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MRCPCHPHYSIO

In hypernatraemic dehydration the increase in osmolality of the extracellular fluid results in


movement out of the cells so that intracellular fluid volume is depleted and depletion of
extracellular fluid is less than expected. The objectives of therapy should be to treat the
volume depletion and correct electrolyte imbalances slowly. Rapid correction of sodium can
lead to seizures. Subdural effusions not haematomas are a recognised complication.

Somatostatin has various significant effects on the gastrointestinal tract: it inhibits the release
of several gastrointestinal hormones, blocks the exocrine function of the stomach and the
pancreas, and decreases the motility of both the stomach and the gut. Its physiological effects
make it potentially useful in the therapy of various gastrointestinal diseases and disorders.
Somatostatin is effective in the management of active variceal bleeding and increases the
effectiveness of sclerotherapy. The somatostatin analogue octreotide has a definitive role in
the medical management of hormone-secreting neuroendocrine tumours of the gut. GH-
releasing hormone (GHRH) and somatostatin (SS) exert stimulatory and inhibitory influences
respectively, on growth hormone.

Endothelin is produced by vascular endothelial cells and functions as a potent vasoconstrictor.
1,25-Dihydroxycholecalciferol is the physiologically active form of vitamin D. It is formed
primarily in the kidney by enzymatic hydroxylation of 25 hydroxycholecalciferol. ANP is a
potent natriuretic and vasodilatory peptide but is secreted by the heart atria. Somatomedin is
an insulin-like polypeptide made by the liver and some fibroblasts. Angiotensin II is the active
form of angiotensin; it is an octapeptide produced and found in blood and is synthesized from
angiontensin.

The main enzyme that cleaves Angiotensin I to Angiotensin II is called Angiotensin-converting
enzyme and is found predominantly in the lungs. This enzyme is a target for drugs (ACE
inhibitors) that inactivate it, decreasing the rate of angiotensin II production.
Angiotensin II has a number of effects throughout the body including:
It is a potent direct vasoconstrictor leading to an increase in blood pressure. It also
potentiates the release of norepinephrine by a direct action on postganglionic sympathetic
fibres.
Angiotensin II acts on the brain to increase the sense of thirst and increases the secretion of
vasopressin and ACTH.
It acts on the adrenal cortex, causing it to release aldosterone.
It has a direct effect on the kidney to increase the glomerular filtration rate by increasing the
renal perfusion pressure.proximal tubules and to increase sodium resorption.
Angiotensin II is degraded by angiotensinases that are located in red blood cells and the
vascular beds of most tissues, and has a half-life in humans of 1-2 minutes. It is degraded to
Angiotensin III.
During the metabolic response to trauma, there is increased secretion of catecholamines,
cortisol, glucagon and growth hormone. The first three of these tend to increase blood glucose
concentration; catecholamines, cortisol and glucagon act directly, whereas growth hormone
appears to potentiate the action of cortisol and opposes the action of insulin. Adrenaline and
glucagon act most rapidly, by stimulating glycogenolysis; cortisol tends to act more slowly,
through the stimulation of gluconeogenesis. Insulin is a hypoglycaemic hormone. C-reactive
protein is a marker of inflammation, but does not affect glucose homeostasis.
About 100 ml of mucus is produced every day. The cilia are under the control of a physiological
motor, dynein (which is absent in Kartageners syndrome). The mucociliary escalator moves at
2 cm/minute. The bronchioles do not have cartilage in their wall (which distinguishes them
from bronchi). The bronchioles can be up to 1 mm in diameter.
The combination of female phenotype on external examination with 46XY karyotype is typical
of complete androgen insensitivity syndrome, which is caused by a mutation that prevents the
binding of androgens to the androgen receptor.
A failure of testosterone secretion alone in a 46XY individual usually results in an ambiguous
phenotype; this may also occur with a failure of conversion of testosterone to
dihydrotestosterone (DHT) (5a-reductase deficiency): the development of the male external
genitalia in utero is largely dependent on DHT. However, in this condition, masculinisation may
occur at puberty as a result of the increased secretion of testosterone. Neither an abnormal
secretion of FSH or prolactin causes this presentation.

