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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