M&R 9.1/9.2 Pharmacokinetics Flashcards
Describe the difference between the pharmaceutical process, the pharmacokinetic process, the pharmacodynamic process, and the therapeutic process
Pharmaceutical process = is the drug getting into the patient
Pharmacokinetic process = is the drug getting to the site of action (what the body does to the drug)
Pharmacodynamic process = is the drug producing the desired effect (what the drug does to the body)
Therapeutic process = is this translated to a therapeutic effect
Which process describes whether the drug is getting into the patient?
The pharmaceutical process
Which process describes whether the drug is getting to the site of action?
The pharmacokinetic process (what the body does to the drug)
Which process describes whether the drug is producing the desired effect?
The pharmacodynamic process (what the drug does to the body)
Which process described whether the desired effect is translated to a therapeutic effect?
Therapeutic process
Describe how properties regarding how patients take drugs can affect the pharmaceutical process (whether the drug gets into the patient)?
Formulation (solid vs liquid, if solid - acid stability, solubility)
Compliance (fewer doses/day - more patient compliance)
Site of administration (focal/systemic, if systemic - enteral/parenteral)
What are some sites of focal drug administration?
Eyes
Skin
Ears
Inhalation
What are 2 advantages of focal drug administration?
Concentrates drug at site of action
Less systemic absorption –> less off target effects/side effects
What are 3 routes of enteral drug administration?
Oral
Sublingual
Rectal
What are 4 routes of parenteral drug administration?
Subcutaneous
Intramuscular
Intravenous
Transdermal
Define ‘oral bioavailability’ of a drug
The proportion of a drug given orally (or by any route other than IV) which reaches the systemic circulation in an unchanged form
In what 2 ways can you measure oral bioavailability of a drug?
- By amount (depends of GI absorption & first pass metabolism) - measure area under curve of a plasma drug level vs time plot (then (AUC oral/ AUC injected) x 100)
- By rate of availability (depends on GI absorption and pharmaceutical factors) - measured by peak height and rate of rise of drug level in blood
Does everyone have the same bioavailability for the same drug?
No!
How do you calculate therapeutic ratio?
LD50/ED50
=maximum tolerated dose/minimum effective dose
What does it mean if there is a large therapeutic window/index?
There is a wider gap between the effective conc of the drug and the toxic conc of the drug
Therefore a mistake in dose is less likely to have a negative effect on the patient
Name a drug with a large therapeutic window
Penicillin
What does it mean if a drug has a small therapeutic window/index?
There is a narrow gap between the effective conc of the drug and the toxic conc
Therefore any mistake in dose can have severe effects
Name a drug with a small therapeutic window
Warfarin
What could we alter to stop a drug entering the toxic window?
The formulation
E.g. if a fast-release formulation causes plasma concentration to rapidly rise and enter the toxic window, then could formulate a slow-release preparation that causes plasma levels to rise slower so the toxic window is not reached
What is first pass metabolism? Why does it happen?
Because blood from the gut goes straight to the liver via the portal system, drugs that are absorbed through the gut can get metabolised by the liver before ever reaching the systemic circulation
(e.g. opiates)
Name 3 routes of administration which would avoid first-pass metabolism
Parenteral routes (e.g. IV, IM, SC)
Sublingual (e.g. use of GTN in angina)
Rectal (rectum has drainage to both portal and systemic systems - so only some of the drug would undergo first-pass metabolism by liver
What is the volume distribution of a drug?
The theoretical volume into which the drug is distributed, assuming that this occurred instantaneously
How would you calculate volume distribution of a drug?
On a time vs serum concentration graph, you would extrapolate back to time zero to find C0 (the hypothetical drug concentration predicted if the distribution had occurred instantly)
Then do: amount given/C0
Do drugs which are bound to plasma proteins exert effects?
No - it is the FREE level of drug that exerts the effect, not the total level
Drugs which have a very high volume distribution tend to be concentrated where?
They tend to concentrate into fatty tissue, which leads to a very high volume distribution
In protein-binding interactions, what are Object (class I) drugs?
Drugs which are used at a dose much lower than the number of albumin binding sites
Most of the drug molecules are bound to albumin, so the concentration of free drug is low
In protein-binding interactions, what are Precipitant (class II) drugs?
Drugs which are used at a dose much higher than the number of albumin binding sites
Most albumin molecules contain a bound drug
the concentration of free drug is significant
What happens when an Object drug and a Precipitant drug are taken together?
The precipitant drug will displace the object drug from its albumin binding sites
This temporarily increases free levels of the object drug, leading to a higher risk of toxicity
When are protein binding drug interactions most important?
- For drugs that are highly bound to albumin (because there is a low amount of free drug - so any displacement leads to a big rise)
- For drugs with a small volume of distribution (so if displaced the conc rise will be much greater)
- For drugs with a small therapeutic window (therefore a rise in levels is more likely to lead to side effects)
Name an object drug that is particularly susceptible to protein binding interactions. Why is it susceptible?
Warfarin
Highly bound to albumin
Has a low volume of distribution
Has a small therapeutic window
Which precipitant drugs can displace warfarin?
Sulphonamides
Aspirin
Phenytoin
Name the two main types of drug pharmacokinetics
First order kinetics
Zero order kinetics
When does first order kinetics occur? What does it mean?
