Muscles of breathing

• Diaphragm – this is the main muscle of inspiration. It flattens out. During normal quiet breathing it is only really the diaphragm that does any work (other muscles are often not involved). It is controlled by the phrenic nerve which has nerve roots in C3-5 [Remember: C3,C4,C5 keep the diaphragm alive])
• External intercostals – they raise the ribcage, and also pull the sternum outwards slightly, which increases the volume of the thorax in a different dimension to the diaphragm (horizontal and vertical vectors)
• Sternocleidomastoid – this will lift the sternum up slightly
• Anterior serrate – this lifts up many of the ribs. It attaches to the inside of the scapula, and its other ends attach to the lateral surfaces of the ribs.
• Scalene – these lift the first two ribs. They attach to the front of the first two ribs, and their other attaches to the transverse processes of the C2-C7 vertebrae.
• Pectoralis minor – this lifts ribs III-IV

Compliance

• However – it is important to remember that this surface tension is only present when there is an air fluid interface in the lungs. I guess the excess mucus produced in COPD will have an adverse effect on this surface tension effect.  

Gas concentrations

Normal air

• 78% nitrogen
• 21% oxygen
• 0.5% water
• 0.04% carbon dioxide

Alveolar Air

• 75% nitrogen
• 13.6% oxygen
• 6.2% water
• 5.3% carbon dioxide

Expired air

• 75% Nitrogen
• 15.7% oxygen
• 3.6% carbon dioxide
• 6.2% water

Nervous control

• Ondine’s curse – this is a condition where there is damage to the autonomic nervous system such that a person may ‘forget’ to breathe, usually during sleep. It occurs in 1 in 200,000 live births, but can also occur as a result of trauma to the brainstem, or poliomyelitis. These patients will require mechanical ventilation for the rest of their lives (but usually only during sleep). It is also known as primary alveolar hypoventilation.
• The DRG (Dorsal respiratory group) is a group of neurons in the medulla. They are ‘I’ (inspiratory) neurons. They are active in every breath, whether quiet or forced.
• The VRG (ventral respiratory group) are also found in the medulla. This contains both I and E (expiratory) neurons, and it is active in forced breathing.

Baroreceptor reflexes

• When blood pressure falls, respiratory rate increases
• When blood pressure rises, respiratory rate decreases

The Hering-Breur Reflexes

Conscious breathing

Accessory muscles of respiration

Gaseous exchange

Ellicit drugs and the respiratory system

• Cannabis – increases the risk of COPD. A very heavy cannabis smoker could possibly get COPD in their 30’s or 40’s even without an α-1 antitrpysin deficiency. Some evidence suggests that one spliff is equivalent to smoking 20 cigarettes
• Cocaine – can cause MI in young people, as well as emphysema
• Heroin – can cause severe respiratory depression – for which you would give naloxone in the acute situation. This drug can be used to treat respiratory depression in any opioid overdose.

Definitions & Terminology

• Kussmaul breathing – this is deep, rapid breathing that is induced by acidosis
• Orthopnoea – this is dyspnoea (shortness of breath) that occurs whilst lying down

The post Respiratory Physiology appeared first on almostadoctor.

Renal physiology is complicated. Don’t worry too much if you don’t feel like you have a full grasp of it – most of us don’t! It seems to be something that only medical registrars and renal physicians truly understand, and for the rest of us it can often remain a mystery. Nonetheless, I’ve attempted to get a handle on the basics in this article.

The job of the kidney is to remove waste products from the blood, as well as to regulate blood volume and plasma osmolarity. In the process, this creates urine.

• Urine consists of mainly water, with some salts and urea
• The kidneys receives a large blood supply to do this – about 20% of blood volume pumped each minute will pass through the kidneys
• Also remember that some of this process of removal of waste products (excretion) is done by the liver, and excreted in the faeces

A nephron is the basic functional unit of the kidney. Nephrons are microscopic in size, and a healthy adult has about 1 million nephrons in each kidney. Nephrons perform three roles; filtration, reabsorption, and secretion.

Firstly, nephrons filter the blood, creating a fluid we sometimes call filtrate. In the healthy kidney this should only contain water and small molecules. It shouldn’t contain any blood cells or any protein, but it contains most of the rest of the ‘stuff’ in the blood – and as such it is chemically similar to serum (without the protein). Secondly, the kidneys reabsorb many of the useful chemical constituents of this filtrate. Thirdly there is a process of exchange that occurs and some components of the blood (e.g. the larger proteins and other large molecules) can be actively secreted. Only once the filtrate has passed through all these processes do we call it urine. 

• Excretion refers to the removal of waste from the body. Thus, the processes of filtration, reabsorption and secretion produce the end result of excretion.

The nephron is made up of:

• The renal corpuscle
  • This bit does the filtering
  • It is made up of the glomerulus and Bowman’s capsule
  • The glomerulus is a bundle of blood vessels, surrounded by a semi-permeable membrane, which allows some of the constituents of the blood to flow through
  • Bowmans capsule collects this fluid and delivers it to the renal tubule
• The renal tubule
  • This bit does the reabsorption
  • It also receives some of the secreted products from the efferent arteriole
  • There are different sections of the tubule that have different roles in the process – which we will discuss later on

Blood arrives via the afferent arteriole into the glomerulus. It is filtered. The filtrate flows on into the renal tubule, whilst the blood flows into the efferent arteriole. The filtrate then has some of its constituents reabsorbed, and then the tubule and the efferent article meet up again at the location of the distal convoluted tubule, so that larger molecules can be actively secreted from the efferent arteriole into the tubule.

