Tell Me About… Flashcards

Question

Classify Pain

Answer 1

By chronicity * Acute - recent onset, limited duration, identifiable cause e.g. injury/disease process * Chronic - persists beyond time of injury, or no clearly definable cause By nature * Nociceptive - response to noxious stimulant of nocicptors — superficial somatic - skin — deep somatic — ligaments/muscles — visceral —organs * Neuropathic - due to dysfunction of the nervous system

Answer 2

The body contains approximately 120L of CO2. CO2 Production * produced by cell metabolism in the mitochondria * dependent on rate of metabolism and relative amounts of carbohydrate, fat and protein metabolised * approx 200ml/min when at rest and eating a mixed diet --> utilises 80% of O2 consumed (RQ 0.8 - carb diet 1.0 and fat diet 0.7) CO2 Transport 1. Dissolved as gas in plasma (7-10%) - 20x more soluble than O2 (Henry's Law) 2. Bound to haemoglobin and other plasma proteins as carbamino compounds (20%) - CO2 binds readily with Hb at a lower partial pressure than oxygen - Hb carries less than 1/4 of the amount of CO2 compared with O2 3. Present as bicarbonate ion in plasma and transported as bicarbonate (70%) - CO2 + H2O --> H2CO3 --> HCO3- + H+ (catalysed by carbonic anhydrase) - CO2/H2O/HCO3 readily pass through cell membranes but H+ can't - Chloride shift occurs with exchange of Cl ions into the cell as HCO3 diffuses out - H+ ions bind easily to reduced Hb

Answer 3

Inputs - central chemoreceptors - ventral medulla - stimulated by fall in CSF pH (indirect response to changes in arterial PaCO2) - peripheral chemoreceptors - carotid (CN IX) and aortic (CN X) bodies stimulated by low PaO2, high PaCO2 and acidemia - mechanoreceptors - stretch receptors in bronchial muscle stimulated by overinflation and stimulate the apneustic centre to reduce inspiratory volumes (Hering-Breuer reflex) - other effects - juxtacapillary receptors in alveolar walls, irritant receptors, pain receptors, thalamus (temperature), limbic system (emotional response), cerebral cortex (conscious control of breathing), muscle spindles Integration and control centres - dorsal respiraory group in the medulla --> controls the diaphragm (inspiratory) - ventral respiratory group in the medulla --> controls the intercostal muscles (inspiratory and expiratory) - apneustic centre in the lower pons - modulates DRG function to prevent overexpansion - pneumotaxic centre in the pons --> also modulates DRG, increasing RR and decreasing VT to maintain MV (fine-tuning inspiration) Effectors - diaphragm - intercostal muscles - abdominal muscles - accessory muscles - sternocleidomastoid

Answer 4

Capacity of the heart to maintain steady myocardial perfusion across a range of perfusion pressures. Coronary blood flow (250ml/min or 5% of CO) remains constant between MAP 60-140 - beyond this range, flow becomes pressure-dependent. Metabolic theory - vasodilatation in the presence of increased metabolic substances e.g. pCO2, pO2, H+, K+, adenosine Myogenic theory - alteration in caliber of vessel when stretch/relaxation is detected Neural - response to ACh (vasodilation of intact endothelium) or NAd (sympathetic stimulation increasing blood flow) Humoral - vasoactive hormones can cause endothelium mediated vasodilation or constriction (e.g. angiotensin II vasoconstricts and releases endothelin which also constricts; ACE inactivates bradykinin which is a vasodilator)

Answer 5

**Production:** Hypothalamus (paraventricular nucleus), T lymphocytes, placenta **Secretion:** Neurosecretrory terminals into the primary capillary plexus of the hypothalamo-hypophyseal portal system **Site of action:** Anterior pituitary **Effects:** Stimulates synthesis of ACTH and beta endorphin **Release stimulated by:** Stress **Release inhibited by:** Glucocorticoids provide a negative feedback loop

Answer 6

**Production:** Adrenal cortex - zona fasciculata (from cholesterol) **Secretion:** Adrenal cortex **Site of action:** Liver, kidneys, small intestine, adipose tissue **Effects:** Stimulation of gluconeogenesis. Inhibition of glucose uptake. Mobilisation of amino acids from extrahepatic tissues. Stimulation of fat breakdown in adipose tissue. Anti-inflammatory and immunosuppressive **Release stimulated by:** ACTH, cytokines, exercise, stress, trauma, ghrelin **Release inhibited by:** raised cortisol inhibits release of ACTH and CRH **Metabolism:** liver and kidney **Hypersecretion:** Cushing's syndrome **Hyposecretion:** Addison's Disease

Answer 7

Production - continuously in the choroid plexus (covers two lateral ventricles, roof of 3rd and 4th ventricles), ~500ml/day (around 150ml present in the body at any given time Circulation - lateral ventricle --> third ventricle via foramen of Munro--> fourth ventricle via aquaduct of sylvius --> subarachnoid space and central canal via foramina of Luschka and Magendie --> arachnoid granulations in dural venous sinuses Functions of CSF * Buoyancy - reduced net weight of brain, preventing excessive pressure on the base of the brain * Protection - limits neural damage in cranial injuries * Homeostasis - buffering, maintain low extracellular K+ for synaptic transmission * Waste clearance - from brain cells

Answer 8

1. Systolic hypertension (widened pulse pressure 2. Bradycardia 3. Respiratory depression (irregular, decreased respirations) Combination of activation of both the sympathetic and parasympathetic nervous system in response to cerebral ischaemia. The body induces hypertension in an attempt to restore cerebral blood flow. Baroreceptors detect the increase in BP and trigger a parasympathetic response via the vagus nerve, inducing bradycardia.

Answer 9

* Second messenger role in regulating cardiac muscle contraction - increases contractility, heart rate and conduction velocity * Important role in regulating contraction of vascular smooth muscle - causes smooth muscle relaxation * Regulation of glycogen, sugar and lipid metabolisms * Synthesised from ATP via adenylyl cyclase (in the presence of magnesium ions) in response to catecholamines binding to b1 and b2-adrenoceptors (coupled to Gs-proteins) * Inhibited by agonists of adenylate cyclase inhibitory Gi-protein couple receptors * Activates protein kinase A -- stimulates calcium ion movement across the sarcolemma and sarcoplasmic reticulum via activation of ion channels -- phosphorylation of contactile and regulatory proteins - allowing them to act on ion channels or become inhibited * Degraded by phosphodiesterase (PDE-3) into AMP

Answer 10

Substrates *tricyclic antidepressants, beta-blockers, chlorphenamine, opioids, SSRIs/SNRIs, flecainide, , haloperidol, promethazine, risperidone, tamoxifen, tolterodine* Inhibitors - decrease efficacy of drugs that require transformation by CYP2D6 to their active metabolites and increase levels of drugs that are eliminated by CYP2D6 metabolism *amiodarone, bupropion, chloroquine, cinacalcet, fluoxetine, haloperidol, imatinib, protease inhibitors, paroxetine, quinidine, systemic terbinafine* Inducers *not very susceptible to enzyme induction*

Answer 11

* Responsible for the metabolism of >50% of medicines * Activity is absent in newborns - reaches adult level around 1yr of age * Considerable variability of activity in the population * Women have higher CYP3A4 activity than men Inhibitors - decrease efficacy of drugs that require transformation by CYP3A4 to their active metabolites and increase levels of drugs that are eliminated by CYP3A4 metabolism *Macrolides, Ca channel blockers, anti-fungals, protease inhibitors, RT inhibitors, mifepristone, grapefruit juice, cimetidine, goldenseal* Inducers - increase efficacy of drugs that require transformation by CYP3A4 to their active metabolites and decrease levels of drugs that are eliminated by CYP3A4 metabolism *Anti-epileptics, rifampicin, glucocorticoids, modafilin, st john's worts*

Answer 12

Pro-inflammatory * IL-1, IL-6, IL-12, IL-18 * TNF alpha * Interferon gamma * GM-CSF Anti-inflammatory * IL-10, IL-11, IL-13, IL-1ra * TGF beta * STNF-R

Answer 13

**Production:** Neurons (predominantly substantia nigra), medulla of adrenals, from L-DOPA (from tyrosine or phenylalanine) **Secretion:** Stored in synaptic vesicles until it is ejected via exocytosis **Site of action:** Dopamine receptors throughout the body - postsynaptic dopamine receptors on dendrites or presynaptic autoreceptors on the membrane of the axon terminal **Effects:** Regulation of cellular cAMP levels, prolactin antagonist, increase blood flow, GFR, natriuresis and diuresis in the kidney, inhibits renin release, facilitates vasopressin release, renal vasodilation **Release stimulated by:** activites that make you feel good **Release inhibited by:** dopamine through D2 autoreceptors **Metabolism:** MAO, COMT and aldehyde dehydrogenase **Hypersecretion:** ?schizophrenia **Hyposecretion:** Parkinson's Disease

Answer 14

Dopamine is a neurotransmitter of the catecholamine family and is formed by removing a carboxyl group from a molecule of L-DOPA **Phenylalanine** ↓ (Phenylalanine hydroxylase) ↓ **L-Tyrosine** ↓ (Tyrosine hydroxylase - rate limiting step) ↓ **L-DOPA** ↓ (DOPA decarboxylase) ↓ **Dopamine** ↓ (Dopamine beta-hydroxylase) ↓ **Noradrenaline** ↓ (Phenylethanolamine N-methyltransferase) ↓ **Adrenaline** Metabolised by Catechol-O-Methyltransferase (COMT) and Monoamine Oxidase (MAOs)

Answer 15

* G protein coupled receptors - act via 2nd messengers e.g. opioid, adrenoceptor * Ion channel receptors --ligand gated e.g. nACH, 5HT3, NMBD, ketamine --voltage gated e.g. RYR1 receptor --other e.g. aquaporins * Nuclear hormone receptors aka steroid receptors aka intracellular receptors - act via gene transcription e.g. thyroid, oestrogen * Kinases - act via phosphorylation e.g. tyrosine kinase (insulin) * Enzymes e.g. COX-1 (aspirin), CA inhibitors (acetazolamide) * Catalytic receptors e.g. GP2b3a

Answer 16

First order kinetics - when a constant proportion of drug is eliminated per unit time. T1/2 is fixed - for every half life that passes the drug concentration is halved. Most drugs are eliminated this way. Elimination mechanisms are NOT saturable. Zero order kinetics - when a constant amount of drug is eliminated per unit time. The rate of elimination is constant and is independent of the total drug concentration in the plasma. T1/2 is not constant - the higher the concentration, the longer the t1/2. Few drugs are eliminated this way although many will show zero order kinetics at high, or toxic, concentrations. Elimination mechanisms (enzymes or transporters) ARE saturable. Examples - ethanol - phenytoin - salicylates (at high doses) - theophyllines - thiopentone - warfarin

Answer 17

Drug metabolism is defined as the biotransformation of lipid-soluble chemicals into water-soluble forms, so that they can be excreted in the urine. Metabolism is divided into two phases - drugs may undergo one phase only, or may be metabolised through both phases sequentially. Phase I reactions - introduction into or unveiling or a polar functional group on the drug molecule --> renders it a suitable substrate for conjudation with another molecule during phase II metabolism. - oxidation - reduction - hydrolysis Involve CYP1A2, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 in more than 90% of drugs undergoing phase I metabolism. If high aqueous solubility is achieved, the derivative from phase I metabolism may be excreted via the urine immediately. Phase II reactions - conjugation of the functional groups of a drug molecule to various hydrophilic endogenous compounds --> renders them sufficiently water soluble to facilitate renal secretion of . May insert a large polar substrate to the molecule to make it more amenable for active secretion into the bile and subsequent excretion into the GI tract. Drugs that do not undergo phase I or II metabolism and are excreted predominantly unchanged in urine include: * aminoglycosides * cephalosporins * ephedrine * digoxin * lithium * milrinone * mannitol * neostigmine * oxytetracycline * penicillins * glycopeptides Doses of these drugs may required adjustment in the event of renal impairment.

Answer 18

Every health and care professional must be open and honest with patients and people in their care when something that goes wrong with their treatment or care causes, or has the potential to cause harm or distress. This means that health and care professionals must: * tell the person when something has gone wrong * apologise to the person * offer an appropriate remedy or support to put matters right (if possible) * explain fully to the person the short and long terms effects of what has happened Ethical Duty - low threshold for notification - any harm or distress to patients - ethical duty to tell patients when things have gone wrong, apologise and try to put things right Statutory Duty - higher threshold for notification, includes prolonged psychological harm to patient - duty applies to organisations rather than indiciduals - patients shoud be told of a "notifiable safety incident" as soon as is practical - NHS body definition - something unintended or unexpected in the patients care that, in the reasonable opinion of a healthcare professional, could result in or appears to have resulted in their death or them uffering severe or moderate harm, or prolonged psychological harm - The organisation has to explain to the patient what's known at the time, what further enquiries will be made, offer an apology and keep a written record of the notification to the patient. Failure to do so could be a criminal offence. - The patient should be given reasonable support - practical or emotional - The patient must get written notes of the initial discussion and of the notification, including details of further enquiries, their results and an apology. The organisation needs to keep copies of all correspondance. Severe harm - a permanent lessening of bodily, sensory, motor, physiologic or intellectual functions, directly related to the incident Moderate harm - needing a moderate increase in treatment, and significant, but not permanent, harm

Answer 19

**Production:** Vascular endothelial cells **Site of action:** pituitary, vascular endothelium, heart, lungs, kidney, brain **Effects:** smooth muscle contraction of medium sized cells, roles in cell survival, angiogenesis, bone growth, nociceptor function **Release stimulated by:** angiotensin II, ADH, thrombin, cytokines, reactive oxygen species, shearing forces on vascular endothelium **Release inhibited by:** NO, NO donor drugs, dilator prostanoids **Metabolism:** predominantly pulmonary uptake, kidneys and liver **Hypersecretion:** high blood pressure, heart disease

Answer 20

**Production:** Brain, adrenal medulla (chromaffin cells) **Site of action:** Opioid receptors - delta and mu **Effects:** regulation of nociception **Release stimulated by:** Pain

Answer 21

**Production:** Extraglomerular mesangial cells of the kidney, liver, pericytes in brain **Site of action:** bone marrow **Effects:** stimulates red blood cell production **Release stimulated by:** Cellular hypoxia **Release inhibited by:** Hb and iron levels **Hypersecretion:** High altitude, polycythaemia **Hyposecretion:** CKD

Answer 22

* The rate of change of quantity of a substance is directly proportional to the quantity of the substance present at that time * Asymptote - a curve/line that constantly approaches but does not reach another line/curve (taken to be "complete" after 5 half lives or 3 time constants) * The absolute amount varies, with a constant percentage * Rate depends on the concentration * Examples of exponential decay include *nitrogen washout in pre-oxygenation, lung volumes during spontaneous expiration, drug wash-out, radioactive decay* * Examples of exponential growth include *bacterial growth, drug wash-in, lung volumes during PCV*

Answer 23

Normal cerebral blood flow is 50ml/100g/minute. This is influenced by: * cerebral metabolism (cerebral metabolic rate for oxygen is normally 3.5ml/100g/min) - increased by pyrexia, seizures; reduced by hypothermia, anaesthesia * carbon dioxide - linear relationship between PaCO2 and CBF between 2.7 and 10.6kPa - mediated by pH of extracellular fluid surrounding central vasculature * oxygen - hyperoxia has little effect, hypoxia (<6.7kPa) causes rapidly progressive increase in CBF * autoregulation - CBF constant over the CPP range 50-150mmHg - myogenic mechanism, metabolic theory. Lower limit represents maximal vasodilatation, upper limit represents maximal vasoconstriction above which the BBB is disrupted, with oedema and ischaemia * autonomic nervous system - more for anterior circulation than posterior via superior cervical ganglion for SNS and sphenopalatine and optic ganglia for PNS, sensory fibres from trigeminal. SNS contributes to vasoconstriction, protects brain in hypotension. PNS contributes to vasodilations, maximal in post ischaemic reperfusion and hypotension. * blood viscosity - balance between reduced Hct improving blood flow and oxygen carrying capacity - 30% optimal In a patient with a head injury, reduced MAP, increased ICP or both compromise cerebral blood flow.

