G1 Absorption and distribution Flashcards
what route of administration has no absorption step?
intravenous injection
what does the speed and extent of drug absorption depend on?
- the properties of the drug molecule
- the environment at the site of administration
what do the physicochemical properties of drug molecules determine? what physiochemical properties are we referring to?
- rate of diffusion
- relative lipid or aqueous solubility
- diffusion constant
- partition coefficient (how much drug is soluble in aqueous and lipophilic phases)
state 2 major factors that go towards the rate of diffusion and solubility of drug molecules
- charge or polarity
- size
what state will molecules cross lipid bilayers by passive diffusion in?
only uncharged (unionised form)
state the 2 equilibrium equations of ionisation and unionisation of weak acids and bases
A represents acidic drugs
B represents basic drugs
what does ionisation state depend on?
- pH of environment
- pKa of drug
what is pKa?
pH at which 50% of molecules are in each state (unionised and ionised)
what is the pH in the mouth? what percentage of drugs are ionised here (acidic and basic)?
- 7.4
- acidic drug: 99.5% ionised
- basic drug: 0.5% ionised
what is the pH in the stomach? what percentage of drugs are ionised here (acidic and basic)?
- 1.5
- acidic drug: 0% ionised
- basic drug: 100% ionised
what is the pH in the small intestine? what percentage of drugs are ionised here (acidic and basic)?
- 5.3
- acidic drug: 40% ionised
- basic drug: 60% ionised
theoretically, where should most acidic drugs be absorbed and why? why is this not the case in reality?
theoretically:
- 100% unionised in stomach due to low pH
- should be absorbed the most in the stomach due to being all unionised
reality:
- most drugs are absorbed in the small intestine
- due to high surface area and with a still high proportion of unionisation
what must drugs do to enter a blood vessel lumen?
cross one or more membrane barriers
what factors affect drugs crossing membrane barriers to enter blood vessel lumen?
- structure of barriers (epidermal / mucosal layer, capillary structure)
- concentration gradient across membrane (influenced by blood flow)
- surface area available for transfer
- residence time at membrane
- first pass metabolism
describe what happens when drugs are given orally in terms of first pass metabolism
- the hepatic system takes the drugs to the liver before it enters the systemic circulation
- some of the drug is metabolised by the liver enzymes so the bioavailability of the drug is reduced
describe bioavailability and how it is determined
- a measure of how much drug is absorbed and reaches the systemic circulation
- normally a fraction or percentage
- determined by comparison of a dose delivered by the oral route to the same dose delivered by intravenous injection
in the image, what are tmax and Cmax?
- tmax: time taken to reach maximum concentration
- Cmax: maximum concentration reached
describe the variations in drug absorption across the lifespan
gut maturation isn’t complete in newborns
- GIT is still developing and changing
- when prescribing, this must be considered
intestinal transit time is shorter in newborns and longer in the elderly
gastric pH is reduced in newborns and elderly
- varies in the first few years of life
what can plasma proteins act as? give an example of a plasma protein that does this
- carriers for poorly soluble metabolites
- eg. serum albumin
explain plasma protein binding of drugs
- plasma proteins (eg. serum albumin) act as carriers for poorly soluble metabolites
- many drugs bind to these carrier proteins and are transported around the circulation
- the binding is reversible (so eg. fatty acids are delivered to cells effectively despite lack of solubility)
what do binding interactions with plasma proteins influence?
strongly influence drug pharmacokinetics
describe the process of drug binding to plasma proteins
binding removes drug from free solution
- drug no longer free to diffuse into surrounding tissue
- binding proteins act as a reversible ‘sink’ which increases amount of drug in blood
- aids absorption and transport of drug
- slows elimination
- binding proteins are normally in excess of active drug concs, but saturation can cause non-linear dosing effects
what can very high affinity plasma protein binding cause?
can restrict the drug to the plasma and it won’t reach tissues
in regards to plasma proteins, how can drug interactions be caused?
if drug compete for binding sites on plasma proteins
which is available for distribution: free or bound drug?
free
bound drug will remain in the plasma with plasma protein
describe and explain the dynamic equilibrium between bound and free drug
- thermodynamic motion leads to chance collision
- electrostatic binding forces can be overcome by thermal energy
- 90% of drug bound is equivalent to one molecule being bound 90% of the time
- drug with lower affinity to plasma protein will be free so more available for absorption (leads to higher therapeutic effect)
describe continuous capillaries and what their structure means for aqueous and lipophilic molecules
- they have leaky junctions between endothelial cells
- aqueous molecules can cross these junctions
- lipophilic molecules can cross the cells (they don’t need gaps)
describe fenestrated capillaries and what their structure means for aqueous molecules
- they have large pores
- aqueous molecules can cross these and be distributed
describe transcytosis
- brings proteins and macromolecules across endothelium
- some vesicles may fuse to create temporary channels
what is meant by teratogenic?
leads to birth defects in baby
what is meant by embryotoxic?
leads to miscarriage
describe what kinds of drugs have access to the foetus via the placenta and which do not
- lipophilic drugs have ready access
- drugs with high plasma protein binding affinity do not have access
describe the diffusion of drugs into breastmilk
- alveolar apical cells form a tight-junction limited lipid barrier between capillaries and alveolar lumen
- diffusion into milk therefore limited by lipophilicity and size
describe drug accumulation in tissue depots
- drug can accumulate in binding sites or intracellular organelles
- may be target site, other proteins, lipid compartments etc.
- time course for accumulation depends on perfusion of organ system and drug pharmacokinetics
- adipose tissue is a major reservoir for lipophilic drugs
- redistribution can occur over time
describe adipose tissue
- located in skin (subcutaneous), around internal organs (visceral), breasts and in bone marrow
- composed of adipocytes: cells with large intracellular vacuoles filled with lipids
- lipid soluble drugs can accumulate in this reservoir
- increase in adipocyte size (and maybe number) with obesity
what different compartments are drugs distributed around the body in?
- extracellular fluid (plasma, interstitial fluid, lymph)
- intracellular fluid (cell contents)
- transcellular fluid (CSSF, peritoneal, intraocular, synovial etc.)
- fat
- bound to protein
what is volume of distribution?
theoretical volume of plasma that would accommodate total drug amount at the measured plasma concentration
volume of plasma fluid
3 L
volume of extracellular fluid
12 L
volume of total body water
40 L
what does a volume of distribution over 40 L indicate?
some storage of drug in tissues
what does a volume of distribution under 15 L indicate?
drug is largely restricted to plasma and interstitial fluid
variation in distribution throughout lifespan
body composition changes with age
- higher fat : lean tissue ratio in infants
- obesity increases with age
- relative volume of fluid compartments varies (volume of distribution tends to be higher in infants)
- pregnancy adds placental and breastmilk compartments
- plasma protein synthesis in the liver declines with age
- renal function affects tissue fluid volumes (oedema and diuretic use)