There are two types of nephrons, based on differences in their structure. The nephrons themselves sit across the boundary between between the medulla and the cortex of the kidney. Those that mostly sit in the cortex, are called cordial nephrons, and those that mostly sit in the medulla are called juxtamedually nephrons.

• 85% of nephrons are cortical nephrons and 15% are juxtamedullary nephrons.
• Juxtamedually nephrons are typically longer with a larger loop of Henle.

Filtration

There is a visceral epithelium that covers the glomerular capillaries inside Bowman’s capsule. This is just one cell thick, and it is made up of cells called podocytes. These podocytes have projections on their edge called pedicels. For stuff to pass out of the glomerular capillaries, it must be small enough to fit through the gaps between pedicels. These gaps are known as filtration slits.
The filtrate initially produced is pretty much the same as serum, but without the proteins.
In normal circumstances, no protein is able to leave and enter the filtrate. Any large molecules that have to be removed from the blood have to be actively removed further down the tubule.
The basement membrane around the glomerular capillaries is called the lamina densa and it is unusual in that cells of the lamina densa may attached to more than one capillary. This gives them greater control over capillary blood flow and capillary diameter.
The endothelium of the capillaries is fenestrated (has holes in it!). Together, this endothelium, the podocytes and the lamina densa make up the filtration membrane.

• Filtration is a passive process – the disadvantage of this being that you lose stuff you want to keep, such as glucose, vitamins, amino acids etc – and thus you have to get these back into the blood later on.
• The size of the ‘gaps’ in the filtration system varies. There are larger gaps in the capillaries than there are between the pedicels, and thus, placma proteins can pass out of the fenestrated capillaries, but cannot pass through the gaps between pedicels in normal renal functioning.
• BP in the glomerulus is atypically high for a capillary network. This is because the efferent arteriole has a smaller diameter than the afferent arteriole, and thus this keeps the pressure in the glomerulus high. Typically, pressure in the glomerulus are 50mmHg, as opposed to 35mmHg in other peripheral capillary beds.
• The pressure in the capsule opposes the pressure in the glomerulus – this pressure is about 15mmHG, and thus the net hydrostatic pressure is about 35mmHg.
• However, there is also colloid pressure due to the presence of proteins in the blood (and hopefully not in the filtrate!). This pressure is about 25mmHg. Thus, the overall pressure  gradient is about 10mmHg, forcing solute in the direction of the tubules

Glomerular physiology. This file is taken from wikimedia commons and is licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license.

Glomerular filtration rate

• The glomerular filtration rate (GFR) refers to the amount of fluid passing through all glomeruli in one minute.
  • The GFR – normal GFR is about 125ml/minute.
• eGFR is a way of estimating GFR using an equation. The values required for calculation are serum creatinine, age, race, and sex.
  • An eGFR is typically reported with blood results, alongside a blood tests for U+Es
  • It is accurate in kidney disease, however, the method consistently underestimates the GRF of healthy people with a GFR of over 60ml/min.
• The GFR is kept pretty much constant in healthy individuals, despite normal fluctuations in blood pressure. For example a drop in blood pressure will cause:
  • Dilation of the afferent arteriole
  • Constriction of the efferent arteriole
  • Dilation of the glomerular capillaries, and relaxation of the supporting cells.
• A rise in BP, will have the opposite effects. These effects are caused by baroreceptors in the wall of the afferent arteriole – if they are stretched (due to high bp), they will cause the arteriole to constrict – thus they oppose the changes.
• GFR is also regulated by hormonal changes – the renin-angiotensin system and natriuretic peptides

Creatinine clearance is another way we can measure GFR. We know that the concentration of creatinine in the blood is fairly stable. We also know that creatinine is freely filtered into the filtrate, as well as actively secreted into the filtrate in small amounts. Thus, we can use creatinine clearance as a measure of kidney function and to estimate GFR.

• Urine creatinine concentration is compared to plasma creatinine concentration. You measure how much creatinine a person excretes within a given time (e.g. 84 mg/hour). This works out at 1.4mg/minute. If we assume that the plasma concentration of creatinine is the same as the urine concentration, (which just happens to be 1.4mg/100ml), then we know that 100ml of plasma was filtered, and thus the GFR is 100ml/min.

Reabsorption and Secretion

Reabsorption can either be passive – by diffusion, or active, where substances are pumped against a concentration gradient from the tubule. Secretion refers to the active removal of molecules from the blood and into the tubular fluid.

Reabsorption occurs in the renal tubule. This can be divided into three main sections:

• Proximal convoluted tubule – PCT
  • About 70% of the processes of reabsorption occurs here
  • It also actively secreted large molecules – typically strong acids and bases – and as such this is where most drugs are secreted by the kidney
• The loop of Henle
  • Causes concentration of the filtrate, by actively reabsorbing ions – such madly sodium, but also magnesium, potassium and calcium
  • Water is then passively reabsorbed in response to this concentration gradient change
• The Distal Convoluted Tubule
  • Its main job is secretion of ions into the filtrate – particularly potassium
  • It can also reabsorb calcium

Proximal Convoluted Tubule

The PCT (proximal convoluted tubule) is primarily involved in reabsorption – it has a cuboidal epithelium with many microvilli. This is the main place where organic molecules are reabsorbed. Reabsorption of ions and water also occurs here, and the cells do have the ability to secrete, although this is not their main function. Anything that is reabsorbed here is then secreted into the peritubular space (extracellular fluid) where it will be taken up by the peritubular capillaries.