Answer 24

The choroid supplies the outer retina with nutrients, and maintains the temperature and volume of the eye. The choroidal circulation is a high flow system with relatively low oxygen content - it accounts for 85% of the total blood flow in the eye. The choroid circulation is controlled mainly by sympathetic innervation and not autoregulated. - arterial PaCO2 - hypoxaemia - vasodilatation - venous pressure - cough/prone etc - transient rise with acute increase in systolic BP

Answer 25

Blood supply * 25% of CO - 1200ml/min (100ml/100g/min), oxygen consumption 6ml/100g/min * from hepatic artery (branch of coeliac trunk) - high pressure, high resistance, less of blood flow but higher oxygen saturations * from portal vein (confluence of mesenteric and splenic veins) - low pressure, low resistance, 70% of total blood flow, lower oxygen saturations Hepatic Blood Flow Regulation * portal venous flow regulation - mainly determined by splanchnic arterial flow rate * portal resistance changes in response to humoral signals (e.g. catecholamines) in shock and local endocrine signals (e.g. VIP) causing vasodilation following a meal * standard arterial regulatory mechanisms of controlling hepatic arterial flow -- myogenic -- flow (shear)-mediated -- conducted vasomotor responses -- immunologically mediated by inflammatory molecules * hepatic arterial buffer response - hepatic arterial flow increases if portal venous flow decreases, and vice versa * external factors -- venous return e.g. during PPV/HF - impairs hepatic venous draining -- CO - influences hepatic arterial flow directly and portal flow indirectly -- shock states and exercise - decrease splanchnic blood flow

Answer 26

Normal IOP is 11-21mmHg with cyclic fluctuations of 2-3mmHg throughout the day. IOP >24mmHg is considered pathologic. Intraocular contents - choroidal blood volume - aqueous humour volume - balance between production and outflow rate - vitreous humour volume Scleral rigidity - severe myopia - old age External pressure - direct pressure - retrobulbar haematoma - extrinsic muscles - venous congestion e.g. prone/steep trendelenberg positioning Anaesthetic management - regional anaesthesia contraindicated for penetrating eye injury (LA increasing IOP + distorted anatomy) unless vision not salvagable - drugs usually decrease IOP (apart from sux but only very transiently increases it) - avoid ketamine due to possibility of nystagmus/blepharospasm affecting surgical conditions - avoid N2O if plan for gas injection/recent gas injection/other injuries of concern - minimise repsonse to laryngoscopy - ?VL - if AFOI required - sedation ++, generous topic anaesthesia - ETT>LMA (limited access to airway and controlled ventilation preferable despite lower sympathetic response and lower increase in IOP with LMA) - smooth emergence to avoid cough - ensure fully reversed etc, deep extubation if appropriate - antiemetics, consider TIVA for high risk PONV - avoid hypotension - arterial line monitoring?

Answer 27

SjvO2 gives an assessment of global oxygenation and the adequacy of cerebral blood flow. A catheter is inserted by retrograde cannulation of the internal jugular vein and advanced into the jugular bulb on the side of worst pathology or on the dominant side for venous drainage. The catheter tip should lie level with the C1/C2 disc in order to avoid error from admixture with extracranial blood. Measurements can be taken intermittently using serial sampling or continuous measurement is possible with spectrophotometric catheters. SjvO2 reflects the balance between the oxygen supply (CBF, SpO2) and demand. Normal SjvO2 is between 55-75%. Low SjvO2 = hypoperfusion with oxygen demand exceeding supply/cerebral ischaemia * reduction in oxygen delivery -- raised ICP -- reduced CBF -- hypoxia -- profound hypocarbia * increased cerebral oxygen demand -- seizures -- pyrexia High SjvO2 = hyperaemia or reduced metabolic demand * reduction in cerebral oxygen consumption -- coma -- hypothermia -- cerebral infarction * increased oxygen delivery -- hypercapnia -- vasodilatation Complications of it's use include: * errors in values * positioning problems * poor sampling technique * subclinical thrombosis or clot formation on the catheter * those associated with central venous cannulation

Answer 28

Site of injection * Surface area * Vascularity * Location IV > tracheal > intercostal > caudal epidural > paracervical > lumbar epidural > brachial plexus > sciatic/femoral > subcutaneous * Intra-vascular injection Drug * Choice of LA bupivicaine > L-bupivicaeine > ropivicaine > mepivicaine > lidocaine * LA dose * Vasoactivity +/- vasoconstriction Patient Factors * Age - elderly, neonates have less a1-acid glycoprotein therefore an increase in unbound LA, as well as reduced clearance compared to adults * Genetics * Cardiac pathology - reduced volume of distribution and clearance * Liver failure - reduced plasma clearance and prolongation of half life * Renal failure - increased absorption, accumulation of metabolites * Pregnancy - reduced plasma protein binding, increased absorption due to high CO, increased sensitivity of cardiac and nervous tissue * Drug interactions - amides are metabolized by CYP450 enzymes in the liver, esters are metabolised by plasma esterases therefore can be affected by drugs that alter plasma esterase activity * Acidosis * Peripheral vasoconstriction * Hyperdynamic circulation * Hypoxia * Hypercarbia

Answer 29

Classified into chest wall, lung or total lung compliance. Lung compliance - increased - lung surfactant - lung volume: compliance is at its highest at FRCA - posture (supine, upright) - loss of lung connective tissue associated with age Static lung compliance - decreased - loss of surfactant (ARDS) - decreased lung elasticity e.g. fibrosis, oedema - decreased functional lung volume e.g. pneumonectomy or lobectomy, pneumonia, atelectasis, small stature - alveolar derecruitment - alveolar overdistension Dynamic lung compliance - decreased - increased airway resistance e.g. asthma - increased airflow e.g. increased RR Chest wall compliance - increased - EDS and other connective tissue diseases associated with increased elasticity - rib resection - cachexia - flail segment, rib fractures - open chest e.g. clamshell Chest wall compliance - decreased - structural abnormalities - kyphosis/scoliosis, pectus excavatum, circumferential burns, surgical rib fixation - functional abnormalities - seizure, tetanus - extrathoracic influences on chest/diaphragmatic excursion - obesity, abdominal compartment syndrome, prone position, pregnancy Physiological - posture - lungs are more compliant when upright than supine - age - compliance is reduced at extremes of age - pregnancy - less compliant lungs, reduced FRC

Answer 30

Drug - pKa (less basic pKa = faster onset due to greater proportion of unionised form) - lipid solubility (increased lipid solubility allows more rapid diffusion and greater Vd, alsoaffects potency) - protein binding (increased binding --> longer duration) - chirality - molecular weight (smaller molecules diffuse through membranes faster) - vasoactivity - (more rapid absorption after lidocaine compared to bupivicaine) - adjuvants - dose used (concentration/volume) Type of block - proximity to nerve (diffusion through tissue to reach nerves delays onset of block) - type and size of nerve fibres - smaller diameter, unmyelinated nerves affected first (C fibres > A-a) Tissue factors - pH of tissue - inflamed or infected tissue is more acidemic, reducing the unionised amount of drug

Answer 31

Alveolar concentration of agent - inspired concentration - FGF, breathing system volume, circuit absorption - alveolar ventilation (MV) - increased dead space will prolong induction - FRC - large FRC dilutes amount of agent inspired with each breath - second gas effect - use of N2O concentrates the gas in the alveoli, increasing the pressure gradient driving diffusion into the blood Drug uptake from the lungs - blood:gas partition coefficient - agents with a low coefficient reach equilibrium more rapidly - affected by temperature, Hct - alveolar blood flow - rate of onset reduced when alveolar blood flow is high due to reduction in concentration of agent in alveoli - affected by CO and shunt - alveolar-venous partial pressure gradient - dependent on tissue blood flow, blood:tissue solubility coefficients

Answer 32

Increased demand * fever * pain * agitation * shivering * hyperdynamic state Decreased demand * hypothermia * anaesthesia/analgesia

Answer 33

Increased supply * hyperoxygenation * augmented cardiac output * mild peripheral acidosis Decreased supply * hypothermia * anaemia * profound alkalosis

Answer 34

* Medications * Sleep deprivation * Illicit drug use * Malnutrition * Uncontrolled diabetes * Withdrawal * Fever * Fasting/starvation * Menstruation * Photic triggers Drugs that lower seizure threshold include: * opioids e.g. pethidine, tramadol * chemotherapeutic agents * antimicrobials e.g. carbapenems, cephalosporins, quinolones * hypoglycaemic agents * immunosuppressants * psychiatric medications * other - aminophylline, stimulants, phenylephrine

Answer 35

* Proportion of gas passing through vaporising chamber (use of bypass) * Efficiency of vaporisation (surface area available - use of wicks/baffles) * Temperature (increased output with increased temperature) * Time (reduced output with increased time due to cooling associated with vaporisation) * Gas flow rate (at high flow rates, gas leaving the chamber will be less saturated) * Carrier gas composition (changes in viscosity and density of the gas mixture) * Ambient pressure (if ambient pressure reduced, output concentration rises)

Answer 36

Coronary blood flow * coronary perfusion pressure - aortic diastolic blood pressure and ventricular end-diastolic blood pressure * perfusion time (heart rate --> diastolic time) * vessel patency and diameter * blood viscosity Arterial oxygen content * CaO2 = [Hb x sats x 1.34] + [PaO2 x ).023] Oxygen consumption by heart * HR * Contractility * Temperature * Ventricular wall tension - preload and afterload * Tissue mass

Answer 37

Left shift of the curve = increased oxygen affinity, thereby decreasing oxygen delivery to the tissues * alkalaemia * hypothermia * decreased 2,3-DPG * fetal Hb * methaemoglobinaemia * carboxyhaemoglobinaemia * high oxygen affinity Hb variants Right shift of the curve = decreased oxygen affinity, thereby increasing oxygen delivery to the tissues * acidaemia * hypercarbia * pyrexia * increased 2,3-DPG * low oxygen affinity Hb variants eg. sickle Hb * sulfhaemoglobin * chronic iron deficiency anaemia

Answer 38

Inhibition * COPD * pregnancy * alkalaemia * haemodilution * cirrhosis * female gender * hypocapnia * sepsis * exercise * hypothermia * drugs: N2O, verapamil, hydralazine, GTN, halothane, nitroprusside, ACEI Promotion * Hypertension * lung retraction * acidaemia * hypercapnia * pyrexia * lateral positioning * epidural * iron deficiency * drugs: phenylephrine, noradrenaline No effect * supine positioning * drugs: NO, iso/sevo/desflurane, ketamine, opioids, diltiazem, sildenafil, dopamine

Answer 39

MAC is a measure of potency - the EC50 of an agent, where the outcome is movement in response to surgical stimulation. The SD is 0.1 - so 95% of patients will not move in response to a stimulus at 1.2 MAC. MAC is inversely proportional to potency - more potent agents require smaller alveolar concentrations to produce anaesthesia. MAC is estimated clinically using end-tidal gas measurement - it is not based on arterial partial pressure of an agent therefore can be inaccurate where there is VQ mismatch in particular. Factors which decrease MAC - age (~6% every 10yrs older) and neonates - hypothermia - hypocapnea - hyponatraemia - hypothyroidism - acute alcohol and other CNS depressant intoxication - chronic amphetamine intake - hypovolaemia/hypotension - lithium - hypoxia - anaemia - pregnancy - N2O/IV anaesthetics/benzos/opioids Factors which increase MAC - youth - hyperthermia - hypercapnoea - hypernatraemia - hyperthyroidism - chronic ETOH and CNS depressant abuse - acute amphetamine intake - SNS activation and anxiety - increased atmospheric pressure - red hair

Answer 40

Epidural filter * disc shaped with hydrophilic supported membrane * filter pore size usually 0.22 microns * filters viruses, bacteria and foreign bodies HMEF * hygroscopic membrane pleated to decrease the dead space * mechanical or electrostatic filters * 0.2 microns pore size * 60-70% humidity * adds up to 100mls dead space * can increase PEEP Filter needles * prevent particular and organism contamination * 0.2 microns Fluid filter * 15 microns to prevent particularte contamination Blood filter * whole blood - 170-250 microns * 70-80% leucocyte depleted - 20-50 microns * electrostatic filters - 100% leucodepletion Filters used in renal haemofiltration

Answer 41

**Initiation** * on a tissue factor bearing cell * damage to endothelium exposes TF and vWF * vWF binds to platelets through the GP1b receptor * platelet membrane provides phospholipid surface on which coagulation factors are active * TF binds to circulating factor VII and activating it, catalysing conversion of FIX → FIXa and FX → FXa **Amplification** * platelets and co-factors are activated in order to prepare for large-scale thrombin generation * FXa catalyses small amounts of IIa from II * thrombin (IIa) binds to GP1b receptors on the platelet surface, activating FXI, FVIII and FV * FXIa helps to amplify the conversion of FIX to FIXa **Propagation** * on the surface of platelets * FVIIIa binds to FIXa and generates large amounts of FXa from FX * FXa combines with FVa to form prothrombinase complex * Complex catalyses the conversion of prothrombin (II) to thrombin (IIa) in large amounts * thrombin converts fibrinogen (I) to fibrin (Ia) which cross-links platelets via the GP2b/3a receptor * formation of platelet plug, stabilised by fibrin mesh at the site of vessel injury **Termination** 3 mechanisms * TFPI (tissue factor pathway inhibitor) - inactivates the complex produced by factor Xa in initiation * Antithrombin - endothelial injury results in heparan sulphate being exposed to the blood - induces a conformational change in circulating antithrombin - binds to IIa and Xa, inactivating them * Thrombomudulin - thrombin binds to thrombodmodulin (expressed on endothelial cell surfaces) - conformational change in TM, allowing it to bind to protein C and activate it. aPC binds to FVa, inactivating it. Protein S is a co-factor for protein C.

