Basic science Flashcards
What is the epidermis?
Outer layer of the skin
Made out of stratified cellular epithelium
What is the Dermis?
Layer below the epidermis
Made of connective tissue
Where does the epidermis form from?
The Ectoderm
Ectoderm cells form single layer Periderm
Gradual increase in layers of cells
Periderm cells cast off
Where does the dermis form from?
Mesoderm
What are melanocytes?
Pigment producing cells from neural crest
What do Blaschko’s lines show?
Developmental growth patterns of skin
DOES NOT follow vessels, nerves or lymphatics
What cells are found in the epidermis?
Keratinocytes (95% of epidermal cells) - contain keratins
Melanocytes
Langerhans
Merkel cells
What are the four layers of the epidermis?
from superficial to deep
Keratin layer
Granular layer
Prickle cell layer
Basal layer
What happens to Keratinocytes?
Migrate from basement membrane to the surface
allows for continuous regeneration of epidermis
28 days from basal layer to keratin layer
Describe the basal layer of the epidermis.
Usually one cell thick
Small cuboidal
Lots of intermediate filaments (keratin)
Highly metabolically active
Describe the prickle cell layer of the epidermis.
Larger Polyhedral cells
Lots of desmosomes ( connections)
Intermediate filaments connect to desmosomes
Describe the Granular layer of the epidermis.
2-3 layers of flat cells
Larger Keratohyalin granules - contain structural filaggrin & involucrin proteins
Odland bodies (lamellar bodies)
origin of cornified envelope
cell nuclei lost
Describe the Keratin layer of the epidermis.
tight waterproof barrier
Corneocytes overlap non-nucleated cell remnants
insoluble cornified envelope
80% keratin and filaggrin
Lamellar granules release lipid
also contains filaggrin, involurcrin and keratin
Give examples of oral mucosa membranes.
Masticatory - keratinised to deal with friction
Lining mucosa - non - keratinised
Specialised Mucosa - tongue papillae ( taste)
Give examples of Ocular mucosa membranes?
Lacrimal glands
eye lashes
Sebaceous glands
What happens to Melanocytes?
they are pigment producing dendritic cells found in the basal layer and above
Migrate from the neural crest to the epidermis in first 3 months of foetal development
What is the function of Melanocytes?
contain melanosomes
converts tyrosine to melanin pigment ( Eumelanin and Phaeomelanin)
Melanin absorbs light
What happens to ‘full’ melanosomes/ melanin granules?
Transferred to adjacent keratinocytes via dendrites
form protective cap over nucleus
What is Nelson’s syndrome?
Disorder where melanin stimulating hormone is produced in excess by the pituitary
Where do Langerhans cells originate from?
Bone marrow ( mesenchymal origin)
Where are Langerhans cells found and what is there function?
a type of dendritic cell found in the Prickle cell level in epidermis and also found in dermis and lymph nodes
ii. it is the main skin resident immune cell and are antigen presenting cells they carry out the following functions:
1. act as sentinels in the epidermis
2. process lipid Ag and microbial fragments and present them to effector T cells
3. They help to activate T cells
different types of dendritic cells are localised in different skin compartments.
Where are Merkel cells found?
Basal layer of epidermis
Found in between keratinocytes & nerve fibres
what is the Pilosebaceous unit?
Consist of:
Arrector pili muscle
Sebaceous gland
External root sheath
cortex
Medulla
Papilla of hair follicle
Internal root sheath
Matrix
Hair shaft
What are the phases of hair follicle growth?
Anagen = growing
Catagen = involuting
Telogen = resting
What are the types of hair in utero?
Lanugo
What are nails made of?
Specialised keratins
What is the role of the Dermo-epidermal junction?
Key role in epithelial - mesenchymal interactions:
- Support, anchorage, adhesion, growth and differentiation of basal cells
- Semi- permeable membrane acting as barrier and filter
What does the Dermo epidermal junction consist of?
Lamina Lucida
Lamina densa
Sub- lamina densa zone
What cells are found in the dermis?
Mainly fibroblasts
Macrophages
Mast cells
Lymphocytes
Langerhans cells
What fibres are found in the dermis?
Collagen
Elastin
Where are lymphatic vessels found in the skin?
Found in sub - epidermal meshed networks
Smaller non contractile vessels carry lymph to larger contractile lymphatic trunks
drain plasma proteins, extravasated cells and excess interstitial fluid
What is the function of Pacinian corpuscles?
Detect pressure in the skin - part of somatic nervous system
What is the function of Meissners corpuscles?
Detect vibration in the skin - part of somatic nervous system
Which nervous systems are free nerve endings associated with in the skin?
somatic nervous system
What is the pilosebaceous unit?
consists of Epidermal component plus dermal papilla of skin
What are Apocrine sweat glands?
