Essentials of Clinical Medicine

1. Essentials of Clinical Medicine Session 17 Lecture 1 Homeostasis Peter Stanfield

2. The concept of homeostasis and the internal environment The concept of homeostasis is the central dogma of physiology. Most physiological quantities – components of the internal environment - are controlled between relatively strict limits. Loss – or alteration - of this homeostatic control occurs in disease. In normal physiology, loss of homeostatic control occurs only in extreme (external) environments.

3. Origins of the concept of the internal environment and its homeostasis Claude Bernard: ‘The constancy of the internal environment is the condition for a free and independent life’.

4. Origins of the concept of the internal environment and its homeostasis The term homeostasis was introduced by WB Cannon in 1932

5. Origins of the concept of the internal environment and its homeostasis The coordinated physiological processes which maintain most of the steady states in the organism are so complex and so peculiar to living beings that I have suggested a special designation for these states – homeostasis. The word does not imply something set and immobile, a stagnation. It means a condition – a condition which may vary, but which is relatively constant. WB Cannon: The Wisdom of the Body (1932)

6. The concept of homeostasis and the internal environment • If control of the internal environment exists – there must be mechanisms capable of exerting it. • The physiological quantity must be sensed: • while the external environment is sensed by exteroceptors (including the special senses), the internal environment is sensed by interoceptors. • Means must exist for correcting errors in this quantity • involving an inbuilt notion of the correct value – a set point; • action – through the nervous and endocrine systems – to correct errors. • There must be balance between input and output.

7. The concept of homeostasis and the internal environment Comparator Set point Often the nervous system Often the nervous or endocrine systems Sensor Effector Controlled quantity

8. The reflex arc is one building block for homeostatic control Integrates multiple inputs afferents carry information to the CNS reflex centre within the CNS efferents carry information from the CNS to effector organs

9. The reflex arc is one building block for homeostatic control Usually in homeostatic control the efferent limb of a reflex arc belongs to the autonomic nervous system • The autonomic nervous system has two divisions: • sympathetic • parasympathetic See Mike Stansbie’s lecture in session 14; more later in semester 2 The sympathetic division has the wider distribution and is the more important in homeostasis.

10. The endocrine system also underlies homeostatic control *Endocrine glands release hormones into the blood stream The pituitary gland links nervous action and control of the output of hormones cell of an endocrine gland Capillary of the blood supply of the gland (* related terms are paracrine, where released agents act on neighbouring cells, and autocrine, where agents acts on the cell that secretes the agent.)

11. The concept of homeostasis and the internal environment Take as an example control of body fluid levels – volume and composition are vital for normal physiological activity, including normal excitability of nerve and muscle as well as for the maintenance of the output of an appropriate volume of blood by the heart. Later this session deal with control mechanisms – controlled quantities are: osmolality and volume This lecture expands concepts of the compartmentalisation of body fluids and the equilibrium between these compartments

12. Water and saline are distributed differently and dealt with by different mechanisms changes osmolality changes volume of ECF and Na+ balance From: G Pocock & CD Richards Human Physiology – The Basis of Medicine 3rd Edition 2006 Fig 28.1

13. The concept of homeostasis and the internal environment Comparator Set point Often the nervous system Often the nervous or endocrine systems Sensor Effector Controlled quantity Different sensors and effectors involved in handling water and saline loads

14. Water compartments in health • 60% body weight is water = 42 litres* • Divided into two major elements: • ICF – 40% of body weight = 28 litres • ECF – 20% of body weight = 14 litres • ECF is divided into • Interstitial = 10 litres • Intravascular/plasma = 3 litres • Transcellular [Secretions, eg CSF†] = 1 litre *Figures are for a 70kg (154lb) male: women typically have ~50% of body weight as water, with intracellular water at 30% of total body weight. †CSF = cerebrospinal fluid

15. Water compartments in health Extracellular fluid (ECF) 14 Plasma Interstitial fluid Secretions Intracellular fluid (ICF) 1 3 28 10 Total body water 42 Equilibrium exists between the fluid compartments; cells do work to produce secretions