Answer 42

**Production:** Anterior pituitary **Secretion:** Anterior pituitary **Site of action:** Testes and ovaries **Effects:** Stimulates spermatogensis in the male and ovarian follicle growth in the female. **Release stimulated by:** GnRH **Release inhibited by:** Oestrogen, testosterone (in men)

Answer 43

* Diffusion * Osmosis * Filtration e.g. Bowman’s capsule * Barrier e.g. BBB * Vasomotor tone - produces NO * Inflammation - synthesises prostaglandins * Coagulation - release of tissue factor triggering the clotting cascade * Secretion - ACE

Answer 44

* Gas exchange * Vascular reservoir * Filtration — physical — chemical * Humidification * Immunological - macrophages/neutrophils * Acid-base balance * Metabolism — removal/inactivation - bradykinins, serotonin, noradrenaline, leukotrienes, prostaglandins E2/F2a — conversion - ATI —> ATII (ACE) * Defence mechanism - cough, mucociliary escalator

Answer 45

* Regulation — Extracellular volume and electrolyte composition — Total body water — Acid-base balance — Arterial blood pressure * Excretion — Endogenous and exogenous waste products * Production — Renin — EPO — Gluconeogenesis — Activation of vitamin D (1,25 dihydroxycholecalciferol)

Answer 46

Metabolism * carbohydrate - gluconeogenesis, glycogenesis, glycogenolysis * protein - amino acid degradation * lipid - fatty acids * nitrogenous compounds - recycling of NH3/NH4+ compounds * breakdown of insulin, bilirubin and various hormones Digestive * bile production * absorption of lipids and fat soluble vitamins Synthesis * coagulation factors I, II, V, VII, IX, X, XI * antithrombin, protein C and S * immunoglobulins * amino acids * albumin and globulins * acute phase proteins * cholesterol and triglycerides * prostaglandins * fatty acids and lipoproteins * ketone bodies * activates vitamin D Drug Biotransformation * Catabolic - phase I --> oxidation, reduction, hydrolysis to form water-soluble compounds * Anabolic - phase II --> conjugation to increase polarity and water solubility Storage * Vitamins A, B12, D, E, K * Copper * Iron * Glycogen Capacitance * 15% of circulating volume (reservoir) Homeostatic functions * immunological functions - Kuppfer/Pitt cells perform phagocytosis of bacteria, erythrocytes, antigens etc) * hormones - IGF1, thrombopoietin, angiotensinogen etc * erthyropoiesis in fetus until 32/40

Answer 47

* Immune -- antigen presentation -- storage of lymphocytes and exposure to the circulation * Filtration and metabolism -- Removes old and damaged erythrocytes and particulate matter -- splenic macrophages release haem from haemoglobin * Storage -- 240ml of RBCs can be stored and mobilized via splenic contraction in time of hypoxia or hypovolaemia -- 30% of platelets -- iron * Production -- Opsonins, such as properdin (complement activation) and tuftsin (immunostimulatory peptide) * Haematopoiesis -- after 5th gestational month, haematopoiesis continues in the bone marrow, except in some pathological disorders of bone marrow disruption e.g. myelofibrosis

Answer 48

Gs - stimulates production of adenylate cyclase --> conversion of ATP to cAMP --> activation of protein kinase A Gi - inhibits production of adneylate cyclase --> decreases levels of cAMP and suppresses cAMP dependent pathway Gq - activates phospholipase C which catalyses the hydrolysis of PIP2 --> DAG + IP3. IP3 opens calcium ion channels --> activates PKC cAMP - smooth muscle relaxation, heart muscle contraction, glycogenolysis PKA - phosphorylates many targets including troponin I, L type Ca channels, K channels IP3 - mobilises calcium ions from storage organelles PKC - phosphorylates many targets with cell type specific effects

Answer 49

* Sympathetic nervous system input T5-L3 * Parasympathetic nervous system input S2-S4 * Enteric nervous system -- submucous (Meissner's) plexus - responsible for secretory function -- myenteric (Auerbach's) plexus - responsible for peristalsis and movements * C5-6 - upper oesophageal sphincter (cricopharyngeus) * Lower oesophageal sphincter - physiological sphincter at the entrance to the stomach 15-25mmHg * LOS tone increased by ACh stimulation, histamine, gastrin, motilin * LOS decreased by ACh inhibition, dopamine, CCK, oestrogen, secretin * Neuroendocrine cells (in the gastric pits) -- G cells - secrete gastrin (stimulates ECL-like cells to release histamine thereby increasing HCl production) -- ECL-like cells - secrete histamine in response to gastrin, mainly in the fundus -- D cells in the pylorus - secrete somatostatin which suppresses gastrin and production of gastric acid -- EC-cells - secrete serotonin, involved in regulating GI motility and fluid secretion -- P/D1 cells - secrete ghrelin (hunger hormone) - increases appetite and promotes fat storage * Chief cells (in the base of gastric glands in the fundus) - secrete pepsinogen (converted to pepsin by HCl) - digest proteins * Goblet cells (in the gastric mucosa) - secrete mucus to protect the epithelium * Parietal cells (present in the gastric pits, mainly in the fundus) - release HCl into the stomach lumen, also secrete intrinsic factor -- stimulated by gastrin, acetylcholine and histamine * Acid secretion increased by food/brain/mouth/stomach, stress, gastrin, ETOH, caffeine * Acid secretion decreased by fatty acids/glucose/amino acids, H2 blocker/PPI, CCK, GIP, secretin, vagotomy * Gastric emptying increased by ACh stimulation, metoclopramide, neostigmine, erythromycin * Gastric emptying decreased by food, stress, pain, increasing age, pregnancy, diabetes, obstruction, opioids, alcohol, anticholinergics, sympathomimetics

Answer 50

A mechanism in the spinal cord in which pain signals can be sent up to the brain to be processed to accentuate the possible perceived pain, or attenuate it at the spinal cord. The gate is the mechanism where pain signals can be let through of restricted. Things which open the gate: * stress/tension, * focussing on the pain, * lack of activity, * catastrophising, * anxiety and depression and * belief of harm. Things which close the gate: * relaxation, * contentment, * distraction, * activity (pacing), * counter-stimulation (heat/massage/TENS), * ACT/CBT.

Answer 51

**Production:** Anterior pituitary **Secretion:** Anterior pituitary **Site of action:** All body systems **Effects:** Protein synthesis, lipolysis, skeletal and fetal growth, gluconeogensis, Na retention and reduced sensitivity to insulin. Some effects are mediated by insulin-like growth factors I and II (produced by the liver in response to GH). **Release stimulated by:** GHRH, exercise, hypoglycaemia, stress, glucagon, dopamine **Release inhibited by:** Somatostatin, GH **Hypersecretion:** Acromegaly (adults), gigantism (children) **Hyposecretion:** Dwarfism

Answer 52

**Production: ** Synthesised in the A cells of the pancreas **Secretion:** From the pancreas **Site of action:** liver, CVS, fat, metabolism **Effects:** glycogenolysis, glucoeogenesis, glucose release, ketone formation, inotropy, lipolysis, increased metabolic rate, GH release, somatostatin release, insulin release **Release stimulated by:** hypoglycaemia, starvation, amino acids, physiological stress, beta agonists, cortisol, acetylcholine, theophylline **Release inhibited by:** somatostatin, secretin, free fatty acids, alpha agonists, insulin, ketones, GABA **Metabolism:** predominantly in the liver **Hypersecretion:** glucagonoma, MEN 1 **Hyposecretion:** total pancreatectomy

Answer 53

Glycolysis = generation of ATP from glucose in the cytoplasm --> glycolyis - breakdown of glucose into glucose-6 phosphate --> pyruvic acid --> Kreb's cycle (aka citric acid cycle) in the mitrochondria + electron transport chain/oxidative phosphorylation in the presence of oxygen - pyruvate is converted to acetyl CoA which enters the Krebs cycle --> 34 ATP per molecule of glucose + CO2 + H2O --> in the absence of oxygen - pyruvate is metabolised in the cytoplasm to lactate --> liver clears >50% of lactate from blood, kidneys and muscles metabolise the remainder Gluconeogenesis = generation of glucose from other substrates e.g. pyruvate, lactate, glycerol, amino acids - usually takes place in the liver and in the cortex of the kidneys Glycogenesis = synthesis of glycogen to store - primarily takes place in liver, skeletal muscles and kidney - consumes energy - enhanced by high levels of insulin Glycogenolysis = breakdown of glycogen to provide glucose - takes place in the liver, muscles and kidney - stimulated by glucagon in the liver or adrenaline in the skeletal muscle

Answer 54

**Production:** Hypothalamus (preoptic area) **Secretion:** Hypophysial portal bloodstream **Site of action:** Anterior pituitary **Effects:** release of FSH and LH from the anterior pituitary **Release stimulated by:** Kisspeptin, sex hormones **Release inhibited by:** Sex hormones, dynorphin, inhibin, prolactin

Answer 55

**Production:** Hypothalamus **Secretion:** Hypothalam-hypophyseal portal system **Site of action:** Anterior pituitary **Effects:** Stimulates GH production and release **Release stimulated by:** pulsatile secretion, a2-adrenergic stimulation, hyoglycaemia **Release inhibited by:** activation of GABAergic neurons, IGF-1, somatostatin

Answer 56

* Theatre environment - temperature, humidity, air circulation * BMR decreased - decreased heat generation by metabolically active tissues eg the liver * Spontaneous respiration - decreased heat generation by respiratory muscle contraction secondary to NMBAs/opioids * Open, moist body cavities * Cold irrigation fluid * Decreased resting muscle tone --> decreases heat production * Physiological response to hypothermia is blunted by anaesthetic agents --> inability to generate heat by moving/shivering, impaired vasoconstriction and piloerection * Behavioural responses removed * Administration of cold fluids/blood products * Pathological conditions e.g. hypothyroidism

Answer 57

**Production:** in the human placenta by the syncytiotrophoblast **Site of action:** ovary, corpus luteum **Effects:** promotes maintenance of the corpus luteum, may facilitate trophoblast invasion **Release stimulated by:** implantation of fertilised egg into the wall of the uterus, GnRH, IL-1B, activin **Release inhibited by:** endorphins, inhibin, follistatin

Answer 58

Core body temperature less than 35 degrees C (mild 32-35, mod 28-32, sev <28). Swiss staging system - I - clearly conscious and shivering, II - impaired consciousness without shivering, III - unconscious, IV - not breathing, V - death due to irreversible hypothermia Mechanisms - increased heat loss - decreased thermogenesis - impaired thermogenesis Risk factors - Age (elderly and infants) - Environmental - exposure, drowning, alpine environment, poverty - Drugs/toxins - alcohol, sedatives, vasodilators - Sepsis - CNS disorders - hypothalamic lesions, hypopituitarism - Endocrine/metabolic - hypothyroidism, adrenal insufficiency, malnutrition - Trauma - burns, spinal cord injury - Shock - Skin disorders - psoriasis, exfoliating conditions - Iatrogenic - cold fluid administration, intraoperative, therapeutic hypothermia - Psychiatric (may lead to exposure)

Answer 59

- simple and safe to use - robust, small and lightweight - efficient, requires low FGF - delivers appropriate gas mixture - allows all methods of ventilation in all age groups - easy removal of waste gases - easy to maintain, low running costs - protects patients from barotrauma - environmentally friendly

Answer 60

Physical properties - water soluble - stable in solution - stable on exposure to light or heat - long shelf life - no pain on IV injection, no thrombophlebitis - painful on IA injection - non irritant on SC injection - cheap - easy to manufacture - environmentally friendly Pharmacokinetics - rapid onset, rapid redistribution to vascular rich group - rapid clearance and metabolism - no active or toxic metabolites Pharmacodynamics - high therapeutic ratio - safe in porphyria/MH - no histamine release/hypersensitivity - minimal CVS/RS effects - anti-emetic - analgesic - no SEs of current IV agents

Answer 61

* Transparent (for good visibility) * Electrically non-conductive (to prevent dispersion of the diathermy current) * Isotonic * Non-toxic * Non-haemolytic when absorbed * Easy to sterilize * Inexpensive

Answer 62

Physical properties - cheap, easy to manufacture - long shelf life without refrigeration - compatible with other drugs/solutions - heat/light stable at room temperature - environmentally friendly Pharmacological properties - non depolarising action - rapid onset - short duration, suitable for infusion - rapid metabolism to inactive products - reversible (cholinesterase inhibitors) - actions confined to neuromuscular junction - no local/systemic side effects

Answer 63

Physical properties - no preservatives needed - compatible with other agents - can be sterilised - cheap, easy to manufacture - stable at room temperature - light stable Pharmacological properties - cross dura rapidly and enter cord - bind with strong affinity to opioid receptors in substantia gelatinosa (increased lipid solubility) - poor CSF solubility - effective analgesia at low dose (high potenct) - minimal side effects - minimal systemic absorption

Answer 64

Physical properties - clear - disposable - flexible - easy to use - wide inner diameter - non compressible - low resistance - thick wall - avoid collapse at maximum negative pressure

Answer 65

Physical properties - long shelf life - stable at room temperature - cheap, easy to manufacture - no interaction with plastic tubing/needle - compatible with other drugs/solutions Pharmacological properties - no/minimal effects on cardiovascular/respiratory systems - no/minimal SEs - rapid, predictable onset and offset - clear end point - low risk of anaesthetic awareness - non toxic/active metabolites - organ independent metabolism and excretion

Answer 66

Physical properties - light - robust - small liquid requirement - minimal maintenance - easy to maintain - safe to use (safety features) - performance not affect by change in temperature/pressure/FGF/volume of agent - low resistance to flow - cheap, easy to manufacture - economical - environmentally friendly - corrosion and solvent reistant - delivers precisely required agent