When a drug is used at a concentration [C] lower than Km
The rate of elimination is proportional to drug level
- > so the higher the drug level, the faster the rate of destruction
- > a constant FRACTION is eliminated per unit time - so can determine HALF LIFE
When does first order kinetics appear linear on a graph?
When log(plasma concentration) is plotted against time
If linear plasma concentration is plotted against time on a graph, which type of kinetics appears curved and which appears linear?
First order kinetics appears curved (only linear if log(conc) used)
Zero order kinetics appears linear
When does zero order kinetics occur? What does it mean?
When a drug is used at a concentration [C] much higher than Km
The enzyme is saturated, so the rate of elimination is CONSTANT
Regardless of drug concentration, it will be eliminated at the same rate (e.g. 9g/hour)
What is the significance of first order kinetics?
There is a predictable therapeutic response from dose increases
(Most drugs behave like this)
What is the significance of zero order kinetics?
The therapeutic response can suddenly escalate as elimination mechanisms saturate
(different in different people, so need to monitor concentrations of the drug and only increase doses incrementally)
Name 2 examples of drugs subject to zero order kinetics
Phenytoin
Alcohol
During repeated drug administration, how long does it take to reach a steady state of the drug?
5 half-lives of that drug
therefore is a property of a drug itself
If an immediate effect is required from a drug which has a long half life (so you can’t wait 5 half-lives), what do you do?
Give a loading does of the drug
This puts the drug concentration into the therapeutic range very quickly
Loading dose often determined by volume of distribution
During drug elimination, drugs tend to be metabolised by…
…the liver
During drug elimination, drugs tend to be excreted by…
… the kidneys
What is the significance of the high volume of distribution of lipid-soluble drugs?
They concentrate in lipid, so when adipose tissue is high, their plasma concentration is lower.
Therefore for the same dose, in a very thin person there would be loads in the plasma, whereas for a very fat person there would be loads in the adipose tissue and hardly any left in the plasma to act
Briefly describe the 2 phases of liver metabolism of drugs
Phase 1 - oxidation, reduction and/or hydrolysis
(drug may get activated, unchanged, or (most often) inactivated
Phase 2 - Conjugation to conjugation products (usually inactive)
(NB - some drugs directly enter phase 2 metabolism)
What kinds of enzymes carry out phase 1 metabolism of drugs in the liver?
What are some main features of them?
Mixed function oxidases (e.g. cytochrome P450)
Low substrate specificity
Affinity for lipid-soluble drugs
Inducible and inhibitable
Regarding phase 1 liver metabolism, what is an enzyme inducer?
A drug which induces liver enzymes and therefore can cause other drugs to be metabolised more quickly
What is an example of an enzyme inducing drug and what drugs does it affect?
Phenobarbitone (Causes warfarin & phenytoin to be metabolised more quickly)
Rifampicin (causes the OCP to be metabolised more quickly)
Regarding phase 1 liver metabolism, what is an enzyme inhibitor?
A drug which can inhibit liver metabolism enzymes, causing other drugs to be metabolised more slowly
Give an example of a drug which acts as a liver enzyme inhibitor, and which drugs it slows the metabolism of
Cimetidine
Causes warfarin and diazepam to be metabolised more slowly
When are metabolism-related drug interactions most clinically important?
When drugs have a low therapeutic ratio (e.g. warfarin)
When a drug is being used at the minimum effective concentration (e.g. the OCP)
When the drug metabolism follows zero order kinetics
Which drugs can potentiate warfarin’s actions and how?
Alcohol - inhibits warfarin metabolism
Aspirin, sulphonamides, phenytoin - displace warfarin from plasma proteins
Broad spectrum antibiotics - reduce vitamin K synthesis by gut bacteria (warfarin normally works against vitamin K to prevent clotting)
Which drugs can inhibit warfarin’s actions and how?
Barbiturates and rifampicin - induce liver metabolising enzymes
Which proportion of a drug is filtered by the glomerulus?
Only the free, unbound fraction
Name a drug that can be actively secreted by kidney tubules
Penicillin
What is the pK of a drug?
The pH at which half of it is ionized and half is non-ionized
What is the key difference between the ionised and un-ionised part of a drug?
Only the un-ionised part is lipid soluble and can cross membranes easily
Therefore whether or not the drug is ionized affects how well it can be reabsorbed (and therefore how much is excreted)
If a drug is a weak acid (e.g. aspirin) describe how the urine pH will affect its excretion
Alkaline urine will ionise the drug
Therefore alkaline urine = decreased reabsorption and increased excretion (more stays in the tubule lumen)
Acidic urine = increased reabsorption and decreased excretion (more leaves tubule lumen and gets reabsorbed)
If a drug is a weak base (e.g. amphetamine) how will the pH of the urine affect its excretion?
Making the urine acidic ionises more of the drug
Therefore acid urine = decreased reabsorption so more excreted
Alkaline urine = increased reabsorption so less is excreted
Explain one way in which the urine pH affecting drug excretion can be exploited clinically
Aspirin poisoning
Aspirin is a weak acid. Give forced alkaline diuresis
The alkalinity causes more of the aspirin to get ionized and therefore remain in tubule lumen to be excreted (rather than reabsorbed)
How can renal disease affect drugs in the body?
Lower rate of excretion = longer half-life
- > = lower maintenance dose required
- > = longer time to reach steady state (5 half lives)
Protein binding of drugs is altered
