Drugs and the kidney -...
Transcript of Drugs and the kidney -...
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Drugs Acting on the Kidney
Dr Alison Ingham Jan 2017
Afferent Arteriole
Efferent Arteriole Glomerular Filtration • 3 layers
1) Fenestrated capillary endothelium 2) Glomerular basement membrane 3) Glomerular epithelial cells have fingerlike
projections with slit-pores
• 100 times more porous than normal capillary membrane
• Size (<8nm) and charge important
Glomerular Filtration
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• GFR = 170L.day-1 (120 ml.min-1)
• Urine = 1L.day-1
• Therefore > 99% of filtrate is reabsorbed
ALMOST ALL ENERGY CONSUMED IS USED IN ACTIVE REABSORPTION
Glomerular Filtration Juxtaglomerular apparatuus
Juxtaglomerular apparatus
• Specialised segment of afferent arteriole • Contains renin secreting cells • Macula densa in the wall of the distal tubule • Renin is released in response to:-
1) sympathetic stimulation 2) decreased wall tension in afferent arteriole 3) decreased Na+ & Cl- delivery to macula densa
Renin-angiotensin system
Angiotensinogen Renin
Angiotensin I ACE vasoconstriction Angiotensin II ADH aldosterone
Angiotensin III (inactive)
Renal Blood Flow • 25% of cardiac output • 1200 ml/min • Considerable regional variation
– cortical blood flow 4ml/g/min. Tissue pO2 6.5kPa
– medullary blood flow 2ml/g/min. Tissue pO2 2kPa
• Major O2 demand is for active Na reabsorption in ascending thick Loop of Henle
Autoregulation
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ACE inhibitors
• Angiotensin II causes efferent arteriolar vasoconstriction
• Maintains pressure in glomerular capillary and GFR
• If on ACE inhibitor difficult to respond to hypotension by efferent arteriolar vasoconstriction
NSAIDS and ARF
• Haemodynamically mediated – renal prostaglandins vasodilate
• Prostacyclin and PGE2
– oppose angiotensin II and noradrenaline – important in renal disease and volume depleted
states • Interstitial nephritis
Proximal Convoluted Tubule
• Reabsorption of:- – 65% of Na & H2O – 100 % of glucose – Bicarbonate as CO2
• Na+K+ATPase in basal membrane
Loop of Henle • Creates hypertonic interstitial
fluid in renal medulla • Divided into:-
– descending limb – thin ascending limb – thick ascending limb
• Ascending limb impermeable to water
• Osmotic gradient created by countercurrent multiplication
• Osmotic gradient maintained by vasa recta (countercurrent exchange)
Thick Ascending Loop of Henle
• Na+ removed from ascending limb by Na+K+2Cl- co-transporter
• Site of action of loop diuretics (e.g. frusemide)
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Loop diuretics
• Furosemide, bumetanide • Indications
– Fluid overload – Hypertension – Hypercalcaemia
Loop diuretics
• Highly protein bound. Secreted • Reduce concentration renal medulla • Reduce oxygen demand • Vasodilate • Variable bioavailability
Loop diuretics Side effects
• Electrolyte imbalance • Na • K • Mg • Ca
• Metabolic alkalosis • Interstitial nephritis • Ototoxic
Distal Convoluted Tubule
• K+ secreted into tubular lumen by passive process depending on concentration gradient
Thiazides
• Bendroflumethiazide, metolozone, chlortalidone, indapamide, (hydrochlorthiazide – combined with ACE inhibitors or potassium sparing diuretics))
• Indications – Hypertension – Synergistic with loop diuretics
Thiazides Side effects
• Hyponatraemia • Severe hypokalaemia • Gout • Hyperglycaemia • Hypercalcaemia • Hypercholesterolaemia • Blood dyscrasias • Hepatic encephalopathy (in liver failure) • Acute pancreatitis
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Distal renal tubular cell
• Cortical collecting duct – Na+ reabsorption &
K+ excretion under influence of aldosterone
– H+ excretion
Potassium sparing diuretics
• Amiloride, triamterene • Block Na absorption in distal tubule in exchange
for K+ or H+
• Independent of aldosterone • With loop or thiazide reduce hypokalaemia
• Side effects: – Hyperkalaemia – Metabolic acidosis
Aldosterone antagonists
• Spironolactone, Potassium canrenoate
• Act at nuclear receptor by gene expression
Aldosterone antagonists - Uses
• Primary hyperaldosteronism • Secondary hyperaldosteronism
– Hepatic cirrhosis with ascites – Chronic heart failure
• With loop diuretics
Collecting Duct
• Inner medullary collecting duct
– Fine tuning of urine composition – Water reabsorption under control of ADH – Na absorption under control of ANP
Vasopressin
• In health acts on V2 receptors in kidney
• In shock acts on V1a receptors in vascular smooth muscle
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Vasopressin
• Low levels in health • High levels in shocked states e.g. cardiogenic • In septic shock initially high then levels fall
within hours • “relative vasopressin deficiency” • Hypersensitivity to exogenous vasopressin
Vasopressin
• More V1 receptors on renal efferent than renal afferent arterioles
• α1 receptors present in same amounts on efferent and afferent renal areterioles
• So vasopressin may improve renal perfusion and preserve GFR when compared to noradrenaline
ADH antagonist
• Tolvaptan • Oral selective V2 antagonist • Treatment of hyponatraemia in:
– SIADH – heart failure
• Recent MHRA alerts for: – Liver toxicity – Neurological problems from rapid sodium rise
Osmotic diuretics
• Properties: – Pharmacologically inert – Small molecules – Poorly reabsorbed
• More water excretion than Na+ excretion
Mannitol
• Mechanism of action: – Reduces reabsorptive gradient for Na+
– Expands intravascular fluid volume • Decreases blood viscosity • Increases medullary flow • Impairs medullary concentration gradient
Mannitol
• Uses?
• Dose?
• Only works if nephron is not blocked
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Dopamine
• DA1 receptors on luminal and basal membranes of PCT
• Inhibit Na+K+ATPase causing natiuresis • In low dose may decrease renal vascular
resistance and increase RBF • No evidence
Theophyllines
• Weak diuretic • Decreases Na+ reabsorption • Probably act by increasing cAMP in renal
tubular cells • Cause hypokalaemia
Other Bits for the Final
• Contrast induced nephropathy: – Fluids for 12 hours before – There may be some evidence for N-acetylcysteine – No evidence for sodium bicarbonate – Modern contrasts less renal toxic
• No evidence for use of dopamine, loop diuretics or mannitol for preventing AKI
• Vasopressin and septic shock
Questions