Answer 67

- lightweight - robust - able to function in demanding environments with minimal maintenance - use available gas/electric supplies sparingly - cheap, easy to manufacture - environmentally friendly - simple to operate - range of effective ventilatory modes

Answer 68

Non Specific/Innate * surface barriers - mechanical, chemical, biological * inflammatory response * activation of alternative complement pathway * phagocytosis Specific/Adaptive * T lymphocytes * B lymphocytes and antibodies * Plasma cells * Classic complement pathway * Immunological memory

Answer 69

* increased perioperative blood loss and coagulopathy - clotting cascade is enzyme dependent and platelet function is temperature dependant * longer post anaesthetic recovery due to altered drug metabolism * post operative shivering and increased oxygen consumption * prolonged action os some NMBAs * thermal discomfort * cardiac events including MI, arrhythmias * delayed wound healing (secondary to reduced tissue oxygenation and immunosuppression) * increased rates of SSI * longer hospital stay * death * increased transfusion requirements

Answer 70

**Production:** synthesised from proinsulin in the rough ER of B cells in the Islets of Langerhans (pancreas) **Secretion:** via exocytosis from the pancreas **Site of action:** specific insulin receptor on the cell membrane, effects mediated by tyrosine kinase **Effects:** increases glucose (active transport via GLUT4), amino acid, ketone and K+ uptake by the muscle, increased anabolism, decreased catabolism, increased glycerol phosphate and fatty acid synthesis, decreased gluconeogenesis and ketogenesis by the liver, increased glycogen synthesis, glycolysis, protein synthesis and lipid synthesis by the liver, general increased cell growth **Release stimulated by:** glucose, GLP-1, GI hormones, ACh, fatty acids, glucagon, GH, cortisol, beta adrenergic stimulation **Release inhibited by:** adrenaline, noradrenaline, fasting, somatostatin, low blood sugar, leptin **Metabolism:** liver, muscle and kidney by glutathione insulin transhydrogenase, with renal elimination of inactive metabolites **Hypersecretion:** Hyperinsulinaemia, insulinoma **Hyposecretion:** Type 1 Diabetes mellitus

Answer 71

Structural * Positional e.g. enflurane/isoflurane * Chain e.g. butane/isobutane * Functional e.g. propranolol/methyl ethyl ether Tautomerism * thiopentone * midazolam Stereoisomers * Geometric (cis-trans) e.g. mivacurium * Optical e.g. bupivacaine/L-bupivacaine, ketamine/S-ketamine

Answer 72

Type A - Due to tissue hypoxia * Tissue hypoperfusion * Abnormal vascular tone or permeability * LV failure * Decreased cardiac output * Reduced arterial oxygen content e.g. asphyxia, hypoxaemia, CO poisoning, life-threatening anaemia Type B - Not due to tissue hypoxia * Sepsis * Hepatic/renal failure * DM * Cancer * Malaria/cholera * Drugs or toxins e.g. biguanides, ethanol, salicylates, isoniazid, methanol, ethylene glycol, cyanide, TPN, nitroprusside, lactulose, theophylline, catecholamines, cocaine, vitamin deficiency, paraldehyde * Strenuous muscular exercise * Grand mal seizures

Answer 73

**Membrane phospholipids/DAG** ↓ (Cytosolic phospholipase A2/Phospholipase C) ↓ **Arachidonic Acid** ↓ (Lipo-oxygenases) ↓ **HPETE (hydroperoxyeicosatetraenoic acid** ↓ (Lipo-oxygenases) ↓ **Leukotriene A4** → (with H2O) → LTB4 *induces adhesion and activation of leukocytes on the endothelium* ↓ Glutathione (Glutathione-S-transferase) ↓ **Leukotriene C4 + Glutamic Acid** *mediator of smooth muscle contraction* ↓ (transpeptidase) ↓ **Leukotriene D4** *triggers contractions in smooth muscles lining the bronchioles* ↓ (dipeptidase) ↓ **Leukotriene E4** *smooth muscle contraction and proliferation, vascular permeability and oedema, increasing expression of adhesion molecules and monocyte activation*

Answer 74

**Production:** Leukocytes, by oxidation of arachidonic acid and eixosapentaenoic acid by arachidonate 5-lipoxygenase **Secretion:** Plasma **Site of action:** leukotriene receptors (GPCR) in the lung, peripheral blood leukocytes and spleen **Effects:** inflammatory response, bronchoconstriction, increase vascular permeability **Release stimulated by:** inflammation **Release inhibited by:** leukotriene antagonists **Metabolism:** partly degraded in local tissues, ultimately become inactive metabolites in the liver **Hypersecretion:** asthma, allergic conditions

Answer 75

**Production:** Anterior pituitary **Secretion:** Anterior pituitary **Site of action:** Testes and ovaries **Effects:** Testosterone secretion in the male, luteinisation of ovarian follicles and ovulation in the female. **Release stimulated by:** GnRH, oestrogen **Release inhibited by:** Oestrogen and progesterone (after ovulation), testosterone (in men) **Hypersecretion:** menopause, Turner syndrome, Klinefelter syndrome, PCOS **Hyposecretion:** Kallmann syndrome, Pasqualini syndrome, hypothalamic suppression

Answer 76

**LVEDP** * Left ventricular end diastolic pressure * Normal range 4-12mmHg * >15-18 = potential for decreased LV function and pulmonary congestion * >20 = probable pulmonary congestion * >25 = pulmonary oedema * Measured by PAWP in normal heart with normal mitral valve and normal pulmonary vasculature **PAWP/PAOP** * Pulmonary arterial wedge/occlusion pressure * Normal range 4-12mmHg * Estimates LVEDP in most patients --> an indicator of preload (LVEDV) * >18 in the context of normal oncotic pressure suggests left heart failure **PAWP > LVEDP** * mitral stenosis * atrial myxoma * mitral regurgitation * non zone III position * left to right shunt * COPD * IPPV +/- PEEP * pulmonary venous obstruction **PAWP < LVEDP** * LVF * high PEEP * aortic regurgitation * non compliant LV e.g. hypertensive cardiomyopathy

Answer 77

* Naturally occurring intracellular calcium antagonist * Normal plasma level 0.7-1.1mmol/L * Approximately half of total body magnesium is in muscle and other soft tissues, remainder within bone and a small amount in erythrocytes * Around 1% in ECF, 99% intracellular * Approx 1/3rd of dietary Mg is absorbed, mostly in the small intestine via a passive and saturatable transport system * Most of Mg is reabsorbed in the ascending limb of the loop of Henle * PTH enhances gut absorption of Mg and reabsorption in ascending limb of the loopn of Henle and distal tubule to maintain plasma concentration * Aldosterone can increase renal excretion of Mg * Effects: * -- CVS - direct depressant effect on myocardial and vascular smooth muscle, inhibitis release of catecholamines --> reduced CO and tone, slows rate of impulse formation at SA node and prolongs SA conduction and AV node refractory period * -- CNS - antagonises Ca ions at presynaptic junction, reducing release of ACh at NMJ, reduces excitability of nerves, anticonvulsant, reverses cerebral vasospasm, blocks NMDA channels --> analgesia * -- MSK - involved in terminating contraction, intiating relaxation in skeletal muscles * -- Resp - bronchodilator, does not effect respiratory drive * -- GU - powerful tocolytic - decreasing uterine tone and contractility, mild diuretic properties * -- Haem - reduces platelet activity Hypomagnesaemia * decreased intake - malabsorption, dietary deficiency * increased loss - diuretics, nephrotoxics, diarrhoea, alcohol abuse, genetic renal disorders * redistribution - massive transfusion of citrated blood, hyperparathyroidism, insulin administration Early symptoms - anorexia, nausea, muscular weakness, cramps, lethargy, weight loss Later - hyperirritability, hyperexcitability, muscle spasms, stridor, tetany, convulsions, hypertension, SVT/VTs Hypermagensaemia * exogenous overadministration * antacids * chronic renal insufficiency 2-3mmol/L - headache, N+V, diarrhoea, decreased tendon reflexes and GCS 3-5mmol/L - muscle weakness, decreased GCS, hypotension, ECG changes (prolonged AV condution, widened QRS) 5-7.5mmol/L - respiratory paralysis 10-12.5mmol/L - cardiac arrest Give calcium gluconate IV if concerns

Answer 78

* Receptors * Ion channels e.g. lignocaine at Na+ channels * Enzymes e.g. aspirin and COX-1 * Hormones e.g. carbimazole * Neurotransmitters e.g. TCAs decreasing noradrenaline reuptake * Transport systems e.g. digoxin acting on Na+/K+ * Physiochemical e.g. sugammadex chelating rocuronium

Answer 79

* Physiochemical - occur due to the physical properties of the drugs themselves — chelation e.g. sugammadex/rocuronium — neutralisation e.g. heparin/protamine — precipitation e.g. thiopentone/suxamethonium — adsorption e.g. halothane/rubber * Pharmacokinetic - occur when one drug alters the way the body handles another — absorption e.g. LA/adrenaline — distribution e.g. Aspirin displaces warfarin — metabolism e.g. CYP450 enzyme inducers and inhibitors — excretion e.g. alkalinisation of urine to increase excretion of salicylates, probenecid inhibit is tubular secretion of penicillins, thereby increasing plasma levels * Pharmacodynamic - action of one drug is altered by the administration of another — summation e.g. nitrous oxide/volatiles — synergism e.g. remifentanil/propofol — potentiation e.g. probenacid/penicillin — antagonism e.g. morphine/naloxone

Answer 80

* Radiation (~45%) Loss of heat through electromagentic radiation *increase theatre temperature, vasodilatation, exposure of patient, reflective blankets, Bair Hugger* * Conduction (3-5%) Transfer of heat (as kinetic energy) by direct contact from a higher temperature object to a lower temperature object *warming mattress, fluid warmer* * Convection (25-30%) Transfer of heat energy through a liquid/gas by movement of the medium itself *theatre air circulation/laminar flow, vasodilatation, exposure of patient, Bair Hugger* * Evaporation Loss of heat energy due to the latent heat of vaporisation *theatre humidity, body cavity exposure, HMEF, skin prep* * Respiration *HMEF (70% efficient), low FGF, soda lime*

Answer 81

**Production:** Pineal gland **Secretion:** Pineal gland **Site of action:** suprachiasmatic nucleus, throughout the body **Effects:** regulation of circadian rhythm, antioxidant ad fere radical scavenger, inhibition of leptin, inhibition of LH and RSH release **Release stimulated by:** darkness **Release inhibited by:** blue light **Metabolism:** proteasomal proteolysis, excreted in urine **Hypersecretion:** seasonal affective disorder **Hyposecretion:** pineal disorders

Answer 82

* Acetylcholine released from the axon terminal binds to receptors on the sarcolemma * An action potential is generated and travels down the T tubule, depolarising the cell membrane * Calcium is released from the SR in response to the change in voltage (L type calcium channels allow calcium into the cell leading to activation of ryanodine receptors) * Calcium binds to troponin leading to exposure of actin active sites; cross-bridges form between actin and myosin * ADP and inorganic phosphate are released from the myosin head allowing the power stroke - the myosin head pivots and bends, pulling on the actin and moving it - muscle contraction * A new molecule of ATP binds to the myosin head, causing it to detach from the actin * Acetylcholinesterase removes acetylcholine from the synaptic cleft * Calcium is transported back into the sarcoplasmic reticulum by active transport * Tropomyosin binds active sites on actin causing the cross-bridge to detach

Answer 83

* 3% of body weight * 0.2g/kg required intake per day * Improtant component of amino acids --> required for peptides and proteins * Essential component of nucleic acids DNA and RNA * Required for synthesis of ATP Nitrogen Balance * Nitrogen intake should = nitrogen loss * Nitrogen intake from meat, fist, dairy foods, eggs, nuts, legumes, grains and cereals * Nitrogen loss in urine, faeces, sweat, hair and skin * Positive nitrogen balance associated with periods of growth, hypothyroidism, tissue repair and pregnancy * Negative nitrogen balance associated with burns, serious tissue injuries, fever, hyperthyroidism, wasting diseases and periods of fasting

Answer 84

**Production:** Adrenal medulla from tyrosine **Secretion:** Adrenal medulla **Site of action:** Adrenergic receptors on nearly all tissues (alpha >> beta effects) **Effects:** Increased SVR, venoconstriction, increased preload, increased myocardial oxygen consumption, increased coronary flow, reflex decrease in HR **Release stimulated by:** Stress - physical threat, excitement, noise, bright lights, high or low ambient temperature, sympathetic stimulation **Release inhibited by:** Alpha and beta antagonists **Metabolism:** Mitochondrial MAO and COMT within liver, kidney and blood to VMA and normetanephrine, urinary excretion of metabolites + 25% pulmonary uptake **Hypersecretion:** Phaeochromocytoma **Hyposecretion:** Autonomic neuropathy, adrenalectomy

Answer 85

Nutritional requirements * Calculate BMR using an equation/formula * Usually need ~25kcal/kg/day in afebrile, healthy individuals * Modify caloric needs depending on resting energy expenditure - fever, sepsis, surgery, burns * Protein - 1.5-2g/day (provides 5.3kcal/g) * Lipid - provides 9.3kcal/g (max 40% caloric intake) * Carbohydrate - provides 3.75kcal/g * Recommended calorie:nitrogen ratio 100:1 Electrolyte requirements (in mmol/kg/day) * Na and Cl 1.0-2.0 * K 0.7-1.0 * PO4 0.4 * Ca and Mg 0.1 * Trace elements - chromium, copper, manganese, selenium, zinc, vitamins A/D/E/K/B1/B2/B3/B5/B6/B7/B9/B12/C Routes 1. Oral 2. Enteral - OG, NG, enterostomy post-pyloric +/- pro-kinetics (erythromycin, metoclopramide) 3. Parenteral - supplemental or sole nutrition Complications * Refeeding syndrome - drops in phosphate, magensium, potassium, calcium (start with 25-50% of energy requirements and increase gradually, monitor electrolytes, give thiamine and B vitamins) * Overfeeding - uraemia, hyperglycaemia, hyperlipidaemia, fatty liver, hypercapnia, fluid overload * Hyperglycaemia - insulin resistance as part of stress response * Specific complications of enteral nutirion - aspiration, pneumonia, diarrhoea * Specific complications of PN - CVC risks, sepsis, hepatobiliary disease, electrolyte imbalances and micronutrient deficiencies

