Year 1 Pharmacology 1A PDF

#separator:tab #html:true #tags column:12 What is a drug?Example: any substance (other than food) with a known chemical structure that produces a biological effect when administered to a living organisme.g. salbutamol - used to treat asthma What is a medicinal product/drug product? any dru...

#separator:tab #html:true #tags column:12 What is a drug?Example: any substance (other than food) with a known chemical structure that produces a biological effect when administered to a living organisme.g. salbutamol - used to treat asthma What is a medicinal product/drug product? any drug substance or combination of drug substances together with added ingredients that is intended to treat, prevent, diagnose, or relieve symptoms of a disease or abnormal condition What is a drug target? a molecule in the body, typically a protein, that is intrinsically associated with a particular disease process and that could be targeted by a drug/medicinal product to reach a therapeutic effect "Lable the cell:" "" What are the components of the cell membrane? (3) PhospholipidsProteins (integral and peripheral)Other lipids (cholesterol) What are the 2 components of a phospholipid? Head (phosphate group)           polar = hydrophilicTails (fatty acids)          non-polar = lipophilic (or hydrophobic) What are the 4 properties of cell membranes? Provide structural supportAsymmetric and dynamicSelective permeability barrierCommunication What are some properties of mitochondria? 1000s in each cell/size of bacteriumdouble membrane structure -important for oxidative phosphorylation/ATP generatuonContains enzymes for the Krebs cycleImportant for aerobic respiration         - Nutrients + O2 in ---> Energy (ATP, GTP) + CO2 out         - 1 molecule glucose = 24 ATP Describe the components of the nucleus and their functions: Nuclear Envelope: 2 membrane containingNuclear pores - allow material in and out of nucleus (mRNA)Chromatin - combination of DNA and proteins that make up the genetic contents of the nucleus of a cell. Packages DNA into a smaller volume to helping to prevent DNA damage.Endoplasmic reticulum - sits outside nucleus main site of protein synthesisNucleolus - non-membranr bound structure made of proteins and nucleic acids. Contains ribosomal RNA - produces ribosomes. Also involved in mRNA exportdegradation Describe/explain the different processes that can occur in port-translational modifications: (5) "Phosphorylation - adds a phosphate to serine, threonine or tyrosineLipidation - attaches a lipid, such as a fatty acid, to a protein chainUbiquitination - adds ubitiquitin to a lysin residue of a target protein marking it for destructionDisulfide bond - covalently links the ""S"" atoms of 2 different cysteine residuesAcetylation - adds an acetyl group to the N-terminus of a protein to increase stability" What is the 'central dogma'? It is the flow of genetic information within a biological system.It is a theory stating that genetic information flows ONLY in 1 direction:from DNA ---> RNA ---> ProteinOR RNA ----> Protein WHat makes different cells able to be drug targets? Their specific protein repetoir allows us to identify them as drug targets. What does it mean that cell membranes are asymmetric and dynamic? That components of the cell membrane can move around they are not in a fixed position/place What molecules can passivey pass through the phospholipid bilayer of the cell surface membrane? Small polar and ANY non-polar molecules can pass through and thus, diffuse into the cell down their concentration gradientSmall polar molecules - e.g. H2O, EtOHNon-polar molecules:       - Gases - e.g. O2, CO2 Lipid-soluble molecules - e.g. cortisol, benzene What molecules CAN'T passively pass thorugh the phospholipid bilayer of the cell surface membrane? The phospholipid bilayer DOESN'T allow the passive transport (simple diffusion) of:Charged particles - e.g. Na+, K+, Ca2+ Large polar molecules - e.g. glucose and neurotransmitterstherefore they use ACTIVE TRANSPORT - either active transport or facilitated diffusion using protein channels or carrier/transport proteins Describe the differences between DNA and RNA: DNA:Bases: Thymine (T), Adenine (A), Cytosine (C), Guanine (G)Double strandedFound in: nucleus, mitochondriaSelf replicatesRNA:Bases: Uracil (U), Adenine (A), Cytosine (C), Guanine (G)Single strandedFound in: Cytoplasm, ribosomes, nucleus (mRNA)NO self-replication - can only be made from DNA Describe the process of making protein from DNA: (6) "In NucleusChromatin remodelingTranscriptionRNA processing (e.g. splicing)IN CYTOPLASMmRNA stabilityTranslation (in ribosome)Post-translational modification (in golgi apparatus OR ER) - folding, glycosylation, transport, activation, degradation of protein  " Describe what happens during post-translational modification: "" Meaning of nascent: recently coming into existence Describe what happens during protein traffic: "Protein syntehsis om bound ribosomes (e.g. RER) and transport into the ER for folding by chaperone proteins, formation of disulfide bridges, glycosylation,etc.Budding and fusion of ER transport vesicles to golgi apparatus (secreted and membrane proteins ONLY) Progression across the golgi network3 Pathways:    1) Sorting to lysosomes     2) Transport of memrbane proteins to cell membrane     3) Regulated secretion - exocytosis via secretory vesicles" What are 4 common drug targets? ReceptorsIon channelsEnzymes Transporters (carrier molecules) Give the 4 common drug targets and their locations: "A G-protein-coupled receptor (GPCR)          - CELL SURFACE MEMBRANEA channel-linked receptor          - CELL SURFACE MEMBRANE An enzyme drug target          - CYTOSOL INTRACELLULAR (liquid within cytoplasm)A transport protein drug target          - CELL SURFACE MEMBRANE" What is the cytosol? it is the fluid that fills a cell and is a component of the cytoplasm Descirbe the general function of most drugs? "Most drugs interfere with cellular communicationThey generally either mimic or modulate communication Either communication between cells (intercellular)Or communication within cells (intracellular)Both results in a change in biological outcome" What does it mean to mimic communication (using drugs)? do what that cell does already but maybe better meanig of modulate (in pharmacology): to alter the function or status of a signal or cell in response to the drug How do drugs effect celllular communication? "They can changee how a ligant binds to a receptor (e.g. changing the complex) - can either increase binding ro decreaseCan change signalling pathways/cange in cell - can switch thing on/offtherefore can change the functional respons of a cell either lose function or activate, etc." What are teh 2 different ways that cells communicate with each other? Communication between cells - intercellular signalling Communication within cells - intracellular signalling Is intracellular signalling fast or slow? Explain: "BOTHas the intracellular signalling pathway can immediately alter protein unction and alter cell behaviour in cytoplasm or it can be slow where it alters DNA and RNA in the nucleus and thus  alters protein synthesis therefore slow (e.g. steroids)" What are the 2 different types of receptors used in cell signalling? Examples: "Cell Surface receptors - the binding of ligand to a cell surface rece[tor catalyses a change inside the cell             - e.g. effect histamine on acid release             - e.g. effect insulin on fat cells             - effect adrenaline on heartIntracellular receptors - receptors within the cell (e.g. within the nucleus)              - e.g. effect testosterone on muscle development              - e.g. effect thyroid hormone on energy expenditure" Describe protein kinases in protein phosphorylation as a form of intracellular signalling: "Protein phosphorylation is a cycle " Describe the 4 types of intercellular signalling: "Intracellular signalling is the starting point and that leads to intercellular signallingContact-Dependent - activates a receptor on a target cellParacrine - a mediator is produced by signalling cell and those go bind and activate many different target cellsSynaptic - FAST - electrical signalling causing neurotransmitters to be released to bing to target receptorsEndocrine - SLOW -hormone is released and travels in the blood to bind to receptor in target cell" What types of long-range signalling (intercellular) is slow and which is fast? Explain: SLOW: Endocrine signallingchemicals take time to travel around the entire bloodstreamFAST: Synapticneurones are long and the action potentials cause cell signalling to be faster - neurotransmitters will travel faster between synapses Descibe the variety in cellula responses to a single signalling molecules using the example of acetylcholine (ACh):How is this linked to how we develop drugs? "It is realsed from parasympathtuc neurones - part of rest and digest response:The reason for muscles contracting and heart muscle not contracting is that there are different types of receptors on muscles causing them to contract whilst heart muscle relaxes more (different receptors could cause different responses using the same signalling molecule).we need to think about drug selectivity in order to activate/bind to ONLY 1 recepto to have only 1 response and NO OTHERS (thats why some can have side effects as they can produce iother reponses as well)" Descibe the variety in cellular responses to a single signalling molecules using the example of adrenaline (and hte effects different drugs have on it): "Adrenaline:          - secreted via adrenal medulla          - used in fight-or-flight response          - noradrenaline via sympathetic neurones2 drugs affect the effects of adrenaline:Propranolol binds to adrenal receptors in the heart  and stops adrenaline binding which stimulates the heart therefroe increasing HR thus more blood pumps around the body - thus more O2 in blood to muscles for aerobic respiration for increased muscle contraction (thus more ATP) - ANTAGONISTSalbutamol - binds to receptors on the lungs and increases the activity of adrenaline on the lungs threfore relaxes the airway thus more O2 gets into the lungs as wider airway - for faster and deeper breathing - AGONIST " Meaning of an agonist in pharmacology: a chemical substance that binds to and activates certain receptors on cells, causing a biological response Meaning of antagonist in pharmacology: a substance that prevents or reserse the action or effect of another substance (called an agonist), by binding to a receptor without activating it Why should salbutamol and propanolol not be taken together? "As salbutamol is an agonist and propaanolol is an antagonist therefore would decrease the effect of salbutamol (as they are kind of cancelling each other out a little bit)" Describe (with eamples) the 4 different types of receptor drug targets: "Ligand-gated ion channels - e.g. AChG protein-coupled receptors (GPCR) - e.g. dopamineKinase-linked receptors etc. - e.g. insulinNuclear receptors - e.g. steroids such as estrogen" Describe how a G protein-coupled receptor looks like: "7 transmembrane receptorsG-protein coupling domain is activated by GTPBut there can be many different representations of these so its important to become familiar with them all:" How does a G-protein activate? When the G protein-coupled receptor is activated Give 4 examples of G protein-coupled receptors and their functions: Gs (α): activation of adenylyl cyclaseGi (α): inhibition of adenylyl cyclaseGq (α): activation of phospholipase CGi (βγ): opening ion channels (K+) What does propranolol do? It is a blocker of the Gs coupled beta-adrenergic receptor: stops effects of adrenaline on the heart (used for high BP and panic attacks) What does salbutamol do? It is the agonist of the Gs coupled beta2-adrenergic receptor: mimics action of adrenaline on lungs (used in asthma) What does atropine do? It is the blocker of the muscarinic coupled ACh receptor (mAchR): blocks effects of ACh on the heard, dialates pupils and inhibits secretion What does Cimetidine do? It is a competitive antagonist of the Gs coupled H2 receptor, blocs acid secretion in the stomach What is the general process of cell signalling (e.g. adrenaline)? 