ADME Flashcards
What is a drug?
chemical substance that affects physiological function in the body
why are drugs administered?
to restore homeostasis - process maintaining a constant internal environment despite external changes
Define pharmacodynamics.
what the drug dose to the body
Define pharmacokinetics.
what the body does to the drug
What is bioavailiablity?
fraction of administered dose dose of intact drug that reaches systemic circulation
what does bioavailability depend one?
absorption
metabolism
What is absorption?
extent to which the intact drug is absorbed from the gut into circulation
Drugs cross through a bio-membrane via what?
Paracellular
- conective absorption
Transcellular
- passive diffusion
- facilitated diffusion
- active transport
- ion-pair absorption
Describe conective absorption
- small molecules e.g. water urea
- sieving effect - if molecule is small enough, ti will pass through small pores
Describe passive diffusion
- non-charged species
- down a concentration gradient
Describe facilitated diffusion
- Spontaneous passage of molecules/ions e.g. Na+/glucose using ion channel/carrier proteins
- small/charged molecules
Describe active transport
- molecules transported AGAINST concentration gradient using ATP
- structurally specific to carrier molecules
- Na+/K+ ATPase - Na+ OUT , K+ IN
Describe ion pair absorption
- ionised compounds form complexes with oppositely charges ions resulting in neutral species
- move through membrane as a pair
State Lipinski’s rule
- Log P <5
- Mw <500amu
- MAX 10 HBAS
- MAX 5 HBDs
Polar drugs that break these rules are poorly absorbed
State Fick’s Law
Rate of diffusion is directly proportional to the membrane SA concentration gradient is inversely proportional to membrane thickness
- If A (SA) increase
- If C2/C1 increase = faster drug absorption
- If P increase
What is pH partition hypothesis
If pH differs on either side of membrane, the drug will be ionised to different extents
What does hydrophilicity mean?
drugs must be in solution to be absorbed
what does lipophilicity mean?
drugs need to reach active site and cross membrane
Define partition coefficient.
equilibrium between 2 phases depends on affinity for each
- If P increase - drug highly lipophilic
- influenced by - temp and solvent
Describe the simple partition law
Ratio of conc between phases is not the same as predicted for unionised drug
- ionised in aq layer
- unionised in aq and org
Papp = Ptrue x fu
Papp = apparent P at pH
Ptrue - P of unionised drug
What is the distribution equation?
Vd = Q/Cp
Q - total amount of drug in body
Cp - plasma drug conc
Vd - measure of a drug’s tendency to move from blood plasma to another site
Equilibrium depends on what?
P
pH
permeability
Describe Evan’s blue dye
high affinity for plasma albumin that enters intravascular space
- Vd measures plasma volume
- Assess permeability of BBB to macromolecules
- When BBB compromised, albumin bound Evan’s blue enters CNS
What does the amount of protein bound drugs depend on?
free drug conc
protein conc
drug affinity for binding site
What are the effects of extensive plasma protein binding?
- increase amount of drug absorbed
- increased competition for protein binding sites
Describe drug metabolism.
- aids elimination in liver and kidney
- detoxification
- metabolism introduces hydrophilic functionality - excretion in urine results in loss of pharmacological activity
- increase therapeutic action
When the If rate of metabolism decreases what happens?
- increase intensity + duration of drug action
- increased amount of parent drug in plasma - increases toxicity
When the If rate of metabolism increases when happens?
- decrease intensity and duration
- increase toxicity due to production of toxic metabolites
Describe Phase I drug metabolism
Introduces polar functional groups to molecules and provides site for Phase II
Oxidation (+ O atom)
- oxidases located in liver
- enzyme - CYP450
Describe the enzyme CYP450
induction/inhibtion of metabolism of one drug by co-admin of another
What does a CYP450 inducer do and give an example?
- increase activity
- rate of metabolism increase
example - carbamazepine
What does a CYP450 inhibitor do and give an example?
- decreases activity
- rate of metabolism decreases
example - erythromycin
Describe Phase II drug metabolism
Detoxification
Attach polar molecules to Phase I metabolites via transferases
increase hydrophilicity
- increase H-bonding via -OH groups
- conjugated excreted in bite liberating free drug
Via conjugated reaction
- most common - glucuronic acid
- sulphate
- glycine
- glucathione
- methyl
- acetyl
