Renal Pharmacology PDF

Renal pharmacology Nuno Coelho Pharmacology and Therapeutics II Master Degree – Veterinary Medicine  Table of contents 01 Introduction to the renal function 04 Types of diuretics 02 Drugs used in renal pharmacology in vet...

Renal pharmacology Nuno Coelho Pharmacology and Therapeutics II Master Degree – Veterinary Medicine  Table of contents 01 Introduction to the renal function 04 Types of diuretics 02 Drugs used in renal pharmacology in vet 05 Other drugs used in renal diseases 03 Principles of diuretic use 06 Conclusion Abbreviations CO: Cardiac output RA: right atria SV: Stroke volume RV: right ventricle HR: heart rate V: ventricle ANS: autonomic nervous system CRI: constant rate infusion CNS: central nervous system AP: action potential S: sympathetic nervous system VSM: vascular smooth muscle PS: parasympathetic nervous system ECF: extracellular fluid RAAS: renin-angiotensin-aldosterone system Na: sodium AV: atrioventricular Cl: chloride Ca: calcium TAL: thick ascending limb EDV: end diastolic volume GI: gastro-intestinal ESV: end systolic volume CHF: cardiac heart failure LA: left atria LV: left ventricle  1) Introduction Main function of kidney electrocyte: K+,NA+, etc maintain constancy of the “internal environment” by eliminating waste products and by regulating the volume, electrolyte content and pH of the extracellular fluid in the face of varying dietary intake and other environmental (e.g. climatic) demands for teaching purposes only  1) Introduction The kidneys are targets of several pathological processes infectious, structural, immunological, toxic (including drug Important the toxicities), etc. understandinf of renal function all converge via impairment of renal function (reduced glomerular filtration rate) to a common end stage of renal failure for teaching purposes only  1) Introduction COX: enzume produce prostaglandin: help regulate blood flow NSAID: inhibit COXso kidney damage Factors regulating renal function RAAS Sympathetic nervous system ADH Cyclooxygenase: NSAIDs can have a profound effect on renal function Organic anion (OAT) or cation transport (OCT) essential for most highly protein-bound drugs (e.g. diuretics) to gain access to their site of action – lumen of renal tubule Loop, thiazide and CA inhibitors: OATs Amiloride and triamterene: OCTs Riviere, 2018 for teaching purposes only  1) Introduction Locations of Secretion and Reabsorption in the Nephron and the substances that are transported Most of the drugs used in renal pharmacology target these places – e.g. diuretics Diuretics are a class of drugs that help the body eliminate excess sodium and water by increasing the production of urine. openstax.org for teaching purposes only  1) Introduction Reabsorption of ions: (1) Na+/H+ exchange (NH3) in proximal convolated tubule (PCT) (2) Na+/K+/2Cl− co-transport (NKCC2), in thick ascending limb (TAL) of loop of Henle (3) Na+/Cl− co-transport (NCC) in distal convoluted tubule (DT) (4) Na+ entry through epithelial sodium channels (ENac) in collecting duct Ritter, 2020 for teaching purposes only  2) Drugs used in renal pharmacology by modifying the content of the filtrate indirectly (not acting on the nephron Diuretics are drugs that increase urine production by the kidneys, leading to the removal of excess fluid and electrolytes (like sodium) from the body Diuretics Osmotic diuretics increase the volume of fluid in the kidney drawing water into the filtrate and promoting water excretion Loop diuretics inhibit NA+, K+, 2Cl- co-transporter thiazides inhibit NA+,Cl- co-transporter direct action on the cells of the nephron aldosterone antagonists carbonic anhydrase inhibitors inhibit enzyme carbonic anhydrase that is involve in the reabsorption of bibocarnate and sodium Other drugs drugs for micturition associated disorders modifiers of urinary pH desmopressin, citrate, aluminium hydroxide, etc for teaching purposes only  for teaching purposes only 3) Principles of diuretic drugs History of diuretics dates back to the Paleolithic humans consumption of cafeine-containing plants Word diuretic has a Greek