Answer 86

Calculated osmolarity = (2 x [Na+]) + [glucose] + [urea]) Osmolar gap = Osmolality (measured) – Osmolarity (calculated) Normal = < 10 Causes of high osmolar gap: * Mannitol * Methanol * Ethylene glycol * Polyethylene glycol (IV lorazepam) * Propylene glycol (IV lorazepam, diazepam, phenytoin) * Sorbitol * Glycine (TURP syndrome) * Maltose (IVIG) * Presence of other osmotically active particles

Answer 87

In each step of the cascade, the PaO2 falls. It demonstrates that oxygen delivery to tissues relies on the passive transfer of gas down partial pressure gradients * Air (dry atmospheric gas) - pO2 = FiO2 x Patm * Trachea (humidified gas) PiO2 = FiO2 (Patm-PH2O) - heated to 37 degrees and has 100% relative humidity * Alveolar gas PAO2 = PiO2-PaCO2/R - dependent on alveolar ventilation * Capillary blood - diffusion * Arterial blood - shunt -- extrapulmonary - bronchial veins, thebesian veins, R--> L cardiac defect -- intrapulmonary - alveolus full (blood, fluid, pus, tumour), atelectasis * Mitochondria - metabolism (oxidative phosphorylation -- Pasteur point - the partial pressure of oxygen at which oxidative phosphorylation ceases * Venous blood - PO2 is greater than mitochrondial PO2 as not all arterial blood travels through capillary beds

Answer 88

**Production:** Hypothalamus - paraventricular nucleus **Secretion:** Posterior pituitary **Site of action:** Breast, kidneys, uterus (from day 22 of pregnancy onwards, increasing as gestation progresses) **Effects:** Stimulates contraction of myoepithelial cells surrounding the milk ducts, therefore causing secretion of milk. Also stimulates contraction of the uterus and water retention by the kidney. **Metabolism:** oxytocinase in the liver, kidneys and plasma (during pregnancy) **Release stimulated by:** Suckling **Release inhibited by:** Dopamine

Answer 89

**Production:** Parathyroid glands **Secretion:** Parathyroid glands (Chief cells) **Site of action:** Bone, kidney, CNS, pancreas, testes, placenta **Effects:** Regulation of serum calcium - enhances release of calcium from bone, prevents action of osteoblasts, reabsorption of calcium in the distal tubules and CDs, stimulates conversion of vitamin D to active form to increase calcium uptake from the intestine **Release stimulated by:** low serum calcium, low magnesium, increased phosphate, adrenaline, histamine **Release inhibited by:** high serum calcium, high magnesium, calcitriol, phosphate **Hypersecretion:** Hyperparathyroidism **Hyposecretion:** Hypoparathyroidism

Answer 90

MDT, patient centred, evidence based approach aimed at optimising the care of patients who may need a blood transfusion, and minimising the blood products that need to be administered. Pre-operative * identify and correct anaemia - PO/IV iron, B12, folate (ideally at least 4 weeks pre-op) * consider deferring elective (high blood loss) surgery until cause of anaemia addressed and treated * ask about bleeding history to identify and manage patients with haemostatic disorders * protocols for anti-coagulation/anti-platelet therapies used perioperatively * determine expected blood loss * confirm patient wishes regarding transfusion therapy and blood conservation modalities * consider EPO * consider preoperative autologous blood donation Intra-operative * cell salvage if blood loss anticipated to be >1000ml * TXA * controlled hypotension * patient position (decreased CVP) * maintain physiologic homeostasis - euvolaemia, avoid hypothermia * minimise surgical blood loss - minimally invasive techniques, electrosurgery decides, meticulous haemostatic techniques, topical haemostatic agents/adhesives * use evidence based transfusion guidelines * consider acute normovolaemic haemodilution Post-operative * post op cell salvage * minimise blood sampling * use evidence based transfusion guidelines * early surgical re-exploration for those with localised internal bleeding * use of ROTEM/coagulation testing and haematology input to ensure correct products provide * consider volume provided if Hb dropped * consider alternatives to transfusion e.g. IV iron

Answer 91

* Inherited genetic differences in drug metabolic pathways which can alter individual response to drugs * Can affect receptors, enzymes or transport processes * Acetylator status - rapid or slow -- autosomal dominant/recessive -- hydralazine, sulphonamides, dapsone, isoniazide, phenelzine, procainamide * Sux apnoea (autosomal recessive) -- autosomal recessive -- 4 alleles - butrylcholinesterase (BChE) - *BChE* gene on chromosome 3 -- Eu - normal (100% activity) -- Ea - atypical (30% activity) -- Ef - fluoride resistant (40% activity) -- Es - silent (0% activity) * CYP2D6 - metabolism of codeine -- autosomal codominant -- about 7-10% of whites have poor CYP2D6 metabolism -- 1-7% of whites and >25% of Ethiopians are classified as having ultrarapid metabolism -- poor metaboliser, intermediate metaboliser, extensive metaboliser, ultra rapid metaboliser * Malignant Hyperthermia -- autosomal dominant -- mutation in RYR1 gene on chromosome 19 (up to 70% of affected individuals) * MTHFR gene variants -- cause reduced ability to convert folic acid or folate into a usable form -- avoid N2O/entonox * CYP2C9 variants - VKORC1 gene -- autosomal dominant -- warfarin resistance or sensitivity * CYP2C19 variants -- autosomal codominant -- clopidogrel resistance (inability to convert clopidogrel to active form)

Answer 92

Prostacyclin receptor agonists (eg selexipag, epoprostenol, iloprost) - selectively bind the PGI2 receptor causing direct vasodilatation and inhibition of platelet activation Endothelin receptor antagonists (eg Bosentan) - inhibit action of endothelin-1 produced by endothelial cells that mediates vascular constriction Guanylate cylase activators (eg riociguat/vericiguat) - increase production of intracellular cGMP leading to vascular smooth muscle relaxation PDE5 inhibitors (eg sildenafil - prevent breakdown of intracellular cGMP Calcium channel blockers Digoxin Diuretics Oxygen Anticoagulation

Answer 93

Pharmacological * Volatile anaesthetics - prolong blockade by depressing somatic reflexes in CNS thereby reducing transmitter release at the NMJ * Aminoglycosides (large intraperitoneal doses), polymixins and tetracyline - prolong blockade by decreasing ACh release, possibly by competition with calcium ions * Local anaesthetics - variable effect on blockade - low doses may enhance blockade through sodium channel blockade * Lithium - prolong blockade through sodium channel blockade * Diuretics - variable effect through impact on cAMP, may have effects via serum K+ in addition * Calcium channel antagonists - prolong blockade by reducing calcium influx, leading to reduced ACh release * Magnesium - decreased ACh release by competition with Calcium ions, and stabilisation of the post-junctional membrane Physiological * Hypothermia - prolongs blockade by reducing metabolism of muscle relaxant * Acidosis - usually prolongs blockade * Hypokalaemia - acute hypokalaemia increases the resting membrane potential (makes it more negative) - non depolarising relaxants are potentiated while depolarising relaxants are antagonised * Hyperkalaemia - resting membrane potential becomes less negative leading to antagonism of non depolarising relaxants and potentiation of depolarising relaxants * Hypermagnesaemia - prolongs blockade by decreasing ACh release through competition with calcium ions, and stabilisation of the post-junctional membrane. When used at suprenormal levels, Mg ions can cause apnoea via a similar mechanism

Answer 94

Phase 1 - within a few seconds, maximal at 15 minutes - probably mediated by K channels Phase 2 - moderate hypoxia sustained for more than 30-60 minutes, further increase in PVR, peaks at 2hrs - probably a result of increased release of endothelin When normoxia returns - it can take several hours for PVR to return to baseline

Answer 95

Inputs * Systemic toxins and drugs --> chemoreceptor trigger zone --> CTZ --> NTS and VC * Vagal (GI tract mechano and chemoreceptors), glossopharyngeal, facial nerve stimulation --> visceral afferents --> NTS and VC * Motion --> vestibular nuclei --> NTS and VC * Pain, emotion, smell, sight --> higher cortex centres --> VC Receptors * M3 - vestibular nuclei, higher cortex centres, CTZ, NTS, VC, efferent nerves * NK1 - vestibular nuclei, visceral afferents, CTZ, NTS, VC * H1 - vestibular nuclei, NTS, VC * 5HT3 - CTZ, visceral afferents, NTS, VC * D2 - CTZ, NTS, VC Processing centres * Nucleus Tractus Solitarius - brainstem * Chemoreceptor Trigger Zone - area postrema of the medulla, on the lateral walls of the 4th ventricle (outside the BBB) * Vomiting centre - dorso-lateral reticular formation of the medulla Outputs * Vasomotor Nuclei - dorsal motor nucleus --> vagal efferents * Respiratory Nuclei - Ventral Respiratory Group --> descending corticospinal tracts * Salivary Nuclei - nucleus ambiguus --> CN 9 and 10 Process of Vomiting - co-ordinated by the vomiting centre in the medulla * Pre-ejection phase -- prodromal nausea -- salivation -- retrograde intestinal contraction which forces intestinal contents into the stomach * Retching phase -- deep inspiration and breath-holding to splint the chest -- epiglottic closure -- elevation of the soft palate to prevent nasal soiling * Expulsive phase -- relaxation of oesophageal sphincters -- pyloric contraction -- violent contraction of the diaphragm and abdominal muscles

Answer 96

* Extracellular potassium concentration - 3.5-5mmol/L * Intracellular potassium concentration - 120-150mmol/L * Intracellular K+ levels are important for enzyme function, cell division and growth, acid-base and cell volume regulation * Freely filtered at the glomerulus * Mostly reabsorbed at the PCT (2/3rds) and LoH (20%) * Some reabsorption and some potassium secretion at the DCT and CD * At PCT - passive reabsorption via a paracellular mechanism - directly proportional to water and Na+ movement (Na+-K+-ATPase) — sodium moves out of the cell, driving K+ into the cell — extrusion of sodium creates an osmotic gradient and an electrochemical radiant — water moves out of the PCT down the osmotic gradient — Cl- moves down the electrochemical gradient — K+ is reabsorbed and follows Cl- into the bloodstream * At LoH - trans cellular and paracellular reabsorption — Na+-K+-ATPase on the basolateral membrane pumps Na+ out into the bloodstream and pumps K+ into the thick ascending limb — gradient created for the NKCC2 cotransporter on the apical membrane — NKCC2 pumps Na+, K+ and 2Cl- into the cell from the lumen — Intracellular K+ can enter the bloodstream through K+-Cl- symporter or through K+ uniporter — movement of K+ through apical renal outer medullary K+ channels - leads to positive voltage in the lumen, providing a driving force for passive reabsorption * Approximately 10% of filtered potassium is reabsorbed in DCT and cortical CD when the body is attempting to preserve potassium — mediated by alpha and beta intercalated cells — apical H+-K+-ATPase mediates movement of H+ into the lumen, driving K+ into the intercalated cell — basolateral K+ channel allows the K+ inside the intercalated cell to leak out into the bloodstream * If potassium is deplete, the number of H+-K+-ATPase pumps increase significantly in order to reabsorbed as much K+ as possible (drives H+ into the lumen generating hypokalaemic alkalosis) * Potassium secretion in the late DCT and CD via principal cells — principal cells contain ENaC on the apical membrane and Na+-K+-ATPase on the basolateral membrane — K+ is driven into the principal cell from the bloodstream by Na+-K+-ATPase leading to intracellular accumulation of K+ — high intracellular K+ creates chemical gradient which allows for secretion of K+ via K+ channels on the apical membrane * Secretion affected by tubular and luminal factors * Tubular factors — High ECF K+ stimulates Na+K+ATPases, increasing permeability of K+ channels and increasing secretion of K+ into the lumen — Aldosterone stimulates Na+K+ATPases in the basolateral membrane, stimulating K+ channels and ENaCs in the apical membrane leading to increased secretion — Acidosis - increased H+ secretion into lumen to correct acidosis — Alkalosis - kidneys try to decrease secretion of H+, increasing K+ in turn * Luminal factors — High luminal flow washes away luminal K+, maintaining a constant concentration gradient and increasing K+ secretion — Increased luminal flow also increases Na+ delivery to the tubule cells —> Na+ uptake through ENaC —> negative potential in the lumen, encouraging K+ secretion through the apical K+ channel

Answer 97

* Predominantly intracellular cation * Daily requirement 0.7-1.0mmol/kg/day * Completely and passively absorbed in upper GI tract * Excretion mainly in collecting ducts * Involved in neuromuscular excitability — gradient across cell membranes determines the excitability of nerve and muscle cells including myocardium * Affects tonicity * Antiport molecule in Na/K transport and control of intracellular volume * Regulation of some Intracellular processes (protein/glycogen synthesis, carbohydrate metabolism) Hyperkalaemia * muscle weakness * lethargy * ascending paralysis * respiratory failure * cardiac arrhythmias - peaked T waves, flattened P waves, increased PR interval —> widened QRS —> deep S waves, merging of S+T waves —> sine wave formation —> VF * membrane stabilisation - calcium chloride/glauconite * ECF—>ICF shift - sodium bicarbonate (in known CKD), insulin/dextrose, salbutamol * removal of K from body - frusemide, resonium, dialysis Hypokalaemia * mild usually asymptomatic * fatigue, muscle cramps, weakness * constipation * rhabdomyolysis * ascending paralysis * respiratory failure * arrhythmias - U waves, T wave flattening, ST depression —> VT/VF, long QT and Torsades * replace magnesium as this facilitates a more rapid correction of hypokalaemia * non acute - 10-20mmol/hr * life threatening can give quicker

Answer 98

- controlling the source of the infection - prescribing antibiotics when they are truly needed - prescribing appropriate antibiotics with adequate dosages - using the shortest duration of antibiotics required based on evidence - reassessing treatment when culture results are available - educating staff - supporting an interdisciplinary approach - enhancing prevention and control of infection - supporting surveillance of anti microbial resistance and HAI and monitoring of antibiotic consumption