• 70% of reabsoprtion occurs here. Sodium is very important in may PCT processes.The things that are reabsorbed are:
• Organic stuff – amino acids and what not are all removed by facilitated diffusion and co-transport. For example, glucose is taken up by co-transport with sodium.
• Active removal of ions – including sodium, potassium, bicarbonate, magnesium, phosphate and sulphate. Sodium is exchanged for hydrogen. The hydrogen then combines with bicarbonate in the filtrate, and this reacts to turn into water and carbon dioxide. The carbon dioxide is taken up by the PCT cell, where the previous reaction is reversed, releasing bicarbonate and hydrogen!. The bicarbonate is removed into the blood, whilst the hydrogen starts its loop cycles again.
• The ion pumps in this region can be directly affected by hormones (e.g. angiotensin II stimulates sodium reabsoprtion in the PCT).
• Water reabsoprtion – due to osmotic changes due to active ion reabsoprtion.
• Passive removal of ions – they follow the water
• At the base of the PCT cells sodium ions are actively pumped out by a sodium potassium pump. This helps drive many of the process of PCT re-absorption, such as glucose uptake, and bicarbonate re-absorption. At the filtrate side of the cell, sodium ions are attracted to the cell by both their concentration gradient, and a negative charge of the cell created by the sodium potassium pump. Sodium ions can then enter by passive diffuse, co-transport (with organic molecules) or counter transport (with H+, allowing the reabsoprtion of bicarbonate ions). Further along the PCT, concentrations of organic molecules is low, and thus not much sodium can be absorbed by con-transport. So in these instances, sodium is absorbed by co-transport with chloride.
• Potassium will passively diffuse out of the filtrate. However, the PCT also has an ability to secrete potassium if levels are very high.
• Secretion by the PCT is generally for strong acids and strong bases – this is generally secretion of DRUGS!.

Loop of Henle

In the loop of Henle, the ‘thick’ and ‘thin’ segments refer to the size of the cells of this region, and NOT to the diameter of the tubule – this remains roughly the same!

• The thick descending limb has a similar role to the PCT and basically pumps out ions and solutes into the peritubular fluid. This creates a high concentration of solutes in the peritubular fluid, and thus in the peritubular capillaries.
• The thin descending limb is only permeable to water, and thus water will passively cross its membrane owing to the high concentration of solutes in the peritubular fluid, created by the PCT and thick descending limb.
• The loop of Henle concentrates the tubular fluid. It will actively pump out lots of sodium and chloride from the tubular fluid.
• In the loop of Henle a phenomenon known as countercurrent multiplication occurs. This basically is the term for the concentration of the urine. The thick parts of the loop pump out ions, and are pretty much impermeable to everything else. The thin part of the loop is permeable to water but not to anything else. Basically the thick part is the ascending part, and the thin part is the descending part. The thick part pumps out lots of ions, and this creates an osmotic gradient in the peritubular region near the descending limb. This then draws water out of the descending limb (before it reaches the thick ascending limb). This is the process of countercurrent multiplication.
• The pump that pumps out ions is the sodium/potassium/chloride pump. It pumps out 1 sodium, 1 potassium and 2 chloride ions, into the loop of Henle cells. However, the potassium ions later diffuse back into the tubular fluid, and thus the net result of this transport is that it removes 1 sodium and 2 chloride ions from the tubular fluid. Potassium ions are also exchanged for sodium and chloride at the base of the cell, but remember that the overall movement of potassium ions in this region is nil.
• Juxtamedually nephrons have a longer loop of Henle, and thus they concentrate the urine more.
• The vasa recta is a system of capillaries that is found surrounding the loop of Henle. These capillaries will exchange water and ions with the extracellular space around the loop of Henle. The capillaries will lose water and gain ions until equilibrium is reached. Water is drawn out of the capillaries as it is also drawn out of the descending loop of Henle. At the bottom of the loop of Henle this creates a capillary blood that is very thick. As the capillary network then travels back up the ascending loop of Henle it absorbs water from the interstitia. This water is drawn from the collecting ducts! – we have just seen how the ascending limb of Henle pumps out lots of ions, thus creating a hypotonic solution. This solution then travels down the collecting duct, alongside the loop of Henle, next to the concentrated blood of the vasa recta, and thus water moves from the collecting system into the capillaries of the vasa recta. This ensures as little urine as possible is lost.
• This process is controlled by ADH (vasopressin). This is a peptide hormone that is synthesised in the hypothalamus and secreted by the posterior pituitary. ADH essentially increases the permeability of the collecting ducts to water, thus allowing more water to be drawn out by the vasa recta, and thus creating a more concentrated urine.

Distal Convoluted Tubule

The DCT (distal convoluted tubule) – this has a thinner diameter than the PCT. It actually heads back towards the glomerulus, and passes between efferent and afferent arterioles, before doing a U-turn and heading back the way it came from. It actively secretes ions, selectively secretes sodium and calcium, and allows the reabsorption of water. Its main job it the further removal of sodium and chloride from the tubular fluid. Aldosterone will increase the rate of this by increasing the synthesis and mobilization of the sodium channels. Essentially, by the time tubular fluid gets to the collecting ducts, there is only water, urea, creatinine, potassium, hydrogen and maybe some urobillogens / stercobillogens left in it! There isn’t much!

• Retention of sodium (i.e. in the presence of aldosterone) is associated with loss of potassium.
• The DCT is also the place where calcium is reabsorbed – a process that is controlled by parathyroid hormone and calcitriol.
• Hydrogen ions are also secreted in this region in some pretty complicated ways! This is important in controlling blood pH.

