biological aspects of drug delivery Flashcards
what is the main pathway for transport around the body
circulatory system
what is extravasation
leakage of blood/lymph/any fluid from blood vessel and into surrounding tissue
functions of lymphatic system
-drain excess interstitial fluid from tissue spaces
-transport dietary lipids and vitamins absorbed by GI tract
-carry out immune responses against microbes and abnormal cells
why are lymphatic capillaries leaky
so interstitial fluid can move in easily, no tight junctions, gaps between cells and overlapping endothelial cells
how is interstitial fluid formed
components of blood plasma filter through capillary walls to form interstitial fluid
How does lymph collect in lymphatic capillaries
flows up ducts past valves, filtered through lymph nodes, returned to circulation by larger lymphatic vessels/ducts
describe the anatomy of epithelium
tissue consisting of cells arranged in sheets, cells closely held together by cell junctions to limit intracellular space between membranes, covers body surface and lines hollow organs
epithelial tissue function
selective barrier- limit/aid substance transfer
secretory surface- release products from cells
protective- prevent physical/chemical injury
describe the apical surface in the epithelium
free surface, cilia/microvilli can be present
describe the lateral surface in the epithelium
free adjacent cells, cell junctions may be present
describe the basal surface in the epithelium
cells adhere to ECM, cell junctions may be present
name the 5 main types of cell junctions
tight junctions, gap junctions, adherens junctions, desmosomes, hemidesmosomes
describe each cell junction
how can cell junctions effect drug delivery
can restrict passage of materials between cells
limit materials from lumen passing unrestricted into underlying tissue
block materials from underlying tissue escaping into environment
prevent migration and exchange of membrane proteins
permeable to water
describe the structure of the basement membrane
thin extracellular layer below epithelium, 20-25nm thick, meshwork of fibrils
function of basement membrane
restricts passage of particles/materials through epithelial, provide support and point of attachment for overlying epithelium tissue
what is basal lamina and where is it secreted
secreted by epithelial cells, contains protein, glycoproteins, proteoglycans
what is reticular lamina
contains proteins secreted by underlying connective tissue
2 main types of epithelial tissue
covering/lining, glandular
where can covering and lining epithelium be found
outer covering of skin, internal organs, blood vessel/ducts lining, interiror of respiratory/digestive/reproductive/urinary systems
ways to classify covering and lining epithelium
arrangement of cells in layers, cell shape
describe how covering and lining epithelium can be classified according to layers
simple- single layer, roles in diffusion/osmosis/filtration/secretion/absorption
pseudostratified- appearance of layers due to uneven distribution of cells, not all cells reach apical surface
stratified- 2 or more cell layers, protects underlying tissue where tearing is common
describe how covering and lining epithelium can be classified according to cell shape
squamous cells- flat/thin ‘tiles’, allow rapid passage of substances
cuboidal- cubes/hexagons, may have microvilli, function in absorption/secretion
columnar- tall/thin, protect underlying tissue, apical surface may have cilia/microvilli, specialised for absoroption/secretion
what is the endothelium lining of blood vessels composed of
simple squamous epithelium
name 3 types of capillaries and where each type can be found
continuous- endothelial cells form continuous tube with cell junctions, continuous underlying basement membrane, contains many intracellular vesicles
-brains, lungs, muscle
fenestrated- plasma membranes of endothelial cells contains pores
-kidney, villi in small intestine, endocrine gland
sinusoid/discontinuous- large fenestrations present in endothelial cells, large intracellular clefts, incomplete/absent basement membrane
-liver, spleen, anterior pituitary
before entering the circulation, name the layers that a drug has to cross
epithelia- layer of cells for protection
basal lamina- network of proteins produced by epithelia as a barrier
endothelia- specialised epithelia cells lining blood vessels
where are most drugs metabolised
liver
what is bioavailability
amount of an administered dose of drug that reaches systemic circulation intact and rate it occurs
what is bioavailable dose
fraction of administered dose of drug that reaches systemic circulation unchanged
barriers a drug has to pass before entering blood/lymphatic capillaries
epithelium, basal lamina, endothelium
what is paracellular route
between cells, through cell junctions, small contribution to drug absorption
passive, requires conc gradient
what is transcellular route
across/through cell membrane, mostly diffusion, major contribution to drug absorption
how does the small intestine epithelium create a large surface area for absorption
folds in villi/microvilli
what is the rate limiting step in paracellular absorption
transport across tight junctions, number of tight junctions decrease down GI tract
what can tight junctions be modulated by
permeation enhancers, increases cell membrane permeability and drug bioavailability
structure of transcellular absorption
materials pass apical membrane, epithelial membrane made of lipids, lipid film acts as aqueous pores
what is the main function of lipid films
acts as small aqueous pores, provides flow of water through membrane
describe the rate of absorption in passive diffusion
first order, directly proportional, increased conc of drug in gut will increase rate of absorption in intestinal lumen, drug readily transported away in bloodstream
what does fick’s first law of diffusion describe
relationship between diffusion rate and factors that affect diffusion
what 3 factors affect the rate of diffusion
surface area of membrane, membrane thickness, concentration difference
what does fick’s first law state
rate of diffusion is proportional to surface area and concentration difference and inversely proportional to membrane thickness
rate of diffusion a (SA x conc diff)/thickness
describe the rate of absorption in carrier mediated uptake
rapid increase then plateaus, plateaus when carrier proteins become saturated
types of carrier mediated uptake
active transport and facilitated diffusion, useful for hydrophilic molecules
adaptation for carrier mediated uptake
lots of embedded membrane proteins to aid transport
what is symport and antiport
symport= movement of 2 molecules in the same direction
antiport= opposite direction
problems with carrier mediated transport
limited number of carrier proteins per cell, rate plateaus when proteins saturated, some carriers only appear in certain locations, competitive inhibitors
name 3 types of vesicular uptake/endocytosis
phagocytosis, pinocytosis, receptor-mediated endocytosis
what is phagocytosis
engulfment of particles, immune system, vesicle around foreign cells
what is pinocytosis
engulfment of small droplets of extracellular fluid by membrane vesicles, fluid phase endocytosis, forms vacuole, low efficiency
what is receptor-mediated endocytosis
uses cell surface receptors, binds ligand to form ligand-receptor complexes, conformational changes initiated, invagination of membrane forming coated vesicle
what is endocytosis
uptake of material in membrane bound vesicles, after uptake vesicle usually transports to other organelles for degradation (eg. lysosomes)
describe what happens in lymphatic uptake
fats formed into micelles with bile salts, triglycerides break down into glycerol and fatty acids, mucosal cell reassembles triglycerides to combine with cholesterol =chylomicrons, chylomicrons enter lacteals in villi and transported away
what happens in the mucosal cell in lymphatic uptake
triglycerides reassembled and combined with cholesterol to form chylomicrons
describe the two ways fat is absorbed
short/medium= taken up through epithelium, endothelium, circulatory system, portal vein, liver
long chain= triglycerides>chylomicrons>lymph vessels, packaging idk
problems/considerations with lymphatic uptake
not efficient, capillaries have low carrying capacity, lymphatics have lots of fatty material but very slow flow
can double the rate of uptake for very lipophilic drugs
why dont all drugs absorb via lymphatic uptake if many are lipophilic
flow differences between circulatory and lymphatic system, capillary has fast flow of blood, lymph vessels are slow and no pump, fat content of diet can effect uptake routes of drugs
list the types of drug uptake routes
transcellular, paracellular, passive diffusion, carrier mediated, vesicular uptake, vascular, lymphatic
