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2008-11-01No history Add My version 
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I am currently studying for a post graduate degree in pharmacology and this is one of my maps to try to get all the info into my head. They do not conform to traditional mindmap standards but I am trying to visualize everything as far as possible. Therefore the maps are quiet large. Diuretic one is 2.48MB at this stage and to date only about 80% complete. 
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1 Functions of the Kidney
1.1 Regulates blood ionic concentrates

1.1.1 sodium

1.1.2 potassium

1.1.3 calcium

1.1.4 chloride

1.1.5 phosphates

1.2 monitors blood osmolarity

1.2.1 difference osmolarity number of particles per litre osmolality number of particles per kg

1.2.2 terms are interchangeable in physiology

1.3 regulation of blood volume

1.3.1 blood volume affects BP

1.3.2 changing interstitual volume gives rise to oedema

1.3.3 kidneys also secrete renin renin effects the RAAS RAAS important in BP and salt control renin is a vasoconstrictor increased renal resistance increased BP

1.4 regulation of blood pH

1.4.1 if you want to change pH change H+ concentration

1.4.2 kidney increased H+ excretion increased HCO3 resorption bicarbonate maintains acid balance acts as a buffer

1.5 regulates hormones

1.5.1 Calcitrol active form of vitamin D stored in kidney main function is calcium metabolism stimulates calcium binding protein synthesis increases calcium uptake difficiency in calcium ricketts

1.6 regulation of blood glucose

1.6.1 controls resorpsion of glucose

1.7 excretion of wastes

1.7.1 by forming urine puts urea and NH4 in urine adds bilirubin formed from breakdown of haemoglobin adds creatine from breakdown of muscle creatinephosphate adds uric acid from breakdown of nucleic acids elimination of drugs and toxins
2 Anatomy
2.1 blood supply

2.1.1 main renal artery interlobar arteries arcuate arteries interlobular arteries afferent arterioles glomerular capillary nexus efferent arterioles efferent arterioles of the superficial glomeruli ascend to the kidney surface split into peritubular capillaries interlobular veins arcuate veins efferent arterioles of the juxtamedullary glomeruli descend into the medulla divide to form the descending vasa recta ascending vasa recta arcuate veins interlobular veins segmental veins main renal vein

2.2 functional apparatus is the nephron

2.2.1 figure

2.2.2 filtering apparatus glumerulus

2.2.3 tubular portion proximal tubule 65% of filtered sodium reabsorbed here highly permeable to water reabsorbsion isotonic intermediate tubule descending thin limb (DTL) highly permeable to water low permeability to sodium and urea ascending thin limb (ATL) permeable to sodium and urea impermeable to water distal tubule thick ascending limb in medulla in cortex actively reabsorbs NaCl impermeable to urea and water 25% of filtered sodium reabsorbed in loop of Henle passes between afferent arterioles makes contact with macula densa senses concentration of NaCl leaving loop of Henle if [NaCl] is high send chemical signal to afferent arteriole of same nephron causing it to constrict decreases GFR known as tubuloglomerular feedback also regulates renin release from adjacent juxtaglomerular cells efferent arterioles distal convoluted tubule (DCT) actively transports NaCl impermeable to water collecting duct system in control of ultrafiltrate composition modulated by aldosterone volume of urine modulated by antidiuretic hormone (ADH) absence of ADH collecting duct impermeable to water diluted urine presence of ADH collecting duct permeable to water concentrates urine
3 Renal epithelial transport
3.1 figure


3.2 Passive transport

3.2.1 Solvent drag during bulk water flow across a membrane solvent molecules will be transferred across the membrane

3.2.2 Simple diffusion lipid soluble solutes may dissolve in membrane diffuse across membrane down their electrochemical gradient

3.2.3 Channel-mediated diffusion solutes with limited lipid solubility diffuse passively through "pores" formed by integral proteins

3.2.4 Facilitated diffusion Uniport carrier mediated diffusion Solute may bind to integral protein and owing to a conformational change in protein be transported down an electrochemical gradient

3.3 Active transport

3.3.1 movement of solute against electrochemical gradient

3.3.2 primary active transport ATP-mediated transport ATP hydrolysis is coupled to conformational changes in integral proteien

