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Pass FRCEM primary in 7 days 1 st edition

  1. 1. 1ST EDITION, 2018 WITHOUT PATHOLOGY
  2. 2. Dear colleagues , IT IS MY PLEASURE TO PRESENT THIS NOTEBOOK FOR ALL DOCROR WHO STUDY OR WILLIN TO STUDY FRCEM PRIMARY ALL OVER THE WORLD THIS NOTES TAKE AT LEAST ONE WEEK TO REVIEW BEFORE THE DATE OF EXAM AFTER YOU FINISHING STUDING WELL AT LEAST 2 MONTHS I HOPE IT WILL BE USEFUL AND ALL DOCTORS PASS EXAM AND GET HIGH SCORE WITH MY BEST WISHES, YOUR COLLEAGUE ABD ELAAL ELBAHNASY EMERGENCY PHYSCIAN MINISTRY OF HEALTH EGYPT EMAIL : ER_REDSEA@YAHOO.COM FACEBOOK: ELBHNASY
  3. 3. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT GIT  The following table summarizes the cell types found in the stomach and shows the substance each cell type secretes and the function of the secretion: Cell type Substance secreted Function of secretion Parietal cells Hydrochloric acid Kills microbes and activates pepsinogen Parietal cells Intrinsic factor Binds to vitamin B12 and facilitates it’s absorption Chief cells Pepsinogen Protein digestion Chief cells Gastric lipase Fat digestion G-cells Gastrin Stimulates gastric acid secretion Enterochromaffin-like cells (ECL cells) Histamine Stimulates gastric acid secretion Mucous-neck cells Mucous and bicarbonate Protects stomach epithelium from acid D-cells Somatostatin Inhibits gastric acid secretion  The gastric parietal cells secrete hydrochloric acid in response to the following three stimuli:  Histamine stimulating H2 histamine receptors (most significant contribution)  Acetylcholine via parasympathetic activity stimulating M3 receptors  Gastrin stimulating CCK2 receptors  The main actions of gastrin are as follows:  Stimulation of gastric parietal cells to secrete hydrochloric acid  Stimulation of ECL cells to release histamine  Stimulation of gastric parietal cell maturation and fundal growth  Causes gastric chief cells to secrete pepsinogen  Increases antral muscle mobility and promotes stomach contractions  Increases the rate of gastric emptying  Induces pancreatic secretions  Induces emptying of the gallbladder
  4. 4. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT  The following table summarises the factors that situmlate and inhibit the release of gastrin: Stimulate the release of gastrin Inhibit the release of gastrin Distension of the gastic antrum Vagal stimulation Presence of partially digested proteins in the stomach (most notably amino acids) Hypercalcaemia (via calcium-sensing receptors) The presence of acid (primarily HCl) Somatastatin Secretin Gastroinhibitory peptide (GIP) Vasoactive intestinal peptide (VIP) Glucagon Calcitonin Other functions of secretin include:  Increase bicarbonate production  Enhances the effects of cholecystokinin  Stimulates insulin release from pancreas following ingestion of glucose  Stimulates pepsinogen release from the pancreas  Stimulates glucagon release  Stimulates pepsin release  Stimulates pancreatic polypeptide release  Stimulates somatostatin release
  5. 5. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT Respiratory  Surfactant in addition to reducing surface tension pulmonary surfactant is also important for:  Maintaining structural integrity and alveolar size  Increasing pulmonary compliance  Preventing atelectasis  Keeping the alveoli dry  Contributing to innate immunity  The dead space can be further classified into: 1. Anatomical dead space: The portion of the airways that conducts gas to the alveoli. No gas exchange is possible in these spaces. 2. Alveolar dead space: The sum of the volumes of those alveoli that have little or no blood flowing through their adjacent capillaries i.e the alveoli that are ventilated but not perfused. This is negligible in healthy people but can increase considerably in individuals with lung disease that causes ventilation-perfusion mismatch. 3. Physiological dead space: the sum of the anatomical and alveolar dead spaces. The physiological dead space can account for up to 30% of the tidal volume. The anatomical dead space can be measured by nitrogen washout test (Fowler’s method). The physiological dead space can be measured by the Bohr equation  Respiratory failure The tidal volume (TV) is the volume of air drawn in and out of the lungs during normal breathing. The usual volume in a healthy male is 0.5 L. The vital capacity (VC) is the maximum volume of air that can be breathed out following a maximal inspiration. The usual volume in a healthy male is 4.5 L. The residual volume (RV) is the volume of air in the lungs after a maximum expiration. The usual volume in a healthy male is 1.0 L. The inspiratory reserve volume (IRV) is the maximum volume of air that can be breathed in at the end of a normal tidal inspiration. The usual volume in a healthy male is 3.0 L.
  6. 6. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT The expiratory reserve volume (ERV) is the maximum volume of air that can be breathed out at the end of a normal tidal expiration. The usual volume in a healthy male is 1.0 L. Total lung capacity (TLC) is the volume of air in the lungs at the end of a maximal inspiration. TLC = RV+VC. The usual volume in a healthy male is 5.5 L. Functional residual capacity (FRC) is the volume of air present in the lungs at the end of a normal expiration. FRC = ERV + RV. The usual volume in a healthy male is 2.0 L. Type I respiratory failure occurs when there is a problem with oxygenation resulting in hypoxaemia. This is most commonly caused by ventilation/perfusion mismatch resulting in reduced diffusion of oxygen from the alveoli into the pulmonary circulation. Type I respiratory failure is characterized by:  Reduced PaO2 (< 8.0 kPa or 60 mmHg)  Normal or reduced PaCO2 (< 6.7 kPa or 50 mmHg) Type II respiratory failure occurs when there occurs when there is inadequate alveolar ventilation resulting in hypoxaemia and hypercapnia. Type II respiratory failure is characterized by:  Reduced PaO2 (< 8.0 kPa or 60 mmHg)  Elevated PaCO2 (> 6.7 kPa or 50 mmHg)  Reduced pH (< 7.35) Type II respiratory failure can be further sub-classified depending on the pre-existing condition of the patient and the speed of onset:  Acute type II respiratory failure: the patient will have no, or minor, evidence of pre- existing respiratory disease and patients typically have a high PaCO2, low pH, and normal bicarbonate  Chronic type II respiratory failure: evidence of chronic respiratory disease, high PaCO2, normal pH, and high bicarbonate (> 26 mmol/l). Acute-on-chronic type II respiratory failure: an acute deterioration in an individual with significant pre-existing type II respiratory failure, high PaCO2, low pH, and high bicarbonate (> 26 mmol/l). Types of obstructive lung disorders include:  Chronic obstructive pulmonary disease (COPD)  Asthma  Bronchiectasis
  7. 7. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT  The following table outlines the affects of obstructive lung disease on the various lung volumes and capacities: Increased in obstructive lung disease Decreased in obstructive lung disease Total lung capacity (TLC) Residual volume (RV) Functional residual capacity (FRC) Residual volume/total lung capacity (RV/TLC) ratio Vital capacity (VC) Inspiratory capacity (IC) Inspiratory reserve volume (IRV) Expiratory reserve volume (ERV) Obstructive lung disorders are characterised by airway obstruction. Many obstructive diseases of the lung result from narrowing of the smaller bronchi and larger bronchioles, often because of excessive contraction of the smooth muscle itself. In obstructive lung disorders the FEV1 is generally reduced and the FEV1/FVC ratio is less than 0.7. Types of obstructive lung disorders include:  Chronic obstructive pulmonary disease (COPD)  Asthma  Bronchiectasis Restrictive lung disorders are characterised by restricted lung expansion. They result in a decreased lung volume, increased work of breathing, and inadequate ventilation and/or oxygenation. In restrictive lung disorders there is a reduction in the FVC and the FEV1. The decline in the FVC is greater than that of the FEV1, resulting in preservation of the FEV1/FVC ratio (> 80%). Types of restrictive lung disorders include:  Pulmonary fibrosis  Sarcoidosis  Pulmonary oedema  Adult respiratory distress syndrome (ARDS)  Neuromuscular diseases e.g. muscular dystrophy  Anatomical e.g. obesity, scoliosis  The functional residual capacity (FRC)
  8. 8. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT the volume of air present in the lungs at the end of a normal expiration. The usual volume in a healthy male is 2.0 L. At FRC, the opposing elastic recoil forces of the lungs and chest wall are in equilibrium and there is no exertion by the diaphragm or other respiratory muscles. The FRC is the sum of the expiratory reserve volume (ERV) and the residual volume (RV): FRC = ERV + RV The FRC cannot be estimated by spirometry as it includes the residual volume. In order to measure the RV precisely one of the following methods is needed:  Nitrogen washout (Fowler’s method)  Helium dilution technique  Body plethysmography The FRC is increased by the following:  Marked airway obstruction (e.g. severe asthma and COPD)  Loss of elastic recoil (e.g. advanced age and emphysema)  Standing in prone position The FRC is reduced by the following:  Abnormally stiff, non-compliant lungs (e.g. restrictive lung disorders such as pulmonary fibrosis)  Bilateral paralysis of the diaphragm  Lying in the supine position  Induction of anaesthesia (FRC falls by 15-20%)
  9. 9. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT  The following table summarises the normal respiratory changes in seen in pregnancy: Parameter Changes Respiratory Rate Unchanged Tidal Volume Increased Minute Ventilation Increased Functional Residual Capacity Decreased PaO2 Increased PaCO2 Decreased (Respiratory Alkalosis) HCO3 - Decreased (Metabolic Acidosis) Types of restrictive lung disorders include:  Pulmonary fibrosis  Sarcoidosis  Pulmonary oedema  Adult respiratory distress syndrome (ARDS)  Neuromuscular diseases e.g. muscular dystrophy  Anatomical e.g. obesity, scoliosis In restrictive lung disorders there is a reduction in the forced vital capacity (FVC) and the forced expiratory volume in one second (FEV1). The decline in the FVC is greater than that of the FEV1, resulting in preservation of the FEV1/FVC ratio (> 80%). In restrictive lung disorders the following lung volumes and capacities are reduced:  Vital capacity (VC)  Total lung capacity (TLC)  Inspiratory capacity (IC)  Residual volume (RV)  Functional residual capacity (FRC) A ventilation defect of the alveoli is seen in atelectasis due to cystic fibrosis. The alveoli are perfused, but there is impaired oxygen delivery to them, and intrapulmonary shunting of blood will be present in the collapsed segment.