stem, diu (through) oυρειη (to urinate) Throughout the time diuretic properties of several plants were compiled in medical books and pharmacopeias garlic, Chinese lantern, saffron, fennel, liquorice, sassafras and dandelion (in French also called “pissenlit”) Then, in the 1900s there were mercurial diuretics (now obsolete) And now the modern diuretics A woman with “dropsy” – generalized swelling indicative most probably of heart failure  for teaching purposes only 3) Principles of diuretic drugs this drugs help to avoid this Increased capillary pressure, diminished colloid osmotic pressure or inadequate lymphatic drainage abnormally increased interstitial fluid i.e. edema medicinehack.com Texte heartsmart.vet.tufts.edu NOTE: cause of the edema should be identified prior to start a diuretic  for teaching purposes only 3) Principles of diuretic drugs General effects Diuretics, saluretics elicit increased production of urine (diuresis) predominant action – augment urine excretion by inhibiting reabsorption of Na and Cl and water increased excretion of Na (natriuresis, or saluresis, in combination with Cl) Lüllmann, 2018  for teaching purposes only 3) Principles of diuretic drugs Mobilization of edemas Antihypertensive therapy diuretic: increased renal excretion of Na+ and H2O decrease peripheral resistance (without significantly causes a reduction in plasma volume with reducing ECF) and normalize blood pressure hemoconcentration (+ relevant in human medicine because of its prevalence) To “compensate” this increase in plasma protein concentration, fluid shift from interstitium to capillary bed: edema ↓ Therapy of congestive heart failure Prophylaxis of renal failure lower peripheral resistance → help heart to eject blood in circulatory failure (e.g. shock due to hemorrhage), renal (↓ afterload), ↑ CO production of urine ↓↓ to try to conserve fluids ECF and venous return ↓ (↓ preload) with diuretic – attempt to maintain urinary flow thiazides and loop diuretics osmotic or loop diuretics  for teaching purposes only 3) Principles of diuretic drugs Riviere, 2018 Although saluresis is the primary clinical goal, diuretics also alter elimination of other ions to varying degrees (e.g., K+, H+, Ca2+, Mg2+, Cl−, HCO3 −, phosphates) and may affect renal hemodynamics General adverse effects: electrolyte imbalances and dehydration (depletion of circulating blood volume) – monitor therapy (older animals and with cardiac or renal disease more prone)  for teaching purposes only 4) Inhibitors of carbonic anhydrase Have been used sparingly in veterinary medicine as diuretics and are more commonly used for ophthalmic purposes as topical formulations Examples: acetazolamide (Diamox®, Dazamide®), tablets (125 and 250 mg), extended-release capsules (500 mg), and injectable Other agents: dichlorphenamide (Daranide®) and methazolamide (Neptazane®), and a topical drug, dorzolamide (Trusopt®), for ophthalmic use. Ritter, 2020  for teaching purposes only 5) Osmotic diuretics Osmotic diuretics: simple solutes of low molecular weight – filtered in the glomerulus, but not reabsorbed; and are pharmacologically inert (not metabolized, only glycerine is biotransformed) increase serum and tubular fluid osmolarity resulting in fluid shifts Mannitol: the most used - six-carbon polyalcohol; Osmitrol®, Resectisol®; 5 to 25%; IV others: glycerin, isosorbide and hypertonic saline solutions  for teaching purposes only 5) Osmotic diuretics Mechanism of action: Hyperosmolar solutions establish an osmotic gradient between plasma and fluid of extravascular compartments → fluid movement into plasma decreases in hematocrit, blood viscosity, plasma sodium and other ions, plasma pH Effect not only in proximal tubule but in whole the lenght of the tubule  for teaching purposes only 5) Osmotic diuretics Therapeutic effects Not metabolized, eliminated renally Mannitol is IV in slow bolus (15-30 min), glycerine and isosorbide PO INDICATIONS: prophylaxis and treatment of renal failure reduction of intracranial and intraocular pressure mobilization of edemas CONTRAINDICATIONS intracranial hemorrhage, anuric