Adverse drugs

• Three main mechanisms by which kidneys are harmed

  • Reduced extracellular fluid
  • Direct effects on renal blood vessels
  • Toxic effect on renal cells
• Toxic effect on renal cells

  1. Drugs may exert toxic effects directly on tubular or interstitial cells

  2. The two most important presentations of toxicity are acute tubular necrosis and acute interstitial nephritis, each of which can be caused by a wide variety of drugs
• Dehydration is associated with contraction in the extracellular fluid volume, this decreases venous return, arterial blood pressure, and tissue profusion
• Protective reflexes in dehydration

  1. Volume (bp pressure) changes are scened by baroreceptors an low pressure stretch receptors in in heart, which cause protective reflexes to occur

  2. Activation of SNS and RAAS to cause vasoconstriction and reduce arterial pressure (especially in capillary beds in kidneys)

  3. Reduces volume of blood in glomerulus, decreasing pressure and filtration rate, decreasing the volume of urine produced
• In mild dehydration, glomerular filtration rate id protected by activation of RAAS
• Diuretics

  Most common drugs causing dehydration, if not monitored carefully, they can result in excessive fluid losses and dehydration
• Signs of diuretic dehydration

  1. Early signs: development of thirst, dizziness (postural)

  2. Urinary volume decreases in dehydration emergencies (even if on diuretics)

  3. Clinical signs to monitor: skin turgor hypotension and postural hypotension, blood test (indicative of impaired renal function, urea and creatinine)
• Other drugs causing dehydration

  • Laxatives
  • PPI's
  • Antibiotics
  • Chemotherapy
  • Digoxin
• How other drugs cause dehydration

  • Decrease fluid volume by inhibiting fluid absorption form the GI tract (by laxatives, PPI's and antibiotics)
  • Fluid loss by vomiting (chemotherapy drugs)
  • Nausea related reduction in fluid causing dehydration (digoxin)
• Drugs that alter renal profusion

  • Drugs affecting RAAS
  • NSAID's
• Drugs affecting RAAS

  • ACE inhibitors (ramipril) and ARB's (losartan)
  • ACE inhibitors inhibits the conversion of angiotensin 1 to angiotensin 2 (reducing peripheral vasoconstriction), while ARB's inhibit the receptors for angiotensin 2 (reducing efferent arteriole vasoconstriction)
• How NSAID's affect the kidney

  • PGE2 and PGI2 are synthesised in the kidney, where they act as vasodilators that increase glomerular perfusion and inhibit the sodium-potassium-chloride co-transporter in the thick ascending limb of the Loop of Henle
  • NSAID's are used to inhibit synthesis of PG's by Cox-enzyme, and thus impair the functions of PG's in the kidneys
  • NSAID's are contra indicated in patients with hypertension or heart failure
• Drugs directly toxic to kidney

  • Acute tubular necrosis
  • Acute interstitial nephritis
  • Tubular dysfunction
• Acute tubular necrosis

  1. Describes the process of direct injury to the renal tubule resulting nin dysfunction and death of cells and obstruction of tubules caused y cellular debris

  2. Can result from: aminoglycoside antibiotics (e.g. gentamicin), amphotericin B, calcineurin inhibitors (e.g. ciclosporin), chemotherapeutic agents (e.g. cisplatin), aciclovir, poisons (e.g. ethylene glycol), radiocontrast media used during imaging procedures

  3. Important non-drug causes are bacterial sepsis and renal ischaemia, the presence of which increases the risks associated with any of these agents
• Acute interstitial nephritis

  1. Describes when there is an acute hypersensitivity reaction manifesting as inflammation in the interstitial space around the renal tubule

  2. Clinical features: low grade fever, skin rash, eosinophilia, protein and white blood cells in urine

  3. Over 66% of acute nephritis is drug-induced, with most frequent causes being antibiotics (e.g. cephalosporins, sulfonamides), NSAID's and PPI's
• Tubular dysfunction

  1. Some drugs directly alter tubular function without inducing acute tubular necrosis including: lithium (causes polyuria secondary to impairing urine concentrating ability)

  2. Proximal tubular function is also impaired by cumulative exposure to heavy metals (e.g. lead, mercury, arsenic, cadmium), manifesting as excessive loss of glucose, amino acids, phosphate and smaller proteins that would normally be reabsorbed
• Drugs are an important cause of renal impairment and this may occur by three main mechanisms: (i) secondary to excessive fluid losses leading to dehydration and poor renal perfusion, (ii) because of local effects of drugs on renal vasculature that reduce glomerular filtration, or (iii) because of direct toxic effects on the kidney (e.g. acute tubular necrosis, acute interstitial nephritis)
• The most common drugs causing dehydration are loop diuretics, and to a lesser extent thiazide diuretics, which reduce the reabsorption of sodium and water by the renal tubules and but significant fluid losses may also result from drug-induced diarrhoea or vomiting
• The commonest drug classes that alter renal perfusion are those that suppress the renin-angiotensin system such as angiotensin-converting enzyme inhibitors (e.g. ramipril) and angiotensin receptor antagonists (e.g. losartan), and non-steroidal anti-inflammatory drugs (e.g. ibuprofen), which impair cortical blood flow by removing the vasodilator influence of prostaglandins
• There are many drugs that can have direct toxic effects on renal tissues by causing acute tubular necrosis (e.g. aminoglycoside antibiotics, ciclosporin, radio-contrast agents) or acute interstitial nephritis (e.g. cephalosporins, non-steroidal anti-inflammatory drugs)
• Excessive loss of extracellular fluid (ECF) causes its volume to contract
• Decreased arterial blood pressure and tissue perfusion result from a reduction in extracellular fluid volume.
• The sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS) activate to protect organ perfusion during dehydration.
• Vital organs such as the brain, heart, and kidneys receive protected blood flow from the SNS and RAAS during mild dehydration.
• • Angiotensin II production counteracts the initial decrease in kidney perfusion by constricting the efferent artery, maintaining GFR.
• Progressive dehydration leads to a fall in glomerular filtration rate (GFR), impairing the clearance of metabolic waste like urea.
• Diuretic drugs are common causes of compromised waste product clearance due to dehydration.
• Renal blood vessels are directly affected by changes in systemic hydration rather than perfusion.
• The balance of vasoconstrictor and vasodilator influences on the afferent artery determines glomerular perfusion.
• The RAAS provides additional protection for glomerular perfusion when it is under threat.
• Renal function can be impaired by drugs that cause constriction of cortical blood vessels or interfere with the RAAS.
• Drugs affecting the RAAS and nonsteroidal anti-inflammatory drugs (NSAIDs) are likely to influence renal blood flow.