Absorption and Distribution of Drugs Flashcards
define absorption
movement of a drug from its site of administration into blood plasma
define distribution
reversible transfer of drug from one location to another within the body
both tend to involve passage through epithelia e.g. BBB & placenta among other general ones.
what is the mechanisms for passage of the drug through layers of cells (epithelia)?
passive diffusion
through cells – involves diffusion through phospholipid bilayer (only lipid-soluble/hydrophobic drugs)
through intercellular pores – diffusion of small water-soluble (see image)
Facilitated diffusion
limited importance for drugs
Pinocytosis (active transport)
endocytosis of liquids
limited importance for drugs
what is lipid solubility and ion trapping?
NB: the weaker the acid/base the larger the pKa value
Many drugs are weak acids/bases so exist in an equilibrium between ionised & unionised forms - only the unionised form of a base/acid is sufficiently lipid soluble to diffuse through membranes.
Once the unionised molecule of a basic chemical crosses the cell membrane to enter the cell, it becomes ionised again and so unable to cross back over the membrane.
The drugs will tend to accumulate where ionisation is favoured (this depends on pH of environment and the type of drug) as it means they can’t cross the membrane.
NB: Ion trapping does not require any enzyme or energy. It is similar to osmosis in that they both involve the semi-permeable nature of the cell membrane.
what is the Henderson-Hasselbach equation?
pH=pKa+log(A-HA)
when pH = pKa, there is an equal conc. of free acid & dissociated anions HA = A-
what happens to acidic drugs in acidic and basic conditions?
Acidic conditions (low pH) (i.e. stomach): eqm for an acidic drug shifts to more unionised form => readily diffuses through membrane
Basic conditions (i.e. small intestine): eqm for acidic drug shifts to more ionised form => less diffuses through membrane.
Therefore, weak acids are better absorbed from acidic conditions and accumulate in basic condition
what happens to basic drugs in acidic and basic conditions?
Acidic conditions: eqm shifts to more ionised form produced (gains H+ ions) –> less diffuses through membrane –> ionised form becomes trapped
Basic conditions: eqm shifts to –> more unionised form –> readily diffuses through membrane
weak bases better absorbed from basic and accumulate in acidic conditions.
where are basic and acidic drugs more concentrated?
because the pH of blood = 7.4
Acidic drugs concentrate in the circulation
Basic drugs have lower concentration in circulation than other body compartments - tend to stay within tissue once introduced
Ion trapping is the reason why basic (alkaline) drugs are secreted and accumulated into the stomach (for example morphine) where pH is acidic, and acidic drugs are excreted in urine when it is alkaline (drug in ionised form so soluble in urine and can’t leave via absorption into other cells)
what does absorption rate depend on?
Route of administration (e.g. oral, rectal, IV injection etc)
Blood flow at site of administration and high surface area allows for maintenance of high conc. gradient so high rate of absorption
Dose of drug - sets up size of conc. gradient
Active vs passive diffusion through a membrane - influenced drug solubility
hydrophilic/lipophobic - active transport
hydrophobic/lipophilic - passive diffusion
what are the chemical and physiological properties that absorption depends on?
what is bioavailability?
- fraction of total dose administered that reaches plasma (a lot of the drug is removed via first-pass metabolism at liver it is either excreted via faeces or destroyed)
- Only IV route ensures 100% bioavailability - all of the drug is absorbed (bypasses absorption/first-pass metabolism)
what are the routes of drug administration?
Intra-thecal – injection into the spinal canal
Intra-peritoneal – injection into the peritoneum
what are the factors affecting drug absorption from GIT?
Blood flow
Effect of meals on the drug
Dispersal/solubility of drug in gut contents – modify e.g. put in shells to enhance/reduce solubility
lipid solubility of drug
Stability of drug - if drug is unstable in acidic/basic conditions or broken down by digestive enzymes, it cannot be given orally e.g. insulin
Concentration of drug
Time available for absorption - e.g. if a disease causes diarrhoea & vomiting (symptoms) the transit time of drug is affected
Effect of drug on GIT – i.e. if irritant, not given orally
First pass metabolism
what are the factors affecting transdermal absorption?
lipid solubility
formulation
skin thickness – determined by area, age, damage (breaches lead to quicker absorption)
blood flow – maintains conc. gradient and heat increases absorption
hydration – faster absorption; occlusive dressings improve absorption
what are the pharmaceutical interventions that influence absorption?
Particle size – smaller particles = increased rate of absorption
Slow/delayed release preparations – lots of granules contained in capsule - different sizes so dissolve at different rates - less has to be taken over course of day
Dry-powder inhaler – inhale powder to ensure delivery deep into lungs
Enteric coated tablets (slow release) – prevents dissolution in acidic stomach but allows dissolution in basic small intestine
Osmotic mini pumps – semi-permeable capsule - water presence causes osmosis of water into capsule - leads to delivery of a constant drug dose
Distribution dependent on:
(recap)
- blood flow – impact on initial distribution (i.e. brain, heart & liver first as they have high blood flow; then skeletal muscle; then fat)
- lipid solubility & diffusion barriers – drugs more able to cross barriers at brain or placenta if lipid soluble
- tissue binding – some drugs have preference for certain tissue types
- plasma protein binding – i.e. albumin; plasma protein prevents some of drug from moving to site of action - acts as a reservoir - equilibrium of bound to free drug dependent on affinity and strength of bond of drug to plasma protein