1st messenger (adrenaline) binds to G protein coupled receptor and activates the G-proteinThis activates the first effector (AC) which then synthesises the 2nd messenger (ATP ---> cAMP)Which leads to the signalling and activation of the 2nd  effector leading to a response Overall what does Gs and Gi GPCR do? "Gs increases adenylyl cyclase activity whilst Gi decreases it. So overall a Gs-coupled receptor would increase cAMP and PKA activity in a cell whilst a Gi-coupled receptor would do the opposite." Describe the signalling pathway of adrenaline with Gs (alpha): Adrenaline is the first messenger and binds to G protein coupled receptor (alpha).This activates the G-protein leading to the activation of the enzyme adenylyl cyclase - which is the 1st effectorAdenylyl cyclase catalyses the formation of cAMP from ATP - which is the 2nd messengercAMP regulates a cascade of protein kinase reactions leading to the phosphorylation of target proteins leading the the biological effects of adrenaline (the common symptoms we know) - PKA is the 2nd effectorThis signal is amplified as adrenaline stimlates a signalling cascade leading to glycogen breakdown What is the most common enzyme-linked receptor? Receptor tyrosine-kinases (RTKs)exist in an inactive state until they bind to a signal molecule Describe the process of signal binding to enzyme-linked receptor - using receptor tyrosine-kinases (RTKs) as an example: "Tyrosine residues are (cross-)phosphorylated           - monomers come together to form a dimer          - phosphorylation provides point of binding for intracellular singal proteins to bind and therefore be activated thus downstream signallingDocking sites for intracellular signalling proteins activatedDownstream signalling (pathways)         - PI-3 kinase singnalling pathway:               1) PI-3 kinase ---> PIP3               2) PIP3 ---> PKB               3) Regulation transcription/translation               4) Cell survival, proliferation and growth         - MAPK signallking pathway:               1) MAPK cascade               2) Regulation transcription/translation               3) Cell survival, proliferation and growth" What is the function of enzyme-linked receptors: They play a role in response to extracellular signalling proteins to promote cell growth, survival, and proliferation Give examples of receptor tyrosine-kinases (RTKs): Insulin receptorEGF (extracellular growth factor) receptorVEGF receptorIGF receptor How do enzyme-linked receptors work within the whole chemical cascade with messengers? "The always work together with GPCRs (sometimes even against each other) Cross-talk/synergy with GPCR signalling" What are the 2 types of nuclear receptors? Cytosolic      - nuclear receptor in cytosol and moves into the nucleus ligand bound      - steroid receptorsNuclear      - found within nucleus      - thyroid receptors Describe the process of signalling/drug action with nuclear receptors: "Hormone/agonist enters cellInteracts with intracellular (IC) nucelar receptor in cytosol or nucleus(Nuclaear recdptors (NR)/drug complex moves to nucleus)NR/Drug complex interacts with DNA to alter gene transcriptionAltered protein synthesis" Give examples of:Endogenous hormones:Synthetic analogues: corticosterone, aldosteronedexamethasone (steroid anti-inflammatory), anabolic steroids What are enzymes: Enzymes are proteins that catalyze chemical reactions, the conveersio of substrate(s) to product(s). The enzyme is NOT DESTROYED and can be used over and over again What is the competitive mode inhibition? mimics the substrate, but not converted What is the non-competitive mode inhibition? binds to allosteric site to alter activity of enzyme towards substrate What is the false substrate mode inhibition? mimics the substrate, converted to abnormal product What is the reversible mode inhibition? high levels of substrate overcome inhibition, if competitive (Km increases, Vmax is unaltered). What is the irreversible mode inhibition? binds very tightly or covalently modifies the enzyme long lasting clinical effect Describe the drug action of aspirin as an example when enzymes are a drug target (inhibition): "Acetyl salicylic acid (aspirin)Anti thrombotic drug (low doses)       - COX-1 is involved in TxA2 synthesis in platelets, which amplified platelet functionPain killer (high doses)       - COX-2 is involved in synthesis of prostanoids which induce inlammation, pain and fever  MECHANISM OF ACTION:irreversible (covalent) inactivation (non-competitive) of COX-1 and COX-2 by acetylation of enzyme" Describe the drug action of ibuprofen as an example of when enzymes are a drug target (inhibition): "IbuprofenPain killer     - COX-2 is involved in synthesis of prostanoids which inuce inflammation, pain and feverReduces inflammation and temperatureMECHANISM OF ACTION:competitive reversible inhibitor of COX-1 and COX-2" Describe briefly enzymes being involve in prodrug activation: (examples) "Involved in the conversion of pro-drugs from an inactive to an active form:cortisone ---> hydrocortisone (anti-inflammatory)clopidogrel ---> active metabolite (inhibites platelet aggregation)" What is passive transport? 3 types: "Don't required energy and go down dconcentration gradientSimple diffusionChennel-mediatedTransporter-mediated" What is active transport? "Require energy (ATP) and go against concentration gradient" What are the properties of transporters? "Multipass transmembrane proteinsBind transported moleculesUndergo a series of conformational changes to transfer bound moleculeInvolved in passive or active transportSlower than ion channels!        - as there are many conformational changesMovement of ions can occur down or against their concentration gradients" What are the 3 types of transporters? "In Symport, it uses the energy released to move A down the concentration gradient to possibly power B to move against the concentration gradientIn Antiport, the movement happens simultaneously" Describe how active transport isessential to maintaining ion concentration gradients (generally): "Maintaining ion concentration gradients accounts for around 1/3 of our total energy expenditure (the use up of energy)!Na+/K+ ATPase - e.g. neurones action potentials (resting potentials)Na+/Ca2+ exchanger - e.g. for muscle conctration (from sarcoplasmic reticulum)" Describe how active transport is essential to maintaining ion concentration gradient using the example of Digoxin and the heart: "This example uses antiport and symport modes of transportDigoxin blocks Na+/K+ ATPaseLeads to increase in intracellular Na+ (accumulates in cell)Decrease in electrochemical gradient for Na+ Decrease in Ca2+  extrusion (movement) from cellIncreased Ca2+ in cellIncreased conctraction of heartUsed to treat:Cardiac insufficiency FibrillationCongestive heart failure" Properties of ion channels: "Small pores formed by proteinsDon't bind transported moleculesSpecificity determined by size and chargeOpen/closed conformationsVoltage or ligand gatedVery fast!!! - faster than transporters (BY A LOT)Movement of ions only occurs DOWN their concentration gradients" Describe how voltage-gated vs ligand-gated ion channels open and close:Give an example for each: "" Describe the actions/functions of voltage-gated and ligand-gated ion channels in neuromuscular junctions: "" Describe the action of transporters and ion channels during insulin release (BRIEFLY): "" What substrances can be drugs? (5) Natural substrances from plants or animalsSynthetic chemicalsProducts of biotechnologyNatural substances in the bodyInorganic poisons Describe the attributes of a drug: (5) Specific effectsParticular targetsTarget recognitionSelectivity of actionBeneficial very adverse effects of drugs What do beta-blockers drug names all have in common? They all end in -loleg:Atenolol Bisoprolol Carvedilol Iabetalol Metoprolol Propanolol Satalol Why are drugs taken? (5 reasons) To produce a cureTo suppress symptomsTo prevent a disease or symptomTo diagnose a diseaseFor recreational reasons What determines whether to give a drug? (4) The likely benefit to the patientThe probability of an adverse effect and its severity        - adverse: preventing success of development; harmfulThe health-care/social cost of adverse effects       - adverse: preventing success of development; harmfulThe financial cost of the drug to be used in relation to benefit Whyy do drugs show side effects and toxicity? (6 reasons) Drugs are insufficiently selective  Drugs may be very selective, but target site may underlie many processes and be widespred in the body, leading to side effects and toxicityThe prolonged use of the drug may lead to long-term or permanent changes in structure and function Lack of knowledge of disease processPatient variability  Drug interactions - particularly in elderly where 1 drug can have many effects Describe the molecular tergets for drug actions: (6) Receptors - transduce signal from drugEnzymes - activate or switch offTransporters - carry molecules across membranesIon channels - open or closeNucleic acids - affect gene transcription Miscellaneous - lipids, metal ions, etc. What is an agonist? A drug that evokes a response What is an antagonist? A drug that prevents the action of another drug, naturally occuring hormone or transmitter  What is the similarity and difference between an agonist and an antagonist? Both have to bind to the receptor for their actionBUT, agonists 'turn on' or 'activate' the receptor WHILE antagonists just bind and occupy the binding site What are the 4 things that drug interactions are influenced by? Chemical structureMolecular sizeLipophllicity - how well a molecule dissolves in fats, oils and non-polar solvents           - determines how well a drug can pass/cross a cell membranepH and ionisation - can influence drug interaction if ionised or not (charges attraction vs repulsion) Describe the properties of ions channels vs the properties of transporters: " Ion channelsTransporters Small pores formed by proteinsDon't bind transported moleculesSpecificity determined by size and chargeOpen/closed conformationsVoltage or ligand gatedVery fast!!! - faster than transporters (BY A LOT)Movement of ions only occurs DOWN their concentration gradientsMultipass transmembrane proteinsBind transported moleculesUndergo a series of conformational changes to transfer bound moleculeInvolved in passive or active transportSlower than ion channels!        - as there are many conformational changesMovement of ions can occur down or against their concentration gradients" Explain the receptor theory: Drugs interact with receptors in a reversible manner to produce a change in the state of the receptorThis interaction can be modeled mathematically and follows the Law of Mass ActionThe binding of drug and receptor determines the quantitative relationship between dose and effectMutual affinity of drugs and receptors determines the selectivity of drug effectsCompetition of mutually exclusive molecules for the THE SAME receptor explains agonist, partial agonist and antagonist drug activity What determines that selectivity of drug effects? The mutual affinity of drugs and receptors What is the law of mass action? "A + B ⇌ A' + B'Rate of a chemical reaction is proportional to the product of the concentration of the reactantsDrug binding - obeys the Law of mass action" Describe/explain how drug binding obeys the Law of Mass Action: "At equilibrium: rate of association = rate of dissociationk+1[D][R] = k-1[DR]" What is the binding of a drug to a receptor governed by? Its affinityThe higher the affinity, the stronger the binding Describe how affinity is quantified: "By the term KD (dissociation equilibrium constant for binding):KD and affinity are inversely relatedDrugs with ↑KD = ↓affinity for the receptorDrugs with ↓KD = ↑affinity for the receptor" What is KD?Give equation "The dissociation equilibrium constant for bindingIt is the concentration of the drug that occupies 50% of the receptors at equilibrium, since at 50% occupancy - [R]=[DR] " What is the total n.o receptors (RT)? It is the sum of the receptors in the DR complex + the free receptors (R) What is the formula for RT? [RT] = [DR] + [R] What is the receptor occupancy equation? "P = fractional receptor occupancy" Under what conditions is the receptor equation valid to use? (5) EquilibriumDrug concentration at the receptors same as that applied to system - not having a small amount of drug1 drug molecule combines with 1 receptor moleculeA negligible amount of the drug added is boundBinding of 1 drug molecule doesn't influence the binding of another Describe the shape of the binding curve for the receptor binding equation: "Asymptote on y-axis provides an estimate of RT KD is the concentration of drug at which 50% of the receptors are occupied" "Draw conclusions from the (shape of the) binding curve of the receptor occupancy equation: (2)" "Receptor occupation increases with [D]Binding is saturable" What are the 2 ways that you can plot the drug-receptor binding curve for P vs [Drug]? Which way is more common to use experimentally?- describe/explain: "Usually plotted though as semi-log plot, witht he position of the curve along the concentration axis being dependent on the affinity of the drug for the binding sitecondensing the axis and gives a more defined RT but spreading out KDThe higher the affinity, the lower the KD/lower potency and the more leftward the binding curve The position of the binding curve along the concentration axis is governed by affinity" What is the position of the bidning relationship/curve along the concentration axis governed by? Affinity Describe the effect of agonists on receptors vs antagonists: "antagonist will block/prevent any response/mechanisms from happening" What is drug efficacy? the ability of a drug,once bound, to activate a receptor responsethe time spent in DR* state Do agonists have efficacy?Do antagonists have efficacy? "" What are the 2 paramaters that the ability of an agonist to product a pharmacological effect in a cell/tissue depends on? "Binding of drug to receptor - determined by its affinity Following binding, activation of the receptors and production of response - determined by efficacy" Explain how the ability of an agonist to produce a phormacological effect in a cell/tissue depends on efficacy: "Think of efficacy being determined by drug switching the DR complex from inactive ([DR]) → active ([DR*])The longer time the drug-receptor complex stays in the [DR*] state the higher the agonist efficacy" Describe the shape of a concentration response curve: "Curve appears similar in shape to that for occupancy (hyperbola)However, during studies and experiments the more usual way of plotting is using a semi-log method:Curve is sigmoidal defined by a maximal responce (Emax) and EC50 value" What is EC50? Effective Concentration 50The concentration of drug that gives 50% of the maximum response Describe and Explain the relationship between pharmacological response and occupancy? (GRAPHICALLY) "The binding curve will always be rightward of the functional response curveThis is due to efficacy      - this ampliies the effect of the bindingof 1 drug molecule to 1 receptor                - due to the cascade of reactions leadind complex to active stateThe higher the efficacy the greater separation of the functional response curve and the binding curveThe plot of both binding and response curves shows that you don't have to occupy all the receptors to get the maximum response           - this will vary depending on the efficacy of the agonist and the n.o receptors " Describe the process that shows the relationship between response and occupancy: "Overall, these steps are likely to amplify the signal several fold, with the EC50 value well to the left of the KD" Do you need to occupy and activeate all receptors to get the tissue's maximum response? "NOyou have spare receptors or receptor reserve Magnitude of response is NOT proportional to receptor occupancy" Describe the relationship between efficacy anf KD and EC50: The greater the efficacy , the bigger separation between KD and EC50 Describe the relationship between KD/EC50 , efficacy and receptor reserve: "The receptor reserve will vary between different agonists that act at the same receptorKD/EC50 gives a rough measure of the reserve         - ""weak"" agonists (low efficacy) have an EC50 close to KD - complex mainly in DR form         - ""strong"" agonists have high efficacy (i.e. EC50 <<<<< KD)     - push complex to DR* form       " Describe the effect of efficacy, /EC50, and receptor reserve on the position of the concetration response curve: "If KD/EC50 gives a rough measure of the reserveIf you lower efficacy:         - EC50 gets larger         - Reduces receptor reserve         - the concentration-response curve moves to the rightSo if you reduce the receptor number,       - you also shift the CRC to the right" State what the position of the functioncal concentration response relationship along th concentratio axis is determined by: (3) AffinityEfficacyReceptor number What is potency? Relates to how much drug is needed to produce a particular response When testing different agonist on the same preparation, what ar the 2 things tha tthe position of the agonists CRC is dependent on? AffinityEfficacyOf EACH AGONIST When testing the same agonist on thedifferent preparations (ith different receptor numbers), what does the position of the agonists CRC dependent on? Receptor number What are full agonists? Agonists that have high efficacy (where the bound agonists resides in the active DR* state for most of the time)Are able to evodke a maximum tissue response What are partial agonists? "Agonists the their efficacy is so low that the maximum response is less than the full response the tissue is capable of where the bound agonist resides in the inactive DR state for most of the timePartial agonists occupy all receptors to evoke their maximum responseThey have NO spare receptors" State what is the receptor reserve? "Spare receptors that remain unbound when an agonist is producing its maximum tissue response" Describe the therapeutic value/use of partial agonist using the example of Buprenorphine: Partial agonist at he mu-opioid receptorMu-opioid agonists are very good analgesics but also have severe side effectsUsed for the treatment of pain ad addictionIt has very high affinity and lowe efficace at the mu opioid receptorTherefore less side effects How is receptor function downgraded? If they are activated continuously for too long or activated too frequently by: receptor desensitisation Occurs over milliseconds to hoursCaused by changes to receptors (e.g. phosphorylation), channels, coupling G-proteins, or 2nd messengers What are the 3 factors that potency is dependent on? AffinityEfficacyReceptor number What is antagonism? "The process of inhibition of an agonist-driven cellular response by another moleculeAntagonists have zero efficacy and don't directly evoke a response" What are the 4 main types of drug antagonism? Describe: "Competitive: binds at the agonist recognition site preventing access of normal ligandNon-competitive: doesn't bind at the agonist ste but inhibits agonist binding in another wayUncompetitive: this is when binding occurs to an activated form of the receptor (i.e. ""use-dependent"")Physiological: when the effect of a neurotransmitter or hormone is countered by the action of another neurotransmitter or hormone" What is competitive antagonism? Binds at the agonist recognition site preventing access of notmal ligand What is non-competitive antagonism? doesn't bind at the agonist site but inhibits agonist binding in another way What is uncompetitive antagonism? "this is when binding occurs to an activated form of the receptor (i.e. ""use-dependent"")" What is physiological antagonism? When the effect of a neurotransmitter or hormone is countered by the action of another neurotransmitter or hormoneThe 2 have opposing effects on the body What are the 2 effects that an antagonist can have on the concentration-response curve to an agonist? "Both effects reflect a decrease in the sensitivity of the system to the agonist in the presence of the antagonist:Depression of maximal response (Emax)Rightward displacement/shift of the curve" How can we overcome the block created by reversible competitive antagonism? By increasing [agonist] What is the effect of competitive antagonism on the concentration response curve of an agonist? "The progressively rightward shifts (but Emax is the same) of the agonist CRC by increasing concentrations of antagonist" WHat is the KB? The equilibrium constant for the antagonist (M)Measures the concentration ratio produced by each concentration of antagonist What is the concentration ratio in pharmagcology? The ratio of the concentration of agonist in the presence of antagonist and the concentration of agonist in the absence of antagonist that produce the same responseThe cocnentration ratio is used to generate a Schild plot Describe the Schild plot: "If the slope = 1, then the antagonist is competitive, the intercept with the x axis give the -logKB" What are the experimental conditions to allow the application of hte Schild analysis? Parallel shift in concentration-effect curve to the rightNo reduction in maximum response Describe how a quick estimate of KB can be obtained using the Gaddum-Schild method: "Concentration-response relationship to agonist alone, followed by concentration-response relationship to agonist in the presence of a fixed concentration of competitive agonistMeasure concentration ratio produced by the one concentration of antagonistApply the Gaddum-Schild equation to calculate KB:[D1]/[D1]' = 1 + [B]/KB" State the Gaddum-Schild equation: "" What are the ADVANTAGES of the Gaddum-Schild equation? Quick only requiring 2 concentration-response curves to be produced What are the DISADVANTAGES of the Gaddum-Schild Equation? Produces only 1 shift by antagonist, which might not be sufficient to ensure the antagonist would produce parallel shifts with no change in the maximum responseThere will be variability in the position of any CRC along the concentration axis.        - This variability is reduced when multiple curves are used, but he sigle curves  allow this variabilityThereofre, there will be error in the determination of KB taken from a single shift What is competitive irreversible antagonism? Antagonist competes with the agonist for the same site but binds irreversibly (covalently)Irreversible binding means that antagonism is NOT overcome by increasing [agonist] Describe the effect of competitive irreversible antagonism on the concentration-response curve of an agonist: "The decrease in Emax observed results from teh irreversible binding of antagonist reducing receptor n.o until there are not sufficient no to meaintain the Emax" What are the 2 types of non-competitive antagonists?What are their effects on the CRC of agonists? "Allosteric modulator          - binds and changes the binding of agonist to its siteBinds and antagonizes response by blocking later in pathway from receptor activation to response         - e.g. enzyme inhibitor or Ca2+ channel blocker" Give examples of physiological antagonism: Histamine stimulates acid secretion, omeprazole blocks this effectNoradrenaline ↑ HR, ACh ↓ HRGlucagon is a physiological antagonist of the actions of insulin Endothelin ↑ BP, nitrates ↓ BP How much efficacy do antagonists have? Do they evoke a response? 0 efficacyNO What does radioligand binding measure? Drug binding (NOT drug response)drug can be an agonist or an antagonist but has to be made radioactive What are the 3 different atoms that can be made radioactive on drugs? 3H - β emitter (t0.5 12.3 years)14C - β emitter (t0.5 5730 years)125I - γ emitter (t0.5 59.4 days) On what can radioligan binding be studied on? cell membrane fragments/homogenateswhole cellsintact tissue What are the reasons for doing radiolignad binding experiments? (5) Tells you whether a receptor is present - MAIN REASONtells you how many receptors are present, and whether this changes e.g. in disease or following a drug treatmenttells you the affinity of the radioligand for the receptortells you how quicklu the drug binds and dissociates from the receptorcan be used to detect how well non-radioactively lablled drugs bind to receptor Describe a basic binding assay - what does it contain: Test tube containing:Buffer (e.g. Tris)Ligand (e.g. 3H)Cell membrane fragmentAll goes into incubation How do you measure how much has bound to the receptors in a  radioligand binding assay? You have to separate bound radioligands from free radioligands How do we separate bound radioactive ligand from free radioactive ligand? "-ve pressure created by suction" What is non-specific binding? When there is binding to non-receptor sites Describe how non-specific binding affect radioligand binding: Competing ligand will block essentially all specific binding to the receptor, but doesn't block non-specific bindingSpecific binding pf ligand to receptor depends upon exact chemical structure of ligandNon-specific binding often involves ligand charge and hydrophobicity What are the differences between specific and non-specific ligand binding? " SpecificNon-specific Ligand binds to receptor binding siteLigand binds to non-receptor binding sitesDepends upon exact cheimcal structure of the ligandOften involves ligand charge and hydrophobicity" How do we account for non-specific binding in basic binding assay? Use an excess/ high [competing ligand] that is NOT radioactively lablled What are the 3 main types of ligand binding assays? Saturation BindingKineticsDispacent Competition Describe how to carry out saturation analysis/binding assay for total binding: "Specific binding + non-specific binding (NSB) mixSpecific binding > NSB" Describe how to carry out saturation analysis/binding assay for Non-specific binding (NSB): "C - Non-radioactive drug that competes with radioligand for receptor           - high [C] and constant" Describe the binding curve for total binding assay: "2 components therefore no full plateu of graphTOTAL - NSB = SPECIFIC" Describe the curve for specific binding: "" What are the units for Bmax? moles.mgprotein-1 What values can be obtained from binding assay? KD and Bmax Equilibrium binding - values of KD and Bmax only valid if equilibrium has been reached            - so incubation must be allowed to reach equilibrium  Give a summary of how saturation analysis is done: Uses lots of radioligand (EXPENSIVE)If only 1 ligand exists for receptor, then saturation is the only option Descirbe the ligand binding kinetics equilibrium equations: "KD = k-1/k+1 k+1 is also called kon k-1 is also called koff KD = koff/kon" Describe the kinetics on specific binding curve: "" Describe the kinetics off specific binding curve: "being replaced by non-radioactive competing/displacing ligand" How can rate constants be determined from the koff and kon curves?2 equations: "These kintetic process are described as exponentialsthus by using the t0.5 values                                    Ct = Co.e-kt                                        OR                                        t0.5 = 0.693/k" How do you determine kon from graph? "" How do you determine koff from graph? "" Describe what binding kinetics are used for: to determine kon, koff and hence KD For new ligands, the on-rate experiment indicates how long is needed to reach equilibriumCan be used to determine hwere ligands bind on the receptor Do we need to radiolabel all drugs to measure their Kd ? NOThis is proved by competition (displacement) experientsbased on competition between radioactively labelled ligand and a adifferent non-radioactive (cold) ligand Describe competion (displacement) binding experiments: "Based on competition between radioactively labelled ligand and a different non-radioactive (cold) ligand" Describe the binding curve generated from competition (displacement) experiments: "Not a kinetic experiment, but an equilibrium binding experimentmax level of binding is less than Bmax for the radioligand as the [radioligand] used is usually around the KD value of the radioligand" What is IC50? Is it the same as KD? "The concentration of the displacing ligand that displaces 50% of specific radioligand binding. NO as KD is a constant and IC50 is not as it depends upon the [radioligand] used in the assay" How can the KD of the displacing ligand be worked out from the data of the curve of displacement binding? "using the Cheng-Prusoff Equation:Ki = IC50/(1 + ([L]/KD))Ki = the KD of the displacing ligandIC50 = is that of the displaicng ligand read off graph[L] = [radioligand] used KD = equilibrium dissociation constant of the radioligand" Give the Cheng-Prusoff Equation: "Ki = IC50/(1 + ([L]/KD))Ki = the KD of the displacing ligandIC50 = is that of the displaicng ligand read off graph[L] = [radioligand] used KD = equilibrium dissociation constant of the radioligand" What can competiotion binding assays be used for? To determine the affinity of multiple ligands in the same assay Competition binding ADVANTAGES: Cheap - not needing to saturate everythingcna analyse multiple ligands at 1 time and get their KD values What are the 2 types of equilibrium assays? Saturaiton bindingCompetition binding What is the 1 types of non-equilibrium assays? Kinetic experiments (koff) Does a receptor only bind 1 drug molecule? "Yes if it is a GPCRNo if it is a ligand gates ion channel receptor" What are biologics? a class of medicines where the active pharmaceutical ingredient (API) is derived from living organisms that can't reasonably be synthesised by chemical means What are biologics (products and sources)? Can be composed of sugars, proteins, or nucleic acids or complex combinations of these substancesMay be living entities such as cells and tissuesA wide range of productsVaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutics proteins If we can't synthesise biologics, how do we get them? "Recombinant DNA technologye.g. recombinant proteins as therapeuticsvector and desired gene are fused together via heat shockbacteria reproduce every 30mins - later go through protein extraction after" Compare the siz eof biologics in comparison to small molecule drugs: They are larger Give common characteristics of biologics: (8) Produced by living cells/organismsStructure depends on cell/organism used for production (PTM - post-translational modification)InjectableNot available via oral routeMay linger in the body for long periodsExtracellular targetsHighly specificMost are too large to cross cell membranes  Give common therapeutic uses of biologics: (3) Replacing a deficient or abnormal proteinEnhancing or inhibiting an existing biological processProviding a novel function or activity What are the 5 types of biologics? Monoclonal antibodies (MAbs)Other proteins and polypeptidesViral and non-viral vectorsOglinucleotidesCells What are antibodies? Proteins that are part of the immune system that identify and neutralize foreign proteins and organismsEach antibody recognises a specific antigen Describe antibody structure and how that relates to its function: "" What are monoclonal antbodies? Antibodies that are identical because they were produced by clones of a single immune cell What are teh 6 mechanisms of therapeutic action of monoclonal antibodies (MAbs)? Ligand blockadeReceptor blockadeReceptor downregulationSignalling inductionCell depletion        - complement-dependent cytotoxicity        - antibody-dependent cytotoxicity        - antibody-dependent phagocytosisPayload delivery Describe Mechanisms of therapeutic action of MAbs: Ligand blockade: "Therefore ligand can't bind to receptor therefore no binding