l23 - gastro

what different SKIN drug delivery routes are there?

1. topical

• so applied directly onto the epidermal surface

2. injection into the various skin layers

A. intradermal injection

• this is a very shallow injection that goes into the dermis

• creates a bubble when injected

B. subcutanous injection

• this is an injection into the hypodermis/underneath the hypodermis

• there is NO bubble created when injected

• this perfuses into the vasculature

topical delivery of a drug - how does the drug move into the skin layers?

1. intercellular route

• this is the drug moving in between the CELLS

• the spaces between our corneocytes is a LIPID matrix

• so therefore, drugs which are sufficiently lipophillic are able to move through this lipid-rich pathway

2. transcellular route

• this is when the drugs PERMEATE each cell - so physically move in and out of each cell

• this means the drugs must repeatedly move in and out of each cell to be able to move deeper into the skin

• these drugs tend to be lipophillic, but also need to be some what water soluble

3. appendagal routes

• our appendages create PORES within our natural skin layers

• so much largers drugs are able to travel via this route

how do we know which route we should design our drug to take topically?

depends on where we are wanting our drug to act

• e.g. in the keratinocytes, down in the dermis, etc.

how are topical drugs formulated?

inactive ingredients are combined with active drug

• the active drug TARGETS a molecule in order to induce a biological response

• all the inactive ingredients are involved in the DELIVERY of the drug - because we want to make sure our drug is reaching the right comprtment

what important things need to be ensured when considering the formulation of a topical drug?

1. we need to be able to release and solubilise the drug

2. need to make sure it reaches the intended compartment

3. needs to maintain contact with the target for an appropriate amount of time

4. we need to LIMIT unintended systemic absorption - we do not want our drug getting into the systemic circulation and going and causing a lot of off target effects - UNLESS THIS IS WHAT IS DESIRED!

5. we need to maintain stability - so can this medication be stored and remain stable?

6. and patient acceptability - is the patient happy to take this drug?

what 4 topical formulations do we have

1. ointments

2. creams

3. lotions

4. gels

describe SKIN OINTMENTS?

ointments are either OILS or WAXES - essentially just made of lipids

• these form an occlusive seal that PREVENTS water loss

• ointments remain on the skin longer - so this prolongs contact time, allowing more time for drug delivery

• enhances drug penetration > because the hydrating property of ointments can disrupt the skin barrier, making it easier for the drug in ointments to get in intercellularly. so ointments can EXPAND the intercellular space.

what are skin ointments a good vehicle for?

LIPOPHILIC DRUGS

so what is the main action of a skin ointment

ointments trap moisture in the skin, hydrating it and increasing drug penetration

describe skin CREAMS?

creams contain a mixture of water and oil - about a 50:50 mix of both

• BUT because these do not like to mix, we also add emulsifiers and humectants

• humectants=water loving jelly molecle

• creams are EASY to spread and absorb very quickly into the skin - absorb a lot quicker then an ointment

what are skin creams a good vehicle for?

hydrophillic AND lipophillic drugs

• we can load either the water bit or the oil bit with the drug - so this is VERY useful

describe SKIN LOTIONS?

skin lotions are also a water and oil mix, BUT a lot more water then it is oil

• also mixed in with humectants and emulsifiers

• easy to spread, absorb

• BUT can have a drying effect because the water evaporates after application - which can leave the skin feeling drier and tighter

what are skin lotions a good vehicle for?

NORMALLY hydrophillic drugs

• since skin lotions are primarily water

describe skin gels?

skin gels are made using gelling polymers-cellulose- ,mixed in with water or alcohol

• these are the EASIEST to spread

• gels can absorb excess fluids from the wound

• has a drying effect - so can evaporate water from the skin - this can also result in a cooling effect

what are skin gels a good vehicle for?

1. hydrophillic peptides

2. protein drugs

what would a gel be good on, and what would it noe be good on

would be good on a BURN - where it could use the drying out effect, and the cooling sensation

but BAD on inflammatory skin, where a drying effect is probably going to irritate it moren

what has a big effect on how much of a topical drug can penetrate the skin?

the CONDITION of someones skin barrier

our 3 topical delivery routes are very dependent on the skin barrier being intact

whats the differencebetween topical delivery of a drug in a healthy skin barrier VS. a damaged skin barrier?

