PHAR0007 Testbank-with 100% verified solutions 2024-2025-tutor verified.docx, Exams of Nursing

Download PHAR0007 Testbank-with 100% verified solutions 2024-2025-tutor verified.docx and more Exams Nursing in PDF only on Docsity! PHAR0007 Testbank-with 100% verified solutions 2024- 2025-tutor verified 772Q&A What is selective toxicity? The ability of a drug to act at target sites possessed only by or more essential to the survival of the pathogen than the host. What is the proprietary name of a drug? The brand name given by the manufacturer. What is the TI? Therapeutic index = TD50/ED50 (TD50 = dose that is toxic to 50% of the population, ED50 = dose that produces therapeutic effects in 50% of the population). What value of TI is preferable? High or low? High since that means that the TD50 is much higher (so less likely to be reached accidentally) than the ED50. What is the variation of the TI used in animal studies? LD50/ED50 where LD50 = the dose which is lethal in 50% of the population. What is Popper's law? Statements can never be shown to be true, only falsifiable. What is Carson's consolation? No experiment is ever useless, it can always be used as a bad example. What is pharmacodynamics? The study of biochemical and physiological effects of a drug on a living organism and its method of action. What is pharmacokinetics? The study of the drug concentrations throughout a living organism over time, including the studies of metabolites and the mathematical interpretation of the data. What are the 4 broad categories of receptors? Ligand-gated ion channels, GPCRs, kinase-linked and related receptors and intracellular/nuclear receptors What is an oligomeric protein? A protein which consists of multiple subunits. What are the three subfamilies of ligand-gated ion channels? Cys-loop receptors (ie nAChR), glutamate receptors and P2X receptors (ATP) What is the difference in the effect of opening a cationic ion channel vs anionic? The opening of a cationic ion channel (ie Na+), will lead to depolarisation of the membrane whereas opening of an anionic ion channel (ie Cl-) will lead to hyperpolarisation of the membrane. Out of Cys-loop receptors, glutamate receptors and P2X receptors, which is pentameric, which is tetrameric and which is trimeric? Cys-loop receptors = pentameric Glutamate receptors = tetrameric P2X receptors = trimeric residues then act as high-affinity docking sites for intracellular proteins with SH2 domains. This interaction of proteins with the kinase domain leads to a kinase cascade which results in modulation of gene expression. What are intracellular/nuclear receptors? Soluble receptors which regulate transcription. Name an example of nuclear receptors. Steroid hormone receptors. Describe the activation mechanism of a nuclear receptor. Ligand binding to a nuclear receptor induces a conformational change which promotes receptor dimerisation. In the dimerised form, the DNA- binding site is exposed meaning the dimer is able to bind to DNA and modulate transcription. What is another term used to refer to nuclear receptors? Ligand-activated transcription factors. Name 6 examples of LGICs. nAChRs, 5-HT3Rs, GABAA-Rs, GlyRs, GluRs and P2XR. Why are pentameric LGICs classed as cys-loop receptors? Because they contain a pair of disulphide-linked cysteines which form a 15 AA loop in the extracellular domain. What is the subunit composition of nAChR in foetal muscle? α2βγδ. What is the subunit composition of nAChR in adult muscle? α2βγε. How many different subtypes of GPCRs are there? >1000. Give 5 examples of GPCRs. mAChRs, mGluRs, 5-HTRs (not 5-HT3R), dopamine receptors and adrenoreceptors. Give 4 examples of kinase-linked and related receptors. RTKs, RTKLs (L=linked), Ser/Thr-kinase receptors and guanylate cyclase receptors. Name the agonist to the oestrogen receptor. Estradiol. Name the antagonist to the oestrogen receptor. Raloxifene. Why are steroid receptors found in both the cytosol and nucleus? They exist in the cytosol when devoid of ligand, but once ligand binds their DNA-binding domain is exposed and they translocate to the nucleus. What is signal transduction? The process of converting information encoded by a signal molecule into a biological effect, usually across a membrane. What occurs when ACh binds to nAChR? A conformational change which causes the opening of an Na+ channel and so depolarisation of the membrane. Which out of the following are excitatory and which are inhibitory: nAChR, GlyR, GABAR, GluR? Excitatory: nAChR and GluR Inhibitory: GABAR and GlyR What level of affinity to receptors on post-synaptic membranes of axons have and why? They tend to have a low affinity for their ligand to facilitate rapid dissociation and termination of depolarisation. The low affinity is offset by the high local concentration of ligand within the small synapse. What is prenylation? Describe the activation process of an insulin receptor. When an agonist/ligand binds to the extracellular domain of the insulin receptor, it causes a conformational change in which there is a structural rearrangement of the intracellular domain leading to autophosphorylation of tyrosine residues in its catalytic kinase domain. This leads to activation of the kinase domain which then phosphorylates two tyrosine residues of insulin receptor substrate 1/2 (IRS 1/2) which forms 2 docking sites for 2 SH2 domains of PI3K to bind to thus leading to a downstream signalling cascade. Which RTK type mediates both smooth muscle relaxation and Na+/H2O excretion in the kidneys and how. Receptor guanylyl cyclases are RTKs with intracellular guanylyl cyclase catalytic domains. When ANP binds, catalytic activity of the guanylyl cyclase domain leads to formation of cGMP which then activates PKG which thus mediates both smooth muscle relaxation and Na+/H2O excretion in the kidneys. What type of protein is PKG? Ser/Thr protein kinase. How does aspirin act to reduce inflammation? Aspirin inhibits COX enzymes and so inhibits formation of inflammatory mediators from arachidonic acid. What are the relative speeds of signalling pathways mediated by RTKs vs GPCRs? Signalling pathways mediated by RTKs are slower than those mediated by GPCRs. Describe the MAPK signalling pathway beginning with RTK activation. An extracellular signal will bind to an RTK and so cause dimerisation and autophosphorylation of the activation loops of the kinase domains as well as phosphorylation of other tyrosine residues on the receptor. Grb2 then binds to a phosphotyrosine residue via its SH2 domain. Grb2 also has 2 SH3 domains which bind to 2 polyproline helices of the GEF Sos, so recruiting it to the membrane. There, Sos exchanges a bound GDP on Ras for GTP, so activating it. Ras-GTP remains associated to the receptor via the Grb2-Sos complex where it is able to interact with and activate Raf which then phosphorylates and so activates MEK. MEK then phosphorylates and so activates ERK 1/2. Active ERK is then able to translocate to the nucleus directly or phosphorylate and so activate Rsk which is able to translocate to the nucleus. Once ERK/Rsk are in the nucleus, they are able to activate TFs which form complexes and bind to an SRE (serum response element), upstream promoters for genes crucial in mediating cell proliferation and growth. Describe the JAK/STAT pathway. Upon cytokine binding to a cytokine receptor, receptor dimerisation occurs with the dimer then associating to the cytosolic tyrosine kinase JAK. JAK then phosphorylates the receptor dimer with STAT binding to the pY residues via its SH2 domains. STAT is then itself phosphorylated and dimerised before entering the nucleus to modulate gene expression. Describe oestrogen receptor activation. Estradiol/oestrogen will bind to the oestrogen receptor in the cytosol leading to a conformational change which promotes receptor dimerisation with the receptor dimer then migrating to the nucleus and the DNA- binding domain of the receptor dimer binding to specific HREs (hormone response elements). How many different nAChR subunits are there? 