Renal Drug Handling and Nephrotoxicity

Renal Renal clearance = volume of plasma containing the drug removed. By the kidney per unit time 3 fundamental processes to renal clearance: 1. Ultrafiltration: in the glomerulus  all drugs under a certain size will pass through the glomerulus into filtrate (most are small enough for this) 2. Secretion: in the proximal and distal tubule  everything that doesn’t go through glomerulus will be transferred in here by one of either: a. Organic anion transporters (for acidic drugs against the electrochemical gradient) b. Organic cation transporters (for basic drugs, facilitated down the gradient) i. These mechanisms can remove bound drugs making it really effective 3. Resorption: in the proximal/distal tubule  passive resorption of lipophilic drugs. Drugs that cross membranes freely will be reabsorbed down the concentration gradient therefore lipid soluble drugs are poorly excreted by the kidney Nephrotoxicity: Aminoglycosides  renal tubular cells particularly in the PCT are vulnerable as they concentrate and reavsorb glomerular filtrate. They cause tubular cell toxicity by: - Accumulating in lysosomes of the PCT epithelial cells - Impair mitochondrial function thereby increasing oxidative stress and free radicals - Thus interfering with tubular transport NSAIDS  the kidney autoregulates intra-glomerular pressure by modulating the afferent and efferent arterial tone to preserve GFR and urine output - Prostaglandins normally dilate the afferent arteriole - NSAIDS are COX2 inhibitors and thus BLOCK prostaglandin production - Therefore they can decrease blood flow to the kidneys and lack of oxygen would cause acute kidney injury - They also cause acute interstitial nephritis by inducing an immunological reaction after period of NSAID exposure leading to the presence of inflammatory cell infiltrate in the kidney interstitium. Diuretics: Diuretics increase the rate of urine flow and excretion of Na and water from the filtrate. They decrease the reabsorption of Na and usually Cl from the filtrate Helpful for oedema, AKI, forced diuresis and correcting ion imbalances DIURETICS: Drug class Mechanism of action Osmotic  Filtered in the glomerulus but not reabsorbed Diuretics  Increase osmolarity of the filtrate in PCT, descending limb Requires IV and collecting ducts admin!!  Water retained in urine  leading to decreased concentration of Na in lumen and decreased reabsorption of Na Carbonic anhydrase inhibitors Loop diuretics Thiazides  block reaction of CO2 with H2O Thus prevent Na/H exchange and HCO3 ion reabsorption in PCT and Na reabsorption also reduced Increased HCO3 in filtrate opposes water reabsorption  HCO3 eliminated in urine = systemic acidosis Consequently plasma HCO3 also depletes which makes its diuretic effects self limiting  Na, K and Cl enter blood by a co transport system  act on Na, K and 2Cl symporter in the thick ascending limb of the loop of henle  inhibit Na, K and Cl reabsorption causing diuresis WITH loss of electrolytes  principal cells in the collecting ducts will respond to increased Na in urine by increasing K secretion in return for Na reabsorption  don’t pass directly into glomerular filtrate but are secreted by organic anion transporters  interfere with tubular feedback control of GFR thus no decrease in GFR  bind to the Cl site of the distal tubules Na/Cl co transport system  act to inhibit Na reabsorption  thus more Na delivered to collecting duct and some Na will be reabsorbed in exchange for K excretion  less powerful than loop diuretics but better tolerated Can be combined with other diuretics as act on different site Indications  Forced diuresis (intoxication, impending kidney failure)  Emerg Tx of acutely raised intracranial or intraocular pressure  glaucoma  idiopathic benign intracranial hypertension  altitude sickness Unwanted effects  Transient expansion of extracellular fluid volume Example Mannitol  Hyponatremia (acute)  oedema (hepatic, cardiac, renal)  heart failure  forced diuresis  excessive water loss  sodium and potassium loss following long term use  hypoCa  adaptive changes in circulation (activation of RAAS)  oedema  heart failure  adaptive changes in circulation  potassium loss following long term use (rare in vet med)  Ca excretion reduced by Mg enhanced Furosemide Potassium sparing diuretics Aldosterone antagonists Well absorbed PO and extensively metabolised by liver to active metabolite Onset of action is slow (DT)  directly blocks the epithelial Na channel  inhibits Na reabsorption in the collecting ducts  promotes loss of Na and water from the body but without depleting K  tubule cells are impermeable to Na in the absence of aldosterone  aldosterone acts via mineralocorticoid receptor within the collecting duct therefore increasing ENaC channel and Na/K ATPase expression, increasing Na and Cl reabsorption and K and Ca excretion from renal tubules  competes with aldosterone at its receptor site and causes mild diuresis and potassium retention  during long term tx in combo w/ thiazides and loop diuretics (can prevent hypokalaemia associated with loop diuretcis)  oedema due to hyperaldosteronism  hyperkalaemia Triamterene and amiloride spirolactone GIL pharm Drug Magnesium hydroxide Aluminium hydroxide gel Alginates and simeticone sucralfate Affects Gastric secretion Mechanism Neutralises gastric secretions Side effects May cause diarrhea Gastric secretion Mucosal protection Activated charcoal Bismuth Kaolin/pectin Gastric secretion May prevent uptake of other drugs that are absorbed through stomach lining Ranitidine cimetidine Gastric secretion Absorbs toxins – coats stomach to mop up acid and binds to bacteria/toxins Histamine Rebound increase on withdrawal antagonist – Cimetidine inhibits cytochrome inhibits P450 and slows metabolism gastrin, histamine and acetylcholine stimulated secretion Pepsin secretion falls Used for/notes Ruminal acidosis Gastritis oesophagitis Omeprazole lansoprazole Gastric secretion misoprostol Gastric secretion apomorphine emetic xylazine emetic Syrup of ipecac chlorpromazine emetic Anti emetic Proton pump inhibitors Irreversibly bind to ATPase Basal AND stimulated release inhibited Stable analogue of PGE1 Inhibits acid secretion Increases mucosal blood flow Increases uterine contraction Dopamine agonist Alpha 2 agonist Direct irritant Dopamine Do not give in late gestation as will cause early labour/abortion Makes cats psyhcho Cause cardiotoxicity in high doses Given IV or mucosa, rapid effect antagonist (centrally acting Metoclopramide Anti emetic Dopamine domperidone antagonist Maropitant (cerenia) Anti emetic Neurokinin-1 antagonist Competes with substance P Opiates: Antimotility Increase Morphine (spasmolytics) contractions Codeine but decrease Loperamide (Imodium) propulsion  increased LI tone leading to constipation Atropine Antimotility Inhibits Hyoscine (buscopan) (spasmolytics) acetylcholine stimulatory effects from vagus nerve Methylcellulose laxative Adds bulk to Agar bran stimulate GIT motility lactulose laxative Broken down Contraindicated if vomit due to obstruction Specifically designed for dogs but also used in cats Must be given IV, short acting Diarrhea/colic and stasis Atropine not really specific enough Diarrhea/colic and stasis cisapride motility Porcine pancreatic enzymes Digestive enzymes prednisolone Antiinflammatory Bloat guard (surfactant) Antifoaming agent in lower gut to lactic acid therefore altering pH to more acidic and trapping ammonia and therefore water Serotenergic 5-HT4 receptor agonsit For exocrine pancreatic insufficiency Detergent causes bubbles to brea down Inflammatory bowel disease Bloat in ruminants (frothy)