Week #4 Flashcards

Question

What are the clinical signs of anaemia?

Answer 1

* Pale * Lethargic * Failure to thrive * Hypoxic * Ischaemia * Tachycardia—fast HR * Acute blood loss—HR will jump up quickly * If chronic iron deficiency then perhaps not as high * Stroke volume may have increased over time instead

Answer 2

* Failure of production * Increased destruction/loss * Inappropriate production

Answer 3

* Grams/L (normal=120-140) * Red cell count-4.5-5 \*10^12 cells per Litre * Heamatocrit * Measure of what proportion of the blood is the cellular components and what portion of the blood is the plasma component—measured as a %. Normally 45% for men and 40% for women * Mean Corpuscular Volume * Average volume of a red blood cell within the body * Mean Corpuscular Heamaglobin * Average amount of heamaglobin per cell * Mean corpuscular haemoglobin concentration * Red cell distribution width—like a standard deviation around the mean * Shows us if the cells are all different or mostly the same * Platelet count * White cell count * differential

Answer 4

* morphology of the red cells, white cells and plts * Red cells * Size (normocytic, microcytic, macrocytic) * Shape (many variations—each with different meaning) * Colour (normchromic, hypochromic, polychomasia)

Answer 5

* Regenerative * So either blood loss, or blood break down * Can be very rapid progression to death * Aregenerative * Bone marrow isn’t making enough cells * Can be slower progression * Microcytic, normocytic or macrocytic

Answer 6

* Signs of increased production * Reticulocytes, polychromasia * Signs of increased destruction * Jaundice (increased serum bilirubin) * Bi product of breakdown of RBC is bilirubin so jaundice * Haptoglobins-picks up bilirubin * LDH * Lactic dehydrogenase-picks up bilirubin * Blood loss * Overt/covert

Answer 7

* Yolk sac—first few weeks * Liver and spleen—6weeks-7months * Sometimes if there is something wrong with the bone marrow than liver and spleen may compensate and blood is made from there instead * Bone marrow—7 months—throughout life

Answer 8

* From an adult it would be best to collect bone marrow from the pelvis * from a child the bone marrow can be taken from the blood * throughout life bone marrow sites are replaced with fat as the bones stop growing

Answer 9

* Pluripotent stem cell * Capable of self renewal * Differentiates into all haemopoietic cell lines * Also gives rise to lymphocytes, and osteoclasts * Exists in small numbers in the marrow * Mice studies 1 in 100,000 nucleated cell * As yet not definitevely identified * So we still cannot look at them down the microscope and identify them

Answer 10

* Bone marrow stromal cells can take the form of macrophages, fibroblasts, endothelial cells, fat cells and reticulum cells. * ECM stroma can include fibronectin, laminin, collagen and proteoglycan, heamonectin. * Provides specific microenvironment for bone marrow to grow * Many elements required * Changes in adhesion molecules mark the progression of cells through the stroma * Every cell in the bone marrow is attached to the stroma * This is why when we do a bone marrow transplant we can inject into a vein because bone marrow cells go to their home * Bone marrow in continuity with blood circulation * Reason cells are able to stay in bone marrow due to the adhesion factors on the stromal cells

Answer 11

* iron, vitamin B12 and folic acid * Erythroblasts require folate and vitamin B12 for proliferation during their differentiation

Answer 12

* Injury * Primary haemostasis (immediately, seconds, minutes) * Vasoconstriction—stop blood loss * Platelet adhesion * Platelet aggregation * Secondary haemostasis (minutes) * Activation of coagulation factors * Formation of fibrin * Fibrinolysis (minutes, hours) * Activation of fibrinolysis * Lysis of the clot

Answer 13

* Factors are contained within the blood plasma * Remeber that Fibrin production results in mesh like formation which fixes platelets together and completes clot * Remember that Thrombin also activates thrombomodulin and TAFI