17. What are the 4 types of enzyme-linked/kinase-linked receptors? RTKs, receptor guanylyl cyclases, receptor ser/thr kinases and tyrosine kinase associated receptors. What does SH2 stand for? Src Homology 2. Why must steroid hormones be hydrophobic? To enable them to diffuse across the PM and the nuclear membrane to access their cognate receptors. What does the law of mass action state? The rate of a reaction is proportional to the concentration of reactants. What is the Hill-Langmuir equation? How is the Hill-Langmuir equation derived? What is Ka equal to? Think about the equilibrium equation showing rates of association and dissociation. State the name of KA. With the fact that the occupancy and response are not directly proportional making the Hill-Langmuir equation insufficient, what was used instead? The Hill equation. If the response is directly proportional to receptor occupancy then what should be seen for a concentration-response curve vs a log(concentration)-response curve? A rectangular hyperbola should be seen for the concentration-response curve whilst a sigmoid curve should be seen for a log(concentration)- response curve. What is the del Castillo-Katz model of receptor activation? What is a full agonist vs a partial agonist? A full agonist is a compound capable of eliciting a maximal tissue response whereas a partial agonist is a compound unable to elicit maximal response regardless of concentration. Explain why partial agonists cannot elicit a maximal tissue response. Because they are not able to stabilise the active receptor conformation as well as a full agonist. They bind as well as a full agonist does and will create the same active conformation but cannot create the same interactions to provide stability to the active receptor conformation. What is intrinsic activity? The ability of a drug to activate a receptor upon binding relative to a full agonist and so is given by the equation: Maximum response to test agonist/maximum response to full agonist acting through the same receptors. What value of intrinsic activity will an antagonist have? 0. What is the issue with the use of intrinsic activity? Because the value can vary greatly between different experimental conditions and isn't constant across all tissues either. What does S=ep mean? S = stimulus caused by receptor activation e = efficacy of the agonist p = proportion of receptors occupied Why is the intrinsic activity not a useful measure of agonist efficacy? Because two full agonists may elicit maximal response with one needing to only activate 1% of receptors to do so whilst the other needs to activate 10% of receptors - yet both will have an equal intrinsic activity of 1. Explain the concept of 'spare receptors'. When the response is limited by a factor such as inability of a muscle to shorten any further, partial and full agonists may provide the same maximal response. The receptors remaining which do not need to be filled in order to achieve maximal response are known as 'spare receptors'. How can the sensitivity of a cell to an agonist be regulated? Through modulation of the density of functional receptors on the PM. What is the effect of reducing the number of receptors on the PM of a cell on the maximal tissue response for a full agonist vs a partial agonist. The maximal tissue response would not reduce for the full agonist since spare receptors are still available, however for a partial agonist the maximal tissue response would decrease. What is the name for the interconversion between AR and AR*? Isomerisation. What is a large limitation in the Hill-Langmuir equation? Receptor occupancy doesn't equal receptor activation. What is orthosteric antagonism? Where the binding sites of an agonist and antagonist are separate, but overlap. What is reversible competitive antagonism? How is tissue response increased and can maximal still be reached? Where the antagonist will form short-lasting associations with the agonist binding site on the receptor and the association is freely reversible meaning that an increase in [agonist] will increase tissue response and so the antagonism is surmountable with the response still able to achieve maximal. That the binding of antagonist does not affect the tissue directly, only reducing the probability of the agonist binding. The same number of agonist molecules need to bind with or without the antagonist in order to provide maximal tissue response. What is the Schild equation? r-1 = [B]/KB. How is the Schild equation derived from the Gaddum equation? Why does the Schild equation predict that a reversible competitive antagonist will cause a parallel shift in the log agonist concentration- response curve? Because the value of r must remain constant provided the values of [B] and KB remain constant. How is the Schild equation expressed in order to produce a Schild plot, what is the Schild plot used for? log(r-1) = log[B] - logKB which is plotted to predict the value of logKB which is equal to the x-intercept. Explain why the value of pA2 is equal to the value of -logKB. How can the Schild equation in non log form be used for a plot? If a series of concentration-response curves are established with increasing concentrations of antagonist, then the value of r-1 can be plotted against [antagonist] to give a line of slope 1/KB. Describe the 4 other methods of antagonist drug action other than competition. - Chemical antagonism - the antagonist combines directly with the substance being antagonised, receptors aren't involved (ie EDTA). - Functional/physiological antagonism - the antagonist is actually an agonist which produces an opposite biological effect to the substance being antagonised. Each substance has its own receptor (ie adrenaline vs histamines). - Pharmacokinetic antagonism - the antagonist effectively reduces the concentration of the active drug at its site of action (ie phenobarbitone vs warfarin). - Indirect antagonism - the antagonist acts at a second downstream receptor which links the actions of the agonist to the final response observed. How can the Schild plot be used to identify receptors in a tissue sample? If an antagonist of known pKB value is added to the tissue sample and then the pKB value achieved, the receptor on which the antagonist acts must be present in the sample. Name a key use of the Schild equation. The Schild equation has an important use in classifying agonists. Since only the ratio of agonist concentrations required to achieve the same response in presence of antagonist is used, for a fixed concentration of antagonist, all agonists for the same receptor should produce the same r value regardless of agonist potency. Why does a low KB value show a highly effective antagonist? Because KB = [B][R]/[BR]. What slope of the Schild plot shows the antagonist to be acting through competitive antagonism? Unity. Can reversible competitive antagonism be insurmountable? Yes, if the [antagonist] is so high that [agonist] cannot feasibly be high enough to negate the [antagonist] then the antagonism is seen as insurmountable. What is the effect of a noncompetitive antagonist on the log(concentration)-response curve in the presence of an abundance of spare receptors? In the presence of an abundance of spare receptors, a noncompetitive antagonist will cause a parallel shift in the curve, until a larger [antagonist] is used at which point maximal response will decrease. What is open channel block? Where an antagonist will bind to the open channel associated to the active receptor and so prevent the conductance of ions. What happens to [A]50 when an antagonist is used vs an open channel blocker? [A]50 will increase with antagonism but will decrease in the presence of an open channel blocker. Where do parasympathetic preganglionic fibres have their cell bodies? In the brainstem and in the S2/S3-S4 of the spinal cord. What is the function of preganglionic fibres? Carry impulses from the spinal cord to the ganglia. What is the function of postganglionic fibres? Carry impulses from the ganglia to the target organ. Which neurotransmitter is released from preganglionic parasympathetic nerves? Acetylcholine. Which neurotransmitter is released from postganglionic parasympathetic nerves? Acetylcholine. Which neurotransmitter is released from preganglionic sympathetic nerves? Acetylcholine. Which neurotransmitter is released from postganglionic sympathetic nerves? Noradrenaline. Name the organ innervated by postganglionic sympathetic nerves which secrete ACh. Sweat glands. Name the tissue which is innervated directly by preganglionic sympathetic nerves. Adrenal medulla. What is the ratio of pre:post for sympathetic ganglia? 