3.3.3 secondary active transport Symport ATP-mediated transport used to create an electrochemical gradient for one solute "free energy"of that solute is then used for the "uphill" transport of other solutes symport co-transport in same direction antiport co-transport in opposite direction Antiport
4 Principles of diuretic action
4.1 Carbonic Anhydrase Inhibitors

4.1.1 Examples Acetazolamide Diamox limited use as diuretics

4.1.2 Mode of Action figure proximal tubular epithelial cells carbonic anhydrase enzyme plays key role in NaHCO3 reabsorbtion acid secretion net effect is to move NaHCO3 from the tubular lumen to the interstitial space followed by the movement of water isotonic reabsorbtion removal of water concentrates Cl- in the lumen Cl- diffuses down its concentration gradient into interstitium via paracellular pathway effects on urinary excretion nett effect due to a few mechanisms loss of bicarbonate-, potassium ions and water effects on renal haemodynamics inhibits proximal reabsorbtion increased delivery of solutes to macula densa triggers TGF system increased afferent arteriole resistance reduced renal blood flow reduced glomerular filtration rate other actions carbonic anhydrase (CA) in numerous other tissues gastric mucosa pancreas CNS can cause parasthesias somnolence used in epilepsy due to metabolic acidosis effect of asetazolamide erythrocytes eye CA mediates the formation of large amounts of bicarbonate ions in cilliary process of the eye inhibition of CA decreases rate of formation of aqueous humour reduced ocular pressure

4.1.3 Adverse effects is a sulphonamide derivate patients hypersensitive to sulphonamides can cause bone marrow depletion skin toxicity allergic reactions most are due to urine alkalisation and metabolic acidosis diversion of ammonia of renal origin from urine to systemic circulation can worsen hepatic encephalopathy alkaline urine calculus formation and urethral colic worsening of metabolic or respiratory acidosis reduction of urinary excretion of weak basis

4.1.4 Contra-indications patients with chirrhosis may cause hyperammonemia hepatic encephalopathy

4.1.5 Uses open-angle glaucoma topical compound Dorzolamide Trusopt single ingredient Cosopt multi ingredient no diuretic effect no systemic metabolic effects oedema epilepsy altitude sickness symptomatic relief give prophylactic symptoms weakness dizziness insomnia headache nausea to correct metabolic alkalosis

4.2 Osmotic Diuretics

4.2.1 Examples glycerin isosorbide mannitol urea

4.2.2 Mode of Action freely filtered by glomerulus limited reabsorbtion relatively inert pharmacologically primary site of action loop of Henle extract water from intracellular compartments therefore expand extracellular fluid volume decrease blood viscosity inhibit renin release these effects increase RBF increase in renal medullary blood flow removes NaCl and urea from the renal medulla reduces medullary tonicity decrease in extraction of water from the DTL limits the [NaCl] in the tubular fluid entering the ATL prostaglandins can have same effect effects on urinary excretion increase urinary excretion of nearly all electolytes Na K Calcium Magnesium Chloride bicarbonate phosphate

4.2.3 Pharmacokinetics oral glycerine isosorbide parenteral (IV) mannitol urea

4.2.4 Adverse effects mostly due to extracellular fluid volume expansion heart failure patients contraindicated pulmonary edema can cause hyponatremia in cells headache nausea vomiting loss of water in excess of electrolytes hypernatremia dehydration urea with extravasation thrombosis pain

4.2.5 Contra-indications severe renal disease not in anuric patients impaired liver function do not give urea can lead to elevation of blood ammonia levels active cranial bleeding urea mannitol glycerin is metabolised can cause hyperglycemia in diabetics

4.2.6 Uses glaucoma by increasing the osmotic pressure of the plasma exctracs water from the eye and brain eye surgery to reduce intra-ocular pressure neurosurgery to reduce brain mass and cerebral edema pre- and post operativly mannitol urea