1. healthy = CONTROLLED penetration of the drug

2. damaged = GREATER penetration of the drug - this is because gaps in the barrier allow substances to penetrate more easily

• so if this skin barrier is damaged, then BOTH the active ingredient and the formulation components are going to go a lot deeper then expected

is it bad if our formulation goes deeper due to the skin barrier being compromised?

can be good sometimes because it means our active drug can get deeper down into the dermis, BUT, our formulation components going deeper can mean that our chances of irritation being caused increase a lot

• so this can set off an itch and an inflammatory response

so potentially greater efficacy, but greater systemic exposure, local irritation, and sensitization

what is atopic dermatitis/excema?

this is a skin barrier dysfunction

• it is driven by LOW filagrin and NMF’s, infection, inflammation, and itch

these flares can come in waves, but it never really goes away

name some treatment optionds of excess/atopic dermatitis

1. emollients - so cream, lotion, gel, ointment

• these can SUPPORT the impaired barrier

2. topical corticosteroids

• these suppress inflammation

• so may suppress the trigger of this excma/atopic dermatitis occurring

3. antihistamines

• THESE HAVE LIMITED BENEFITS

what can contribute to excess/atopic dermatitis?

the itch scratch cycle

what do emollients do in regards to the skin barrier?

they help to repair the skin barrier by replacing missing lipids, preventing water loss, and INCREASING skin hydration

• so they provide an occlusive surface to help the skin RETAIN moisture - and prevent the loss of it

• and they replenish intercellular lipids - e.g. an emollient may contain cholesterol, so this can help replenish our lost lipid matrix

• the humectants in emollients increase hydration by attracting and retaining water

what can emollients mimic?

NMF’s

NMF’s are water attracting molecules found within corneocytes that help to keep them hydrated

• so emollients can mimic their function

How do humectants in emollient formulations increase skin hydration?

Humectants, such as glycerin and hyaluronic acid, attract and retain water in the skin, increasing hydration and mimicking the function of natural moisturising factors (NMFs).

how are topical corticosteroids useful in treating skin barrier compromisation conditions?

while other drugs work on treating the skin barrier - topical corticosteroids work on treating the UNDERLYING INFLAMMATION

• they range a lot, from mild to very potent

what are topical corticosteroids typically used for?

flare ups or chronic lesions

what is hydrocortisone?

this is a cortisol DERIVATIVE

Hydrocortisone is a corticosteroid drug that reduces inflammation in the skin. It works by mimicking cortisol, a hormone naturally produced by our body that has anti-inflammatory effects.

how does hydrocortisone work?

it enters the EPIDERMAL, ENDOTHELIAL, and IMMUNE CELLS

• it then binds intracellularly to the nuclear glucocorticoid receptor

• this receptor-drug complex then enters the nucleus to alter gene transcription

• this INDUCES the expression of anti-inflammatory proteins

• and SUPPRESSES the expression of pro-inflammatory proteins

what concentration of hydrocortisone do we use?

the LOWEST effective concentration possible - we do this to avoid adverse side effects

solubility of hydrocortisone?

hydrocortisone dissolves better in ALCOHOL or GLYCEROL based solvents than in water

stability of hydrocortisone?

hydrocortisone needs to be protected from things like heat, light, and oxidation

what happens if hydrocortisone undergoes degredation?

it LOSES its potency - this means it becomes less effective

describe antihistamines as a drug

these are typically used to treat allergeis - so are an anti-allergy drug

• have greater efficacy with ACUTE itch - because this is stimulated by histamine

• but BAD efficacy with CHRONIC itch - because this is stimulated by cytokines

what types of anti histamine do we have

1st and 2nd generations

1st generation = MORE side effects

2nd generation = LESS side effects

whats the best administration type for anti-histamines?

topical formulations are safer to administer, BUT oral administrations are more effective

are anti-histamines a good treatment for atopic dermatitis?

NO - because atopic dermatitis is a chronic condition

whats an example of a first generation anti-histamine?

Mepyramine

• this binds to the histamine #1 receptor on enodothelial cells and sensory neurons

• it is an inverse agonist - so stabilises the receptor in its inactive state

• 
  

what does Mepyramine prevent?

prevents GPCR signaling AND histamine induction of itch, vascular permeability, and vasodilation

what is mepyramine the best treatment for?

short term relief of itch

• so e.g., from an insect bite

what is mepyramine normally incorporate into?

gels, lotions, and creams

• has a high solubility in alcohols and water - which is way it can be incorporated into those emollients

How is mepyramine kept stable in its formulation?

It is protected from heat, light and oxygen to prevent the drug from breaking down.

What happens if mepyramine degrades (breaks down)?

It loses potency, meaning it becomes less effective, and impurities can form.

what is acne vulgaris?

this is the common term for COMMON acne

how does acne develop?