  10. 10. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT Pulmonary capillary blood will have similar PO2 and PCO2, as there is no exchange of gas at the capillary-alveolar interface of the collapsed segments. Atelectasis is an example of a ventilation defect (not a perfusion defect). Perfusion defects produce pathological dead space in which the lung alveoli are ventilated adequately, but are not perfused, and there is no gas exchange.  The oxygen dissociation curve is a graph that plots the proportion of haemoglobin in its oxygen-laden saturated form on the vertical axis against the partial pressure of oxygen on the horizontal axis. The curve is a valuable aid in understanding how the blood carries and releases oxygen. At high partial pressures of oxygen, haemoglobin binds to oxygen to form oxyhaemoglobin. All of the red blood cells are in the form of oxyhaemoglobin when the blood is fully saturated with oxygen. Each gram of haemoglobin can combine with 1.34 mL of oxygen At low partial pressures of oxygen (e.g. within tissues that are deprived of oxygen), oxyhaemoglobin releases the oxygen to form haemoglobin. The oxygen dissociation curve has a sigmoid shape because of the co-operative binding of oxygen to the 4 polypeptide chains. Co-operative binding means that haemoglobin has a greater ability to bind oxygen after a subunit has already bound oxygen. Haemoglobin is therefore most attracted to oxygen when 3 of the 4 polypeptide chains are bound to oxygen. There is often a P50 value expressed on the curve, which is the value that tells us the partial pressure of oxygen at which haemoglobin is 50% saturated with oxygen. At an oxygen saturation of 50% the PaO2 is approximately 25 mmHg (3.5k Pa).  A table summarizing these effects is shown below: Factor Decrease Increase pH Right shift Left shift CO2 Left shift Right shift Temperature Left shift Right shift 2,3-DPG Left shift Right shift
  11. 11. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT  The compliance of the respiratory system is analogous to the capacitance in the cardiovascular system. It is defined as the change in volume for a given change in pressure {C = ∆ V/∆P}. Compliance is inversely related to elastance and stiffness, and is charted as a slope of the pressure volume curve. It is comprised of static (no air flow) and dynamic (during continuous breathing) components. The static compliance is dependent on factors such as age, size and sex of the person, whereas the dynamic lung compliance is dependent on the airway resistance, which is depicted by the area of the curve.
  12. 12. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT Renal ANP is a peptide hormone released from cardiac myocytes in response to stretching of the atria. ANP plays a key role in regulating fluid volume and sodium/potassium homeostasis by a number of mechanisms with the ultimate aim of increasing fluid losses. ANP acts to:  Vasodilate afferent arterioles and vasoconstrict efferent arterioles in the glomerulus, which increases renal blood flow and glomerular filtration  Inhibit aldosterone secretion from adrenal glands  Inhibits renin secretion from juxtaglomerular cells  Inhibits sodium resorption at the collecting duct  Inhibits the release of ADH  Inhibits the action of ADH at the collecting duct  Cause systemic vasodilatation The kidneys receive 20-25% of the cardiac output. This equates to 1-1.2 L per minute. Weight for weight this is approximately six times what the brain receives and five times what the heart receives. Organ % of cardiac output Liver 28% Kidneys 22% Skeletal muscle 16% Brain 14% Skin 9% Heart 5% Rest of body 6% Blood flow is not evenly distributed throughout the kidney. The metabolically active medulla receives 10% of renal blood flow while the less active cortex receives 90%. This counter- intuitive arrangement of blood flow, inversely proportionate to metabolic demand, provides the high hydrostatic pressures needed to maintain filtration at the glomerulus. 125 ml of plasma is filtered per minute at the glomerulus. This equates to 180 L of plasma filtered per day. Considering urine output is typically 1-2 L per day, it becomes apparent how significant resorption along the nephron is.  The juxtaglomerular apparatus (JGA) is located in the renal cortex, where the distal convoluted tubule (DCT) lies next to the afferent and efferent arterioles of it's own glomerulus.
  13. 13. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT The JGA consists of: 1. Macula densa cells – tall, densely clustered epithelial cells of the DCT 2. Juxtaglomerular cells – smooth muscle fibres in the walls of the afferent arteriole which synthesise and release renin 3. Extraglomerular mesangial cells – the function of which is unclear but is proposed to be structural The anatomical structure of the JGA facilitates a feedback loop (tubuloglomerular feedback) between the glomerulus at the start of the nephron and the DCT near the end of the nephron. Changes in tubular fluid composition at the DCT result in adjustments to glomerular blood flow to regulate glomerular filtration rate (GFR). This is intrinsic auto-regulation. The macula densa can be considered a sensor; monitoring the sodium content of tubular fluid arriving at the DCT. High sodium levels are taken to reflect a high GFR (increased flow rates mean reduced time for absorption in the preceding tubule). The response is vasoconstriction of the afferent arterioles to reduce renal blood flow and GFR. The underlying mechanism is not known but it is proposed that increased sodium at the DCT results in greater uptake by the macula densa cells, which is followed by water through osmosis. The resultant swelling of the cells causes an ATP leak, ATP is converted to adenosine, and adenosine binds to receptors on the afferent arteriole causing vasoconstriction and decreased GFR. Conversely low sodium levels at the macula densa triggers a signalling cascade that ultimately results in increased PGE2, which acts on juxtaglomerular cells to trigger renin release and activate the renin-angiotensin-aldosterone pathway Fluid entering the loop of Henle has an osmolality of approximately 300 mOsm, and the main solute is sodium. The thin descending loop is permeable to water but has no solute transporters. As the loop descends into the medulla, the peritubular fluid is increasingly concentrated, so water leaves the tubule by osmosis. The tubular fluid equalises to the osmolality of the peritubular fluid, to a maximum of approximately 1200 mOsm in a long medullary loop of Henle and 600 mOsm in a short cortical loop of Henle. The thin ascending limb allows passive movement of sodium, chloride and urea down their concentration gradients, so urea enters the tubule and sodium and chloride leave. The thick ascending limb is impermeable to water but actively transports sodium, potassium and chloride out of the tubular fluid. The osmolality of the tubular fluid falls compared to the surrounding peritubular fluid. Water cannot follow by osmosis because this limb is impermeable. The result is that tubular fluid leaving the loop of Henle has an osmolality of approximately 100 mOsm, lower than that of the fluid entering the loop, and the main solute is now urea.
  14. 14. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT  Renin is an enzyme that plays an important role in the renin-angiotensin-aldosterone system (RAAS). Through this it helps to regulate the mean arterial blood pressure. It is released from juxtaglomerular cells that are situated in the afferent arterioles of the kidney in response to the following stimuli:
  15. 15. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT  Decreased arterial blood pressure (reduced renal perfusion)  Decreased sodium load delivered to the distal tubule of the kidney  Sympathetic nervous system stimulation The main action of renin is to cleave the peptide bond between the leucine and valine residues on angiotensinogen, converting it to angiotensin I. This activates the RAAS and eventually causes an increase in mean arterial blood pressure and restoration of renal perfusion. Angiotensin I is converted to angiotensin II by the removal of two C-terminal residues by the enzyme angiotensin-converting enzyme (ACE). This primarily occurs in the lungs, although it does also occur to a lesser degree in endothelial cells and renal epithelial cells. Angiotensin I is converted to angiotensin II by the removal of two C-terminal residues by the enzyme angiotensin-converting enzyme (ACE). This primarily occurs in the lungs, although it does also occur to a lesser degree in endothelial cells and renal epithelial cells. Angiotensin II will therefore have the following effects on renal measurements:  Decreased renal plasma flow  Increased filtration fraction  Increased glomerular filtration rate  Aldosterone is a steroid hormone produced in the zona glomerulosa of the adrenal cortex. It is the main mineralocorticoid hormone and plays a central role in the regulation of blood pressure. Aldosterone is released in response to:  Increased angiotensin II levels  Increased potassium levels  Increased ACTH levels The main actions of angiotensin II are:  Vasoconstriction of vascular smooth muscle (resulting in increased blood pressure)  Vasoconstriction of the efferent arteriole of the glomerulus (resulting in an increased filtration fraction and preserved glomerular filtration rate)  Stimulation of aldosterone release from the zona glomerulosa of the adrenal cortex  Stimulation of anti-diuretic hormone (vasopressin) release from the posterior pituitary  Stimulation of thirst via the hypothalamus  Acts on the Na+/H+ exchanger in the proximal tubule of the kidney to stimulate Na+ reabsorption and H+ excretion
  16. 16. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT  Lactic acidosis is defined as a pH <7.35 and a lactate >5 mmol/L. It is a common finding in critically ill patients and is often associated with other serious underlying pathologies. There are major adverse consequences of severe acidaemia, which affect all body systems, and there is an associated increased mortality in critically ill patients with a raised lactate. The mortality associated with lactic acidosis despite full supportive treatment remains at 60-90%. Acquired lactic acidosis is classified into two subtypes:  Type A is due to tissue hypoxia  Type B is due to non-hypoxic processes affecting the production and elimination of lactate Patients with type A lactic acidosis are generally hypotensive, not hypertensive. The anion gap is raised in lactic acidosis. The normal range for the anion gap is 8-16 mmol/L. There is generally a large base deficit (> - 5 mmol/L). Some causes of type A and type B lactic acidosis are shown below: Type A lactic acidosis Type B lactic acidosis Shock (including septic shock) Left ventricular failure Severe anaemia Asphyxia Cardiac arrest CO poisoning Respiratory failure Severe asthma and COPD Regional hypoperfusion Renal failure Liver failure Sepsis (non-hypoxic sepsis) Thiamine deficiency Alcoholic ketoacidosis Diabetic ketoacidosis Cyanide poisoning Methanol poisoning Biguanide poisoning The main actions of aldosterone are:  Reabsorption of Na+ from the distal convoluted tubule  Reabsorption of water from the distal convoluted tubule (follows Na+ )  Reabsorption of Cl– from the distal convoluted tubule  Secretion of K+ into the distal convoluted tubule  Secretion of H+ into the distal convoluted tubule
  17. 17. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT The mean values for GFR in healthy young adults are 130ml/min/1.73m2 (men) and 120ml/min/1.73m2 (women). The GFR declines with age after the age of 40 at a rate of approximately 1 ml/min/year.  The following table summarises some common causes of the various different acid-base disorders: Acid-base disorder Causes Respiratory alkalosis Hyperventilation (e.g. anxiety) Pulmonary embolism CNS disorders (e.g. CVA, SAH, encephalitis) Altitude Pregnancy Early stages of aspirin overdose Respiratory acidosis COPD Life-threatening asthma Pulmonary oedema Sedative drug overdose (e.g. opiates, benzodiazepines) Neuromuscular disease Obesity Metabolic alkalosis Vomiting Potassium depletion (e.g. diuretic usage) Cushing’s syndrome Conn’s syndrome Metabolic acidosis (with raised anion gap) Lactic acidosis (e.g. hypoxaemia, shock, sepsis, infarction) Ketoacidosis (e.g. diabetes, starvation, alcohol excess) Renal failure Poisoning (e.g. late stages of aspirin overdose, methanol, ethylene glycol) Metabolic acidosis (with normal anion gap) Renal tubular acidosis Diarrhoea Ammonium chloride ingestion Adrenal insufficiency  the nephron have different morphologies, reflecting the differences in their function. The proximal convoluted tubule is where the majority of solute resorption occurs and this resorption is driven by ATP-dependant transporters. Cells are cuboidal with abundant mitochondria to provide energy and multiple microvilli (a brush border) to increase surface area.