Develop as part of pilosebaceous unit
Found in the Axillae and perineum
Dependent on Androgen
produces oily fluid - turns to odour after bacterial decomposition
What are eccrine sweat glands?
Found in whole skin surface ( palms, soles and axillae)
supplied by sympathetic cholinergic nerves
stimulated by mental, thermal and gustatory
function is to moisten palms/soles to aid grip
What are the functions of the skin?
Barrier function
metabolism and detoxification
Thermoregulation
immune defence
communication
sensory functions
What happens if the barrier function of the skin fails?
Fluid loss leads to dehydration
protein loss leads to hypoalbuminaemia
Infection risk higher
What happens if Thermoregulation function of the skin fails?
Heat loss leads to Hypothermia
What happens if immune defence of skin fails?
Spread of infection
What happens if metabolic function of skin fails?
Disordered thyroxine metabolism occurs
what happens if sensation function of skin fails?
Pain can be felt more often
How does the skin carry out its barrier function?
Two-way barrier: epidermis
Physical: stops friction, UV radiation
Chemical: stops irritants, allergens and toxins effecting body
Pathogens prevented from entering body
How does the skin carry out its metabolic function?
involved in vitamin D metabolism
Involved in thyroid hormone metabolism
What occurs in Vitamin D metabolism?
Cholecalciferol is converted to vitamin D 3 via UV light ( 290 - 320 nm)
Vitamin D3 stored as hydroxycolecalciferol in liver or converted to 1,25-dihydroxycholecaliferol in kidney
What occurs in thyroid hormone metabolism?
Thyroxine(T4) is converted to Triiodothyronine (T3)
20% of this conversion occurs in thyroid while rest occurs in peripheral to thyroid tissues including the skin
How does the skin carry out its immune defence function?
contains Langerhans’ and T cells
Epidermis and dermis interact
Non specific responses
what is the role of keratinocytes?
- structural and functional cells of the epidermis
- sense pathogens via cell surface receptors and help mediate an immune response
- Produces antimicrobial peptides (AMPs) that can directly kill pathogen. AMPs are found in high levels in skin of patients with psoriasis
- Produce cytokines and chemokines
what T cells are found in the epidermis/dermis?
mainly CD8+ T cells are found in the epidermis
CD4+ and CD8+ T cells are found in the dermis
NK cells also found
CD4 Th cells include :
Th1 for psoriasis
Th2 for atopic dermatitis
TH17 psoriasis and atopic dermatitis
where are T cells produced?
bone marrow
where are T cells sensitised?
thymus
what is the role of CD4+ helper t cells?
Th1 - activate macrophages to destroy microorganisms
Th2 - helps B cells to make Antibodies
what do CD4+ TH1 release?
IL2
IFN gamma
what do CD4+ Th2 release?
IL4
IL5
IL6
what are the roles of CD8+ (CTLs)?
can kill infected cells directly
important protection against viruses and cancer
which dendritic cells are found in the dermis?
- Dermal dendritic cells
2. Plasmacytoid dendritic cells (pDC)
what is the role of dendritic cells?
- antigen presenting
2. secrete cytokines during the inflammatory response
what do Plasmacytoid dendritic cells produnce?
Interfeon alpha
these cells are found in diseased skin
which immune cells are found in the dermis?
- Macrophages
- Neutrophils
- Mast cells
- T cells
- NK killer cells
- Dendritic cells
which immunoglobulin activates Mast cells?
IgE
what mediators are released by mast cells when they are activated by IgE ?
- Preformed mediators: Tryptase, Chymase, TNF and histamine
2. Newly synthesised mediators: IL (3,5,6,8,13,16,18), TNF, TGFbeta, Interferon gamma, PGD2,PGE2, LTB4,LTC4
which immune cells are found in the epidermis?
- Langerhans cells
2. t cells - especially CD8+
which chromosome is the Major histocompatibility complex found on?
6
what is the pathogenesis of psoriasis?
- Keratinocytes under stress release factors that stimulate pDC to produce interferon alpha
- Keratinocytes also release IL-1/IL-6 and TNF
- Chemical signals activate Dendritic cells which migrate to skin draining lymph nodes to present and activate T cells (Th1 and Th17)
- cytokines attract T cells to the dermis and then release IL 17A/17F/22
- these interleukins stimulate Keratinocytes proliferation, AMP release and neutrophil- attracting cytokines
- CD8+ cells also contribuete to the pathogenesis
- dermal fibroblasts become involved which increase keratinocytes and epidermal growth factors
what type of hypersensitivity reaction is an allergy?