16. The concept of balance of body water We take in and give out variable amount of water during the day. But these variable amounts must balance each other. IN (ml.day-1): Drink: 1600 Food: 500 Metabolism: 500 Total: 2600 OUT (ml.day-1): Urine: 1500 Faeces: 100 Skin: 500 *Lungs: 500 Total: 2600 *Through saturation of expired air with water vapour

17. Intake of fluid and output of urine are the controlled quantities But the threat to homeostasis may come from other elements. For example: In a hot, dry environment, evaporative losses through sweating and through adding water vapour to expired air may become severe. In diarrhoea, faecal losses become severe. In cholera – may lose several litres of fluid each day, leading to circulatory collapse and rapid death.

18. The balance of body sodium Similarly with sodium – as Na+ - there is a need to balance intake and output. However this can be more difficult to achieve: OUT 10 – 15 g.day-1 Urine – controlled physiologically Faeces Sweat IN (in diet) 10 – 15 g.day-1: Intake of Na+ is greater than required as the minimum (0.5g.day-1), and greater than what is recommended (*<6g of NaCl.day-1) *Equivalent to 2.4g Na+

19. The concept of osmolality • The osmotic pressure of a solution is measured clinically as its osmolality – • It gives a measure of the number of osmotically active particles dissolved in one kg of solvent (water). • Extracellular fluid – plasma, interstitial fluid – typically has an osmolality of ~300mOsm.kg-1 (per kg of H2O). • Contributed principally by electrolytes (NaCl etc), which dissociate in solution (NaCl to Na+ and Cl-), but also by non electrolytes such as glucose, protein etc. • In cytoplasm, a higher fraction of the osmolality (~300mOsm.kg-1) is contributed by non electrolytes. • A solution of osmolality 1 Osm.kg-1 exerts an osmotic pressure equivalent to 22.4 atmospheres (~2300kPa or 17000 mm Hg).

20. The equilibrium between compartments The equilibrium between the cellular and interstitial fluid is principally osmotic. If the osmolality of extracellular fluid is lowered by absorbing water from the gastrointestinal tract – water will move into cells to maintain osmotic equilibrium The equilibrium between interstitial fluid and plasma is determined by osmotic pressure and hydrostatic pressure differences. Gravity can contribute to considerations of hydrostatic pressure differences, increasing these pressures eg in dependent limbs.

21. In osmotic terms, cells are in equilibrium with the interstitial fluid that surrounds them

22. The equilibrium between interstitial and intracellular fluid Three principles to bear in mind: 1. There will be osmotic equilibrium between the compartments. 2. The total number of positive charges on cations will be balanced by the total number of negative charges on anions both in the intracellular and the interstitial fluid. 3. If an ionic species can permeate the cell membrane, these permeant ions will move towards equilibrium.

23. How is an equilibrium established between interstitial and intracellular fluid? Consider a condition where the first two of these conditions are met: cell extracellular K+ K+ Organic anions A- Cl- Is this situation stable?

24. How is an equilibrium established between interstitial and intracellular fluid? Not stable if K+ and Cl- are able to permeate the cell membrane cell extracellular K+ K+ 2. K+ will follow Impermeant organic anions A- 1. Cl- will move in Cl- 3. H2O will also move to maintain osmotic equilibrium

25. How is cellular swelling avoided? Cell volume is stabilised with Na+ as the principal cation of the extracellular space – held there by its relative impermeance and by active transport cell extracellular K+ K+ Na+ Na+ Cl- Cl- Organic anions A- Stable if A- cannot permeate & Na+ is kept out of the cell by the Na+-K+ ATPase.

26. How is an equilibrium established between interstitial and intracellular fluid? Tendency for Cl- to move in is balanced by the tendency for K+ to move out cell extracellular K+ K+ Na+ Na+ Cl- Cl- Organic anions A- Donnan equilibrium

27. How is an equilibrium established between interstitial and intracellular fluid? Are there situations where this equilibrium is upset? Physiologically, cells of the kidney are exposed to considerable variations in osmolality and electroyte composition. If Na+-K+ ATPase is blocked - by cooling or by cardiac glycoside – a drug that blocks the ATPase In open heart surgery, the heart may be paralysed by perfusing it with a cardioplegic solution containing high KCl. (What effect will cardioplegic solutions have on cell volume?)

