Pharmacokinetics - Absorption and Distribution Flashcards
Pharmacokinetics
what the body does to the drug
ADME
absorption
distribution
metabolism
excretion
What are the minimum requirements for clinical efficacy?
- absorption: overcome physiological barriers
- distribution: achieve the target with appropriate conc
(overcome internal physiological barriers)
If a drug is not readily absorbed,
it can be difficult to get its concentration up to the therapeutic level
If a drug is absorbed well but distributed to compartments where it is not needed, then
the drug may not have much effect
If a drug is not metabolised well, then
too much of the drug may be circulating
if a drug is not excreted quickly enough, then
it may exist at dangerous levels in the body
Advantages of an oral route of administration of drugs
- convenient
- acceptable
- no special skills
- variety of pharmaceutical solutions for different
patients
Three categories of factors influencing absorption:
- pharmaceutical properties
- physicochemical properties
- physiological properties
Factors influencing absorption: pharmaceutical properties:
- pharmaceutical form
Factors influencing absorption: physicochemical properites:
- solubility
- pH drug (acidic drugs are better absorbed in the
stomach; alkaline drugs better in the intestine) - molecular weight
Factors influencing absorption: physiological properties:
- surface area ( stomach vs intestine; massaging area
after IM admin) - contract time (mouth vs stomach vs intestine)
- concentration of the drug on the absorption site
- absorption site (blood flow, pH)
- interactions (drug-drug, drug-food)
- transport systems (glycoprotein P, amino acids,
transporters)
Factors influencing absorption: oral route:
- drug stability in the digestive tract
- presence of food/other drugs/interactions
- alteration in gastric emptying and intestinal motility
- physicochemical properties suitable for crossing
membranes - resistance to drug metabolism (first pass metabolism)
Oral route
Clinical relevance: drug interactions:
Bioavailability definition
the fraction of (oral) administered drug which reaches the systemic circulation of the patient as an intact drug
Bioavailability equation
oral area under curve/ IV area under curve
AUC = determines the total amount of drug in the systemic circulation
If a drug has an oral bioavailability of 20%, the oral dose needed for therapeutic effectiveness will be how different to the corresponding IV dose?
oral dose needs to be 5x the IV dose
What does bioavailability take into account?
- both absorption and metabolic degredation by enzymes in the gut wall and liver
Absorption and bioavailability
a change in motility changes the amount of absorption of a drug.
true or false?
false
changes the rate of absorption of a drug
first pass metabolism
administration and absorption
administration and AUC
A 55-year gentleman admitted to Emergency department with chest pain. He has a history of angina.
Amongst his other medications he reports that he has some GTN (glyceryl trinitrate) tablets which he was told to use when required for chest pain.
On questioning he tells you that he does not use them as he does not find any benefit from them when he swallows them.
GTN if taken orally is 100% metabolised by first pass metabolism
Distribution: four compartmental model:
How does distribution of drugs occur?
- most drugs transfer by passive diffusion
- across capillary walls down a conc grad
- into interstitial fluid until conc of free drug in
interstitium is equal to that in plasma
Volume of distribution
a measure of how widely a drug is distributed between various body fluids and tissues
Volume of distribution equation
amount of drug in the body (dose)/ measured plasma conc) Cp
For drugs that accumulate outside the plasma compartment, Vd may be
greater than the volume of total body water
Factors influencing distribution
- drug physicochemical properties (solubility)
- drug protein binding
- drug particle size
- blood flow
- pH
- lipid solubility
- plasma protein binding
Lipid Solubility and volume of distribution:
- drugs can have a higher or lower lipid/water solubility
- water soluble are mainly confined to the blood and
body water compartments = lower Vd - lipid soluble drugs are widely distributed to tissues =
higher Vd
routes that avoid first pass metabolism
- IV
- IM
- IS
- inhaled
- transdermal
Plasma protein binding and Vd
drugs highly bound to proteins remain in plasma hence not as much in other compartments so a lower Vd
Plasma protein binding:
- reversible and saturable
- unbound or free fraction distributes
- unbound portion is responsible for clinical effect
Advantage of plasma protein binding drugs
- half-life is longer
- less tablets to take
plasma protein binding
Plasma protein binding: most important protein:
albumin
amount of drug that binds to a protein depends on:
- concentration of free drug
- affinity for the binding sites
- concentration of protein
Factors that increase the fraction of unbound drug:
- saturability
- displacement
- late pregnancy
- renal impairment
- low plasma albumin
Process of the transfer of the drug from the site of administration into the systemic circulation is the definition for:
- absorption
- distribution
- excretion
- metabolism
- volume of distributino
absorption
If you want to convert an IV dose to an oral dose, and the drug has an oral bioavailability of 25%, how much higher would the oral dose need to be?
- 2x
- 3x
-4x
-5x
-10x - same dose
4x higher than IV dose
A water soluble drug would have a volume of distribution higher or lower when compared with a lipid soluble drug?
lower Vd
