Pharmacology Flashcards
Major routes of administration for diseases of the skin
Topical, transdermal, subcutaneous/depot
Other epithelial routes for drug administration
Airways, conjunctival sac, nasal mucosa, vaginal
Most important barrier to drug penetration into the skin or diffusion across it
Stratum corneum
Brick and mortar model of stratum corneum
‘bricks’ - corneocytes containing keratin macrofilaments embedded in a filaggrin matrix surround by cornified envelop
‘mortar’ - multiple lamellar structures of intercellular lipids. Intercellular glue that can also act as a reservoir for lipid-soluble drugs
Drug delivery into and across the stratum corneum is a/an __ process, mediated by __ when the drug is applied topically
Active, diffusion
Topical route of administration
Drug is applied in a pharmacologically inactive vehicle to the skin
The topical route of administration is most often used local effects in the treatment of what?
Superficial skin disorders (psoriasis, eczema) Skin infections Itching Dry skin Warts
Vehicles for topical route of administration from greatest water content to least
Lotions Creams Ointments Gels Pastes Powders
What is the choice of vehicle dilated by?
Physiochemical properties of the drug and the skin condition
Factors influencing the absorption of topically applied drugs
Rate of absorption
Nature of the skin
Drug/pharmaceutical preparation
What does rate of absorption depend on?
Permeability coefficient and concentration of drug in the vehicle
Lipophilic drug in a lipophilic base is soluble/insoluble in the vehicle and soluble/insoluble in the skin
Lipophilic drug in a lipophilic base is soluble in the vehicle and soluble in the skin and partitions between the two
Lipophilic drug in a hydrophilic base is more/less soluble in the skin
Lipophilic drug in a hydrophilic base is more soluble in the skin and so preferentially partitions into it
Hydrophilic drug in a lipophilic base has good/limited solubility in both the vehicle and the skin
Hydrophilic drug has limited solubility in both the vehicle and the skin and partitions into it weakly
Hydrophilic drug in hydrophilic base is soluble/insoluble in the vehicle and soluble/insoluble in the skin
Hydrophilic drug in hydrophilic base is soluble in the vehicle but insoluble in the skin and so remains on the surface
How can drug solubility and absorption be enhanced?
By inclusion of excipients within the vehicle
What provides the driving force for skin penetration for drugs applied topically?
The fraction within the vehicle solubilised
Advantage of using transdermal patches
They include excess, non-dissolved drug which can increase duration of effectiveness and provide a constant rate of delivery
Topically applied drugs are generally well/poorly absorbed
Poorly absorbed - only a small fraction partitions into the skin
Physical and chemical factors that can improve partitioning of topically applied drugs
Hydration of the skin by occlusion
Inclusion of excipients that increase solubility of hydrophobic drugs
Factors relating to nature of the skin that influence the absorption of topically applied drugs
Site of application (thickness of stratum corneum)
Hydration of the skin
Integrity of epidermis
Glucocorticoids are widely used topically in which conditions?
Eczema, psoriasis and pruritus
Formulations of topical glucocorticoids available
Lotion, cream, ointment
Adverse effects of long term use of high potency steroids
Steroid rebound Skin atrophy Systemic effects Spread of infection Rosacea Stretch marks and small superficial dilated blood vessels
Main nuclear receptor glucocorticoids signal via
GR alpha
What do glucocorticoids bind with once in the cytoplasm and what does this produce?
