Chapter 24 Farmaco

7/30/2019 Chapter 24 Farmaco

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Chapter 24. The kidney.

The main function is to maintain the constancy of the interior environment byeliminating waste products and by regulating the volume, electrolyte content and pH ofthe extracellulair fluid in the face of varying dietary intake and varying environmental

demands. The kidneys receive about of the cardiac output.

1. The structure and function of the nephron.

Each nephron consists of a glomerulus, proximal tubule- comprising convoluted andstraight segments, loop of Henle, distal convoluted tubule and collecting ducts. Theglomerulus comprises a tuft of capillaires projecting into a dilated end of renal tubule.

1.1.1 The blood supply tot he nephron.The special characteristic of having two capillarybeds in series with each other. The afferentarteriole of each cortical nephron branches toform the glomerulus; branches to form a secondcapillary network in the cortex. By contrast,efferent arterioles of juxtamedullary nephronslead to vessel loops that pass deep into the

medulla with the thin loops of Henle. These loopsare called vasa recta and play a key role incounter-current exchange.

1.1.2 juxtaglomerular apparatus.A conjunction of afferent arteriole, efferent arterioleand distal convoluted tubule near the glomerulusforms the juxtaglomerular apparatus. There arespecialised cells in both the afferente arteriole and inthe tubule. Macula densa cells, respond to change inthe rate of flow and the composition of tubule fluid,and they control renin release. Other mediators alsoinfluence renine secretion, including beta2-anta, vasodilator prostaglandins and feedback

inhibition ang-II acting on At1-receptors.


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1.1.3. Glomerular filtration.Fluid is driven from the capillaries into the tubular sapsule by hydrodynamic forceopposed by the oncotic pressure of the plasma proteins to which glomerular capillariesare impermeable.

1.2. Tubular function.

The apex of each tubular cell is surrounded by a tight junction. This is a specialised regionof membrane that separates the intercellular space from the lumen. The movement ofions and water across the epithelium can occur through cells and between cells.

1.2.1. Proximal convoluted tubule.The epithelium is leaky, being permeable to ions and water, and permitting passive flowin either direction. The most important mechanism for Na+ entry into tubular cells fromthe filtrate occurs by Na+/H+ exchange. Intracellular carbonic anyhydrase is essential forproduction for H+, and transported out of cells into the interstitium and thence into theblood by a Na+/K+ ATPase. Both Na+/H+ and Na+/K+ are instances antiport-systems.

Bicarbonate is normally completely reabsorbed in the proximal tubule. This is achieved by

combination with protons, yielding carbonic acid, which dissociated to form carbondioxide and water, followed by passive reabsorption of the dissolved carbon dioxide.

Plaatje: Cells are depicted as an orange bored round the yellow tubular lumen. Mechanisms of ionabsorption at the apical margin of the tubule cell: 1.) Na+/H+ exchange; 2.) Na+/K+/2Cl-cotransport; 3.) Na+/Cl- cotransport; 4.) Na+ entry through sodium channels. Sodium is pumpedout of the cells into the interstitium by the Na+/K+ ATPase in the basolateral margin of the tubularcells. The numbers in the boxes give concentration of ions as millimoles per liter of filtrate, and the

percentage of filtered ions still remaining in the tubular fluid at the sites specified.


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Plaatje proximale tubule:Sodium ions are absorbedand H+ secreted at thelumenal surface by anantiport mechanism (a). The

primary active transportmechanism is the Na+ pump(p).

1.2.2. The loop of Henle.Consists of a descending and an ascending portion. Up to 30% of filtered Na+ isreabsorbed by this part of the nephron, which enables the kidney to excrete urine that iseither more or less concentrated than plasma.- Descending limb: permeable to water, which exits passively because the interstitial fluidof the medulla is kept hypertonic.

- Ascending limb: has a very low water permeability, the tight junctions are really tight,enabling the build-up of a substantial concentration gradient across the wall of thetubule. 20-30% of filtered Na+ is reabsorbed. There is active reabsorption of NaCl,unaccompanied by water. Ions move into the cell acros by a Na+/K+/2Cl- symporter.Reabsorption of salt is not balanced by reabsorption of water, so tubular fluid is hypotonicwith respect to plasma.

1.2.3. Distal tubule.In the early distal tubule, NaCl reabsorption fruther dilutes the tubular fluid. Transport isdriven by Na+/K+ ATPase. This lowers cytoplasmic Na+ concentration, and consequentlyNa+ enters the cell from the lumen down its concentration gradient, accompanied by Cl-.PTH and calcitriol both increas Ca2+ reabsorption.

