Paper 1 Question 2 Antiepileptic drugs a. Different mechanisms of action Sodium channels i. Carbamazepine ii. Phenytoin GABA mediated inhibition i. Benzodiaspines e.g. Clonazapam, Clobazam, ii. Phenobarbitone Calcium currents i. Ethosuximide ii. Valproate Unknown i. Gabapentin Transaminase blockage i. Vigabatrin Inhibits release of excitatory amino acids i. Lamotrigine b. Influences choice of drug: titrate one drug to maximum and if not adequate seizure control add a second drug with a different mechanism of action c. Steady state reached after 4x t1/2, need to take into account when to increase the dose d. Need to know t1/2 if drug needs to be stopped e. Short half life, can get rapid control of seizure f. Need to know what the dose intervals should be given g. Select antiepileptic drugs appropriate for the seizure type h. Start with a single drug i. Need to know interaction with different drugs in order to know if the plasma level is increased or decreased Carbamazepine by erythromycin, Fluoxetine, cimetidine Carbamazepine by valproate Lamotrigine by valproate Phenobarbitone and Phenytoin decrease the levels of Clonazepam, valproate, Phenytoin Phenobarbitone, rifampicin warfarin j. Avoid polypharmacy k. Short onset of action ideal for use in status Benzodiazepine Phenytoin Phenobarbitone b. Drug Mechanism of Daily schedule Indications Effect on action (T1/2 in hours) seizure types 2+ Valproate Effect on Ca 2-4 Broad (Epilim, current (7-15) spectrum Convulex) Increase availability of GABA + Carbamazepi Blocks Na 2-3 Partial Worsens ne channels (8-24) T/C myoclonus, (Tegretol) atonic absences, Lennox Gastaut, + Phenytoin Blocks Na 1-2 T/C Worsens infantile (Epanutin) channels (9-40) Partial spasms, Lennox Status Gastaut and absence seizure Lorazepam Enhances GABA Not for daily Status (Ativan)) mediated inhibition use epilepticus Higher affinity to 8-35 bind to receptors than diazepam and loger effective at receoptor site Phenobarbito Enhances GABA 1-2 T/C May worsen ne mediated inhibition (37-73) Status myoclonic (Lethyl) Neonatal epilepsy seizures Paper 1: Question 3 a) Write short notes on the pathophysiological explanation for the constituents of oral rehydration solution for diarrhoea in children. Essentially what I was looking for is the concept that sodium absorption is enhanced by the presence of glucose in oral rehydration solution (ORS) by taking advantage of the sodium-glucose co-transporter present in the brush border of intestinal epithelium. Glucose enhances sodium absorption by an active carrier and water absorption by solvent drag. I looked for the concept that glucose concentration should be too high as it may result in osmotic diarrhoea. An ideal concentration is around 20 - 25 g/L. I also wanted the candidate to have the concept of replacement of other losses eg K and bicarbonate. I gave extra marks for the recognition that ORS originated in treating cholera, and for alternative forms of carbohydrate. There is debate concerning the appropriate concentration of sodium, potassium, chloride, and base. Extra marks were also earned for sodium and potassium concentrations, and the type of base used. The appropriate concentration of sodium depends on the clinical circumstances. A sodium concentration of 90 mmol/L in the World Health Organization (WHO) formula was based on studies in patients who had cholera. Solutions containing less than 90 mmol/L of sodium are more palatable than the WHO formula and may also be clinically effective because sodium loss in most diarrhoeal illnesses is lower than in cholera (> 90 mmol/L). The SAPA formulation contains 60 mmol/L. The potassium concentration of most oral rehydration solutions is 20 mmol/L. This level of potassium is less than the concentrations present in the stool of many patients who have diarrhoea. Oral rehydration solutions usually contain bicarbonate or citrate because of their potential benefits in correcting metabolic acidosis and because of increased palatability compared with sodium chloride. Citrate is preferable to bicarbonate because it is more stable and equally efficacious in treating acidosis. The addition of base or base precursor is usually not necessary for managing acidosis because acidosis is often corrected by rehydration alone. b) Write short notes on cotrimoxazole Marks given for virtually every point. I really wanted something about the mechanism of action, metabolism and excretion, indications. Bonus marks given for doses in preventing and treating PCP (it appears that these doses differ in some areas – candidates not penalised). Trimethoprim: blocks action of bacterial dihydrofolate reductase; inhibition of folate synthesis in susceptible microorganisms Sulphamethoxazole: bacteriostatic; arrest cell growth by inhibiting bacterial folic acid synthesis Action of two synergistic Emergence of resistance a problem, esp enterobacteriaceae Main indication: prophylaxis and Rx PCP o doses Rx PCP 10mg/kg load, 5 mg/kg/dose 6hrly for 14-21 days IV o prophylaxis HIV exposed from 6 weeks 5 mg/kg/day 3 or 5 days per week also Rx nocardia, UTI Does not cross BBB well SMP metabolised in liver, rapidly excreted in urine TMP excreted unchanged in urine C/I in infants under 1-2 months (interferes with bilirubin metabolism) S/E: hypersensitivity reactions; GIT c) Write short questions on the pathophysiology of empyaema My question originally focused on pleural empyaema but the question in the exam read only empyaema. Candidates who included subdural empyaema were given extra marks. Commonly secondary to infected parapneumonic effusion, bacterial pneumonia. Marks for staph aureus and strep pneumoniae as the most common causes. 3 stages: exudative; fibrin deposition (bacteria, pleural invasion from contiguous pneumonic process, PMN accumulation, membrane formation, loculated); organisation (fibroblasts grow into exudate from pleural surfaces – pleural peel). o Exudate may drain through chest wall or into lung with pleurocutaneous or bronchopleural fistula May also complicate pneumonectomy or other procedure Rarely may extend from adjacent site eg retropharyngeal, peritonsillar, subdiaphragmatic abscesses d) Write short notes on the pathophysiological basis for the development of cor pulmonale (pulmonary hypertension) secondary to upper airway obstruction. Paper 1; Question 4 Discuss acute renal failure in the neonate under the following headings: i) Classification Pre-renal Intrarenal/renal parenchymal disease Postrenal/obstructive. ii) Causes In most episodes of acute oliguria occurring outside of hospitals,there is usually a single renal cause and a good prognosis. Most episodes of acute oliguria, however, occur in in the hospital and are associated with hypovolaemia, decreased cardiac output, the effects of anaesthesia or surgery, or in the use of diuretics, nephrotoxic agents, or radiographic contrast agents.Patients with acute oliguria that develop in the hospital have multiple renal injuries. The renal insufficiency is frequently severe, and the prognosis is not good as it is with acute oliguria that develops outside the hospital. PRE RENAL (1) HYPOVOLAEMIA Haemorrhage Dehydration Third space losses (2) Normovolaemic hypotesion Sepsis Vasodilator drugs Low cardiac output (congenital heart disease, post-cardiopulmonary bypass, post –asphyxial) INTRINSIC RENAL FAILURE Intrinsic renal failure may progress from severe prerenal failure owing to prolonged hypoxic/ ischaemic injury with resultant acute tubular necrosis. (1) Anoxia/asphyxia (2) Sepsis (3) Nephrotoxic drugs Aminoglycosides Nonsteroidal anti-inflammatory drugs (4) Disseminated intravascular coagulation , Postrenal/obstructive Urethral obstruction (posterior urethral valves) iii) Typical biochemical features TABLE SUBSTANCE Direction of change from normal Creatinine Incr Urea Decr Uric Acid Incr Sodium Decr Potassium Incr Chloride Inc or Decr ** Hydrogen ion Incr Bicarbonate Decr Calcium Decr Inorganic Phosphate Incr Hyponatraemia is diltional in oliguric renal falure but may reflect sodium depletion in non-oliguric renal failure. ** The chloride level may be low,reflecting dilution or salt depletion, but may be paradoxically raised as a result of metabolic acidosis. URINARY INDICES IN THE DIAGNOSIS OF ARF TEST PRE-RENAL FAILURE ACUTE TUBULAR NECROSIS Urine urea High Low Urine creatinine High Low Urine osmolality High (>500mOsm/kg) Low (<300 mOsm/kg) Urine specific gravity High (>1.025) Low (<1010) Urine sodium Low (<10mmol/L) High (>20mmol/L) Urine : plasma urea High (> 10) Low Urine: plasma creatinine High (>40) Low Urine:plasma osmolality High (>2) Low (<1) Fractional Na excretion Low (<1%) High (>4) FE Na (%) = U Na x P Cr U Cr x P Na FE Na of over 2.5 -3.0 % is consistently present in oliguric ATN in term infants. Very preterm babies (<32 weeks) have a high urinary sodium concentration and excretion rate even in health. In this sub-group , suitable cut-off points for the diagnosis of ATN are an FE Na of greater than 6%. iv) Clinical diagnosis The diagnosis of pre-renal failure is confirmed by an improvement in urine flow and renal