4 - Pharmacokinetics Flashcards
What is meant by pharmacokinetics?
what the body does to the drug
how the drug is absorbed, metabolised and excreted by the body
the journey of a drug through the body
State the five stages of the journey of a drug through the body.
Administration Absorption Distribution Metabolism Excretion (Voiding)
(ADME)
What is the usual route of an ingested drug?
enters GI tract, gets absorbed in the SI, goes through the liver via hepatic portal system before entering the systemic circulation (some may go into the bile and back to the liver again)
What is the difference between enteral and parenteral administration?
Enteral – using the GI tract
Parenteral – everything except the GI tract
What are the advantages of intravenous administration?
It gives rapid systemic exposure (onset) and a high bioavailability
State the two ways in which drug molecules move around the body.
Bulk Flow Transfer – in the bloodstream it will move in bulk to the tissues
Diffusion Transfer – molecule by molecule over short distances
State four methods by which drugs can cross lipid membrane barriers.
Diffusion through the lipid membrane (if appropriately lipophilic)
Diffusion through aqueous pores
Carrier molecules
Pinocytosis
Finish the sentence: most drugs are either …… or …….
Weak acids or weak bases
exist in ionised (polar) or non-ionised (non-polar) form
Which factors affect the ratio of ionised to non-ionised drug (the dynamic equilibrium)?
pH of the environment
pKa of the molecules
Is aspirin acidic or basic?
What is its pKa?
acidic
pKa of 3.4
Describe and explain the difference in absorption of aspirin in the stomach and the small intestine.
Stomach pH of around 1
The pH of the stomach is lower than the pKa of aspirin, the equilibrium of the aspirin is shifted towards the unionised state
So in the stomach, aspirin mainly exists in the unionised state and is rapidly absorbed
In the small intestines which has a much more basic pH (which is greater than the pKa of aspirin)
So aspirin in the small intestine is mainly ionised and hence absorption is SLOWER in the small intestine
What is ion trapping?
When ionised aspirin enters the systemic circulation, it is in an aqueous environment. However, it will not be able to move into the tissues and hence is ‘trapped’
State four factors affecting drug distribution.
Regional blood flow
Extracellular binding (plasma-protein binding)
Capillary permeability
Localisation in tissue
What percentage of acidic drugs tend to bind to plasma proteins?
50-80%
In which state can albumin bind to drugs? Ionised or non-ionised?
Both ionised and unionised
State three types of capillary architecture.
Continuous
Fenestrated
Discontinuous
Give a broad example of localisation of a drug in tissue.
Lipophilic drugs tend to localise in fatty tissues e.g. brain and testes
What are the two main routes of drug excretion?
Kidneys (mainly)
Liver
(other methods include exhalation and through sweating)
What happens to drugs in the kidneys that means that many drugs are excreted through them?
converting the drug into something water soluble
How are drugs processed and excreted through the liver (generally)?
concentrated in the bile, which is secreted into the small intestines
What types of molecule tend to get excreted via the biliary route?
Large molecule weight molecules
The liver allows concentration of large molecular weight molecules that are very lipophilic
What happens to drug-protein complexes at the glomerulus?
They are not filtered into the filtrate
Where does active secretion of acids and bases occur in the nephron?
Proximal convoluted tubule
What can happen to lipid soluble drugs in the proximal and distal convoluted tubules?
They could be reabsorbed
Compare how you would take aspirin to cure a headache to how you would take it in the treatment of Parkinson’s
- take it in its double form for an immediate effect
- for a prolonged effect, take it in its insoluble form (with a coating that is only broken down in the conditions of the small intestine)
Why might treatment with I.V. sodium bicarbonate increase aspirin excretion?
- increase in pH of the blood
- increase the amount of aspirin that is ionised
(ionised aspirin = more water-soluble and less lipid-soluble) - less aspirin is reabsorbed in the proximal and distal tubules
- increase in the rate of aspirin excretion
What is the main purpose of the active transport systems that secrete drugs into bile? How do drugs use this mechanism?
They are meant to be for the active transport of glucuronides and bile acids into the bile but drugs can hitch a ride on this mechanism
What is a potential problem with biliary excretion of xenobiotics?
Enterohepatic cycling – it can become reabsorbed and return to the liver via the enterohepatic circulation
This leads to drug persistence
Define bioavailability.
The proportion of the administered drug that is available within the body to exert its pharmacological effect
Define apparent volume of distribution.
(theoretical mathematical value)
The volume in which a drug appears to be distributed – an indicator of pattern of distribution
Define biological half-life.
The time taken for the concentration of a drug (in blood/plasma) to fall to half its original value
Define clearance.
The volume of plasma cleared of a drug per unit time
linked to excretion
Define First-Order kinetics.
When the rate of drug excretion is proportional to the concentration of drug remaining within the body
Log of drug concentration is proportional to time
Depends on the concentration of the drug in the body at any given time
How is the volume of distribution derived from a first-order kinetic graph?
dose divided by the initial concentration of the drug in plasma
State the equation for half-life in first-order kinetics reactions.
T1/2 = Vd x log(2)/Cl
(NOTE: log(2)=0.7)
Vd = volume of distribution
Cl = clearance
Define Zero-Order kinetics.
A constant amount of drug is removed from the body per unit time
(it is independent of the concentration of the drug in the body)
How is a zero-order kinetics graph drawn differently to that of a first-order kinetics graph?
y-axis [drug] is linear/analogue (rather than logarithmic)
What does zero-order kinetics suggest about the enzymes involved?
It suggests that the enzymes are saturated
Once the enzymes are saturated, the rate of removal of a drug peaks and remains constant
Which order kinetics do most drugs follow?
first-order