  18. 18. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT The descending loop of Henle has flat cells with few microvilli and few mitochondria, reflecting that in this segment there is the movement of water by osmosis and no solute transport. The ascending thick loop of Henle has cuboidal cells which are impermeable to water and contain plentiful mitochondria providing energy to Na.K.2Cl transporters. These measures contribute to the formation of the medullary concentration gradient and countercurrent multiplication. The distal convoluted tubule allows variable resorption and secretion to fine-control urine composition. Mitochondria provide energy for membrane transporters. There are few microvilli. The collecting duct allows the final adjustments in urine concentration. The upper collecting duct is lined by columnar epithelium, which transitions into urothelium in the lower duct. Aquaporin channels are present in the cell membranes to allow the transcellular movement of water. The number of aquaporin channels is controlled by ADH.  Erythropoietin is a glycoprotein hormone that is responsible for the control of erythropoiesis (red cell production). It is produced by interstitial fibroblasts in the kidney and also in perisinusoidal cells in the liver. Hypoxia stimulates the production and secretion of erythropoietin in the kidney. Erythropoietin has two main effects on red blood cells: 1. It stimulates stem cells in the bone marrow to increase the production of red blood cells 2. It targets red blood cell progenitors and precursors in the bone marrow and protects them from apoptosis The resultant increase in red cell mass results in increased oxygen carrying capacity and increased oxygen delivery. The mechanisms of sodium resorption and excretion by the nephron are complex, with numerous transporters and channels involved, influenced by hormonal regulatory mechanisms and the osmolality of plasma, tubular and peritubular fluids. In general sodium resorption is driven by electrochemical gradients established by ATP-ase pumps. The movement of Na is often used to co-transport other solutes and provides the main osmotic drive for the passive movement of water in the tubules. As a basic overview:  Sodium is freely filtered at the glomerulus so the ultrafiltrate is isotonic with the plasma.  65% of filtered sodium is resorbed at the proximal convoluted tubule.
  19. 19. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT  Na.K.ATP-ase pumps on the basolateral membrane set up a chemical gradient (primary active transport). This gradient then drives sodium resorption from the lumen by Na.Solute symporters and Na.H anti-porters.  A further 20% of filtered sodium is resorbed at the Loop of Henle, mainly by the Na.K.2Cl (triple) transporter on the ascending limb. This is also driven by ATP-ase and is an example of primary transport.  A further 5-10% of filtered sodium is resorbed at the distal convoluted tubule. Again a basolateral Na.K.ATP-ase pump sets up a chemical gradient, driving a Na.Cl symporter on the luminal membrane.  Sodium transport in the collecting duct is via an epithelial sodium channel (ENaC). Resorption through the channel is driven by a chemical gradient established by a Na.K.ATP-ase transporter on the basolateral membrane.  Aldosterone is a steroid hormone that enters the cells of the collecting duct and binds to cytoplasmic receptors to stimulate the transcription of mRNA encoding ENaC and Na.K transporters, thus increasing sodium resorption at this site.  Sodium transporters in the Loop of Henle and distal convoluted tubule are load dependent – i.e. the more sodium in the plasma, the higher the transport rate (until maximum rate of transport or Tmax is reached). This is an example of positive feedback.  In the Loop of Henle, load-dependent sodium transport contributes to establishing the medullary concentration gradient in the peritubular fluid; tubular fluid arriving at the ascending limb is highly concentrated so large amounts of sodium are actively transported out of the tubule.  As tubular fluid ascends the limb it becomes less concentrated and less sodium transport out of the tubule occurs.  Causes of hypokalaemia include:  Inadequate dietary intake  Gastrointestinal loss e.g. diarrhoea  Drugs e.g. diuretics and insulin  Alkalosis  Hypomagnesaemia  Renal artery stenosis  Renal tubular acidosis (types 1 and 2)  Conn’s syndrome  Bartter’s syndrome  Gitelman’s syndrome  Hypokalaemic periodic paralysis  Excessive liquorice ingestion Bartter’s syndrome is a rare inherited defect in the ascending limb of the loop of Henle. It is characterized by a hypokalaemic alkalosis with normal to low blood pressure. Type 1 and 2 renal tubular acidosis both cause hypokalaemia whereas type 4 renal tubular acidosis causes hyperkalaemia.
  20. 20. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT Gitelman’s syndrome is a rare inherited defect of the distal convoluted tubule of the kidney. It causes a metabolic alkalosis with hypokalaemia and hypomagnesaemia. Excessive liquorice ingestion can cause hypermineralocorticoidism and result in hypokalaemia.  The filtration fraction (FF) is the percentage of the plasma (not blood) delivered to the glomerulus that is filtered through the glomerulus to become ultrafiltrate. In health 15-20% of plasma is filtered to become ultrafiltrate (i.e. FF = 15-20%). FF = GFR / RPF Where:  GFR is the glomerular filtration rate (ml/min) i.e. the amount of ultrafiltrate produced per minute.  RPF is the renal plasma flow (ml/min) i.e. the volume of plasma passing through the glomerulus per minute RPF is subtly different to renal blood flow (RBF), which is the volume of blood flowing through the glomerulus per minute. RPF = RBF x (1-Haematocrit). Afferent arteriole constriction decreases RBF and RPF, and thus decreases the pressure across the glomerulus and GFR. However as both RPF and GFR decrease equally, FF remains constant. Efferent arteriole constriction doesn't affect RBF or RPF but increases the pressure across the glomerulus to increase GFR. As RPF remains steady but GFR increases, FF increases. Decreased plasma protein (e.g. hypoalbuminaemia) has no impact on RPF but decreases the oncotic pressure in glomerular vessels so GFR increases. As RPF remains steady but GFR increases, FF increases.  1,25-dihydroxycholecalciferol (also known as calcitriol) is the hormonally active metabolite of vitamin D. Its actions increase the plasma concentration of calcium and phosphate. The main actions of 1,25-dihydroxycholecalciferol are:  Increases calcium and phosphate absorption in the small intestine  Increases renal calcium reabsorption  Increases renal phosphate reabsorption
  21. 21. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT  Increases osteoclastic activity (increasing calcium and phosphate resorption from bone)  Inhibits 1-alpha-hydroxylase activity in the kidneys (negative feedback  The anion gap represents the concentration of all the unmeasured anions in the plasma. It is the difference between the primary measured cations and the primary measured anions in the serum. It can be calculated using the following formula: Anion gap = [Na+] – [Cl-] – [HCO3-] The reference range varies depending upon which methodology is used to make the measurement but is usually 8 to 16 mmol/L. Generally speaking the value of K+ is low relative to other three ions and has little effect on the equation. An alternative formula, which includes K+ is sometimes used, particularly by Nephrologists. In Renal units the K+ covers a wider range and therefore has a greater effect on the measured anion gap. In these circumstances an alternative formula is used: Anion gap = [Na+] + [K+] – [Cl-] – [HCO3-] A high anion gap metabolic acidosis usually occurs as a consequence of the accumulation of organic acid or the impaired excretion of H+ ions. The mnemonic CAT MUDPILES is a useful way of remembering the causes of a high anion gap metabolic acidosis:  Carbon monoxide  Alcoholic ketoacidosis  Toluene  Metformin, Methanol  Uraemia  Diabetic ketoacidosis  Propylene glycol  Iron, Isoniazid  Lactic acidosis  Ethylene glycol  Salicylates A normal anion gap metabolic acidosis usually results from the loss of HCO3- ions from the extracellular fluid. The mnemonic CAGE is a useful way of remembering the causes of a normal anion gap metabolic acidosis:  Chloride excess  Acetazolamide, Addison’s disease  Gastrointestinal causes (diarrhoea, vomiting, fistulae)  Extra (Renal tubular acidosis)
  22. 22. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT A low anion gap is very rare indeed and if present is usually due to some sort of analytical error. When genuinely present it can be caused by a decrease in unmeasured anions (e.g. low albumin) or by an increase in unmeasured cations (e.g. IgG paraprotein in multiple myeloma or hypercalcaemia).  Calcitonin is a 32 amino acid polypeptide that is primarily synthesized and released by the parafollicular cells (C-cells) of the thyroid gland. Its main role is to reduce the plasma calcium concentration, therefore opposing the effects of parathyroid hormone. Secretion of calcitonin is stimulated by:  Increased plasma calcium concentration  Gastrin  Pentagastrin The main actions of calcitonin are:  Inhibition of osteoclastic activity (decreasing calcium and phosphate resorption from bone)  Stimulation of osteoblastic activity  Decreases renal calcium reabsorption  Decreases renal phosphate reabsorption Vasodilatation of the efferent arteriole of the glomerulus will increase renal plasma flow, decrease the filtration fraction and decrease the glomerular filtration rate.  The following table summarises the effects that various haemodynamic changes on the glomerulus have on common renal measurements: Haemodynamic change Renal plasma flow Filtration fraction Glomerular filtration rate Vasoconstriction of afferent arteriole Decreased No effect Decreased Vasodilatation of afferent arteriole Increased No effect Increased Vasoconstriction of efferent arteriole Decreased Increased Increased Vasodilatation of efferent arteriole Increased Decreased Decreased
  23. 23. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT ENDO  Vasopressin which is also known as antidiuretic hormone (ADH), is a peptide hormone that regulates the body’s retention of water. It is derived from a prohormone precursor in the hypothalamus and then transported via axons to the posterior pituitary, where it is stored in vesicles. There are several mechanisms that regulate the secretion of vasopressin from the posterior pituitary: 1. Increased osmolality of the plasma: Hypothalamic osmoreceptors sense an increase in osmolality and stimulate vasopressin release. 2. Hypovolaemia: This results in decreased atrial pressure that is detected by stretch receptors in the atrial walls and large veins (cardiopulmonary baroreceptors). Atrial receptor firing normally inhibits vasopressin release but when stretched the firing decreases and vasopressin release is stimulated. 3. Hypotension: This decreases baroreceptor firing, which leads to enhanced sympathetic activity and increased vasopressin release. 4. Angiotensin II: An increase in angiotensin II stimulates angiotensin II receptors in the hypothalamus to increase vasopressin production. Vasopressin has two principal sites of action: 1. The kidney: The primary function of vasopressin is to regulate the volume of the extracellular fluid. It acts on the renal collecting ducts via V2 receptors to increase permeability to water (via a camp-dependent mechanism). This results in decreased urine formation, an increase in blood volume and a resultant increase in arterial pressure. 2. Blood vessels: A secondary function of vasopressin is vasoconstriction. Vasopressin binds to V1 receptors on vascular smooth muscle to cause vasoconstriction (via the IP3 signal transduction pathway). This results in an increase in arterial pressure.  Addison's disease is caused by underproduction of the steroid hormones by the adrenal glands. Glucocorticoid, mineralocorticoid and sex steroid production are all affected.