function in response to fluid repletion. Provided there is no clinical evidence of circulatory overload, a “fluid challenge” of isotonic saline 10ml/kg should be given intravenously over 1 h. Failure to respond confirms ATN as the diagnosis. clinical history -oliguria -non-oliguric renal failure is infrequently identified -non-oliguric renal failure is in fact more common than oliguric renal failure and represents the mild end of the spectrum of renal injury. -most common sign in infants : oedema (due to continuation of normal fluid intake in the presence of unrecognized oliguria) -oedema is NOT a feature of non-oliguric ARF , and polyuria and natriuresis may occasionally lead to salt depletion and dehydration. - physical signs are frequently ABSENT; ARF is often recognized by typical biochemical abnormalities during the investigation of an ill infant. -congenital chronic (ie irreversible) renal failure commonly mimics ARF in its presentation. (this is because the homeostatic and excretory needs of the foetus are met by the maternal,rather than foetal, kidneys via the placenta. Hyperkalaemia (manifest with muscle weakness or paralasis or by ECG changes) Metabolic acidosis (resulting in Kussmaul’s respirations,hypotension, and hyperreflexia). Pulmonary oedema, ascites, or pleural effusions due to salt and water retention. Other complications : nausea, vomiting,altered level of consciousness, pericarditis, confusion, and coma. QUESTION Discuss the pathophysiology, biochemical features and causes of distal (type1) and proximal (type2) renal tubular acidosis. Renal tubular acidosis occurs when the kidneys are unable to maintain a normal bicarbonate concentration.Plasma acid-base homeostasis is achieved predominantly by the kidneys controlling the amount of bicarbonate in the plasma. Usually 85% of filtered bicarbonate is reabsorbed in the proximal convoluted tubule in exchange for hydrogen ion excretion (at normal bicarbonate concentrations). The remaining 15% of the filtered bicarbonate is reabsorbed by the distal convoluted tubules, again in exchange for hydrogen ion excretion. DISTAL PATHOPHYSIOLOGY -inability of distal nephrons to secrete hydrogen ions -& failure to reabsorb filtered bicarbonate -Na fails to be absorbed (via Na/K/H pump)since there are no hydrogen ions for excretion -this leads to intravascular depletion -intravascular depletion leads to aldosterone release (promoting potassium loss) BIOCHEMICAL FEATURES -normal anion gap -hyperchloraemic metabolic acidosis -inappropriately high urinary pH CAUSES -idiopathic -familial -drugs eg amphotericin inherited disease eg sickle cell disease, osteoporosis -systemic disease: eg SLE, -disease causing nephrocalcinosis: -interstitial renal disease : chronic pyelonephritis, obstructive uropathy PROXIMAL PATHOPHYSIOLOGY _reduced proximal absorption of bicarbonate -(the extra bicarbonate in the tubular fluid reaches the DCT and here there is some compensatory reabsorption of bicarbonate ions) -eventually this capacity is exceeded and bicarbonate spills into the urine -the plasma bicarbonate falls until an equilibrium is reached between the plasma and tubular fluid (that is all the filtered bicarbonate is reabsorbed : this occurs when the plasma bicarbonate is usually between 15 and 20 mmol/l -urine can be acidified since distal hydrogen ion excretion is normal -in an attempt to hold on to hydrogen ions, potassium is lost in the DCT in exchange for sodium ions at the Na/K/H pump. -proximal RTA can occur in isolation but is usually part of a more global proximal renal tubular dysfunction called Fanconi syndrome BIOCHEMICAL FEATURES -normal anion gap -hyperchloraemic metabolic acidosis (with inappropriately high urinary pH CAUSES -primary/idiopathic -as part of Fanconi syndrome -familial cases :eg cystinosis -drugs and toxins :heavy metal poisoning ,acetazolamide (carbonic anhydrase inhibitor), -others: interstitial nephritis In order to distinguish between the two types of RTA firstly demonstrate that the child has a normal anion gap metabolic acidosis, and an inappropriately high urinary pH (a pH > 6 in the presence of metabolic acidosis is always abnormal). Next you must demonstrate that the patient can acidify their urine by lowering the urine pH to <5.5 . This can be achieved by using the NH4Cl loading test. If the urinary pH falls below 5.5 then the diagnosis is likely to be proximal RTA; if the urinary pH stays above 5.5 the diagnosis is likely to be distal RTA. Paper 2; Question 2: Write short notes on the following with particular