The Collecting System

The collecting system – allows secretion of hydrogen and bicarbonate ions, and thus allows the control of blood pH. It also allows the reabsoprtion of bicarbonate, sodium and urea in varying amounts.

The juxtaglomerular apparatus refers to cells of the DCT in juxtaglomerular nephrons that are at the site of the efferent and afferent arterioles. The cells in this region are specialized, and referred to as the macula densa. Together with unusual cells of the afferent arteriole, the macular densa makes up the juxtaglomerular apparatus. These cells are endocrine in function, and secrete erothropoiten and renin.
The three most important waste products in urine are urea, creatinine and uric acid. Urea comes mainly from the breakdown of amino acids, creatinine is a waste product of creatinine phosphate produced by muscle contraction, and uric acid is a waste product from the recycling of RNA molecules. These products can only be excreted when dissolved in water – and thus excretion of them results in unavoidable water loss.
The kidneys can produce a solution that is 4x as concentrated as plasma
The renal threshold is the concentration at which a substance will no longer be able to be completely reabsorbed, and thus will begin to appear in the urine. For example, glucose has a renal threshold. Once concentration in the blood exceeds this threshold, then glucose will appear in the urine. As a substance approaches its renal threshold, its rate of removal from tubular fluid also increases because this is related to its concentration. Glucose renal threshold is about 10mmol/L. so when blood glucose levels are higher than this, the PCT cannot remove all the glucose from the filtrate, and glucose starts to appear in the urine.
The renal threshold for water soluble vitamins is particularly low, and thus if you take vitamin supplement, you are likely to just pee them all out!

Secretion or Excretion?

• Secretion refers to the process of active transfer of a molecule from one place to another – in the case of the kidney it refers to products being secreted into the tubule
• Excretion refers to the process of removal of waste products from the body. Thus the kidney is involved with excretion, and the whole process of filtration, reabsorption and secretion can be thought of collectively as excretion. 

References

• Guyton, AC., Hall, JE. (2005). Textbook of Medical Physiology. Saunders
• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
• Beers, MH., Porter RS., Jones, TV., Kaplan JL., Berkwits, M. The Merck Manual of Diagnosis and Therapy

Read more about our sources

The post Renal Physiology appeared first on almostadoctor.

Only 1% of pancreatic tissue is endocrine. This tissue is found in the Islets of langerhans. Surrounding the islets are adipose tissue deposits. The older you get, the more adipose tissue you have.
There are four types of cell in the islets of langerhans, alpha, beta, delta and F. Alpha and beta secreted substances involved with control of glucose, delta and F cells control the level of action of the gastrointestinal tract.   

Alpha cells

Secrete glucagon – a protein that causes break down of glycogen in liver and muscle cells, thus increasing the level of glucose in the blood. The three main effects of glucagon are:

• Increase in breakdown of glycogen
• Increase in breakdown of fat
• Increased synthesis and release of glucose by the liver

Beta cells

Secrete insulin – this increases the rate of synthesis of glycogen.  The five effects of insulin are:

• Increase in glucose uptake and utilisation by cells
• Increased synthesis of glycogen
• Increased synthesis of adipose tissue
• Increased amnio acid absorption and protein synthesis
• Increased rate of ATP production

Delta cells and F Cells

These secrete growth hormone inhibiting hormone – GHIH (also secreted by the hypothalamus). This is a regulatory hormone that inhibits the release of both glucagon and insulin. GHIH also reduces the motility and absorption of the GI tract.
F cells secrete pancreatic polypeptide (PP) – this is a hormone that reduces secretions of the gallbladder, and reduces the absorptive capacity of the GI tract

Glucose

• The normal level of glucose is 4-6mmol/litre. Insulin will be released when blood glucose levels rise above this. Insulin is a peptide hormone.
• At 2mmol/ you are in danger of unconsciousness
• Levels of 10-15 are sometimes seen in healthy individuals after a meal – this is why when testing for diabetes fasting glucose is the most useful measurement.
• In the post-absorptive state, levels are about 5-6, in the absorptive state, they are usually about 8-10.
• Levels above 20 are getting quite serious and can cause electrolyte imbalance.
• Insulin acts on a tyrosine kinase receptor.
• Insulin itself is mostly responsible for the effects of the absorptive state. Insulin will act on nearly all cells of the body, the main exceptions are brain cells and erythrocytes.

ATP and energy production

Insulin

Control of insulin release

• Insulin is released by beta cells as a result of increased intracellular calcium. Beta cells respond both to a high glucose level, and a relative increase in glucose levels. High glucose in the blood will mean an increase in glucose uptake by beta cells. This then causes an increase in ATP in the cell due to an increase in cellular metabolism. This increase in ATP will cause the closure of an ATP regulated potassium channel, which will then result in the opening of voltage dependent calcium channels and an influx of calcium into the cell. This sets off a second messenger system, causing ultimately a release of insulin by exocytosis.
• Meals high in carbohydrate will cause a sharp rise and early peak in insulin levels, and may also result in glucose levels dropping to below normal levels an hour or so after the meal is eaten. In some people, with reactive hypoglycaemia there is an exaggerated response, similar t that described above. Patients who have had a gastrectomy can suffer similar consequences due to rapid influx of food to the small intestine. This can be treated by eating lots of small meals regularly and limiting the intake of carbohydrate.
• Large numbers of amino acids can also cause the release of glucose, because they are cationic, and will thus depolarise the membrane of beta cells ad result in an influx of calcium into the cell.
• In obese people, the normal insulin response is altered. They release more insulin than a normal individual, however, this does not cause reactive hypoglycaemia, and thus from this we can deduce that obese people have a higher insulin tolerance than normal people, and thus have to secrete more insulin to compensate for this.

