Processes of drug absorption Flashcards
how is an aqueous solution absorbed after administration?
drugs must be in solution to be absorbed in the body - this usually requres the process of dissolution. however an aqueous solution already contains the drug in solution so it is the fastest route of administration to get a solution of drug in the GI fluids ready for absorption.
what can affect the absorption of an oral aqueous solution?
you may get some precipitation leading to a suspension of fine particles in GI fluids that must then dissolve before absorption can occur.
how is an aquoes suspension absorbed?
when you take an oral aquoesu suspension you get a suspension of fine particles in the GI fluids - this must then dissolve to form a solution of drug in GI fluids to then be absorbed.
how is an immediate release dosage form absorbed?
the immediate release dosage form will form aggregate granules, then a suspension of fine particles in the GI fluids then a solution of drug in GI fluidswhich can then be absorbed.
what is a solution?
a molecular dispersion formed by 2 or more components which form a 1 phase homogenous system - this can be applied to solid liquid and gaseous state.
whats a solvent?
a solvent is the component that determines the phase of the solution - it usually constitutes the largest proportion of the system.
what are solutes?
other components of the solution that are dispersed as molecules or ions throughout the solvent.
whats a saturated solution?
a solution is saturated when the solute is in equilibrium with the solid phase.
what is solubility?
the maximum mass/volume of solute that will dissolve in a given mass or volume of a solvent at a particular temperature. it is the concentration of solute in a saturated solution at a certain temperature.
whats a supersaturated solution?
a supersaturated solution contains more of the dissolved solute than it would normally contain at a definite temperature. for example salts like sodium thiosulphate dissolve in large amounts at an elevated temperature, upon cooling they fail to crystallize from the solution hence they will be at a higher concentration than usual.
whats molarity?
the number of moles of solute in 1L of solvent
whats molality?
the number of moles of solvent in 1kg solvent.
name some other liquid systems that are not solutions
disperse systems with two phases (emulsions and suspensions)
colloidal dispersions (2 phases)
solutions of macromolecular material like polymer material
association colloids like micelles
microemulsions: 1 phase that is isotropic hence its both homogenous and heterogeneous.
what is dissolution?
the process by which the drug particles dissolve - it must dissolve in the fluid at the site of absorption in order for absorption to occur.
describe the dissolution process
the drug molecules in the surface layer dissolve to form a saturated solution around the particle called the diffusion layer. dissolved drug molecules then pass throughout the dissolving fluid to contact absorbing mucosaand are absorbed. there is continued replenishement of the diffusing layer by further drug dissolution so absorption continues until all the drug is absorbed/dissolved.
The rate of dissolution is determined by the slowest steps, what are the steps involved and which one is rate limiting?
step 1 - release of solute molecules from the solid phase at the interface.
step 2 - solution in contact with the solid becomes saturated (Cs)
step 3 - solute molecules migrate through the diffusion layer - from the solid-liquid interface to the bulk of the solution (C)
the interfacial steps 1 and 2 are virtually instantaneous - the rate of dissolution is therefore determined by the diffusion of the solute through the static boundary layer - stp 3 .
diffusion follows ficks law - what is this?
J = (DxKxAx^C)/h
what can you see from ficks law?
the rate of mass transfer through a diffusion layer is directly proportional to the area for migration and the concentration difference whilst its inversely proportional to the thickness of the diffusion layer.
whats the noyes whitney equation for drug dissolution?
dm/dt = k A (Cs-C)
dm/dt is the mass of solute passed int solution per unit of time
how can dissolution rate be increased?
increasing the surface area of the drug (by reducing particle size), increasing the drug solubility in the diffusing layer and increasing K.
whats the dissolution rate constant?
k = D/Vh
how can dissolution rate be raised?
by increasing k - this would involve drug diffusion coefficient and the diffusion layer thickness.
drug bioavailability relies on both absorption and dissolution. how may these affect the bioavailability?
if a drug has high dissolution rates or is delivered already in solution, the rate of absorption relies on its ability to transverse the absorbing membrane.
Where as if drug dissolution is slow, dissolution may be the rate limiting step of absorption.
what factors affect the dissolution rate?
- surface area of the undissolved solid which is influenced by size of particles, porosity, dispersibility and surfactants.
- solubility is dissolution medium affected by the nature of the solute and solvent and pH
- concentration in the bulk solutionaffceted by the volume of dissolution, absorption and GI fluid available
- diffusion coefficient of the solute in the solvent - affected by the viscosity of the solvent and presence of food.
- thickness of boundary layer - affected by stirring and GI motility.
how does particle size affect dissolution rate?
a reduction in particle size increases the dissolution rate due to increased exposure of solute to solvent. if particle size is les than 0.1 um solubility will also be increased.
sodium sulphate is a decahydrate - how does this affect its dissociation?
initially dissociation in water is endothermic - its solubility increases with temperature rise until 32.5, the solid is then converted into the anhydrous form so dissolution is exothermic.
using the salt form of a drug can increase solubility, however in some cases we may reduce the aqueous solubility through esterification of the parent drug for a variety of reasons?
- masking the taste e.g chloramphenicol palmitate is used rather than base form.
- protect from GI degradation e.g. erythromycin propionate instead of erythromycin although this form is less soluble and less readily degraded.
