Core pharmacology. What causes macrocytosis?
Question.
Which one of the following is NOT a cause of macrocytic anaemia ?
- Alcohol abuse
- Hyperthyroidism
- Methotrexate
- Phenytoin
- Gastrectomy
Core pharmacology. Is a benediction in order?
Question.
A young patient’s median nerve is injured by a supracondylor fracture of the humerus. The resulting motor deficits may include all of the following EXCEPT which one?
- Weakness of pronation
- Weakness of ulnar deviation of the wrist
- Loss of thumb opposition
- Loss of abduction of the index and middle fingers
- Loss of index and middle finger flexion
Core Anatomy : Where does all your K+ go?
Question.
Potassium excretion by the kidney is increased by which one of the following?
- Aldosterone
- Reduced renal tubular flow
- Falling serum pH (acidaemia)
- Spironolactone
- ACE inhibitors
Answer.
1.
Explanation.
Potassium is readily filtered by the glomerulus with around 7-8% of this filtered potassium load ultimately excreted by the kidney. Of the remainder, the majority (70%) is re-absorbed in the proximal tubule (K+-CL- symport and K+-H+ exchanger) and a smaller amount (20%) in the ascending loop of Henle (Na+-K+-2Cl co-transporter) while the distal tubule and collecting ducts can either reabsorb or secrete potassium and are the main point of control of potassium balance.
Influences over the absorption or secretion of K+ in the distal tubule and collecting duct include:
- Aldosterone increases K+ secretion by increasing both numbers and activity of Na+/K+ ATPase in the distal tubule and collecting ducts. These reabsorb Na+ in exchange for pumping out K+ into tubular fluid. Aldosterone secretion from the adrenal cortex is stimulated by rising plasma [K+].
- Secretion of K+ is into tubular fluid also occurs by passive diffusion, and is therefore proportional to the flow rate of tubular fluid; increasing flow causes increased K+ secretion.
- A rise in serum [H+] (acidaemia) causes an increase in K+ reabsorption. The H+-K+ antiporter in the proximal tubule and H+/K+ ATPase of the intercalating cells of the collecting duct both reciprocally pump H+ out into the tubular fluid in exchange for K+ into the cell for reabsorption. Upregulation of these transporters to secrete more H+ in acid excess will cause a reciprocal increase in K+ reabsorption. This in one of the mechanisms through which metabolic acidosis and hyperkalaemia are linked.
Of the diuretics, the loop and thiazides will increase K+ excretion through increasing distal tubular flow rates (and both have the complication of hypokalaemia), while spironolactone increases potassium reabsorption through its effect as an aldosterone antagonist (hence known as a potassium sparing diuretic). ACE inhibitors suppress the renin-angiotensin-aldosterone system and so reduce aldosterone secretion and lead to greater potassium reabsorption.
Core Physiology: Cerebral blood flow
Question.
Which one of the following is NOT correct regarding the cerebral circulation?
- Cerebral oxygen consumption is about 20% of total body oxygen consumption
- The brain uses glucose as its main energy source
- Autoregulation maintains a constant cerebral blood flow for mean arterial pressures (MAP) between 60-160mmHg.
- Cerebral blood flow is very sensitive to arterial pO2
- Local metabolites, ADP, K+ and H+ ions, all increase cerebral blood flow
Answer.
4.
Explanation.
The brain is metabolically very active and under normal condition, cerebral oxygen consumption is about 20% of total body oxygen consumption.
Glucose is the source of 90% of energy of brain in normal conditions. This energy is required for maintaining electrical gradient across cell membrane and transmission of electrical impulses. Rest of energy comes from ketone bodies and other small energy metabolites but very little from fatty acids.
Cerebral blood flow is closely autoregulated and kept constant for mean arterial pressures (MAP) between around 60-150mmHg. Typically, cerebral blood flow is about 750ml per minute or round 15% of cardiac output.
Cerebral autoregulation relies on
- Vasomotor reflex. Increased sympathetic tone moderates blood flow through cerebral arteries at higher blood pressures
- Local metabolites produced when a region of brain tissue becomes more active (e.g. CO2, ADP, K+, H+) cause vasodilatation of local arterioles, thereby increasing blood flow to that region. Occurring throughout the brain this mechanism matches cerebral blood flow to demand both at the local level and for the brain as a whole.
- While marked hypoxia (pO2 < 6-8KPa) will stimulate cerebral arteriolar vasodilatation to increase blood flow to the brain, throughout the physiological range of arterial pO2 (8-15Kpa) cerebral arterioles are largely insensitive to oxygen. Furthermore, supplemental oxygen above this level, if anything, tends to cause vasoconstriction of cerebral arterioles and reduced blood flow.
Core Physiology: A shunt too far.
Question.