Answer 14

* Blood vessel wall * Blood composition * Blood flow

Answer 15

* TAFI is for clot stabilisation * Thrombomodulin is for control of activation as it inhibits VIIIa and Va it does this with activated Protein C

Answer 16

Activation of PAR’s (protease-activated receptors) * Group of cellular receptors that regulate platelet activation * Tumour growth and spread * New blood vessel formation * Inflammation * Atherosclerosis * Neutrophil and monocytes migration * Survival and growth of neurons Importance in embryonic growth, tumour spread and vascular disease

Answer 17

* Letters are inhibitors * roman numerals push the coagulation cascade forward

Answer 18

* Blood vessel wall * test bleeding time? no longer done * no other tests that could test this * Platelets * number, function, appearance * Coagulation system (and fibrinolytic system) * Lots of different tests could be done

Answer 19

* ACT * activated clotting time * APTT-Activated partial thromoboplastin time * Takes patient sample at 37 degrees, we add calcium to reverse citrate in the tube and then we add an activator, an APTT reagent, that activates the system and measure the time in seconds until fibrin is formed * Just tells us about the integrity of the factors in that line * Doesn’t inform about the physiological situation * So this test can tell us about the presence or absence of a drug called heparin—most frequently used IV anti-coagulant * And also tells us the presence of a Lupus anti-coagulant, a non-specific inhibitor of the phospholipid antibody that gives a prolonged APTT-but actually causes a risk of clotting So a prolonged APTT shows that the patient may have an increased risk of bleeding or indicates the presence of one of the two anti-coagulants * PT/INR-pro-thrombin time, converts to an INR * Add a thromboplastin and then measure time until fibrin is formed * Also the test used to monitor warfarin (for a long time the standard anti-coagulant for long term use) * INR is the international normalised ratio This was to normalize the PT number High level of standardization Because the problem with these results is that they may use different reagents for the tests and different labs may get very different results So there is a strong need for standardisation and we still don’t have it for the APPT measurements INR= (patient PT/mean normal PT)ISI ISI= international sensitivity index—reflects the sensitivity of reagent to reduction in Vit K dependent factors

Answer 20

* Factor assays * measure specific protein concentrations * Functional assays * measure how well Von-Willebrand factor binds collagen

Answer 21

* Funtional clot based assays may better reflect the physiological situation (?) but are more technically difficult * Chromogenic assays—use substrate that will be clipped by protein of interest and illicit colour change and then we can compare to a standard and infer how much protein is present * More reproducible but may be less physiologically relevant * Immunological assays—measure amount of proteins, doesn’t tell us if the protein is working though

Answer 22

* Do global test to look at which part of the pathway we want to look at and then specific test to work out the specific protein deficiency * remember that factors vary in concentration as we age so we need age matched controls

Answer 23

* Re-uptake into the neuron that released it where it is then metabolised * Or metabolism in the synapse where it is degraded

Answer 24

* sweat glands, heart, blood vessels and glands which occurs through innervation from post ganglionic nerves which arose from the sympathetic chain where the pre-ganglionic neuron terminated. Also the adrenal gland which is directyl innevated by the pre-ganglionic neuron * Heart, glands and smooth muscle

Answer 25

Somatic (Voluntary) * Single fibre leaves CNS * Innervates Skeletal Muscle Autonomic (Involuntary) * Two fibre system: * Preganglionic fibres from CNS * Postganglionic fibres from autonomic ganglia * Innervates Most Organs/Tissues in the body

Answer 26

* Choline acetyltransferase takes choline and adds AcetylcoA (from mitochondria) and makes acetylcholine which is then transported into the synaptic vesicle

Answer 27

* Synthesis starts with tyrosine * Tyrosine hydroxylase then converts it to L-DOPA and then DOPA decarboxylase converts it into Dopamine. * Then dopamine is transported into the synaptic vesicle * If dopanergic neurons there would be no dopamine Beta-hydroxylase and dopamine would be released * In sympathetic nerves dopamine is conveted to noradrenaline and released at the synapse from synaptic vesicles