Glycolysis

• Glycogenesis – the process of forming glycogen. This generally occurs in the liver and skeletal muscles.
• Glucose-6-phosphate is a molecule that is formed both at the start of glycolysis and glycogenesis. Thus this molecule is the one that is the ‘intermediary’.
• Glycogenolysis is the process of glycogen breakdown to form glucose from glycogen.

Gluconeogenesis

The post Physiology of Metabolism appeared first on almostadoctor.

The two roles of the liver are:

• Processing of absorbed materials
• Excretion of unwanted products and secretion of stuff to help with fat digestion

Structure

• The liver is divided into many thousands of ‘lobules’ – each of which is about 1mm across. These are the functional units of the liver.
• A lobule has a central canal, into which drain many sinusoids. The sinusoids contain a mixture of oxygenated blood (~ 20% – from hepatic arteries) and deoxygenated blood (~80% from the portal venous system)

 

• Bile flows the opposite way to the blood, away from the central canal, in small canaliculi. These canaliculi drain into bile ducts.
• The sinusoids and canaliculi do not have an endothelial lining – they are in direct contact with hepatocytes. The sinusoids do have some sort of sparse lining make up of a collagenous substance, and a few small endothelial cells, and some specialised cells called Kupfer cells. These cells are phagocytotic, and will pick up and old RBCs as well as performing other general cleaning jobs.
• There are tight junctions between hepatocytes that separate the canaliculi and sinusoids; however, these are not totally impermeable, and allow the flow of stuff between these two spaces.
• Conjugation is basically just a process by which molecules have another molecule (usually glycine or taurine) added to them, which then makes them water soluble, and thus easy to secrete. The main thing that the liver conjugates is Bile salt. Bile salts are the conjugated form of bile acid, and thus, bile acids are what we have circulating in our blood, and bile salts are what we secrete in bile.

Bile

• The main constituents of bile are lipids, cholesterol, bile salts and lecithin. These are basically all secreted together in micelles.
• Bile salts are taken up by hepatocytes against their concentration gradient. A hepatocyte will pump out Na⁺, then Na⁺ will want to travel down its concentration gradient back into the cell, and as it does this, it brings a bile salt with it. Bile salts are quickly bound to receptors within the cell to keep the concentration of free bile salts low. Bile acids are pumped out into bile by a separate mechanism.
• Initially, the micelles are composed entirely of bile acids. These are called primary micelles. These can’t incorporate much cholesterol, but are able to incorporate phospholipid. As the micelle takes up more phospholipid it will become a mixed micelle. Generally, the micelles will grow in size as they absorb more phospholipid.

 

• Cholesterol is held at the core of a micelle.
• Micelles are negatively charged and so will repel each other.
• Micelle formation determines the volume of bile secreted – a micelle counts as only one osmotic particle – so if micelles don’t form, then the number of osmotic particles will be greatly increased, even though the actual number of particles present is less than if there were enough present to form micelles. This will mean that as bile is isotonic with plasma, the volume of bile will be greatly increased.
• Bile contains conjugates of loads of waste products, as well as bile salts! These toxins will be at much higher concentrations than in plasma, and so are actively secreted into the bile.
• Conjugation occurs inside hepatocytes. The whole point of conjugation is to give the molecule a negative charge which will make it hydrophilic. Conjugation usually occurs in two steps – in the first (usually oxidation, and involving cytochrome p450) the molecule is polarised. Then in the second it is fully conjugated and given an overall negative charge.
• Usually conjugates are less toxic than their precursors.
• Many substances are conjugated by the liver, but then excreted by the kidneys. Generally, smaller molecules are secreted by the kidney, and larger ones by the liver. Conjugation makes molecules larger, and thus usually conjugated substances are excreted in bile, and unconjugated ones are more likely to be excreted by the kidney.
• Bacteria in the colon can metabolise conjugated products and thus make them less hydrophilic, and then they are more likely to be reabsorbed again by the gut.
• The inside of a hepatocyte is negatively charged relative to the canniculi (about 40mV) and thus this helps to ‘push’ things into the canniculi. However, most things are also actively secreted into the bile against their concentration gradient anyway.
• Bilirubin is normally bound to albumin in the circulation – as are just about all organic molecules!
• Bilirubin is red/orange, but it may degrade in the presence of oxygen to become a green colour. Unconjugated bilirubin cannot be excreted at all. Once bilirubin has been conjugated in hepatocyctes, some may escape (possibly from the calliculi into the sinusoid) into the blood, and be excreted in the urine – giving urine its colour!
• Conjugated bilirubin cannot be absorbed in the gut, but unconjugated can be. Some bilirubin becomes unconjugated by the action of bacteria, and thus is absorbed. Urobillogen is a colourless compound that is absorbed by the gut, having been metabolised by bacteria. Urobillogen that isn’t absorbed will oxidise to stercobillogen and this is a brown colour and it is excreted in faeces; giving the faeces its colour.
• Bile salts are rarely actually excreted in the faeces – they just go round and round in a cycle of excretion and absorption – their role being to help absorb fat.
• Proteins are also present in the bile. These are generally plasma proteins, the main one being IgA, which helps prevent the gut from getting infected. This is actively secreted into the bile.
• The gallbladder ‘concentrates’ bile – i.e. it absorbs stuff out of it! The gallbladder will absorb bicarbonate, sodium and chloride ions, and thus the bile becomes less alkaline. The sodium ions are actively pumped out of the bile – and this also causes water to passively flow out of the bile.  Other stuff present in the bile will become more concentrated as water leaves the bile – thus potassium, calcium and organic molecules all become more concentrated in gallbladder bile.
• Hepatic bile is a brown colour, but after concentration in the gallbladder, bile will become almost black.

