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Flashcards by Wannie Chisala, updated more than 1 year ago
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Created by Wannie Chisala
over 8 years ago
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| Question | Answer |
| Pharmacodynamics | The effect of a drug on the body. Involves 1) Molecular interactions by which drugs exert their effects 2) Influence of drug concentration on the magnitude of response (conc-effect relationships) |
| Studying pharmacodynamics allows us to... | - Determine the appropriate dose ranges for patients - Compare effectiveness and safety of one drug to another |
| Pharmacokinetics | What the body does to the drug 1) Absorption - from site of administration to blood 2) Distribution - drug can reversibly leave the bloodstream and distribute to the interstitial and intracellular fluids of tissues 3) Metabolism - Body inactivates (or activate) the drug through enzyme modification 4) Excretion - Drug eliminated from the body in urine, bile or faeces |
| Naturally occurring sources of drugs | - Extracted from plants - Previously the major source - Important source of new drugs - e.g. Taxanes (anti-cancer) from yew tree bark = more expensive |
| Synthetic source of drugs | - Current major source, 3 catagories 1)There are totally synthetic drugs 2) Indentical, derived from natural compounds. These are semisyntetic (e.g. insuline which is identical and codine which is derived) 3) Biologics |
| Biologics | New drug source, it is classed as synthetic Genetically engineered proteins that are naturally present in the body - Derived from human genes e.g. via recombination therapy |
| Drug interaction with targets | 1) Shape interactions - Determines ability of drug to bind 'lock and key' mechanism. Shape of drug determines function 2) Charge distribution interactions - Determines type of bonds that holds the drugs to the target |
| Van der waals | Shifting electron density in a molecule results in generation of transient positive or negative charges. These react with transient areas of opposite charge on another molecule |
| Hydrogen bonding | Hydrogen atoms bound to oxygen or nitrogen become more positively polarised. These bond with more negatively polarised atoms. |
| Ionic bonds | Atoms with an excess of electrons (negatively charged) are attracted to atoms with a deficiency of electrons (positively charged) |
| Covalent bonding | Two bonding atoms share electrons. Strongest type so usually irreversible. For effect to be countered new receptors must be synthesised |
| Further considerations when it comes to drug interactions with target | 1) Hydrophobicity, ability to solubalise and pass through membranes 2) Ionisation of drug pKa, some targets only bind to ionised drugs 3) Conformation of target 4) Sterochemistry of drug molecule, different stereoisomers have different effects e.g. thalidomide |
| 4 main types of target protein | 1) Receptors - targets for endogenous transmitters e.g. hormones and neurotransmitters 2) Carriers - transort ions and small organic molecules across cell membrane 3) Enzymes - biological catalysts which facilitate biochemical reactions 4) Ion channels - Pores which span membranes to allow the selective passage of ions |
| Drugs acting by virtue of their physico-chemical properties | Not all drugs act on receptors 1) Antidotes e.g. acetylcysteine to treat paracetamol poisoning 2) Antacids e.g. aluminium hydroxide with neutralise pH 3) Laxatives e.g. lactulose which is osmotic laxative |
| How do drugs targeting receptors work | - Agonists activate the receptor e.g. Salbutamol - Antagonists block the action of agonists e.g. antihistamines |
| How do drugs targeting ion channels work | Either block or modulate the opening/ closing of the ion channel. Change frequency the ion channels open or close |
| Orthosteric site | Normal binding site of endogenous compound in body |
| Allosteric site | Binding site on channel different than the endogenous compound. Where modulators mind |
| How do drugs that act on enzymes work | - Either inhibit or act as a false substrate |
| Non steroidal anti-inflammatory drugs (NSAIDs) | Used in pain control - Target enzymes e.g. Cyclooxygenase targeted by ibuprofen and asprin. So no prostaglandins produced from arachidonic acid |
| How do drugs working on carriers (transporters work) | Either transported in place of endogenous compound so less substrate transported or inhibit transport |