thus no activation therefore no downstream signalling" Describe Mechanisms of therapeutic action of MAbs: Receptor blockade: "Antibody binds to receptor blocking ligand from binding to it therefore no binding therefore no activation thus no downstream signalling" Describe Mechanisms of therapeutic action of MAbs: Receptor downregulation: "Similar to COMPETITIVE ANTAGONISMantibody binds to receptor and blcoks lignad interactionthis causes the receptor to be internalised into the ell - no longer on surface therefore ligands can't bind" Describe Mechanisms of therapeutic action of MAbs: Signalling induction: "Antibody binding to receptor causes a cascade within the cell to activate apoptosis (cell death)Ideal for treating cancer cells" Describe Mechanisms of therapeutic action of MAbs: Cell depletion: "Works on the basis of activating the body's immune response- Variable region binding to antigen- Conserved region activates immune response causing complimentary cascade to be initiated and thus causing cell death- conserved region is activating the complementary cascade in the body to cause cell death- employing natural killer cell to cause cell death- conserved region of antibody activating macrophagesn leading to phagocytosis and therefore cell death" Describe Mechanisms of therapeutic action of MAbs: Payload delivery: "Antibody binding to specific antigen on tumor cellantibody is able to deliver a mechanism to kill the cell (using something attached to the antibody)DOESN'T use body's own immune system" What are teh 3 types of payloads (conjugates)? Radioactive ligandsCytotoxinsLigands (immunocytokines) What are 3 common diseases that might be amenable to treatment with MAbs? Auto-immune diseases (e.g. rheumatoid arthiritis)CancerInflammatory diseases Describe the role of TNF-α in arthiritis: "" List 2 therapeutic ADVANTAGES and 2 LIMITATION of biologics compared to synthetic small molecules. Justify your answers: "AdvantagesBiologics are more targeted and less likely to interact with other drugs:  More targeted: Biologics are more precise than other treatments, targeting a specific cytokine or receptor subunit.  Less likely to interact with other drugs: Biologics aren't metabolized by cytochrome-based mechanisms or excreted renally, which minimizes potential drug interactions. LimitationsBiologics are more complex and require special handling and storage:  More complex: Biologics are larger and more complex than small molecule drugs, and require injections instead of pills.  Special handling and storage: Biologics are unstable and require special handling and storage." What is a polypeptide? a polymer consisting of a large n.o amino-acid residues bonded together in a chain What are proteins? large molecules composed of 1 or more polypeptide chains Describe the properties of fast-acting insulin analogues:UsePropertiesExamples: "Meal controlQuicker absorptionFast actingCombination therapyInsluin aspart produced in yeastInsulin lispro produced in bacteria" Describe the properties of long-acting insulin analogues:UsePropertiesExamples: "Basal controlSlow releaseLonger lasting (42h)Safer - ↓hypoglycaemiaFlexible dosingInsulin degludec produced in yeast" Describe the 4 barriers for vector delivery? "an immune response could hapen and the cells can be destroyed" What does DNA integration promote? Stable transfection Describe the 2 types of Transfections (characteristic of DNA) "A - DNA incorporated in genome and then expressedB- DNA injected into cell and remains free in the nucleus" Which characteristic is better? Stable or Transient transfection? Depends on what you are treatingOncology       - transient       - immunogeneticGenetic mutations - long-term effect       - stable       - non-immunogenetic (we don't want an immune response) Describe the process of in vivo vs ex vivo gene delivery: "" Describe the characteristics of an ideal vector for monogenic diseases: (7) ↑[ ]Amenable to large scale productionStableSite-specific genome integration OR stable episome'Tunable' expression levelsSelective (cell specific expression)Non-immunogenic Describe the structure of adeno-associated viral vectors (AAV): "the gene of interest is inserted and trasfected into the cell" Describe adeno-associated iral (AAV) vector transfection: "lots of vector fragments could cause immune response - NOT IDEALpreffered for in vivo applicationse.g. AAV2 for treatment of retinal dystrophy - in vivo gene delivery" Describe the structure of retroviral vectors (lentiviral vectors - favoured): "" Describe what do retroviral vectors do: "They integrate into the host's DNAPreferred for ex vivo applicationshave caused oncogenes to be activated in the past - NOT GOODcould be used to treat cystic fibrosis" Give the cells that are used as biologics (autologous or allogeneic): Blood and blood products         - Whole blood         - RBC concentrate         - Platelet concentrateEmbryonic stem cells (ESCs)Induced pluripotent stem cells (iPSCs)Genetically modified cells What are induced pluripotent stem cells? Stem cells that can differenciate into any cell in the bodyvast therapeutic applications for degenerative diseases Meaning of autologous cells: cells that come from the person that's being infected Meaning of allogeneic cells: cells that come from the same species Describe the immune control mechanism of how cell-mediated immune response destroys a tumor: "proliferation - T-cells recognise antigens and proliferate        - increase n.o macrophages" Describe the process causing Acute lymphoblastic leukaemia: "" What are oglionucleotides?Properrties: "Short DNA or RNA molecules (at least 15-mer)Complementary to part of a gene or gene productThey suppress expression of a harmful geneEnzyme-resistantDon't reach central nervous system" What are pharmacokinetics? interpreting data on changing concentrations or amounts of a drug and its metabolites in blood, plasma, urine and other body tissues and fluidsWhat the body does to the drug What is ADME also known as? Pharmacokinetics What is ADME? Dose of drug administered and Absorbed Drug in systemic CirculationDrug in tissues of Distribution Drug Metabolised or Excreted Why is ADME important? "Important to know if a drug is going to be absorbed if given by a particular route (e.g. insulin)important to estimate accurate plasma concentrations (Cp) of drug as a function of time - [plasma] is dynamic - it changes with timeTo know where the drug goes once inside the body - how it distributes (e.g.imodium, hay fever antihistamines)Drug metabolist - are the metabolites safe? (e.g. paracetamol)" What is the enteral durg route? Via G.I. tract What is the parenteral drug route? Not via G.I. tract Give the specific route, and comments of the enteral route of drug administration: OralEasyComplianceVomiting1st pass metabolism Give the specific routes, examples and comments of the parenteral route of drug administration: " Specific RouteExampleComments I.V.ThiopentoneNo absorption phaseRapid effectsI.M. (inter-muscular)MorphineFluophenazinedepotS.C. (sub-cutaneous)beneath/under all layers of the skininsulinrelatively easy" What is the oral bioavailability of a drug (F)? Fraction of the oral dose that reaches the systemic circulation How do we measure oral bioavailability (F) experimentally? "Compare the Cp vs. time curves for a drug following oral and iv. bolus administration of the same drug.The drug is given on difference days so that the Cp vs. time curves are not confusedF = AUCoral/AUCiv " What is the equation for oral bioavailability (F)? F = AUCora/AUCiv What are the 3 factors affecting the bioavailability of a drug? "Poor absorption from the gutBreakdown of drug in gut1st pass effect" What is the main factor effecting drug absorption at a membrane? The lipid solubility of the drugsince in general the more lipid solube the drug, the more likely it is to cross membranes and be absorbed What are factors affecting drug absorption at a membrane? Lipid solubility of drugDrug preparationArea of absorbing surfaceRate of blood flow to other side of absorbing surfacePresence of food in gutEffect of other drugs taken by patientpKa of the drug (pH at which it is 50% ionised)pH at absorbing surface Why are pKa and pH important for drug absorption at a membrane? "Ionised durgs DON'T cross membranesMany drugs are either weak acids or weak bases, and so can exist either ionised or unionised forms, depending upon the pKa of the drug and the pH of the solution.The ratio of ionised:unionised drug can be calculated using the Henderson-Hasselbalch equation" What  is the Henderson-Hasselbalch equation for a weak acid? "pH = pKa + log[ionised/unionised]" What  is the Henderson-Hasselbalch equation for a weak base? "pH = pKa + log[unionised/ionised]" What is the meaning of drug distribution? "The penetration of drug into tissues and organs from the bloodCan be considered in terms of body compartments       - e.g. in the average adult:                - Total body water ~40L                - Extracellular water ~14L                - Blood ~6L" What does the degree/overall extent of drug distribution often depend on? Lipid solubilityPlasma protien binding What does the rate of drug distribution depend in part upon? Rate of blood flow How can drug distribution be measured? "Using Apparent Volume of Distribution (Vd)Vd = (amount of drug in body)/Cp Vd expressed as volume (eg. L), or volume/mass (e.g L.kg-1)" What is the apparent volume of distribution (Vd)? The volume of water in which drug would have to be distributed to give its plasma concentration What is the formula for Vd? Vd = (amount of drug in body)/Cp Give examples of drugs with small Vd: Insulin Warfin Give examples of drugs with high Vd: ProzacImpramine What are the uses of Vd? Partly determines plasma half-life (t0.5) of the drug - how long the drug stays around in the bodyUsed in pharmacokinetic calculations to design dosing schedules "What is the route of this drug administration:" "Oral" "What is the route of this drug administration:" "Sublingual" "What is the route of this drug administration:" "Rectal" f7609662b54a4751a56b44c337c92828-oa-1 What is the route of this drug administration: "" "" "" "" 0d514a89a4d04802aa65f710b56d81b6-oa-1 What is the route of this drug administration: "" "" "" "" "What is the route of this drug administration:" "Subcutaneous" "What is the route of this drug administration:" "Intradermal" "What is the route of this drug administration:" "Inhalation" "What is the route of this drug administration:" "Intra-nasal" "What is the route of this drug administration:" "Transdermal patch" "What is the route of this drug administration:" "Transdermal gel" "What is the route of this drug administration:" "Intra-articular" "What is the route of this drug administration:" "Eye drops" "What is the route of this drug administration:" "Intravaginal" "What is the route of this drug administration:" "Creams and ointments" What are the 3 central pharmacokinetic parameters? Vd t0.5 Cl (clearance) What is