Pharmacokinetics and Drug Metabolism Flashcards
State the 5 stages of the journey of a drug through the body.
Administration Absorption Distribution Metabolism Excretion
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?
Rapid systemic exposure
High bioavailability
State the 2 ways in which drug molecules move around the body.
Bulk Flow Transfer: in the bloodstream
Diffusion Transfer: molecule by molecule over short distances
State 4 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
Which factors affect the ratio of ionized to non-ionized 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.
Aspirin has a pKa of 3.4
Stomach pH is ~1 so when aspirin enters, as the pH of the stomach is lower than the pKa of aspirin, equilibrium of the aspirin is shifted towards the unionized state and is rapidly absorbed
In small intestines pH is more basic (greater than the pKa of aspirin) Thus, aspirin is ionized and hence absorption is SLOWER in the small intestine
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 4 factors affecting drug distribution.
Regional blood flow
Extracellular binding (plasma-protein binding)
Capillary permeability
Localisation in tissues
In which state can albumin bind to drugs? Ionized or non-ionized?
Both ionised and unionised
State 3 types of capillary architecture.
Continuous (tight junctions)
Fenestrated (small gaps)
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 2 main routes of drug excretion?
Kidneys (mainly)
Liver
What types of molecule tend to get excreted via the biliary route?
Large MW molecules
Liver allows concentration of large MW molecules that are very lipophilic
Via what form of molecular movement do most drugs tend to get excreted into urine?
Active secretion
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
Why might treatment with I.V. sodium bicarbonate increase aspirin excretion?
IV sodium bicarbonate increases pH of the blood and increases the amount of ionised aspirin.
Thus, 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
Increases rate of aspirin excretion
What is the main purpose of the active transport systems that secrete drugs into bile?
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:
Gut bacteria breakdown water soluble conjugate
Free drug released, returns to liver via the enterohepatic circulation
Leads to drug persistence
Define bioavailability.
Proportion of the administered drug that is available within the body to exert its pharmacological effect
Define apparent volume of distribution.
Volume in which a drug appears to be distributed – an indicator of pattern of distribution
Define biological half-life.
Time taken for the concentration of a drug (in blood/plasma) to fall to half its original value
Define clearance.
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
What is a difficulty faced in deciding solubility of a drug?
Drugs have to traverse both aqueous (compartments e.g. blood) and lipid (barriers e.g. membranes) environments
Non polar substances can freely dissolve in…
Non polar solvents
i.e. can penetrate lipid membranes freely
When are drugs more unionised?
Weak acids: Acidic environment
Weak bases: Alkaline environment
Standard rule for acids
If pH is below pKa = more unionised
If pH is above pKa = more ionised
Standard rule for bases
If pH is below pKa = more ionised
If pH is above pKa = more unionised
Calculating ratio of unionised/ ionised
pKa - pH = y
10^y
How does regional blood flow effect drug distribution?
The more blood to a certain tissue the more drug to a certain tissue
Highly metabolically active tissues have denser capillary networks
How does plasma protein binding effect drug distribution?
If PPB, drug won’t leave blood
Need to adjust dose so sufficient amount of drug is unbound and active