1:20. What is the ratio of pre:post for parasympathetic ganglia and where is the exception to this? 1:1 apart from in the gut where it can be as high as 1:8000. How is ACh release from presynaptic membranes modulated? Through M2 autoreceptors which form a -ve feedback loop. How is NA release from presynaptic membranes modulated? Through α2-adrenoreceptors which act as autoreceptors through Gi activation and so reduced Ca2+ channel opening and so reduced NA release. How else is NA release from presynaptic membranes modulated? Through β-adrenoreceptors which act through +ve feedback to increase the release of NA. What is NANC transmission? Non-adrenergic non-cholinergic transmission at target sites which refers to all transmission which is mediated by transmitters other than Adr/Nor or ACh ie GABA, dopamine, 5-HT etc. What was NO originally called? EDRF (endothelium derived relaxation factor). What are the receptors within parasympathetic ganglia vs at the target tissue? The receptors within the parasympathetic ganglia are nAChR (fast) whilst at the target the receptors are mAChR (slow). Describe how NO is synthesised and what its effects are. NO production in the smooth muscle cells of blood vessels is stimulated by either the Shearing forces of the blood opening stress-activated Ca2+ channels or ligand-binding to ligand-activated Ca2+ channels with the increased Ca2+ activated nitric oxide synthase which then converts L- arginine to NO. The NO then diffuses into neighbouring smooth muscle cells of the blood vessel and activate guanylyl cyclase. This leads to A benzene ring with two hydroxyl groups attached adjacent to one another (catechol) and an amine group at the distal end connected by a C- chain. Name two differences between β1 and β2 receptors. β1 receptors are excitatory and innervated whereas β2 receptors are inhibitory and aren't innervated; they are stimulated by circulating adrenaline. What do α2-adrenoreceptors normally function as? Autoreceptors. How many α-adrenoreceptor subtypes are there? There are 2 main subtypes, α1 and α2, however there are then 3 subtypes of α1 (α1A, α1B and α1C) and 3 subtypes of α2 (α2Α, α2B, α2C). How many β-adrenoreceptor subtypes are there? 3. Which G-proteins are α1-adrenoreceptors coupled to? Gq. Which G-proteins are α2-adrenoreceptors coupled to? Gi. Which G-proteins are β1-adrenoreceptors coupled to? Gs. Which G-proteins are β2-adrenoreceptors coupled to? Mostly coupled to Gs, but may also couple to Gi under high stimulation. Which G-proteins are β3-adrenoreceptors coupled to? Mostly coupled to Gi, but may also couple to Gs. Where is adrenaline mostly released from? Adrenal medulla. Where is noradrenaline mostly released from? Postganglionic nerve terminals. Which receptors does noradrenaline have highest affinity for? Noradrenaline has higher affinity for α-adrenoreceptors than β- adrenoreceptors and also a higher affinity for α1 than α2. Which receptors does adrenaline have highest affinity for? Adrenaline has higher affinity for β-adrenoreceptors than α- adrenoreceptors. What is isoprenaline? A synthetic catecholamine. Which receptors does isoprenaline have highest affinity for? Isoprenaline is an extremely selective agonist for β-adrenoreceptors. What is the general rule/order for α-adrenoreceptors and the relative potencies of each of adrenaline, noradrenaline and isoprenaline. Noradrenaline >= Adrenaline > Isoprenaline What is the general rule/order for β-adrenoreceptors and the relative potencies of each of adrenaline, noradrenaline and isoprenaline. Isoprenaline > Adrenaline > Noradrenaline What is phenylephrine used for? What is its method of action? Phenylephrine is an α1-adrenoreceptor agonist which acts mainly as a nasal decongestant, but can also be used to dilate the pupils and to increase blood pressure. Which transmitter is released along with noradrenaline at nerve terminals? ATP. What is salbutamol used for? What is its method of action? blood at a slower rate and will remain in the area of injection for a longer time period - thus increasing the anaesthetic effect. Which adrenoreceptors control smooth muscle contraction? What is the exception? α1-adrenoreceptors apart from in the gut where relaxation is mediated by β2-adrenoreceptors. Which adrenoreceptors are responsible for vasoconstriction? Both α1 and α2, more-so α1. Which adrenoreceptor stimulates glycogenolysis in the liver and skeletal muscle? β2-adrenoreceptors. What is another function of β2-adrenoreceptors other than stimulating glycogenolysis in skeletal muscle? They act to increase K+ uptake from blood to restore K+ levels in active muscle to precontraction levels as well as preventing excessive uptake and so preventing toxic levels being reached. What is clonidine used for? What is its method of action? Clonidine is an agonist used to treat hypertension by selectively binding to α2-adrenoreceptor autoreceptors in the brainstem thus reducing peripheral resistance. How is the application of adrenaline to treat anaphylactic shock an example of functional antagonism? Because it is counteracting the effects of histamine. What are the two main actions that adrenaline has in treating anaphylactic shock? It will act as an agonist at α1-adrenoreceptors to cause vasoconstriction and so reduce laryngeal oedema as well as acting as an agonist at β2- adrenoreceptors to increase blood pressure and cause bronchodilation. What is dipivefrine used for? What is its method of action? Dipivefrine is a prodrug formed through esterification of adrenaline with piveric acid. This allows it to cross the cornea of the eye, since lipid solubility is increased with the addition of piveric acid, and so is able to treat open-angle simple glaucoma through converting back to adrenaline and binding to α2-adrenoreceptors in the afferent arterioles of ciliary bodies to cause vasoconstriction and so reduce rate of aqueous humour production as well as increase absorption. What is open-angle simple glaucoma? Where intra-ocular pressure increases to above 21 mmHg due to an over- production of aqueous humour and can lead to loss of vision if left untreated. How else can open-angle simple glaucoma be treated and why is this an advantageous method? A direct α2-adrenoreceptor agonist can be used as opposed to dipivefrine such as bimonidine which will therefore prevent any unwanted side effects from α1 and β2 binding. What is timolol used for? What is its mechanism of action? Timolol is a β-adrenoreceptor antagonist which can also be used to treat glaucoma since it blocks aqueous humour production. What is dobutamine used for? What is its mechanism of action? Dobutamine is a β1-adrenoreceptor agonist which is used to treat cardiogenic shock. In what context is adrenaline administration useful in the treatment of cardiac arrest and why? During cardiopulmonary resuscitation adrenaline can be administered since it will bind to α1-adrenoreceptors to increase arterial blood pressure and coronary perfusion. Name three indirectly acting sympathomimetic amines and explain their function and mechanism of action. Tyramine, amphetamine and ephedrine are all examples of indirectly acting sympathomimetic amines which mimic the structure of noradrenaline. They have weak affinity for adrenoreceptors though, so produce their effects by mimicking noradrenaline and so being taken up into nerve terminals by NET (norepinephrine transporter) and then into vesicles by VMAT (vesicular monoamine transporter), in exchange for noradrenaline which then escapes to the