emphasis on paediatric aspects: a. Severe acute respiratory syndrome (SARS) b. Avian influenza virus disease in humans (“bird flu”) c. Immunization against respiratory syncytial virus d. Immunization against rotavirus Answer a. SARS is a new infection recognized a few years ago and due to a coronavirus Outbreak was mainly confined to the Far East but due to modern air travel spread to a number of other countries Paediatric cases relatively few (about 5% of all SARS cases) Severity of illness in children relatively mild compared to adults with low mortality Various phases of disease: viral replication, immune hyperreactive, pulmonary destructive Children have few extrapulmonary manifestations apart from diarrhoea Treatment largely supportive and symptomatic though antivirals have been tried Risks to health workers high as maximal viral replication at about 1 week when patient still in hospital Public health implications Note: Since SARS was not seen in SA, only a few of the above points were necessary for a pass b. “Bird Flu” due to mutation of the influenza virus – new mutation has the combination of haemagglutinin 5 and neuramidase 1 (H5 N1) Can only be contracted from direct contact with birds- no human to human contact recognized thus far Initial cases described in the Far East but has spread to many other countries – no cases yet in SA Causes severe pulmonary infection with high mortality Vaccine in the development phase Treatment largely supportive but antiviral (Tamiflu) useful Major danger occurs if and when human to human transmission becomes a reality – public health implications Note: Since avian influenza has not been seen in SA, only a few of the above points were necessary for a pass c. Past attempts to develop an active vaccine met with failure and a higher mortality in treated subjects New initiatives at a vaccine but nil on the immediate horizon Monoclonal antibody available for passive immunization – cost extremely high Mainly given to selected ex-premature infants <32 weeks as monthly injection during the RSV season. Also a role for infants with congenital heart disease and other chronic respiratory conditions. Knowledge of SA guidelines gained extra marks Funding provided by medical aids in selected cases but not affordable in the public sector d. Rotavirus accounts for a major proportion of cases of acute diarrhea Vaccine developed a few years ago highly effective but rare complication of intusseption – vaccine withdrawn Two new vaccines been through full testing and shown to be highly effective. Becoming commercially available in SA but at significant cost Should be recommended as part of standard immunization program but will probably take a while before introduced in the public sector Likely to have a major impact on morbidity and mortality from acute gastroenteritis Paper 2; Question 4 Discuss the Human Immunodeficiency Virus (HIV) with respect to: a. Viral structure and replication Diagram as in textbook Marks allocated for: RNA virus; retrovirus family; cylindrical eccentric core that encloses diploid RNA genome and enzyme reverse transcriptase. Outer coat contains lipid and glycoprotein 120 (gp120). Gp41, intermembranous portion of envelope, anchors gp120. Associated antigens (Ag) p24 (capsid Ag) which encloses the nucleoid components; p17 is matrix Ag surrounds core of virus. 3 enzymes: reverse transcriptase, integrase, protease. Replication: portion of gp120 domain of viral envelope binds to CD4 molecule with high affinity; gp41 important in fusion of viral envelope with host cell. Virus enters cell; uncoating of virus; reverse transcriptase produces double-stranded virally encoded DNA that enters nucleus and integrates into host genome. Virus now latent, may remain so for some time. Various stimuli initiate transcription of HIV messenger RNA and viral proteins; new viruses assemble at membrane of cell and bud out of cell, which then undergoes apoptosis. b. Effects on the immune system T cells Decreased total lymphocyte count; CD4 cells (T helpers, T4) decreased numbers (infected, apoptosis, direct damage) and function Increased frequency and numbers of CD8 cells; cells activated Reversal of CD4:CD8 ratio B Cells Hypergammaglobulinaemia; abnormal antibody response to variety of Ags Polymorphonuclear neutrophils Neutropaenia impaired chemotaxis, phagocytosis c. Laboratory tests used in the diagnosis of HIV infection Antibody tests Measure immunological response; Rapid and ELISA tests: measure maternal antibodies therefore unsuitable in young infants (< 