Drug Absorption, Distribution and Excretion

Question 1

What is meant by the bioavailability of a drug?

Answer 1

Bioavailability: proportion of administered drug reaching the systemic circulation – 100% for drugs given i.v.
Oral drugs must be digested, absorbed etc, ~50% of og dose actually ends up in circulation

Question 2

What is first pass metabolism?

Answer 2

Oral drugs–> liver via the systemic circulatory pathway, gets absorbed in the liver, then goes into the circulation again.

Liver breaks down the drug= first past metabolism
If pt has poor absorption and high first past metabolism - oral administration not suitable, find alt.

Question 3

What type of drugs get absorbed?

Answer 3

Absorption requires drugs to cross biological barriers (layers of cells with semi-permeable, lipophilic membranes)
Lipophilic= not good at allowing charged ionised molecules go across their membranes.

For a drug to easily be absorbed by the body, it must be lipophilic

Question 4

Absorption can occur by…

Answer 4

For good permeability:
Small molecular size
High lipid solubility
Low charge/ionised groups

Question 5

Describe the behaviour of weak acid and weak base drugs and why they are preferred

Answer 5

Weak acid drugs in a basic environment will act as a proton donor- goes from unionised state (AH), to an ionised state (A-).

Weak acidic drug in acidic environment accepts protons- gets unionised and more lipid soluble.
Vice versa for weak basic drug.

Weak acid/ base drugs are much easier to be absorbed across membranes.

Question 6

Explain the concept of ion trapping using aspirin as an example. Note- aspirin is a weak acid

Answer 6

When it reaches the v acidic stomach, aspirin acts as a base: it accepts protons, becomes unionised/lipophilic.
This means it can cross barriers in gastric mucosa, into the circulation.

Now in the circulation, the pH is 7.2. Aspirin acts as an acid. So it gets across the membrane and then dissociates, becomes ionised. This is good bc it now cant go back into the stomach= ion trapped.
Trapped aspirin the circulation, to go to the site of action, by using its weak acid properties.

Question 7

What is ion trapping in weak acid vs weak base drugs?

Answer 7

Acidic drugs are absorbed efficiently from the stomach then ‘ion trapped’ in the circulation

Basic drugs are absorbed less efficiently in the stomach as they are more ionised in an acidic environment
Similar principles apply to renal drug excretion
e.g., alkaline urine traps and enhances excretion of acidic drugs

Question 8

So, given the concept of ion trapping, can basic drugs be given orally?

Answer 8

Yes – unless v basic or permanently ionised
Basic drugs r absorbed poorly from stomach
But absorbed better from the intestine (pH 6.6-7.5)
Intestine SA (200 m2) compensates
for low absorption efficiency.

Question 9

What is the average time course of a drug concentration in the circulation?

Answer 9

Note - No absorption process when administering IV.
Drug in blood delivered quick to well perfused areas (brain, liver, kidney) then after delay –>poorly perfused
Drug conc in plasma decreases as drug moves to well perfused and poor perfused area = distributed from plasma to surrounding
While being taken up the drug is also being metabolised and excreted

Question 10

What contributes to the fall in plasma drug conc?

Answer 10

Drug distribution- Dispersion of a drug among
fluids and tissues of the body
Elimination/metabolism process of body of drug, half-life

Question 11

Many drugs obey first order kinetics. What is the importance of this?
NOTE: First order kinetics= many enzymes available waiting to work

Answer 11

A constant FRACTION of drug is removed (ie increased dose=increased excretion) –> constant clearance and half life, drug not building up in body
When a drug has a constant half-life its kinetics= predictable. You can estimate time for body to remove the drug after a blood test – important for designing dose regimes

Question 12

A few drugs obey zero-order kinetics. What is meant by this and why is it important?

Answer 12

Linear decline bc we have a constant AMOUNT of drug being removed, not constant fraction.
This is bc the distribution, elimination, clearance processes are saturated- enzymes/transporters in liver/kidneys working at max
Therefore rate of drug metabolism independent of drug conc, so drugs can accumulate v quickly!

Question 13

How can some drugs have mixed kinetics?

Answer 13

If you give big drug bolus–> may behave as zero order at first as they quickly cause saturation But over time as the drug conc reduces, they then return to first order kinetics–> nice constant half life.

So don’t give too much of a drug to start with
Instead start low and then build up the concentration

Question 14

Describe volume of distribution and what it indicates

Answer 14

If hay large volume of distribution, the drug is spread out all over the body (fat, muscles), not just in the circulation.
This is important in adjusting dose- the conc may not show up in circulation, but its still stored in other places.

Vd indicates the extent of distribution for a drug
Influenced by lipid/water solubility, binding to plasma proteins, where it is distributed (e.g., muscles etc.)

Question 15

How do you calculate volume of distribution?

Answer 15

Apparent vol of distribution (Vd)= Drug amount / [Plasma]
e.g., 20 mg i.v. dose and 2 mg/L drug in plasma–> V=10L,

So 20mg IV drug is distributed over 10L of your body.
We know we have 4/5L in our vascular space/plasma, but theres 10L distribution. 10L-4L= 6L
That means 6L in the extravascular space (in fat/muscles).

Question 16

What is plasma clearance?

Answer 16

Plasma clearance (CL): Volume of plasma cleared of drug per time (ml/min)
A constant for 1st order reactions (constant half-life, t1/2)
Changing CL= changes half life, e.g CL decreases in liver/kidney disease, so half life increases.
That’ll change the dose that you give and also the regime.

Question 17

How do you calculate bioavailability (F)?