  24. 24. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT Automimmune adrenalitis is the commonest cause and this accounts for approximately 70-80% of cases. It is more common in women than men and most commonly occurs between the ages of 30 and 50. The clinical features of Addison's disease include: • Weakness and lethargy •Hypotension (notably orthostatic hypotension) • Nausea and vomiting • Weight loss • Reduced axillary and pubic hair •Depression • Hyperpigmentation (palmar creases, buccal mucosa and exposed areas more commonly affected) The classical biochemical features of Addison's disease are as follows: • Increased ACTH levels (rise in an attempt to stimulate the adrenal glands) • Hyponatraemia • Hyperkalaemia •Hypercalcaemia • Hypoglycaemia • Metabolic acidosis An ACTH level of greater than 80ng/l in the presence of a low or normal serum cortisol level is highly suggestive of primary hypoadrenalism. Hyponatraemia causes a raised serum renin level. Random cortisol measurements have a low sensitivity for detecting Addison's disease due to the diurnal variation of cortisol secretion.
  25. 25. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT Addison's disease is associated with an increased incidence of the following conditions: • Type I diabetes mellitus (not type II) • Hashimoto's thyroiditis •Grave's disease • Premature ovarian failure • Pernicious anaemia • Vitiligo •Alopecia Management should be by an Endocrinologist. Typically patients require hydrcortisone, fludrocortisone and dehydropiandrosterone. Some patients also require thyroxine if there is hypothalamic-pituitary disease present. Treatment is life-long and patients should carry a steroid card and a MedicAlert bracelet and be aware of the possibility of Addisonian crisis.  Hormones of adrenal gland  Hormones of the anterior pituitary: • Adrenocorticotropic hormone (ACTH) •Thyroid-stimulating hormone (TSH) •Follicle-stimulating hormone (FSH)
  26. 26. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT • Luteinizing hormone (LH) •Growth hormone (GH) • Prolactin  Hormones of the posterior pituitary: • Antidiuretic hormone (ADH), also known as vasopressin •Oxytocin Corticotropin-releasing hormone (CRH) and thyrotropin-releasing hormone (TRH) are both secreted by the hypothalamus.  Calcitonin is a 32 amino acid polypeptide that is primarily synthesized and released by the parafollicular cells (C-cells) of the thyroid gland. Its main role is to reduce the plasma calcium concentration, therefore opposing the effects of parathyroid hormone. Secretion of calcitonin is stimulated by: •Increased plasma calcium concentration •Gastrin •Pentagastrin The main actions of calcitonin are: • Inhibition of osteoclastic activity (decreasing calcium and phosphate resorption from bone) •Stimulation of osteoblastic activity • Decreases renal calcium reabsorption • Decreases renal phosphate reabsorption Approximately 99% of the body's calcium is stored in bones, but it is also present in some cells (most notably muscle cells) and in the blood. The normal adult diet contains about 25 mmol of calcium per day, of which only about 5 mmol is absorbed by the body. Calcium is essential for a number of important functions including: • Formation of bone and teeth
  27. 27. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT • Muscle contraction • Blood clotting • Normal heart rhythm • Enzymatic reactions • Intracellular signaling • Nerve conduction The total plasma calcium concentration is in the range if 2.2-2.5 mmol/l (note that there is some slight variation between laboratories). The usual range for ionized calcium is 1.3-1.5 mmol/l. The amount of total calcium in the blood varies with the plasma albumin level, which is the main carrier of protein-bound calcium in the blood. The biological effect of calcium is, however, determined by the amount of ionized calcium. It is therefore the plasma ionized calcium level, which is tightly regulated to remain within tight limits by homeostasis. Calcium in the plasma is: • Approximately 50% unbound in its ionized form • Approximately 40% bound to albumin •Approximately 10% bound to other plasma proteins The corrected calcium concentration estimates the total concentration as if the albumin concentration was normal. The albumin concentraion is usually taken as being 40 g/l. A typical correction is that for every 1 g/l that the albumin concentration is below this mean, the calcium concentration is 0.02 mmol/I below what it would be if the albumin concentration was normal. The foods that are highest in calcium include: •Dairy products e.g. milk, cheese and butter • Green vegetables e.g. broccoli, spinach, green beans •Whole grain foods e.g. bread, rice, cereals • Bony fish e.g. sardines, salmon • Eggs
  28. 28. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT • Nuts The foods that are lowest in calcium include: •Fruits e.g. kiwi fruit, raspberries, oranges, papaya • Meats such as chicken and pork •Carrots  Cushing's syndrome The most common cause of Cushing's syndrome is the iatrogenic administration of corticosteroids. The endogenous causes of Cushing's syndrome include: • Pituitary adenoma (Cushing's disease) • Ectopic corticotropin syndrome e.g. small cell carcinoma of the lung • Adrenal adenoma • Adrenal carcinoma • Adrenal hyperplasia The clinical features of Cushing's disease include: • Truncal obesity and weight gain • Supraclavicular fat pads • Buffalo hump • Facial fullness and plethora ('moon facies') •Proximal muscle weakness and wasting •Diabetes mellitus or impaired glucose tolerance •Hypertension •Skin atrophy and easy bruising •Hirsutism
  29. 29. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT •Acne •Osteoporosis •Depression  Diabetes insipidus This patient has a diagnosis of diabetes insipidus, likely secondary to her sarcoidosis. Diabetes insipidus is the inability to produce concentrated urine. It is characterised by the presence of excessive thirst, polyuria and polydipsia. There are two distinct types of diabetes insipidus: 1. Cranial (central) diabetes insipidus and; 2. Nephrogenic diabetes insipidus Cranial diabetes insipidus is caused by a deficiency of vasopressin (anti-diuretic hormone). Patients with cranial diabetes insipidus can have a urine output as high as 10-15 litres per 24 hours but adequate fluid intake allows most patients to maintain normonatraemia. 30% of cases are idiopathic and a further 30% are secondary to head injuries. Other causes include neurosurgery, brain tumours, meningitis, granulomatous disease (e.g. sarcoidosis) and drugs, such as naloxone and phenytoin. Avery rare inherited form also exists that is associated with diabetes mellitus, optic atrophy, nerve deafness and bladder atonia. Nephrogenic diabetes insipidus is caused by renal resistance to the action of vasopressin. As with cranial diabetes insipidus urine output is markedly elevated. Serum sodium levels can be maintained by secondary polydipsia or can be elevated. Causes of nephrogenic diabetes insipidus include chronic renal disease, metabolic disorders (e.g. hypercalcaemia and hypokalaemia) and drugs, including long-term lithium usage and demeclocycline. The water deprivation test, also known as the fluid deprivation test, is the best test to determine if a patient has diabetes insipidus as opposed to another cause of polydipsia. It also helps to distinguish cranial from nephrogenic diabetes insipidus. Patients are deprived of water intake for up to 8 hours and weight, urine volume, urine osmolality and serum osmolality are all measured. 2 micrograms of IM desmopressin is administered at the end of the 8 hours and further measurements are made at 16 hours  The effects of catecholamines on glucose metabolism include: •Stimulation of glycogenolysis • Inhibition of insulin secretion
  30. 30. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT • Promotion of glucagon secretion •Promotion of lipoylsis (free fatty acids and glycerol are used in preference to glucose) Glucocorticoids, such as cortisol, are released in response to hypoglycaemia and have a number of effects on glucose regulation. These include: •Inhibition of glucose uptake •Promotion of gluconeogenesis • Increase glycogen storage (in the liver) •Promotion of lipoylsis (free fatty acids and glycerol are used in preference to glucose)  The effects of the thyroid hormones on glucose regulation include: •Promotion of glucose uptake into cells •Stimulation of glycogenolysis •Stimulation of gluconeogenesis • Increased absorption of glucose from the gastrointestinal tract • Enhances rate of insulin-dependent glycogenesis Glycogenolysis is the breakdown of glycogen to glucose-6-phosphate and glucose. This provides energy for muscle contraction and allows glycogen to broken down to release glucose into the bloodstream. Lipolysis is the breakdown of lipids and involves hydrolysis of triglycerides into glycerol and free fatty acids. It makes fatty acids available for oxidation. Gluconeogenesis is a metabolic pathway that results in the biosynthesis of new glucose from noncarbohydrate substrates. Glycolysis is the metabolic pathway that converts glucose into pyruvate. The free energy released by this process is used to form ATP and NADH. Glycolysis is inhibited by glucagon and glycolysis and gluconeogenesis are reciprocally regulated so that when one cell pathway is activated the other is inactive and vice versa.