28. What are the actual ionic concentrations? Concentration in mmol.l-1 cell extracellular K+ 4 160 K+ 10 Na+ Na+ 150 3 Cl- Organic anions A- Cl- 115 Other ions, including HCO3-, Ca2+ and Mg2+ , make up the balance of charges and the osmotic pressure of solutions

29. Equilibrium between plasma and interstitial fluid is determined by osmotic forces and by hydrostatic pressure differences. Equilibrium is established in capillary beds.

30. Capillary beds are the site of exchange between blood and metabolising tissues From: JB Kerr Atlas of Functional Histology Fig. 7.10b Capillaries are thin-walled and permit electrolytes and water to move downhill between blood and tissues. Most capillaries are impermeable to plasma proteins.

31. The osmolality of plasma is contributed by two components: Overall osmolality is ~300mOsm.kg-1 Most (>99%) is contributed by electrolytes - crystalloid osmotic pressure A small amount (~0.3%) is contributed by plasma protein - colloid osmotic pressure or oncotic pressure. In units of mm Hg, used in cardiology, this equates to 25mm Hg. But the blood in capillaries is also under pressure – owing to the pumping action of the heart.

32. Impermeance of plasma proteins generates a colloid osmotic pressure Colloid osmotic pressure draws fluid into capillaries from interstitial space arteriolar venular Colloid osmotic pressure 25mm Hg This simplifies: there is some protein in interstitial fluid

33. However, hydrostatic pressure tends to force fluid out of the plasma across capillary walls arteriolar venular hydrostatic pressure 35mm Hg capillary hydrostatic pressure 15mm Hg filtration of plasma This also simplifies: there are effects of gravity increasing hydrostatic pressures in organs below the heart

34. Equilibrium between plasma and interstitial fluid Filtration pressure = hydrostatic pressure – colloid osmotic pressure arteriolar venular filtration at arteriolar end colloid osmotic pressure 25mm Hg hydrostatic pressure 15mm Hg hydrostatic pressure 35mm Hg reabsorption at venular end

35. Errors in this equilibrium may result in oedema. • Loss of oncotic pressure gradient • Loss of plasma protein in • starvation, • liver disease, • kidney disease. • Alterations of capillary permeability – for example in anaphylaxis Alterations of hydrostatic pressures Cardiovascular disease – especially in heart failure, where venous pressures rise

36. Pitting oedema – interstitial fluid is a gel From: G Pocock & CD Richards Human Physiology – The Basis of Medicine 3rd Edition 2006 Fig 28.10

37. Pitting oedema – interstitial fluid is a gel Interstitial space contains collagen, salts of hyaluronic acid, and proteoglycans. Hydrated hyaluronates and proteoglycans form a gel. Interstitial fluid does not trickle through the body under the influence of gravity. Indeed oedema – for example associated with heart failure – is described as pitting oedema. From: G Pocock & CD Richards Human Physiology – The Basis of Medicine 3rd Edition 2006 Fig 28.10

38. Secretion and secretion pressure • Note that movements between interstitial fluid are downhill, so that the electrolyte composition of the compartments will be similar. • Transcellular fluids are usually secretions – CSF, aqueous humour etc. These are formed by cells doing work. • The electrolyte composition will in general not be the same as that of interstitial fluid. • Further, a secretion pressure can be developed. • Failure of normal drainage leads to an increase in pressure. Eg • CSF – hydrocephalus • Aqueous humour - glaucoma

39. To summarise: • Homeostasis – central to understanding physiology – consider systemic regulation of body fluids in lecture 2. • Body fluids are compartmentalised. • These compartments are in equilibrium with each other, particularly in terms of their osmotic pressure. • Impermeant cellular anions and active transport of Na+ affect the distribution of other, permeant ions (K+ and Cl-). • Interstitial fluid and plasma are in equilibrium because of the balance of hydrostatic and osmotic pressure gradients. • Secretion involves cells doing work, altering ionic composition and generating a secretion pressure.