Which one of the following statements is true regarding the pathophysiology of pulmonary shunts?
a. Alveolar ventilation and the alveolar–arterial (A-a) gradient are both increased
b. Alveolar ventilation and gas exchange are both reduced
c. Alveolar ventilation is decreased and dead space is increased
d. Alveolar ventilation is normal while perfusion is decreased
e. Alveolar ventilation and the alveolar–arterial (A-a) gradient are both unaffected.
Answer.
The answer is b. Alveolar ventilation and gas exchange are both reduced in a pulmonary shunt, while the alveolar-arterial (A-a) gradient is increased.
Explanation.
A pulmonary shunt is a volume of lung with adequate perfusion but poor or absent ventilation. This creates regions of little or no gas exchange so that blood leaving the shunt remains de-oxygenated. When the deoxygenated blood from the shunt mixes with the oxygenated blood from rest of the lung, it lowers the overall arterial oxygen concentration (PaO2) and if the shunt is large enough, cause systemic arterial hypoxia. Shunts may be as small as a few alveoli in a tiny patch of atelectasis or large as an entire lung. A common cause of pulmonary shunting is pneumonia where the alveoli fill with inflammatory fluid (consolidation).
The alveolar-arterial (A-a) gradient is a measure of the difference between the alveolar concentration of oxygen (PAO2) and the arterial concentration of oxygen (PaO2): A-a gradient = PAO2 – PaO2. Now, the ‘ideal’ alveolar oxygen concentration (PAO2) calculated by the alveolar gas equation is largely unaffected by pulmonary shunts while the arterial oxygen concentration (PaO2) measured by blood gas analysis is markedly reduced, resulting in an increase in the A-a gradient.
Dead space refers to areas of lung that are ventilated but not perfused (the opposite of a shunt) and therefore shunts do not affect dead space.
Five and five useful FOAMed articles for your FRCEM Primary revision! – Revision essentials
Below is a list of ten educational modules, five from RCEM learning and five from Doctors.net.uk Education, which have a basic science focus and are useful for FRCEM primary revision. FOAMed articles are a great way to supplement your learning. If you haven’t found RCEM learning before, it is a great free resource from the College and found at www.rcemlearning.co.uk/landing/. Modules take about an hour to complete and can be added to your CPD folder! If you are not a member already you will need to register to view the Doctors.net.uk education modules.
Understanding the adverse effects of Lithium. – Core pharmacology
Question.
Which one of the following statements regarding lithium (Li) is FALSE?
a. It has a narrow therapeutic range
b. Lithium levels are increased by drugs which induce cytochrome p450
c. Serum lithium levels for monitoring should be measured 12 hours after the last dose
d. Lithium inhibits the action of anti-diuretic hormone (ADH)
e. Hypothyroidism is a frequent adverse effect of lithium therapy
Answer.
The answer is b.
Explanation.
Lithium is a monovalent cation used in the treatment of bipolar disorder, depression and Schizoaffective disorders.
When administered orally it is fully absorbed from the gut with peak levels 4 hours after ingestion. It has a narrow therapeutic index; adverse effects and toxicity are common. Hence patients on lithium require monitoring with blood taken for serum lithium levels 12 hours after the last dose.
Lithium is not metabolised at all by the liver and so enzyme inducers and inhibitors have no effect on levels. It is, however, almost entirely eliminated via the kidneys so that pre-existing renal impairment as well as concomitant use of nephrotoxic drugs (diuretics, ACE inhibitors and NSAIDS) are causes of lithium accumulation and toxicity. Symptoms of lithium toxicity are mostly GI (nausea, vomiting and diarrhoea) and, with more serious poisoning, neurological (tremor, ataxia, confusion and coma).
Lithium inhibits the action of anti-diuretic hormone (ADH) in the collecting duct of the kidney and is a well-recognised cause of nephrogenic diabetes insipidus. It also causes hypothyroidism of varying degrees in around 1 in 5 patients.
When the pulse oximeter and blood gas disagree! – Core physiology
Question.
A normally well 17yr old woman is noted to have marked peripheral cyanosis. Pulse oximetry shows oxygen saturations of 79% though a follow up arterial blood gas records a normal Pa02. Which of the following conditions might explain the discrepancy between clinical signs, pulse oximetry and arterial PaO2?
a. Carbon monoxide poisoning
b. Methaemoglobinaemia
c. Red nail polish
d. Cyanide poisoning
e. Peripheral vasoconstriction
Answer.
The answer is a. Methaemoglobinaemia
Explanation.
Pulse oximetry measures the ratio of oxygenated to de-oxygenated haemoglobin in arterial blood using their differential absorption of red and infrared light. It reports the result as a percentage oxygen saturation of a patient’s blood.
