L5: Pharmacokinetics II Flashcards
What % is IV administration bioavailavable?
100%
What is meant by first pass metabolism?
- pre-systemic elimination
- drug is absorbed in GIT and goes into portal circulation and is metabolised by liver
- Drug may no longer work
What is an exipient?
inactive substance used to carry an active substance (what drug is carried in)
Why would you use a hydrophilic dispersant (excipient), such as lactose?
- Fast release as it is water soluble
Why would you use an inactive substance, such as talcum, as an excipient?
- slow release (not water soluble)
Which is more important when considering drug absorption:
size of molecule or route of admin?
- route of admin
Absorption of drugs by all routes is dependant on?
- lipophilicity of drug (not an absolute though)
- pH of drug and enviro
- SA
- 1st pass metabolism
- vascularity and disease process
- presence of ingesta
- microbial metabolism (species dependent)
How are drugs absorbed?
- Need to be lipophilic and hydrophilic, though more lipophilic
- This is so they can pass through cell membranes and dissolve in our aqueous body fluids
- Charged molecules leave circulation via phenustrates in capillaries => interstitial fluid => membrane => become uncharged => target organ
- Non-polar lipophilic best at crossing membranes
Can strongly ionised compounds cross membranes?
- helllll nawwww
- The greater the difference b/w drug pH (pKa) and enviro pH, the more ionised the drug is
Drug distribution reflects?
- ability of the drug to cross lipid membranes (lipophilicity)
- the extent that the drug binds to tissue and fluid constituents
How do we calculate volume of distribution (Vd)?
- Vd = Dose (mg/kg)/Co
- Co is concentration at time zero
- only time Co is accurately known is immediately after IV injection
How do we calculate a loading dose (LD)?
- LD = Vd x target c (concentration steady state aka Css)
- Target c is determined by dose-response curves
What is the pharmcokinetic definition of metabolism?
- Essentially the conversion of a lipophilic compound to a more hydrophilic one in order to facilitate elimination
Describe phase I reactions (presynthetic)
- Conjugation of a chemical group or molecule via hydroxylation, oxidation, reduction or hydrolysis
- adding charge
Describe phase II reactions
- Involves the conjugation of endogenous hydrophilic compound
- no fucking idea what that actually means
What are the sites of drug metabolism for the different phases?
- Phase I primarily hepatic
- Phase II hepatic, renal and gut wall
- For many drugs metabolism is proportional to hepatic blood flow
What factors may affect drug metabolism?
- species, breed
- induction or inhibition of HME (hepatic microsomal enzymes)
- hepatic function
- age
- diet
- obesity
- concurrent meds
What are the major modes of elimination?
- hepatic excretion -passed in faeces
- renal excretion -passed in urine
- miscellaneous -exhalation, sweat etc
Will glomerular filtration remove those drugs or metabolites that are bound to proteins present in blood plasma?
No. Will only remove unbound drugs
Only unbound drug is able to equilibrate across membranes
True or False?
True
What is clearance?
- the volume of blood (or plasma) from which a drugf would appear to be removed per unit time to account for its elimination
- is the sum of all modes of metabolism/elimination
- Usually expressed in units of mL/min/kg or L/hr/kg
- affects half-life and accumulation
- Cl = [urine] x rate of urine formation
/
[plasma]
A drug candidate is very hydrophilic and does not bind to plasma proteins- is it likely to have a short or long half-life?
- It will have a shorter half life
- Lipophilic drugs may have an increased volume of distribution (Vd) with a prolonged half-life
- Lipophilic = distributes through membranes with preference for adipose tissue and muscle (greater volume of distribution)
- Hydrophilic = remains mostly in blood compartment until the drug is eliminated
- An increase in the volume of distribution of a drug will generally increase its elimination half-life
- A decrease in volume of distribution with an increase in elimination clearance will generally decrease elimination half-life
Bioavailability is determined using? (parameter)
- AUCt
- “ratio of area under the curve”