  31. 31. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT  The non-drug causes of hyperkalaemia include: • Renal failure • Excess potassium supplementation •Addison's disease (adrenal insufficiency) •Congenital adrenal hyperplasia • Renal tubular acidosis (type 4) • Rhabdomyolysis • Burns and trauma • Tumour lysis syndrome • Acidosis  Drugs that can cause hyperkalaemia include: • ACE inhibitors • Angiotensin receptor blockers
  32. 32. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT • NSAIDs • Beta-blockers •Digoxin •Suxamethonium
  33. 33. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT  Effect of insulin  PTH PTH is released in response to the following stimuli: •Decreased plasma calcium concentration • Increased plasma phosphate concentration (indirectly by binding to plasma calcium and reducing the calcium concentration) PTH release is inhibited by the following factors: •Normal/increased plasma calcium concentration • Hypomagnesaemia The main actions of PTH are: • Increases plasma calcium concentration • Decreases plasma phosphate concentration • Increases osteoclastic activity (increasing calcium and phosphate resorption from bone)
  34. 34. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT •Increases renal tubular reabsorption of calcium • Decreases renal phosphate reabsorption •Increases renal conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol (via stimulation of 1-alpha hydroxylase) • Increases calcium and phosphate absorption in the small intestine (indirectly via increased 1,25-dihydroxycholecalciferol)  hypocalcemia Other causes of hypocalcaemia include: • Hypoparathyroidism • Hypovitaminosis D • Sepsis •Fluoride poisoning • Hypomagnasaemia • Renal failure • Tumour lysis syndrome • Pancreatitis • EDTA infusions
  35. 35. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT
  36. 36. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT CARDIO  Haemorrhage classification can be classified into four separate classes based on physiological parameters and clinical signs: CLASS I CLASS II CLASS III CLASS IV Blood loss (mL) Up to 750 750-1500 1500-2000 >2000 Blood loss (% blood volume) Up to 15% 15-30% 30-40% >40% Pulse rate (bpm) <100 100-120 120-140 >140 Systolic BP Normal Normal Decreased Decreased Pulse pressure Normal (or increased) Decreased Decreased Decreased Respiratory rate 14-20 20-30 30-40 >40 Urine output (ml/hr) >30 20-30 5-15 Negligible CNS/mental status Slightly anxious Mildly anxious Anxious, confused Confused, lethargic Under normal circumstances the left bundle branch consists of three fascicles:  The left anterior fascicle, which supplies the upper and anterior parts of the left ventricle  The left posterior fascicle, which supplies the posterior and infero-posterior parts of the left ventricle, and;  The septal fascicle, which supplies the septal wall  In left anterior fascicular block (LAFB) the anterior portion of the left bundle branch is defective. In LAFB the cardiac impulses are therefore conducted to the left ventricle via the left posterior fascicle first, which creates a delay in the activation of the anterior and upper parts of the left ventricle. The diagnostic criteria for LAFB are:  Left axis deviation (axis usually between -45 and -90 degrees)  Small Q waves with tall R waves in leads I and AVL (‘qR complexes)  Small R waves with deep S waves in leads II, III and AVF (‘rS’ complexes)  QRS duration normal or slightly prolonged (80-110 ms)  Prolonged R wave peak time in AVL > 45 ms  Increased QRS voltage in limb leads
  37. 37. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT  Cardiac enzyme  ACTION POTENTIAL The standard model used to understand the cardiac action is the action potential of the ventricular myocyte. The cardiac action potential has five numbered phases (0-4). Phase 0 - Rapid depolarization phase  An action potential is triggered once the membrane potential reaches the threshold (approximately -70 mV)  Fast Na+ channels open and there is a rapid influx of Na+ ions  Na+ channels automatically inactivate after a few milliseconds  L-type Ca2+ channels open Phase 1 - Early repolarisation phase • Commences once Na+ channels inactivate • Some K+ channels open briefly •Efflux of K+ and Cl" ions Phase 2 - Plateau phase  Slow influx of Ca2+ ions via L-type channels that opened in phase 0  Efflux of K+ ions via delayed rectifier K+ channels
  38. 38. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT  Plateau sustained by balance between movement of Ca2+ and K+ ions Phase 3 - Rapid repolarisation phase • L-type Ca2+ channels close • K+ channels remain open and there is further efflux of K+ ions Phase 4 - Resting phase  Resting potential restored by Na+/K+ ATPase and Na+/ Ca2+ exchanger  Resting potential is approximately -90 mV  Na+ and Ca2+ channels are closed in the resting phase  Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice. The lifetime risk over the age of 40 years is approximately 25%. AF is characterized by an irregularly irregular rhythm with an absence of P waves and an isoelectric baseline on the ECG. The ventricular rate is variable and the QRS complexes are usually narrow unless there is a co-existing bundle branch block or accessory pathway. Fibrillatory waves may be present and can be fine (amplitude < 0.5 mm), or coarse (amplitude > 0.5 mm). There are many potential causes of atrial fibrillation including: •Ischaemic heart disease • Hypertension • Valvular heart disease •Electrolyte disturbance (e.g. hypokalaemia)
  39. 39. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT • Thyrotoxicosis • Drugs (e.g. sympathomimetics) •Sepsis •Alcohol excess  Atrial flutter is a supraventricular tachyarrhythmia caused by a re-entry circuit within the right atrium. Atrial activity is seen on the ECG as 'flutter waves', which occur at a rate of approximately 300 per minute. These flutter waves have a 'saw-tooth' appearance and are usually best seen in the inferior leads (II, III, and aVF). The ventricular rate is determined by the AV conduction ratio, the commonest being a 2:1 block, which results in a ventricular rate of around 150 per minute. Higher-degree AV blocks can occur (e.g. 3:1, 4:1 block, or even higher as in this case) and result in lower rate of ventricular conduction. A variable block may also occur, which results in a variable rate. Atrial flutter is frequently caused by underlying disease. As it originates in the right atrium it is most strongly associated with pathology of the right atrium, such as COPD, pulmonary emobolus, and congenital cardiac conditions. Axis of the heart
  40. 40. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT
  41. 41. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT  Central venous pressure (CVP) is the pressure recorded from the right atrium or superior vena cava. The normal value for CVP is 0-8 cmH20 (0-6 mmHg) in a spontaneously breathing patient. CVP should be measured with the patient lying flat at the end of expiration. The tip of the catheter should be in the junction between the superior vena cava and the right atrium. It is measured by an electronic transducer that is placed and zeroed at the level of the right atrium (usually in the 4th intercostal space in the mid-axillary line).
  42. 42. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT CVP is a useful indicator of right ventricular preload. A volume challenge of 250-500 ml crystalloid causing an increase in CVP that is not sustained for more than 10 minutes suggests hypovolaemia Central venous pressure (CVP) is the pressure returned from the right atrium or superior vena cava. The normal value for CVP is O-8 cmH;0 (0-6 mmdg) in a spontaneously breathing patient. CVP should be measured with the patient lying flat the end of exp Pat on. The tip of the catheter should be ir. the junction between the superior vena cava and the right atrium. It s measured by an electron c transducer mat is placed and zeroed at the eveI of the right atrium (usually in the 4 h intercostal space in the mid-axillary line). CVP is a useful indicator of right ventricular preload.. Factors that increase CVP include:  Hypervolaemla  Forced exhalation  Tension pneumothorax  Heart failure  Pleura] effusion  Decreased cardiac output
  43. 43. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT  Cardiac tamponade  Mechanical ventilation (and PEEP)  PuImonary hypertension  PuImonary emholism Factors that decrease CVP include:  Hypovolaemia  Deep inhalation  Distributive shock  Negative pressure ventilation  Chamber pressure  The PQRST wave P WAVE is the first positive deflection on the ECG. It is a small smooth contoured wave and represents atrial depolarization. Atrial repolarisation is not visible as the amplitude is too small. The normal P wave is: •< 120 ms in duration (3 'small squares') • < 2.5 mm in amplitude in the limb leads
  44. 44. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT • < 1.5 mm in amplitude in the chest leads •Positive in lead II and negative in lead AVR The second wave seen on the ECG is the QRS complex. The QRS complex is a series of 3 deflections that represents ventricular depolarization. It is less than 0.12 seconds in duration (3 'small squares') under normal circumstances. By convention the first deflection in the complex, if it is negative, is called a Q wave. A Q wave represents the normal left-to-right depolarization of the interventricular septum. A normal Q wave is: • < 40 ms wide (1 'small square') •< 2 mm in amplitude • < 25% of the depth of the QRS complex Small Q waves are usually normal, but if they exceed the normal criteria listed above they are termed 'pathological Q waves' and can be indicative or an evolving or past myocardial infarction. The first positive deflection in the complex is called an R wave. This is the largest wave in the QRS complex and represents depolarization of the thick ventricular walls. A negative deflection after an R wave is called an S wave. This small wave represents depolarization of the Purkinje fibres. S waves travel in the opposite direction to the R waves because the Purkinje fibres spread throughout the ventricles from top to bottom and then back up though the walls of the ventricles
  45. 45. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT  The diagnostic criteria for LBBB are: • Broad QRS complex (> 120 ms) •Dominant S wave in lead V1 • Broad, monophasic R wave in lateral leads (I, AVL, V5 and V6) •Prolonged R wave peak time > 60 ms in left praecordial leads (V5-V6) •Absence of Q waves in lateral leads (I, V5 and V6) A useful mnemonic for distinguishing between the ECG patterns of left bundle branch block (LBBB) andRBBB is 'WiLLiaM MaRRoW': • WiLLiaM - in LBBB there is a 'W' in lead V1 and an 'M' wave in lead V6 • MaRRoW - in RBBB there is an 'M' wave in lead V1 and a 'W' wave in lead V6
  46. 46. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT LBBB, unlike right bundle branch block, is almost always an indication of heart disease. The pathologicalcauses of LBBB include: • Ischaemic heart disease • Anterior myocardial infarction • Hypertension • Aortic stenosis •Dilated cardiomyopathy •Primary fibrosis of the conducting system (Lenegre's disease) • Hyperkalaemia • Digoxin toxicity  The mean arterial pressure (MAP) is defined as the average arterial pressure during a single cardiac cycle. It normally lies within the range of 65 and 110 mmHg and needs to be a minimum of 65 mmHg for adequate organ perfusion to occur. It is considered a better indicator of vital organ perfusion than systolic blood pressure. MAP can be calculated by non-invasive means using one of the following equations: MAP = [(2 x diastolic BP) + systolic BP] / 3 or; MAP = diastolic BP + [(systolic BP - diastolic BP) / 3] Diastole counts roughly twice as much as systole because 2/3 of the cardiac output is spent in diastole. MAP is determined by the cardiac output (CO), systemic vascular resistance (SVR), and the central venous pressure (CVP), according to the following relationship: MAP = (CO X SVR) + CVP
  47. 47. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT Because the CVP is generally close to zero and does not significantly impact on the end result of the equation, this relationship is often simplified to: MAP = CO X SVR  PEDIA VITAL SIGNS  Pulse pressure is the difference between the systolic and diastolic blood pressure, measured in mmHg. It represents the force generated by the heart each time it contracts. The usual resting pulse pressure in healthy adults is approximately 30-40 mmHg. Pulse pressure is considered to be abnormally low (narrow) if it is less than 25% of the systolic value. Causes of a narrow pulse pressure include: •Reduced cardiac output (e.g. blood loss) • Aortic stenosis
  48. 48. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT •Cardiac tamponade • Congestive cardiac failure Pulse pressure is generally considered to be high (wide) if it is greater than 60 mmHg. A resting pulse pressure greater than 100 mmHg is highly indicative of the presence of a disease state. Causes of a wide pulse pressure include: • Atherosclerosis (stiffness of major arteries) • Aortic regurgitation • Arteriovenous malformation • Aortic root aneurysm • Aortic dissection • Hyperthyroidism  The first heart sound (S1) is produced by vibrations generated by the closure of the mitral and tricuspid valves. It corresponds with the end of diastole and the beginning of ventricular systole and precedes the upstroke of the carotid pulsation. The following conditions are associated with a loud S1: •Increased transvalvular gradient (e.g. mitral stenosis, tricupsid stenosis) •Increased force of ventricular contraction (e.g. tachycardia, hyperdynamic states such as fever and thyrotoxicosis) •Shortened PR interval (e.g. Wolff-Parkinson-White syndrome) • Mitral valve prolapse • Thin individuals
  49. 49. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT The following conditions are associated with a soft S1: • Inappropriate apposition of the AV valves (e.g. mitral regurgitation, tricuspid regurgitation) •Prolonged PR interval (e.g. heart block, digoxin toxicity) • Decreased force of ventricular contraction (e.g. myocarditis, myocardial infarction) •Increased distance from the heart (e.g. obesity, emphysema, pericardial effusion) The following conditions are associated with a split SI: •Right bundle branch block • LV pacing •Ebstein anomaly The Sgarbossa criteria are: •> 1 mm concordant ST elevation in leads with a positive QRS complex (5 points) • > 1 mm concordant ST depression in leads V1-V3 (3 points) •> 5 mm discordant ST elevation in leads with a negative QRS complex (2 points)  The typical ECG features of WPW in sinus rhythm are: •Shortened PR (< 120 ms) •Delta wave (slurring of the initial rise in the QRS complex) •Widening of the QRS complex (> 110 ms) In addition there are two distinct recognisable types of WPW:
  50. 50. PHYSIOLOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT • Type A - the delta waves and QRS complexes are predominantly positive in the praecordial leads with a dominant R wave in V1. The dominant R wave in V1 can be mistaken for RBBB • Type B - The delta wave and QRS complex are predominantly negative in leads V1 and V2 and positive in the other praecordial leads, resembling LBBB
  51. 51. Pharmacology PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT  the following table summarises the relative constituent compositions of the commonly used IV fluid mixtures (values taken from the BNF): FLUID Na+ mmol/l K+ mmol/l HCO3- mmol/l Cl- mmol/l Ca2 + mmol/l Normal plasma values 142 4.5 26 103 2.5 0.9% Sodium Chloride 150 - - 150 - Compound Sodium Lactate (Hartmann’s) 131 5 29 111 2 5% Glucose (1 L contains 50 g of dextrose) - - - - - 0.3% Potassium Chloride and 5% Glucose - 40 - 40 - 0.3% Potassium Chloride and 0.9% Sodium Chloride 150 40 - 190 - 1.26% Sodium Bicarbonate 150 - 150 - - 4.5% Albumin (1 L contains 40-50 g of albumin) < 160 < 2 - 136 - 4% Gelatin (Gelofusine) 154 < 0.4 - 120 < 0.4  GOUT In the absence of any contraindications, high-dose NSAIDs are the first-line treatment for acute gout. Naproxen 750mg as a stat dose followed by 250 mg TDS is a commonly used and effective regime. Aspirin should not be used in gout as it reduces the urinary clearance of urate and interferes with the action of urosuric agents. Naproxen, Diclofenac or Indomethacin are more appropriate choices. Allopurinol is used prophylactically, preventing future attacks by reducing serum uric acid levels. It should not be started in the acute phase as it increases the severity and duration of symptoms.
