PHARMACOKINETICS Flashcards
A key determinant of the effectiveness and usefulness of a drug depends on achieving what?
The correct concentration:
too low and there will be no effect, too high and you will get non specific effects
What are the bodily processes that affect drug concentration?
Absorption
Distribution
Metabolism
Excretion
Throughout the body, different compartments will mean that drugs will reach a different constant concentrations. How well a drug can diffuse between compartments is governed by what?
The diffusion coefficient.
1/MW^1/2
Diffusion is proportional to the size of the drug.
Drugs must cross barriers to cross compartments. What might these be?
Diffusion through lipid
Diffusion through channels
Carriers
Pinocytosis
The lipid solubility of a drug is measure by what?
The partition co-efficient.
The higher, the more easily diffusible.
Non polar (uncharged) molecules dissolve freely in lipids and penetrate cell membranes freely. What can this also increase?
Rate of absoption
Penetration into other tissues
Renal elimination
What is one of the most important determinants of the pharmacokinetic characteristics of a drug.
Lipid solubility.
What are the routes of administration?
Oral/rectal Percutaneous Intravenous Intramuscular Intrathecal Inhalation
Why must route of administration be considered?
It affects drug absorption.
It also affects how much of the drug get into the system (bioavailability) and how quickly the drug can act.
What is bioavailability?
The free concentration of drug in plasma/the amount of drug taken
What are the factors that affect absoption?
Site/Method of administration Molecular Weight Lipid Solubility pH and ionization Carrier mediated transport
Many drugs are salts of what?
Weak acids and weak bases.
What is the formula for a weak acid?
HA —– H+ + A-
What is the formula to describe the ratio of dissociated to undissociated form of acid?
pKa= pH + log10(HA/A-)
At low pH, weak acids will be ………………………..
unionized
The ratio of dissociated to undissociated form of acid depends on what?
The pH of the environment.
If the pKa = 3, what does this number mean?
There is 3x more drug in its undissociated form than dissociated form.
Basic environments (pH>7) favour dissociation of acids. What does this mean for the drug?
The drug will become trapped in that compartment because it is in dissociated form and polar, therefore it cannot diffuse between compartments.
What is an advantage of drug trapping (ie a weak acid in a basic compartment)?
In the event of toxicity, by alkalinising the urine you can trap the drug in the urine to be excreted faster.
What is the disadvantage a weak acid in a basic compartment?
Since a drug cannot diffuse between compartments in dissociated form, it is trapped. This can lead to accumulation and toxicity.
Polar molecules can be transported between compartments by what?
Passive or active carrier mediated transport.
Genetic variations (polymorphisms) of transporters can also affect drug action. How?
Different variations of the same transporter are associated with different degrees of response and so certain drugs may not work as effectively.
What are the major body compartments?
Extracellular fluids (plasma, interstitial, lymph)
Intracellular fluids
Transcellular fluids (CSF)
Fat
Drug distribution is affected by what?
Body compartments and how well a drug can enter them.
What regulates drug access to the CNS?
Endothelial cells lining the blood vessels in the CNS form tight junctions impermeable to water soluble molecules. This is the blood brain barrier.
What can cross the blood brain barrier easily?
Lipid soluble molecules.
What is the advantage of tight junctions of the blood brain barrier becoming leaky during inflammation?
You can treat the inflammation with water soluble drugs that could not normally enter.
If a drug binds to a protein what can it not do?
It is not free to associate with its receptor.
Protein binding of drugs affects what?
Drug distribution and elimination.
What is a danger of high protein binding?
Can lead to large unexpected increases in concentration of the drug as binding sites become saturated.
What is another factor that can influence drug distribution?
Partitioning into specific tissues such as body fat.
What is the issue of drugs and body fat?
Highly lipophilic drugs will partition into specific tissues like body fat. Drugs can reservoir in fat making it difficult to achieve the concentration required.
It also means the drug can stay for a prolonged amount of time in the system.
Drugs are metabolised in two biochemical reactions. What are these?
Phase 1 - catabolic reactions -
Phase 2 - anabolic reactions
How are catabolic and anabolic reactions carried out?
By microsomal enzymes.
Give an example of a microsomal enzyme.
Cytochrome P450
How many genes encode for P450 enzymes?
57
Why can you alternate ibuprofen with paracetamol?
Because they are metabolised by different isoforms of the P450 enzyme.
What can affect P450 enzymes?
Some other drugs, foods and drinks can induce and inhibit the level of transcription of the enzymes.
Why is overdose of paracetamol so dangerous?
Catabolism of paracetamol creates a toxic intermediate. If p450 is overwhelmed due to saturation then the toxic intermediate is not broken down and accumulates in the liver.
What are the routes of excretion of drugs?
Urine
Faeces
Milk, sweat
Expired air
Drug excretion can be impaired in elderly for what reasons?
Decreased renal function
Decrease lung capacity
Decreased GI function
What are the types of renal excretion?
- Glomerular filtration
- Active tubular secretion
- Passive diffusion
What is the function of glomerular filtration in drug excretion?
Filter small molecules
What is the function of active tubular secretion in drug excretion?
Active transport across the cell membrane (anion and cation exchangers)
What is the function of passive diffusion in drug excretion?
This is the exit of lipophilic drugs
What is the time course of a drug determined by?
The rate of metabolism and excretion.
What is drug equilibrium?
When the rate of intake = rate of excretion
Some drugs show saturatino kinetics. What does this mean?
When there is a disproportionate increase in steady state plasma concentration and enzymes become overwhelmed.
This can have side effects and toxicity.
What is the advantage of multiple doses of a drug throughout the day as opposed to one large dose?
If the drug does not have a high safety margin, one large dose can risk overdose or increase chance of side effects.
