of inflammatory mediators from mast cells on first exposure
Drugs causing URTICARIAL drug reactions
Beta-lactam abx; carbazepine
Aspirin, opiates, NSAIDs, muscle relaxants, vancomycin quinolones
Pustular/Bullous drug eruptions
> Acne
- glucocorticoids
- Androgens, lithium, isoniazid, phenytoin
> Acute generalised exanthematous pustulosis
> Reactions can range from mild –> severe
Acute generalised exanthematous pustulosis (AGEP)
- Rare
- Antibiotics
- Calcium channel blockers
- Antimalarials
Drug induced bullous pemphigoid
- ACE inhibitors
- Penicillin
- Furosemide
Linear IgA disease
Can be triggered by Vancomycin
Fixed drug eruptions - features
- 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.
Drugs associated with fixed drug eruptions
> Tetracycline, doxycycline
Paracetamol
NSAIDs
Carbamazepine
Severe Cutaneous Adverse reactions
> Combine cutaneous and systemic symptoms
> Stevens-Johnson syndrome
Toxic epidermal necrolysis
> Drug reaction with eosinophilia and systemic symptoms (DRESS)
> Acute generalised exanthematous pustulosis (AGEP)
Toxic epidermal necrolysis (TEN)
drugs causing this
also causing Stevens Johnson Syndrome
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
Drug reaction w/ eosinophilia and systemic symptoms (DRESS)
Sulfonamides, anticonvulsants, allopurinol, minocycline, dapsone, NSAIDs, abacavir, nevirapine, vancomycin
Phototoxic Drug Reactions
Acute//
- Skin toxicity
- systemic toxicity
- photo degradation
Chronic//
- pigmentation
- photo ageing
- photocarcinogenesis
What type of UV light can get through windows?
UVA
Phototoxic cutaneous drug reactions
> 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
Patterns of Cutaneous Phototoxicity
> 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
Drugs associated with phototoxicity
> Abx > Thiazide diuretics > Chlorpromazine > NSAIDs > Psoralens > Amiodarone > Porphyrins/tetrapyrroles > BRAF inhibitors > Antifungals > Immunosuppressants
Drug reaction information
- 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?
Drug eruption Investigations
History & physical examination
In less clear situations:
> Phototesting
Biopsies
Patch and photo patch tests
Skin prick/ intradermal tests for specific drugs
When is skin testing not indicated?
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
Drug eruptions - Management
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).
Are immunocompromised patients more likely to suffer from a severe cutaneous reaction?
Yes
What can furosemide cause?
A blistering rash
Advantages and disadvantages of topical treatments
Advantages//
- direct application
- reduced systemic effects
Disadvantages//
- time consuming
- correct dosage can be difficult
- messy to use
What should you consider when prescribing topical treatments?
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?
Bases/Vehicles
Gels Creams Ointments Pastes Lotions
Creams - topical therapeutics
> Semisolid emulsion of OIL in WATER
> Contains emulsifier and preservative
> High water content
> Cool and moisturises
> Non greasy
> Easy to apply
> Cosmetically acceptable
Ointments - topical therapeutics
> Semisolid grease/oil (soft paraffin)
> no preservative
> Occlusive and emollient
> Restrict transepidermal water loss
> Greasy - less cosmetically attractive
When do you need to prescribe an ointment?
If skin is very dry or cracked
Lotions - topical therapeutics
> Liquid formulation
Suspension or solution of medication in water, alcohol or other liquids
If contain alcohol, may sting
Treat scalp, hair bearing areas
Gels - topical therapeutics
> Thickened aqueous lotions
Semi-solids, containing HMW polymers (methyl cellulose)
> Treat scalp, hair bearing areas, face
Pastes - topical therapeutics
> Semisolids > Contain finely powdered material (ZnO) > Stiff, greasy, difficult to apply > Protective, occlusive, hydrating > Often used in cooling, drying, soothing bandages
Types of topical therapies
> Emollients > Topical steroids > Antiinfective agents -- antiseptics, abx, antivirals, antifungals > Antipruritics >Keratolytics > Psoriasis therapies
Emollients - topical therapeutcs
> Enhance rehydration of epidermis
For all dry/scaly conditions esp eczema
Need to be effective and cosmetically acceptable
Prescribe 300-500g weekly
Frequent application
Emollient prescribing tips
> 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
Why should you use a clean spoon or spatula to remove emollient from tub?
Reduce risk of bacterial contamination
Why shouldn’t you smoke when you have applied emollient?
Could set fire to yourself as some emollients are paraffin based
More cosmetically acceptable means the patient is more likely to be
Compliant with the treatment
Wet wrap therapy
Used for very dry (xerotic) skin
Difficult and time consuming to apply
Topical corticosteroids
Mode of action - vasoconstrictive, anti inflame, anti proliferative
MILD, MODERATE, POTENT, VERY POTENT
Used for eczema, psoriasis, lichen plans, keloid scars
Steroid rebound in psoriasis can lead to
Pustular psoriasis
Steroid quantities
> 1 application to whole body (adult): 20-30g ointment
> 1 fingertip unit = 1/2g
> Covers 2 hand areas
> Patient education essential for correct use
Topical steroids - side effects
> 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
Antiseptics - therapeutics
Bacteriostatic or bactericidal
Povidone iodine
Antiseptic
skin cleanser
Chlorhexidine
Antiseptic
Hibitane, savlon
Triclosan
Antiseptic
aquasept, sterzac
Hydrogen peroxide
Antiseptic
Crystacide
Herpes simplex
Cold sore
Topical antiviral
Eczema herpeticum
Oral antiviral
Herpes Zoster
Shingles
Oral antiviral
Treatment for Candida
Anti yeast
Nystatin
Clotrimazole
Treatment for dermaphytes
Antifungal
Clotrimazole
Terbinafine cream
Pityriasis versicolor treatment
Ketoconazole
Menthol
Antipruritic
Added to calamine & other lotions and creams to impart cooling sensation
Capsaicin
Antipruritic
Shingles
Chili peppers
Depletes substance P at nerve endings and reduces neurotransmission
Camphor/ phenol
For pruritis
Crotamiton
Antipruritic
Eurax cream
Keratolytics
Used to soften keratin
When are keratolytics used?
> Viral warts
Hyperkeratotic eczema & psoriasis
Corns and calluses
Keratin plaques in scalp
Warts - treatment
Mechanical paring
+
Keratolytics e.g.Salicylic acid Formaldehyde Glutaraldehyde Silver nitrate Cryotherapy (usually liquid nitrogen) Podophyllin (genital warts)
Psoriasis - topical treatments
Emollients and choice of:
- coal tar
- vitamin D analogue
- keratolytic
- topical steroid
- Dithranol
Based on sites affected, extent, severity, side effects, compliance.
Stable Chronic Plaque psoriasis treatment
> 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
Calcipotriol
Vitamin D analogue
Used to treat stable chronic plaque psoriasis
Scalp psoriasis - treatment
Greasy ointments to soften scale
Tar shampoo
Steroids in alcohol base or shampoo
Vitamin D analogues
Psoriasis in axilla
Topical steroids for face, flexures and groin/ genitals.
Consider combo antibacterial, antifungal, calcineurin inhibitors.
Overall side effects of topical therapies
> Burning or irritation
Contact allergic dermatitis
Local toxicity
Systemic toxicity
Can people be sensitive to sunscreen?
Yes