  52. 52. Pharmacology PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT Colchicine acts on the neutrophils, binding to tubulin to prevent neutrophil migration into the joint. It is as effective as NSAIDs in relieving acute attacks. It also has a role in prophylactic treatment if Allopurinol is not tolerated. NSAIDs are contraindicated in heart failure as they can cause fluid retention and congestive cardiac failure. Colchicine is the preferred treatment in patients with heart failure or those who are intolerant of NSAIDs. The European League Against Rheumatism (EULAR) guidelines for diagnosis state that the development of acute pain in a joint which becomes swollen, tender and erythematous and which reaches its crescendo over a 6-12 hour period is highly suggestive of crystal arthropathy. There is little benefit in checking serum urate levels to confirm hyperuricaemia prior to initiating treatment in acute attacks of gout and treatment should not be delayed. Although they can be helpful in monitoring response to treatment they often decrease during an acute attack and can be normal. If levels are checked and are normal during the attack they should be repeated once the attack has resolved. The first-line treatment for acute attacks of gout is non-steroidal anti-inflammatory drugs (NSAIDs), such as naproxen. NSAIDs should, however, be used with caution in patients with a history of hypertension. Given that this patient has had difficulty controlling his blood pressure and remains hypertensive it would be prudent to avoid them in this case. Colchicine is an effective alternative to gout, although it is somewhat slower to take effect. It is often used in patients with contraindications to NSAIDs, such as in patients with hypertension and those with a history of peptic ulcer disease. It is the most appropriate choice in this case. Allopurinol should not be used during an acute attack of gout as it can both prolong the attack and precipitate a further acute attack. In patients already established on allopurinol, it should be continued and the acute attack treated as normal with NSAIDs or colchicine as appropriate.  Abciximab (ReoPro) is a chimeric monoclonal antibody that is a glycoprotein IIb/IIIa receptor antagonist. It inhibits platelet aggregation and is mainly used during and after coronary artery procedures such as angioplasty. The following are contraindications to the use of abciximab:  Active internal bleeding  Major surgery, intracranial surgery or trauma within the last 2 months  Stroke within the last 2 years  Intracranial neoplasm  Arteriovenous malformation or aneurysm  Haemorrhagic diathesis  Vasculitis  Hypertensive retinopathy
  53. 53. Pharmacology PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT  Prolongation of the QT interval can lead to a life threatening ventricular arrhythmia known as torsades de pointes, which can result in sudden cardiac death. There are a number of widely used drugs that are known to cause QT prolongation. Hypokalaemia and hypomagnesaemia can increase the risk of QT prolongation e.g. diuretics can interact with QT prolonging drugs by causing hypokalaemia. The QT interval varies with heart rate and formulae are used to correct the QT interval for heart rate. Once corrected it is expressed as the QTc interval. The QTc interval is generally reported on the ECG printout. The normal QTc Interval is <440 ms. The QTc interval is considered to be borderline if it is >440 ms but <500 ms. Although literature differs, a QTc interval within these values is considered borderline prolonged. Consideration should be given to dose reduction of QT prolonging drugs or changing to an alternative non-QT prolonging drug. A prolonged QTc interval >500 ms is clinically significant and likely to confer an increased risk of arrhythmia. Any drugs that prolong the QT interval should be reviewed immediately.  Some of the more commonly encountered drugs that are know to prolong the QT interval are shown below: Antimicrobials Erythromycin Clarithromycin Moxifloxacin Fluconazole Ketoconazole Antiarrhythmics Dronedarone Sotalol Quinidine Amiodarone Flecainide Antipsychotics Risperidone Fluphenazine Haloperidol
  54. 54. Pharmacology PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT Pimozide Chlorpromazine Quetiapine Clozapine Antidepressants Citalopram/escitalopram Amitriptyline Clomipramine Dosulepin Doxepin Imipramine Lofepramine Antiemetics Domperidone Droperidol Ondansetron/Granisetron Others Methadone Protein kinase inhibitors e.g. sunitinib Some antimalarials Some antiretrovirals Telaprevir Boceprevir  Tricyclic antidepressants (TCAs) are mainly used in the treatment of depression but are also used in the treatment of anxiety disorders, chronic pain conditions and attention-deficit hyperactivity disorder (ADHD). The majority of TCAs act primarily as serotonin-noradrenaline reuptake inhibitors (SNRIs) by blocking the serotonin transporter (SERT) and the noradrenaline transporter. This results in an elevation in the synaptic concentrations of serotonin and noradrenaline, and therefore an enhancement of neurotransmission. Many of the common side effects of TCAs are related to their antimuscarinic properties. These include:  Dry mouth and mucous membranes  Blurred vision  Constipation  Urinary retention  Cognitive impairment
  55. 55. Pharmacology PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT Other side effects include:  Anxiety  Apathy and anhedonia  Akathisia  Confusion  Sexual dysfunction  Gynaecomastia and lactation  Dysrrhythmias TCAs should not be used concomitantly with monoamine oxidase inhibitors (MAOIs), such as selegiline, and should be started at least 2 weeks after stopping the MAOI. There is a risk of developing serotonin toxicity is the two drug classes are used together. Serotonin syndrome may occur with TCA overdose. Features of this syndrome include CNS effects (including agitation and coma), autonomic instability (including hyperpyrexia) and neuromuscular excitability (including clonus and raised serum creatine kinase).  Proton pump inhibitors act by blocking the hydrogen/potassium ATPase enzyme system of the gastric parietal cells. The proton pump is the terminal stage in gastric acid secretion and this makes the proton pump an ideal target for inhibiting acid secretion. The outcome is similar with both oral and intravenous PPI use and there is no appreciable benefit for using the intravenous formulation in patients that can tolerate oral medication. Long-term PPI use has been associated with an increased risk of hip, wrist and spine fractures, but not pelvic fractures. There is an increased risk of both Clostridium Difficile infection and community-acquired pneumonia with PPI usage. It is suspected that acid suppression caused by PPI usage results in poor elimination of pathogenic organisms leading to increased infection risk Contraindications to the use of TCAs include:  The recovery period from MI  Heart block  Arrhythmias  Manic phase of bipolar affective disorder  Acute porphyria
  56. 56. Pharmacology PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT Febuxostat (Uloric) is an alternative to allopurinol used in the management of chronic gout. Like allopurinol it should not be used in the management of acute episodes.  The current NICE recommendations for the management of warfarin in the presence of bleeding or an INR outside of the normal range is as follows: In the presence of major active bleeding, regardless of the INR:  Stop warfarin  Administer 5-10 mg IV vitamin K (phytomenadione)  And/or prothrombin complex concentrate (factors II, VII, IX and X)  Or fresh frozen plasma 15 ml/kg If the INR is greater than 8.0 with no bleeding or minor bleeding:  Stop warfarin  Administer 0.5-1 mg vitamin K (phytomenadione) by slow injection  Or 5 mg oral vitamin K  The dose may be repeated after 24 hours if INR remains high  Restart warfarin when INR is less than 5.0 If the INR is 6.0-8.0 with no bleeding or minor bleeding:  Stop warfarin  Restart warfarin when INR is less than 5.0 If the INR is high, but less than 5.0  The warfarin dose will need to be reduced and/or one or two doses may need to be omitted  The INR should then be measured in 2 or 3 days to ensure that it is falling  A 15% change of dose is expected to result in a change in the INR of 1, and a 10% dose adjustment is expected to result in a 0.7-0.8 change in the INR  Adenosine is a purine nucleoside that is primarily used in the diagnosis and treatment of paroxysmal supraventricular tachycardia. It acts by stimulating A1-adenosine receptors and opening acetylcholine-sensitive potassium channels. This hyperpolarizes the cell membrane in the atrio-ventricular (AV) node and, by inhibiting the calcium channels, slows conduction in the AV node.