Answer 28

* PNMT is present in the secretory vesicles of the adrenal gland and converts noradrenaline to adrenaline

Answer 29

* Co-transmission is where autonomic nerves release more than one substance * For example ATP seems to be an immediate neurotransmitter that is released to exert effects * and Neuropeptide Y is a later released neurotransmitter * NA is the intermediate response * The degree of co-transmission that occurs can varry given the nerve in question

Answer 30

* Through the action of acetylcholine esterase (AChE), which is on the surface of the effector tissue cell, converts Acetylcholine to choline

Answer 31

* transporter molecules pump NA out of the synapse * re-uptake through a neuronal receptor

Answer 32

* Parasympathetic nerve

Answer 33

* Atropine is a muscurinic receptor antagonist * From deadly nightshade

Answer 34

* Nicotinic receptor antagonist

Answer 35

* Blood pressure drops due to decreased vascular tone and decreased HR * Blood pressure rises due to vasoconstriction and increased HR

Answer 36

* Ligand gated ion channels * G-protein coupled receptors

Answer 37

* Oxygen can be dissolved in water but at a fairly low concentration and it would not be enough for us to survive * O2 is soluble at \<0.1mM = 1% of needs * Also oxygen is very reactive = oxidation

Answer 38

* Fe(II) has 6 coordinating bond positions * 4 bonds to nitrogens in the porphyrin ring * 5th bond to histidine F8 (His F8, i.e. 8th residue of the F helix)=proximal histidine * 6th bond is unoccupied in deoxygenated Hb; histidine residue from helix E7 hovers; in oxygenated Hb, oxygen binds here * Oxygen binds to Fe at 120 degree angle—easily removed

Answer 39

* Electron transport e.g. cytochrome C * Enzymes that perform redox reaction e.g. catalase reduced hydrogen peroxide to water

Answer 40

* Notice when oxygen binds the Fe is pulled back into the plane of the haem * Which then pulls on the proximal histidine * Has dramatic effects for the whole organisation of the protein

Answer 41

* scarlet red * dark red (looks at bit blue through skin) * cherry red (CO binds 200 x more tightly than O2) * MetHb is when Fe2+ is oxidised to Fe3+ * old (aged) blood—dark brown (old meat and dried blood)

Answer 42

* Hb needs to have high affinity for O2 in the lungs (Hb is 90% saturated) * Once the Hb—O₂ molecules reach the tissue that consumes oxygen, the O2 needs to be transferred to myoglobin. (Hb in venous blood is 60% saturated) * Sigmoidal curve represents weak-binding state at low pO₂ and strong binding state at high pO₂. So we want the Hb to pick up as much oxygen as possible when the partial pressure is above a certain threshold but then give away as much oxygen as possible when the oxygen pressure is below a certain level * Curve A is high affinity * Curve B is low affinity * We want the sigmoidal curve

Answer 43

* Myoglobin in monomeric * 153 amino acids (Mr 16,700)—single polypeptide chain * O2 storage protein =\> mainly in skeletal muscle * Compact globular structure * Tertiary structure **8 alpha helices (A-H)** * Haem bind in pocket between helix F and E. * Involves His (F8) (i.e. the 8th histidine on the F alpha helix) and His (E7) * Transient “breathing” of the alpha helices allow O2 to access haem in its buried hydrophobic pocket * Myoglobin has a high O2 affinity. Affinity does not change with O₂ concentration (_P50 is the partial pressure of a O₂ giving 50% saturation. Mb _P50 = 2 Torr) * So Mb will actually take O₂ from Hb * Monomer =\> no cooperativity hyperbolic curve.