the elimination of a drug? "The excretion and metabolism of drugs together constitute elimination  ie. the overall removal of the drug from the body" What is the excretion of a drug? "the movement of drug from inside to outside of body" What is the metabolism of a drug? "the chemical change in drug structure" what is the plasma half-life of a drug (t0.5)? The time it takes for the Cp ([plasma] of drug) to fall to 1/2 its initial valueA short t0.5 means that the body eliminates the drug quicklu and that doses have to be given more often than drugs with long t0.5               - e.g. prpranolol ~4h vs. amphteric ~18h What is the formula for rate of elimination?How can you rearrange that to find clearance? Rate of elimination = Clearance x Cp Cl = (rate of elimination)/Cp Clearance units are volume/time (mLmin-1) What is clearance (Cl)? It is equal to the amount of plasma which is cleared of its drug content in unit time. It is a useful measure sinc ethe rate of elimination of most drugs varies with Cp, but Clearance (Cl) stays fairly onstant (but it is not a constant and can change under certain cirumstances (e.g. liver or renal disease)) What iis the most common order for drug elimination? Describe how it looks like on a Cp vs. t graph: "1st orderThe t0.5 is constantCl is not changing, but the rate of elimination depends on how much drug is present↑rate of elimination = ↑Cp " What is the less common order for drug elimination? Describe the graph of Cp vs t: "Zero orderrate of process is independent of [drug]t0.5 can varyHOWEVERMore usual to get Pseudo-zero order Zero order at ↑Cp 1st order at lower Cp " What is the more usual order to get for drug elimination rather than just zero order? "More usual to get Pseudo-zero order Zero order at ↑Cp 1st order at lower Cp " What exponential equation describes the 1st order drug elimination process: "Ct = Coe-kt Ct = [plasma drug] at time tCo = [plasma] at time 0 (when the drug is injected)t = timek = the rate constant of elimination" What is the equation for the length of time a drug persists in the blood? What does the equation predict? "t0.5 = (0.693 x Vd)/Cl It predicts that if ↑Vd or ↓Cl, then ↑t0.5 Thus Vd and Cl are critical values when planning drug dosage regimes" Compare the graphs of Cp vs t for i.v. bolus, i.m., s.c., and oral drug administration:What happens as the rate of absorption decreases? "" Describe and explain the Cp vs t graph of intravenous infusion: (use equations) "Here the drug is being eliminated as it is being infusedeliminated by 1st order processThen Cp rises until a steady state is reached (Css)This is because as the Cp rises so does the rate of elimination until:              rate of infusion = rate of eliminationFrom before steady state - rate of elimination = Cp x Cl So at Css - rate of elimination = Css x Cl Therefore to give a particulat Css:                    rate of infusion = Css x Cl" What is the equation for rate of infusion? Rate of infusion = Css (steady state) x Cl (clearance) How long does it take to reach Css? Explain: "It takes up to 5 half-lives to reach Css (effectively), irrespective of the infusion ratethe actual value of Css depends upon the infusion rate, but the time to reach Css will NOT vary" How long does it take to reach new Css after rate of infusion is changed? "5 half-lives" Describe the Cp vs t graph for oral dosing: "It can be shown that:CssAV = (D x F)/(T x Cl) D = individual doseF = oral bioavailabilityT = time interval between dosesCl - clearance" Give the equation to illustrate oral dosing: It can be shown that:CssAV = (D x F)/(T x Cl) D = individual doseF = oral bioavailabilityT = time interval between dosesCl - clearance What are 2 examples of drugs that are subject to extensive renal excretion (i.e. unchanged, not metabolised): gentamicinmethotrexate Describe drug excretion via the kidney: "Can involve the drug, the drug and its metabolistes, or the metabolites aloneGenerally drugs and metabolites that are NOT lipid soluble are excreted by this route3 process that determine drug excretion:" What are the 3 processes that determine drug excretion? "Glomerular filtrationActive secretion in PCTPassive reabsorption in DCT" For a weak acid, how can urinary excretion be increased? By making the urine more alkaline e.g. with sodium bicarbonate For a weak base, how can urinary excretion be increased? By making the urine more acidic e.g. with ammonium chloride What in all cases increases urine production and drug excretion? "A diuretic drugfor a weak acid, a combination of bicarbonate + diuretic is called a ""forced alkaline diuresis""" What can drug metabolism be called as well? biotransformation Where does drug metabolism occur? include  Mainly occurs in the liver  but can occur elsewhere:Plasma: suxamethaniumIntestine: cocaine What do drug metabolites do? include examples: (4) The convert:Drug → Inactive metaboliteActive drug → Active metabolite   - codeine→morphine   - Diazepam→NordiazepamDrug → Toxic metabolite   - Halothane→Trifluoraecetic acid   - Paracetamol→N-Acetyl--p-benzoquinone imineInactive Drug (prodrugs) → Active drug   - Clopidogrel→Active metabolite   - Azathioprine→Mercaptopurine- prodrugs thus has bioavailability therefore given to ↑bioavailability of the active drugs Describe what happens during Hepatic drug metabolism: "Occurs in 2 phases:Phase I: Drug derivative formed by oxidation, reduction or hydrolysis, often introducing a reactive site into, or exposing a reactive site on, the drug molecule       - this is to make the product ↑reactive               - for ↑likelihood for derivative to go through phase 2, so more likely to undergo conjugationPhase II: Conjugation(joining together) of the species formed in phase 1 with polar molecules, making metabolites less lipid soluble, and hence easier to excrete in urine             - ↓lipid soluble = ↑likely to be excreted in urine" Describe phase 1 of hepatic drug metabolism: "Drug derivative formed by oxidation, reduction or hydrolysis, often introducing a reactive site into, or exposing a reactive site on, the drug moleculethis is to make the product ↑reactive for ↑likelihood for derivative to go through phase 2, so more likely to undergo conjugationdrug metabolising enzymes in the endoplasmic reticulum of the liver are called microsomal enzymes. In particular, mixed function oxidases are importantMost important group being cytochrome P450" Describe phase 2 of hepatic drug metabolism: "Conjugation (joining together) of the species formed in phase 1 with polar molecules, making metabolites less lipid soluble, and hence easier to excrete in urine↓lipid soluble = ↑likely to be excreted in urine" What are microsomal enzymes? Drug metabolising enzymes in the endoplasmic reticulum of the liver (and other tissues) Describe the preferences of Cytochrome P450 isoforms: In the human liver there are a n.o P450 isoforms.Individual isoforms have preferences for different drugs, but this tends to be overlapping rather than absoloute>1 isoform cna deal with 1 drug Where does phase 2 of hepatic drug metabolism generally occur?  In the cytosol of liver cells State the 5 factors affecting drug metabolism: Enzyme InductionEnzyme inhibitionGenetic polymorphismsDiseaseAge Explain how enzyme induction effects drug metabolism: "Some drugs and environmental pollutants induce increased expression of cytochrome P450 enzymes over a n.o days/weeksThis can cause the failure of some drugs (and itself) to produce a significant therapeutic effect" Explain how enzyme inhibition effects drug metabolism: "Some drugs directly inhibit cytochroe P450 enzymes This can ↑likelihood of seeing adverse effects/toxicity in the patient" Explain how genetic polymorphism effects drug metabolism:  "Poor ability to metabolise drugs by some groups of people" Explain how disease effects drug metabolism: "↓ ability to metabolise  Liver function for drugs mainly metabolised in the liver        - Hepatitis         - Liver Cancer        - Cirrhosis Renal function for drugs mainly excreted unchanged in urineThyroid function         - affects liver metabolising enzymesCardiovascular disease         - rate of delivery of drug to liver/kidney" Explain how age effects drug metabolism: Generally drug metabolism is lower in the very young and the elderly Explain how the pharmacokinetics of biologics can differ from that of small molecules: (explain bilogics pharmacokinetics) Absorption Administration: parenteral sc./i.v.Time to peak Cp: long time (e..g days)DistrubutionApparent Vd: usually smallMechanisms: LymphElimination:t0.5: longMechanisms: proteolysis in lysosomes What are the 2 main thypes of drug interaction: Describe using examples: Pharmacodynamic - based on mechanism          - e.g. aspirin→warfarin, excessive stomach bleedingPharmacokinetic     - Absorption - trtracycline antibiotics in milk (inhibits absorption)    - Distribution    - Metabolism - induction/inhibition    - Excretion - methotrexate + NASAIDs (e.g. aspirin) - inhibits renal excretion of methotrexate Describe the 4 main principles of neuropharmacology: The main coordinator of the body's functions (together with the endocrine system)In charge of interactions between the body and the environmentComprised of central (CNS) and peripheral (PNS) componentsA major target for neurotropic drugs and for drugs treating conditions in organs that are controlled by the nervous system Describe and explain how neurones communicate with each other: "Via electrochemical transmissionNeurones are excitable cells: they react to and propagate electrical signals            - depends on voltage-gated Na+ channelsThey can pass units of info to the neighbours they are connected with: via chemical signalling - at synapses              - depends on transmitter release and receptors" State the components of a synapse: "" Describe the sequnce of events in synaptic transmission (6): "" What 3 things can different neurones do (specialised funcitions)? What do these specialised functions depend on? Neurones canExciteInhibitModulateThe activity of other neurones or end organsDepends onwhich neurotransmitter(s) they releasewhich eceptors the post-synaptic neurones express "State the name of each of these neurotransmitters and neuromodulators:" "GlutamateNitric oxideCadic element - noradrenalineAcetylcholine (ACh)GABBAATPNeuropeptide" How does the neurotransmitter get into vescicles? (2 ways) "Vesicular uptakePresynaptic uptake - to clear extracellular speace of neurotransmitter" Describe the neurodiversity in neurotransmitter production and storage between an inhibitory neurone (e.g GABAergic) and a modulatory neurone (e.g noradrenergic): "" Describe how neurotransmitters are eliminateed from the synaptic cleft: "" What actions and receptors induce fast-onset signals?Examples of neurotransmitters: "Ionotropic actionsIon channelsExamples:GlutamateGABAACh" What actions and receptors induce slow-onset signals?Examples of neurotransmitters: "Metabotropic actionsGPCRs EnzymesExamples:GluamateGABAAChMonoamines (most)" Describe the neuronal diversity in postsynaptic responses: "Fas-onset and slow-onset signalsDifferences in intracellular signal transduction" State the diseases/conditions that we would like to treat using neuropharmacology (drug targets): EpilepsyCerebral palsyNeuromuscular weaknessParkinson's diseaseDementia, Cognitive declineAnxietyDepressionADHDAcute or chronic painAnaesthesiaSurgery State the different drug targets in neuropharmocology: "" Describe the different targets in neuropharmacology including examples: (9) "1) Voltage-gated Na+ channels - blockers stop electrical transmission (stop presynaptic excitability):Local anaesthetics for pain relief (Ligocaine)Treatment of epilepsy (Phenytoin)2) Voltage-gated Ca2+ channels- blcokers inhibit transmitter releaseZiconotide3) Exocytosis - blocker inhibits transmitter release Botulinum toxin A - 'Botox'         - Balancing muscle tone in cerebral palsy        - Treatment of hypersecretory disorders4) Transmitter synthesis - precursor of transmitter (e.g. dopamine) stimulated production:Treatment of Parkinsonism (L-DOPA, Carbidopa)5) Vesicular Storage - blockers of vesicular transporters lead to empty vesiclesDisplacement agents (such as amphetamine) cause initial uncontrolled release6) Presynaptic transmitter uptake - blockers prolong transmitter actionsTreatment of depression (Fluoxetine)7) Transmitter breakdown - blockers prolong transmitter actionsTreatment of myasthenia gravis (Neostigmine)8) Postsynaptic inotropic receptors (ion channels) Blockers inhibit transmitter effects, muscle relaxation by nicotinic ACh receptor antagonist (Tubocurarine)+ive allosteric modulators enhance transmitter effects, e.g. treatment of anxiety, insomnia, epilepsy by enhancing GABAA receptor action (e.g. Benzodiazepines such as valium)9) GPCRs - pre- & postsynaptic Majority of prescribed and experimentally used drugseg. morphine, potent opioif analgesic" Describe what is and the function of Ligocaine and its drug target: Local anaesthetics for pain reliefDRUG TARGET: Votage-gated Na+ channels      -  Blockers stop electrical transmission Describe what is and the funciton of Phenytoin and its drug target: Treatment of epilepsyDRUG TARGET: Voltage-gated Na+ channels          - Blockers stop electrical transmission Describe what is and the funcitons of Botox and its drug target: Botulinum toxin ABalancing muscle tone in cerebral palsyTreatment of hypersecretory disordersDRUG TARGET: Exocytosis       - Blocker inhibits transmitter release Describe what is and the function of L-DOPA and its drug target: Treatment of ParkinsonismDRUG TARGET: Transmitter synthesis         - Precursor of transmitter (e.g. dopamine) stimulates production Describe what is and the function of Carbidopa and its drug target: Treatment of ParkinosonismDRUG TARGET: Transmitter synthesis       - Precursor of transmitter (e.g. dopamine) stimulates production Describe how drugs can interfere with neurotransmission by affecting: Presynaptic excitability - Voltage-gated Na+ channels:Use examples: Blockers stop electrical transmission:Local anaesthetics for pain relief (Lignocaine)Treatment of epilepsy (Phenytoin) Describe how drugs can interfere with neurotransmission by affecting: Voltage-gated Ca2+ channels: Blockers inhibit transmitter release Describe how drugs can interfere with neurotransmission by affecting: Exocytosis:Use examples: Blocker inhibits transmitter release:Balancing muscle tone in cerebral palsy (Botulinum toxin A - 'Botox')Treatment of hypersecretory disorders (Botulinum toxin A - 'Botox') Describe how drugs can interfere with neurotransmission by affecting: Transmitter synthesis:Use examples: Precursor of transmitter (e.g. dopamine) stimulates production:Treatment of Parkinsonism (L-DOPA, Carbidopa) Describe how drugs can interfere with neurotransmission by affecting: Vesicular storage: Blockers of vesicular transporters lead to empty vesiclesDisplacement agents (such as amphetamine) cause initial uncontrolled release Describe how drugs can interfere with neurotransmission by affecting: Presynaptic transmitter uptake:Use examples: Blockers prolong transmitter actions:Treatment of depression (Fluoxetine) Describe how drugs can interfere with neurotransmission by affecting: Transmitter breakdown:Use examples: Blockers prolong transmitter actionsTreatment of myasthenia gravis (Neostigmine) Describe how drugs can interfere with neurotransmission by affecting: Postsynaptic ionotropic receptors (ion channels):Use examples: Blockers inhibit transmitter effects, muscle relaxation by nicotinic ACh receptor antagonist (Tubocurarine)+ive allosteric modulators enhance transmitter effects, e.g. treatment of anxiety, insomnia, epilepsu by enhancing GABAA receptor action (Benzodiazepines such as Valium) Describe how drugs can interfere with neurotransmission by affecting: GPCRs - pre- & postsynaptic:Use examples: Majority of prescribed and experimentally used drugse.g. morphine, potent opioid analgesicactivation/inhibition of presynaptic GPCRs modulates transmitter releaseactivation/inhibition of postsynaptic GPCRs modulates neuronal/muscle excitation  What is neuromodulation? The physiological process by which a given neuron uses one or more chemicals to regulate diverse populations of neurons What local anaesthetic blocks the action potential conduction along neuronal axon? Lignocaine What drug is the blocker of choligernic neurotransmitter release? Botox What drug blcoers the re-uptake of neurotransmitters (presynaptic transmission uptake)? The anti-depressant Fluoxetine Describe the importance of the autonomic nervous system in actions and why it is 'autonomic': "" Describe how the nervous and endocrine system is split into unconscious and conscious control: "" Describe the 2 branches of the ANS: PROPERTIES "Parasympathetic nervous system     - ""Rest and Digest"" scenario     - Energy acquisition, storage & conservationSympathetic Nervous system     - ""Fight or Flight"" scenario     - Directed acute energy supply & expenditureThe SNS and PSNS have antagonistic functional roles and their tones alternate depending on requirements in most organs and situaitons, the SNS and PSNS exert opposite effectsBoth systems are active at all times but 1 branch will dominate over the other at any 1 timeSNS components tend to tune up/down together; separate PSNS activities are initiated when requiredNot all organs are innervated equally by both the SNS and the PSNSNeither branch is designed to run on high over long periods of time" "Describe what happens in the vital organs during the ""Fight or Flight"" scenario:Heart and vasculatureAirwaysEnergy metabolismeyessweat glandsdigestive functionsType of action" Acute and Directed energy supply is vitalHeart & vasculature - blood supply (to muscles, brain)Airways - facilitated breathingEnergy metabolism - provision of glucose (broken down by glycolysis)Eyes - adjusted to 'widefield'Sweat glands - cooling during sustained exertionDigestive functions - suppressedFast, concerted action "Describe what happens in the vital organs during the ""Rest and Digest"" scenario:Digestive functionsCardiac activityAirwaysEyesFeature/property of action:" Energy Storage and ConservationDigestive Functions - stimulatedCardiac activity decreased (↓HR), ↓BPAirways - breathing efficiency decreasedEyes - adjusted to near visionCan be upregulated separately and at leisure Describe the Neuronal orginisation of the ANS: FEATURES " PSNSSNS LONG preganglionic neuroneSHORT preganglionic neuroneSHORT postganglionic neuroneLONG postganglionic neurone" Compare the main function of PSNS and SNS: " PSNSSNS ""Rest and Digest"" Scenario""Fight or Flight"" scenarioEnergy acquisition, storage & conservationDirected acute energy supply & expenditure" What is a ganglion? A collection of neuronal bodies found in the voluntary and autonomic branches of the PSNS Describe the vital organs that the SNS and PSNS have antagonistic/opposite effects over: "" Describe briefly an autonomic reflex: "Visceral and somatic afferents can trigger responses via the NSE.g. the baroreceptor reflex" What are the key points to note about Autonomic control? (4) "1) SNS and PSNS have antagonistic functional roles and their tones alternate depending on requirements In most organs and situations, the SNS and PSNS exert opposite effects (e.g. HR slowed by PSNS, accelerated by SNS)Both systems are active at all times but 1 branch will dominate over the other at any one timeSNS components tend to tune up/down together; separate PSNS activites are initiated when required 2) Not all organs are innervated equally by both the SNS and the PSNSe.g. sweat glands and most blood vessels receice ONLY SNSeg. airways PSNSe.g. PSNS predominates in GIT, bladder, salivary glands3) The same autonomic transmitter can interact with different types of receptors in different synapses Different effects in different organs, e.g. NA: β1 - heart, β2 - bronchi, α1 - vasculature4) Neither branch is designed to run on high over long periods of time especially not the SNS's ""Fight-or-flight' response!" What does it mean that SNS and PSNS have atagonistic functional roles? In most organs and situations, the SNS and PSNS exert opposite effects eg. ↓HR PSNS, ↑HR SNSBoth systems are active at all times but one branch will dominate over the other at any one time Describe how SNS and PSNS have their tones alternate depending on requirements: SNS components tend to tune up/down together Separate PSNS aactivities are initiated when required Why is the drug treatment of the ANS important? (2)Include examples: 1) Major physiologival role in control of body function (homeostasis)2) Site of action of many drugs, for example for:AnginaCardiac arrhythmiasCardiac arrest HypertensionAsthmaAllergic shockUrinary problemsOpthalmologyHomeostasis (cardiovascular, digestive, respiratory) during surgeryIrritable bowel syndromeHypersecretion What is the function of the ANS? "It controls the body's internal environment - HR, BP, respiration, blood pH, digestion, metabolism, etc. WITHOUT our conscious input" What is the ANS the site of action for many drugs for? (11) (Give at least 8) AnginaCardiac arrhythmiasCardiac arrest HypertensionAsthmaAllergic shockUrinary problemsOpthalmologyHomeostasis (cardiovascular, digestive, respiratory) during surgeryIrritable bowel syndromeHypersecretion What do we call ANS neurones with cell bodies in the CNS that mediate 'rest and digest' functions? Parasympathetic preganglionic Describe what happens and the componenst at the cholinergic nerve terminal: "" Describe how ACh signal is terminated? "It is broken down the the enzyme acetylcholine esterase (AChE)" Describe the properties /features of nicotinic AChRs in the autonomic ganglia: "Pentametric structure (mainly (α3)2(β2or4)3) in ganglia; neuromuscular junciton uses different subunit isoforms)2 ACh brinding sitesionotropic receptors = ion channels: fast activation (<1 msec)permeable to cations (Na+, K+)depolarisation of the post-ganglionic