Pharmacology Flashcards
Name the major routes of drug administration
- topical; largely for local effect, but also to treat underlying issues (eg. topical NSAIDs)
- transdermal
- subcutaneous / depot
- airways
- conjunctival
- nasal mucosa
- vaginal
Name the single most important barrier to drug penetration into the skin, or diffusion across it
The stratum corneum
The stratum corneum consists of what?
- hardened, dead, keratinocytes
- surrounded by intercellular lipids formin 10 - 30 sheets of tissue (typically 20) that are constantly shed (desquamated) and renewed
The stratum corneum can be described as the brick and mortar model. Explain this
- bricks; cornerocytes containing keratin microfilaments embedded in a filaggrin matrix surrounded by a cornified (protein) cell envelope. Corneocytes are highly cross linked by protein rivets (corneodesmosomes) providing tensile stength
- mortar; multiple lamellar structures of intercellular lipids (mainly ceramides that link to corneocyte envelope, cholesterol, free fatty acid). A largely hydrophobic intercellular glue that can also act as a reservoir for lipid-soluble drugs (eg. topical glucocorticosteroids)
How is drug delivered across the stratum corneum?
- via a passive process
- mediated by diffusion, when a drug is applied topically
Which conditions are treated topically for use for local effects?
- superficial skin disorders (eg psoriasis, eczema)
- skin infections (ie viral, bacterial, fungal and parasitic)
- itching (pruritus)
- dry skin
- warts
The choice of vehicle for topical administration is dictated by what?
- physiochemical properties of the drug
- the clinical condition
Which drugs contain the most water and which contain the least?
Most to least
- lotions
- creams
- ointments
- gels
- pastes
- powders
The vehicle (or base) can profoundly affect rate and extent of absorption of a topically applied drug. Name some important factors
- dissolved concentration of the drug in vehicle (Cv)
- the movement (or partitioning) of the drug from vehicle into the stratum corneum and deeper (Km)
Lipophilic drug in lipophilic base is soluble where?
- soluble in both vehicle and skin and partitions between the two
Lipophilic drug in hydrophobic base is soluble where?
Most soluble in the skin and preferentially partitions into it
Hydrophilic drug in lipophilic base is soluble where?
- has limited solubility in both vehicle and skin and partitions into it weakly
Hydrophilic drug in hydrophilic base is soluble where?
- soluble in vehicle but not skin and remains on the surface
For drugs applies topically, what provides the driving force for skin penetration
- the fraction within the vehicle solubilised (Cv), not that undissolved
Inclusion of what within the vehicle can enhance drug solubility and enhance absorption?
Excipients (eg. propylene glcyol)
Are topically applied drugs well or poorly absorbed?
Poorly - only a small fraction partitions into the skin
Name some physical and chemical factors that can improve partitioning
- hydration of the skin by occlusion (prevention of water loss by evaporation)
- may be achieved by choice of vehicle (eg. ointment versus oil in water cream)
- cling film
- inclusion of excipients that also increase the solubility of hydrophobic drugs
Increased partitioning results from what?
A reduction in the barrier function of the stratum corneum
Describe the nature of the skin as a factor that influences absorption topically
- site of application (thickness of stratum corneum / skin)
- hydration of the skin (vehicles and occlusive dressings)
- integrity of the epidermis (absorption influenced by trauma, inflammation/ other disease processes)
Describe drug / pharmaceutical preparation as a factor influencing absorption topically
- drug concentration and properties
- the drug salt
- the vehicle (betamethasone valerate more active as an ointment than as a cream, or lotion)
Describe the features of glucocorticoids
- widely used topically in the treatment of atopic eczema, psoriasis and pruritus
- posses anti-inflammatory, immunosuppressant and vasoconstricting effects plus anti-proliferating action upon keratinocytes and fibroblasts
- available in several formulations
- adverse events less likely with topical application, but system adverse events can occur
Penetration, potency and clinical effect varies with what?
- body site; eg thickness of stratum corneum
- state of the skin; eg infants and children have thin skin that is more permeable to glucocorticoids
- occlusion
- specific drug and its concentration
- vehicle; affects potency, affects compliance
- formulation of drug; 1% hydrocortisone acetate is mild but 0.1% hydrocortisone butyrate is potent
Name some serious adverse effect of long term use of higher potency steroids
- steroid rebound (glucocorticoid receptor down-regulation)
- skin atrophy (that may not be totally reversible)
- systemic effects (HPA axis depression due to systemic absorption)
- spread of infection (due to immune suppression in the skin)
- steroid rosacea (skin reddening and pimples of facial skin)
- production of stretch marks (striae atrophica) and small superficial dilated blood vessels (telangiectasia)
True or flase?
