drug movement

Question 1

what is pharmacodynamics?

Answer 1

what the drug does to the body
- involves drug acting at particular drug target resulting in activation or inhibiting of cellular signalling pathway

Question 2

what is pharmacokinetics?

Answer 2

what the body does to the drug
- involves how easily the drug is absorbed in the body & how distributed in certain tissues & how metabolised

Question 3

how can we characterise pharmacokinetic processes?

Answer 3

by calculating the measures such as the apparent volume of distribution (Vd) , elimination half-life, clearance or the bioavailability of a drug.

Question 4

how can we characterise pharmacodynamics?

Answer 4

by looking at the affinity, potency or efficacy of a drug and calculating such things as Ki, EC50, or Emax

Question 5

what is goal of pharmacokinetics?

Answer 5

finding dose that will be safe & have high efficacy

Question 6

what is ROAand what is used to help determine?

Answer 6

routes of administration - used to help work out dose
- some ROA straight forward like IV, some are more complicated like oral

Question 7

what is IV ROA?

Answer 7

drug goes straight into blood circulation, avoiding first pass metabolism

Question 8

what is oral ROA?

Answer 8

goes through GI tract which means drug highly metabolised and less efficacious
e.g. salbutamol given orally would be less efficacious

Question 9

what is the effect of increasing plasma concentration of drug?

Answer 9

• 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

Question 10

what is EC50 and on graph of plasma concentration & response what does it mean if:
a) below EC50?
b)between EC50 & Emax?

Answer 10

EC50 = the half life

a) sub-therepeutic
b) therepeutic

Question 11

what does NOAEL & LOAEL stand for on graph of plasma concentration & response/adverse effects and what are they used for?

Answer 11

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

Question 12

what does a narrow therapeutic window mean?

Answer 12

only small window of benefits before starts having severe damaging affects

Question 13

why do we do pharmacokinetic analysis?

Answer 13

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

Question 14

what are the ways drugs can move around in our body?

Answer 14

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

Question 15

what are cell and plasma membranes barriers between?

Answer 15

cell membrane = barrier between aqeous compartments of body
plasma membrane = seperates extracellular & intra-cellular compartments

Question 16

what are the 4 ways small molecules can pass across membrane? (all past knowledge)

Answer 16

• passive diffusion
• faciliated diffusion
• active transport
• endocytosis

Question 17

what are types of transport that cause saturation kinetics and what does that mean?

Answer 17

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

Question 18

what are the principal sites of carrier mediated drug transport?

Answer 18

• blood brain barrier
• GI tract
• placenta
• renal tubule
• biliary tract

Question 19

other than diffusion or active transport - what is another way drugs can get across membrane?

Answer 19

they can become un-ionised -> drugs can be ionised or unioinised, they can switch depending on environments pH levels

Question 20

what does the proportion of ionisation of a drug depend?

Answer 20

both the pKa of the drug and the local pH

Question 21

what is the pKa?

Answer 21

pH at which 50% of drug is ionised and 50% un-ionised
(acid-dissociation constant)

Question 22

what can the henderson-hasselbach equation be used to determine?

Answer 22

the proportions of ionised & un-ionised drugs in a given pH environment
(pKa = pH + log (AH/A-))

Question 23

whats an example and explain the process of a drug ionising to move across membrane?

Answer 23

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

Question 24

what is relationship between acidic/basic drugs and ionisation levels in acidic/basic environment?

Answer 24

acidic drugs = less ionised in acidic environment (HA)
basic drugs = less ionised in basic environment

Question 25

what is absorption of weak acids facilitated by? when are weak bases absorbed?

Answer 25

weak acids absorption facilitated by pH of stomach lumen (acidic)
weak bases not readily absorbed until small intestine(alkaline pH)

Question 26

where does the majority of absorption occur?

Answer 26

in small intestine (weak acids & weak bases)

small intestine over stomach as larger surface area in small intestine

Question 27

where do
a) weak bases
b) weak acids
accumulate? what does this help explain?

Answer 27

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

Question 28

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

Answer 28

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

Question 29

what is total body water split into?

Answer 29

1. intracellular
2. extracellular
   
   • plasma water
   • interstitial water

*extra-cellular parts separated by capillary epithelium

Question 30

what does it mean by drugs that are bound?

Answer 30

it means they are bound to particular protein that helps facilitate movement

Question 31

what is Vd?

Answer 31

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

Question 32

what does Vd describe?

Answer 32

the extent to which a drug partitions between the plasma & tissue compartments
Vd = dose/ drug plasma concentration

Question 33

why is Vd equation important?

Answer 33

because you can rearrange it to find the dose for the target plasma concentration

Question 34

physiochemical properties largely determine a drugs Vd - explain examples

Answer 34

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

Question 35

how do you determine Vd from blood plasma concentration? (using experiments)

Answer 35

• administer drug dose
• obtain blood sample
• seperate plasma from RBC
• assay fro drug
• calculate Vd with equation

Question 36

if 2 drugs had same potency but one had high Vd and one had low Vd - which drug would require higher dose?

Answer 36

high Vd = higher dose
low Vd= lower dose

higher distribution = higher dose

Question 37

a)what is an example of drug with low Vd?
b) what is an example of drug with high Vd?

Answer 37

a) aspirin (Vd = 10L)
b) amitriptyline (Vd = 1221L)

Question 38

do drugs in
a) vascular components
b) non-vascular components (like tissue)
have high or low Vd and why?

Answer 38

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

Question 39

what is albumin?

Answer 39

the most abundant plasma protein that mostly binds to acidic drugs

• many drugs bind with low affinity via electrostatic & hydrophobic forces

Question 40

what are examples of plasma proteins that bind drugs?

Answer 40

• albumin (most abundant)
• beta globulin
• glycoprotein

Question 41

what is negative of plasma proteins binding to drugs?

Answer 41

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

Question 42

what is positive of plasma proteins binding to drugs?

Answer 42

can slow drug elimination by preventing metabolism in the liver and glomerular filtration

Question 43

what is relationship between drug concentration in plasma and Vd and plasma binding proteins?

Answer 43

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