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Pharma Lec 1
| Question | Answer |
|---|---|
| What are the four main drug targets | Receptors, Enzymes, Carrier molecules (transporters) and Ion channels |
| What is Pharmacology? | The study of the action of drugs on living systems: what they do and how they work |
| Definition of a drug? | Chemical applied to a physiological system that affects its function in a specific way |
| Essentials to produce a pharmacological response? | Non-uniform distribution of drugs in the body, drug molecules must exert some chemical influence on one or more constituents of cells. Must be bound to particular components of cells and tissues to produce an effect-'components referred to as drug targets |
| Define receptor: | Protein molecule whose function is to recognise and respond to endogenous chemical signals- hormones, neurotransmitters. E.g. adrenergic receptors, acetylcholine receptors and steroid receptors |
| Define 'drug specificity': | Drug must act selectively on particular cells and/or tissue- exhibit high degree of binding site specificity |
| Define 'ligand specificity': | Selectivity of proteins for the drug that binds to them, usually high |
| Can drugs be completely specific? | No, no they cannot |
| How does potency of a drug relate to observed side effects? | Low potency drugs need higher doses, leading to activation of both primary and secondary sites of action- both to a significant level. This can induce side effects. |
| Agonists are... | Agonists activate receptors, initiating changes in cell function and eliciting a response |
| Antagonists are... | Antagonists don't activate receptors but block the effect of agonists. |
| Affinity of a drug is... | Affinity of a drug governs the tendency of a drug to bind to the receptor. |
| Efficacy of a drug is... | Efficacy of a drug is it's ability to activate the receptor once bound. |
| What is K(d)? | Concentration of a drug required to bind 50% of the receptor sites. (Affinity) |
| What use is K(d)? | Useful measure of affinity of a drug molecule for it's binding site on the receptor. |
| What does a small K(d) mean? | Greater affinity and vice versa. |
| What efficacy (e) value do you expect for a full agonist? | 1 (equal to the endogenous ligand) |
| What efficacy (e) value do you expect for a partial agonist? | 0<B<1 |
| What efficacy (e) value do you expect for a full antagonist? | 0 |
| What is the potency of a drug? | Amount of drug needed to produce a given effect. |
| What is the EC(50) of a drug? | The [agonist] causing 50% of the maximal effect, seen in graded dose-response measurements |
| What determines potency of a drug? | The affinity of the receptor for the drug and the number of receptors available. |
| What is a competition assay? | Membrane particles are exposed to a constant concentration of a radioligand and varying concentrations of an unlabelled competitive ligand until equilibrium. Graphed as % of maximum binding against log conc. of unlabelled ligand. |
| What is the IC(50)? | Concentration of unlabelled ligand which displaces 50% of the radioligand in a competition assay. |
| What should you take into account when calculating actual affinity- K(I)? | K(d) and [L]. So K(I) = IC(50)/([L]/K(d)+1. If [L] = K(d), K(I) = IC(50)/2 If [L]<< K(d), K(I) ~ IC(50) If [L]>> K(d), K(I) << IC(50) |
| Define E(max) | Maximal response of a drug (efficacy) |
| What does a small EC(50) mean? | Greater potency of drug. |
| What does receptor theory assume? | All receptors should be occupied to produce a maximal response- EC(50)=K(d) |
| What is meant by 'spare receptors'? | Maximal response can be seen without total receptor occupancy, indicates increased sensitivity of the system. |
| What is 'receptor occupancy'? | Amount of binding of a drug to its receptor, related to magnitude of response. |
| What is 'B(max)'? | Maximal occupation by a drug of the receptors |
| When can we say spare receptors exist? | If EC(50)< K(d) |
| What is the law of mass action? | Rate of reaction is proportional to the product of the concentration of reactants |
| What does the law of mass action mean for drugs? | Different tissues respond differently to specific [drug] due to receptor numbers present |