  57. 57. Pharmacology PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT Adenosine is administered by a rapid IV bolus, followed by a saline flush. The initial adult dose is 6 mg, followed if necessary by a 12 mg, and then a further 12 mg bolus at 1-2 minute intervals until an effect is observed. Adenosine has a very short half-life of less than 10 seconds and acts rapidly within 10 seconds. The duration of actions is 10-20 seconds. Because of the short half-life any side effects experienced are generally very short lived. These include:  Sense of ‘impending doom’  Facial flushing  Dyspnoea  Chest discomfort  Metallic taste Patients with a heart transplant are very sensitive to the effects of adenosine and should receive a reduced initial dose of 3mg, followed by 6 mg and then 12 mg. The effects of adenosine are potentiated by dipyrimadole and the dose should be reduced in patients taking it.  The peak therapeutic range for gentamicin is 5-12 mg/L. The trough therapeutic range for gentamicin is < 2 mg/L.  Supraventricular tachycardia (SVT) is the most common non-arrest arryhthmia during childhood and is the most common arrhythmia that produces cardiovascular instability during infancy. The current APLS guidelines recommend that if the patient has no features of shock and remains haemodynamically stable then vagal maneovres should be attempted initially. If this is unsuccessful then: • An initial dose of 100 mcg/kg of adenosine should be given. Contra-indications to the use of adenosine include:  2nd or 3rd degree AV block  Sick sinus syndrome  Long QT syndrome  Severe hypotension  Decompensated heart failure  Chronic obstructive lung disease  Asthma
  58. 58. Pharmacology PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT •After two minutes another dose of 200 mcg/kg adenosine should be given is the child remains in stable SVT • After a further two minutes another dose of 300 mcg/kg adenosine should be given If the child remains in stable SVT despite these measures then the guidelines recommend that following be considered: • Adenosine 400-500 mcg/kg • Synchronous DC shock • Amiodarone Amiodarone, if given, should be administered initially at a dose of 5-10 mg/kg over 20 minutes to 2 hours, then by continuous infusion 300 mcg/kg/hour increased according to response by 1.5 mg/kg/hour. The infusion rare should not exceed 1.2 g in 24 hours.  ACE inhibitors prevent angiotensin converting enzyme (ACE) from converting angiotensin I to angiotensin II. Angiotensin II several different effects: •Increased sympathetic activity •Arteriolar vasoconstriction •Vasopressin secretion • Aldosterone secretion The arteriolar vasoconstriction causes an increase in systemic blood pressure. Vasopressin stimulates reabsorption of water in the kidneys and stimulates the sensation of thirst. Aldosterone causes the reabsorption of sodium and water from the urine in the distal convoluted tubules and collecting ducts, in exchange potassium is secreted. Therefore ACE inhibitors tend to reduce systemic blood pressure and cause hyperkalaemia. ACE inhibitors are contraindicated in the presence of renal artery stenosis as they can induce or exacerbate renal failure in its presence. ACE inhibitors are used in a variety of clinical settings including heart failure. Meta-analysis has shown ACE inhibitors to result in a 28% reduction in death, Ml and overall admission in patients with heart failure. Other clinical uses of ACE inhibitors include: •Hypertension •Chronic kidney disease •Diabetic nephropathy • Post myocardial infarction ACE inhibitors have numerous side effects, the commonest being a dry cough secondary to increased bradykinin production. There is, however, no recognised association with lung fibrosis. The recognized side effects of ACE inhibitors include: •Dry cough (in approximately 20%) •First dose hypotension • Sore throat • Angioedema • Hyperkalaemia •Agranulocytosis •Hepatitis •Cholestatic jaundice • Renal impairment • Hypoglycaemia
  59. 59. Pharmacology PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT  Adrenaline should be given as soon as circulatory access has been obtained in non-shockable (PEA/asystole) cardiac arrests. The dose is 1 mg (10 mL of 1:10,000 or 1 mL of 1:1000) via the IV or IO routes. Adrenaline should be given after the 3rd shock in a shockable (Vf/pVT) cardiac arrest once chest compressions have resumed. The dose is 1 mg (10 mL of 1:10,000 or 1 mL of 1:1000) It should subsequently be given every 3-5 mins (i.e. alternate loops) and it should be given without interrupting chest compressions. The alpha-adrenergic effects of adrenaline cause systemic vasoconstriction, which increases coronary and cerebral perfusion pressures. The beta-adrenergic effects of adrenaline are positively inotropic (increased myocardial contractility) and chronotropic (increased heart rate) and may increase coronary and cerebral blood flow. Concomitant increases in myocardial oxygen consumption and ectopic ventricular arrhythmias (particularly in the absence of acidaemia), transient hypoxaemia because of pulmonary arertiovenous shunting, impaired microcirculation, and increased post-cardiac arrest myocardial dysfunction may, however, offset these benefits. Although there is no evidence of long-term benefit from its use in cardiac arrest, the improved short-term survival documented in some studies warrants its continued use.  Aminophylline is a compound of theophylline with ethylenediamine in a 2:1 ratio. The ethylenediamine improves its solubility. It is less potent and shorter acting than theophylline.  Aminophylline acts as a: 1. Competitive phophodiesterase inhibitor: which raises intracellular cAMP and relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels 2. Non-selective adenosine receptor antagonist: which results in stabilization of mast cells It has mild positive inotropic and chronotropic effects, producing an increase in cardiac output and a decrease in systemic vascular resistance, leading to a decrease in arterial blood pressure. It has been used historically in the treatment of refractory heart failure and is recommended by the current ALS guidelines as an alternative treatment for bradycardias. It is used in the treatment of: • Asthma •COPD •Heart failure • Bradycardias
  60. 60. Pharmacology PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT The adult daily oral dose is 900 mg administered in 2-3 divided doses. The intravenous loading dose for severe asthma or COPD is 5 mg/kg over 10-20 minutes and this may be followed by a maintenance infusion of 0.5 mg/kg/hour. The therapeutic range is narrow (10-20 microgram/ml) and estimations of the plasma concentration of aminophylline are of value during chronic therapy.  Amiodarone has many potential toxic side effects and a full and thorough clinical assessment prior to commencing therapy with it is essential. Optic neuritis is a very rare side effect of amiodarone. If it does occur then the amiodarone should be stopped immediately due to the risk of blindness. Most patients taking amiodarone develop corneal microdeposits, this reverses after treatment has been ceased and rarely interferes with vision. Amiodarone chemically resembles thyroxine and can bind to the nuclear thyroid receptor. It can cause both hypothyoidism and hyperthyroidism, although hypothyroidism is far more common, occurring in 5-10% of patients.  Anti-D is an IgG class antibody directed against the Rhesus D (RhD) antigen. Anti-D is only given to RhD negative women. RhD negative women do not carry the RhD antigen on their RBC. If a fetus does carry the RhD antigen (i.e. is RhD positive) and the mother is exposed to fetal blood, she may form antibodies to RhD that pass through the placenta to attack fetal red cells (causing haemolytic disease of the newborn) in this or subsequent pregnancies. Anti-D is given to bind fetal red cells in the maternal circulation to neutralise them before an immune response is triggered. Side effects associated with amiodarone include: •Corneal microdeposits •Photosensitivity • Nausea •Sleep disturbance • Hyperthyroidism •Hypothyroidism • Acute hepatitis and jaundice •Peripheral neuropathy • Lung fibrosis • QT prolongation
  61. 61. Pharmacology PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT RhD should be given in the event of a sensitising event. Potentially sensitising events include: • Birth • Antepartum haemorrhage • Miscarriage • Ectopic pregnancy • Intrauterine death • Amniocenetsis • Chorionic villus sampling • Abdominal trauma It the event of a sensitising event occurring, the sooner anti-D is given the better, but it is maximally effective within 72 hours and the BNF states it is still likely to have some benefit if administered outside of this deadline. Routine antenatal prophylaxis is recommended for RhD negative women at 28 and 34 weeks. This is irrespective of whether they have already received Anti-D earlier in the same pregnancy for a sensitising event. Before 12 weeks gestation, confirmed by scan, in uncomplicated miscarriage (where the uterus is not instrumented), or mild painless vaginal bleeding, prophylactic anti-D is not necessary because the risk of feto-maternal haemorrhage (FMH) is negligible. However 250 IU of prophylactic anti-D immunoglobulin should be given in cases of therapeutic termination of pregnancy, whether by surgical or medical methods, to confirmed RhD negative women who are not known to be already sensitised to RhD.  Extrapyramidal side effects occur most commonly with the piperazine phenothiazines (fluphenazine, prochlorperazine and trifluoperazine) and butyrophenones (benperidol and haloperidol). Haloperidol is the most common causative antipsychotic drug. Tardive dyskinesia (rhythmic, involuntary movements of tongue, face and jaw) usually develops after long-term treatment or with high dosage. It is the most serious manifestation of extrapyramidal symptoms as it may be irreversible on withdrawing the causative drug and treatment is generally ineffective. Dystonia (abnormal face and body movements) is more common in children and young adults and tends to appear after only a few doses. Acute dystonia can be treated with procyclidine 5mg IV or benzatropine 2mg IV as a bolus. Akathisia is characterized by an unpleasant sensation of restlessness. Akinesia is an inability to initiate movement. There is increased cerebral sensitivity in renal impairment and reduced doses should be used. There is an increased risk of mortality in elderly patients with dementia-related psychosis treated with haloperidol. This appears to be due to increased risk of cardiovascular events and infections such as pneumonia. The contraindications to the use of antipsychotic drugs include: •Reduced conscious level / coma •CNS depression •Phaeochromocytoma
  62. 62. Pharmacology PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT  The current APLS algorithm for the treatment of the convulsing child is as follows: Step 1 (5 minutes after start of convulsion): In a child that has been convulsing for 5 minutes or more an initial dose of benzodiazepine should be given: • Lorazepam 0.1 mg/kg should be given IV or IO if vascular access is available • Buccal midazolam 0.5 mg/kg or rectal diazepam 0.5 mg/kg can be given as alternatives if no vascular access is available Step 2 (10 minutes after start of step 1): If the convulsion continues for a further 10 minutes a second dose of benzodiazepine should be given and senior help should be summoned. Step 3 (10 minutes after start of step 2): At this stage senior help is needed to reassess the child and advise on management. The following management is recommended: • If not already on phenytoin then a phenytoin infusion should be set up (20 mg/kg IV infusion over 20 minutes) •If already taking phenytoin then phenobarbitone can be used in its place (20 mg/kg IV infusion over 20 minutes) • Rectal paraldehyde can be considered at a dose of 0.8 ml/kg of the 50:50 mixture whilst preparing the infusion Step 4 (20 minutes after start of step 3): If the child is still convulsing at this stage then an anaesthetist must be present and a rapid sequence induction with thiopental is recommended  Aspirin irreversibly blocks cyclo-oygenase by covalently acetylating the cyclo- oxygenase active site in both COX-1 and COX-2. At low doses (75 mg per day) aspirin only inhibits COX-1, the enzyme responsible for making thromboxane A2, and therefore principally exhibits an anti-thrombotic effect. At medium to high doses (500-5000 mg per day) aspirin inhibits both COX-1 and COX-2. COX 2 is responsible for the production of prostaglandins and therefore has an anti-inflammatory effect at these doses. The effects of a single dose of aspirin last 7-10 days, the time required for the bone marrow to generate new platelets. When used as an anti-pyretic for childhood viral illness, aspirin can cause Reye's syndrome. Reye's syndrome is a potentially fatal disease that causes liver failure and encephalopathy. Aspirin resistance is the inability of aspirin to reduce platelet production of thromboxane A2 and thereby platelet activation and aggregation. The exact frequency and mechanism of aspirin resistance are not known, however it may occur in approximately 1% of users. This phenomenon occurs more commonly in women than men.