GR alpha producing dissociation of inhibitory heat shock proteins and the activated receptor translocates to the nucleus aided by importins
Subcutaneous route of administration
Drug delivered by a needle, inserted into the adipose tissue just beneath the surface of the skin
Advantages of subcutaneous route of administration
Absorption is fairly slow (advantage/disadvantage)
Relatively simple and fairly painless
Can be used to introduce a depot of drug under the skin that is very slowly released into circulation
Route of administration of many protein drugs and suitable for administration of oil-based drugs
Disadvantages of subcutaneous route of administration
Injection volume limited
Absorption is fairly slow (advantage/disadvantage)
Why is the skin an attractive route for drug administration for systemic effect
Application is simple and non-sterile
Avoids first pass metabolism
Potentially allows for a steady state concentration of drug to be achieved over a prolonged period of time
Transdermal drug delivery
The drug is usually incorporated into an adhesive patch applied to the epidermis
Features of drugs that make them suitable for transdermal drug delivery
Low molecular weight
Relatively lipophilic
Potent
Of relatively brief half-life
Advantages of transdermal drug delivery
Steady rate of drug delivery Decreased dosing frequency Avoidance of first pass metabolism Rapid termination of action (if half-life short) User friendly Convenient Painless
Disadvantages of transdermal drug delivery
Few drugs suitable for this method
Allergies
Costly
Examples of drugs that can be used by the transdermal drug delivery method
GTN
Fentanyl
Buprenorphine
Estradiol
Advantages and disadvantages of topical treatments
Advantages - direct application, reduced systemic effects
Disadvantages - time consuming, correct dosing can be difficult, messy to use
What is a cream?
Semisolid emulsion in water, containing emulsifier and preservative
Creams have a high/low water content
High
Advantages of creams
Cool and moisturise
Non-greasy
Easy to apply
Cosmetically acceptable
What is an ointment?
Semisolid grease/oil (soft paraffin) with no preservative
Advantages and disadvantages of ointments
Advantages - occlusive and emollient, restrict transepidermal water loss
Disadvantage - greasy - less cosmetically acceptable
What is a lotion?
Suspension or solution of medication in water, alcohol or other liquids
What areas do lotions treat?
Scalp and hair-bearing areas
Disadvantage of lotions
May sting if they contain alcohol
What is a gel?
Thickened aqueous solution. Semi-solid containing high molecular weight polymers
Which areas are gels used to treat?
Scalp, hair-bearing areas, face
What is a paste?
A semisolid that contains finely powdered materials
Advantages and disadvantages of pastes
Advantages - protective, occlusive, hydrating
Disadvantages - stiff, greasy, difficult to apply
What is a foam?
Colloid with two-three phases. Usually a hydrophilic liquid in continuous phase with foaming agent dispersed gaseous phase
Advantages of foams
Increased penetration of active agents, can spread over large areas of skin with no oily/greasy film
Types of topical therapies
Emollients Topical steroids Antinfective agents Antipruritics Kertolytics Psoriasis therapies Cytotoxic and antineoplastic therapies
Benefit of emollients and which conditions they are used in
They enhance rehydration of the epidermis and are used in all dry/scaly conditions
Dose of emollients prescribed
300-500g
Tips to tell a patient when prescribing emollients
They need frequent application
Apply immediately after bathing
Apply in the direction of hair growth (prevent infection)
Use a clean spoon or spatula to remove from tub (prevent infection)
Can make skin and surfaces slippy - hazard
Fire risk if paraffin based
Avoid those containing SLS in leave-on products
When is wet-wrap therapy used?
For xerotic skin
Disadvantage of wet-wrap therapy
Very difficult and time consuming to apply
Mode of action of corticosteroids
Vasoconstrictive, anti-inflammatory, anti-proliferative
Examples of topical corticosteroids:
- Mild
- Moderate
- Potent
- Very potent
Mild = hydrocortisone 1%
Moderate = modrasone, clobetasone, butyrate 0.05%
Potent = mometasone, betamethasone, valerate 0.1%
Very potent = clobetasol propionate 0.05%
Quantity of topical corticosteroids
1 application to whole body (adult) = 20-30g
1 fingertip unit = 1/2 gram - covers 2 hand areas
Side effects of topical corticosteroids
Thinning of skin Purpura Stretch marks Steroid rosacea Telangiectasia Perioral dermatitis May worsen or mask infections Systemic absorption Tachyphylaxis Rebound flare of disease Glaucoma and cataract
Alternative to steroids
Calcineurin inhibitors
How to calcineurin inhibitors work?