Glucocorticoids are lipophilic molecules
True
Within the cytoplasm, glucocorticoids combine with what?
- GRalpha producing dissociation of inhibitory heat shock proteins (eg. HSP90)
- the activated receptor translocated to the nucleus aided by importins
Describe the action of glucocorticoids within the nucleus
- activated receptor monomers assemble to homodimers and bind to glucocorticoid response elements (GRE) in the promotor region of the specific genes
How does the drug reach the systemic circulation when administered subcutaneously?
- diffusion into either capillaries or lymphatic vessels (particularly high molecular weight compounds)
Describe the advantages of the subcutaneous route of administration
- absorption is relatively low due to poor vascular supply
- route for administration for many protein drugs (eg insulin) and suitable for administration of oil based drugs (eg steroids)
- can be used to introduce a depot of drug under the skin that is very slowly released into the circulation
- relatively simple and fairly painless
Describe the disadvantages of the subcutaneous route of administration
- injection volume limited
Why is the skin an attractive route of drug administration for a systemic effect?
- application is simple and non-sterile (when drug is applied topically
- potentially allows for a steady state plasma concentration of drug to be achieved over a prolonged period of time
- avoids first pass metabolism, for example by the intestine and liver and potential toxicity to those organs
- drug absorption can be terminated rapidly (with the caveat that some drug may have accumulated in the skin)
What is a disadvantage of the skin as a route of drug administration?
- intact skin is a water tight barrier
- only a limited number of drugs diffuse across the epidermis to reach the superficial capillaries of the dermis to be systemically available at an effective concentration
Describe transdermal drug delivery
- drug absorption is partially controlled by a drug release membrane - occurs by diffusion across cutaneous barrier
- most suitable for drugs that are low molecular weight, moderately lipophilic, potent or have a relatively brief half-life
Describe advantages of transdermal drug delivery
- steady state of drug delivery, decreased dosing frequency, avoidance of first pass metabolism, rapid termination of action ( if t1/2 is short)
- user friendly, convenient, painless, increased patient concordance
Describe disadvantages of transdermal drug delivery
- relatively few drugs suitable for TDD (although increasing)
- allergies
- cost
Name some drug examples of transdermal drug delivery
- scopolamine
- nicotine
- GTN
- fentanyl
- buprenorphine
- estradiol
Describe the chemical enhancement of transdermal drug delivery
- enhancers interact with the lipid matrix of the stratum corneum to increase permeability, mianly to drugs that already cross the skin reasonably well
Name some agents that chemically enhance transdermal drug delivery
- water; prolonged occlusion (via topical formulation or patch, causes increased hydration of the stratum corneum and the formation of a pore pathway
- a variety of solvents (eg ethanol) and surfactants (eg sodium dodecyl sulphate)
Describe the advantages of topical treatments
- direct application
- reduced systemic effects
Describe the disadvantages of topical treatments
- time consuming
- correct dosage can be difficult
- messy to use
Drugs used on the skin are dissolved in bases or vehicles, name some
- gels
- creams
- ointments
- pastes
- lotions
- foams
Describe creams
- semisolid emulsion of oil in water
- contain emulsifier and preservative (to increase shelf life)
- high water content (to help with cooling)
- cool and moisturise
- non greasy
- easy to apply
- cosmetically acceptable
Describe ointments
- semisolid grease/oil
- no preservative
- occlusive and emollient
- restrict transepidermal water loss
- greasy; less cosmetically attractive
- no sharing of ointment to avoid bacterial infection due to no preservative
Describe lotions
- liquid formulation
- suspension or solution of medication in water, alcohol or other liquids
- if contain alcohol, may sting
- treat scalp, hair bearing areas
Describe gels
- thickened aqueous lotions
- semisolids, containing high molecular weight polymers eg methylcellulose
- treat scalp, hair bearing areas, face
Describe pastes
- semisolids
- contain finely powdered material eg ZNO
- stiff, greasy, difficult to apply
- protective, occlusive, hydrating
- often used in cooling, drying, soothing bandages
Describe foams
- colloid with two-three phases
- usually hydrophilic liquid in continuous phase with foaming agent dispersed in gaseous phase
- advantage of increased penetration of active agents (eg steroid, vitamin D)
- advantage that can spread easily over large areas of skin, no greasy / oily film
What form of treatment would you give for icthyosis?