neurone → action potential is generated and travels to effector organ" State the major receptors in the ANS: "" Describe the different Muscarinic AChRs on ANS effector organs (their effects):DESCRIBE MECHANISMS "1) M2 - HeartGi/o-protein-coupledDecrease cAMP and Ca2+ signalling Decrease electrical excitability 2) M3 & M1 - GI tract, airways, bladder, eyeGq-protein-coupledIncreased Ca2+ signallingContract smooth muscle Stimulate glandular secretion" Describe parasympathetic stimulation of secretion using muscarinic receptors:DESCRIBE MECHANISM "ACh:M3 - e.g. saliva and tears, bronchial secretions      - M3 leads to ↑Ca2+       - you can get Cl- influx into lumen and Na+ increase in the lumen therefore ↑NaCl therefore increased salinity of waterM1 - acid secretion in the stomach" Describe prasympathetic contraction of smooth muscle contraction:DESCRIBE MECHANISM "↑Ca2+ stimulates myosin phosphoylating      - Gq increases [Ca2+] which increases contraction" Define a drug: A substance (other than food) with a known chemical structure that produces a biological effect when administered to a living organism What is a medicinal poduct or drug product? A drug or combination of drugs with added ingredients intended to treat, prevent, diagnose, or relieve symptoms of a disease What is a drug target?: A molecule, typically a protein, associated witha  disease process that can be targeted by a drug to achie Name an example of a drug and its target: Salbutamol targets adrenergic β-2-receptors in the alveoli of the lungs to treat asthma What are the 4 main properties of the cell membrane? Provides structural supportAsymmetric and dynamicSelective permeability barrierFacilitates communication What is the primary funciton of mitochondria? To generate energy (ATP) through aerobic respiration and oxidative phosphorylation What is the central dogma of molecular biology? """DNA makes RNA, and RNA make protein"", describing the flow of genetic information in clels" What are common drug targets within cells? ReceptorsIon channelsEnzymesTransporters (carrier molecules) What is the role of the nucleus in a cell? It houses DNA (in chromatin), regulates gene expression, and facilitates ribosome production in the nucleolus What is the role of the endoplasmic reticulum (ER)? It is the main site of protein synthesis and is located near the nucleus What is post-translational modification? Chemical changes to proteins after synthesis, which regulate their activity, location, and function How do drugs influence different cell types? Drugs act on divers targets such as receptors, ion channels, enzymes, and transporters, which vary in role across physiology and pathophysiology WHat is protein trafficking within cells? The process of directing synthesised proteins to their correct location, ensuring prooer cellular funciton What are the 2 main types of cellular communication? Intercellular communication - between cellsIntracellular communication - within a cell How do pharmacological drugs typically affect cellular communication? Drugs mimic or modulate cellular communication, resulting in changes to biological outcomes What are receptor proteins, and why are they important drug targets? Receptors bind to ligands (e.g. hormones or drugs) and trigger intracellular signalling pathways, altering cellular functions What are G protein-coupled receptors (GPCRs)? GPCRs are a large family of receptors that mediate cellular responses to various ligands.They are major drug targets, with roles in sensory and non-sensory functions Name 2 exampes of GPCR-targeting drugs and their functions: Propanolol: Blocks β1-adrenergic receptors, reducing heart activity        - used for high BP and panic attacksSalbutamol: Activates β2-adrenergic receptors, relaxing airway muscles         - used for asthma What is signal amplification in G-protein signaling? Signal amplfication occurs when a single activated receptor activates multiple downstream molecules, greatly anhancing the cellular response What are the 2 main types of G-protein signaling pathways related to adenylate cyclase? Gs pathway: ↑cAMP levels, activating protein kinase A (PKA) (e.g. salbutamol)Gi pathway: ↓cAMP levels and can open K+ channels What is the effect of acetylcholine (ACh) on different tissues? ACh can cause varied responses, such as stimulating HR, contracting smooth muscle, or promoting secretion depending on the tissue What is the difference between agonists and antagonists in drug action? " AgonistsAntagonists Activate receptorsBlock receptorsMimicking natural ligandsPreventing ligand binding and signallinge.g. salbutamole.g. propanolol" How does the binding of a ligand to a receptor lead to a cellular response? Ligand binding activates the receptor, triggering, intracellular signaling cascades that alter cellular function, such as protein phosphorylation or ion channel opening What role do protein kinases play in intracellular signalling? Protein kinases phosphorylate proteins, altering their activity, creating binding sites, or targeting them for degradation How do drugs targeting muscarinic acetylcholine receptors (mAChRs) work? Atropine, a blocker of mAChRs, inhibits ACh effects such as slowing the heart, dilating pupils, and reducing secretions What is the role of cAMP in G-protein signalling? Acts as a 2nd messenger, activating PKA anf mediating various cellular responses to hormones like adrenaline Wat are some effects of adrenaline on the body? Stimulates the heart to pump more bloodRelaxes airway muscels to improve breathingMobilizes energy reserves What is cimetidine, and how does it work? It is a competitive antagonist of H2 receptors, blcoking acid secretion in the stomach What are enzyme-linked receptors? Receptors with intrinsic enzymatic activity or associated with enzymes, such as receptor tyrosine kinases (RTKs), which phosphorylate tyrosine residues upon activation What are some examples of receptor tyrosine kinases (RTKs)? (4) Insulin receptor Epidermal growth factor (EGF) receptorVascular endothelial growth factor (VEGF) receptorInsulin-like growth factor (IGF) receptor What are the downstream effects of activated receptor tyrosine kinases (RTKs)? RTKs regulate transcription, translation, cell survival, proliferation, and growth via pathways like MAP kinase and PI3 kinase, which are often mutated in cancer What are nuclear receptor, and how do they function? Nuclear receptors are intracellular receptors that bind hormones or drugs, translocate to the nucleus, and alter gene transcription, leading to changes in protein synthesis Give examples of nuclear receptors and their ligands: (3) Steroid receptors (e.g. corticosterone, aldodesterone)Thyroid hormone receptorsSynthetic analogues like dexamethasone (anti-inflammatory) and anabolic steroids What is competitive inhibition of enzymes? A competitive inhibitor mimics the substrate, binds to the active site, and prevents the normal reaction without being converted into a product How does a non-competitive inhibitor affect enzymes? It binds to an allosteric site, altering the enzyme's activity toward the substrate, and can't be overcome by increasing [substrate] What is the difference between reversible and irreversible enzyme inhibitors? " ReversibleIrreversible Bind temporarily, and inhibition can be overcome by increasing [substrate]Bind tightly or covalenty, leasing to long-lasting effects" How does aspirin (acetylsalicylic acid) work as a drug? Aspirin irreverisbly inhibits COX-1 and COX-2 enzymes through acetylation, reducing thromboxane A2 (anti-thrombotic effect) and prostanoid synthesis (pain and inflammation relief). How does ibuprofen differ from aspirin in its mechanism? Ibuprofen is a competitive, reversible inhibitor of COX-1 and COX-2, reducing pain, inflammation, and fever without covalent enzyme modification What are some examples of drugs targeting nuclear receptors? (3) Dexamethasone: synthetic steroid for inflammationAnabolic steroids: enhance muscle growthHormones like corticosterone and aldosterone What are the key functions of transporters and on channels? control cellular cytosolic ion and chemical concentrationsenable manipulation of cellular function by drugs What are the properties of transporters? (5) Multipass transmembrane proteinsBind transported moleculesUndergo conformational changesInvolved in passive or active transportSlower than ion channels What are the 3 types of transporter action? Symport: 2 molecules move in the SAME directionAntiport: 2 molecules move in OPPOSITE directionsUniport: 1 molecule moved down its gradient What is the role of active transport in cells? Essential for maintaining ion gradients  How do antidepressants interact with transporters? They block transporters responsible for serotonin reuptake, increasing serotonin levels in the cell What are the properties of ion channels? (5) Small protein-formed poresDo not bind moleculesSpecificity based on size and chargeOpen/close via voltage or ligand gatingVery fast (>107 ions/sec) What are examples of ion channels? (2) Voltage-gated Na+ and Ca2+ channelsLigand-gated channels like the nicotinic ACh receptor What is the function of the nicotinic acetylcholine receptor at the neuromuscular junction? Facilitates muscle contraction by transmitting signals, blocked by drugs like tubocurarine What is a drug? (5) Natural substances from plants or animalsSynthetic chemicals Products of biotechnology Natural substances in the bodyInorganic popisons (e.g. tetrodotoxin) What are the key attributes of a drug? (5) Specific effectsTarget specific moleculesSelectivity of actionRecognises targetsBalances beneficial and adverse effects Why are drugs taken? (5) To produce a cureTo supress symptomsTo prevent disease or symptomsTo diagnose diseaseFor recreational reasons What factors determine whether to admiinster a drug? (4) Likely benefit to the patientProbability and severity of adverse eventsHealth-case/social cost of adverse effectsFinancial cost vs. benefit Why do drugs cause side effects or toxicity? (6) Insufficient selectivityWidespread effects of target siteLong-term structural or functional changesLack of knowledge about disease processes Patient variability Drug interactions Wha are the molecular targets for drug action? (6) Receptors (signal transduction)Enzymes (activate or inhibit)Transporters (molecule movement)Ion channels (open/close)Nucleic acids (gene transcription)Miscellaneous (e.g. lipids, metal ions) What is the difference between agonists and antagonists? " AgonistsAntagonists Activate receptors and produce a responseBlcok receptors without producing a response" WHat is receptor theory? Drug-receptor interaction is reversibleModeled by the Law of Mass ActionDetermines the relationship between dose and effectAffinity influences selectivity of effectsExplains agonists, partial agonists, and antagonist activity What is the Law of Mass Action in drug binding? The rate of chemical reaction is proportional to the product of reactant concentrations:k+1[D][R] =