cytosol. In the cytosol, some of the noradrenaline is degraded by MAO (monoamine oxidase), but most escapes degradation and instead is pumped into the synapse via NET in exchange for another amine, likely one of the indirectly acting sympathomimetic amines. Therefore indirectly acting sympathomimetic amines act to increase noradrenaline release which therefore leads to increased sympathetic activity. Are the chronotropic/inotropic effects of β1, β2, β3 and α1 adrenoreceptors positive or negative? β1 - +ve chronotropic and +ve inotropic β2 - +ve chronotropic and +ve inotropic (atrial) β3 - -ve inotropic α1 - +ve inotropic Which adrenoreceptors mediate insulin release? α2-adrenoreceptors inhibit insulin release whilst β2 stimulate insulin release. What are the general effects of α1-adrenoreceptors? Vasoconstriction, minor glycogenolysis and gluconeogenesis in the liver, hyperkalaemia through increased K+ release in the liver, smooth muscle contraction in the bladder, contraction of radial muscle of the eye and GI motility inhibition. What are the general effects of α2-adrenoreceptors? Vasoconstriction, inhibition of lipolysis in white adipose tissue, GI smooth muscle relaxation, platelet aggregation and decreased NA release from nerve terminals through action as autoreceptors. What is the initial vs long term effect of adrenaline on potassium levels in the blood? Adrenaline will cause initial hyperkalaemia followed by sustained hypokalaemia. What is mirabegron used for? What is its mechanism of action? Mirabegron is a β3-adrenoreceptor agonist used to treat overactive bladders. Name a drug which acts as a selective α1-adrenoreceptor agonist. Phenylephrine. Name a drug which acts as a selective α2-adrenoreceptor agonist. Clonidine. Name a drug which acts as a selective β1-adrenoreceptor agonist. Dobutamine. Name a drug which acts as a selective β2-adrenoreceptor agonist. Salbutamol. Name a drug which acts as a selective β3-adrenoreceptor agonist. Mirabegron. What are two common side effects of α-adrenoreceptor agonists? Reflex bradycardia (low HR) and headaches. What are three common side effects of α-adrenoreceptor antagonists? Tachycardia, postural hypotension and cardiac dysryhmias. What is another way of saying postural hypotension? Orthostatic hypotension. What are three common side effects of β-adrenoreceptor agonists? Hypertension, increased heart rate and anxiety. What are three common side effects of β-adrenoreceptor antagonists? Bronchoconstriction, bradycardia and hypoglycaemia. What are ergot alkaloids? Ergot alkaloids are alkaloids extracted from ergot, a product of a fungal contaminant of rye grain. What is the use of ergotamine? What is its mechanism of action? Ergotamine is a drug used to treat migraines through acting as an α- adrenoreceptor antagonist. What is the use of ergometrine? What is its mechanism of action? Ergometrine is a drug used to treat postpartum haemorrhage (often administered in combination with oxytocin) through antagonising α- adrenoreceptors and 5-HT receptors on relaxed uterine smooth muscle to How is noradrenaline synthesised? L-Tyrosine is converted to L-DOPA by Tyrosine hydroxylase. This enzyme is inhibited by noradrenaline and so negatively regulates its synthesis. L- DOPA is then converted to dopamine by dopa decarboxylase. Dopamine is then converted to noradrenaline by dopamine-β-hydroxylase. How can overall sympathetic activity be shown using dopamine-β- hydroxylase? Since DBH is released from vesicles along with noradrenaline, but is not degraded. This means that cytosolic [DBH] can be used as a measure of sympathetic activity. How can noradrenaline synthesis be pharmaceutically increased? Through the administration of L-dopa. What is α-methyltyrosine used for? What is its mechanism of action? It is a tyrosine hydroxylase inhibitor and can be administered as an antihypertensive. What is α-methyldopa used for? What is its mechanism of action? It will be converted by L-DOPA decarboxylase to α-methyldopamine which is then converted to α-methylnoradrenaline which acts as a false transmitter and is resistant to MAO degradation and so α-methyldopa can be used as an antihypertensive drug. What is carbidopa used for? What is its mechanism of action? It is a drug used in Parkinson's disease which acts to inhibit dopa decarboxylase peripherally so allowing more L-DOPA to pass into the CNS and be converted to dopamine. What is disulfiram used for? What is its mechanism of action? Disulfiram is a drug which is used in the treatment of alcoholism since it acts to inhibit acetaldehyde dehydrogenase which therefore increases blood [aldehyde] which has toxic side effects and is very unpleasant for the user. Other than acetaldehyde dehydrogenase, what other enzyme is disulfiram able to inhibit? Dopamine-β-hydroxylase so preventing the conversion of dopamine to noradrenaline. Along with noradrenaline, what two other molecules are present in the storage vesicles in postganglionic sympathetic nerve terminals? ATP and the protein chromogranin A. What is reserpine? Reserpine is a drug used to block VMAT and so deplete noradrenaline stores leading to noradrenaline escape into the cytosol and MAO inactivation. What is tetrabenazine? It is a short-acting noradrenaline and dopamine depletory drug (inhibits VMAT2) used to treat hyperkinetic movement disorders such as Huntington's. What is the function of ATP release at nerve terminals along with noradrenaline? The ATP functions to cause fast excitatory synaptic potentials and rapid phases of contraction in smooth muscle. What is guanethidine used for? What is its mechanism of action? Guanethidine is an antihypertensive which acts by displacing NA from vesicles via uptake by VMAT as well as interfering with exocytosis of the vesicles. Once NA is released into a synapse, how is it taken back up into the presynaptic knob? NET will recapture NA once it has stimulated a response, using an Na+ gradient to do so, before the NA is repackaged into vesicles by VMAT using an H+ gradient. Name two compounds which inhibit NET and their effect. Both cocaine and tricyclic antidepressants inhibit NET and so potentiate the effects of sympathetic nerve stimulation. What % of NA is recaptured through reuptake by NET and what happens to the remainder? Only 75% of NA is removed from the synapse in this way, with the remaining 25% being taken up by extra-neuronal cells. Water soluble β-blockers have a longer half-life since they are excreted by the kidneys whereas lipid soluble are metabolised by the liver and so have a shorter half life. How is it suggested that β-adrenoreceptor antagonism may increase the risk of type II diabetes? They may act to increase risk of insulin resistance and so type II diabetes through decreasing skeletal muscle blood flow and so decreasing insulin dependent glucose uptake. What are GRKs? G-protein coupled receptor kinases which function by phosphorylating Ser/Thr residues of GPCRs. They function in tandem with arrestin proteins to regulate GPCR sensitivity. The arrestin protein will bind to pS/pT residues of the GPCR and act to prevent G-protein binding. What type of receptors are adrenoreceptors? GPCRs. Out of the β-adrenoreceptors, which have GRK phosphorylation sites and which don't? Both β1 and β2 have GRK phosphorylation sites whilst β3 doesn't. How do both carvedilol and nebivolol act to inhibit downstream signalling of β1 and β2 adrenoreceptors? They stimulate GRK phosphorylation of the receptors leading to arrestin binding and so the prevention of Gs protein binding and activation. What is the rate-limiting step of NA synthesis? Conversion of L-Tyrosine to L-DOPA by tyrosine hydroxylase. What is the main agonist for mAChRs? Muscarine. What is the main antagonist for mAChRs? Atropine. What is the main agonist for nAChRs? Nicotine. What is the main antagonist for nAChRs? Tubocurarine. Which receptor type does low doses of ACh tend to stimulate vs high doses? Low doses of ACh tend to stimulate mAChRs whilst high doses tend to stimulate nAChRs. What are nAChRs in autonomic ganglia