Lotion
What form of treatment would you give child hand dermatitis?
Cream
What form of treatment would you give scalp psoriasis?
Gel
What form of treatment would you give hyperkeratotic hand eczema?
Ointment
Name some types of topical therapies
- emollients
- topical steroids
- anti-infective agents; antiseptics, antibiotics, antivirals, antifungals
- antipruritics
- keratolytics
- psoriasis therapies
- cytotoxic and antineoplastic agents
Describe emollients
- enhance rehydration of epidermis
- for all dry/scaly conditions especially eczema
- need to be effective and cosmetically acceptable
- prescribe 300-500g
- needs frequent application
Describe the prescribing tips for emollient
- apply immediately after bathing
- apply in direction of hair growth (can block hair follicles and cause infection)
- make skin and surfaces slippery
- use clean spoon or spatula to remove from tub
- fire risk if paraffin based
- avoid these containing SLS in leave on products
What is wet wrap therapy used for?
Very dry (xerotic) skin
What is the mode of action for topical corticosteroids?
- vasoconstrictive
- anti inflammatory
- antiproliferative
Name topical steroids in order of mild to high potency
- mild; hydrocortisone 1%
- moderate; modrasone, clobetasone butyrate 0.05%
- potent; mometasone, betamethasone valerate 0.1%
- very potent; clobestaol proprionate 0.05%
Name some uses for topical corticosteroids
- eczema (dermatitis)
- psoriasis (eg flexures, face, hairline, scalp) beware round, triggering pustular psoriasis
- other non-infective inflammatory dermatoses eg lichen planus
- keloid scars (intralesional or tape)
Describe calicneurin inhibitors
- tacrolimus, pimecrolimus
- suppress lymphocyte activation
- topical treatment of atopic eczema (esp. face, children)
- no cutaneous atrophy
- may cause burning sensation on application
What are the four types of antiinfectives?
- antiseptics
- antibiotics
- antivirals
- antifungals
Name some examples of antiseptics and their function
- have bacteriostatic or bactericidal effects
- povidone iodine skin cleanser
- chlorhexidine (hibitane, savlon)
- triclosan (aquasept, sterzac)
- hydrogen peroxide (crystacide)
Describe the clinical uses of antiseptics
- recurrent infections (broad spectrum)
- skin cleansing
- wound irrigation
Describe some clinical uses of antibiotics
- treatment of acne and rosacea
- treatment of skin infection eg impetigo
- treatment of infected eczematous process eg otitis externa
Name some topical antifungals
- candida; antiyeast eg nystatin, clotrimazole
- dermatophytes; antifungal eg clotrimazole, terbinafine cream
- pityriasis versicolor; ketoconazole (cream or shampoo)
Name some antipruritics
- menthol; added to calamine and other lotions and creams to impart cooling sensation
- capsaicin; depletes substance P at nerve endings and reduced neurotransmission, effect gradually builds
- camphor / phenol; for pruritus ani
- crotamiton; eg eurax cream, used after treatment of scabies to relieve residual itch
What are keratolytics used for?
- to soften keratin
- viral warts
- hyperkeratotic eczema and psoriasis
- corns and calluses
- to remove keratin plaques in scalp
Describe the treatment of warts
- mechanical paring plus
- keratolytics eg salicyclic acid
- formaldehyde
- glutaraldehyde
- silver nitrate
- cryotherapy (usually liquid nitrogen)
- podophyllin (genital warts)
Describe some topical psoriasis treatments
- emollients and choice of;
- coal tar
- vitamin D analogue
- keratolytic
- topical steroid
- dithranol
- based on; sites affected, extent, severity, side effects, compliance
Describe coal tar
- mild solutions to strong crude coal tar
- messy and smelly
Describe vitamin D analogues
- clean, no smell
- easy to apply
- can be an irritant
- use limited to 100g weekly
Describe dithranol
- effective
- difficult to use
- irritant and stains normal skin
Describe treatment for scalp psoriasis
- greasy ointments to soften scale
- tar shampoo
- steroids in alcohol base or shampoo
- vitamin d analogues
Describe cytotoxic and antineoplastic therapies
- 5 fluorouracil for solar damage, bowens disease and superficial basal cell carcinoma
- imiquimod for solar damage and superficial basal cell carcinoma