Answer 44

* (Mr 64,500)—two alpha chains of 144 residues; two beta chains of 146 residues * The alpha and beta subunits (50% identity) associate more strongly with each other than the same subunits * so alphaneta binds to alphabeta * 3D structures look very similar to each other and to Mb * Cooperativity in binding and release of O2, i.e. affinity for O2 varies with O2 concentrations

Answer 45

* When oxygen binds it pulls the iron atom into the plane of the haem. * Histidine F8 is also pulled changing the tertiary structure of the entire subunit. * Conformational changes at one subunit affects adjacent subunits. When one changes they all change cooperatively. The switch between deoxy [T] and oxy [R] states involves: * Fe²⁺moves relative to the porphyrin ring (pulls His F8) =\> initiates conformational change * alpha/beta subunits slide past each other and rotate * 8 electrostatic bonds in deoxy Hb are broken * H‐bonds between α and β‐subunits reorganise (Tyr‐Asp in T, Asp‐Asn in R) * so this is a lock in, break, and lock in again * BPG (bisphosphoglycerate) (which locks deoxy Hb) is released

Answer 46

* As the first oxygen is added the Hb becomes more relaxed and then the other molecules change conformational state as well and become more "open" for oxygen binding * We call this a homotrophic allosteric modulataor

Answer 47

* **heterotrophic allosteric effector** * 2,3‐BPG **binds** at a cavity between the subunits of the **deoxy‐Hb** molecule. It is the **5 negative charges** on the molecule that enables it to bind * 2,3‐BPG **stabilises deoxy‐Hb** and locks out oxygen from rebinding. * 2,3‐BPG is obliged to dissociate when oxygen binds in the lungs and closes the cavity. * 2,3‐BPG is synthesised in RBC through the **glycolysis** pathways **How does it exert its effect and why is it important at high altitudes?** * Decreases Hb affinity for oxygen so we can give more off in the tissues * In situations of high altitude the partial pressure of oxygen is lower so we can change the concentration of 2,3-BPG so that we can move the oxygen dissociation curve.

Answer 48

* Hb carries ~15% of CO formed in tissues to the lungs on the amino terminal groups of deoxy‐Hb as carbamate: * CO₂ + Hb-NH₂ \<=\> H⁺ + NH‐COO^- * O₂Hb binds CO₂ less readily than deO₂Hb * =\> CO₂ is released in the lungs * The rest of the CO₂ is converted to HCO₃^- by carbonic anhydrase * CO₂ + H₂O \<=\> HCO₃^- * HCO₃^- is soluble in plasma and is so transferred to the lungs * Both these reactions cause decreased pH but we use this to our advantage as the **Bohr effect** *

Answer 49

* Acid is produced in the tiissues\the binding of protosn to Hb decreases its affinity for O₂ * Explanation: Two histidines that salt bond become more positively charged in acid =\> stabilises the T state * This stimulates HbO₂ to yield more O₂in the tissues in a state of low pH * It also transports ~40% of the protons produced back to the lungs and kidneys. * This Bohr effect is another example of allosteric iinteraction which involves communication between the different subunits

Answer 50

* HbF(α₂γ₂)binds oxygen with greater affinity than the mother'sHbA (the adult form of haemoglobin) * This gives the foetus access to oxygen carried by the mother’s HbA. * This is due to the fact that HbF binds 2,3 BPG less avidly than adult Hb

Answer 51

* HbS, HbE, HbC, Hb D, Hb H * Different Hb may protect against malaria and so may be selected for.

Answer 52

* HbA has a glutamate at position 6 whereas HbS has a valine, caused by one base change. * So is a hydrophobic residue * hydrophobic pocket in deoxyHb leads to binding to the surface and results in a polymer of HbS and if it gets large enough it can precipitate * So in low O₂ we can get vaso-occlusions and crisis * HbS, HbS homozygositgy is partciularly susceptible to sickle cell crisis-RBC removed by spleen etc * Homozygosity is very bad but heterozygosity is protective from malaria whithoout as bad symptoms