18 months) Combination ELISA Ag + Ab: esp early infection Antigen tests p24 Polymerase chain reaction (PCR) Viral RNA load Western blot Surrogate markers of immune suppression IgG CD4 Inverse CD4:CD8 ratio Tests may be done on blood, serum, plasma, oral fluid and urine Many candidates confused between Ag and Ab tests Extra marks earned for discussing sensitivity, specificity of tests, and when should be done and reliability of positive / negative test Paper 3; Question 1 Discuss shock in children under the following headings: a) Classification b) Clinical signs c) The pathophysiology of vasodilatory shock SHOCK (a) Classification CARDIOGENIC: eg-cardiomyopathy,heart failure HYPOVOLAEMIC eg-haemorrhage DISTRIBUTIVE eg septicaemia (>>vasodilation) OBSTRUCTIVE eg.tension pneumothorax DISSOCIATIVE eg carbon monoxide poisoning b) clinical signs COMPENSATED (Vital organ function viz brain and heart is conserved by sympathetic reflexes which increase systemic arterial resistance, divert blood away from non-essential tissues, constrict the venous reservoir and increase the heart rate to maintain cardiac output) (the systolic BP remains normal whereas the diastolic pressure may be elevated due to increased systemic arterial resistance) -mild agitation -confusion -skin pallor increased heart rate cold peripheral skin decreased capillary return UNCOMPENSATED (compensatory mechanisms start to fail and the circulatory system is no longer efficient) -falling blood pressure -very slow capillary return -tachycardia cold peripheries -acidotic respiration -depressed cerebral state absent urinary output IRREVERSIBLE SHOCK (a retrospective diagnosis) (damage to key organ viz heart and brain is of such magnitute that death occurs despite adequate restoration of the circulation.) VASODILATORY SHOCK Vasodilatory shock occurs when hypotension occurs as a result of failure of the vascular smooth muscle to constrict (as a compensatory mechanism in situations in which arterial pressure is too low for adequate tissue perfusion). Such so- called vasodilatory shock is characterized not only by hypotension due to peripheral vasodilatation but also by a poor response to therapy with vasopressor drugs. CAUSES Sepsis Inadequate tissue oxygenation : Prolonged and severe hypotension – Shock with probable vasodilatation –eg metformin intoxication MECHANISMS PROMOTING VASODILATATION IN VASODILATORY SHOCK Despite increased plasma catecholamine concentration and the activation of the renin- angiotensin system, vasodilatation and hypotension occur due to failure of the vacular smooth muscle to constrict. Factors accounting for this failure include the death of vascular cells due to prolonged hypotension,inadequate oxygen extraction by the tissues, and increased activity of prostaglandins with vasodilatory activity. 5 Recently three mechanisms implicated in the vasodilatory shock occurring in sepsis : (1) activation of ATP – sensitive potassium channels (2) Activation of inducible form of nitric oxide synthase (3) Deficiency of the hormone vasopressin. : 5 Septic shock comprises a cascade of metabolic, immunologic, and clinical changes that is initiated by a focus of infection or injury and that ends with severe endothelial damage, profound hemodynamic derangements, and, often death. There are interactions of endotoxin or polysaccharide from the cell wall of gram negative bacteria with various inflammatory pathways. Inflammatory cells and cytokines also play a central role . Cytokines are released upon stimulation not only by lipopolysaccharides but enterotoxin, toxic shock syndrome toxins, gram-positive or yeast cell-wall products, and viral and fungal components. Inflammatory mediators are released .The monocyte /macrophage is the principal source of these cytokines (although they may be produced by by a variety of other cells). These mediators stimulate metabolism of arachodonic acid to form leukotrienes,thromboxane A2, and prostaglandins (PGE2 & PGI2). Almost all of these agents have direct effects on the vascular endothelium. Endotoxin,TNF,PAF,leukotrienes, and throboxane A2 each increase endothelial permeability. The endothelium is stimulated to synthesize and elaborate a number of secondary factors that contribute to the inflammatory process. Activation of the coagulation cascade occurs through stimulation of factor XII by microbial cell-wall components. The activation of these pathways may lead to the consumption of coagulation factors and to disseminated intravascular coagulation. TNF is the systemic soluble mediator