Answer 99

* A compound that has negligible, or lower, activity against a specified pharmacological target than one of its major metabolites. * Can be used to improve drug delivery or pharmacokinetics, to decrease toxicity, or to target the drug to specific cells or tissues * 2 major types based on how the body converts the prodrug into the final active drug form * Type 1 prodrugs are bioactivated inside the cells (intracellular) * Type 2 prodrugs are bioactivated outside cells (extracellular), especially in digestive fluids or in the blood * Subtypes based on whether the bioactivation site is also the site of therapeutic action Examples * diamorphine --> morphine + 6-acetylmorphine (via blood esterases) * codeine --> morphine + codeine 6-glucuronide (via CYP2D6) * enalapril --> enalaprilat (hydrolysis by esterases) * prednisone --> prednisolone (liver by 11-beta-hydroxysteroid dehydrogenase) * parecoxib --> valdecoxib (enzymatic hydrolysis) * omeprazole --> acid or sulfonamide form (acidic environment in the stomach) * levodopa --> dopamine (DOPA decarboxylase) * methyldopa --> alpha-methylnorepinephrine (decarboxylation) * terlipressin --> lysine vasopressin (endothelial peptidases) * carbimazole --> methimazole (hydrolysis and enzyme decarboxylation in the blood) * aspirin --> salicylate (stomach, intestinal mucosa, blood, liver) * valaciclovir --> aciclovir monophosphate (viral thymidine kinase) --> acivlovir triphosphate (host cell kinases)

Answer 100

**Production:** Anterior pituitary, dicidua, myometrium, breast, lymphocytes, leukocytes, prostate **Secretion:** Anterior pituitary **Site of action:** Breasts, ovaries, pituitary glands, heart, lung, thymus, spleen, liver, pancreas, kidney, adrenal gland, uterus, skeletal muscle, skin, CNS **Effects:** Development of the breasts ready for lactation, stimulates milk production, reduces fertility, sexual gratification **Release stimulated by:** PRLH, dopamine antagonists, suckling, prolactin (positive feedback mechanism), stress, exercise **Release inhibited by:** Dopamine (aka prolactin-inhibitory hormone) **Hypersecretion:** Hyperprolactinaemia, polactinomas **Hyposecretion:** Hypoprolactinaemia (uncommon in isolation)

Answer 101

**Production:** Endothelial cells which line the walls of arteries and veins **Secretion:** Endothleial cells **Site of action:** platelet prostacyclin receptors **Effects:** inhibits platelet activation, vasodilation, antiproliferative, antiinflammatory **Release stimulated by:** vascular damage **Release inhibited by:** NSAIDs **Metabolism:** broken down into a weaker vasodilator

Answer 102

**Membrane phospholipids** ↓ (Cytosolic phospholipase A2) ↓ **Arachidonic Acid** ↓ (COX 1, COX 2) (PGH synthase) ↓ **Prostaglandin G2** ↓ (PGH synthase) ↓ **Prostaglandin H2** ↓ PGD2 (PGD2 synthases) → *allergic response - mast cells, brain, airways* PGE2 (PGE2 isomerases) → *uterine contraction, inhibition of sodium absorption, patency of PDA, vascular smooth muscle contraction* PGF2 (PGF2 synthase) → *uterine contraction, bronchoconstriction, vascular smooth muscle contraction, increase sclera's permeability to aqueous fluid* PGI2 aka Prostacyclin (PGI2 synthase) → *vasodilation, inhibition of platelet activation* TXA2 (TXA2 synthase) → *stimulates activation of new platelets + increases platelet aggregation*

Answer 103

**Production:** Derived enzymatically from arachidonic acid in almost every tissue in the body **Secretion:** Via prostaglandin transporter and passive diffusion **Site of action:** Most tissues and organs **Effects:** locally acting vasodilators (smooth muscle relaxation), inhibit aggregation of platelets, involved in inflammation **Release stimulated by:** activation of COX 2 by injury or inflammation **Release inhibited by:** NSAIDs and corticosteroids **Metabolism:** rapidly metabolised in the lungs by a dehydrogenase enzyme

Answer 104

Factors affecting PVR - increased PVR * Decreased pulmonary blood flow * Low and high lung volumes (compression or larger and smaller vessels respectively) * HPV * Catecholamines * Serotonin * Arachidonic acid metabolites * Histamine * Hypercapnia * Hypothermia * Acidemia * Alpha 1 receptors - cause vasoconstriction * Increased Hct * Pulmonary vasoconstrictors - adrenaline, noradrenaline, adenosine Factors affecting PVR - decreased PVR * Increased pulmonary blood flow * Lung volume - "U" shaped curve, PVR is lowest at FRC * Alkaelaemia * Hyperoxia * Hypocapnia * Beta 2 and muscarinic 3 receptors - cause vasodilation * Pulmonary vasodilators - NO, milrinone, levosimendan, vasopressin, Ca-channel blockers, sildenafil, ACE-I, prostacyclin, Bosentan

Answer 105

* Normal QTc = 440ms (M) or 460ms (F) * QTc >500ms is associated with increased risk of torsades de pointes which may be fatal **Aetiology** - Pharmacological - Long QT syndrome - Jervell and Lange-Neilson syndrome - rare autosomal recessive disorder (bilateral sensorineural hearing loss + prolonged QTc) - Romano-Ward syndrome - most common form of congenital long QT syndrome causing abnormalities in transport of positive ions through cardiac ion channels - Electrolyte abnormalities - hypocalcaemia, hypokalaemia, hypomagnesaemia - Hypothyroidism - Hypothermia Many commonly used medications exhibit QT prolonging effects, however, the degree of QT prolongation is not severe enough to warrant caution in health patients. * Antiarrhythmics - sotalol, amiodarone, quinidine, flecainide * Antihistamines - terfenadine, astemizole * Prokinetics - cisapride * Neuroleptics/antipsychotics - phenothiazines, haloperidol, chlorpromazine, proclorperazine, olanzapine, risperidone, droperidol * TCAs - amitriptyline, doxepin, desipramine, imipramine, clomipramine * Antibiotics - macrolides (erythromycin, clarithromycin), fluoroquinolones * Antifungals * Antimalarials * Ondansetron * Sumatriptan * Methadone **Management** * Caution is advised when combining QT prolonging medications or using these medications in those with electrolyte abnormalities. * Patients with long QT syndrome (or other genetic causation) should use QT prolonging medications with caution.

Answer 106

Red Blood Cells * formed in the bone marrow by erythropoiesis * biconcave discs measure 7.5 microns in diameter * thicker outer rim, thher centre * deformable - squeeze thorugh narrow capillaries without disrupting cell membrane * enhances diffusion of gases due to greater surface area * reduces wall tension as the cells well after taking up CO2 from the tissues * contain approximately 30pg of Hb * erythrocytes survive approximately 120 days Haemoglobin * 4 globin chains (2 alpha, 2 beta) * Each contains a haem molecule which reversible binds to oxygen, containing a Fe2+ ion * Fe2+ ion forms 6 bonds within the haem moiety Functions of Hb * transport of oxygen from the lungs to the tissues - to facilitate oxidative phosphorylation in the mitochrondroa * carriage of CO2 from tissues to lungs as carbaminohaemoglobin * buffering of H+ formed in the erythrocyte from conversion of CO2 into bicarbonate * NO metabolism

Answer 107

* High pressure baroreceptors respond to decreased vessel stretch and decrease firing — carotid sinus (CN IX) — aortic arch and heart (CN X) - Vasomotor centre (nucleus tractus solitarius in the rostral ventrolateral medulla) detects decreased afferent impulses —> decreased parasympathetic outflow — increased heart rate (SA node) AND —> increased sympathetic outflow — increased contractility and increased HR —> increased CO — vasoconstriction —> increased MAP —> increased CO — venoconstriction —> increased venous return * Low pressure (cardiopulmonary) baroreceptors detect changes in blood volume — vena cava — pulmonary arteries — atria * Chemoreceptors in the aortic and carotid bodies detect changes in blood pH, O2 and CO2 levels —> respond to decreased arterial pO2 by increasing firing of afferent nerves —> increased sympathetic outflow (vasoconstriction), increased parasympathetic outflow (transient decreased HR) and increased ventilation * Central chemoreceptors in the medulla respond to changes in pCO2 and pH —> respond to decreased pCO2 by increasing vasoconstriction in the brain, decreasing cerebral blood volume and therefore ICP * RAAS - Renin - released from granular cells in the juxtaglomerular apparatus in espouse to increased concentration of salt in the blood, reduction in renal blood flow, or stimulation from the SNS acting on B1 receptors — converts angiotensinogen into angiotensinogen I which is converted by ACE (from the lungs) into angiotensin II - Angiotensin II - causes vasoconstriction, increases salt reabsorption through activation of aldosterone and increases plasma volume through stimulation of ADH release - Aldosterone - acts on the cells in the DCT and CD to increase Na+ reabsorption while increasing K+ secretion into tubules *ADH - release triggered by increased plasma Osmolarity (osmoreceptors in the hypothalamus), reduced blood volume and increase in levels of angiotensin II —> increases water reabsorption through insertion of aquaporins in the CD and DCT thereby increasing intravascular fluid volume —> direct action on V1 receptors on vascular smooth muscle causing vasoconstriction * ANP - released by increased stretch of atria due to increased BP — causes generalised vasodilation —> increased GFR —> increased Na+ and H2O filtration and excretion —> decreased blood volume — stimulates decreased renin, ADH and aldosterone release *Other contributory factors - Sodium - increased sodium leads to increased water reabsorption and therefore increased plasma volume - Bradykinin - causes dilation of arterioles via release of prostacyclin, NO and endothelium-derived hyperpolarizing factor and makes veins constrict, via prostaglandin F2 - Nitric oxide - potent vasodilator produced in response to shear stresses in vessels - Glucocorticoids - overstimulation of the mineralocorticoid receptor, resulting in sodium retention in the kidney, volume expansion and subsequent increase in BP - Renal function - kidneys are responsible for regulating circulatory volume by controlling sodium and water balance, damaged kidneys are less able to do this - Psychological stress - leads to temporary increase in sympathetic outflow - Obesity - multiple mechanisms that impact on BP control - including renal medullary compression, increased RAAS activity and increased SNS activity (via release of leptins) - Atherosclerosis - narrowing and stiffening of vessels, impairment of baroreceptor response - Other hormones and neurotransmitters including thyroxine, histamine, acetylcholine and serotonin

Answer 108

* Sodium intake - dietary intake, absorbed in the colon and sitar small bowel * Sodium output - urinary excretion, insensible losses (sweat, faeces) * 99% of sodium ions which pass through the glomerulus are reabsorbed, driven across the basolateral membrane by Na-K-ATPase pumps * Renal sympathetic nerve activity - stimulated by hypotension (carotid and aortic bodies) and hypovolaemia (atrial natriuretic peptide) —> activation of alpha-1 and alpha-2 receptors lead to increased Na reabsorption in the PCT and fluid retention * RAAS - reduced renal perfusion and/or reduced sodium delivery to the nephron stimulates renin release —> ATII —> aldosterone secretion * ATII stimulates the Na+/H+ antiporter in the PCT * Aldosterone increases the expression of epithelial sodium channels (ENaC) in the collecting duct * ANP/BNP - stretch as a result of increased blood volume leads to release of ANP/BNP - reduce aldosterone and renin secretion, thereby decreasing Na reabsorption * Increase in plasma osmolality is detected by osmoreceptors in the hypothalamus —> release of ADH —> insertion of aquaporins in the DCT and CD —> increased water resorption by osmosis

Answer 109

**Compartments** - Core (66% of adult body mass) - 37 degrees - Peripheral - absorbs or releases thermal energy to maintain core normothermia - 28-36 degrees - neonates and infants have a very small peripheral compartment **Components** - Afferent thermal sensing from peripheral thermoreceptors via the lateral spinothalamic tract and central thermoreceptors brainstem hypothalamus spinal cord deep thoracic and abdominal tissue free nerve endings in the skin - cold receptors and warm receptors - Central Integration primarily in the hypothalamus hot - anterior hypothalamus - preoptic nuclei cold - posterior hypothalamus - shivering centre - Efferent response cardiovascular - vasodilation/vasoconstriction CNS - behaviour modification e.g. clothing, relocation and skeletal muscle activity MSK - sweating, piloerection, shivering Metabolic - non shivering thermogenesis (hormonal and brown fat) and increase in BMR

Answer 110

* Renal blood flow and GFR are subject to autoregulation * MAP 80-180mmHg Myogenic Theory (faster response) * stretch of smooth muscle in preglomerular arteriole wall leads to reflex constriction to maintain blood flow Tubuloglomerular Feedback (slower response) * alterations in GFR due to perfusion cause an altered composition of fluid due to a change in flow rate * an increase in sodium chloride concentration in the early distal tubule is detected by the macula densa (at the end of the ascending limb) which acts to alter arteriole tone by * increased sodium concentration leads to release of ATP and reduced prostaglandin E2 that act on the nearby juxtaglomerular cells --> constriction of afferent arteriola and decreased renin secretion from both afferent and efferent juxtaglomerular cells --> lower GFR * further increase in Na concentration --> release of NO to prevent excessive vasoconstriction * decreased sodium concentration results in juxtaglomerular cells being stimulated to release more renin --> RAAS --> increased angiotensin II --> preferential constriction of the efferent arteriole --> increased GFR Also affected by sympathetic nervous system, RAAS, atrial naturietic peptide and prostaglandins.

