Session 2: Clinical Pharmacokinetics and Pharmacodynamics Flashcards
Key factors to consider in pharmacokinetics
Bioavailability
Half-life
Drug elimination
Inter-subject variability
Drug-drug interactions
How might the patient alter the pharmacokinetics of their medication?
Smoking
Renal function
Stress
Pyrexia
Alcohol
Age
Sex
Exercise
Infection
Diet
Liver function
Albumin
GI function
etc…
What is bioavailability?
Describes the proportion of a drug given via a specific administration route that will actually be available to target sites within the body.
Fraction is what is available from the original dose to exert a pharmacological and therapeutic effect.
What is bioavailability of IV?
100%
What is the bioavailability of a medication taken orally?
A fraction of the same medication and dose given but in IV.
Bioavailability = ( AUC oral / AUC IV ) x 100%
What is bioavailability affected by?
Absorption
Formulation
Age
Food
Vomiting/malabsorption
First pass metabolism (metabolism before reaching systemic circulation)
Why is rate of absorption important?
Because it dictates visibility of distribution and elimination phases.
Explain what modified release preparation is.
When a medication is altered in order for the medication to be released more slowly and steadily.
This is also called extended release.
Why might modified release preparation be beneficial?
Because you don’t need to take the same medication and dose as frequently because of its slower release.
Give factors affect therapeutic agents
Blood flow
Capillary structure
Lipophilicity
Hydrophilicity
Protein binding
Volume of distribution
What does albumin bind to?
Acidic drugs
What do globulins bind to?
Hormones
What do lipoproteins bind to?
Basic drugs
What do glycoproteins bind to?
Basic drugs
Why is it important to consider protein bound drugs and free drugs?
Because usually the free drug is the only one able to afford response and/or be eliminated.
Why is it important to note the binding or dissociation of a drug from binding?
Some drugs may be highly protein bound and not found free in large concentrations.
This might be due to a narrow therapeutic index
A low volume of distribution.
This also makes the drug harder to eliminate.
Why is it important to know if a medication will bind in high amounts to a protein?
Because a second drug might displace the first drug leading to more free first drug to elicits its reponse.
This can be potentially harmful if the medication is intended to bind in high amounts to protein.
Give examples of when it is important to be careful with drug that bind in high amounts.
Pregnancy where fluid balances are off
Renal failure
Hypoalbuminaemia
Define volume of distribution.
A proportionality factor between the total amount of drug in the body against the concentration of the drug measured in the plasma.
Total amount of drug in body vs drug in plasma.
Vd = Dose / Drug concentration in plasma
The concentration of drug in the plasma is measured as an amount/volume and the amount of drug in the body simply as a mass.
This means that volume of distribution will be reported as only volume in litres (L).
You give a drug of a dose of 100 mg.
The plasma concentration of that drug is measured to be 20 mg/L
What will the volume distribution be?
100/20 = 5
5 litre
What does a small volume of distribution indicate?
It suggest that the drug is confined to plasma and extracellular fluid.
What does a large volume of distribution indicate?
Suggests that the drug is distributed throughout tissues.
A dose of 100 mg of a drug is given.
The plasma concentration is 500ng/mL.
What is the volume of distribution?
What does this suggest?
Vd = 200L
This suggests that the drug has distributed in 200L of plasma.
I.e. most of the drug has left plasma and sequestered by body tissue.
What does volume of distribution vary by?
Age
Health status
Weight
Tissue loss
Where does the majority of metabolism of drugs take place?
Liver
Give examples of properties of drugs which will change the volume of distribution.
Highly charged and hydrophilic drugs will have a low Vd.
Highly bound drugs to proteins will have a low Vd.
Highly lipophilic drugs will have a high Vd.
Briefly explain the metabolism of a drug.
A drug under goes Phase 1 with enzymes such as Cytochrome P450 (CYPs)
They oxidase, dealkylates, reduces and hydrolyse the drugs.
The drug can now either be excreted via kidneys or gall bladder (to urine and bile) or can undergo Phase 2.
In phase 2 enzymes will conjugate the drug with glucuronide, sulphate, glutathione or N-acetyl for example.
It will then be excreted via kidneys or gallbladder.
Why are CYP450 enzymes important?
They inactivate a lot of drugs.
They can also activate drugs. An example is levodopa into dopamine.
It can also cause an active drug to become active in another way such as codeine to morphine.
Give examples of factors inducing or inhibiting CYPs.
Age
Hepatic disease
Blood flow
Alcohol
Cigarette smoking
Grapefruit/juice inhibits CYP3A4.
CYP3A4 deactivates lovastatin.
Explain why this might be beneficial/harmful.
It will increase the bioavailability of the lovastatin as it is not metabolised as readily.
Can be harmful if the patient is drinking grapefruit juice on a high medication of it without knowledge of its effect. This means that patients are generally advised not to drink it whilst on medicine.
This means that it is important to provide adequate information about the drug that is being prescribed.
CYP 2D6 is another example of an enzyme which varies in individuals.
CYP 2D6 metabolises beta blockers, many SSRIs and some opioids.
CYP 2D6 is absent in 7% of caucasians and is hyperactive in 30% of East Africans.
What is the affect of this?
The drugs given such as beta blockers may potentially be harmful in caucasians as they might not be able to metabolise it quickly enough.
It may have a reduced effect in East africans.
What else is CYP 2D6 inhibited by?
Some SSRIs
Antiarrhytmic agents
Other anti-depressants.
Where does the majority of drug elimination take place?
Via the kidneys
Where else might drug elimination take place?
Fluids like sweat, tears, lactation, saliva
Solids - faeces and hair
Gases - volatile compounds
What is renal elimination affected by?