Type I (immediate) hypersensitivity
which receptor does IgE bind to on mast cells to cause a Type I hypersensitivity reaction?
FCER1
what do Type I (immediate) hypersensitivity reactions cause?
Early response - wheal and flare
Late response - cellular infiltration, nodule
which immunoglobulins mediate type II & III hypersensitivity reactions?
IgG and IgM
what are Type II mechanisms important in?
Autoimmunity and transplantation e.g. Haemolytic disease of the newborn and blood transfusion recipients
which cells mediate Type IV hypersensitivity reactions?
Th1 cells
compare Type I to Type IV hypersensitivity reaction?
Type IV is a delayed T cell mediated response
Type I is an immediate IgE mediated response
what reaction is caused by Type III hypersensitivity in skin testing?
arthus reaction
Which two reaction types are most commonly seen in the skin?
Type I and type IV
what is released in a Type I hypersensitivity reaction?
- Histamines
- heparin
- Leukotrienes
- prostaglandins
what are the main phases of type IV hypersensitivity reaction?
A. Initial sensitisation phase
- Dendritic antigen presenting cell (langerhans cell in skin) migrates to regional lymph nodes
- APCs interdigitates with T-cells to produce expansion of specific memory T cell pool in the lymph node
- Specific memory t cells released and distributed throughout circulation to encounter antigen in future
B. subsequent challenge with antigen
- APCs bind to antigen and migrate to dermis where they encounter and activate specific t cells
- Release of cytokines from T cells leads to further cell recruitment and typical cellular infiltrate histology.
- antigen also activates macrophages which stimulates mast cells to increase vascular permeability
Give examples of cutaneous type I hypersensitivity reactions.
- Urticaria - red wheals develop resembling nettle rash
- Angio-oedema - deeper cutaneous reaction than urticaria causing swelling of sub cutaneous tissues, including mucuous membranes e.g. lips
- Anaphylaxis - life threatening generalised reaction which has urticaria and/or angio-oedema, laryngeal swelling, bronchospasm or hypotension
Give examples of cutaneous type IV hypersensitivity reactions.
- allergic contact dermatitis
- photo-allergy- delayed reaction to sun-exposure
- skin response to bacteria, fungi and virsuses
- abnormal delayed response in atopic eczema
what are the main routes in the skin for drug administration?
- Topical - applied to skin surface
- Transdermal - drugs diffusing across the skin and subsequently entering dermal capillaries for distribution to the body tissues and organs
- Subcutaneous - skin is bypassed by the drug it is injected in a small volume of vehicle directly into the fat between skin and muscle
What is the difference between topical and transdermal/subcutaneous route of drug administration?
Topical route - drug is required for local effects. also used to treat underlying tissues
transdermal/subcutaneous - for systemic effects
Give examples of drugs used in these three skin routes for drug administration.
- Topical - NSAIDS in form of lotions ,creams, ointments e.g. diclofenac diethylammonium
- transdermal e.g. GTN patch
- Subcutaneous - herapin and insulin
Besides the skin what are the other epithelial routes of drug administration?
- Airways e.g salbutamol, beclomethasone dipropionate
- conjunctival sac - chloramphenicol drops for bacterial infection
- nasal mucosa- azelastine for seasonal allergies
- vaginal - clotrimazole for fungal infection
what are the layers of the skin
- Epidermis superficial to deep :
i. stratum corneum - consists of corneocytes
ii. stratum lucidum - only found in thick skin of the palms, soles, and digits.
iii. stratum granulosum (granule layer)
iv. stratum spinosum (spinous layer)
v. stratum basale ( basal layer) - Basement membrane
- Dermis
- subcutaneous layers
what layer of the skin is the most significant barrier to drug distribution?
stratum corneum - outermost layer
what is a corneocytes?
terminally differentiated keratinocytes
what does the ‘brick and mortar’ model of the stratum corneum refer to?
bricks’ - corneocytes containing keratin macrofilaments embedded in a filaggrin matrix surrounded by a cornified (protein) cell envelope. Corneocytes are highly cross linked by protein ‘rivets’ (corneodesmosomes) providing tensile strength
‘mortar’ - multiple lamellar structures of intercellular lipids (mainly ceramides) . A largely hydrophobic ‘intercellular glue’ that can also act as a reservoir for lipid-soluble drugs (e.g. topical glucocorticosteroids
what are the main two principle routes which a drug may diffuse through the skin?
- Intercellular pathway - between the corneocytes i.e. the ‘mortar’ - main form
- Transcellular pathway - enter through and leave the layers of corneocytes i.e ‘the bricks’
what is the equation to calculate the rate of absorption (J) of a topically applied drug?