1.2.4. Collecting tubule and collecting duct.Collecting tubules include principal cells, which reabsorb Na+ and secrete K+ and twopopulations of intercalated cells, alfa and beta, which secrete acid and base. The tightjunctions are impermeable to water and ions. It is under independent hormonal control:absorption of NaCL by aldosterone, and absorption of water by ADH. Aldosteroneenhances Na+ reabsorption and promotes K+ excretion. It promotes Na+ reabsorptionby:- A rapid effect, stimulating Na+/H+ exchange;- A delayed effect, via nuclear receptors;- Long-term effects, by increasing the number of basolateral Na+ pumps.ADH is secreted by the posterior pituitary and binds V2 receptors in the basolateralmembranes, increasing expression of aquaporin. This renders this part of the nephronpermeable to water, allowing passive reabsorption of water as the collecting duct

traverses the hyperosmotic region of the medulla and hence the excretion ofconcentrated urine. In the absence of ADH collecting duct epithelium is impermeable to


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water.

Athanol inhibits the secretion of ADH, causing water diuresis as a kind of transientdiabetes inspidus.

DUS!

Na+/K+ ATPase in the basolateral membrane is the main active transporter. It providesthe gradients for passive transporters in the apical membranes. 60-70% of the filteredNa+ and > 90% of HCO3 is absorbed in the proximal tubule.

The thick ascending limb of Henles loop is impermeable to water; 20-30% of filtered NaClis actively reabsorbed in this segment. Ions are reabsorbed from tubular fluid bijNa+/K+/2Cl- cotransporter in the apical membranes of the thick ascending limb ( hierwerken diuretica op in). Filtrate is diluted as it traverses the thick ascending limb as ionsare reabsorbed, so that it is hypotonic when it leaves.

Na+/Cl- cotransport (inhibited by thiazide) reabsorbs 5-10% of filtered Na+ in the distaltubule. K+ is secreted into tubulair fluid in the distal tubule and the collecting tubules

and the collecting ducts. In the absence of ADH, collecting tubules have low permeabilityto salt and water. Na+ is reabsorbed from collecting duct through epithelial sodiumchannels.

1.3.1 Acid-base balance.

Carbonic anyhydrase is essential for acid-base control both because of its lumenal andcellular roles in the proximal tubule.

1.3.2. Potassium balance.Extracellular K+ is tightly controlled through regulation of K+ excretion by the kidney.Potassium ions are transported into collecting duct cells from blood and interstitial fluidby Na+/K+ ATPase and leak into the lumen through a K+ selective ion channel. Thus K+secretion is coupled Na+ reabsorption. Consequently K+ is lost when:- More Na+ reaches the collecting duct;- Na+ reabsorption in the collecting duct is increased directly;K+ is retained when:- Na+ reabsorption in the collecting duct is decreased.

1.3.3. Natriuretic peptides.Nedogenous A, B and C natriuretic peptides are involed in the regulation of Na+excretion. They are released from the heart in response to stretch (A+B), fromendothelium (C) from brain (B). They activate particulate form of guanylate cyclase, andcause natriuresis both by renal haemodynamic effects. The tubular actions include theinhibition of angiotensin-II and of the action of ADH.

Prostaglandings and renal function.Modulate its haemodynamic and excretory functions. Vasodilator and natriuretic. Factorsthat stimulate their synthesis include ischaemia, angio-II, ADH and bradykinin.

2.0. Drugs acting on the kidney.

2.1. Diuretics.Increase the excretion of Na+ and water. They decrease the reabsorption of Na+ and Cl-from the filtrate. Because a very large proportion of salt (NaCl) and water that passes intothe tubule in the glomerulus is reabsorbed, a small decrease in reabsorption can cause amarked increase in Na+ excretion.

2.1.1. Diuretics acting directly on cells of the nephron.Affect those parts of the nephron where solute reabsorption occurs. Most Na+ absorptionoccurs in the proximal tubule -> anyhydrase inhibitors though are not particularly potent.


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This is because they inhibit NaHCO3 rather than NaCl absorption.

The main therapeuticallyu usefull diuretics act on the:- Thick ascending loop of Henle;

- Early distal tubule;- Collecting tubules and ducts.

2.1.2. Diuretics acting on the proximal tubule.carbonic anhydrase inhibitors increase excretion of bicarbonate with accompanying Na+,K+ and water. These agents are now not used as diuretics, but are still used in thetreatment of glaucoma to reduce formation of aqueous humour.

2.1.3. Loop diuretics.Are the most powerful diuretics, capable of causing the excretion of 15-25% of filteredNa+. They also have incompletely understood vascular actions. Loop diuretics increasethe delivery of Na+ to the distal nephron, causing loss of H+ and K+. Because Cl- but notHCO3- is lost in the urine, the plasma concentration of HCO3- increases as plasma volume

is reduced.

They are readily absorbed from the gastrointestinal tract. Given orally, they act within 1hour. They are strongly bound to plasma protein, and so do not pass directly into theglomerular filtrate. They reach their site of action by being secreted in the proximaltubule by the organic transport mechanism. In nephrotic syndrome loop diuretics becomebound to albumin in the tubular fluid, and consequently are not available to act on theNa+/K+/2Cl- carrier.

Unwanted effects: excessive Na+ loss and diuresis are common, and can causehypovolaemia and hypotension. Potassium loss, resulting in low plasma K+, andmetabolic alkalosis. If necessary, hypokalaemia can be averted or treated by concomitantuse of K+-sparing diuretics.