4.3 Loop Diuretics

4.3.1 Examples Furosemide Lasix Puresis Torasemide Utin

4.3.2 Mode of Action figure of normal action Site of action Thick ascending limb inhibitors of Na+-K+-2Cl-Symport symporter captures free energy in the sodium electrochemical gradient established provides energy for uphill transport of potassium and chloride into the cell diuretics inhibit symporter for sodium,potassium and chloride reduce the reabsorbtion of NaCl up to 25% of filtered sodium excreted by these diuretics also diminish the positive potential that comes from K+ recycling positive potential drives divalent cation reabsorbtion therfore magnesium and calcium excretion is increased by loop diuretics prolonged use can cause hypomagnesia induce synthesis of renal prostaglandins effects on blood vessel NSAIDS can inhibit this formation effect is worse in patients with nephrotic syndrome and hepatic cirrhosis loop diuretics increase renal blood flow loop diuretics block the kidneys abillity to concentrate the urine during hydropenia are powerful stimulators of renin release due to interference of NaCl transport by the macula densa increase systemic venous capacitance decrease left ventricular filling rate especially furosemide benefits patients with pulmonary edema chronic administration increased uric acid levels due to increased reabsorbtion of uric acid competition between diuretic and uric acid for organic acid secretion in proximal tubule reduced uric acid secretion

4.3.3 Pharmacokinetics are rapidly absorbed highly bound to proteins eliminated kidneys glomerular filtration tubular secretion reduction of secretion by NSAIDs Probenecid short elimination half-life two drugs mentioned - liver as well Torasemide Utin Bumetanide Burinex elimination of above prolonged by liver disease

4.3.4 Adverse effects due to abnormalities of fluid and electrolyte balance extra cellular fluid volume depletion hypotension reduced GFR circulatory collapse thromboembolic episodes patients with liver disease hepatic encephalopathy hyponatremia hypokalemia if dietary intake of potassium not sufficient can cause cardiac arrhythmias hypomagnesia due to incresed excretion of magnesium risk factor in cardiac arrhthmias

4.3.5 Toxicity ototoxicity tinnitus hearing impairment deafness vertigo mostly with rapid intravenous administration hypochloremic alkalosis caused by due to increased sodium delivery to distal tubule combined with activation of the RAS leads to increased urinary excretion of potassium and hydrogen ions gout patients hyperuricemia can lead to gout

4.3.6 Contra-indications postmenopausal woman calcium excretion bad for bone metabolism diabetic patients hypoglycemia can be caused by loop diuretics cholesterol can increase plasma levels of LDL decreases HDL levels hypersensitivity to sulfonamides

4.3.7 Interactions Aminoglycosides synergism of ototoxicity anticoagulants increased anticoagulant activity digitalis glycosides increased risk of arrhythmias Lithium increased plasma levels to Lithium Propranolol increased levels of Propranolol Sulfonylureas hyperglycemia NSAIDs blunted diuretic response Probenecid blunted diuretic response Thiazide diuretics synergy can lead to profound diuresis Amphotericin B increased chance of ototoxicity

4.3.8 Uses Acute pulmonary edema chronic congestive heart failure hypertension nephrotic syndrome often unresponsive to other classes of diuretics liver cirrhosis to treat edema ascites use with care hypercalcemia combine with isotonic saline to prevent fluid loss some drug overdose to induce forced diuresis

4.4 Thiazides

4.4.1 Examples Hydrochlorothiazide Ridaq Hexazide sulphonamides with thiazide effects Chlorthalidone Hygroton Indapamide Natrilix Dapamax Hydroless Metolazone Zaroxolyn

4.4.2 Mode of Action inhibit Na+Cl- symport in DCT increases Na+Cl- excretion only moderately effective 90% of filtered sodium is reabsorbed before reaching the DCT Increases K+ excretion by sodium channels chronic administration increased uric acid levels due to increased reabsorbtion of uric acid competition between diuretic and uric acid for organic acid secretion in proximal tubule reduced uric acid secretion decrease Ca2+ excretion can be used to treat kidney stones caused by hypercalciuria can cause magnesium deficiency do not alter kidney's ability to concentrate urine effects on renal haemodynamics do not effect RBF do not effect TGF thiazides act on a point past the macula densa

