Pharmacokinetics Flashcards
What is ADME?
- Absorption
- Distribution
- Metabolism
- Excretion
What is bulk flow?
Movement of blood from a high pressure region to a low pressure region
What is the diffusion coefficient? (2)
- 1/sqrt(molecular weight)
- Larger molecular weight = slower diffusion
What is pinocytosis?
Cell takes in extracellular fluid along with any dissolved molecules
What is the partition coefficient?
Describes how well a substance dissolves into water vs oil
What are the properties of a non-polar drug? (3)
- Fast rate of absorption from the gut
- High penetration of the brain and other tissues
- Efficient renal elimination
What kind of substance are many drugs?
Weak acids/bases
What is the pKa value for weak acids?
Always below 7
What is the pKa value for weak bases?
Always above 7
What form are weak acids in at low pH?
Un-ionized form (i.e. associated)
In which form can weak acids/bases cross lipid membranes?
Uncharged (i.e. associated)
What is the Henderson Hasselbalch equation?
pKa = pH + log10(HA/A-)
What kind of substance is aspirin?
Weak acid
What is ionic trapping?
When a substance dissociates into its ionic form in the plasma, it can’t enter cells across the lipid membrane so is trapped and circulated around the body
What reduces excretion of weak acids?
Urine acidification
How can you increase the rate of excretion of weak acids from the body?
Increase the pH of plasma e.g. sodium bicarbonate causes the drug to be trapped in the plasma in its ionic form
What is the most direct route of drug administration?
Intravenous injection
What is an intrathecal injection?
Injection into the spinal chord
What is percutaneous administration?
Application of medication to the skin for absorption
What is the most common route of administration?
Oral
Why can the rectal route be favourable over the oral route?
- Avoids the issue of the portal blood system from the gut to the liver
- Drug sent to the liver from the gut, metabolised and excreted via the kidneys
What is bioavailability?
Fraction of ingested does which gains access to the circulation
What are the factors affecting absorption? (5)
- Site/method of administration
- Molecular weight (diffusion rate)
- Lipid solubility
- pH and ionisation
- Transporters available
What is metformin used for?
Type 2 diabetes
What are the major body compartments? (4)
- Extracellular fluid
- Intracellular fluid
- Transcellular fluid
- Fat
What is included in extracellular fluid? (3)
- Plasma
- Interstitial fluid
- Lymph
What is transcellular fluid?
Fluids contained with epithelial-lined spaces e.g. CSF, endolymph and perilymph in the ear, fluid in the eyes
Which body compartments are water compartments? (3)
- Extracellular fluid
- Intracellular fluid
- Transcellular fluid
What is the Volume of Distribution (Vd)?
- Vd is the volume of fluid that would be required to hold the concentration of drug in the plasma if it was throughout the body at the same concentration
- Measure of drug distribution throughout the body compartments
How do you calculate Vd?
Vd = dose / concentration in the plasma
What does high Vd indicate?
The drug is well distributed throughout the body tissues and not much stays in the plasma
What does low Vd indicate?
The drug mainly stays trapped in the plasma and isn’t distributed to body tissues very much
What is the Blood-Brain Barrier?
The endothelial cells lining blood vessels are joined by tight junctions which prevents large/water soluble molecules passing through
What can cross the Blood-Brain Barrier?
Lipid soluble molecules
How is meningitis treated?
- IV penicillin
- Antibiotics usually can’t cross the Blood-Brain Barrier but inflammation caused by meningitis causes the tight junctions to be leaky so penicillin can enter the brain to kill the bacteria
What is the main protein in plasma?
Albumin
What kind of drug binds to albumin in plasma?
Acidic drugs (anionic)
How does binding to plasma protein impact drug distribution? (3)
- Drug bound to protein can’t diffuse into tissues/act on receptors
- Plasma concentration of the drug would appear lower because bound to protein so not ‘free’
- Can cause unexpected large increases in drug concentration when all the plasma protein is saturated with drug
How does lipid solubility impact drug distribution? (2)
- Lipophilic drugs accumulate in body fat and stay in the body for longer
- Less of the drug in the plasma membrane of the body cells so the effect is ‘diluted’
What is the pH of compartments where weak acids accumulate?
High pH (alkaline)
What is the pH of compartments where weak bases accumulate?
Low pH (acidic)
Where in the body does metabolism take place for most drugs?
Liver
What are the 2 phases of metabolism in the liver
- Phase 1 catabolic reactions
- Phase 2 synthetic (anabolic) reactions
Which enzymes are involved in drug metabolism?
- Microsomal enzymes
- Intracellular so drug must cross the plasma membrane to be metabolised
What is the largest family of enzymes involved in drug metabolism?
Cytochrome P450
What happens in phase 1 of drug metabolism?
The catabolic reactions can produce a more reactive compound
What happens in phase 2 of drug metabolism?
The anabolic reactions combine the reactive compound with other molecules to form a larger and inactive product
What are pro-drugs?
Only become active after they’ve undergone phase 1 metabolism
How can bile interfere with drug metabolism?
- Drugs administered orally may go straight to the liver from the gut via the portal system and be bound up by bile
- The bile with the drug is then secreted into the gut again and the drug is lost in the faeces without being metabolised/having its effect
How is aspirin eliminated from the body? (3)
- Phase 1 converts aspirin to salicylic acid
- Phase 2 conjugates the salicylic acid to glucuronide
- End product re-enters the plasma and is taken to the kidneys for excretion
Which environmental factors can interfere with drug metabolism? (2)
- Grapefruit juice can inhibit some cytochrome P450 enzymes
- Brussel sprouts can induce some cytochrome P450 enzymes
What determines which P450 enzyme will be metabolising a drug?
Chemical structure of the drug rather than its pharmacological family e.g. paracetamol metabolised by a different enzyme to the other NSAIDs
What effect do P450 inducers have?
Induce metabolism which can lower the plasma concentration of the drug to a point where it doesn’t achieve its therapeutic effects
Why are lipophilic drugs not well excreted by the kidney?
If they are lipophilic they will just as easily leave the kidney cells as re-enter them so the phase 2 reactions are important to combine them with something that will facilitate excretion
What are the 3 mechanisms of renal excretion?
- Glomerular filtration
- Active tubular secretion
- Passive diffusion
How can drugs be excreted via glomerular filtration?
If they have a small molecular weight after conjugation (<20kDa) they can be filtered at the glomerulus and enter the filtrate to be excreted
How can drugs be excreted via active tubular secretion?
Most widely used method for excretion of weak acids/bases via transporters
How can drugs be excreted via passive diffusion?
- Method used by lipophilic drugs, diffusion across the renal epithelium
- Not very efficient
How is penicillin excreted?
Active tubular secretion
What are the 3 methods of drug excretion?
- Renal excretion
- GI excretion (bind to bile)
- Lung excretion (expired air)
What is the t 1/2 value?
Time it takes for the plasma concentration of a drug to reduce by 50% (half life)
What is Kel?
Elimination rate constant
What shape does the time course of drug elimination follow?
Mono-exponential decay
What is saturation kinetics?
When the dose overwhelms the systems involved in metabolism/excretion of the drug so plasma concentration increases linearly with each dose instead of reaching a steady state and can causes toxicity e.g. alcohol dehydrogenase and excessive alcohol consumption