Answer 53

* Innervation of the sweat glands * post ganglionic nerves release ACh

Answer 54

* Acts to prevent vesicualr exocytosis of the synaptic vesicle and blocks process of membrane fusion * Can result in muscle weakness and even paralysis * Can used therapeuticallyh to combat some conditions such as muscle dystonias etc * also can be used for powerful sweating **How does it actually work?** * Botulinum toxin is an enzyme/ a protease * Normally the synpatic vesicles (containing ACh) use surface proteins (SNARE proteins) to bind to proteins on the innersurface of the membrane which leads to fusion of the membranes and then ACh is released. * However once Botulinum toxin is in its active form it cleaves some of the SNARE proteins, which results in the lack if release of the ACh

Answer 55

* Blocks the action of acetlycholine Esterase (AChE) * Some of the drugs in this group show some selectivity in their action * Can be utilised clinically * may also vary in CNS activity * i.e. ablity to cross the BBB * Also have variable length of activity * short acting, medium duration and irreversible

Answer 56

**Edrophonium** * short acting * used in the diagnosis of myasthenia gravis **Neostigmine/ Pyridostigmine** * medium duration drugs * used to reverse effects of (non-depolarising) neuromuscular blockers (nicotinic receptor) * used in the treatment of myasthenia gravis **Donepezil** * Enters CNS well * Used in the treamtent of Alzheimer's disease * one componenet of AD is decreased cholinergic signalling in CNS

Answer 57

* Autoimmune disease where Ab against nicotinic cholinergic receptors on skeletal muscle * Ab target the skeletal muscle ones (there are different forms) * Ab binding leads to complement recruitment and this can lead to destruction of the post junctional membrane * Local immune response triggers loss of architecture and we get re-distribution of the receptors * binding itself can lead to internalisation of the receptors * there are also some indications that Ab may out-compete the ACh * Disease tends to start with face and then moves to the skeletal muscle

Answer 58

* Blocking degredation of the ACh can lead to higher ACh and longer ACh half life and so there may be enough nicotinic receptors left that can be bound ACh

Answer 59

* The Tensilon test * to see if short acting ant-cholinergic improves symptoms * Tensilon=Edrophonium

Answer 60

* The Nicotinic receptor is a Ligand-gated ion channel * Depending on the subunits of the nicotinic receptor it may have different uses and be targetted by different drugs-5 subunit structure * The muscle for is Nm type * the ganglion type is reffered to as Nn type

Answer 61

* Smoking cessation * nicotine (patches etc) * Varenicline (particla agonist)

Answer 62

* Preventing skeletal muscle contraction * Pre-surgical skeletal muscle relaxants (may allow for lower dose of anaesthetic * non depolarising (e.g. tubocurarine/vecuronium) * reversed by neostigmine (anti-cholinesterase) * reverse paralysis * Ganglion blockers (rare) act on the nN type * Hexamethonium

Answer 63

* G-protein coupled receptor * Parasympathetic receptors * Salivation, Lacrimation, Urination, Defecation * Sweating * Slowing of heart * Bronchoconstriction * Vasodilation * Clinical uses of agonists * Pilocarpine * enhances drainage from eye in glaucoma and can reduce the pressure

Answer 64

* Atropine * reduce secretiins and produce bronchodilation (in anaesthesia) * for certain types of bradycardia * pupil dilation (for examination of the eye) * AChE-inhibitor poisoning (organophsophates) * Hyoscinne * motion sickness * Ipratropium/Tiotropium (inhaled) * COPD * and maybe asthma too

Answer 65

* **Blocking the uptake of NA** * **Cocaine** blocks the re-uptake resulting in more NA in the synapse * can produce a tachycardia and increase in BP * **Blockage of metabolism** * Monamine oxidase deals with leaked NA and metabolises it * Can use Monoamine oxidase inhibitors (MOAinhibitor) * more leakage of NA * **Indirectly acting Sympathomimetics** * cause release of NA but in a Non-exocytotic release (calcium independent) * Indirectly acting sympathomimetics are taken up by the presynpatic neuron from the synapse where they procede to displace some of the NA from the synaptic vesicle within the neuron which then leaks out some of the NA inot the synapse * **Amphetamines, ephedrine (psuedoephedrine) and tyramine** * Tyramine can be in vegamite and cured sausage and cheese etc but nis ussually no a problem due to the action of the Monoamine oxidase * but if patients are on MAO-inhibitors are taken then we could get HR increase and BP increase