Suppress lymphocyte activation
Disadvantages of calcineurin inhibitors
May cause burning sensation on application, perhaps risk of cutaneous infections and cancer
Clinical uses for antiseptics
For recurrent infection, skin cleansing, wound irrigation
Examples of antiseptics
Povidone iodine skin cleanser
Chlorohexadine
Triclosan
Hydrogen peroxide
Clinical uses of antibiotics
Treatment of acne and rosacea
Treatment of skin infections
Treatment of infected eczematous process
Caveats of antibiotics
Antibiotic resistance, sensitisation
Antipruritics and how they work
Menthol - added to calamine and other lotions and creams to impart cooling sensation
Capsaicin - from red chilli peppers - depletes substance P at nerve endings and reduces neurotransmission
Camphor/phenol for pruritus ani
Crotamiton is used after scabies to relieve residual itch
What do keratolytics do? Which conditions are they used in?
Soften keratin Viral warts Hyperkeratotic eczema and psoriasis Corns and calluses To remove keratin plaque in scalp
Treatment of warts
Mechanical paring plus:
- Keratolytics
- Formaldehyde
- Glutaraldehyde
- Silver nitrate
- Cryotherapy
- Podophyllin (for genital warts)
Example of a keratolytic
Salicylic acid
Topical psoriasis treatment
Emollients plus either:
- Coal tar
- Vitamin D analogue
- Keratolytic
- Topical steroid
- Dithranol
Advantages and disadvantages of coal tar
Advantages - effective, comes in mild solutions to strong crude coal tar
Disadvantages - messy and smelly
Advantages and disadvantages to vitamin D analogue
Advantages - clean, no smell, easy to apply
Disadvantages - can be irritant, use limited to 100g weekly as can cause hypercalcaemia
Advantages and disadvantages of dithranol
Advantages - effective
Disadvantages - difficult to use, irritant, stains normal skin
Treatment for scalp psoriasis
Greasy ointments to soften scale
Tar shampoo
Steroids in alcohol base or shampoo
Vitamin D analogues
Type I anaphylactic reaction presentation
Anaphylaxis and/or urticaria
Type II cytotoxic reaction presentation
Blistering reactions - pemphigus and pemphigoid
Type III immune complex mediated reaction presentation
Purpura/rash/vasculitis
Type IV cell-mediated delayed hypersensitivity reaction presentation
Erythema/rash
Examples of non-immunological cutaneous drug reactions
Eczema Drug induced alopecia Phototoxicity Skin erosion (topical 5-fluorouracil) Atrophy (topical steroids) Psoriasis Pigmentation Cheilitis
Who to consider as having cutaneous drug eruptions
Any patient who is taking medication who suddenly develops a symmetrical skin eruption
When does the effect of cutaneous drug eruptions usually resolve?
When the drug is withdrawn
Factors that can cause cutaneous drug eruptions to continue on withdrawal of the drug
Half-life of drug
Ability of drug to be retained/accumulated in tissues plays a role
May cross react with a similar class of drugs
Risk factors for drug eruptions
Age - elderly > infants Gender - females > males Genetics Concordant disease (e.g. viral infections, CF) Immune status
Most common type of drug eruption
Exanthematous drug eruptions
What is an exanthematous drug eruption?
An idiosyncratic, T-cell mediated delayed hypersensitivity reaction
Clinical presentation of exanthematous drug eruptions
Mild and self limiting widespread symmetrically distributed rash, which usually spares mucous membranes and is associated with itch.
Mild fever is common
Onset is 4-21 days after first taking drug
Indicators of a potentially severe exanthematous drug eruption
Involvement of mucous membrane and face Facial erythema and oedema Widespread confluent erythema Fever Skin pain Blisters, purpura, necrosis Lymphadenopathy, arthralgia SOB, wheezing
Drugs associated with exanthematous eruptions
Penicillins Sulphonamides Erythromycin Streptomycin Allopurinol Anti-epileptics - carbamazepine, phenytoin NSAIDs Chloramphenicol
Urticarial drug reactions
Usually an IgE mediated hypersensitivity reaction (type I) after rechallenge with drugs
or
Direct release of inflammatory mediators from mast cells on first exposure
Acneiform
Looks like acne but there are no comedones or greasy skin
In which people can acneiform be seen in?
