PHARM Y1 S2: Pharmacokinetics Flashcards
1
Q
4 stages of pharmacokinetics
A
- absorption
- distribution
- metabolism
- excretion
2
Q
routes of administration
A
- injections: IV, IM, SC (rapid onset, esp IV)
- oral: preferred for Pt compliance
- sublingual (directly into vena cava): avoids stomach acid + gut enzymes
- rectal (rapid if the Pt can’t take orally)
3
Q
why can’t all drugs be taken orally?
A
- some drugs are unstable or inactivated by GIT enzymes
- absorption may be compromised by vomiting or disease
- Pt unconscious
- don’t want systemic effects, only localised
4
Q
properties of drugs that affect distribution
A
- dispersion e.g. from tablet
- lipid solubility and ionisation
- molecular shape and size
- binding to plasma proteins
- quality of blood supply
5
Q
3 ways a drug can move across the membrane
A
- passive diffusion across bilayer (most common but drug must be lipid soluble and therefore not ionised)
- passive diffusion thru aqueous channels
- carrier-mediated transport (when related to endogenous substances)
6
Q
how does ionisation affect drug absorption
A
- ionised drugs are more water-soluble
- unionised are more fat-soluble > can cross plasma membrane more readily
7
Q
how does ionisation affect lipid solubility?
A
- the un-ionised (uncharged) form is more lipid soluble and can cross the plasma membrane
- weak acid drugs are well absorbed in an acidic environment and vice versa
8
Q
how to interpret pKa value of a drug
A
- the pH @ which 50% of the drug has ionised
9
Q
bioavailability
A
- the % of drug that gets into the bloodstream after it is taken compared to IV administration (100%)
10
Q
when might it be desirable to delay absorption of a drug?
A
- when we want a longer, localised effect and prevent it becoming systemic
11
Q
ion trapping
A
- trapping a drug in an area where it has low lipid solubility (ionised)
- occurs when the pH is opposite to the drug e.g. an acidic drug in a basic environment
12
Q
binding of drugs to plasma proteins
A
- when bound to albumin = can’t cross cell membrane = reduces amount of “free”, active drug = prevents excessive concentration and hence toxicity (also decreased GFR)
- drugs can displace each other from albumin binding site = can be problematic b/c changes ratio of free:bound drug = too much/little in blood
13
Q
therapeutic index/window
A
- index: ratio of drug producing adverse effect : desired effect
- window: difference between adverse effect and desired effect
14
Q
purpose of liver in drug metabolism
A
- makes them more water soluble so they can be excreted by the kidneys
15
Q
first order vs zero order elimination kinetics
A
- first order: rate of drug breakdown is proportional to plasma drug concentration (rate of elimination keeps increasing)
- zero order (e.g. alcohol, aspirin): enzymes saturated so rate of drug breakdown plateaus and becomes independent of plasma drug concentration (fixed rate) - need to have longer dosing intervals b/c higher risk of OD, more narrow therapeutic window
16
Q
main sites for drug excretion
A
- kidneys: excretes water soluble drugs & water soluble versions of lipid soluble drugs (post liver metabolism)
- lungs: removes gases + volatile liquids
- GIT: lipid soluble drugs broken down via bile > faeces
- sweat, saliva, tears, mucus, milk
- plasma: contains esterases
17
Q
what is it called when a drug is encased in a secondary substance to ensure it doesn’t damage the structure it passes through?
A
- enteric coating
18
Q
what are P-glycoproteins and which cells are they found in?
A
- efflux pump in plasma membrane
- influences uptake and efflux of drug and hence plasma and tissue concentration
- found on epithelial cells with excretory roles (e.g. GIT, kidneys, brain)
19
Q
what is volume of distribution and how do we calculate it?
A
- volume into which a drug APPEARS to be distributed with a concentration equal to that of plasma
- essentially, high Vd = more distributed throughout body and less left in plasma = less elimination = longer 1/2 life
- Vd = total amount of drug in body / [plasma]
- units are L or L/kg body weight
20
Q
what is loading dose and how do you calculate it
A
- if there is a high Vd, may require a loading dose to “fill up” extravascular sites and achieve the target plasma concentration
- loading dose (mg) = Vd x required plasma drug conc.