Answer 66

* Alpha and Beta Adrenoceptors * Beta selective * alpha selective

Answer 67

* B1 receptors on the heart and B2 receptors in the airways * Isoprenaline used t beused for asthma treatment but is now replaced with salbutomol due to the increased specificty for B2 receptors

Answer 68

* B1 Adrenoceptor antagonist * to treat hypertension

Answer 69

* B1 and B2 adrenoceptor antagonist

Answer 70

* alpha1 adrenoceptors arte foound on blood vessels and cause vasocontriction * Agonist-phenylephrine-nasal decongestent * antagonist-praxosin-hypertension treatment

Answer 71

* small amine * peptide * gas

Answer 72

* Antigen via IgE * Complement fragments C3a, C5a * Neuropeptides * Cytokines and chemokines * Bacterial components * Bacterial components * Physical trauma

Answer 73

* H1, H2, H3, H4 * All are GPCR

Answer 74

* Reddening-vasodilation * Wheal-increase in vascular permeability * Flare-spreading response through sensory fibres

Answer 75

* Useful in treating * hayfever * atopic dermatits * urticaria * anaphylaxis and angiodema * bites and stings * pruritus * motion sickness * (**not effecitve in asthma)**

Answer 76

* Sedative-**chlorpheniramine. promethazine** * sedation may be neutral/beneficial in treatment of allergic condition, but sifficient to interfere with lifestyle * Non-sedative (poor entry into CNS)-**terfenadine, astemizole** * lack of anti-muscurinic activity and GIT effects but can cause rare, sudden ventricukar arrythmia (withdrawn) * Nwe non sedative agents-**citirizine, loratidine** * reduced risk of unwanted cardiac effects

Answer 77

* Used to be used for peptic ulcer treatment * but now we know that the disease is bacterial * prevented gastric acid secretion * HA released from Enterochromaffin-like cell acts on the parietal cells of the stomach and causes H+ release from the cell and acidification of the stomach

Answer 78

* Bradykinin is a local peptide mediator in pain and inflammation * Generated after plasma exudation during inflammation * Upon increased vascular permeability and leak of plasma proteins we get Prekallikrein (inactive plasma protein) being activated by Hageman factor (factor XII) converting is to Kalikrein * Kalikrein acts on plasma protein High molecule weight kininogen * HMWK is cleaved into bradykinin

Answer 79

* Bradykinin is a 9 amino acid peptide and the end can be cleaved by Kininase I and II * Kininase II is otherwise commonly known as angiotensin converting enzyme (ACE)

Answer 80

* Vacular * dilate arterioles and venules (released PGs/NO) * Increased vasculare permeability * Neural * stimulate sensory nerve endings-Pain * Other * contract uterus, airways and gut * epithelial secretion in airways and gut

Answer 81

* Both are GPCRs * There are B1 and B2 receptors

Answer 82

* B2 Bradykinin receptor antagonist * used to treat hereditary angioedema * patient have genetic C1esterase inhibitor deficiency (a SERPIN (serine protease inhibitor)) * so a deficiency in the enzyme that inhibits kalikrein etc * so people have heightened levels of bradykinin and can cause deeper tissue swelling

Answer 83

* People found that by adding NA the vessels would contract * But then upon adding ACh different labs found different things such that some labs noticed a further vasoconstriciton and other labs noted a vasodilation * People were confused by this * Turns out it was due to the different vascular preperations where: * The situation where ACh produced a vasodilation were using a transverse ring of the blood vessel * the situation where ACh produced a vasoconstriction the blood vessel was a helical strip where the endothelium had actually been removed * This lead to the realisation that the vascular endothelium was not just serving as a barrier but was a regulator of vascular tone * where ACh stimualtion would result in NO release and casue a vasodilatory response.