Oxidation of fatty acids occurs in the mitochondria. The transport of fatty acyl-CoA into the
mitochondria is accomplished via an acyl-carnitine intermediate, which itself is generated by
the action of carnitine acyltransferase I, an enzyme that resides in the outer mitochondrial
membrane. The acyl-carnitine molecule is then transported into the mitochondria where
carnitine acyltransferase II catalyses the regeneration of the fatty acyl-CoA molecule.
Deficiencies in carnitine lead to an inability to transport fatty acids into the mitochondria for
oxidation. This can occur in newborns and particularly in pre-term infants. Carnitine
deficiencies are also found in patients undergoing haemodialysis or exhibiting organic aciduria.
Carnitine deficiencies may manifest systemic symptomatology or may be limited to only
muscles. Symptoms can range from mild occasional muscle cramping to severe weakness or
even death. Treatment is by oral carnitine administration.
The luteal stage lasts from day 15 to day 28 of the menstrual cycle. The follicular stage lasts
from day 1 to 14 of the menstrual cycle. Rising levels of oestrogens occur during the follicular
stage. Rising levels of oestrogens cause an increase in the production of luteinising hormone-
releasing hormone (LHRH) and a reduction in the production of follicle stimulating hormone-
releasing hormone (FSHRH).
The zona glomerulosa of the cortex is predominantly responsible for mineralocorticoid
production, the zona fasciculata for glucocorticoid production and the zona reticularis for sex
corticoid production. The adrenal medulla originates from the neural crest and hence there is
almost complete demarcation of function, with the medulla being responsible for the
production of catecholamine-related compounds.
Low-frequency waves are detected in the scala tympani, high-frequency waves are detected in
the scala vestibuli. Both contain perilymph. The scala media is filled with potassium-rich
endolymph. Normal hearing frequency ranges from 20 to 20,000 Hz. The scala media contains
the organ of Corti
The measurement of faecal fat excretion (now regarded as obsolete by many physicians) is a
test for malabsorption, but it does not distinguish between its possible causes. The
pancreolauryl test can be abnormal in pancreatic or biliary disease. Breath hydrogen excretion
is increased with increased bacterial activity in the gut, but this can be a cause of
malabsorption (colonisation of the small gut causes deconjugation of bile salts) and also a
consequence (fermentation of unabsorbed nutrients in the large intestine). The absorption of
xylose may be decreased in various small intestinal diseases.
The lactose tolerance test, in which the rise in blood glucose following a test dose of lactose is
compared with that following a test dose of glucose, is, however, specific for lactase deficiency
(though definitive diagnosis is by measurement of the enzyme in a biopsy sample).
Furosemide is a loop diuretic. Metolazon (a thiazide like diuretic) inhibits Na
+
and Cl
-
transport
in the cortical thick ascending limb and early distal tubule. Mannitol is a non-metabolizable
osmotic diuretic and is filtered into the tubular space where it markedly increases tubular fluid
osmolality. Spironolactone is a competitive antagonist of aldosterone. Therefore it blocks
aldosterone-stimulated Na
+
reabsorption and K
+
and H
+
excretion in the late distal tubule and
collecting duct.

2-adrenoreceptor agonists have effects on smooth and skeletal muscle, including
bronchodilatation, relaxation of the uterus and tremor. 2-agonists also have mild anti-
inflammatory action. 2-agonists enhance mucociliary clearance and have metabolic effects
such as raising free fatty acid, glucose and insulin concentrations. Hypokalaemia also occurs
commonly, especially following intravenous administration, and is thought to be related to
linkage of 2-receptors to Na+/K+-ATPase.
1-receptors agonism causes an increase in heart rate and myocardial contractility.

The insulin-like growth factors (IGF-I and IGF-II; IGFs) share 50% homology with insulin. Both
are present in human serum with molecular sizes of approximately 7.6 kDa. IGFI, previously
known as somatomedin-C, is a basic peptide of 70 amino acids. The liver is a major site of
expression, although almost all tissues express these peptides. IGF-I is an important postnatal
growth factor and its concentration increases at term and postnatally.

In human infants suffering from intrauterine growth retardation. IGF-I concentrations are lower
than in age-matched controls and in macrosomic infants of diabetic mothers, circulating levels
of IGF-I are elevated.

The primary endocrine factors mediating the pubertal growth spurt are sex steroids and growth
hormone. Increasing sex steroid production stimulates increased amplitude of growth hormone
secretion at puberty, with subsequent increased production of IGF-I.

Patients with primary hyperaldosteronism will have an increased aldosterone production
associated with a decreased renin. Patients with secondary hyperaldosteronism (caused by
kidney disease or renal vascular disease) will have increased plasma levels of renin and
aldosterone. Diuretic therapy may enhance renin release probably because of
diuresis/natriuresis . Beta blockers slow down the release of renin from the kidneys.
Deficiency of red cell glucose 6-phosphate dehydrogenase is a common inherited
disorder, which renders red cells susceptible to increases in oxidative stress.
Antimalarial drugs are among several that can cause haemolysis by increasing oxidative
stress in such patients, although many different mutations in the enzyme have been
described, and the range of clinical severity is wide. Glucose 6-phosphatase deficiency is
the cause of type-1 glycogen storage disease.
Pyruvate kinase deficiency is a rare cause of haemolytic anaemia. Decreased activity of
bilirubin glucuronyltransferase can cause unconjugated hyperbilirubinaemia (eg
Gilberts syndrome, CriglerNajjar disease); because the excess bilirubin is
unconjugated, there is no bilirubin in the urine. Deficiency of hydroxymethylbilane
synthase is the cause of acute intermittent porphyria. During acute attacks, the urine
darkens on standing but there is no jaundice. Quinine-like antimalarials do not
precipitate acute attacks of porphyria in susceptible patients.

