Session 2.1c - Group Work Flashcards
18th January 2019 16:00
1) A new antibiotic drug is given orally and its pharmacokinetics are being established. In a group of trial patients it is found that 80% of the original oral dose is physically absorbed across the gut wall. During its passage across the tissues of the gut wall, a further 10% of the drug is metabolised. The remaining antibiotic drug molecules then pass through the hepatic portal vein into the liver. In the first pass of the liver, a further 20% of molecules are then metabolised by hepatic first pass metabolism.
In the trial, a single oral dose of 200 mg of the antibiotic drug is given.
From the above information
a) Calculate the oral bioavailability of this drug
57.6%
80% of 100% = 80
10% of 80% lost = 72%
20% of 72% lost = 57.6%
57.6%
1) A new antibiotic drug is given orally and its pharmacokinetics are being established. In a group of trial patients it is found that 80% of the original oral dose is physically absorbed across the gut wall. During its passage across the tissues of the gut wall, a further 10% of the drug is metabolised. The remaining antibiotic drug molecules then pass through the hepatic portal vein into the liver. In the first pass of the liver, a further 20% of molecules are then metabolised by hepatic first pass metabolism.
In the trial, a single oral dose of 200 mg of the antibiotic drug is given.
From the above information
b) The amount in mg of this single dose that finally reached the circulation
57.6% of 200 mg = 115.2 mg
OR
80% of 200 mg = 160 mg
10% of 160 mg lost = 144 mg
20% of 144 mg lost = 115.2 mg
2.1) Apparent Volume of Distribution: Relative Penetration of Major Body Fluid
Compartments
As a clinician, you are given differing apparent Volumes of Distribution for three drugs that are being investigated for treating elevated blood pressure with distinct target sites. The three drugs have been tested in a Phase II clinical trial with over 100 male patients aged between 30-35 yrs old and are of normal physical build. Their Vd values are given below in the question box below.
How do you think this indicates how each of these drugs then tend to distribute between the major fluid compartments?
Drug 1: 0.12 L/kg
Drug 2: 0.26 L/kg
Drug 3: 3.4 L/kg
Drug 1 - drug remains in the plasma
Drug 2 - drug has travelled in the plasma and into the ECF (interstitial spaces)
Drug 3 - drug is intracellular (not extracellular because the drug has diffused into the intracellular compartment)
Note: You will not need to learn these specific Vd numbers, you just need to be able to make an inference from the numbers.
Is Vd is small, then it remains in the plasma, if Vd is large, then it leaves the plasma and enters intracellular compartments
2.2 Apparent Volume of Distribution: Effect of Adipose Tissue Mass on Drug Distribution
It is important to recognise that values for pharmacokinetic parameters are primarily based on clinical trial data on normal healthy subjects. These values are meant to provide guidance to the clinician and not be seen as absolute invariant values.
Values can and do show variation between individuals. They can also vary even in individuals depending on changes e.g.: Developmental status - from a child to an adult; health status - cancer often causes significant weight/tissue loss.
The following provides an example of how Vd may vary between individuals being treated for the same condition.
Two female patients in their early twenties were being assessed for treatment with haloperidol for psychotic illness. Both patients were 1.7m in height, but one patient weighed 46 kg, the other 92 kg.
a) Given the normal Vd for haloperidol is about 18L/kg, how would you expect this weight difference to affect its value?
A higher Vd means the drug is more likely to spread to other places other than the plasma, such as adipose tissue.
The heavier person has more adipose tissue so more places for the drug to spread and be distributed, increasing the Vd.
2.2 Apparent Volume of Distribution: Effect of Adipose Tissue Mass on Drug Distribution
It is important to recognise that values for pharmacokinetic parameters are primarily based on clinical trial data on normal healthy subjects. These values are meant to provide guidance to the clinician and not be seen as absolute invariant values.
Values can and do show variation between individuals. They can also vary even in individuals depending on changes e.g.: Developmental status - from a child to an adult; health status - cancer often causes significant weight/tissue loss.
The following provides an example of how Vd may vary between individuals being treated for the same condition.
Two female patients in their early twenties were being assessed for treatment with haloperidol for psychotic illness. Both patients were 1.7m in height, but one patient weighed 46 kg, the other 92 kg.
b) How do you think this information may affect your initial choice of dosing regimen with haloperidol in these patients?
The heavier person will need a bigger dose.
The reason for this is 2-fold:
- firstly, larger patients need a larger dose because they have more plasma anyway (as they are bigger)
- however, because the Vd is large meaning it will spread out of the plasma, the larger patient needs the dose to be further adjusted for this factor. (If the Vd was smaller and stayed in the plasma, the dose for the larger person still needs to be larger but only because they have more mass; not the Vd)
2.3. Drug Elimination Kinetics - Metabolism and Excretion
Many drugs over their therapeutic range will follow first order kinetics. This is when the mechanisms involved in elimination are not overwhelmed or saturated by the amount of drug to metabolise or excrete.