1. too many skin cells build up

• so cells lining the hair follicle MULTIPLY and become corneocytes - which are dead keratinocytes cells

• and these can accumulate within the hair follicle

AND

2. sebum build up

• sebaceous glands produce sebum

• so this sebum can mix with the corneocytes and block the hair follicle

so then this build up forms a COMEDONE

whats a comedone?

clogged skin pores filled with sebum, dead skin cells, and bacteria

closed comedone = a white head

open comedone = a blackhead

what bacteria is an acne, and what does this lead to?

cutibacterium acnes

• this leads to inflammation

• immune cell recruitment

• potential dermal scarring

what can happen due to acne?

we can get hair follicle destruction - and this destruction can go deep into the hypodermis layer

• this can result in a depressed sunken scar, because it can be very hard to fill again

how does a retinoid work to treat acne?

retinoid is a form of skin RENEWAL drug - so it makes the skin replace itself

how is retinoid usually administered?

normally topicaly as it is safer than oral formulations

what types of retinoid do we have

we have different generates, 1 through 4

• the LATER generations are LESS irritating then the earlier generations

how does tretinoin work to treat acne?

tretinoin is a type of retinoid drug, and is a vitamin A derivative

it ENTERS keratinocytes and activates nuclear retinoic acid receptors

• this ALTERS gene transcription

how does tretinoin alter gene transcription?

it induces expression of growth factors that PROMOTE epidermal turnover and desquamation - which is the flaking off of the old, outer layer - so that a NEW fresh layer can come through

aside from aiding in skin renewal - what can trentinoin help to PREVENT?

helps to prevent keratin clogged follicles and comedone formation

what formulation is trentinoin given in?

the LOWEST concentration possible, to avoid irritation

trentinoin solubility?

best given in OILS - so e.g. given in a cream

- or can be formulated into a microsphere if given in a gel

what is trentinoin very susceptible to?

OXIDATION

why can benzoyl peroxide NOT be taken at the same time as trentinoin?

because it will OXIDSE trentinoin, which will degrade it, making it useless

• so if using both, need to be taken at ENTIRELY different times

what is a good acne treatment if we have an active infection in our molecules

antiseptics

• these are chemical agents which are applied topically to prevent or stop infection

what do antiseptics work on?

a LOT - they are very broad acting

• but it is important to NOT leave these on the skin long - because if so, they can start to damage our skin cells too

• so they are best used to wash the face

how is benzoyl peroxide used as acne treatment?

it breaks down into FREE OXYGEN RADICALS within our skin pores

• this is beneficial as free oxygen radicals DAMAGE bacterial lipids, protein and DNA

• but can be quite NON-specific and have off target effects on our actual skin cells - which is not good

what concentration of benzoyl peroxide do we use for acne treatment?

the lowest possible to avoid irritability and to avoid drying out

how is benzoyl peroxide best administered

best in oils, or formulated into a microsphere

if in microsphere will be delivered via a gel

stability of benzoyl peroxide?

benzoyl peroxide can be VERY reactive with certain things - SO need to be careful about what we are using it alongside

what can benzoyl peroxide be broken down into

BENZENE > this is BAD because this is a carcinogen

in a chronic wound, what is skin healing typically impeded by?

1. bacterial infection

2. local inflammation

3. systemic dysfunction

what is LIKELY if someone comes in with a chronic wound?

it is likely they have some form of underlying factor which is contributing - such as diabetes

why would we maybe NOT want to use anti inflammatories as a treatment for chronic wound healing?

because we do NEED inflammation, so that it it can convert our monocytes into the correct form of macrophages needed for the proliferative stage - M2 macrophages

• so if we knock back inflammation ENTIRELY, then we are not able to progress onto proliferation

• so we instead prefer to get RID of the stimuli for inflammation, and promote healing

when would we use recombinant therapy as a chronic wound treatment?

if BOTH the underlying factors and the infection have been adressed and it is STILL not healing

what is nepidermin?

a type of growth factor therapy - recombinant epidermal growth factor protein

how does nepidermin work?

it binds to epidermal growth factor, EGF, receptors on keratinocyts

• this induces: migration, proliferation, and re-epithelilialsation

• it kicks off a LOT of important pathways - which result in these 3 things happening

what is nepidermin usually given as a treatment for?

1. diabetic ulcers

2. burns

what does recombinant mean?

produced OUTSIDE of the body

so normally a lot of our recombinant therapies, are proteins which we make naturally, but we can make our body have lots more of it by making it outside of the body, and then delivering it this way

what is becaplermin?

a recombinant human platelet derived growth factor protein

how does becaplermin work?

it binds to platelet derived growth factor, PDGF, receptors, ON FIBROBLASTS

• this induces the fibroblast to migrate, proliferate, and form granulation tissue

what is becaplermin normally used for?

diabetic ulcers

how do we apply becaplermin?

the application is relative to the wound size

• we normally put a LOT though, as growth factors are big proteins and can be hard to get to the target site. so unlike the others, we actually want a decent amount of this

becaplermin solubility?

HIGH in water

• normally prepared in cellulose gel and administered under some form of dressing

what risk does becaplermin have?

immunogenicity risks

= a substance's ability to trigger an adaptive cellular or humoral immune response in the body