| What types of antagonism can occur? Define them | Competitive- antagonist competes with agonist for receptor binding site Non-competitive- antagonist binds to a site away from agonist binding site to inhibit binding |
| What is the difference in bonding between reversible and irreversible antagonists? | Reversible- antagonist binds non-covalently, can be 'washed out' Irreversible- antagonist covalently bonded, cannot be displaced |
| What effect is seen in reversible competitive antagonist? | Need more agonist to produce same effect. Slope of action unchanged, E(max) same, reached by increasing agonist concentration |
| What effect is seen in irreversible competitive antagonism? | E(max) not reached. |
| Briefly explain the two-state receptor model | Activated and resting receptors exist in equilibrium. When lacking agonist, usually much more resting than activated. Agonists have higher affinity for activated, inverse agonists for resting. A neutral antagonist has equal affinity for both. |
| What is an inverse agonist? | Has greater affinity for resting receptors, so reduces levels of activated receptors. |
| Of the 4 receptor types or superfamilies, what are the 3 cell-surface receptors? | Ligand-gated ion channels, G-protein-coupled receptors and kinase-linked receptors |
| What molecules do cell-surface receptors respond to? | Hydrophilic signalling molecules |
| Of the 4 receptor types, what is the intracellular receptor? | Nuclear receptors |
| What signalling molecules do intracellular receptors respond to? | Lipid based (lipophilic/hydrophobic) signalling molecules. |
| What is the role of Ligand-gated ion channels? | Rapid synaptic signalling between electrically excitable cells. Very fast (milliseconds) |
| How do drugs affect Ligand-gated ion channels? | Binding of drug causes conformational change in the channel protein to allow specific ions to flow through channel, altering the cells electrical membrane potential. |
| Describe the structure of Ligand-gated ion channels. | Similar to voltage-gated ion channels, ligand-binding site on extracellular side, 4-5 heteromeric subunits around central pore. E.g. nAChR, GABA, GlyR, 5-HT(3)R |
| Describe the structure of G-protein coupled receptors. | Integral membrane protein receptor, single polypeptide comprising 7 membrane-spanning alpha helical regions, NH(2)-terminus on extracellular side, COOH-terminus in cytosol. |
| How do ligands bind to G-protein coupled receptors? | Interact with extracellular loop regions and/or transmembrane domains. |
| What are the targets of G-protein coupled receptors? | Peptide hormones, neurotransmitters |
| Examples of G-protein coupled receptors? | Muscarinic ACh, adrenoreceptors, angiotensin II receptors |
| Which is the largest of the receptor types or 'superfamilies' | G-protein coupled receptors. |
| What are some common second messengers? | Cyclic AMP, Cyclic GMP, Diacylglycerol (DAG) and IP(3) |
| What are the subunits of G-proteins? What are their roles | Heterotrimeric complex: alpha, beta and gamma. Alpha contains GTPase activity. Alpha and gamma are attached to the cell membrane with lipid residues. Beta and gamma are also signalling molecules. |
| What happens to G-proteins when an agonist binds to the receptor | Binding of agonist allows alpha subunit to exchange GDP for GTP, this complex then detaches and attaches to secondary target. Alpha GTPase activity increases and GTP->GDP, so it reattaches to the original comples |
| When are G-proteins activated? | Activated when bound to GTP, inactive when bound to GDP. |
| What toxin found in dirty water affects G-protein activity? How? | Cholera. Prevent GTPase activity, stays activated, overstimualts adenylate cyclase and cAMP accumulates. In intestinal cells lead to; loss of chloride ions and thus water- diarrhoea and dehydration. |
| How does pertussis toxin affect G-protein coupled activity? | Prevents GDP/GTP exchange, inhibitory G-alpha cannot activate. Inability to inhibit adenylate cyclase results in cAMP accumulation. Increased insulin secretion and histamine sensitivity contribute to symptoms. |
Created by:
Alex_Olney
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