| Agonists | - Mimic the action of endogenous chemical messengers - Ligand that combines with receptors to elicit a cellular response e.g. histamine acts as an agonist at H1 receptor in smooth muscle to increase local blood flow |
| Antagonists | - Block the action of endogenous chemical messengers. - Blocks response to an agonist e.g. terfenadine acts at H1 receptor in smooth muscle to decrease blood flow (antihistamine) |
| Types of receptor | - Ligand gated ion channels - G-protein coupled receptors - Enzyme (kinase) linked receptors - Intracellular receptors |
| G-protein coupled metabotropic receptors | - Most highly expressed and commonly targeted - Can be indirect i.e change secondary enzyme and direct, i.e. directly affect proteins - largest family of receptors, single polypeptide chain with 7 trans-membrane helices - Consist of 3 subunits, alpha, beta and gamma (intracellular) |
| Alpha subunit in g-protein receptor | - Gs = stimulatory, activates adenylyl cyclase, activates Ca2+ channels - Gi = inhibitory, inhibits adenylyl cylase and activates k+ channels - Gq = activates phospholipase C |
| Kinase linked receptors | - Autophosphorylaton - Slower because it initiates a phosphorylation cascade that leads to gene transcription - e.g. insuline receptor which is a tyrosine kinase receptor which responds to imatinib - Also includes, guanylyl cyclase linked, cytokine and serine/ threonine kinase |
| Nuclear receptors | - Family of 48 soluble receptors - Two classes 1) class 1 = located in cytoplasm and form homodimers (same type), ligands are endocrine (steroids and hormones) 2) class 2 = present in nucleus, form heterodimers. ligands are lipids (fatty acid) |
| Multiple drug binding sites | - well established that most receptor operated channels have multiple binding sites - binding at one site will alter binding at another site (positive or negative) e.g. binding at allosteric site can modulate receptor interactions at authosteric site |
| Graded dose-response relationship | - Response of one particular system - e.g. isolated tissue, animal or patient - Measured against agonist concentration |
| Quantal dose-response relationship | - Drug doses (agonist or antagonist) - Based on population data - Required to produce a specific response determined in each member of a population (as a %) |
| Why plot a dose-response curve | - Allow estimation of Emax - Allow estimation of of concentration or dose required to produce 50% of maximal response (EC50) - Allow efficacy to be determined - Allow potency to be determined |
| Efficacy | Max response drug produces regardless of dose (Emax) |
| Potency | Amount of drug needed to produce a given response e.g. EC50, amount of drug needed to produce 50% of maximal response. Determined by affinity and number of receptors |
| Two state hypothesis, K1 | Is the rate of association of the agonist with receptor |
| Two state hypothesis, K2 | The rate of AR complex dissociation |
| Affinity | Describes the stregnth which an agonist/ drug binds to a receptor /K-1, A high affinity drug has a much greater tendency to bind to the receptor, large K1 value relative to a small K-1 value |
| Kd | equilibrium dissociation constant. Concentration of ligand where 50% of the available receptors are occupied |
| Bmax | Receptor saturation, maximum number of binding sites, easily measured using radio ligands. But it is difficult to measure how avidly the drug bind - affinity (Kd) |
| Use of Kd | - Discover an unknown receptor - Used to quantitatively compare affinity of different drugs on the same receptor |
| Potency | Potent drugs are those which elicit a response by binding to a critical number of receptors at low conc (high affinity) compared with drugs acting on the same system with a lower affinity Depends on: - Affinity of drug - Efficacy of drug - Receptor density - Efficacy of stimulus-response mechanisms used |
| True affinity | Can only be discovered with binding dose relationships |
| EC50 vs Kd | - If there is a linear relationship between receptor occupation and biological effect then Kd and Ec50 are equal e.g. 50% receptor occupation causes 50% effect - However many receptors amplify signal duration and intensity - Because of this only a fraction of total receptors for a specific ligand may be needed to elicit a maximal cell response - Systems like this are said to have spare receptors or receptor reserves |