GFR and protein bindning (gentamicin)
Competition for transporters (penicillin)
Lipid solubility, pH and flow rate (aspirin)
What is typically cleared renally?
Low molecular weight polar metabolites
What is typically cleared hepatically?
High molecular weight conjugated with glucuronic acid.
Briefly explain the hepatic clearance.
Conjugation with glucuronic acid and then into bile.
Elimination via faeces or reabsorbed again.
What are zero and first order kinetics?
A zero order drug is cleared in a linear manner
A first order drug is cleared in an exponential manner.
How does half-life of first order kinetics vary with concentration?
It doesn’t. It is independent of concentration.
What is clearance?
Volume of blood cleared per unit time.
Clearance = rate of elimination from body / drug concentration in plasma.
What is the relationship between half-life, volume of distribution and clearance?
What is the clinical significance of half-life, volume of distribution and clerance?
They all need to be determined in order to know the correct dosage of a patient.
Most drugs exhibit first order kinetics at therapeutic doses.
Give examples of zero order.
High doses of alcohol, salicylic acid and phenytoin.
How does half-life change with first order and zero order kinetics?
In first order kinetics half-life is constant.
In zero order kinetics half-life can vary and is not calculable.
Why are zero order kinetics potentially harmful?
Because dose change can produce an unpredictable change in plasma concentration.
Give examples of why drug monitoring might be important.
Zero order kinetics
Long half-life of a drug
A narrow therapeutic window of a drug
Drug to drug interactions
Reported or expected toxic effects.
When has a drug reached a steady state (called Css)?
Steady state plasma concentration
After 5 half-lives of the drug when the drug is given regularly.
After how many half-lives is a drug considered to be negligible?
5 half-lives as well.
Why is steady state important?
Because the therapeutic benefit is optimal then.
This is because at the steady state the infusion = elimination.
At oral administration, how is steady state calculated?
Remember that steady state means administration = elimination
How is loading dose calculated?
Loading dose = Css x Vd
Amiodarone has a large Vd and a long half life (50-60 days).
How long will it take for Css to be reached?
Why is it important to note?
How is this fixed?
250-300 days for a steady state to be reached.
This means that it can almost take a year for amiodarone to have the optimal effect.
A loading dose is used instead to achieve a steady state quicker.
In terms of elimination, what is important to consider about amiodarone?
Due to its long half-life it will take many months before the drug is negligible in the body.
This is important to consider in termination of the drug.
Give examples of each:
Full agonist
Partial agonist
Inverse agonist
Competitive antagonist
Non-competitive antagonist
Full agonist - adrenaline
Partial agonist - formoterol
Inverse agonist - propranolol
Non-competitive antagonist - Some alpha-blockers
Competitive antagonist - naloxone
What does the somewhat steep decrease in the curve indicate?
The volume of distribution
Explain how antibiotics can change the drug interaction of e.g. warfarin and morphine in the body.
Antibiotics can reduce the bacteria in the gut where warfarin would be reactivated and then reabsorbed into the circulation.
If this happens warfarin/morphine will not have the same effect anymore.
Explain what an inverse agonist is.
Contrary to antagonists which only blocks the receptor response to its basal activity an inverse agonist will also decrease the basal activity.
Why might a drug be preferntially delivered by oral administration?
Drug might need activation by gut
You can’t give drug IV at home
Buprenorphine is an opioid receptor partial agonist that is prescribed in a number of formulations as an analgesic. It is also prescribed in combination with naloxone - an opioid receptor antagonist as an adjunct to opioid dependency therapy. The combination therapy is given sublingually where the bioavailability of the naloxone like oral route is extremely low.
Explain in the terms of bioavailability why the combination preparation helps manage patients who are susceptible to narcotic abuse.
Because the addict might mix the drug out with water in order to inject it instead. If it was only buprenorphine then it would just be a doctor giving an addict a high. Instead with naloxone the bioavailabilty will be at full and the buprenorphine will not have a great effect.
If it is taken sublingually instead the buprenorphine will have a bioavailability of around 50% and the naloxone’s bioavailability will be negligible.
Why is adrenaline often co-administered with lidocaine?
Because a high concentration of adrenaline act on alpha-1 adrenoceptors on the blood vessels and cause vasoconstriction. This causes the drug to remain local for longer and just act locally.
How does volume of distribution change with weight?
The more someone weigh the more the drug distributes in extracellular tissue. This means that a higher dose needs to be given to give the same effect.
A 53 year 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.
Before you begin any drug therapy, what effect might you expect there to be on clearance of any drugs you might prescribe?
Renal failure
Liver failure
Infection
Alcohol abuse
This all leads to decreased clearance meaning that the drug will stay in the body for longer and can have an increased effect.
The BMI also caused Vd to be lower so the same dose will have a larger effect than in someone that will have a higher BMI.
Average Vd = 70 L
Overall clearance = 35 ml/min
What is the half.life in hours for this new drug?
(0.693 * 70) / 0.035 = 1386
1386/60 = 23 hrs
The minimum effective dose of gentamicin is 2 microgram/ml and the maximum plasma concentration measured that should be achieved is 5 microgram/ml.
What is the therapeutic index for gentamicin?
5/2= 2.5
The Vd is 0.25 L/kg of gentamicin.
The man is 36 years old and weigh 75 kg.
What IV dose should be administed to achieve 5 microgram/ml plasma concentration?
- 25*75=18.75
- 75L * 5 mg/l = 93.75 mg
The reported half-life for gentamicin is between 2 and 3 hours. The measured clearance of gentamicin in this patient is 5 L/h.
Does your patient show similar pharmacokinetics with respect to half-life?
(0. 693 * 18.75) / 5 = 2.6
2. 6 hrs = half-life
How do you increase Css?
Increase dose
Increase frequency of dose