Answer 84

* Prostacyclin-**Vasodilator** * nitric oxide-**Vasodilator** * Endothelin-**Vasoconstrictor**

Answer 85

**NO generation** * receptor mediated genration of NO * ACh/Bradykinin stimualtion or mechanical shear stress * could result in intracellualr release of Ca²⁺ * this would activate nitric oxide synthase (NOS) * NOS would convert arginine to liberate gas NO and citrulline * Endothelial cell would then release the NO **NO produces vasodilation** * .NO enters smooth muscle cell and activates enzyme guanylate cyclase * Guanylate cyclase (active) then converts GTP to cGMP * cGMP produces vascular relaxation of the smooth muscle cell *

Answer 86

* nNOS-(nerves, epithelial cells) * iNOS (inducible-macrophages, smooth muscle) * eNOS (endothelial cells)

Answer 87

* L-arginin analogues * (**L-NAME**) * Produce * vasoconstriction * hypertension

Answer 88

* Flow-dependent vasodilation * NO release in response to shear forces * consequences for endothelial damage/dysfunction * Inhibits platelet adhesion and aggregation * Neurotransmitter

Answer 89

* C20:4 * 20 carbon molecules with 4 double bonds * Eicosatetraenoic acid * Omega-6 * has its first C-C double bond at Carbon 6

Answer 90

* From poly-unsaturated fatty acids (PUFA) * Diet usually consists of omega-6 PUFA * Usually consumed as C18; 2 but that can be converted to C20;4 through elongation and desaturation

Answer 91

* Carefully stored * Esterified into the plasma and nuclear membranes * Arachadonic acid must be kept at lower concentrations so to avoid conversion to more active components * Esterified in the phospholipds and the PUFA are esterified at the C2 position * C3 position has the base * and C1 is commonly a mono-unsaturated or saturated fatty acids

Answer 92

* Through activation of phospholipase A₂ * cleavage at the seconf carbon of the glycerol backbone * The enzyme is controlled in tight ways * Cytoplasmic calcium dependent * can also be phosphorylated by Erk to increase activity * Many snale venoms contain Phospholipase A₂ and works on the outside of the cell membrane and actually breaks it down

Answer 93

* AA is not in itself biologically active and must be metabolised to form **eicosanoids** * The type of eicosanoids generated depends on the cell type * through the expression of particular enzymes that transform AA * these enzymes are **COX-1...** * the form that is making the pre-curser to make prostacyclin continuously * housekeeper role-constitutively expressed * ...and **COX-2...** * inducible enzyme * In the promoter of the COX-2 there are components that respond to inflammigons * So COX-2 expression is increased inf inflammatory conditions * IL-1 etc * ...and **Lypoxygenases** * 5-Lypoxygenase expressed highly in eosinophils, mast cells and neutrophils and restricted to these cells

Answer 94

* "Unstable" prostoglandins are termed Cyclic Endoperoxidases * They are converted to **"stable"** **prostoglandins** by **isomerases**. * And depending on the relative abundance of the different isomerases they can be converted to PGE2, PGF2, PGD2. * various substitutions on the cyclo-pentane ring are what define each of the molecules. * allows for highly selective action * these are relatively stable but still have quite a short half-lige

Answer 95

* PGE₂ * Relaxes vascular smooth muscle * vasodilator/natriuretic-decreased blood pressure. * hyperaslgesic-sensitises nerves to painful stimuli * but does not elicit oain itself * pyrogenic-fever producing * angiogenic (wound healing/ tumour growth) * in the long term * Bronchodilator * not used as a bronchodilator drug though... why? * PGF₂ * Bronchoconstrictor * PGD₂ * Bronchoconstrictor

Answer 96

* PGE₂ * Anti-inflammatory * acute and chronic conditions, e.g. RA, gout (not aspirin) * Analgesia * headache, menstrual pain, musculo-skeletal pain * Antipyretic * Paracetamol often preferred though * Side-effects are gastric irritationa nd ulceration

