Pharmacokinetics Flashcards
What is pharmokinetics?
Looks at what the body does to drugs
What are the 4 main processes involved in the processing of drugs by the body?
Absorption
Distribution
Metabolism
Elimination
Administration of drugs can be grouped into which 2 categories?
Enteral = entry into the body via GI tract
Parenteral = entry into the body by all other routes (not GI tract)
What are the 3 methods of administering drugs enterally?
Oral
Sublingual
Rectal
What are some parenteral methods of administering drugs?
Subcutaneous Intravenous Intramuscular Inhalation Intranasal Transdermal
How are most drugs usually administered? Where is most of the drug absorbed?
Orally
In the small intestine
What happens to drugs administered orally in the stomach?
There is little absorption here - mixes with chyme —> small intestine
By which methods are drugs absorbed at the molecular level? (3)
Passive diffusion
Facilitated diffusion
Secondary active transport
Which drugs are likely to be absorbed by passive diffusion?
Lipophilic steroids
Weak acids/bases can diffuse passively - effectively lipophilic
Which drugs are likely to be absorbed by facilitated diffusion?
Molecules with an ionic charge, using its electrochemical gradient
What are SLCs
Solute carriers used to absorb drugs by facilitated diffusion
What two types of SLC are there? What does each SLC transport?
OATs (weak acids)
OCTs (weak bases)
Where are SLCs highly expressed?
In the GI, hepatic and renal epithelia
Does secondary active transport use ATP?
No
How is secondary active transport driven?
By pre-existing electrochemical gradients
Give an example of a drug that is transported via secondary active transport?
Fluoxetine - cotransported with Na ions
What factors can affect drug absorption?
Blood flow Surface Area/GI length Lipophilicity of the drug Density of SLC expression GI motility Food/pH
How are drugs metabolised in the liver?
By cytochrome P450 (phase 1 enzyme) and conjugating (phase 2 enzyme)
What is first pass metabolism? What effect does this have on the [drug] reaching the systemic circulation?
Metabolism of drugs in the liver by phase 1 and phase 2 enzymes —> decreases [drug] reaching systemic circulation
What is bioavailability?
The fraction of a defined does that reaches its way into a specific body compartment
What is used as a reference when calculating the bioavailability of a drug?
IV used as a reference to compare to other routes
Bioavailability values are always…
Between 0 and 1 (decimal preferred)
What is the importance of the bioavailability value, how is it used?
Used to inform choice of administration route
How are drugs distributed in the body?
By bulk flow from arteries to capillaries
Then by diffusion from capillaries to interstitial fluid to cell membranes to targets
What factors affect drug distribution in the body?
Drug lipophilicity/hydrophilicity
Capillary permeability
Drug pKa and local pH
Presence of OATs and OCTs
What can drugs bind to which prevent them reaching their target sites?
Blood plasma proteins, such as albumin/globulins
What is the nature of the bonding of drugs to plasma proteins?
Not strong, bound and unbound in equilibrium
How many litres of water are there in the body of a typical adult?
42 litres
How is the 42 litres of water found in a typical adult split into intracellular and extracellular?
Intracellular = 28 litres (2/3) Extracellular = 14 litres (1/3)
How is the 14 litres of extracellular water found in a typical adult split?
3 litres in the plasma
11 litres interstitial
What is Vd (volume of distribution) a measure of?
Summarises the movement of the drug through body compartments
What does a small Vd value mean?
What does a large Vd value mean?
Low penetrance of the drug into interstitial and intracellular compartments
Greater penetrance of the drug into interstitial and intracellular compartments
How does drug metabolism largely take place?
In the liver via phase 1 and phase 2 enzymes
What do enzymes in the liver do to drugs to enhance renal elimination?
Increase their ionic charge
What happens to lipophilic drugs during elimination?
They diffuse back into the plasma
What typically happens to drugs after metabolism?
They are inactivated
What is phase 1 metabolism carried out by? Where are the enzymes found?
Cytochrome P450 enzymes
On the ER
What happens to drugs in metabolism?
They are given an increased ionic charge - through oxidation/reduction reactions (phase 1 metabolism) or through conjugating (phase 2)
Give an example of a drug that is metabolised into its active form by phase 1 metabolism?
Codeine to morphine
What is phase 2 metabolism carried out by?
Hepatic enzymes
What is the function of phase 2 metabolism?
Enhances hydrophilicity by further increasing ionic charge
Enhances renal elimination
What is CYP450 induction? How can this affect the effectiveness of the drug?
Where certain drugs induce specific CYP450 isoenzymes
Can result in decreased plasma levels of the drug and activity of certain drugs as they are being metabolised at a greater rate
What is CYP450 inhibition? What affect can this have on the effectiveness of the drug?
Certain drugs can inhibit specific CYP450 isoenzymes
Results in increased plasma levels of the drug and increased activity as metabolism of drug is slowed
Most drug elimination is carried out by the…
Kidney
How are drugs eliminated in the kidneys?
Via active tubular secretion
There is a high expression of OATs and OCTs which carry ionised molecules into the proximal tubule for secretion
What is clearance of a drug?
The RATE of elimination of a drug from the body
Generally Total Body Clearance is equal to…
Hepatic clearance + Renal clearance
What is clearance measured in?
Ml/min
What 2 factors is drug half life dependent on?
Drug clearance
Volume of distribution of a drug
What is drug half life?
The amount of time over which the [drug] in plasma reduces to half of its initial concentration when it was first measured
Assuming there are plenty of OATs/OCTs and phase 1/2 enzymes, metabolism and excretion of a drug is said to be _________ to the [drug] and is described as showing __________ kinetics
Proportional
First order
When does zero order kinetics for a drug occur?
When the elimination processes are saturated
At higher doses for most drugs - zero order kinetics will occur
Drugs at or near the dose that gives zero order kinetics are more likely to result in….
Adverse drug reactions
Toxicity
Eliminations are more likely to become saturated in what circumstances?
Reduced hepatic/renal capacity