The post Liver Physiology appeared first on almostadoctor.

The stomach can be roughly divided into two regions, which contain two different lots of cells, with different functions

• Oxyntic glandular area – this contains oxyntic (parietal cells) that secrete gastric juice and intrinsic factor, as well as chief (peptic cells) that secrete pepsinogen
• Antral (lower) region – this contains G cells that secrete gastrin. G cells are also found in the duodenum.

There are also two other types of cell found all over the stomach:

• ECL cells – which secrete histamine
• D cells – which secrete somatostatin

Most functional cells of the stomach are found in gastric pits. The endocrine (G cells) tend to be closer to the bottom of the pit, as this is closer to blood vessels. At the top of the pits are the mucous secreting cells. This helps to protect cells in the pit from acid.

• Note how mucous cells secrete an alkaline juice, as opposed to the acid secretion of oxyntic (parietal) cells.

The higher the rate of secretion of gastric juice, the more acidic it is. Remember it is hydrochloric acid (H+ and Cl-) that is secreted by the oxyntic cells.

• Pernicious anaemia – this can result from not enough vitamin B12. Thus it can result from destruction of oxyntic cells, which leads to insufficient secretion of intrinsic factor.

The alkaline tide

The production of hydrochloric acid can produce an alkaline tide. This is the relatively high level of bicarbonate found in the blood around the stomach during the production of stomach acid. In patients with severe vomiting, this can produce metabolic alkylosis. Oxyntic cells will take up CO2 from the blood. Once inside the cell, it will dissociate, in the presence of water and carbonic anhydrase to form H+ and HCO3-. The bicarbonate ions are exchanged for chloride ions in the blood, thus producing the outflux of bicarbonate, responsible for the alkaline tide. Remember with high levels of secretion of gastric juice, the juice is also more acidic, hence the exaggerated effect of the alkaline tide in persistent vomiting. Hydrogen ions are then pumped by an active process into the lumen of the gastric pit, by an ATPase that exchanges 1 hydrogen for 1 potassium. Chloride ions are also excreted actively in a process that exchanges them 1:1 with bicarbonate ions.

• Note that it is the CFTR transported that brings in CL- from the blood, but it is not this transporter that transports it out into the lumen.

Intrinsic factor binds with vitamin B12, to form vitamin B12 complexes. These are then absorbed in the distal ileum.  Gastroferrin is another thing released by oxyntic cells. Iron can only be absorbed in its Ferrous (Fe2+) form and not its ferric (Fe3+) form. The acid of the stomach helps keep iron in its ferrous form, but also gastroferrin can bind to fe2+ and prevent it from forming other complexes with other ions, and thus help aid its absorption. Pepsinogen requires an acid environment to become active, and pepsin also requires an acid environment in which to act.

• Pepsin and ulcers – pepsin is actually partly responsible for the formation of ulcers. In situations where the stomach lining is not properly protected, then pepsin can act on your own mucosa and digest it. PPI’s reduce the acidity of the stomach and thus reduce the action of pepsin, thus helping the mucosa to heal.
• Pepsin potentiates, but does not initiate ulcer formation.
• Remember though that most ulcers are in the duodenum, not in the stomach – and the duodenal mucosa in unprotected!

Mucous secretions not only are alkaline and thus help protect the mucosa, but they also help lubricate the food. Note that the mucous does not continually cover the whole of the gastric epithelium. The fact that the stomach also has an excellent blood supply can also help ‘protect’ it due to the fact it can heal very quickly.

• Also remember that food itself buffers a lot of the acid in the stomach.

Absorption in the stomach – the stomach is pretty much impermeable to everything (including water) however, alcohol and aspirin are absorbed here.

• Aspirin reduces prostaglandin secretion and thus reduces cell healing. However, this effect also reduces cell turnover, which is handy in the colon as it reduces the risk of colon cancer.

Control of gastric activity

• This is mostly down to the effect of gastrin. This not only increases the rate of production of acid, but also ‘prepares’ the rest of the stomach for digestion. It is released in response to the presence of amino acids and peptides (mainly peptides) in the stomach. It is also released in response to nervous stimuli (i.e. caused by the presence of a bolus in the stomach, causing the release of ACh by the vagus nerves).
• It is produced by G cells which are open APUD cells – open APUD cells are found all along the GIt and basically they are cells that sample the contents of the lumen and then release something in response to this.
  • Note that ‘closed’ APUD cells still secrete stuff (generally in an endocrine manner) but that they cannot respond to changing luminal contents because they don’t have receptors for this.
• The turnover of G cells is quite slow – and is related to the level of acid in the stomach:
  • Rebound hyperacidity – when you give a PPI you reduce the amount of acid in the stomach. This will cause proliferation of G cells. this will cause an increase in the level of serum gastrin. Thus, when you stop the PPI, then your high levels of serum gastrin will lead to the overproduction of acid.
• Gastrin will also cause increased expression of its own receptor on oxyntic cells, thus causing a ‘multiplying effect’.
• Histamine – the release of histamine will also cause the release of gastric acid from oxyntic cells. It acts on H2 receptors on the oxyntic cells to cause the release of acid. it is released by ECL cells. The ECL cells can be stimulated by the presence of gastrin, or by ACh released by the vagus nerves.
• Histamine causes secretions that are particularly rich in acid.
• Somatostatin is released by D cells. Somatostatin will inhibit gastric acid secretion. It is released by D cells in response to gastrin, and thus this is a feedback mechanism to stop gastric acid secretion getting out of control. It is also released in very large amounts in response to H+ ions. Thus in very acid conditions it strongly inhibits gastric acid production. When the pH is less than 3 it is virtually impossible to stimulate gastric acid secretion.
  • Somatostatin acts in both paracrine and endocrine manners.
• Note that CCK and gastrin have similar effects on stomach mucosa – thus everything that gastrin does, CCK does too – HOWEVER – CCK has a stronger effect on D cells than it does on other cells, and thus it probably actually reduces overall gastric acid secretion. CCk also has a weaker effect than gastrin on cells responsible for increased gastric acid production. Thus when it competitively binds on gastrin receptors it can prevent gastrin from doing so, and thus reduce the potential gastric acid output.
• Nervous stimulation – generally cholinergic (ACh – vagus nerves) will cause an increase in motility and secretion, and adrenergic fibres (sympathetic chain) will have the opposite effect.
• Secretin, GIP and VIP – these are all released by the duodenum, and all bind to the same gastric receptors. They basically inhibit gastric acid production.