Answer 111

Techniques * Peritoneal dialysis * Intermittent haemodialysis (IHD) * Continuous renal replacement therapy (CRRT) -- continuous veno-venous haemofiltration (CVVH) - uses convection for solute removal -- continuous veno-venous haemodialysis (CVVHD) -- continuous veno-venous haemodiafiltration (CVVHDF) - uses a filter that allows a countercurrent of dialysate, combines diffusion with convection for solute -- slow continuous ultrafiltration (SCUF) - removal of plasma water with smaller molecules from the blood stream (corrects volume overload) Aims * Solute removal * Water removal * Correction of electrolyte abnormalities * Normalization of acid-base disturbances Mechanisms * Ultrafiltration/haemofiltration - fluid can cross a semi-permeable membrane in response to a pressure gradient -- osmotic/onchotic/hydrostatic -- generated by increasing pressure on blood side or decreasing pressure at effluent pump to alter "transmembrane pressure" (TMP) -- allows removal of fuid from the patient * Convection - one way movement of solutes across a semipermeable membrane with the flow of H2O (aka "solute drag") -- filtration with larger membrane pores, allows water, electrolytes, urea and creatinine to be carried across the membrane and removed from the circulation * Adsorption - adherence of solutes and other biological matter to the surface of the membrane e.g. cytosorb filters -- may decrease clearance of solutes as more are adhered to the membrane and decrease it's efficiency * Diffusion/haemodialysis - movement of particles from a higher concentration to a lower concentration across a semi-permeable membrane -- effective for small molecules due to pore size "selective diffusion" -- flow of dialysate in the opposite direction (countercurrent) to ensure a good concentration gradient -- slower process Contents of Dialysate * Sodium, chloride and magnesium - equivalent to normal serum levels * Potassium - either at a decreased level to aid clearance of high potassium or a more equivalent level * Bicarbonate - to aid addition of bicarbonate to the blood * Urea and creatinine are not present in any volume Anticoagulants for CRRT * None - poor filter life, useful if risks of anticoagulation outweigh benefits or if anticoagulation is contraindicated * Systemic anticoagulation - useful where systemic anticoagulation is indicated but high risk for bleedings - heparin/LMWH, direct thrombin inhibitors * Regional anticoagulation -- citrate - binds calcium which is required for activation of factors 2, 9, 10 and therefore thrombin generation. Citrate/Ca complexes that reach the systemic circulation are rapidly metabolised but can accumulate if there is liver of skeletal dysfunction -- heparin/protamine -- prostacyclins Complications of CRRT * Risks associated with central vascular access -- catheter placement - infection, bleeding, bruising, haematoma, damage to vessels, PTX, arrhythmias, emboli -- catheter dysfunction - fibrin deposition, distortion, kinking * Risks associated with extracorporeal circuit - air embolism, reduced filter life and dialysis dose, hypothermia, bioincompatibility, immunologic activation, anaphylaxis, hypotension * Haematological complications - associated with anticoagulation * Electrolyte disturbances - low phosphate, magnesium, calcium, potassium, sodium, high sodium * Acid-base disturbances - metabolic acidosis/alkalosis, citrate induced alkalosis/acidosis * Nutritional losses - amino acids, proteins, poor glycaemic control, vitamin deficiencies, trace minerals * Volume management errors * Altered drug removal * Delayed renal recovery

Answer 112

**Production:** Juxtaglomerular cells of the kidney **Secretion:** Pericytes **Site of action:** Bloodstream **Effects:** activates RAAS by converting angiotensinogen to angiotensin I **Release stimulated by:** decrease in arterial BP detected by baroreceptors, decrease in Na load delivered to the distal tubule (measured by macula densa), b1 adrenergic stimulation **Release inhibited by:** angiotensin II

Answer 113

Organic molecules that are produced within a cell to initiate the response to a signal carried by an agonist that does not itself enter the cell. * In most cases, a ligand binds to a membrane-spanning receptor protein molecule --> * causes conformational change in the receptor --> * activity of receptor affected --> * production of active second messengers 3 basic types of secondary messenger molecules: * hydrophobic molecules - water insoluble which are membrane-associated and diffuse from the plasma membrane into the intermembrane space where they can reach and regulate membrane associated effector proteins e.g. diacylglycerol (DAG) * hydrophilic molecules - water soluble molecules that are located within the cytosol e.g. cAMP, cGMP, IP3 and Ca++ * gases - can diffuse through cytosol and across cellular membranes e.g. NO, CO, H2S G Protein Coupled Receptors * Gs protein --> activation of the receptor stimulates conversion of ATP to cAMP via adenyly cylase --> production of protein kinase A (secondary effector) * Gq protein --> activation of the receptor stimulates conversion of PIP2 to IP3 and DAG via phospholipase C --> IP3 then binds to calcium pumps on the endoplasmic reticulum, transporting calcium into the cytoplasm, DAG causes production of protein kinase C Other examples * ANP/NO --> activation stimulates conversion of GTP to cGMP via guanyly cylase --> production of protein kinase G

Answer 114

* Life threatening state whereby there is globally insufficient delivery and/or utilisation of oxygen at the cellular level. * Characteristically but not always associated with low blood pressure and impaired tissue perfusion * Consequence of shock is cellular and tissue hypoxia, ultimately cellular death and organ dysfunction Cardiogenic Shock * impaired contractility * inadequate CO as a result of cardiac failure * myocardial ischaemia and complications, myocarditis, myocardial contusion, septic shock, poisoning or toxic exposure, end stage cardiomyopathy, dysrhythmia, valvular dysfunction, LVOT obstruction Hypovolaemic Shock * inadequate circulating volume secondary to fluid loss * haemorrhage - traumatic or non-traumatic * fluid losses - GI losses, excessive diuresis, excessive diaphoresis, burns, third spacing (pancreatitis, severe sepsis, anaphylaxis), iatrogenic (e.g. post dialysis) Distributive Shock * inadequate perfusion secondary to maldistribution * neurogenic shock * liver failure * adrenal insufficiency * anaphylaxis * septic shock * post bypass vasoplegia * drugs and toxic exposures Obstructive Shock * inadequate CO as a result of mechanical obstruction * within the circulatory system - massive PE, atrial thrombosis or myxoma, occlusive valvular lesion, other emboli (e.g. air, amniotic fluid) * external to the circulatory system - tamponade, abdominal compartment syndrome, PTX, dynamic hyperinflation, tension pneumomediastinum, caval compression

Answer 115

* Quitting smoking before surgery leads to a reduced incidence of postoperative complications * The longer the period of cessation before surgery, the greater the benefit * RCOA advises that people who smoke should quit for at least several weeks preoperatively and may benefit from abstaining on the day of surgery — half life of CO when breathing air is 4hrs — half life of nicotine is 30 mins * There is no clear evidence of harm from smoking cessation within a few hours or days * NICE recommends that patients who smoke should be identified and offered intensive support to quit * More likely to quit if offered a combination of interventions - combined behavioural support and pharmacotherapy * All HCPs should be trained to give brief advice on stopping smoking — Ask and record smoking history — Advise that the most effective way to quit is with a combination of medication and specialist support — Act on the patient response - give information, refer and prescribe Drugs * Nicotine replacement therapy - patches, inhalators, vapes, chewing gum, lozenges * Varenicline - nicotinic receptor partial agonist * Bupropion - nicotinic receptor antagonist with dopaminergic and adrenergic actions - may work by blocking the effects of nicotine, relieving withdrawal or reducing depressed mood

Answer 116

* Used to absorb expired CO2 from the breathing system to prevent CO2 retention. * 100g of soda lime can absorb >15L of carbon dioxide. * Contains 75% calcium hydroxide Ca(OH)2, 20% water and 5% NaOH/KOH * Granules are 4-8 mesh (mesh with 4 holes per square inch) size - balance between surface area (speec/efficacy of reaction) and resistance to flow **Reactions** * Carbon dioxide reacts with water in the soda lime to form carbonic acid: * H2O + CO2 --> H2CO3 * Carbonic acid reacts with sodium hydroxide to form sodium carbonate and water: * H2CO3 + 2NaOH --> Na2CO3 + 2H2O + heat * Carbonic acid reacts with slaked lime (calcium hydroxide) to form calcium carbonate and water: * H2CO3 + Ca(OH)2 --> CaCO3 + 2H2O * Sodium carbonate reacts with the calcium hydroxide to form calcium carbonate and sodium hydroxide: * Na2CO3 + Ca(OH)2 --> CaCO3 + 2NaOH

Answer 117

* Most abundant cation in the Extracellular fluid compartment * Requires 1.0-2.0mmol/kg/day * Normal plasma sodium concentration is 135-145mmol/L * Intracellular fluid concentration is approximately 10-12mmol/L * Maintenance of this transmembrane concentration gradient is necessary for generating the resting membrane potential and for action potential propagation * Also the main osmotic solute in the ECF - water travels in the direction of increasing Na concentration via osmosis * Essential in regulating intravascular volume and is highly linked to fluid balance and BP Hyponatraemia * speed of onset more important than level * most patients won’t be symptomatic until Na+ <125mmol/L * nausea + vomiting * neuropsychiatric symptoms * headache, lethargy * seizures, coma * if hypovolaemic - treat cause, give isotonic saline * if euvolaemic (SIADH) - fluid restrict, frusemide, NaCL tables, demeclocycline * if hypervolaemic - fluid restrict, frusemide * if chronic symptomatic - max 10mmol/L/day correction * if acute symptomatic - raise by 1-5mmol/hr until symptoms resolve or Na+ 125-130mmol/L (hypertonic saline 3% 1-2ml/kg/hr) Hypernatraemia * excessive thirst * CNS dysfunction - lethargy weakness, confusion, irritability, myoclonic jerks, seizures * evidence of dehydration - dry mouth, abnormal skin turgor, oliguria, tachycardia, orthostatic hypotension * treat cause * rehydrate * central DI - DDAVP + 5% dex to correct H2O deficit * nephrogenic DI - Na+ restriction, thiazide diuretics, DDAVP

Answer 118

AKA growth hormone inhibiting hormone **Production:** ventromedial nucleus of the hypothalamus **Secretion:** delta cells at several locations in the digestive system **Site of action:** parietal cells, anterior pituitary **Effects:** inhibits secretion of pancreatic polypeptides including insulin and glucagon, inhibits release of GH, TSH and PRL, decreases gastric emptying and motility of GI tract **Release stimulated by:** Glucose, amino acids, ketone bodies, CCK, gastrin, secretin, insulin (at high glucose concentration) **Release inhibited by:** Splanchnic nerve stimulation, noradrenaline **Metabolism:** Peptidase enzymes in plasma and tissues **Hypersecretion:** somatostatinoma

Answer 119

RBCs - collected into bag containing CPD —> C = citrate - chelates calcium, anticoagulant —> P = phosphate - prevents decrease in pH —> D = dextrose - supports ATP generation - store at 2-6 degrees C - added preservatives - SAGM - shelf life 35 days —> S = saline —> A = adenine - synthesises ATP —> G = glucose - supports ATP generation —> M = mannitol - prevention of haemolysis - stored RBCs —> decrease in % of viable RBCs, decrease in pH, decrease in 2,3-DPG, decrease in O2 affinity, decrease in Na+, increase in K+ Platelets - stored at room temperature (20-24 degrees C) - gentle agitation - platelet additive solution (NaCl, citrate, acetate, phosphate, K, Mg) - shelf life 5-7 days FFP - stored in freezer (<25 degrees C) - shelf life 36 months - can keep for 24hrs at 4 degrees C after thawing - A/AB is universal donor - RhD matching not required

Answer 120

Barbituric acid * addition of phenyl group —> anticonvulsant * addition of alkyl group —> hypnotic * increase in number of side chains —> increased hypnotic potency * more than 6 carbon side chains —> convulsant properties * addition of sulphur at C2 —> increases solubility and increases speed of onset as it allows the molecule to cross the blood brain barrier more easily * addition of methyl group at N1 —> increases excitatory/convulsant side effects Volatiles * Cl/Br —> increases potency * F —> increases stability and SVP, minimises flammability, decreases toxicity and potency * Ether —> increases stability * large number of hydrogen atoms increases flammability and potency * CF2H moiety can liberate CO in reaction with dry soda-lime Local Anaesthetics * composed of lipophilic aromatic group, intermediary link and hydrophilic amine group * intermediary group categorises LA into esters (cocaine, chlorpromazine, prilocaine) or amides (bupivacaine, lidocaine, Ropivacaine) * increased bulk of amine side chain groups added to aromatic portion leads to increased lipid solubility and protein binding leading to increased potency and prolonged duration of action * replacement of the tertiary amine by a pipe riding ring increases lipid solubility and duration of action * addition of butyl group in place of the amine on the benzene ring of procaine —> amethocaine/tetracaine * addition of propyl group to the amine end of mepivacaine —> ropivacaine (lower lipid solubility that allows more selective sensory block than bupivacaine) * addition of butyl group to the amine end of mepivacaine —> bupivacaine (longer duration of action)

Answer 121

Anterior Pituitary (production and secretion) * ACTH - stimulates adrenal gland to produce cortisol in response to CRH * TSH - stimulates thyroid to secrete thyroxine in response to TRH * LH/FSH - controls reproductive function and sexual characteristics, stimulates ovaries to produce oetrogen/progesterone and tests to produce testosterone in response to GnRH * Prolactin - stimulates breasts to produce milk in response to PRLH * GH - stimulates growth and repair in response to GHRH * MSH - exact role in humans unknown Posterior Pituitary (secretion) * ADH - affects water retention by kidneys to control body fluid and electrolytes in response to changes in plasma osmolality/tonicity and baroreceptor detection of reduced circulating volume * Oxytocin - affects uterine contractions and release of breast milk in response to suckling

Answer 122

G1 - cell growth. The cell is metabolically active and protein synthesis occures. No DNA replication occurs. S - synthesis stage where DNA replication occurs. DNA helicase unwinds the DNA strands and DNA polymerase extends the DNA chain. Topoisomerase prevents the supercoiling of DNA during the cell replication process G2 - cell growth and protein synthesis in preparation for mitosis M - mitosis (cell division) G0 - resting phase Mitosis: * prophase - condensation of chromosomes and the beginning of the formation of microtubules. Centromeres migrate to the poles of the cell to form mitotic spindles. * prometaphase - nuclear membrane breakdown and attachment of microtubules to the chromosomal kinetochores * metaphase - chromosomes migrate to the equatorial centre of the cells with centromeres at the poles of the cells * anaphase - separation of daughter chromatids by depolymerisation of microtubules * telophase - reassembly of the nuclear membrane with the disassembly of microtubule complexes. Decondensation of chromosomes occurs.

