Pharmacokinetics Flashcards
Explain the relevance of the concentration of drug molecules
- The concentration of drug molecules around receptors is critical in determining drug action.
- Drugs of equivalent molar concentrations have the same concentration of drug molecules.
- Drugs of equivalent concentrations by weight may not.
Molecular Weight X Molarity = Grams per litre
Explain affinity and efficacy
Some drugs bind to receptors and cause a response (Agonists) - these drugs have both affinity and efficacy.
Some drugs bind to receptors but do not cause a response (Antagonists) - these drugs have affinity only.
Affinity – Likelihood of a ligand binding to its target
Efficacy – Likelihood of activation. Efficacy governed by intrinsic efficacy (ability of a ligand to activate the receptor) amongst other factors.
How can information on drug receptor binding be obtained?
Binding information is often obtained by the binding of a radioligand (a radioactive version of the ligand).
What is Bmax?
Maximum binding capacity. This gives information about the number of receptors.
What is Kd?
Dissociation constant. This is a measure of affinity. The concentration needed for 50% occupancy. A lower Kd value relates to a higher affinity.
Kd is reciprocal of affinity
What is a logarithm
exponent by which a base value has to be raised by to give a particular number
What is the difference between concentration response curves and dose response curves?
Concentration Response Curves – Used in measuring a response in cells/tissues
Dose Response Curves – Used when measuring a response in a whole animal.
What is the difference between concentration and dose?
Concentration – known concentration of drug at site of
action – e.g. in cells and tissues
Dose – concentration at site of action unknown – e.g. dose to a patient in mg or mg/kg
Terms often used interchangeably
What is EC50?
- effective concentration giving 50% of the maximal response. This is a measure of agonist POTENCY - it depends on BOTH affinity and intrinsic efficacy (ie. ability to activate receptor)
- PLUS cell/tissue-specific components (that allow something to happen)
Discuss affinity and efficacy in a clinical setting (asthma)§
In Asthma, the treatment goal is to activate beta2-adrenoceptors to relax the airways. However, there are beta-adrenoceptors elsewhere in the body, e.g. beta1 in the heart increase the force and rate of contraction.
Salbutamol is a beta2-adrenoagonist that has a Kd of 20 mM for beta-1 and 1mM for beta-2. As the Kd for b2-adrenoceptors is lower, it has a higher affinity. As well as this, beta-2-selective efficacy and route of administration (Oral spray), limits 1 activation and side effects.
Salmeterol is a longer acting 2-adrenoagonist than Salbutamol. It has no selective efficacy, preventing beta-1 activation and side effects purely through differences in affinity. Salmeterol has a Kd of 1900nm for beta-1 and 0.55nm for beta-2. Beta-2’s lower Kd value gives it 3,455 times greater affinity than beta-1.
Explain what is meant by “partial agonist”
In some cases, less than 100% receptor occupancy will give 100% response. I.e. EC50
What is the relevance of altered receptor number?
Receptor numbers are not fixed:
- tend to increase with low activity (up-regulation)
- tend to decrease with high activity (down-regulation.(physiological, pathological or drug-induced changes). for drugs this can contribute to tolerance/tachyphylaxis
What is a partial agonist?
-low intrinsic efficacy
When comparing the ability of different agonists to evoke responses in a tissue, it is sometimes observed that some drugs cannot produce a maximal effect, even with full receptor occupancy. These drugs are referred to as partial agonists.
The EC50 of a partial agonist is equal to its Kd. The potency of a drug is dependent on both its affinity and efficacy; therefore partial agonists can be more or less potent than full agonists.
A partial agonist may not always be a partial agonist, depending on the tissue and the biological response. For example in Tissue A, the activation of all receptors does not produce sufficient signal for a full response. Tissue B however has more receptors to contribute to the signal therefore has a stronger response.
What is the relevance of a partial agonist?
- Can allow a more controlled response
- Work in the absence or low levels of (endogenous) ligand
- Can act as antagonist if high levels of full agonist
Discuss the clinical use of Partial Agonists
Morphine is a full agonist of the u-opioid receptor, used for pain relief. Buprenorphine is a partial agonist, with a higher affinity but lower efficacy than morphine. This can be advantageous if it provides adequate pain control, as there is less respiratory depression.
