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
What are the advantages of intravenous administration?
It gives rapid systemic exposure 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 (pressure gradient)
Diffusion Transfer – molecule by molecule over short distances (conc gradient)
State four methods by which drugs can cross lipid membrane barriers.
- Diffusion through the lipid membrane (if appropriately lipophilic)
- Diffusion through aqueous gap junctions
- 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
(this is related to henderson hasselbach equation)
Ka is the ‘equilibrium constant’ of the drug when it is partially dissociated. Some drugs are naturally more skewed towards one side of the equilibrium than others.
pH has the ability to shift this equilibrium
Describe and explain the difference in absorption of aspirin in the stomach and the small intestine.
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
What is ion trapping?
Ion trapping is when membranes cause compartments on both sides of the membrane to have different pH. Unionised drugs can freely diffuse between the membrane (as they’re hydrophobic) but the level of dissociation of the unionised drug is different on both sides of the membrane due to the different pH environments. Ionised drugs after dissociation cannot cross the membrane back into the other compartment due to its charge and so are effectively trapped. within that compartment
State four factors affecting drug distribution. (Drug distribution refers to the movement of a drug to and from the blood and various tissues of the body )
Regional blood flow - some tissues are better perfused than others
Extracellular binding (plasma-protein binding can extend their half life and also affect where drugs go to in the body)
Capillary permeability (eg blood brain barrier may stop some drugs crossing)
Localisation in tissue (lipophilic tissues such as breast tissue tend to retain lipophilic drugs and hence extend their half life)
In which state can albumin bind to drugs? Ionized or non-ionized?
Both ionised and unionised
State three types of capillary architecture.
Continuous
Fenestrated
Discontinuous
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?
Kidneys (mainly)
Liver
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
some drugs are concentrated in the bile
(usually large molecular weight conjugates that cannot be handled by the kidney.) The bile then goes back to GI tract and is excreted via faeces
Via what form of molecular movement do most drugs tend to getexcreted 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 will increase the pH of the blood
This will increase the amount of aspirin that is ionised because it shifts eqm to the right.
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 the body to exert its pharmacological
effect. (basically means the proportion of the administered drug that can actually enter the SYSTEMIC CIRCULATION UNCHANGED, ie not changed by first pass metabolism)
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
this is a rearrangement of the equation on side 27 for clearance
Define Zero-Order kinetics.
A constant amount of drug is removed from the body per unit time, irrespective of the concentration of the drug
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