Plaatje ascending limb ofHenles loop: the sodium

pump (P) is the mainprimary active transportmechanism, and Na+, K+and Cl- enter by cotransportsystem (C1). Chlorideleaves the cell both troughbasolateral chloridechannels and by anelectroneutral K+/Cl-cotransport system (C2).Some K+ returns to the

lumen via potassiumchannels in the apicalmembrane, and some Na+is absorbed paracelluarlytrough zonula occludens.


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2.1.4. Diuretics acting on the distal tubule.Thiazides are less powerful than loop diuretics but are preferred in treatinguncomplicated hypertension. They are better tolerated than loop diuretics. They bind to

the Cl- site of the distal tubular Na+/Cl- cotransport system, inhibiting its action andcausing natriuresis with loss of sodium and chloride ions. The resulting contraction inblood volume stimulates rennin secretion, leading to angiotensin formation andaldosterone secretion. Thiazides reduces Ca2+ excretion.

They have anincompletelyunderstoodvasodilator actionand can causehyperglycaemia.When used in thetreatment of

hypertension theinitial fall in bloodpressure resultsfrom decreasedblood volumecaused bydiuresis, but thelater phase is alsorelated to anaction on vascularsmooth muscle.Thiazides have aparadoxical effectin diabetesinspidus, wherethey reduce the

volume of urine by interfering with the production of hypotonic fluid in the distal tubule,and hence reduce the ability of the kidney to secrete hypotonic urine.

They can be taken orally and are all excreted in urine, mainly by tubular excretion. Mildunwanted effects are common. These re-enact the features of Gitelmans syndrome, aredisorder due to an inactivating mutation in the thiazide-sensitive Na+/Cl- cotransporter inthe distal tubule. The clinical features are milder but as in Barterrs syndrome includerenal salt loss, low blood pressure and hypokalaemic metabolic alkalosis; hypocalciuria isa feature, in contrast to Bartters syndrome, and hypomagnesaemia is characteristic. It

can also give erectile dysfunction!

Plaatje distal tubule: the sodium pump (p) in the basolateral membrane is the primary activetransport mechanism. Sodium and chloride ions enter by an electroneutral carrier (c1). Some Cl- istransported out of the cel by K+/Cl- contransport carrier (c2); some leaves the cell trhough chloridechannels. Some K+ is transported out of the cell by the cotransport carrier (c2) and some passesback into the tubule lumen through the potassium channels.

2.1.5. Aldosterone antagonists.


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glomerulus but not reabsorbed by the nephron, they must constitute an appreciablefraction of the osmolarity of the tubular fluid. A larger volume of fluid remains within theproximal tubule. This has the secondary effect of reducing Na+ reabsportion. They arenot useful in treating conditions such as heart failure associated with Na+ retention butmuch more limited therapeutic indications.

3.0 Drugs that alter the PH of the urine.

3.1. Agents that increase urinary PH.Citrate is metabolized via the Krebs cycle with generation of bicarbonate, which isexcreted to give an alkaline urine. Alkalinisation is important in preventing certain weakacid drugs with limited aquous solubility. Sodium bicarbonate is sometimes used to treatsalicylate overdose.

DUS!Normally < 1% of filtred Na+ is excreted. Diuretics increase the excretion of salt andwater. Loop diuretics, thiazides and K+-sparing diuretics are the main therapeutic drugs.Loop diuretics cause copious urine production. They inhibit the Na+/K+/2Cl- cotransporterin the thick ascending loop of Henle. They are used to treat heart failure and other

disease complicated by salt and water retention. Hypovolaemia and hypokalaemia areimportant unwanted effects.

Thiazides are less potent than loop diuretics. They inhibit the Na+/2CL- cotransporter inthe distal convoluted tubule. They are used to treat hypertension. Erectile dysfunction isan important adverse effect. Hypokalaemia and other metabolic effects can occur.

4.1. Drugs that alter the excretion of organic molecules.Uric acid passes freely into the glomerular filtrate, and most is then reabsorbed in theproximal tubule while small amount is secreted into the tubule. The secretory mechanismis generally inhibited by low doses of drugs affect uric acid excretion, whereas higherdoses are needed to bock reabsorption. Such drugs therefore tend to cause retention ofuric acid at low doses, while promoting its excretion at higher doses.

5.1. Drug used in renal failure.

5.1.1. Hyperhosphatataemia.Phosphate causes vascular smooth muscle cell differentiation into osteoblast-like cellsable to sustain mineralization. Hyperphosphataemia is common in renal failure. It mayasymptomatic, but an acute increase in plasma phosphate causes symptoms by causingacute hypocalcaemia. Large calcium phosphate deposits around joints limit mobility butotherwise cause surprisingly few symptoms.

Phosphate binders: approximately half of patient on chronic haemoldialysis are treatedwith such drugs. Calcium-containing phosphoate binding agents are widely used. They

are contraindicated in hypercalcaemia or hypercalciuria but until recently have beenbelieved to be otherwise safe.

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Chapter 24 Farmaco