| Efficacy | When an agonist binds to a receptor this induces a confromational change that sets off a chain of biochemical events - Describes the ability of an agonist to activate a receptor i.e to evoke an action at cellular level - Determined by nature of receptor effector system - refers to maximum effect an agonist can produce regardless of dose |
| Full agonist | High efficacy AR* very likely Produce maximum response while occupying only a small % of receptors available |
| Partial agonist | Low efficacy AR* less likely Unable to produce a maximum response even when occupying all the available receptors |
| Example of partial agonist | - Varenicline, nicotine receptor, partial agonist for smoking cessation - Tamoxifen, estrogen receptor partial agonist used in estrogen dependant breast cancer - Aripiprazole, partial agonists at selected dopamine receptors antipsychotic |
| Ternary complex model | - Two state model predicts that a receptor can exist in two forms, AR and AR* - Ternary complex model (four active states) - Receptors can activate in absence of ligands i.e R* or change depending on GPprotein function |
| Inverse agonists | - Higher affinity for the AR (inactive state) than for for AR* (active state) - Bind to to active receptor and inhibit it to inactive state - Many classical competitive agonists display inverse agonist activity |
| Allosteric modulators | Benzodiazepines acting on GABAa receptor, increases affinity and efficacy of drug PAM (positive) = not acting alone but increases affinity and efficacy NAM (negative) = not acting alone but decreases affinity and efficacy |
| Desensitisation of receptors | - Effect of the drug reduces with continual/ repeated administration - Termed tachyphylaxis - Contributing factors include conformational changes in receptor internalisation of receptors depletion of mediators altered drug metabolism other physiological responses (homeostatic) |
| Pure antagonists | Do not by themselves cause any action by binding to receptor, simply block response to agonist |
| Classes of antagonists | 1) Chemical - binding of two agents to render active drug inactive - commonly called chelating agents - E.g. protamine binds to heparine 2) Physiological - two agents with the opposite effect cancel each other out e.g. glucocorticoids and insulin 3) Pharmacoloical - binds to receptor and blocks the normal action of an agonist on receptor responses |
| Effect of antagonist on efficacy | - Antagonist has no efficacy - AR* doesnt exist |
| Competitive antagonist | - Binds and prevents agonist action but can be overcome with increased agonist concentration - Causes parallel shift to the right of the agonist-response curve - Increased EC50 - Shift to right propotional to strength of antagonist |
| Irreversible non-competitive anagonist | - Binds and forms irreversible covalent bond with receptor - Causes parallel shift to right of the agonist-response curve and reduced maximal asymptote - Long lasting - Increased Ec50 - Receptor reserves allow parallel shift right |
| Non-competitive antagonist | - Signal transduction rather than receptor effects - Downstream responses are blocked e.g. Ca2+ influx - Reduces slope and maximum of dose response curve |
| The dose ratio | Agonist plus increasing concentrations of competitive antagonist. Curve shifts to the right = Agonist + antagonist EC50 DIVIDED BY Agonist EC50 - Long lasting |
| Schild plot | - Graph to show the linear relationship between dose ratio (log) antagonist concentration (log). As antagonist conc increases, more agonist needed to overcome |
| Kb | - Antagonist conc dissociation constant - Where schild plot crosses x axis - Shows how great of an inhibitor the antagonist is - Shows the conc of antagonist that you need to apply to reduce the effect of the agonist by 1, half effect of agonist so shows efficacy of antagonist |
| PA2 values | - Describes the activity of a receptor antagonist in simple numbers = -logKb - Used only if relation ship is linear and slope of schild plot = 1, if not then it isnt a competitive antagonist |
| Weak partial agonists | These are the same as irreversible non competitive agonists |
| Competitive vs non-competitive antagonists | - Common type of antagonism is competitive e.g. H1 receptor to cimetidine - Less common is irreversible e.g. phenoxybenzamine at a1 adrenocecptor |
| Therapeutic window/ index (TI) | Risk: Benefit ratio. TD50/ED50 Large TI, therapeutic window needed for a mild condition and smaller window can be used for more serious conditions |
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