Motility

• The gastric cells have an oscillating membrane voltage. Then this reaches the threshold, then the cells will contract. This potential can be altered by stretch (the presence of food in the stomach), and also by nervous stimulation. These two factors will ensure the voltage goes over the threshold and causes contraction.
• Sympathetic stimulation will hyperpolarise the membrane and thus result in reduced motility. Exercise has this effect!

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This article looks at adrenal physiology and explains the production and effects of adrenal products. For more information on mechanisms of blood pressure regulation, secretion of ions, and other effects related to the action of mineralocorticoids, please see the control of renal function.

• The adrenal glands are also sometimes known as suprarenal glands
• They sit on top of the kidneys. They weight about 4g, and have a medulla and a cortex, like the kidneys themselves.
• The medulla – is directly connected to the sympathetic nervous system, and will secrete adrenaline and noradrenaline in response to sympathetic stimulation.
• These two hormones cause almost the exact same effects on body tissues as direct sympathetic stimulation itself does.
• The cortex secretes an entirely different type of hormone – corticosteroids. The corticosteroids are all synthesised from cholesterol, and have similar chemical formulas.
• There are three types of corticosteroid:
  • Mineralcorticoids – e.g. aldosterone – these are so called because they effect the ‘minerals’ (electrolytes) of the blood. They particularly effect sodium and potassium.
  • Glucocorticoids – e.g. cortisol – so called due to their effects on glucose metabolism – however they also have important effects on protein and fat metabolism.
  • Androgens – these are sex hormones that exhibit similar effects to testosterone. They are not particularly important, except in disease of the adrenal glands where their hypersecretion can result in masculization.

Anatomy

• The zona glomerulosa – this constitutes about 25% of the adrenal cortex, and it is where aldosterone is produced – this region contains the enzyme aldosterone synthase. The production of aldosterone is controlled by extracellular fluid concentrations of angiotensin II and potassium. Both these two chemicals will increase the synthesis of aldosterone. Prolonged stimulation of this zone can lead to its hypertrophy.

  

• The zona fasciculata – this constitutes about 75% of the adrenal cortex, and secretes glucocorticoids as well as small amounts of androgens and oestrogens. The secretion of these hormones is largely controlled by the hypothalamic-pituitary axis – and the release of ACTH (adrenocorticotropic hormone).
• The zona reticularis – this is responsilbe for most of the androgen output of the adrenal galnd and it also secretes some oestrogens and glucocorticoids.
• The mechanisms of androgen secretion are not well understood in comparison with the mechanisms of mineralcorticoid and glucocorticoid secretion.

Corticosteroids

• ACTH will cause an increase in corticosteroid synthesis by both increasing the number of surface receptors for LDL’s and it will also increase the number of enzymes used to liberate cholesterol from endocytosed LDL’s.
• Note that stress also causes an increase in cortisol production.
• The rate limiting step in to production of adrenal hormones is the first step in cholesterol breakdown, which occurs in the mitochondria by the enzyme cholesterol desmolase.
• ACTH and angiotensin II will both increase the rate of this reaction.
• There are then a series of reactions in the mitochondria, and then later on the ER that lead to the production of hormones. Obviously, some of these reactions differ depending on which region of the cortex you are in.

Mineralocorticoids 

Effects of aldosterone

• Aldosterone causes increased absorption of sodium, and increased secretion of potassium by the renal tubules. Therefore, in the extracellular fluid, aldosterone causes an increase in sodium and a decrease in potassium levels.
• Conversely, a lack of aldosterone can result in high extracellular potassium levels and low sodium levels.
• Despite these effects, the actual amount of sodium retained is very small, and thus excess sodium retention is rarely an issue. However, the sodium retention causes secondary fluid retention and thus increases arterial pressure significantly. It also causes a sensation of thirst.
• Any excess fluid and sodium will then be removed by normal kidney function – due to pressure diuresis. This method of maintaining normal fluid and salt levels despite high levels of aldosterone is known as the aldosterone escape. Once this level is reached, the level amount of salt and water gain by the body is zero. However, by this stage, the individual will be in a state of hypertension.
• Excess aldosterone will cause hypokalaemia which will lead to muscle weakness as a result of altered cell permeability. It also leads to alkalosis; because aldosterone causes retention of sodium – and this occurs by two mechanisms. The first (already discussed) is where potassium is exchanged for sodium in the renal tubules, but another mechanism involves the exchange of sodium for hydrogen, thus resulting in mild alkalosis. Lack of aldosterone can lead to cardiac failure as a result of high potassium levels.
• Aldosterone also has effect on the GIt and on sweat glands.
• Sweating – normally, we secrete sodium chloride, potassium and bicarbonate in our sweat. The bicarbonate and potassium tend to be subsequently lost, but the sodium chloride can be re-absorbed along the sweat gland. In the presence of aldosterone, this process is enhanced.
• GIt – aldosterone enhances the absorption of sodium from the diet. This effect mainly occurs in the colon. Without aldosterone, this sort of sodium absorption can be poor. This also means that fewer chloride ions and less water is absorbed, which can in turn cause diarrhoea, exaggerating the effect.