To illustrate the shape of first order kinetics, on the graph below draw a simple plot of drug concentration in the plasma vs. time
a) For a drug given IV that is eliminated rapidly within about two hours
Drug concentration 100% at T0
Drug concentration 0% at T2
2.3. Drug Elimination Kinetics - Metabolism and Excretion
Many drugs over their therapeutic range will follow first order kinetics. This is when the mechanisms involved in elimination are not overwhelmed or saturated by the amount of drug to metabolise or excrete.
To illustrate the shape of first order kinetics, on the graph below draw a simple plot of drug concentration in the plasma vs. time
b) For a drug given IV that is completely eliminated more slowly within about 12-16 hours
Drug concentration 100% at T0
Drug concentration 0% at T12-16
2.3. Drug Elimination Kinetics - Metabolism and Excretion
Many drugs over their therapeutic range will follow first order kinetics. This is when the mechanisms involved in elimination are not overwhelmed or saturated by the amount of drug to metabolise or excrete.
To illustrate the shape of first order kinetics, on the graph below draw a simple plot of drug concentration in the plasma vs. time
c) If these two drugs had similar values for their Vd, what would most easily explain the difference in their respective half-lives?
If the Vd are similar, then the drug that is eliminated more rapidly shows a faster metabolism and/or clearance
(metabolism is the breakdown of the drug in the body
clearance is the drug leaving/removed from the body, e.g. through urine, sweat)
2.4 Drug Elimination Kinetics – Clearance
The functional status of three major body systems are recognised to affect drug clearance.
a) Name these three systems, and briefly state why their functional status can affect clearance.
Renal - reduced GFR means reduced clearance
GI - 1st pass metabolism and CYP inactivation of the drug
Cardiac - distribution of the drug in the body through blood flow to liver where it is metabolised and kidneys where it is excreted
- 4 As with Vd, variation in clearance between and within individuals affects their ability to eliminate drugs. In this example, a 53 yr old man is admitted to hospital with a chronic skin infection and suspected pneumonia. He has a long history of alcohol abuse and is severely jaundiced with suspected renal failure. He is also malnourished with a BMI of 19.
b) Before you begin any drug therapy, what effect might you expect there to be on clearance of any drugs you might prescribe?
It is severely reduced, due to the renal and liver failure (cirrhosis of the liver due to alcoholism).
2.5 Drug Elimination Half Life – t1/2
The terms for the volume of distribution and clearance are clinically used to calculate the overall figure summarising first order elimination kinetics of a drug or its half-life.
This is approximately
t1/2≈ 0.7 x Vd/CL
A new antiepileptic drug GSK7890 being trialled in patients the average total body Vd was 70 L and the overall clearance was 35 ml min-1
.
Using the above equation what would the t1/2 in hours for this new drug be?
In this example remember to convert L to ml and minutes to hours for your final answer
- 7 x 70L/35 ml/min
- 7 x 7000ml / 35 ml/min
= 1400 min
= 23.333 hours
2.5 Use your answer for 2.5a (1400 min)
The steady state plasma concentration (CpSS) with repeated doses is usually reached within 4-5 half-lives of a drug. Assuming linear elimination kinetics, approximately how long will it take to get to the CpSS for GSK7890?
It will take 7000 min
= 116.6666 hours
= 4.861 days
Approximately 5 days
2.5c Use your answer from 2.5b (it will take approximately 5 days to get an effective dose)
How do you think this information may be relevant in prescriptive practice?
This means that it will take about 5 days for the drug to reach the CpSS. This is impractical for patients suffering from seizures as it will take too long for it to take an effect. To counteract this, in prescriptive practice, you would give a higher dose to start with immediately so the desired concentration is reached quicker, or give a supplement of another short-lasting drug to control the symptoms before the initial one takes an effect.
Pharmacodynamics
3.1 Binding and Affinity:
Kd is the term used to describe the degree of interaction or affinity between the binding site and a ligand. The following values given in Table 1 below in mixed notation for concentration were obtained for a number of experimental drugs. These were designed to target binding to a class of GPCRs that bind glutamate known as NMDA receptors.
In the RHS of the Table, order the drugs by rank in terms of affinity and express the concentration in exponential form.
Drug - Kd A = 3.2 x 10-7 M B = 246 nM C = 41 uM D = 1.7 x 10-8 M E = 0.5 nM
A = 3.2 x 10-7 M B = 2.46 x 10-7 M C = 4.1 x 10-5 M D = 1.7 x 10-8 M E = 5 x 10-10 M
The smaller the Kd, the better the affinity
E, D, B, A, C
3.1 Drug - Kd A = 3.2 x 10-7 M B = 2.46 x 10-7 M C = 4.1 x 10-5 M D = 1.7 x 10-8 M E = 5 x 10-10 M
Further experimentation showed that Drugs A, C and D elicited increased neural responses in a concentration dependent manner similar to glutamate. Drug B and E did not elicit any neural response at any concentration.
Based on this evidence what classification would you give to these two groups?
Drugs A, C and D are agonists because they elicit responses
Drugs B and E do not elicit any neural response, and are therefore antagonists.