blocked by? Hexamethonium. Where are mAChRs found? Visceral smooth muscle, eyes, heart, glands and erectile tissue. Where are nAChRs found? Autonomic ganglia, adrenal medulla and skeletal muscle. What are parasympathomimetic drugs and what are their two possible mechanisms of action? Parasympathomimetic drugs are drugs which mimic the effects of stimulating parasympathetic nerves through either acting as mAChR agonists or through inhibition of ChE (cholinesterase) leading to prolonged action of ACh. What are the clinical uses of muscarinic agonists? Uses of muscarinic agonists are limited since they accentuate parasympathetic activity, which is normally undesirable. What are the effects of muscarinic agonists? Bradycardia, decreased cardiac output, vasodilation, salivation/sweating, bronchoconstriction, bladder contraction, increased GI motility, miosis (pupillary constriction) and ciliary muscle contraction. Where are mAChRs mostly localised to in the heart and what are the subsequent effects of mAChR agonists on the heart? What is the general effect of mAChR antagonisms? Reduction in parasympathetic activity. What are the specific effects of mAChR antagonists? Block of secretions, tachycardia, mydriasis (pupillary dilation), GI motility and decreased secretion, smooth muscle relaxation (bladder/bronchi). What is the tachycardic effect of muscarinic antagonism a result of? Why is not accompanied by change in blood pressure? Vagal inhibition. It is not accompanied by a change in blood pressure because most blood vessels have no parasympathetic innervation. Why does mydriasis occur as a result of mAChR antagonism? Mydriasis occurs as a result of the block of parasympathetic influence on sphincter pupillae. This interferes with drainage of aqueous humour and can lead to an increase in intra-ocular pressure. It also leads to cycloplegia in which the ciliary muscles are paralysed and accommodation is paralysed. Why is efficacy of muscarinic antagonists in asthma treatments limited? Because many other mediators other than ACh are involved in asthma. Why will inhibition of motility/secretions in the GI tract as well as relaxation of bronchi/bladder smooth muscle require high levels of the muscarinic antagonist and be incomplete? Because many other mediators other than ACh are involved in both processes. What are the effects of atropine at low vs high doses? In low doses, atropine has no significant effect on the CNS, but at high doses it can cause stimulation resulting in restlessness, disorientation and hallucinations. Which group of patients may experience attention and memory deficits at low atropine doses? The elderly. What are the main three effects of hyoscine? What is it commonly used as? The three main effects of hyoscine are sleep, amnesia and anti-emesis meaning it is often used as an anti-seasickness drug. What is a common function of atropine-like drugs? They are able to suppress the tremor caused by Parkinson's by blocking cholinergic transmission at basal ganglia. Give some examples of therapeutic uses of mAChR antagonists? Anaesthesia, ophthalmology, AChE poisoning, smooth muscle spasm, Parkinson's, motion sickness and bladder overactivity (trospium). Describe the uses of muscarinic antagonists in anaesthesia. Muscarinic antagonists are used in anaesthesia both pre-surgery and during surgery. Pre-surgery they act to inhibit salivary and bronchial secretions as well as cause drowsiness whilst during surgery they are used to prevent vagal inhibition of the heart and to prevent parasympathomimetic actions of anti-cholinesterases. Describe the different muscarinic antagonists that can be used in ophthalmology and their differing effects. Homatropine is often used in ophthalmological examinations to dilate pupils and paralyse the eye lens. Atropine and hyoscine can also be used but cause blurred vision for several days afterwards so the shorter acting homatropine is preferentially used. Long-lasting atropine/hyoscine may be used after surgery to prevent contraction of ciliary muscles/pupils. In what context may muscarinic antagonists be used clinically to cause bronchodilation? In asthma when other first-line agents have been ineffective and also in COPD (chronic obstructive pulmonary disease). Name the 7 stages of synaptic transmission that a drug can act at. - Precursor/transmitter uptake into nerve terminal - Transmitter synthesis - Transmitter packaging into vesicles - Exocytosis of transmitter - Transmitter binding to receptors - Production of postsynaptic response (either inhibition or excitation) - Degradation of transmitter post-response Why do different drugs effect nAChRs at ganglia vs NMJs differently? Suxamethonium is an NMJ blocker which has a fast onset and short duration and is used to help with intubation procedures. What are the two classes of clinically used drugs which target NMJs? Competitive/non-depolarising blockers and depolarising blockers. What are competitive blockers and depolarising blockers otherwise known as? Antagonists and agonists respectively. What are competitive blockers? Competitive blockers are antagonists which work by occupying the nAChR on post-junctional membranes meaning that the resulting synaptic potential is too small to elicit an AP. An example is tubocurarine. Why are competitive blockers classed as non-depolarising? Because they prevent depolarisation from occurring. How can block caused by competitive blockers be reversed? Through administration of AChEs. Tubocurarine is rarely used clinically, what two synthetic competitive blockers are used instead? Pancuronium and vecuronium. What is the structure of these drugs and what does it mean for their action? They are quaternary amines and so are absorbed poorly and rapidly excreted. What proportion of receptor sites must be blocked before transmission fails and why? 70-80% of receptor sites must be occupied before transmission is blocked since a several-fold excess of ACh is released at NMJs. Why is tetanic fade increased by competitive blockers? Because pre-synaptic autoreceptors are also antagonised meaning transmitter release can't be sustained during a tetanus and so the muscle can't be stimulated enough to cause a fused tetanus. What are depolarising blockers? Depolarising blockers are nAChR agonists which are resistant to AChE hydrolysis meaning they bind to the nAChRs and cause sustained depolarisation of the endplate meaning that the fibre is inexcitable following the first AP and so further APs cannot be propagated, thus blocking AP transmission. What are the main features of a depolarising blocker (agonist)? - Initial fasciculation (twitching) which can cause post-operative muscle pain if pronounced - The block will either be unaffected or enhanced by antiChE application - Myasthenia gravis patients are insensitive - Causes hyperkalaemia (since action at endplate causes release of K+ from muscle cell) What are the main features of a competitive, non-depolarising blocker (antagonist)? - Causes relaxation of muscle without preliminary excitation - The block can be antagonised by antiChE - Myasthenia gravis patients are usually sensitive - Tetanic fade is more pronounced What is myasthenia gravis? An autoimmune disease in which the immune response produces antibodies against nAChRs so causing muscle weakness and degeneration. What are both depolarising/competitive and non-depolarising blockers examples of? Muscle relaxants. Is the hyperkalaemia caused by depolarising blockers dangerous in normal circumstances? No. In what situations may the hyperkalaemia caused by depolarising blockers be dangerous? If the plasma [K+] is already high due to severe burns or crush injuries. synthesis and leads to low ACh availability. Highly active synapses are preferentially affected since choline uptake rates are much higher. What is streptomycin and what is its mechanism of action? Streptomycin is an aminoglycoside antibiotic which blocks Ca2+ entry and so causes ACh release inhibition and muscle weakness as a side effect. What are the two forms of AChEs? Acetylcholinesterase