Drug Distribution Flashcards
What is the definition of drug distribution?
Dispersion of a drug among fluids and tissues of the body.
- Reversible - distributes into tissues and back out of them
- Occurs most efficiently in tissues with a good blood supply e.g the liver
- Rates of blood flow varies means amount of drug reaching tissues varies as well
What order kinetics do most drugs follow, and how could it be described?
- Most drugs, if used in the right concentration range, follow first-order kinetics.
- Constant half-life (t1/2) and a constant clearance (volume of blood cleared of drug per unit time). Therefore, time to remove the drug is independent of the dose given.
- Rate of absorption, metabolism and elimination of a drug are proportional to drug concentration
- No saturation of processes, so no enzymes, etc. needed are at saturation point (i.e the point where rate of elimination is constant).
Describe when drugs follow zero-order kinetics.
- Few drugs obey zero-order kinetics, examples being alcohol and phenytoin.
- Follow ‘saturation kinetics’ in which t1/2 and clearance fluctuate with the drug’s concentration. Difficult to use t1/2 to decide dosage regimes
- Constant amount (not fraction) of the drug is removed, which means that the bigger the dose, the longer it takes to remove it.
- Rate of drug metabolism is independent of the concentration of the drug (rate of drug metabolism is constant)
- As the dose decreases and fall below saturation point, the processes return to first-order kinetics.
What are the four pharmacokinetic parameters and briefly explain each of them?
Half-life (t1/2)
- Time taken for initial concentration to reduce by half
Clearance (CL)
- Volume of plasma cleared of a drug per unit time.
- Constant in first-order reactions.
- As clearance increases, half-life decreases.
- Influenced by lipid/water solubility, binding to plasma proteins
- The equation is:
CL = rate of elimination/[drug plasma]
Volume of distribution (Vd)
- Indicates the extent of distribution of a drug.
- Influenced by lipid/water solubility and binding to plasma proteins.
- The equation is:
total amount of drug/[plasma] = apparent volume of distribution (Vd)
- VD depends on the drug’s ability to enter tissues and extravascular fluids
Bioavailability (F)
- Fraction of the drug in circulation compared to the dose.
- Measures the extent of absorption, and is normally represented by a percentage.
- Calculated using area under (the plasma concentration time) curve for both oral and intravenous doses
- Low bioavailability caused by - poor absorption, chemical reactions at the site of delivery, and first-pass metabolism
What is the choice of route guided by?
- bioavailability
- chemical properties of the drug
- convenience
- need to control specificity of action
- desired onset/ duration/ offset of action
What happens with dosing regimens?
- Multiple dosing leads to a ‘steady state’ where the amount of drug absorbed equates to the amount of drug eliminated. Dosing rate = Rate of elimination
- Additional doses are administered before the drug concentration reaches zero.
- Drug concentration variation depends on the half-life and dose interval.
- For drugs with a long half-life, the achievement of a ‘steady state’ can be accelerated by a loading dose.
What are the general rules of achieving a ‘steady state’?
- repeated doses of the drug eventually produce a steady state (plateau) concentration
- the time to plateau and reach steady state is 4-5 times longer than the half-life
- steady-state levels are not actually flat
- fluctuation size is inversely proportional to the number of daily doses
- fluctuations create the potential for sub-therapeutic treatment or toxicity
- Maintenance dose used when concentration of drug starts to drop to ensure concentration remains in therapeutic range
What is the aim of good therapeutics and multiple dose therapy?
- Aim of good therapeutics is to deliver medicine to their site of action at effective concentrations
- In multiple dose therapy, aim is to keep drug levels as stable as possible
What is the time course of the concentration of drug in circulation?
- When intravenously administered to inside the blood vessel - drug concentration exponentially decays
○ Drug moves fast into well-perfused areas (e.g inside blood vessel)
○ Drug moves into poor perfused areas at a slower rate (outside blood vessel)
What are the factors affecting drug distribution?
- Blood flow/rate of presentation of the drug to the tissues: drug stays in a fat tissue for a long time
- Membrane transfer/fat: physicochemical properties of the drug; pH partition, pKa (influence degree of ionisation)
- Binding to plasma membranes/tissue components
- Drug + plasma protein → no pharmacological action; unbound drug → therapeutic action
What three factors are the concentration of the drug within circulation, determined by?
Drug in the circulation is determined by:
* Supply rate, distribution and removal from the body
* Concentration of dissolved drug at site(s) of action
* Metabolism and excretion of the drug from the body
In what ways does drug binding influence volume of distribution?
- Drug-protein binding decreases the apparent VD of a drug; drug binding to
tissues increases the apparent VD of the drug
How does being ionised affect a drug’s ability to cross a membrane?
- Ionised drugs can only cross membranes paracellularly; unionised/free drug can cross paracellularly or transcellularly
