PHAR2: Introduction - pharmacokinetics Flashcards
With regard to pharmacokinetics, how is absorption defined?
as the passage of a drug from the site of administration into the plasma
Define bioavailability
Fraction of the initial dose that gains access to the systemic circulation.
Overall, absorption deals with the ______ for drug transfer into the systemic circulation, whereas bioavailability deals with the _______ of drug transfer into the systemic circulation
process
outcome
What are the five main methods of drug administration?
- Intra-venous
- Oral
- Inhalational
- Dermal (percutaneous)
- Sub-lingual
What is the bioavailability for intra-venous?
100%
What are the two ways molecules move around the body from the initial site of administration?
- Bulk flow transfer (in the bloodstream)
- Diffusional transfer (i.e. molecule by molecule across short distances)
For intravenous what is the method of delivery to the intended site of action?
Bulk flow
Except for intra-venous administration, what do all other methods of administration have to do?
diffuse across at least one lipid membrane
What are the different mechanisms by which drugs can cross the lipid membrane
- Diffusion through lipid membrane
- Diffusion through aqueous pores
- Carrier proteins
- Pinocytosis
Why do most drugs not cross the lipid membrane by diffusion through aqueous pores?
Most pores are 0.5nm in diameter, most drugs are larger than this
Which method do most drugs cross the lipid membrane?
- diffusing across lipid membranes
- carrier mediated transport
Describe carrier mediate transport
which involves a transmembrane protein, which can bind drug molecules on one side of the membrane and then transfer them across to the other side of the membrane.
What do drugs need to be in order to cross the lipid bilayer by diffusion?
Drugs need to be suitably lipid soluble to do this
What determines: drug absorption from the gut or drug penetration into tissues or drug elimination in the kidneys?
lipid solubility
For oral administration of the drug, which barriers need to be crossed?
a) small intestine microvilli
b) blood vessel wall to enter blood
c) blood vessel wall to access relevant tissue for effect
For inhalation of the drug, which barriers need to be crossed?
a) alveoli/bronchi
b) blood vessel wall to enter blood
c) blood vessel wall to access relevant tissue for effect
For intra-nasal administration of the drug, which barriers need to be crossed?
a) mucous membranes of nasal sinus
b) blood vessel wall to enter blood
c) blood vessel wall to access relevant tissue for effect
Why will drugs exist in both ionised and unionised states?
Most drugs are either WEAK ACIDS or WEAK BASES
Is aspirin a weak acid or base?
weak acid
Is morphine a weak acid or base?
weak base
At physiological pH (7.4), how would aspirin and morphine act?
Aspirin would be more likely to donate protons (H+) and morphine to accept protons (H+)
Which of the ionised or unionised forms of aspirin and morphine going to be more lipid soluble?
Unionised/non-polar = more lipid soluble
Lipid membrane = non polar
Therefore like for like -> more lipid soluble
What is a huge determinant of absorption of drugs across lipid membranes?
pH of the tissue
Weak acids will be more unionised in What type of environments?
Acidic
Weak bases will be more unionised in what type of environments?
Alkaline
What does dissociation constant mean?
quantitative measure of the strength of acid in a solution
How do you determine the ratio of ionised to unionised drug?
By the dissociation constant (pKa) and the pH in that particular part of the body
How are weak bases represented?
B + H+ BH+
How are weak acids represented?
A A- H+
What does dissociation involve?
Loss of a proton
What is the dissociation constant determined by?
The Henderson-Hasselbalch equation
What is the Henderson-Hasselbalch equation for weak bases?
pKa = pH + log [BH+]/[B]
What is the Henderson-Hasselbalch equation for weak acids?
pKa = pH + log [AH]/[A-]
Does the pKa of the drug change as it passes through the body?
No
Why does the body compartment have a significant impact on the amount of ionised versus unionised drug in that particular compartment?
The pH of the body compartment will change, therefore ratio of ionised to unionised drug will change
How do you rearrange the Henderson-Hasselbalch equation to calculation the ratio between ionised and unionised acid
antilog[pKa-pH]=[AH]/[A-]
How do you rearrange the Henderson-Hasselbalch equation to calculation the ratio between ionised and unionised base
antilog[pKa-pH]=[BH+]/[B]
If the pH and pKa are the same then what does that mean about the ratio between ionised and unionised drug ratio?
50% 50%
If the pKa of Aspirin is 3.5, if the urine pH is 8, then work out the ratio of the ionized and unionized forms of aspirin
0.00003
If the pKa of Morphine is 8, if the urine pH is 8, then work out the ratio of the ionized and unionized forms of morphine
1
If the pKa of Morphine is 8, if the blood pH is 7.4, then work out the ratio of the ionized and unionized forms of morphine
3.98
If the unionised:ionised drug ratio is high, what does this mean about the delivery of the drug?
a significant proportion of the drug (the unionised portion) should easily cross the lipid membranes of one body compartment and thus gain access to other body compartments.
If the unionised:ionised drug ratio is very low, what does this mean about the delivery of the drug?
a very significant proportion of the drug will struggle to diffuse across the lipid membranes of the body compartment and will remain ‘trapped’ in these compartments
What is known as the pH partition hypothesis?
The proportion of drug in any body compartment is dependent on pH. It also results in the phenomenon of ‘ion trapping’ – acidic drugs tending to become ‘trapped’ in compartments with high pH and basic drugs tending to become ‘trapped’ in body compartments with low pH.