and butyrylcholinesterase. What are the key differences between AChE and BuChE? - AChE is specific for ACh and closely related esters whereas BuChE is unspecific and so hydrolysis many different esters, but will preferentially hydrolyse BuChE. - AChE is membrane-bound and found at all cholinergic synapses whereas BuChE is usually soluble, but can be membrane-bound, and is found in blood plasma, the liver and many other tissues. What may a mutation in BuChE result in? Slow hydrolysis of suxamethonium and reduced sensitivity to dibucaine. Describe the mechanism of action of a ChE hydrolysing AChE. The ChE has two sites: a catalytic site and an anionic site. The anionic site will bind the cationic quaternary ammonium group of ACh whilst the catalytic site will catalyse the hydrolysis. This involves the acetyl group being transferred to the serine -OH group of the catalytic site followed by dissociation of the choline and a spontaneous hydrolysis of the acetylated serine -OH. What is another name for the catalytic site of ChE? Esteratic site. What are the three different classes of ChE inhibitors (anticholinesterases)? - Short-acting - Medium/long acting reversible - Long acting irreversible Name an example of a short-acting anticholinesterase. Describe its method of action. Edrophonium functions by binding competitively to the anionic site with an ionic bond, but it has no complementary group to the esteratic site. Name an example of a medium/long-acting reversible anticholinesterase. Describe its method of action. Neostigmine functions by binding to both the esteratic and anionic sites. It forms an ester bond with the serine -OH and is hydrolysed by the ChE. Spontaneous hydrolysis of the serine -OH bound to the inhibitor is much slower than when bound to acetyl and so the ChE is inactive for several minutes. Name an example of a long-acting irreversible anticholinesterase. Describe its method of action. Ecothiopate is an organophosphate compound which phosphorylates the serine -OH of the esteratic site. Hydrolysis of the serine -OH bound to the phosphate is so slow that recovery normally requires new enzyme synthesis. Which class of antiChEs is most important clinically? The medium/long-acting reversible inhibitors which can be used to reverse muscle relaxation caused by non-depolarising muscle relaxants. What are the effects of antiAChEs? They cause inhibited hydrolysis of ACh and lead to accumulation of ACh in the synapse which causes: - Increased parasympathetic effects (salivation, sweating, increased GI motility, bronchoconstriction etc.) - Repetitive firing at NMJs leading to muscle twitches - Restoration of transmission at NMJs blocked by competitive, non- depolarising blockers (ACh increases so can outcompete the blocker) - Increased NMJ transmission in myasthenia gravis patients - Can cause depolarising neuromuscular block at high concentrations of antiAChE due to increased ACh leading to continuous nAChR activation What are the central effects of antiChEs? Excitatory leading to agitation, convulsions and respiratory depression. What are the main therapeutic uses of antiAChE? - Treatment of glaucoma (eserine/organophosphate) - Treatment of myasthenia gravis (neostigmine/pyridostigmine) - Reversal of competitive neuromuscular block following anaesthesia Name three chemical stimuli capable of stimulating VSM contraction. Noradrenaline, angiotensin II and vasopressin. Describe how noradrenaline leads to VSM contraction. Noradrenaline is released from sympathetic nerve endings and binds to α1-adrenoreceptors present on the post-junctional membrane leading to Gq activation and so activation of PLC which forms DAG and IP3 with the latter acting on IP3-gated Ca2+ channels on the SR and causing increased intracellular [Ca2+]. ATP and NPY are also released as co-transmitters along with noradrenaline with ATP binding to P2X non-selective cation channels and therefore stimulating contraction along with NPY also acting to potentiate the action of noradrenaline. What is the effect of α1-adrenoreceptor antagonists? Decreased blood pressure as a result of vasodilation. How do indirect acting vasoconstrictors work? They cause NA release from the nerve terminal, with that then causing VSM contraction. Give 3 examples of indirect acting vasoconstrictors. Amphetamine, tyramine and ephedrine. How does cocaine function? It blocks uptake of NA back into the nerve terminal so has sympathomimetic effects. What receptor does AngII bind to? ATI. What is captopril? An ACE inhibitor which therefore decreases AngII production from AngI and therefore acts as an antihypertensive by reducing vasoconstriction. What is endothelin? Endothelin is a peptide mediator produced by the endothelium which binds to ETA and ETAB2 receptors (coupled to Gq) to cause VSM contraction and so vasoconstriction. What is vasopressin? How does it affect VSM? Vasopressin is a hormone secreted by the posterior pituitary gland and binds to V1 receptors causing VSM contraction via Gq protein activity. What is felypressin used for and how does it work? Felypressin is a drug which acts as a vasopressin analogue, is selective for V1 receptors and is used as a vasoconstrictor and administered along with LAs as an alternative to adrenaline. How are ergotamine and sumatriptan able to reduce migraine symptoms? They can act as vasoconstrictors in the cranial arterioles. What are the three VSM vasodilators? Adrenaline, NO and histamine. Which receptor in arterioles does adrenaline bind to to cause vasodilation? β2-adrenoreceptors. What is the function of nitrovasodilators? They act to cause NO synthesis and therefore indirectly cause vasodilation. How does viagra lead to prolonged erection, what is it therefore used to treat? Viagra is used to treat erectile dysfunction and acts by inhibiting the enzyme PDE-5 (cGMP-specific phosphodiesterase 5) which therefore doesn't degrade cGMP in the VSM and so the cGMP accumulates and continues to cause vasodilation in the corpus cavernosum of the penis leading to prolonged erection. Other than erectile dysfunction, what may PDE-5 inhibitors also be used to treat? PDE-5 inhibitors may also be used to treat pulmonary hypertension since PDE-5 is present in high concentrations in the VSM of the arterioles in the lungs. Describe how NO-mediated vasodilation occurs. NO production in the smooth muscle cells of blood vessels is stimulated by either the Shearing forces of the blood opening stress-activated Ca2+ channels or ligand-binding to ligand-activated Ca2+ channels with the Single unit smooth muscle features only a few cells which are innervated by the ANS, with most contractions being myogenic in origin through the spontaneous depolarisation of pacemaker cells. Single unit smooth muscle exists as a syncytium with depolarisation spreading through gap junctions between neighbouring cells. Describe multi unit smooth muscle. In multi unit smooth muscle, all cells are innervated by the ANS with there being little or no communication between cells. How does Rho-GEF activation lead to increased calcium sensitivity of smooth muscle cells? Rho-GEF is activated by Gq proteins. Rho-GEF will then activate Rho- kinase which acts to inhibit myosin light chain phosphatase meaning that more myosin light chain is phosphorylated and able to contract at any one time: thus increasing the smooth muscle cell's sensitivity to Ca2+. What does an increase in cAMP in smooth muscle cells lead to? Explain what this means for Gs proteins? An increase in cAMP leads to decreased contraction since it acts to inhibit MLCK meaning it is unable to be activated by Ca2+-CaM and so myosin isn't phosphorylated meaning cross-bridges don't form and contraction doesn't occur. This means that, since Gs proteins cause increased cAMP, their activation leads to vasodilation. With the above information, suggest which G-protein α2-adrenoreceptors are coupled to. α2-adrenoreceptors lead to vasoconstriction through coupling to Gi proteins and so leading to decreased cAMP and so decreased MLCK inhibition meaning that myosin is phosphorylated