Prostaglandins (PGs) are biosynthesised from straight-chain C20 fatty acids, arachidonic acid
being the precursor. The responsible enzyme is cyclooxygenase, leukotrienes are formed by
lipoxygenase. Glucocorticoids and aspirin inhibit the prostaglandin synthesis. Prostaglandins
lead to vasodilatation. The amounts of PGs in the tissues are very low, indicating that they are
biosynthesised immediately before hormone-stimulated release. PGs seem to be metabolised by
all body tissues.
The chemoreceptors that regulate respiration are located both centrally and peripherally.
Normally control is exercised by the central receptors located in the medulla, which respond to
the CSF hydrogen ion concentration, in turn determined by CO
2
, which diffuses freely across
the blood-brain barrier from the arterial blood. The response is both quick and sensitive to
small changes in arterial CO
2
(PaCO
2
). Whilst central chemoreceptors are therefore
(indirectly) sensitive to levels of carbon dioxide, peripheral chemoreceptors are also highly
sensitive to oxygen. There are three clusters of peripheral chemoreceptors: the aortic body
located in the wall of the arch of the aorta, and the two nodular carotid bodies in the left and
right common carotid arteries. When the concentration of carbon dioxide in the blood rises, a
condition known as hypercapnia, the central and peripheral chemoreceptors stimulate the
inspiratory areas to stimulate the rate and depth of breathing. This hyperventilation causes
more carbon dioxide to be exhaled until levels return to normal.
Clearance is calculated using the formula (U V)/P where U = urine concentration in mg/ml, V
= urine production in ml/min, P = plasma concentration in mg/ml.

Gas exchange can occur in the final seven branches of the bronchoalveolar tree (the
respiratory zone). The first 16 branches of the bronchial tree are collectively known as the
conducting zone. The equilibration of gases takes about 0.25 s in the resting lung. Only about
1.5% of oxygen is carried in solution in the plasma. Carbon dioxide is more water-soluble than
oxygen, between 5 and 10% of and this is the predominant method of carriage of CO
2
is carried
in dissolved form.
During exercise, increased oxygen consumption and increased venous return to the heart result
in an increase in cardiac output and an increase in blood flow to both skeletal muscle and
coronary circulation, when oxygen utilisation is greatest. The increase in cardiac output is due
to an increase in both heart rate and stroke volume. Systemic arterial pressure also increases
in response to the increase in cardiac output. However, the fall in total peripheral resistance,
which is caused by dilatation of the blood vessels within the exercising muscles, results in a
decrease in diastolic blood pressure. The pulmonary vessels undergo passive dilatation as more
blood flows into the pulmonary circulation. As a result, pulmonary vascular resistance
decreases. The decrease in venous compliance, caused by sympathetic stimulation, helps to
maintain ventricular filling during diastole.
The alveoli at the apex of the lung are larger than those at the base so their compliance is less.
Because of the reduced compliance, less inspired gas goes to the apex than to the base. Also,
because the apex is above the heart level, less blood flows through the apex than through the
base. However, the reduction in air flow is less than the reduction in blood flow, so that the
V/Q ratio at the top of the lung is greater than it is at the bottom. The increased V/Q ratio at
the apex makes PaCO
2
lower and PaO
2
higher at the apex than they are at the base.
Growth hormone (GH) is synthesised, stored, and secreted by the endocrine cells of the
anterior pituitary. Its release is stimulated by growth hormone-releasing hormone and inhibited
by somatostatin. Numerous factors serve as a stimulus for GH release, including hypoglycaemia
(e.g. insulin administration), moderate to severe exercise, stress due to emotional
disturbances, illness, and fever, and dopamine agonists such as bromocriptine.

The history is typical of hypoglycaemia. Blood glucose concentration is maintained in
the fasting state through glucose release from glycogen (glycogenolysis) and
gluconeogenesis (glucose synthesis from lactate and other precursors). Glycolysis
consumes glucose: the activity of the glycolytic pathway is reduced during starvation, to
conserve glucose, with complementary increases in the production and oxidation of
ketones and fatty acids. Abnormalities of the tricarboxylic acid cycle are very rare and
do not cause hypoglycaemia.