Pulse oximetry only measures oxygenated and deoxygenated haemoglobin and may give falsely high readings in the following circumstances:
- Methaemoglobinaemia (MetHb). MetHb contains an oxidised form of haemoglobin, ferric (Fe3+) Hb which cannot bind oxygen. In the presence of MetHb, therefore, the average haemoglobin oxygen saturation is reduced causing cyanosis and low saturations as measured by pulse oximetry. Arterial blood gas analysis does not take into account the presence of methaemoglobin and so shows high PaO2 levels, reflecting the near full saturation of normal ferrous (Fe2+) Hb, even in the presence of cyanosis.
- Carbon monoxide has a much higher affinity for haemoglobin than oxygen, causing a cherry red appearance of the skin and falsely high pulse oximetry readings.
- Cyanide interferes with the dissociation of oxygen from haemoglobin in tissues, and while the high pulse oximeter readings in cyanide poisoning reflect the true state of haemoglobin oxygen saturation, they do not reflect at all the profound hypoxia occurring at the tissue level.
Falsely low pulse oximeter readings may arise from, motion artefact, venous congestion, tachycardia, poor tissue perfusion and opaque nail polish (of any colour!).
Hormones and renal blood flow – Core physiology
Question.
Renal blood flow is increased by which one of the following set of circulating hormones?
a. Dopamine and angiotensin II
b. Dopamine and renin
c. Angiotensin II and renin
d. Prostaglandins and angiotensin
e. Prostaglandins and dopamine
Answer.
The correct answer is e. Dopamine and prostaglandins both increase renal blood flow.
Explanation.
Renal blood flow is highly auto regulated and maintained at about 25% of cardiac output (or 1.2-1.3L/min for a 70kg adult). Renal blood flow depends on renal vascular resistance as well as on systemic arterial and venous pressures.
Circulating factors which increase renal blood flow include:
- Dopamine: Vasodilation of renal vessels
- Prostaglandins: Increases renal blood flow by vasodilating afferent* arterioles particularly at times of renal hypoperfusion (hence the nephrotoxic effect of NSAIDS which inhibit prostaglandin synthesis)
- Atrial natriuretic peptide (ANP) also vasodilates afferent renal vessels to promote promote glomerular filtration and reduce blood volume.
Those which reduce renal blood flow include:
- Angiotensin II: Vasoconstriction of both afferent and efferent arterioles*, though with greater effect on efferent vessels to increase glomerular filtration
- Norepinephrine: Vasoconstriction.
Local factors: CO2, lactate, H+, K+, hypoxia all vasodilation renal vessels and increase renal blood flow.
[* afferent arterioles branch from the renal artery and supply blood to the glomerulus; efferent arterioles remove blood from the glomerulus and supply it to the capillaries of the renal medulla (vasa recta) and renal cortex.]
Antigen and anaphylaxis. – Core pathology
Question.
A young boy with known peanut allergy presents with an anaphylactic reaction after eating Thai food. Which one of the following statements is most true of the pathophysiology of this condition in this boy?
a. Antigen binding to surface IgM has triggered mast cell degranulation
b. Antigen binding to surface IgE has triggered mast cell degranulation
c. Antigen has directly stimulated neutrophil mediated inflammation
d. Antigen has directly stimulated mast cell degranulation
e. Antigen binding to surface Ig has triggered neutrophil degranulation
Answer.
The answer is b.
Explanation.
NICE Defines anaphylaxis as “a severe, life-threatening, generalised or systemic hypersensitivity reaction. It is characterised by rapidly developing, life-threatening problems involving: the airway (pharyngeal or laryngeal oedema) and/or breathing (bronchospasm with tachypnoea) and/or circulation (hypotension and/or tachycardia). In most cases, there are associated skin and mucosal changes.” It is a type I hypersensitivity reaction.
Anaphylaxis requires pre-sensitisation. During the initial exposure to an antigen, antigen specific IgE is produced and attached to the surface of mast cells. During subsequent exposure(s), the antigen binds and crosslinks surface IgE triggering mast cell degranulation and release of inflammatory mediators most notably histamine but also serotonin, bradykinin and others. This may occur locally and cause a local inflammatory condition (allergic rhinitis for example) or systemically where the inflammatory response causes the life threatening features of anaphylaxis.
Mast cells are produced by the bone marrow from where they migrate to many different body tissues. They are found in high number in sub-epithelial (sub-cutaneous and sub-mucosal) tissues and around blood vessels and nerves. Hence, skin rashes (hives), swelling (angioedema), bronchospasm and vascular changes are prominent.
In many cases of anaphylaxis, an initial immediate reaction is followed by a late phase reaction, usually 2-8 hours after the initial exposure (rarely up to 24 hours). This late phase reaction happens due to the infiltration of tissues with eosinophils, basophils, neutrophils, monocytes and CD4+ T cells.