Week 1/2 Flashcards

Question

Agonist

Answer 1

- promotes a receptor mediated biological response (promotes normal response). * Eg. Hormones, neurotransmitters, drugs…. * Also called ligands if endogenous agonists

Answer 2

- promotes a receptor mediated biological response (opposite to the normal physiological response)

Answer 3

Generally, the binding of an agonist causes small changes in the receptors shape which can then lead to the activation of ‘second messenger’ systems (called ‘effectors’) Binding of an agonist to its receptor is a reversible process

Answer 4

1. Receptor-agonist interactions involve physical contact 2. Bound agonist (or drug) remains in contact with the receptor for only a very short time (so relies upon a high enough local concentration to ensure that agonist is always bound to the receptor) 3. Agonists only bind to receptors at the active site that have the correct shape 4. Binding of an agonist to the receptor must change the receptor in some way to elicit a physiological response (activation of second messenger system) 5. Agonist-receptor interactions are usually reversible Agonist-receptor interactions are concentration dependant

Answer 5

Affinity: How readily an agonist binds to its receptor and stays bound. Efficacy: the tendency of a drug, once bound to the receptor, to activate the receptor and cause a physiological response (how effectively does the drug induce the tissue to respond MAXIMALLY).

Answer 6

- binding affinity is measured as KD – the ‘reciprocal affinity constant’, or ‘equilibrium dissociation constant’ - KD are in concentration (in M or molar) - KD is roughly the concentration of drug at which 50% of the available receptors are bound to drug/agonist * A bigger KD means a smaller affinity for the receptor, a smaller KD means a higher affinity for the receptor

Answer 7

There's a direct correlation between the concentration of a drug and its ability to exert a physiological response. * ‘efficacy’ is easier to measure than ‘affinity’, so we normally measure the efficacy of a drug instead. These responses can include: * Tissue contraction or relaxation (eg. organ bath experiments) * Blood flow (eg. vasodilation) * Enzyme activation * This is evaluated by changing the concentration of the drug and measuring how this changes the physiological effect (like in your virtual ileum or organ bath pracs) * At the higher concentrations of drug we observe a plateau in physiological response (ie. all receptor binding sites are bound to drug and no further increase in response can be observed). * The maximal physiological response that the tissue can exert (when all receptor sites are bound to agonist/drug) is termed Emax or 100% Effect. All other responses (at lower drug concentrations) are reported as a % of this maximal response.

Answer 8

Partial agonists only have part efficacy (limited %Emax) Inverse agonists cause tissue response to have the opposite effect Eg. An agonist may cause tissue contraction, an inverse agonist would cause the tissue to relax - Requires the tissue to have a baseline level of ‘response’

Answer 9

refer to a phenomenon where a cellular response can be achieved with only a fraction of the total available receptors. In other words, a drug or signaling molecule can produce a maximal effect even when it doesn't bind to all the receptors on a cell's surface. - suggests that a significant portion of receptors can remain unoccupied, and the cell can still respond to a stimulus because the signalling pathway is highly efficient.

Answer 10

The biological response of agonist drugs is almost proportional to the fraction of receptors that are bound to the drug (eg. KD and EC50 are almost the same) in the following systems: * Smooth muscle relaxation * Hormone secretion

Answer 11

- where a cell's receptor is constantly and spontaneously active, even in the absence of its normal activating ligand (molecule that binds to the receptor to trigger a response). - can result from genetic mutations, structural changes in the receptor, or other factors that cause the receptor to be in an "on" state. Agonists have a higher affinity for ‘active state’ receptors and therefore promote MORE receptor activation (eg. more muscle contraction than usual) Inverse Agonists have a higher affinity for ‘inactive state’ receptors and therefore promote LESS receptor activation (eg. more muscle relaxation than usual)

Answer 12

reduced responsiveness of a receptor to a drug that occurs over a few minutes

Answer 13

reduced responsiveness of a receptor to a drug that occurs slowly over prolonged use

Answer 14

loss of effectiveness of chemotherapeutic drugs (anticancer/anti-microbial drugs)

Answer 15

- Change in receptors (eg. shape) - Translocation of receptors away from (e.g.) the cell surface - Run out of mediators - More accelerated metabolism of the drug - Physiological adaption (homeostatic regulation in the body to counter the physiological effect of the drug. E.g. increased baseline blood pressure in response to long term treatment with a BP lowering drug)

Answer 16

Where one drug binds to another drug in solution and prevents it from binding to its receptor Clinical example: Heparin = negatively charged polysaccharide used as an anticoagulant during surgery. It works by binding to a number of heparin binding proteins. Protamine = given after surgery to ‘mop up’ left over heparin and prevent it from binding to heparin binding proteins, to prevent bleeding and blood loss after surgery

Answer 17

Where one drug acts to reduce the concentration of another drug at its binding site, limiting the number of drug molecules that can bind receptors Clinical example: Phenobarbital is an anticonvulsant used to treat seizures and also upregulates cytochrome P450 enzymes (increases their expression in the liver) These P450 enzymes can then metabolise drugs such as warfarin (an anticoagulant, like heparin)

Answer 18

Where one drug binds to a different and unrelated receptor to another drug to produce an effect that is the opposite to the second drug Clinical example: * Glucocorticoid drugs (eg. cortisone) bind to the glucocorticoid receptor   blood glucose * Insulin binds to the insulin receptor  promotes glucose uptake into cells   blood glucose

Answer 19

Where one drug directly competes with an agonist drug for receptor binding, but does not stimulate a physiological response. * Three types of pharmacological antagonism: * Reversible competitive antagonism (antagonist can come off of receptor) * Irreversible competitive antagonism (antagonist sticks and doesn’t let go) * Non-competitive antagonism (antagonist binds to a different part of the receptor)

Answer 20

* similar in structure to agonists, but they do not allow the promotion of second messenger signalling * The agonist and the antagonist compete in a concentration dependant manner for binding to the receptors ‘active’ binding site (as in the binding site that promotes second messenger signalling)

Answer 21

- Binding of antagonist is reversible - Time antagonist stays bound relates to its affinity (KD) - Emax is the same as agonist alone - EC50 is larger than agonist alone

Answer 22

- antagonist sticks and doesn’t let go (or leaves very slowly) * These types of antagonists often have reactive groups that form covalent bonds with the receptor * Since they only decrease the number of available receptor sites, they usually reduce efficacy (Emax), but the EC50 stays the same.

Answer 23

antagonist binds to a different part of the receptor

Answer 24

- Some receptor classes have a high degree of orthosteric binding site similarity, making it hard to develop drugs that just target one specific receptor. - Targeting the allosteric site increases drug target selectivity