and cross-bridges thus form more readily. What are the main functions of adrenaline, noradrenaline and phenylephrine? Adrenaline treats anaphylactic shock, noradrenaline can be used to treat septic shock and phenylephrine is used as a nagal decongestant. By what different mechanisms does SM relaxation occur following a contraction? - Passive relaxation in which Ca2+ is taken up into the SR via SERCA and also out of the cell via Na+/Ca2+ exchangers. - Active relaxation is stimulated by either increased cAMP leading to MLCK inhibition (and so decreased MLC phosphorylation and decreased cross- bridge formation) or is stimulated by increased NO which activates guanylyl cyclase and leads to increased cGMP (which activates cGMP- dependent protein kinase which inhibits Ca2+ entry, activates K+ channels and decreases IP3 production) Name 5 mediators which act as nitrovasodilators by stimulating NO synthesis and so indirectly leading to vasodilation. For each one name the receptor it acts at to cause increased synthesis of NO. ACh (M3), histamine (H1), ATP (P2Y), bradykinin (BK2) and substance P (NK1). How does PGI2 act as a vasodilator? Prostacyclin acts to stimulate adenylyl cyclase so increasing cAMP and therefore causing SM relaxation. What are EDHFs? EDHFs are endothelium-derived hyperpolarisation factors which cause hyperpolarisation in VSM and so contribute to the relaxant effects of NO and PGI2. What are natriuretic peptides? Natriuretic peptides such as ANP are potent vasodilators which act on the receptors NPR-A and NPR-B to activate guanylyl cyclase, leading to increased cGMP production which therefore activates PKG and causes relaxation. What type of receptors are NPR-A and NPR-B? Particulate guanylyl cyclase receptors. Name 6 different types of drugs which act to relax smooth muscle. β2-adrenoreceptor agonists, prostacylin analogues, Ca2+ channel blockers, K+ channel openers, nitrovasodilators and phopshodiesterase inhibitors. What is iloprost and what is it used for? Iloprost is a prostacyclin analogue used to treat pulmonary arterial hypertension. What is prazosin and what is it used for? Prazosin is an α1-adrenoreceptor antagonist which is used as an antihypertensive. Because inflamed tissues have acidic extracellular fluid meaning that more of the LA will be in its ionised form and so unable to diffuse into the axon and so cannot block the Na+ channels. Why do LAs which readily dissociate from the Na+ channels function better in axons with high rates of AP propagation? Because there is minimal time between APs for the LA to dissociate. Which pathways are tertiary amine LAs able to act through? Tertiary amine LAs are able to act through both the hydrophobic and the hydrophilic pathways. Which pathways are quaternary amine LAs able to act through? Quaternary amine LAs are able to act through the hydrophilic pathway only. Which type of axons do LAs preferentially block and why? What does this mean for the initial effects of LA? LAs preferentially block C-fibres and Aδ-fibres since they are both small fibres and so have large SA:V ratios meaning less LA is required to plug channels to cause a block. This means that, since both fibre types are nociceptive, that LAs will first block pain transmission. If the degree of block afforded by an LA is insufficient to block conductance, what happens to the amplitude of the LA once it has traversed the anaesthetised portion of the nerve? It will return to normal. What will happen to the compound AP of a nerve trunk as a result of LA action and why? The compound AP of the nerve trunk will decrease because fewer nerve fibres are contributing and also slowing of impulses will lead to more temporal dispersion (spreading out) so reducing the compound AP. What is the difference between the duration of action of ester vs amine LAs? Ester LAs have short durations whereas amine LAs have long durations. This is because esters are hydrolysed relatively rapidly by plasma cholinesterases whereas amine LAs are metabolised in the liver and so have a longer duration of action. Give 3 examples of ester LAs. Procaine, tetracaine and benzocaine. Give 2 examples of amine LAs. Lidocaine and prilocaine. What are the side effects of LAs? - Local tissue injury - CNS effects including depressant (at low [LA]) and stimulant (at high [LA]) effects; causing restlessness or even convulsions - Hypotension caused by cardiac depression and vasodilation - Rare severe allergic reactions Name the LA which doesn't cause hypotension and why it doesn't. Cocaine doesn't cause hypotension because it also has sympathetic potentiating effects meaning that it causes hypertension instead. What are the 6 different methods of LA administration? - Surface anaesthesia which is applied topically - Infiltration anaesthesia in which the LA is injected directly into tissues to anaesthetise nerve endings - Nerve block anaesthesia in which the LA is injected close to (but not in) the nerve trunk to anaesthetise the whole area of distribution of a nerve - Spinal anaesthesia in which the LA is injected into the subarachnoid space between the 2nd and 5th lumbar vertebrae to ensure spinal injury is avoided - Epidural anaesthesia in which the LA is injected into the epidural space (outside dura mater) and it diffuses to block nerve roots - Intravenous regional anaesthesia in which the LA is injected intravenously, distal to a cuff on the limb with anaesthesia diffusing retrogade into the tissues. Which type of body surface is surface anaesthesia usually applied to? Mucous membranes such as the mouth or the cornea. What is EMLA? EMLA is a mixture of lidocaine and prilocaine. What is the major issue with infiltration anaesthesia? Large quantities of the LA are required and so there's a danger of systemic toxicity. What is a delayed after-polarisation? What is it caused by? When the after-depolarisation occurs in late phase 3 or early phase 4 when the membrane is nearly fully repolarised. This can be caused by certain drugs which bind K+/Ca2+ channels in cardiac tissue. What is re-entrant dysrhythmia? Where the impulse circulates indefinitely in a localised region of the myocardium, acting as a source of excitation (independent of the normal pacemaker) for the rest of the heart. What is this re-entrant dysrhythmia caused by? Anatomical abnormalities or myocardial damage. What is the AP known as in re-entrant dysrhythmia? A slow response. What are the effects of β-agonists and β-antagonists on re-entrant dysrhythmia and why do they have this effect? Since the AP has a slow rising phase and very slow conduction, it relies more on Ca2+ currents than Na+ and so is sensitive to Ca2+ modulation by β-agonists, which promote the dysrhythmia, and β-antagonists which suppress the dysrhythmia. What is the affect of prolonging the refractory period on re-entrant dysrhythmia? It will suppress the dysrhythmia since the for the continuous circulation of the AP to occur, the refractory period must be shorter than the circulation time of the impulse. What is abnormal pacemaker activity and how is it caused? Abnormal pacemaker activity is where ectopic pacemaker cells cause ectopic beat production which are often triggered by the normal wave of depolarisation since increased intracellular [Ca2+] triggers secondary depolarisation and so pacemaker activity. Abnormal pacemaker activity is often caused by myocardial damage forming the ectopic pacemaker cells. What are the possible causes of a heart block? The impulse may fail to initiate at the SAN, the impulse may fail to transmit from the AVN or may fail to propagate along the conducting system. What is the result of heart block? Ventricular contraction cannot be maintained by normal SAN pacemaker activity and so is instead maintained by secondary pacemaker activity causing abnormal slow rhythm that is often unreliable and can lead to loss of consciousness or even death. What condition may abnormal pacemaker activity lead to? Ventricular tachycardia. What condition may re-entrant rhythm lead to? Ventricular fibrillation. What condition may a high