  63. 63. Pharmacology PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT  The BTS guidelines for the management of acute asthma in children aged over 2 advise the following: 1. Bronchodilator therapy •Inhaled (3 agonists are the first line treatment for acute asthma. • A pmDI + spacer is the preferred option in children with mild to moderate asthma. • Individualise drug dosing according to severity and adjust according to the patient's response. • If symptoms are refractory to initial (3 agonist treatment, add ipratropium bromide (250 micrograms/dose mixed with the nebulised (32 agonist solution). • Consider adding 150 mg magnesium sulphate to each nebulised salbutamol and ipratropium in the first hour in children with a short duration of acute severe asthma symptoms presenting with an oxygen saturation less than 92%. • Discontinue long-acting (32 agonists when short-acting (32 agonists are required more often than four hourly. 2. Steroid therapy • Give oral steroids early in the treatment of acute asthma attacks. • Use a dose of 20 mg prednisolone for children aged 2-5 years and a dose of 30-40 mg for children >5 years. Those already receiving maintenance steroid tablets should receive 2 mg/kg prednisolone up to a maximum dose of 60 mg. •Repeat the dose of prednisolone in children who vomit and consider intravenous steroids in those who are unable to retain orally ingested medication. •Treatment for up to three days is usually sufficient, but the length of course should be tailored to the number of days necessary to bring about recovery. Tapering is unnecessary unless the course of steroids exceeds 14 days. 3. Second Line Treatment of Acute Asthma •Consider early addition of a single bolus dose of intravenous salbutamol (15 micrograms/kg over 10 minutes) in a severe asthma attack where the patient has not responded to initial inhaled therapy. •Aminophylline is not recommended in children with mild to moderate acute asthma. •Consider aminophylline for children with severe or life-threatening asthma unresponsive to maximal doses of bronchodilators and steroids. IV magnesium sulphate is a safe treatment for acute asthma in children, although its place in management is not yet established This patient has features of life-threatening asthma and the only drug given with the appropriate dose in the options is that of an aminophylline loading dose. The features of acute severe asthma in adults are: • PEF 33-50% best or predicted • Respiratory rate > 25/min • Heart rate > 110/min •Inability ot complete sentences in one breath
  64. 64. Pharmacology PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT The following are the recommended drug doses in adult acute asthma: • Salbutamol 5 mg delivered by oxygen-driven nebuliser •Ipratropium bromide 500 meg via oxygen-driven nebuliser • Prednisolone 40-50 mg orally •Hydrocortisone 100 mg IV •Magnesium sulphate 1.2-2 g IV over 20 minutes Intravenous salbutamol can be considered (250 meg IV slowly) only when inhaled therapy is not possible (e.g. a patient receiving bag-mask ventilation). The current ALS guidelines recommend that following senior advice IV aminophylline can be considered in severe or life-threatening asthma. If used a loading dose of 5 mg/kg should be given over 20 minutes, followed by an infusion of 500-700 meg/kg/hour. Serum theophylline levels should be maintained below 20 mcg/ml to avoid toxicity.  atypical pneumonia  secondary to Mycoplasma pneumoniae infection. The clinical features of Mycoplasma pneumoniae infection include: •Flu-like illness preceding respiratory symptoms •Fever • Myalgia •Headache •Diarrhoea • Cough (initially dry but often becomes productive) •Focal chest signs develop later in the illness  The X-ray features of the pneumonia are often more striking than the severity of the chest symptoms.  Mycoplasma pneumoniae can be treated with either macrolides, such as clarithromycin, or with tetracyclines, such as doxycycline. The minimum treatment period should be 10- 14 days making option C preferable over option D in this question. The features of life-threatening asthma are: • PEF < 33% best or predicted • Sp02 < 92% • Pa02 < 8 kPA •Normal PaC02 (4.6-6.0 kPa) •Silent chest •Cyanosis • Poor respiratory effort •Exhaustion, altered conscious level • Hypotension
  65. 65. MICROBILOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT  Virulence factors are molecules produced by organisms that contribute to the pathogenicity of the organism and enable them to achieve one or more of the following:  Colonisation of a niche of the host (e.g. attachment to cells)  Evasion of the host’s immune response (immunoevasion)  Inhibition of the host’s immune response (immunosuppression)  Entry into and exit out of cells (if the pathogen is intracellular)  Obtain nutrition from the host M protein is an anti-phagocytic virulence factor produced by certain species of Strepotococcus including Streptococcus pyogenes.  The following table summarizes important virulence factors utilized by different organisms: Virulence factor Example organisms IgA protease secretion Neisseria meningitidis Haemophilus influenzae Streptococcus pneumoniae Protein A Staphylococcus aureus M protein Streptococcus pyogenes Lecthinase alpha toxin Clostridium perfringens Toxin mediated epithelial irritation Vibrio cholerae Spore formation Clostridium perfringens Clostridium tetani Bacillus anthracis Bacillus cereus Flagella Vibrio cholerae Helicobacter pylori Campylobacter jejuni Salmonella typhi Escherichia coli  Miliary tuberculosis, otherwise known as disseminated tuberculosis is when the disease is widely disseminated via the blood or lymphatics and affects other organs. Pott’s disease is extrapulmonary TB that affects the spine. It usually affects the lower thoracic and upper lumbar regions. The only current vaccine available is the BCG (Bacillus Calmete-Guerin). Tuberculosis is spread by aerosol transmission. The Ghon focus is a primary lesion that develops in the lung of previously unaffected patients. It typically occurs in the mid or lower zones of the lung.
  66. 66. MICROBILOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT  The HACEK organisms are a group of Gram-negative bacteria that form part of the human flora and cause culture- negative endocarditis. The HACEK organisms are:  Haemophilus spp.  Actinobacillus spp.  Cardiobacterium hominis  Eikenella corrodens  Kingella kingae  Aerosols are airborne particles that are less than 5 pm in size, such as droplet nuclei (residue from evaporated droplets) containing infective organisms. They typically cause infection of the upper or lower respiratory tract. These organisms can survive outside the body and remain suspended in the air for long periods of time. They can be spread over large distances and transmitted via ventilation systems. For this reason masks and negative pressure rooms are required to prevent spread. Examples of organisms transmitted by the aerosol route include: • Mycobacterium tuberculosis • Varicella zoster virus • Measles virus  Droplets are airborne particles that are more than 5 pm in size. Droplet transmission occurs when respiratory droplets are generated via coughing, sneezing, or talking. Respiratory droplets are large and are not able to remain suspended in the air. For this reason they are usually only dispersed over short distances. Aersoloisation does not occur and special ventilation precautions are not required. Masks and simple hygiene measures (covering mouth when coughing) can prevent spread
  67. 67. MICROBILOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT Examples of organisms transmitted by the droplet route include: • Neisseria meningitidis • Bordatella pertussis •Influenza virus •Parainfluenza virus •Respiratory syncytial virus In clinical practice the two most important groups of alpha-haemolytic Streptococci are: • Streptococcus pneumoniae and; •Streptococcus viridans  Bacillus cereus is a Gram-positive, rod-shaped, beta-haemolytic bacterium. It is the cause of 'fried rice syndrome'. Hardy spores in rice can survive boiling and then leaving the rice at room temperature for long periods prior to frying allows these spores to germinate. Emetic enterotoxin- producing strains cause nausea and vomiting, usually between 1 and 6 hours after consumption. The vomiting can be severe and typically lasts between 6 and 24 hours. There are also diarrhoegenic enterotoxin-producing strains also exist. These predominantly cause abdominal pain and vomiting, which starts 8-12 hours after ingestion and usually resolves within 12 to 24 hours. This is more commonly associated with ingestion of meat, vegetables and dairy products.  The current recommendations by NICE and the BNF on the treatment of animal and human bites are: • Cleanse wound thoroughly • Give tetanus immunoglobulin +/- vaccine if tetanus prone wound • Consider rabies prophylaxis for bites from animals in endemic countries • Assess risk of blood-borne viruses and give appropriate prophylaxis
  68. 68. MICROBILOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT •First-line recommended antibiotic is co-amoxiclav • If penicillin allergic give doxycycline plus metronidazole  Infective causes of bloody diarrhoea include: Campylobacter spp Shigella sp Salmonella spp Clostridium difficile Enteroinvasive Escherichia coli Yersinia spp Shistosomiasis Amoebiasis (Entamoeba histolytica) Enterotoxigenic E.coli is a non-invasive strain and does not cause inflammation and bloody diarrhoea. The enterogenic strains present with profuse watery diarrhoea and are usually not associated with abdominal cramping.  The current recommendations by NICE and the BNF for Campylobacter enteritis is that clarithromycin is used first-line if treatment is required. Azithromycin and erythromycin can be used interchangeably and ciprofloxacin is a suitable alternative.  The National Institute for Health and Care Excellence (NICE) currently recommends three options for the management of acute sore throat: 1. No antibiotics: Patients that have a Centor score of less than 3 and no features that warrant immediate prescription of antibiotics should be advised that antibiotics are likely to make little difference to symptoms and may make things worse due to side-effects. They should, however, be advised to return for further assessment if their condition persists or worsens. 2. Delayed antibiotics: Patients that have a Centor score of 3 or greater and have no features suggesting that an immediate prescription is required should be considered for a two-day or three-day delayed prescription for antibiotics. They should be advised that antibiotics are not currently indicated but that if the situation changes they may be used. They may consider using the antibiotic if the sore throat has not settled within a week as expected or if symptoms worsen. They should be given the option of returning for reassessment and be advised they should do so if symptoms continue to worsen despite using the antibiotic prescription. 3. Immediate prescription of antibiotics: This option should be offered to patients who: •Are systemically very unwell
  69. 69. MICROBILOGY PASS FRCEM PRIMARY IN 7 DAYS DR ABD ELAAL ELBAHNASY EGYPT • Have signs of serious illness and/or complications such as peritonsillar abscess or cellulitis. • Are immunosuppressed • Have valvular heart disease • Have a significant comorbidity (eg, heart, lung, renal, liver or neuromuscular disease, cystic fibrosis) The Centor Criteria are a set of criteria that were originally developed as a tool to identify the likelihood of group A beta haemolytic Streptococcus (GABHS) infection in adult patients complaining of a sore throat. A study published in the BMJ in 2013 looked at whether they could be applied to children. As a consequence of this study the modified criteria were developed, which add in the patient's age and can be used to assess children over the age of 2. Scores may range from -1 to +5. Patients are judged on the following criteria, with one point for each positive criterion: • History of a fever (Temp > 38oC) •Exudate or swelling on tonsils •Tender or swollen anterior cervical lymph nodes • Absence of cough The patient's age is scored as follows: • 3-14 years = +1 point •15-44 years = 0 points •45 years = -1 point  Chickenpox (varicella zoster) has an incubation period of between 7-21 days. It is highly contagious and airborne spread. There is often a prodromal phase when there is a fever, aches and headaches. Dry cough and sore throat may also occur. The rash appears as crops of spots that are itchy and vesicular. They can occur anywhere and several crops may appear over several days.

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