4.4.3 Adverse effects rarely CNS effects vertigo headache paresthesias Def: abnormal sensation of burning/prickling weakness gastrointestinal anorexia pancreatitis nausea vomiting haematological blood dyscrasias Def: disorder of the cellular components of the blood patients hypersensitive to sulphonamides can cause bone marrow depletion skin toxicity allergic reactions photosensitivity erectile dysfunction greater than with other antihypertensive drugs still tolerable related to volume depletion more serious due to electrolyte and fluid imbalance caused extracellular volume depletion hypotension hypochloremia hypokalemic metabolic alkalosis hypomagnesemia hypercalcemia hyponatremia important due to combination of hypovolemia causes increased level of ADH reduction in diluting capacity of kidney increased thirst impaired carbohydrate tolerance can cause hyperglycemia hyperuricemia hyperlipidemia 5-15% increase in total serum cholesterol LDL

4.4.4 Interactions effects anticoagulants uricosuric agents sulfonylureas insulin effects anesthetics Diazoxide digitalis glycosides lithium loop diuretics vitamin D their effectiveness can be reduced by NSAIDs bile acid sequestrants increased risk of hypokalemia Amphotericin B corticosteroids torades du pointes increased risk if given with Quinidine increased risk factor potassium depletion

4.4.5 Uses edema due to liver cirrhosis renal nephrotic syndrome chronic renal failure acute glomerulonephritis heart congestive heart failure hypertension have additive and synergistic effects when combined with other hypertensive agents use only low doses HCT 25mg per day good choice few contraindications once daily dose do not require dose titration reduced calcium excretion to treat kidney stones to treat osteoporosis nephrogenic diabetes insipidis

4.5 Potassium sparing diuretics

4.5.1 inhibitors of sodium channels Examples Triamterene Dyazide Amiloride No single ingredient drug Subtopic Mode of Action acts on collecting tubules and ducts inhibits Na+ reabsorbtion and K+excretion Amiloride blocks luminal sodium channels by which Aldosterone produces its main effect also has a Mg2+ sparing effect both have mild uricosuric effect Pharmacokinetics Triamterene rapid but incomplete oral absorption 30-70% 67% protein bound half-life 1.5-2.5 hrs diuretic effect starts 2-4 hrs lasts 7-9 hrs elimination extensive hepatic metabolism mainly in faeces and bile Amiloride poor oral absorption 15-50% minimal protein bound half-life 6-9 hrs elimination unchanged in urine and faeces Uses usually in combination with other diuretics where potassium sparing effect is required hypertension oedema Adverse effects hyperkalemia mostly skin rashes less often nausea anorexia abdominal pain flatulance Triampterene poorly soluble in water may precipitate in urine cause kidney stones drink plenty of water

4.5.2 Aldosterone antagonists Examples Spironolactone Aldactone Spiractin Mode of Action metabolised in liver to active metabolite canrenone also an antagonist of aldosterone aldosterone receptors in distal tubule only diuretic that acts on
blood side of tubule and collecting duct antagonist competes with aldosterone for
intracellular aldosterone receptors this complex inhibits the sodium retaining action of aldosterone also causes concomitant decreae in potassium secretion Figure of action has some affinity for progesterone and androgen receptors causes side effects see below renal hemodynamics no effects Pharmacokinetics orally well absorbed protein bound highly liver 25 - 30% metabolised to canrenone half-life of 13-24 hrs elimination mostly renal half-life short 1.6 hrs canrenone long (see above) high concentrations can inhibit cytochrome P450 steroid hydroxylase uses mostly in cases of mineralocorticoid excess due to hypersecretion aldosteronism due to chronic heart failure hepatic cirrhosis nephrotic syndrome in combination with loop and thiazide diuretics to limit potassium loss esp where hypokalemia is dangerous patients on digitalis Adverse effects frequent hyperkalemia where potassium excretion is reduced risk is increased in renal disease drugs that reduce renin NSAIDs beta-blockers reduce angiotensin activity ACE inhibitors angiotensin receptor inhibitors less frequent hyponaturemia dehydration oestrogen-like effects gynocomastia decreased libido impotence benign prostatic hyperplasia menstrual irregularities postmenopausal bleeding hirsutism gastric effects diarrhoea gastritis gastric bleeding and peptic ulcers contraindicated in people with ulcers CNS effects drowsiness lethargy ataxia DEF: failure of muscular coordination confusion headache in cirrhotic patients can induce metabolic acidosis by inhibiting H+ secretion has advantage of not effecting glucose metabolism uric acid elimination