Answer 123

Physiochemical properties - liquid at room temperature - high SVP (vaporisable at room temperature) - low specific heat capacity - long shelf-life - light stable - heat stable - does not react with the components in the breathing circuit - rubber, metal, plastic, soda lime - not flammable/explosive - smells nice - preservative free - environmentally friendly - cheap - easy to manufacture Pharmacokinetic properties - high oil:gas partition coefficient - low MAC (high potency) - low blood:gas partition coefficient - rapid onset and offset - not metabolised/minimal metabolism to non toxic metabolites - non toxic Pharmacodynamic - does not cause laryngospasm or airway hyperreactivity - bronchodilation - no effect on haemodynamic parameters - analgesic - hypnotic - amnestic - anti-epileptic - no increase in ICP - skeletal muscle relaxation - anti-emetic - no tocolytic effects - not teratogenic or otherwise toxic - no drug interactions - not a trigger for MH

Answer 124

Glomerulus * loop of capillaries, surrounded by Bowman's capsule * filtration under pressure (generated by afferent and efferent arterioles) of 7L/hr * small molecules are freely filtered, larger molecules barely cross the barrier * negatively charged molecules filter less easily than positively charged Proximal Convoluted Tubule * Reabsorption of many ions - 70% Na/H2O/K/Cl, 100% glucose/amino acids, 85-90% HCO3 * Sodium glucose linked transporters - then facilitated diffusion of glucose * Na+/H+ antiporter * Na+/amino acid symporter * Na+/HCO3- symporter * Na+/K+ antiporter * H2O reabsoprtion via osmosis * H+ + HCO3~ --> H2CO3 via carbonic anhydrase * Secretion of organic acids and bases e.g. bile salts, oxalate, catecholamines, H+ ions and drugs/toxins (via H+/OC+ exchanger) into tubular lumen Thin descending limb of Loop of Henle * Passive reabsorption of water via AQP1 channels * Small amounts of urea, Na and other ions are reabsorbed * Active reabsorption of sodium in the thick ascending limb drives the counter-current multiplier system Thin ascending limb * Impermeable to water * Passive sodium reabsorption via epithelial Na+ channels (eNaC) * Cl- ion reabsorption through chloride channels Thick ascending limb * Impermeable to water * Active sodium reabsorption via Na+/K+/ATPase - low intracellular concentration of sodium creates an electrochemical gradient * NKCC2 transporter - 1x Na, 1x K, 2x Cl taken up from tubular lumen * K+ transported back tinto tubule by renal outer medullary potassium (ROMK) channels * Some paracellular reabsorption of Mg, Ca, Na, K Early Distal Convoluted Tubule * Absorption of ions including Na, Cl, Ca * Impermeable to water * Macula densa in 1st segment - involved in tubuloglomerular feedback * Na/K-ATPase transporter * Sodium-chloride cotransporter * Chloride ion uniporter moves chloride into the extracellular fluid * Sodium-calcium antiporter * PTH inserts calcium channels to increase calcium reabsorption Late Distal Convoluted Tubule * Principle cells - involved in uptake of sodium and extrusion of potassium * Na+/K+-ARPase * Sets up gradient for sodium to enter through ENaC channels * Intercalacted cells assist in acid base control by controlling levels of H+ and HCO3- * Type A intercalated cells - actively secrete H+ whilst reabsorbing HCO3- * Type B intercalated cells - net effect is secretion of HCO3- and reabsorption of H+ Collecting Duct * Determines final urine concentration via H2O excretion * ADH from hypothalamus inputs AQP2 channels, increasing ability to reabsorb water from the filtrate * UO 100ml/hr

Answer 125

**Production:** Platelets from arachidonic acid **Secretion:** Platelets **Site of action:** Thromboxane receptor (Gq) in lung, spleen, uterus + placenta, aorta, heart, intestin, liver, eye, thymus, kidney, spinal cord and brain **Effects:** vasoconstrictor, potent hypertensive agent, facilitates platelet aggregation **Release stimulated by:** vascular damage **Release inhibited by:** aspirin, dipyridamole, naproxen (high dose) **Metabolism:** degraded to weaker form

Answer 126

**Production:** Hypothalamus (parvocellular neurons of the paraventricular nucleus) **Secretion:** Hypothalamo-hypophyseal portal circulation **Site of action:** Anterior pituitary **Effects:** Stimulates release of TSH and prolactin **Release stimulated by:** cold, stress, exercise, low T3/T4 **Release inhibited by:** ghrelin, increased T3/T4, dopamine

Answer 127

**Production:** Follicular cells of the thyroid gland, from tyrosine **Secretion:** From thyroid **Site of action:** Thyroid hormone receptors (nuclear receptors) on nearly every cell in the body. Metabolised to more active T3 form **Effects:** Increased metabolism - increased MV due to increased CO2 production, increased HR, increased inotropy, increased CO, decreased SVR and DBP, increased CNS excitability, increased osteoblastic activity, impotence/oligomenorrhoea, increased GIT motility, increased BMR **Release stimulated by:** TSH from the anterior pituitary gland **Release inhibited by:** Negative feedback loop, elevated T3/T4 inhibit production of TSH **Metabolism:** as sulphate and glucuronide form in the bile, urinary excretion **Hypersecretion:** Hyperthyroidism **Hyposecretion:** Hypothyroidism

Answer 128

**Production:** Thyroid follicular cells, liver, kidney, CNS, pituitary, brown adipose tissue, heart vessel, synthesised from thyroxine **Secretion:** From site of production **Site of action:** Thyroid hormone receptors (nuclear receptors) on nearly every cell in the body **Effects:** Increased metabolism - increased MV due to increased CO2 production, increased HR, increased inotropy, increased CO, decreased SVR and DBP, increased CNS excitability, increased osteoblastic activity, impotence/oligomenorrhoea, increased GIT motility, increased BMR **Release stimulated by:** TSH from the anterior pituitary gland **Release inhibited by:** Negative feedback loop, elevated T3/T4 inhibit production of TSH **Metabolism:** as sulphate form in bile, glucuronide form in bile or urinary exretion **Hypersecretion:** Hyperthyroidism **Hyposecretion:** Hypothyroidism

Answer 129

**Production:** Anterior pituitary **Secretion:** Anterior pituitary **Site of action:** Thyroid **Effects:** Stimulates follicular activity and the synthesis and release of thyroid hormones (T3 and T4). **Release stimulated by:** TRH **Release inhibited by:** Somatostatin, thyroid hormones **Hypersecretion:** Secondary hyperthyroidism **Hyposecretion:** Secondary hypothyroidism

Answer 130

* Polypeptides e.g. ADH, oxytocin, ACTH, PTH, FSH-RH, LH-RH, ACTH-RH, TRH, calcitonin, insulin, glucagon, somatostatin * Glycoproteins e.g. FSH, LH, TSH * Steroids e.g. aldosterone, corticosteroids, androgens * Amines e.g. dopamine, adrenaline, noradrenaline, thyroxine, tri-iodothyronine * Fatty acid derivatives e.g. prostaglandins, vitamin D

Answer 131

* Type I - Immediate/Anaphylctic — IgE mediated — mast cells, basophils * Type II - antibody dependent — cytotoxic — IgM, IgG + surface antigen — e.g. transfusion reactions, HIT-2 * Type III - immune-complex mediated — antigen + IgM/IgG form complex —> activate complement pathway — e.g. RA/SLE * Type IV - delayed — antigen + T cell —> macrophage activation — e.g. contact dermatitis, Tuberculin test

Answer 132

* Hypoxic hypoxia —> low PaO2 and PvO2 — decreased FiO2 — decreased MV — diffusion defect — VQ mismatch * Anaemic hypoxia —> normal PaO2, low PvO2 — low Hb — decreased ability of Hb to carry O2 (eg. CO) * Stagnant hypoxia —> normal PaO2 and PvO2 — decreased tissue or organ perfusion * Histotoxic hypoxia —> normal PaO2, increased PvO2 — tissues unable to utilise O2

Answer 133

* Skeletal muscle - striated, sarcoplasmic reticulum present, t-tubules — Type I - slow oxidative — Type IIa - fast oxidative — Type IIb - fast glycolytic Troponin binds to calcium. Nerve impulse initiates contraction. No gap junctions. * Cardiac - striated, moderately developed SR present, t-tubules Troponin binds to calcium. Pacemaker cels initiate contraction. Gap junctions present - intercalated discs. * Smooth muscle - not striated, poorly developed SR, no t-tubules Calcium binds to calmodulin Pacemaker potential. Gap junctions.

Answer 134

SENSORY and MOTOR * A - alpha: motor - large, heavily myelinated, fast * A - beta: touch/pressure - medium, heavily myelinated, moderately fast * A - gamma: intrafusal fibres - medium, heavily myelinated, moderately fast * A - delta: touch/pressure/temperature/fast pain - small, heavily myelinated, moderately fast * B: preganglionic autonomic nerves, small, lightly myelinated, moderately fast * C: slow pain, postganglionic autonomic nerves, olfaction - small, unmyelinated, slow SENSORY ONLY * Ia: muscle spindle afferents - large myelinated, fast * Ib: Golgi tendon organ afferents - large myelinated, fast * II: secondary afferents of muscle spindles: touch/pressure - medium, myelinated, moderate * III: touch/pressure/fast pain/temperature - small, myelinated, moderate * IV: pain/temperature/olfaction - small, unmyelinated, slow

Answer 135

* Ligand gated ion channel receptor - integral membrane proteins that contain a pore which allows the regulated flow of selected ions across the plasma membrane - bind neurotransmitters and open in response to ligand binding * G-protein coupled receptor - integral membrane proteins that are activated, creating a conformational change in the receptor leading to activation of a G protein * Tyrosine kinase linked receptor - cell surface receptors that when bound, phosphorylate and propogate a signal through the plasma membrane. * Intracellular nuclear receptors - once bound, undergo conformational change which triggers a cascade of events that direct the receptor to DNA transcription regulation sites, resulting in up or down regulation of gene expression

Answer 136

Pre-Renal — urine osmolality >500mOsm/kg (normal) —— high = serum osmolality = 100 — low urinary sodium — high urine/plasma urea and creatinine — high specific gravity — hyaline casts Renal — low urine osmolality <350 — high urinary sodium — low urine/plasma urea and creatinine — fixed/normal specific gravity — brown sediment, granular casts Post-renal (late) — low urine osmolality <350 — high urinary sodium — low urine/plasma urea and creatinine — low specific gravity — bland sediment

Answer 137

There are four mechanisms which result in variable response to a drug: * Alteration in drug that reaches the receptor - typically due to pharmacokinetic factors * Relative difference in presence of exogenous and endogenous ligands * Variation in receptor function and number * Alteration in function distal to the receptor Physiological * age - liver function, GFR, Vd * gender * pregnancy * tobacco * ETOH Pharmacological * idiosyncratic - individual patient response to a drug - typically mediated by a reactive metabolite rather than the drug itself * pharmacogenetic * tachyphylaxis - rapid decrease in response to repeated dosing over a short time period, usually due to depletion of transmitter * up/down regulation of receptors * Densistisation - loss of response over a long period of time, usually due to change in receptor morphology or loss in receptor numbers * tolerance - requirement for a larger dose to achieve the same effect - due to altered sensitivity of the receptors to the stimulant *-- pharmacokinetic - altered drug metabolism (increased or decreased) -- pharmacodynamic - change in receptor morphology, receptor down-regulation, receptor up-regulation, exhaustion of mediators, physiological adaptation, active removal of the drug from the cell* * drug interactions -- *synergistic -- additive -- antagonistic* Pharmacokinetic * factors affecting absorption -- *food, PPIs altering gastric pH, gut microbiome, CO and blood flow to site of injection (central vs peripheral, SC vs IV), rate of administration* * factors affecting distribution -- *protein metabolism, fluid balance* * factors affecting metabolism -- *metabolising organ function, metabolising organ blood flow, factors affecting chemical reaction rate (e.g. body temperature, pH)* * factors affecting clearance -- *clearance organ function, clearance organ blood flow* Pathological * liver function * renal impairment * cardiac disease - CO * obesity * neurological e.g. myaesthenia, myopathy, autonomic neuropathy

Answer 138

* Causes of laryngeal nerve damage -- malignant - thyroid, lung -- vascular - aortic aneurysm -- cervical lymphadenopathy/infective -- iatrogenic - surgery, ETT -- traumatic - neck or chest -- neurological - MG, CMT, MS -- congenital - hydrocephalus, TOF Partial RLN damage: Cords are held in midline position as abductors are more affected than adductors * Unilateral palsy - hoarse voice * Bilateral palsy - complete airway obstruction Complete RLN damage: Cords are held midway between midline and abducted position * Unilateral - stridor * Bilateral - loss of voice and aspiration Superior laryngeal nerve damage * weak voice because of slack vocal cords

Answer 139

Afferents * GI tract - mechano and chemoreceptors vis the vagus nerve to the NTS in the brain stem (involving cholinergic, 5HT3, dopamine and NK1 receptors) * CTZ - area postrema in the floor of the 4th ventricle, outside BBB - responsible for detecting toxins in blood and CSF (5HT3), also the nausea associated with sleep deprivation * Vestibular system - especially motion sickness (H1 and H2) * CVS - afferents mainly from the baroreceptors * Higher centres - sights, sounds, smells, unpleasant thoughts * Pharyngeal afferents * Auricular branch of the vagus nerve * Visceral pain Vomiting Centre * not an anatomical entity * several nuclei in the brain stem responsible for coordinating the efferent limb of the vomiting reflex — nucleus tractus solitaries — dorsal vagal nuclei — reticular formation — respiratory neural networks * receives input from the afferent limbs of the reflex

Answer 140

Drug properties - % plasma protein binding - % tissue protein binding - molecule size - molecule charge - pKa - lipid/water partition coefficient (aka lipid solubility) Patient factors - blood flow to the various tissues - age - gender - body muscle/fat proportion - level of hydration - water distribution (oedema, effusions, ascites, pregnancy) - extracorporeal sites of distribution (circuit, filters, oxygenator etc)

Answer 141

- age (increased in children) - gender (higher in men than men) - body surface area - stress - catecholamines - increased temperature - hyperthyroidism - muscle activity - pregnancy/breast feeding

Answer 142

* Reflex contraction of vascular smooth muscle in the pulmonary circulation in response to a low partial pressure of oxygen * Aims to divert blood flow away from hypoxic areas of the lungs to areas with better ventilation and oxygenation * Increases PVR and PAP - can precipitate right heart failure Stimulus = tissue partial pressure of oxygent in the region of the pulmonary arteriole (determined by ppO2 in alveolus or in mixed venous blood Biological oxygen sensing theories - direct modulation of K channels - changes to cytoplasmic redox state - mitochrondria reactive oxygen species production - cellular energy state e.g. concentrations of high-energy compounds - alteration of membrane-bound protein function - activation of transcription enzymes via hypoxia inducible factor - alterations of cyclo-oxygenase or lipoxygenase systems Site of action = pulmonary arterial smooth muscle cells (PASMCs) PASMC contraction --> narrowing of vessels --> reduced blood flow - membrane depolarization after sodium ion influx - leads to increase in cytosolic calcium ion concentration - increase in Ca ions binding to calmodulin, activiating myosin light chain kinase - alteration in shape of myosin results in contraction of the smooth muscle Modulation = localised mediators produced by pulmonary endothelial cells in the presence of hypoxia - NO - smooth muscle relaxation caused by reducing intracellular calcium - prostacyclin - vasodilator - stimulates cyclic adneylate cyclase and increases cAMP - endothelin-1 - small peptide paracrine mediator with potent vasoconstrictor properties - acts via G protein receptors

Answer 143

Signs suggestive of insulinoma 1. Signs and symptoms of hypoglycaemia 2. Low plasma glucose level 3. Resolution of symptoms once glucose level raised

Answer 144

Psychosocial risk factors for chronicity and disability * Belief that pain is potentially severely disabling * Fear avoidance behaviour * Low mood and social withdrawal * Expectation of passive treatment rather than belief that active participation can help STARTback tool --> risk of developing chronic pain * Attitudes * Beliefs e.g. catastrophising * Compensation * Diagnosis * Emotions e.g. depression/anxiety * Family e.g. overbearing/undersupportive * Work (relationship with)