- facilitate absorption from the GI tract e.g the use of erythromycin proprionate as its more readily absorbed than erythromycin.
how does the salt form increase solubility?
using a salt form rather than a weak acid helps solubility as the salt has a higher degree of dissociation in water leading to an increased interaction with the solvent and increased solubility.
whats the difference between simple and stratified epithelium?
simple epithelium is just one layer of cells whilst stratified epithelium is greater than 1 layer of cells
different parts of the body have different epithelium for different functions. explain how the epithelium is different and why for the alveoli, skin and the gi tract.
- the alveoli has a single layer of squamous epithelium to aid gas exchange - this can make drug absorption accross the airways rapid.
- the skin is very thick with stratified squamous epithelium to provide the body with a protective layer - this also means drug absorption accross the skin is relatively slow.
- the gi tracthas columnar epithelium built for absorption of nutrients making it ideal for drug absorption. within the columnar epithelium are goblet cells that secrete mucus into the GI tract.
what steps are involved when a drug is taken orally?
the oral dosage form must be released from the dosage form and then absorbed across the epithelium into the systemic circulation - the slowest step controls the overall rate of absorption.
what are the two pathways in which a drug may be absorbed accross the epithelium?
transcellular - the drug travels through the epithelial cell - this is the usual pathway.
paracellular - the drug goes between two epithelial cells.
there are a number of barriers a drug must cross to undergo paracellular absorption, what are they?
- tight junctions - the membranes of neighbouring cells are fused together by intimate connections between cell surface proteins forming a band around the entire cell. this is the rate limiting step for the paracellular pathway. tight junctions allow the passage of small hydrophilic molecules generally less than 1000 Da.
- adherens junctions - these connect actin filaments of neighbouring cells together.
- desmosomes - these are the most common cell junction - fibrous proteins cross the gap between cells and anchor keratin filaments in the cytoskeletons together.
- gap junctions - these are intercellular hydrophilic pores. membranes close together but not fused. they allow small molecules like amino acids sugars nucleotides and vitamins to pass directly between neighbouring cells. it also enables direct cell to cell electrical conductance.
describe the purpose and functions of the cell membrane
the cell membrane separates the interior of the cell from the surroundings nd transmits information from the exterior environment and neighbouring cells. it provides shape and anchorage points for attachment to the extracellular matrix and neighbours.
the cell membrane is selectively permeable allowing some substances to enter the cell but not others. it also regulates the transport of moleculesinto and out of the cell using carrier proteins, channel proteins and ion pumps to maintain chemical and electrical potentials.
whats the main obstacle in drug absorption?
the lipid bilayer of the cell membrane is the major obstacle in drug absorption - its hydrophobic nature prevents the passage of most polar and charged molecules.
transcellular absorption involves going through the epithelial cells . what are the different ways in which transcellular absorption can occur?
- passive diffusion - solutes diffuse into cells down a concentration gradient, the drug must be lipophilic enough to partition into the lipid bilayer but not too lipophilic as they must then exit into the cytoplasm.
- aqueous pore - a hydrophilic channel created by transmembraen aquaporin proteins. it allows the transport of very small hydrophilic molecules or small neutral molecules like urea and glycerol.
- facilitted diffusion - a carrier mediated transport of a drug down a concentration gradient - it is selective so the drug must be a substrate of the carrier protein.
- active transport - this is carrier mediated transport of a drug down or against a concentratin gradient. it requires an energy input e.g from the breakdown of atp to adp. once again its selective so the drug must be a substrate.
why do facilatated diffusion and active transport eventually come to s astop?
as they are carrier mediated they can become saturated at which point diffusion would stop.
what is endocytosis?
endocytsois is a minor pathway of drug absoprtion in which the plasma membrane is intenalised hence engulfing extracellular fluid. it can then be released from the vesicle from the basolateral membrane. however sometimes the endosome may fuse with lysosomes and the contents are then degarded by lysosomal enzymes.
what is pinocytosis?
cell drinking - small solutes or fluid is engulfed into the cell - this is a constant process and is adsorptive or receptor mediated.
what is phagocytosis?
engulfement of particles by monocytes and macrophages - it is not relevant to soluble drug absorption but significant for advanced delivery systems.
how does passive diffusion occur?
when a system is not in equilibrium it will move toward equilibrium hence when theres a concentration gradient, flux will occur - flux is proportional to the concentration gradient.
what equation can you use for diffusion and what does tgis tell us about the parameters?
Ficks first law of diffusion - it shows that increasing the membrane thickness will reduce flux whilst increasing the area of the membrane will increase flux.
what does the stokes einstein equation?
the stokes einstein equation relates diffusivity to environmental conditions, properties of the medium through which diffusion occurs and properties of the diffusing molecule.
surfactants can lower viscosity to increase diffusivity.
why is diffusion not a fully efficient process?
molecules are blind and move randomly hence in an ensemble of molecules undergoing diffusion the mean displacement x is proportional to the square root of time.
in ficks first law of diffusion, what does the partition coefficient K quantify?
K quantifies the distributionof a drug between the aqueous phase and the membrane - this is analogous to the oil/water partition coefficient P.
How is the oil/water partition coefficient P claculated?
Mix a drug in water then mix this solution with oil. you then leave this solution to settle and separate the layers that form. measure the concentration of drug in the water and the oil to see how the drug is distributed.
the oil/water partition coeffient is often expressed as logP, what doe the range of values of logP mean?
- lipid soluble drugs have a log p of greater than 0
- water soluble drugs have a log P of less then 0
equally distributed drugs will have a log P of 0.