that plays a central role in sepsis and septic shock. Paper 3;Question2 The role of iron in children a. Daily requirements: Normal infants Low birth weight 1-15 mg/kg/day 2-15 mg/kg/day Initially breast milk adequate until 6 months Increased demand in those with further: then needs supplementation Low initial Hb Who had blood loss later on Lower gestation store, requires earlier supplementation b. Factors that lead to an increased demand. Low birth weight Increased growth rate High altitude Chronic hypoxia Low hb at birth Twins Adolescence Congenital cyanotic heart lesion Blood loss o Pre natal o Post natal o Intranatal Impaired absorption e.g o chronic diarrhoea o malabsorbtion c. Dietary factors that lead to an increased demand Predominantly cow’s milk vs breast milk 49% absorbed from breast milk and only 10% from cow’s milk Huge amounts of tea or rooibos tea Early cow’s milk intake Early solid intake Low vitamin C intake Low meat intake Breast-feeding for > 6 months without Fe supplementation Low socioeconomic status Frequent infections d. Value of a full blood count The following indices in a FBC could assist in the diagnosis of Iron deficiency anaemia: Hb for age MCV, MCH < 27 pg, MCHC < 30% Widened RDW > 17 Hypochromic, microcytic Sometimes poikilocytosis Retic count in severe cases platelet count platelet count in severe Fe deficient case In repeat FBC after Fe was started a therapeutic response could be seen\ o Reticulocytosis o Hb rises e. Clinical effects on CNS Irritability Fatigue Conduct disorders Reduced cognitive performance Breath holding spells Papilledema Slower motor development Poor concentration Short attention span Poor school performance Tiredness and apathy Paper 3; Question 4: a. Define what is meant by the following types of samples in a research project and briefly give an example of how you would obtain such a sample in each case: random sample, systematic sample, stratified sample and convenience sample b. Define what is meant by each of the following principles that guide us in the ethical practice of medicine: autonomy, benevolence, non-maleficence and justice. Give an example where two of these principles may be in conflict. a. Random sample – truly random giving everyone an equal chance of being selected into the sample – e.g. drawing names out of a hat or computer generated random sample. The Lotto also a good example of a random sample. Systematic sample – using a system to select sample e.g. every third household in a street. Stratified sample – ensuring that there is representation from defined groups in the final sample e.g. going to a school and ensuring representation of children of each age: 9 yr olds, 10 yr olds etc or ensuring representation of boys and girls. This requires specific selection strategies with these categories. Convenience sample – using a sample that is easily accessible such as measuring lead levels in hospital admissions to get an idea as to whether this is a problem in the community. Such samples are often used for pilot studies. b. Autonomy – respecting the right of all people as individuals to make decisions as to their health, such as treatment options etc. In the case of children parents usually exercise this right but as children get older their assent and, eventually, consent is required. Some discussion around autonomy with respect to children should be included. Benevolence – the principle underlying most of clinical medicine i.e. trying to do good for one’s patient Non-maleficence – the principle of “do no harm”. While this may sound like benevolence, it is not the same and one may look at the two in terms of the benefits of a treatment versus the potential side effects Justice – this expresses the principle that there should be a sense of fairness in human relations and that one individual should not utilize too many resources of society at the expense of others. In the public health sector this often implies limiting certain forms of expensive treatment for a few and giving priority to less expensive forms of treatment for the many. There are many examples of how two of these principles could be in conflict: e.g. autonomy and benevolence may be overridden in the interests of justice when an expensive form of therapy may be denied to an individual or group as it is thought to be unaffordable; doctors may override the autonomy of the parent in the interests of benevolence to the child if it is considered that the parent was not acting in the best interests of the child. Any reasonable example would be accepted.