Drug Interactions with Receptors and Ion Channels (Concepts) Flashcards
What are the different drug targets?
- Rceptors (40%)
- Enzymes (30%)
- Hormones (10%)
- Ion channels (5%)
- DNA (4%)
- Nuclear receptors (3%)
- Others (8%)
What is a receptor?
Protein acting as a signal transucer for a number of different chemical messengers and activating a number of different intracellular chemical cascades in their presence.
What are the different types of drug-receptor interactions (from strongest to weakest)?
- Covalent bonding
- Ionic bonding
- Hydrogen bonding
- Van der Waals interactions
- Hydrophobic interactions
What is the ‘zipper model’ of drug-receptor interaction?
- Ligand initially forms one interaction with receptor, stabilising the structure of ligsnd.
- It becomes more energitically favourable for further interactions to form between ligand and receptor.
- More interactions form between ligand and receptor and the ligand ‘zips’ onto the receptor.
What evidence may be used to support fact that a drug may not act on receptors (or specific drug target)?
- Higher potency: Effective concentration of drug needs to be high in order to produce pharmacological effect.
- Reduced biological specificity: Affects multiple tissues in very similar ways.
- Reduced chemical specificity: Slight changes in chemical structure have little effect on function.
- No antagonist: No other molecules can inhibit their action in an indirect manner.
What is the difference between selectivity and specificity?
- Selectivity is when a drug has a higher preference for one receptor to others, but still acts on a broad range of receptors.
- Specificity is when a drug acts on one type of receptors alone and no others.
- Most drugs are highly selective, but there are few drugs that are 100% specific.
What is the therapeutic index?
- Theapeutic index = Toxic dose ÷ Therapeutic dose
- High therapeutic index → Drug causes few side effects as toxic dose >> therapeutic dose
- Low therapeutic index → Drug causes lots of side effects as toxic dose ≥ therapeutic dose
What is affinity and efficacy?
- Affinity is a measure of the tendency for a drug to bind to a specific receptor.
- Efficacy is a measure of the ability for a drug to induce a response once bound to a receptor.
What is an agonist?
Molecule that has high affinity for receptor and some degree of efficacy as well (determining type of agonist)
What an antagonist?
Molecule that has high affinity for a receptor but zero efficacy.
What are the different type of antagonism?
- Competitive antagonism: Antagonist competes with receptor ligand for binding to active site.
- Non-competitive antagonism: Antagonist binds to allosteric site on receptor, inducing conformational change affecting ligand binding/receptor function.
What are the mechanism by which a ligand-receptor system can be antagonised?
- Inhibition of enzymes in synthesis or conversion from precursor to active molecule.
- Inhibition of molecule binding to receptor by occupation of binding site (competitive inhibition).
- Inhibition of molecule binding to receptor by occupation allosteric site away from binding site (non-competitive inhibition).
- Inhibition of elements involved in intracellular downstream response cascade from receptor activation.
What is the shape typical shape of a [ligand] - % response curve and log([ligand]) - % response curve?
- [ligand] - % response curve is hyperbolic in shape
- log([ligand]) - % response curve is sigmoidal in shape
What change occurs to the sigmoid log [agonist] - % response curve under competitive antagonism?
- Shifts to right
- No change in maximum response
What is the significance of a structure-activity relationship?
If multiple receptors respond to the same ligand, structure-response relationships can be used to ‘fingerprint’ each type of receptor as it is unique for each type.
What is differentential antagonism?
- Different receptors that respond to the same ligand should be structurally different enough that they react to different antagonists
- Some receptors are inhibited by some antagonists while being ignored by others
- This can be used to identify receptors
What is relationship between affinity constant (Ka), drug concentration ([D]) and % occupancy (α) = 50%?
When α=0.5, [D] = Kd = 1/Ka
What is the method of a radioligand binding experiment?
- Radioactively labelled ligands (with 3H or 125I) are added to test tube with isolated receptors bound to liposomes.
- Mixture left for sufficient time until equilibrum is achieved.
- Receptors are isolated by centrifugation or filtration and are thoroughly washed so that any unbound ligand is removed.
- Radioactivity present is counted using scintillator.
How is specific binding achieved in a radioligand experiment?
Adding an excess of a non-radiolabelled ligand and repeating experiment should allow non-specific binding to be measured as the specific binding should be abolished. Subtracting non-specific binding from total binding allows specific binding to be achieved.
What are the characteristics of specific and non-specific binding?
Specific binding:
- Low capacity
- High afinity
Non-specific binding:
- High capacity
- Low affinity
What is the Scatchard plot and how can K1 and Bmax be obtained from it?
Gradient = -K1
X-intersect = Bmax
What is the key asumption made when using the 2 ligand fraction occupation equation?
When response is the same as when only 1 ligand present, fraction occupancy of receptor is also the same.
What is the dose ratio equation and what is it used for?
[D]2/[D1] = 1 + [A]K2
Where:
[D]1 = Dose of agonist needed to produce response x
[D]2 = Dose of agonist needed to produce response x in presence of antagonist A
K2 = Affinity constant of A
This equation is used to obtain K2
What assumption is made when using the “Inhibition of radioligand binding equation”?
Unlabelled ligand cannot distinguish between receptors bound and unbound to the radioligand. It is assumed that statistically, when half of radioligands bound have been displaced by unlabelled ligand, half of all receptors have been occupied, so fraction occupation (α) = 0.5.