Weightlifters who have taken steroids
Drugs that can be associated with acneiform
Androgens
Lithium
Isoniazid
Pustulosis
Acute generalised exanthematous pustulosis
Rare, sheets of monomorphic pustules
Drugs that can be associated with acute generalised exanthematous pustulosis
Antibiotics, calcium channel blockers, antimalarials
Drugs that can cause drug-induced bullous pemphigoid
ACE inhibitors, penicillin, furosemide
Clinical presentation of fixed drug eruptions
Well demarcated round/oval plaques which are red and painful and often seen on hands, lips, genitalia, and occasionally oral mucosa.
Can present with eczematous lesions, papules, vesicles or urticaria
What happens in fixed drug eruptions when the drug is stopped and then re-introduced?
When the drug is stopped, the fixed drug eruption resolves with persistent pigmentation
The reaction can re-occur at the same site on re-exposure to the drug
Drugs associated with fixed drug eruptions
Tetracycline, doxycycline
Paracetamol
NSAIDs
Carbamezapine
Severe cutaneous adverse drug reactions
Stevens-Johnson syndrome (SJS)
Toxic epidermal necrolysis (TEN)
Drug reaction with eosinophilia and systemic symptoms (DRESS)
Acute generalised exanthematous pustulosis (AGEP)
Drugs that can cause toxic epidermal necrolysis
Sulfonamides Cephalosporins Carbamezapine Phenytoin NSAIDs Nevirapine Lamotrigine Sertraline Pantoprazole Tramadol
Drugs that can cause drug reaction with eosinophilia and systemic symptoms
Sulfonamides Anticonvulsants Allopurinol Minocycline Dapsone NSAIDs Abacavir Nevirapine Vancomycin
Clinical presentation of drug reaction with eosinophilia and systemic symptoms
Facial oedema, lymphadenopathy, liver involvement, fevers ≥40˚C
Consequences of severe cutaneous drug reactions
Hypothermia Fluid loss Protein loss Sepsis Multi organ failure Permanent sequelae Death
Acute phototoxic drug reactions
Skin toxicity - photosensitivity
Systemic toxicity
Photodegradation
Chronic phototoxic drug reactions
Pigmentation
Photoageing
Photocarcinogenesis
What is a phototoxic cutaneous drug reaction?
Non-immunological skin reaction due to light activation of a photo-reactive drug
Patterns of skin phototoxicity
Immediate prickling with delayed erythema and hyperpigmentation
Exaggerated sunburn
Exposed telangiectasia
Delayed 3-5 days erythema and pigmentation
Increased skin fragility
Which drugs cause immediate prickling and delayed erythema and pigmentation pattern of skin phototoxicity?
Chlorpromazine, amiodarone
Which drugs cause exaggerated sunburn pattern of skin phototoxicity?
Quinine, thiazides, demeclocycline
Which drugs cause exposed telangiectasia pattern of skin phototoxicity?
Calcium channel antagonists
Which drugs cause delayed 3-5 days erythema and pigmentation pattern of skin phototoxicity?
Psoralens
Which drugs cause increased skin fragility due to skin phototoxicity?
Naladixic acid, tetracycline, naproxen, amiodarone
Drugs associated with phototoxicity
Antibiotics Thiazides Chlorpromazine NSAIDs Quinine Psoralens Amiodarone Poryphrins BRAF inhibitors Antifungals Immunosuppressants
Investigations for suspected cutaneous drug eruptions
History and physical examination Phototesting (for suspected phototoxic reactions) Biopsies Patch and photo patch tests Skin prick/intradermal tests
Management of cutaneous drug eruptions
Discontinue drug if possible and use an alternative
Topical corticosteroids
Antihistamines (help with type I or itch)
Allergy bracelets