Answer 97

* If PGE₂ is given in isolation to a subject than it causes vasodilation and heat but NO pain * But if PGE₂ is given with a directly algesic substance like bradykinin the repsonse elicited by the bradykinin is much more intense and much more protracted * Does not matter what the pain stimulis is

Answer 98

* IL-1Beta induced increases in Bradykinin-1 receptors and increase in COX-2 and phospholipase A₂ * So in inflammation the production levels of PGE2 is much higher and gives rise to all the symptoms

Answer 99

* Prostoglandins do not travel in the blood * pulmonary circualtion metabolises prostoglandins before they reach systemic circulation * But cytokines (TNF-alpha, IL-1Beta do travel in circulation and they can travel to regions of the hypothalumus where they can pass across in regions where the blood brain barrier is not as strong and at these site there is induction of phospholipase A₂ and Cycloxygenase and PGE₂ synthesis * This leads to cAMP release which raises the temperature set point

Answer 100

* We lose the gastro-protective role of PGE₂: * promotes blood flow * promotes angiogenesis * increases mucus secretion * reduces gastric acid secretion * So with a patient on NSAIDs chronically we can get significant ulceration

Answer 101

* Prostacyclin and Tromboxane A₂

Answer 102

* Prostacyclin does not have the cyclo-pentane ring so is not a prostaglandin * chemically unstable-half life of 3 min * produced by thin layer of **endothelial cells** constitutively * **reduced platelet activation** * **vasodilation** * **protects against coronary artery disease** due to the vasodilationa and reduced platelet activation

Answer 103

* Thromboxane is not a prostoglandin with a siz memberred ring * even more chemically unstable-half life of 30 seconds * Produced by mainly by platelets and a bit by macrophages * positive feedback as it causes further platelet activation * vasoconstrictor * Promotes coronary artery disease * These actions oppose those of prostacyclin (PGI₂)

Answer 104

* Binds to a serine at the active site of the COX * Can be given at low dose to afford a cardioprotective effect * still high dose in the gastric circulation though so can target platelts in th gastric circulation * the platelets in the systemic circulation recieve less aspirin though * Because the aspirin has no nucleus you stop that platelets ability to make thromboxane. * But the Prostacyclin is still generated... why? * because the endothelial cells are only exposed to realatively low levels of COX they can require the ability to produce prostacyclin and thromboxane but the platelets (which poreviously produced the majority of the thromboxane) are now stunted so the balance has now shifted

Answer 105

* Aspirin covalenently acetylates the COX-2 but the oxygenation capacity is changed rather than destroyed so the acetylated COX-2 produces a 15-hydroxy version of arachadonic acid which can be further converted by other lypoxygenases which produce analogues of the endogenous lypoxins * inflammation resolving lipids which may reduce inflammation

Answer 106

* Consuming omega-3 fatty acids rather than omega-6 PUFA then we get the omega-3 version of arachadonic acid and this will results in a conversion from C18:3 to C20:5 and this kind of arachodonic acid confers prostoglandins with 3 double bonds for some reason prostacyclin (PGI₃) is able to still function whereas thromboxane (TxA₃) is not effective in this form * so it confers vascular disease protection

Answer 107

* generates 5-HPETE which is converted into Leukotriene A-4 * 5-Lypoxygenase is resticted to inflammatory cells * no known physiological role beyond inflammation * so is a good target for drugs-but it has been hard to get specificity * activated by increase in intracellular calcium by stimuli produced in infection, allergic responses and other forms of inflammation. * There are two sets of products made by transforming the Leukotriene A4 * the important set is the **cysteinyl leukotrienes** * highly active lipid causing bronchospasm and vasodilation * targetted in asthma-antagonists * Leukotriene B4 is a chemoattractant but perhaps not that important.

Week #4 Flashcards

(138 cards)