Mechanism of action

• Potassium ion concentration
• Renin-angiotensin system

Glucocorticoids

Mechanism

Metabolic actions

• Carbohydrates – Glucocorticoids cause a decrease in the utilization of circulating glucose (mechanism unknown – thought o involve modification of enzymes involved with glucose breakdown within a cell), and an increase in gluconeogenesis. This leads to a tendency for hyperglycaemia. There is also an increase in glucose storage, which is probably a result of increased secreted insulin as a response to the hyperglycaemia.
• Proteins – causes increased catabolism and decreased anabolism – i.e. they cause an overall increase in ‘metabolism’ – breakdown of products to release energy, but a decrease in ‘growth’. Overall there is an increase in protein breakdown, and a decrease in protein synthesis – which can lead to muscle ‘wasting’. However, there is an increase in synthesis of liver proteins. This effect is thought to result from an enhanced transport of amino acid into liver cells (whereas with most other cells, amino acid transport into cells in decreased – but catabolism carries on as normal, and thus over time, proteins are removed from peripheral cells).
• Fats –Initially it causes mobilisation of fat from adipose tissue into the blood, allowing their utilisation for energy needs. This effect probably results from reduced glucose transport into adipose cells, thus they think that glucose levels are low, and so they release fats.
• Later, it has an effect on lypolitic hormones, and causes a redistribution of fat, like that seen in Cushing’s syndrome (e.g. Moon face and buffalo hump). This peculiar type of obesity results from the deposition of fat on the torso and around the head.
• Electrolytes – glucocorticoids tend to reduce the amount of calcium in the body by reducing its uptake from the GIt, and increasing its excretion by the kidneys. This can induce osteoporosis. Glucocorticoids are also likely to cause sodium retention and potassium loss.

Regulatory actions

Hypothalamus and anterior pituitary – causes a feedback effect resulting in reduced release of endogenous glucocorticoids
Cardiovascular system – reduced vasodilation and decreased fluid exudation (oozing)
Musculoskeletal system – decreased osteoblast, and decreased osteoclast activity
Inflammation and immunity

• Acute inflammation – decreased influx and activity of leukocytes
• Chronic inflammation – decreased activity of mononuclear cells, decreased angiogenesis (development of new blood vessels)
• Lymphoid tissues – decreased action of B and T cells, and decreased release of inflammatory mediators by T cells.
• Decreased production of cytokines
• Decreased expression of COX-2 and thus decreased prostaglandin synthesis
• Decreased generation of nitric oxide
• Decreased histamine release from basophils
• Decreased production of IgG
• Decreased complement components in the blood
• Increased anti-inflammatory factors such as IL-10 and annexin-1
• Overall, this results in decreased immune response – both to acquired auto-immune problems, but also to the protective role of the immune system.

Cortisol and stress

• Trauma
• Infection
• Extreme temperature
• Surgery
• Almost any debilitating disease!
• Environmental / social factors – feeling ‘stressed’!

However, it is not always certain why cortisol and its effects are useful in stressful situations. The most obvious thing is that glucose is made available for utilisation, although its actual utilisation is slowed and impeded. Also it is thought that the proteins released in catabolism can, in the very short term, be used by cells to create proteins that are essential to life (such as in the case of trauma). This is possible due to the fact that the most important proteins in a cell are affected last by cortisol – i.e. the ones you need to least are the ones that are broken down first.

Anti-inflammatory effects

1. Stabilisation of lysosomal membranes – this makes it much more difficult for membranes of lysosomes to rupture, and thus the inflammatory proteins often released in the first stages of inflammation are much less likely to be released.
2. Decreased capillary permeability – this is probably secondary to the first effect.
3. Decreased migration and activity of white blood cells – this is a result of reduced release of inflammatory proteins.
4. General immune system suppression – especially that of T cells. This reduces inflammation, due to the inflammatory actions of T cells on affected areas.
5. Reduction of fever – this is mainly a result of reduced secretion of IL-1 from white blood cells. The reduced temperature will also reduce the amount of vasodilation, and thus reduce oedema.

Regulation of secretion

Glucocorticoids as treatments

Unwanted effects

• Poor wound healing
• Peptic ulceration
• Cushing’s syndrome – which is basically a manifestation of all the metabolic and systemic effects described above.
• Diabetes – as a result of the hyperglycaemia
• Weakness and muscle wasting
• Stunted growth in children – particularly if the treatment is continued for more than 6 months – even if the dose is low.
• CNS effects – often the patient may experience euphoris, but it can also manifest as depression. In depressed patients, the depression may be due to a disruption of the circadian rhythm secretion of the steroids.
• Oral thrush (candidasis) often occurs when the drugs are taken orally, as a result of suppression of local inflammatory processes.

Pharmacokinetics

References

• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.

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