drug movement Flashcards
what is pharmacodynamics?
what the drug does to the body
- involves drug acting at particular drug target resulting in activation or inhibiting of cellular signalling pathway
what is pharmacokinetics?
what the body does to the drug
- involves how easily the drug is absorbed in the body & how distributed in certain tissues & how metabolised
how can we characterise pharmacokinetic processes?
by calculating the measures such as the apparent volume of distribution (Vd) , elimination half-life, clearance or the bioavailability of a drug.
how can we characterise pharmacodynamics?
by looking at the affinity, potency or efficacy of a drug and calculating such things as Ki, EC50, or Emax
what is goal of pharmacokinetics?
finding dose that will be safe & have high efficacy
what is ROAand what is used to help determine?
routes of administration - used to help work out dose
- some ROA straight forward like IV, some are more complicated like oral
what is IV ROA?
drug goes straight into blood circulation, avoiding first pass metabolism
what is oral ROA?
goes through GI tract which means drug highly metabolised and less efficacious
e.g. salbutamol given orally would be less efficacious
what is the effect of increasing plasma concentration of drug?
- you want the drug to have plasma concentrations that makes therapeutic effects
- if plasma concentration increased then makes toxic effects
- if plasma concentration decreased then sub-therapeutic effects
what is EC50 and on graph of plasma concentration & response what does it mean if:
a) below EC50?
b)between EC50 & Emax?
EC50 = the half life
a) sub-therepeutic
b) therepeutic
what does NOAEL & LOAEL stand for on graph of plasma concentration & response/adverse effects and what are they used for?
NOAEL = no observed adverse effect level
= it’s the concentration in plasma when no adverse effects
LOAEL = lowest observed adverse effect level
- they’re measured to try help map out range where drug efficacious = the therapeutic window
what does a narrow therapeutic window mean?
only small window of benefits before starts having severe damaging affects
why do we do pharmacokinetic analysis?
to help us determine the dose (e.g., mg of a drug) that will result in the appropriate blood plasma concentration (mg/L or mol/L) to be safe and effective
what are the ways drugs can move around in our body?
bulk flow = via circulatory system
diffusion = of drug molecules over short distances
solubility is also important as lipid soluble drugs more likely to diffuse across lipid bilayer membranes
large drug molecules = move slower than small one
what are cell and plasma membranes barriers between?
cell membrane = barrier between aqeous compartments of body
plasma membrane = seperates extracellular & intra-cellular compartments
what are the 4 ways small molecules can pass across membrane? (all past knowledge)
- passive diffusion
- faciliated diffusion
- active transport
- endocytosis
what are types of transport that cause saturation kinetics and what does that mean?
facilitated diffusion & active transport
- they both involve carrier proteins that work at fixed rate so when high drug concentration it makes a pile up which means protein can’t keep up and gets saturated
what are the principal sites of carrier mediated drug transport?
- blood brain barrier
- GI tract
- placenta
- renal tubule
- biliary tract
other than diffusion or active transport - what is another way drugs can get across membrane?
they can become un-ionised -> drugs can be ionised or unioinised, they can switch depending on environments pH levels
what does the proportion of ionisation of a drug depend?
both the pKa of the drug and the local pH
what is the pKa?
pH at which 50% of drug is ionised and 50% un-ionised
(acid-dissociation constant)
what can the henderson-hasselbach equation be used to determine?
the proportions of ionised & un-ionised drugs in a given pH environment
(pKa = pH + log (AH/A-))
whats an example and explain the process of a drug ionising to move across membrane?
aspirin, pKa = 3.5
- it becomes un-ionised so it can pass through gut mucosal barrier with simple passive diffusion
->it then enters different pH environment so then becomes ionised again and therefore trapped in plasma
what is relationship between acidic/basic drugs and ionisation levels in acidic/basic environment?
acidic drugs = less ionised in acidic environment (HA)
basic drugs = less ionised in basic environment
what is absorption of weak acids facilitated by? when are weak bases absorbed?
weak acids absorption facilitated by pH of stomach lumen (acidic)
weak bases not readily absorbed until small intestine(alkaline pH)
where does the majority of absorption occur?
in small intestine (weak acids & weak bases)
small intestine over stomach as larger surface area in small intestine
where do
a) weak bases
b) weak acids
accumulate? what does this help explain?
a) weak bases accumulate in compartments with low pH
b) weak acids accumulate in compartments with high pH
- The low pH of the stomach facilitates absorption of weak acids (think about ionisation and crossing membranes!) , whilst the higher pH of the intestine facilitates absorption of weak bases = because absorption happens when unionised so for acids, low pH is where unionised
what types of drugs are distributed in each body compartment?:
a) body water
b) extracellular water
c) blood plasma
d) adipose tissue
e) bone & teeth
a) small water-soluble molecules
b) large water-soluble molecules
c) highly plasma protein-bound molecules, large molecules, highly charged molecules
d) highly lipid soluble molecules
e) certain ions
what is total body water split into?
- intracellular
- extracellular
- plasma water
- interstitial water
*extra-cellular parts separated by capillary epithelium
what does it mean by drugs that are bound?
it means they are bound to particular protein that helps facilitate movement
what is Vd?
the apparent volume distribution
= it’s a theoretical volume
= Vd for certain drug is essentially the result of a pull between blood & tissue
= it’s like the distribution
what does Vd describe?
the extent to which a drug partitions between the plasma & tissue compartments
Vd = dose/ drug plasma concentration
why is Vd equation important?
because you can rearrange it to find the dose for the target plasma concentration
physiochemical properties largely determine a drugs Vd - explain examples
hydrophilic & ionised drugs find it more difficult to cross membranes = Vd closer to total body volume of water (41L)
lipophilic drugs cross membranes easily = Vd generally greater than total body volume
how do you determine Vd from blood plasma concentration? (using experiments)
- administer drug dose
- obtain blood sample
- seperate plasma from RBC
- assay fro drug
- calculate Vd with equation
if 2 drugs had same potency but one had high Vd and one had low Vd - which drug would require higher dose?
high Vd = higher dose
low Vd= lower dose
higher distribution = higher dose
a)what is an example of drug with low Vd?
b) what is an example of drug with high Vd?
a) aspirin (Vd = 10L)
b) amitriptyline (Vd = 1221L)
do drugs in
a) vascular components
b) non-vascular components (like tissue)
have high or low Vd and why?
a) low Vd as initial restriction of drug
b) high Vd as eventual free access of drug to many areas of body following slow equillibrium
*blood needs lower dose and tissue needs higher dose
what is albumin?
the most abundant plasma protein that mostly binds to acidic drugs
- many drugs bind with low affinity via electrostatic & hydrophobic forces
what are examples of plasma proteins that bind drugs?
- albumin (most abundant)
- beta globulin
- glycoprotein
what is negative of plasma proteins binding to drugs?
it reduces the availability of the drug for diffusion to the drug target organ
- since like merry-go-round, it keeps going round circulatory system and hard to get off/stop
- may also reduce transport to non-vascular compartments
what is positive of plasma proteins binding to drugs?
can slow drug elimination by preventing metabolism in the liver and glomerular filtration
what is relationship between drug concentration in plasma and Vd and plasma binding proteins?
Vd= distribution
drugs that don’t exhibit high plasma binding = low drug plasma conc and higher Vd as more available for diffusion
drugs that exhibit high plasma binding = high drug plasma conc and lower Vd as harder to get off carousel (circulatory system) and diffuse