Answer 17

F: Fraction of drug in circulation compared to dose
F= Equal oral/iv doses, measure AUC oral / AUC iv
e.g., oral dose, F = 0.1 (10% bioavailability)
AUC = area under curve

This relates to the amount of the drug that you’ve had in the circulation over time and this will relate to your bioavailability.
Remember:
Giving something IV - the fraction is 100%, F=1.

Question 18

What does multiple dosing lead to?

Answer 18

Multiple dosing leads to a ‘steady state’
Additional doses administered before [drug] falls to zero
[Drug] variation depends on half-life and dose interval

Idea of dosing regime is for dosing rate = elimination rate. Dosing rate = Clearance x C(steady state)

Question 19

A 70kg patient with asthma is to be treated with theophylline
(non-selective phosphodiesterase inhibitor, causes bronchorelaxation)

Narrow therapeutic range and potentially fatal effects in overdose
Treatment aims at a ‘steady state’ level of 15 microg/ml in plasma
The clearance of the drug is 48ml/min/70kg and its half life is 8h
Treatment by intravenous bolus injection
Calculate the daily dose for this patient

Answer 19

Dosing rate x F = Clearance x Css
Dosing rate x 1 (i.v.) = 48ml/min/70kg x 15µg/ml
This means that dosing rate = 720µg/min/70kg
Therefore daily dose = ~1.02g for this patient (720µg x 1440 min = 1.02 g)

Question 20

What is theophylline and explain the dosing regimen using this graph

Answer 20

Giving 1g= not good, [drug] goes too high. Only effective for a few hrs each day.
Giving 340mg - fewer fluctuations, you stay around the steady state concentration, w no toxicity

Better to give a lower dose more regularly. However be wary that high dose Hz= less compliance
Fluctuation size= inversely proportional to the dose Hz

Question 21

What is the relationship between half life and the steady state level?

Answer 21

E.g. If you have a half life of 6 hours.
The time to plateau is normally 5 times that.
Within 30 hours, you’ll get plateau phase (steady state level)
For drugs with long half lives steady state can be accelerated by a loading dose
Large dose to start with and then go on a regime - so smaller dose but more often to reach the plateau phase.

Question 22

Why is metabolism involved in making drugs more water soluble?

Answer 22

Lipid soluble drug molecules are reabsorbed by the kidneys. So if you want to get rid of a drug, you metabolise it, make it less lipid soluble, more water soluble and the its going to be secreted by the kidneys.

Question 23

What is plasma clearance?

Answer 23

The volume of plasma cleared of drug per unit time
A constant clearance for drugs following 1st order kinetics
For a drug that is removed by liver metabolism and kidney excretion:
Plasma CL = hepatic CL + renal CL

Question 24

What happens during drug metabolism?

Answer 24

Loss of (or reduced) biological activity: drugs have a high charge/polarity - that often produces less receptor binding
Some drugs are “activated” by metabolism (prodrug)
e.g., enalapril (ACEi) into active form enalaprilat by esterases in liver
Some drugs eliminated unchanged, e.g., digoxin

Question 25

There are 2 phases to drug metabolism. Describe these

Answer 25

Phase 1 main process is oxidation w/in the liver
Addition of oxygen molecules to carbon, nitrogen, sulphur in drug structure
This is done by cP450 enzymes!!!
Phase 2 increases water solubility of drug
It conjugates the phase 1 product to make it more polar and hence able to be excreted
e.g., glucuronidation (reaction with glucose)

Question 26

Explain how paracetamol is metabolised and the importance of this + treatment for overdose

Answer 26

Paracetamol is mainly just a phase 2 route
This is important bc in paracetamol OD, phase 2 routes become saturated quickly. This pushes it through phase 1 metabolism. This uses CYP450 to create a toxic metabolite –> liver damage

This toxic metabolite is lowered by conjugation to Glutathione but in OD Glutathione runs out-> dont produce inert N-acetylcysteine conjugate.
Treatment: N-acetylcysteine conjugate. This produces Glutathione

Question 27

Describe glomerular filtration and its clinical importance

Answer 27

Glomerulus allow drugs of MW < 20kDa to be filtered, but not when bound on albumin (albumin MW ~ 68kDa)

eg warfarin: 98% bound to albumin : 2% into filtrate
This results in a long half-life, steady state becomes harder
Toxicity w continued dosing e.g excess bleeding, need to monitor

Question 28

Describe passive tubular reabsorption

Answer 28

Re-absorption of H2O increases [Drug] in tubular filtrate
This increases drug re-absorption back into blood plasma from filtrate
Mainly in the PCT, DCT
Urinary pH is an important determinant of passive re-absorption
This only occurs for drugs in the lipophyllic state

Question 29

What happens in tubular secretion of drugs? What is the clinical importance of this?

Answer 29

Cation transporter e.g., Morphine (weak base, proton acceptor at physiological pH)
Anion transporter e.g., Penicillin (weak acid, proton donor at physiological pH)

Competition occurs between drugs at these transporters (as they are non-specific, non-selective binding sites)

e.g., Penicillin and Probenecid (for gout)
If Probenecid is administered with Penicillin
Half-life of penicillin is increased – both act at anion transporter

Question 30

What is renal clearance?

Answer 30

Example
Plasma [drug] is 10 µg/ml
Urine [drug] at 500 µg/min

Renal clearance is 50 ml of plasma per min
Reduce renal elimination –> Increase in plasma half-life
Plasma CL = hepatic CL + renal CL

Question 31

Factors Affecting Drug Metabolism & Excretion?

Answer 31