J = KpCv
Kp = permeability coefficient Cv = concentration of drug in the vehicle (a simplification of the concentration gradient across the barrier)
what two factors does Kp represent when calculating the rate of absorption of a drug?
i. The drug
ii. the barrier and their interactions:
Km- partition coefficient
D- diffusion coefficient
L-length of diffusion pathway
can rewrite the equation to be: J = (DKm/L)Cv
why is the concentration gradient of the skin not taken into consideration when calculating the rate of absorption?
The skin, the concentration of the drug in deep skin layers is assumed to be negligible in comparison to the concentration of the drug in the vehicle
what must you take into consideration when calculating the distance of diffusion pathway in the intercellular route in the skin?
not just the thickness of the stratum corneum but also the distance over which drug must diffuse following the convoluted route between corneocytes
what important factors determine the effect of the vehicle(base) has on drug absorption?
- Dissolved concentration of the drug in the vehicle (Cv)
2. Movement of the dug from vehicle into the stratu, corneunm and deeper (Km)
State the solubility of a:
- Lipophilic drug in a lipophilic vehicle
- Lipophilic drug in a hydrophilic base
- Hydrophilic drug in lipophilic base
- hydrophilic drug in hydrophilic base
- soluble in both vehicle and skin and partitions between the two
- More soluble in skin and preferentially partitions to it resulting in high skin penetrance
- limited solubility in both and so partitions weakly
- Soluble in vehicle but no skin and remains on surface
when describing the skin diffusion pathway it is….?
hydrophobic
For drugs applied topically, the fraction within the vehicle solubilized (Cv), not that undissolved, provides the driving force for skin penetration
TRUE OR FALSE?
TRUE
what is the role of excipients within the vehicle ?
increases drug solubility and absorption
give examples of factors which can increase absorption?
Skin factors
- site of application Rank permeability is: nail «_space;palm/sole < trunk/extremities < face/scalp < scrotum)
- hydration - water and occlusion dressings
- integrity of the epidermis (absorption influenced by trauma, inflammation / other disease processes
Drug factors
- Drug concentrations and properties
- the drug salt
- the vehicle
when would glucocorticoids be prescribed agents for skin conditions?
ii. what other properties aside from anti-inflammatory do they possess?
administered topically, largely for a local anti-inflammatory effect upon the skin
e. g. atopic eczema, psoriasis and pruritus
ii. immunosuppressant and vasoconstriction and anti-proliferative action on keratinocytes and fibroblasts - useful in diseases that involve hyper-proliferation and an immunological component.
How are glucorticoids classified in the uk?
mild, moderate, potent and very potent
what are the side effects of a very potent glucorticoid?
- 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)
explain the molecular mechanism of a glucorticoid
- Glucocorticoids are lipophilic molecules - enter cells by diffusion across the plasma membrane.
- Within the cytoplasm, they combine with GR producing dissociation of inhibitory heat shock proteins (e.g. HSP90). 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 promotor region of specific genes
- The transcription of specific genes is either ‘switched-on’ (transactivated) or ‘switched off’ (transrepressed) to alter mRNA levels and the rate of synthesis of mediator proteins
how is the drug administered in subcutaneous administration?
Drug delivered by a needle inserted into the adipose tissue just beneath the surface of the skin - 45 degrees
how does the drug reaches systemic circulation via subcutaneous administration?
diffusion into:
- capillaries
- lymphatic vessels
what are the advantages of subcutaneous administration?
- absorption is relatively slow due to poor vascular supply - can be disadvantage too
- suitable administration for both protein and oil-based drugs e.g. insulin and steroids
- relatively simple and cheap
- avoids degradation of drugs (phase 1 metabolism of liver)
what are the disadvantages of subcutaneous administration?
injection volume limited
how are drugs usually administered in the transdermal route? (TDD)
- via adhesive patch applied to skin
2. rate is controlled by a drug release membrane
which drugs is transdermal drug delivery suitable for
- low molecular weight
- moderately lipophilic
- potent
- brief half life
e. g. nictoine, GTN, fentanyl and scopolamine
what are the advantages of TDD?
- steady rate of drug deliverance
- decreased dosing frequency
- avoids phase 1 metabolism
- user friendly and painless
what are the disadvantages of TDD?
- allergies
- few drugs can be used like this
- cost
which grow faster toenails or finger nails?
fingernails
which cells in the skin are responsible for vitamin D metabolism?
keratinocytes
which layer is responsible for epidermal proliferation?
basal cell layer
Eccrine glands are the commonest sweat glands on the face true or false?
true
Sebaceous glands are attached to hair follicles in the skin true or false?
true
Apocrine glands are affected in acne true or false?
false - sebaceous glands are
A main function of apocrine glands is cooling of the skin true or false?
false its main function is involved in scent