frequency re-entrant rhythm lead to? Atrial flutter. What is the most common tachyarrhythmia and what is it caused by? Atrial fibrillation is the most common tachyarrhythmia and is caused by high frequency chaotic rhythm. What are the 4 classes of anti-dysrhythmic drugs? Name the class, the type of drug and their function. - Class I - drugs that use-dependently bock voltage-sensitive Na+ channels and so decrease excitability, conduction velocity and re-entry - Class II - β-blockers which block β1-adrenoreceptors and so reduce slow inward Ca2+ current and SAN and AVN activity through reducing sympathetic excitation - Class III - K+ channel blockers which prolong cardiac AP and increase refractory period so decreasing the time in which dysrhymthia can occur - Class IV - Ca2+ channel blockers which inhibit L-type Ca2+ channels and so slow AVN conduction and inhibit ectopic beats as well as decrease SAN activity Which class of anti-dysrhythmic drugs can be subdivided further, what are they subclassified depending on? Class I can be split into a, b and c: - Class Ia - dissociates from Na+ channels at an intermediate rate and prolongs repolarisation as well as blocking Na+ channels - Class Ib - dissociates from Na+ channels at a rapid rate and preferentially binds to inactivated channels thus meaning they preferentially block depolarised regions What is the use and method of action of digoxin? It causes partial AVN block and so reduces rate of conduction meaning it is useful in the treatment of atrial fibrillation or flutter. What will digoxin cause if used on a patient with no underlying health issues? Digoxin will lead to dysrhythmias through the increase of intracellular [Ca2+] as well as increasing force of contraction as a result of blocking the Na+/K+-ATPase. How does the blocking of Na+/K+-ATPases by digoxin lead to increased force of contraction? Since it increases intracellular [Na+] and so reduces the Na+ gradient across the SR membrane which reduces the Na+/Ca2+ exchanger activity and causes Ca2+ accumulation by the SR thus increasing force of contraction. What can adenosine be used to treat and how does it achieve this? Adenosine can be used to treat arrhythmias and dysrhythmias by blocking AVN conduction and so reducing rate of conduction and HR. It is commonly used to treat supraventricular tachycardias. What is the only reliable treatment for heart block? Implanted electrical pacemakers. How is pulseless ventricular tachycardia treated? Using electrical defibrillation (defibrillator). In what form are LAs administered? LAs are administered as water soluble hydrochlorides with the tertiary amine base being liberated by the relatively alkaline pH of the tissue fluid. To which part of the Na+ channel do LAs bind? They bind to the S6 domain of the α-subunit in the inner pore of the Na+ channel. Which property of LAs is the most significant in determining anaesthetic potency? Lipid solubility. What is pKa? The pH at which 50% of the drug is ionised. What does a low pKa mean for the onset of an LA? A low pKa means a fast onset of the LA since a higher proportion of the LA is unionised and so able to cross the axon membrane. What is the equation for pKa? Why can an LA cause a severe allergic reaction in certain patients? One of the main breakdown products is PABA (para-amino benzoate) which can cause allergic/hypersensitivity reactions. How does sympathetic activity affect the refractory period? Sympathetic activity will shorten the refractory period by stimulating β1- adrenoreceptors which then activate Na+ and Ca2+ currents so increasing the rate of depolarisation and thus shortening the refractory period. How does parasympathetic activity affect the refractory period? Parasympathetic stimulation of M2 receptors increases K+ conductance and so decreases depolarisation therefore increasing the interval between APs and so increasing the refractory period. What is the name of the 4 class classification system of anti-dysrhythmic drugs? The Vaughan-William's classification. What are the limitations to the Vaughan-William's classification? There are now a much wider range of drugs than when it was created as well as a greater understanding of mechanisms and the understanding that many drugs are not wholly selective for only one channel type. What does the QT interval show? The duration of ventricular depolarisation. such as Ikr and Ik1, resulting in the outwards current progressively outweighing the inwards. Describe the mechanism of phase 3. The L-type Ca2+ channels close and the outward movement of K+ ions means that the resting potential of the membrane is restored. Describe the mechanism of phase 4. The resting membrane potential is restored and stabilised by a current known as the inward rectifying current (Ik1) - this is now the resting phase. Describe the phases of AP generation in the SAN. Phase 0 - As the membrane potential reaches -50mV during depolarisation, T-type Ca2+ channels open causing further depolarisation of the membrane. L-type Ca2+ channels then open causing full depolarisation. Phase 1 - absent in the SAN. Phase 2 - T-type Ca2+ channels close and repolarisation of the membrane commences. Phase 3 - Ikr and Iks channels both open due to the depolarisation. Iks channels then deactivate during repolarisation and so are closed in the latter stages of repolarisation. Phase 4 - Ikr channels remain open to permit repolarisation of the membrane back to its resting potential of about -60mV. This causes activation of the non-selective cation channels which cause the funny/pacemaker current. What 4 things is cardiac function influenced by? Myocardial contractility, preload, afterload and neuroendocrine activation. What is the basic contraction mechanism of a myocardial cell? Ca2+ binds to troponin which facilitates actin-myosin cross-bridge formation through causing a conformational change in tropomyosin, exposing the myosin-binding sites on the actin filament. What is preload? Preload is the degree of tension caused by the stretch of the myocardial fibres as blood returns to the right ventricle. What is the Frank-Starling law? That the higher the preload, the higher the tension and the greater the stretch and so end-diastolic length in the myocardial fibres leading to an increased force of contraction and so increased stroke volume. What is afterload? Afterload is the pressure against which the heart must work to eject blood during systole. What effect does arterial vasoconstriction have on afterload? Arterial vasoconstriction will increase afterload and so increase cardiac work and O2 consumption. What does neuroendocrine activation refer to regarding regulation of cardiac function? Neuroendocrine activation refers to a reduction in C.O. leading to a reduced renal blood flow and so activating the renin-angiotensin system. ADH and ANP are also released. The overall net effect of neuroendocrine activation is for vasoconstriction and increased stroke volume which thus increases preload and afterload and may aggravate heart failure. How can nifedipine be used to treat heart failure? It will cause vasodilation and so lead to reduced preload and afterload. What are the side effects of nifedipine? Hypotension, headache, flushing and tachycardia. What is the use of ACE inhibitors and what is their method of action? ACE inhibitors inhibit the conversion of angiotensin I to angiotensin II and so reduce vasoconstriction. They also act to reduce oedema since AngII can be converted to AngIII which can stimulate aldosterone secretion in conjunction with AngII leading to H2O and Na+ retention. Because of the reduction in vasoconstriction and so vasodilation (so reduced afterload) as well as reduced oedema (so reduced afterload), ACE inhibitors are commonly used as antihypertensive agents. Give an example of an ACE inhibitor which is used as an antihypertensive. Enalapril. What is a common side effect of ACE inhibitor use and why? Coughing due to the secondary effect of ACE inhibitors which is to inhibit bradykinin metabolism, with persistent bradykinin promoting coughing.