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Physiology and Pharmacology

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Two main functions of capillaries   Solute exchange -nutrition of tissue ad hormone/drug delivery - uses diffusion along conc gradient obeying Fick's law Fluid exchange - regulation of plasma and interstitial fluid volume - by bulk flow due to pressure gradients obeying starlings principle  
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Classes of capillaries   Continuous - moderate permeability in brain and nervous system, muscle, lungs, skin etc Fenestrated - High water permeability in exocrine glands, endocrine glands etc Discontinuous - allows rbc movement in liver, spleen etc  
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Intercellular cleft   Provides a tortuous pathway for small hydrophobic solutes Interactions of proteins embedded in membranes forms a tight barrier between cells Not continuous - small gaps allow formation of narrow channels  
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Glycocalyx   Blocks protein access to the intercellular cleft Transmembrane proteins conjugated to sugar molecules Water and small molecules can move Proteins are repelled - 4-5nm gaps too small Hyaluronidase (released by macrophages) destroys this in inflammation  
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Vesicle transport   Allows slow permeation of proteins across the capillary wall Transcytosis Proteins cannot cross junctions so rely on vesicles Can visualise by dinitrophenol conjugated albumin  
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Types of solutes   Lipid soluble - fast diffusional transfer across endothelial wall Small lipid insoluble - fairly fast but confined to small pours not the wall Large lipid insoluble - very slow as confined to a few large pours and vesicles  
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Fick's law of diffusion   Solute flux is proportional to diffusion coefficient, surface area and conc difference but inversely proportional to thickness Permeability is the diffusion flux/(area of membrane x conc difference) Diffusion flux = Permeability x area x conc difference  
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How can diffusion be regulated   Increased blood flow Reduced interstitial concentration Reduce capillary permeability e.g. in response to shear stress Recruitment of capillaries  
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Effect of blood flow on diffusion   Less steep decay in luminal concentration - faster replenishment Lower interstitial conc Maintains concentration difference Increased flow increases shear stress that increases permeability  
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Recruitment of capillaries   Some capillaries are not perfused at rest Recruitment of capillaries reduces radius of Krogh cylinder and improves diffusional transport Increases diffusional area and decreases diffusion distance  
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Oedema   A feature of lymphatic disorder, cardiac failure, renal failure, pleural effusions, peritoneal swelling and joint effusions Dysregulation of fluid exchange leads to accumulation  
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Fluid absorption   A feature of haemorrhage and shock Renal and gut mucosa function  
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Starling principle of fluid exchange - evidence   Cannulated artery of dog leg Injected saline or serum into the muscle With saline dilution of blood was seen Serum produced no change - proteins cannot be reabsorbed and maintain water in interstitial fluid  
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What affects flow   Flow is affected by plasma protein osmotic pressure as well as hydraulic pressure Pc - capillary blood pressure Pi - interstitial fluid pressure Pip - osmotic pressure of plasma proteins Pii - osmotic pressure of interstitial fluid  
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Starling principle of fluid exchange   Flow = LpA[(Pc-Pi)-sigma(Pip-Pii)] Lp = hydraulic conductance of endothelium A = wall area Sigma = osmotic reflection coefficient (capillary is leaky so only a fraction of osmotic pressure is exerted)  
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Medical importance of sigma   Usually around 0.9 in continuous endothelium Falls to around 0.4 in inflammation due to gap formation So the effective retaining force is greatly reduced Fluid leaks out faster causing inflammatory effusions and swelling  
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Unbalance of starling forces   Usually favour filtration and formation of lymph Increased imbalance causes oedema e.g. pulmonary oedema or mitral stenosis (due to increase in Pc or decrease in Pip) If blood pressure falls e.g. haemorrhage these favour absorption (Pc reduced)  
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Causes of excessive capillary filtration   Increased Pc - gravitational oedema, deep vein thrombosis and cardiac failure Low Pip - malnutrition, malabsorption, hepatic failure and nephrotic syndrome Inflammation - high protein oedema (severe and rapid forming), blister, nettle sting, allergy  
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