21
Q
how is elimination related to volume of distribution?
A
- higher Vd = more distribution of drug = less drug in plasma = less elimination = longer 1/2 life
22
Q
how are drugs eliminated?
A
- can be excreted by kidneys in ACTIVE form
- OR inactivated by liver and then excreted by liver or kidneys
23
Q
what drug clearance rate and how does this relate to Vd?
A
- the volume of plasma cleared of drug per unit time
- higher Vd = lower clearance b/c it’s been distributed throughout the body so takes longer to clear
24
Q
rate of elimination calculation
A
- RE = drug clearance rate (CL) x drug plasma conc.
25
Q
phase I reactions re: enzymatic metabolism of drugs
A
- catabolic/functionalisation e.g. oxidation, reduction, hydrolysis
- expose or introduce a functional group to make it more water soluble for excretion
26
Q
phase II reactions re: enzymatic metabolism of drugs
A
- synthetic, conjugation, anabolic reactions
- b/c after phase I, not all products are inactive/non-toxic
- attaching a large molecule to increase size, make it more water soluble
27
Q
what does “broad substrate specificity” mean with regards to drug metabolism
A
- 1 enzyme may catalyse the metabolism of many diff drugs
- a drug may be metabolised by >1 enzyme isoform (isoenzyme)
28
Q
what is an isoenzyme (isoform)?
A
- catalyse the same reaction but have diff AA sequences, regulation, substrate specificity or kinetic parameters
29
Q
cytochrome p450 (CYP450) family
A
- family of phase I (catabolic) enzymes in liver > expose or introduce a functional group to increase polarity or make it more water soluble to be eliminated
30
Q
examples of interactions w/ CYPs
A
- INHIBITED by grapefruit, pomegranate and cranberry juice = decreased drug metabolism
- ACTIVATED by St John’s Wort = increased metabolism
- codeine gets ACTIVATED by CYPs
31
Q
what is enzyme induction?
A
- some drugs can increase activity of their own metabolic enzymes e.g. alcohol
32
Q
enterohepatic recycling
A
- drugs conjugated w/ glucose may find their way back into the gut
- microflora may cleave the drug and digest the glucose > drug is reabsorbed back into the body and redistributed by liver
33
Q
half life calculation
A
- half life = 0.693 x Vd/CL
- CL = clearance rate
34
Q
why is the half life important?
A
- determines duration of action after a single dose
- determines time needed to eliminate the drug
- determines time required to reach steady state w/ repeat dosing i.e. when the dosage coming in = amount being eliminated
- determines dose frequency to avoid large fluctuations in concentration
35
Q
how to calculate maintenance dose rate
A
- MAINTENANCE DOSE RATE (DR) MUST EQUAL RATE OF ELIMINATION to reach steady state (approx 4-5 half lives)
- DR = clearance rate x target drug conc
36
Q
how does age affect drug metabolism?
A
- foetuses: have less efficient drug metabolism b/c renal function not fully developed
- children: by 2yo can oxidise drugs more rapidly than adults but conjugation reactions develop more slowly
- elderly: may have multi-drug regimens so increased risk of drug interactions. also there are less CYP isoforms expressed so less metabolism
37
Q
how do diseases affect drug metabolism
A
- liver diseases inc. cirrhosis: phase II preserved relative to phase I = slower metabolism
- renal disease: less filtration = slower metabolism
- intestinal diseases e.g. coeliac changes CYP activity and leads to variability in 1st pass eliminations
- viral infections: may suppress hepatic CYP
38
Q
how does genetics impact drug metabolism
A
- many polymorphisms in metabolic enzymes
- leads to extensive vs poor metabolisers
39
Q
why do we give bicarbonate for an aspirin overdose?
A
- aspirin is a weak acid so better absorbed in acidic environments
- therefore giving alkaline bicarbonate means it won’t be absorbed into cells and more will be excreted
40
Q
how does enzyme inhibition relate to drug metabolism?
A
- 2 drugs that are broken down by the same enzyme will compete for the active site if administered together
= decreased metabolism of one or both
