Pharmacokinetics and Drug Metabolism Flashcards
State the five stages of the journey of a drug through the body.
Administration Absorption Distribution Metabolism Excretion (Voiding)
What is the difference between enteral and parenteral administration?
Enteral – using the GI tract
Parenteral – everything except the GI tract
enteral is easier, paraentral generally requires more skill
What are the advantages/disadvantages of intravenous administration?
It gives rapid systemic exposure and a high bioavailability, but is invasive and requires training
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 barriers. And define barriers and compartments
- barriers are lipid (eg cell membrane) and compartments are aqueous
- 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
Drugs exist in an equilibrium between ionized and non-ionized forms. Which factors affect the ratio of ionized (polar) to non-ionized (non-polar) drug?
pKa of the drug
pH of the environment
Describe and explain the difference in absorption of aspirin in the stomach and the small intestine. and liver
Aspirin has a pKa of 3.4
The stomach has a pH of around 1 so when the aspirin enters the stomach, as the pH of the stomach is lower than the pKa of aspirin, the equilibrium of the aspirin is shifted towards the unionized state
So in the stomach, aspirin mainly exists in the unionized state and is rapidly absorbed
Eventually, the aspirin will reach the small intestines which has a muchmore basic pH (which is greater than the pKa of aspirin)
This means that aspirin in the small intestine is mainly ionized and hence absorption is SLOWER in the small intestine.
Once aspirin gets to liver and gets into hepatic portal circulation and systemic circulation it is in an aqueous fair;y basic enviroment. So is effectively trapped in its ionized form and ion trapped bc cant leave circulation as easily.
What is ion trapping?
Some ionized aspirin will enter the systemic circulation, which is an aqueous environment
As it is ionized it will not be able to move into the tissues and hence is ‘trapped
State four factors affecting drug distribution.
Regional blood flow (more perfused - exposed to more of the drug, some tissues increase perfusion in activities such as exercise. Highly metabolically active tissues tend to have greater perfusion)
Extracellular binding (plasma-protein binding, 50-80% of drugs are plasma protien bound)
Capillary permeability
Localisation in tissue
In which state can albumin bind to drugs? Ionized or non-ionized?
Both ionised and unionised
State three types of capillary architecture. And their affect on drug distribution
Continuous (found in normal vessels, has water filled gap junctions)
Fenestrated (more permeable to drugs)
Discontinuous (large gaps)
Give a broad example of localization 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? and details
Kidneys (mainly) - body often converts drugs to water soluble substances you then wee out
Liver - drugs conc into bile which is then released into the intestines
What types of molecule tend to get excreted via the biliary route? and which by kidneys?
LIVER: Large molecule weight molecules
The liver allows concentration of large molecular weight molecules that are very lipophilic
KIDNEYS: excrete most xenobiotics
Via what form of molecular movement do most drugs tend to getexcreted into urine? & why
Active secretion, because can’t use ultrafiltration for large, protien bound drug complexes
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, if have something that is a lipid that was secreted into the urine from the glomerular filtration, or something that has become more lipid by becoming unionized bc of urine pH (if its pKa is larger than urine pH) it has the ability to be reabsorbed
Why might treatment with I.V. sodium bicarbonate increase aspirin excretion?
IV sodium bicarbonate will increase the pH of the blood
This will increase the amount of aspirin that is ionised
Becoming ionised will mean that the aspirin is more water-soluble and less lipid-soluble so the kidneys can more easily excrete it and less aspirin is reabsorbed in the proximal and distal tubules
This increases the rate of aspirin excretion
What is the main purpose of the active transport systems that secrete drugs into bile?
They are meant to be for the active transport of glucuronides and bileacids 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 thebody to exert its pharmacological effect
Define apparent volume of distribution.
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
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
State the equation for half-life in first-order kinetics reactions.
T1/2 = Vd x log(2)/Cl Vd = volume of distribution Cl = clearance
Define Zero-Order kinetics. And examples
A constant amount of drug is removed from the body per unit time (ethanol, salicylates, phenytoin)
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
NOTE: most drugs follow first-order kinetics
explain absorbtion
- drug goes to the liver and absorbed into the blood stream
- travels in hepatic portal circulation into the systemic circulation
- inhalation is also a good route as lungs are well perfused
- there is a risk with inhalation though if inhaling something like a powder
effect of plasma protiens on absorbtion
if p.protein is bound to a drug cant be absorbed
how can ionised aspirin travel
can travel through aqueous enviroment in gaps between endo cells
what would first order and zero order kinetics graphs look like and how would you work out inital conc of drug in plasam
1st ORDER:
x axis: t1/2
y axis: log plasma concentration
straight line graph, extropolate back to y axis to work out inital dose
ZERO ORDER:
x axis: time
y: drug concentration
straight line for zero order drugs, extrapolate to y to get inital conc
- if plotting a 1st order on this graph start high and curve down lower steeply
are most drugs first order or zero order kinetics?
first
what would you treat a patient with to increase aspirin excretion?
I.V sodium bicarbonate
