Pharmacokinetics I Flashcards
What 3 things does the effect of a drug depend upon?
1) Mechanism of action and effects on cellular proteins
- Receptors
- Ion channels
- Enzymes
- Transporters
2) Physiochemical properties
3) Concentration
What are the physiochemical properties of a drug?
- Affinity
- Efficacy
What are the 4 considerations of concentration of a drug?
ADME
- Absorption
- Distribution
- Metabolism
- Excretion
What are ‘pharmacokinetics’?
The factors which come together to regulate the CONCENTRATION of the drug in the body
and therefore the concentration at the SITE of action
ADME
Why must we be aware of the pharmacokinetics of a drug?
In order to look at the possible effects of the concentration of the drug in different parts of the body
In order to know what the concentration will be at the site of action
Helps to understand possible side effects and also know if the drug will be effective
How are drugs mainly transported around the body?
In the cardiovascular system
What can happen to the distribution of the drug if the CV system is damaged?
- Impact on distribution and absorption into the different compartments of the body
How do drugs get across the various plasma membranes in 4 ways?
1) Diffuse through the lipid bilayer
2) Through aquaporins
3) HIjack carriers
4) Pinocytosis
What is pinocytosis and what is it important for?
- Cell engulfs extracellular fluid and internalises it
- Large peptides and antibodies
Why is the movement of drugs through aquaporins limited?
Drugs are normally too large to do this
What chemical properties determine how well a drug can diffuse through the membrane?
- Lipid solubility
- Diffusivity
What is the lipid solubility of a drug defined by?
The partition coefficient
What does a high partition coefficient mean and what molecules normally have this?
Very efficient at entering into the lipid compartment
Usually non-polar
When is a high partition coefficient beneficial?
Drugs used in the CNS - can cross the blood brain barrier
What is the disadvantage of a high partition coefficient?
More rapidly filtered by the kidney - quicker elimination
What is diffusivity defined by?
The diffusion coefficient
What is the diffusion coefficient proportional to?
- The molecular weight of the drug
1/√molecular weight
Which molecules are slower to equilibrate in lipids and why?
- Large molecular weight as diffusion coefficient = 1/√molecular weight
- Smaller diffusivity
What 4 things influence drug absorption into the body?
1) Site and method of administration
2) Molecular weight
3) Lipid solubility
4) pH and ionisation
Why does the site and method of administration of a drug influence drug absorption in the body?
- Determines what barriers the drug will encounter
- Depends how the drug will make access to the CV system for transport
What are 6 ways that drugs can get into the body?
1) Intravenous
- Straight into the blood
2) Intramuscular
- Into the muscle
3) Intrathecal
- Into the CSF
4) Oral/rectal
5) Percutaneous
- Through the skin
6) Inhalation
- Through the lungs
Why is intravenous delivery advantageous?
- Bypass the gut and limit breakdown
- Fast and reliable way to control the drug concentration in the plasma
What is the disadvantage of intravenous delivery?
Requires specialist knowledge - restricted to emergency situations
What are the advantages of intramuscular delivery?
Avoid digestive system
What are the disadvantages of intramuscular delivery?
- Drugs need to cross barriers to get access to the plasma, where is it distributed = slower delivery
- Must consider local blood supply to the muscle
What are the advantages of oral/rectal delivery?
Easiest way
What are the disadvantages of oral/rectal delivery?
- Encounters many barriers
- Need to consider BIOAVAILABILITY
- Gut has an additional perfusion system (portal system)
- Takes drug directly to the liver, where most drugs get metabolised
What are the barriers of the GI tract?
pH
Enzymes
What is the bioavailability of a drug and what does it determine?
What proportion of the drug makes it to the plasma, compared with the amount ingested
Determines if the drug is suitable for oral administration
What 3 things alter the bioavailability of a drug?
1) Binding of the drug to food
2) Particle size of the drug
(large - less available to be absorbed)
3) Coating around the drug
What is the portal system?
Additional perfusion system of the gut, takes drug directly to the liver to be metabolised
What are the advantages of percutaneous delivery?
Goes straight to the plasma
What are the disadvantages of percutaneous delivery?
- Skin is impermeable
- Drug must have a very high lipid solubility
What are the 2 types of drugs which can be delivered by inhalation?
- Drugs used in the lungs
- Anaesthetics
What things must you consider once the drug is in the plasma?
- Perfusion to other compartments (non targets) which may limit the drug travelling around the body
- Charge on the drug - may not be able to cross the plasma membrane
What happens to the drug when it is in the body - due to pH
- pH causes dissociation of the drug
- HA H+ + A-
What is the active part of the drug and what can it not do?
A-
Can’t cross the plasma membrane
Describe the Henderson Hussle back equation
- Looks at the relatonship between pH and the pKa of a molecule
pH = pKa + log10 (A-/HA)
pKa = pH + log10 (HA/A-)
What is the pKa of a drug?
- A constant
- Describes the pH at which 50% of the drug is at its dissociated form
At 37 degrees pKa = 6.1
What favours diffusion of a drug and why?
- Low pH (lots of H+)
- HA H+ + A-
- Pushes towards the UNDISSOCIATED form of the drug
- Can pass across the membrane (A- is the active drug - cannot pass across the membrane)
What affects the distribution of drugs between aqueous compartments?
pH
What is the pKa of aspirin?
3.5
Describe the state of aspirin throughout the different compartments of the body?
- Stomach
- Plasma
- Urine
Stomach - undissociated form
(pH 3 - very acidic)
Plasma - pH 7.4
- Dissociated drug starts to rise (trapped in plasma)
Urine - pH 8
- High amount of dissociated drug
- Trapped in the urine and excreted
What is one way we can accelerate the excretion of drugs in the body?
Give an example
Alter the pH of different compartments
- Add sodium bicarbonate to increase plasma pH and reduce acidic drugs moving into the plasma (eg. aspirin poisoning)
What can cause acidic drugs to be extracted from the CNS and trapped in the plasma?
Add sodium bicarbonate
What is the passage of drugs through carriers dependant upon? (4)
- Saturation and competitive inhibition
- Amount of transporter available
- Rate of transporter
How do drugs move through carriers?
‘Hijack’ them
What is the problem with drugs hijacking carriers? (2)
- Drugs can bind up on one side of the transporter
- Carrier become saturated, affecting the concentration of the drug on either side of the carrier
- Drugs can ‘take over’ the carrier - preventing the endogenous molecules from crossing the membrane
What else must be considered once the drug is in the plasma? Some examples?
Perfusion to other compartments - limit drug travelling around the body
- Hard to travel across the placenta
- Drugs may enter breast milk
- Drugs may need to cross epithelial layer of kidneys