renal failure or severe dehydration  for teaching purposes only 5) Osmotic diuretics Side, adverse effects Acute: Blood pressure alterations Dehydration and electrolyte disturbances Due to loss of electrolytes, including K, phosphate, and Mg → cardiac arrhythmias and neuromuscular complications osmotic compensation with prolongued treatment with cells increasing the presence of intracellular, idiogenic osmoles – limit effectiveness by decreasing osmotic gradient  for teaching purposes only 6) Loop diuretics The most common and powerful diuretics “torrential urine flow” furosemide (Salix, Disal), by far the most common Other drugs: ethacrynic acid (Edecrin®), bumetanide (Bumex®), and torasemide (Demadex®, Upcard, Isemid) sulfonamide derivates (not ethacrynic acid) Ritter, 2020  6) Loop diuretics NKCC2 Mechanism of action 1. After being secreted to lumen (by OATs) 2. block the Na+-K+-2Cl− symporter (NKCC2) in TAL, by binding to its Cl− binding site → DIURESIS 3. Cl− intracellular concentrations falls, and Antonietta, 2022 paracellular cation reabsorption (Ca2+ and Mg2+) is blocked Loop diuretics interfere with establishment of a hypertonic medullary interstitium (due to impaired Na reabsorption) and disrupt countercurrent mechanism → ability to concentrate and dilute urine appropriately is diminished for teaching purposes only  for teaching purposes only 6) Loop diuretics PK Furosemide ≈ 77% bioavailable in dogs, with elimination half-life of about 1 hour following an IV dose of 5 mg/kg → duration of effect is short (≈ 2–4h) Sleeper, 2019 Peak diuretic effects of an IV dosage of furosemide in the dog around 30 min for IV and 1–2h for PO PO: absorption in the upper parts of the canine GI tract relation between the natriuretic/diuretic response and the concentration of diuretic in the urine (sigmoidal curve)  for teaching purposes only 6) Loop diuretics PK Horse similar T1/2; IV or IM, TID or QID renal insufficiency: prolonged plasma half-life – adjust dose Limited biotransformation of bumetanide can explain its higher potency in dog; also good oral bioavailability (80- 100%) bumetanide: 67% eliminated unchanged in urine and feces  6) Loop diuretics Clinical uses Furosemide (Dimazon, Salix – vet, Lasix; oral tablet – Libeo, furosoral or oral solution, large animal boluses for cattle and injectable (wtidrawal times of 2 days– meat and milk) Bumetadine (Bumex) is more potent than furosemide; PO, IV torsemide also with diuretic effects but last longer (cat dog) – Upcard, Isemid - tablets Therapeutic for: edema of cardiac, hepatic or renal origin (small animals), and management of congestive heart failure (concomitant with other drugs, as ACEI, pimobendam, etc. establish diuresis in renal failure (acute) promote excretion of other substances large animals: edema in cattle (udder) and edema and exercise-induced pulmonary hemorrhage (EIPH) in horses  for teaching purposes only 6) Loop diuretics Clinical uses dose of 0.5–1 mg/kg, BID, or as needed; to control edema has been recommended in large animals (furosemide)  for teaching purposes only 6) Loop diuretics Adverse/side effects ↓ K, Ca, Na, Cl, Mg and volume; also water-soluble vitamins most effects come from abnormalities of fluid and electrolyte (dys)balance – patients with renal, cardiac or hepatic disease with more risks Dehydration and hypotension (may impact kidney) cardiac dysrhythmias GI disturbances hyperglycemia cardiology vs. nephrology  for teaching purposes only 7) Thiazides benzothiadiazines or analogs and are derivatives of CA- inhibiting sulfonamides promote renal excretion of Na and CL (true saluretic effect) Commonly used in vet: chlorothiazide (Diuril®, tablets, suspension and injectable) and hydrochlorothiazide (Hydrozide®, Co-amilozide, Moduret; injectable, tablets and oral suspension – can be used in cattle water soluble; newer generation - more lipid-soluble: cyclothiazide and methychlothiazide Lüllmann, 2018  for teaching purposes only 7) Thiazides Mechanism of action Inhibit reversibly the Na+/Cl− co-transporter (NCC) in the luminal membrane of the DCT NCC 90% of filtered Na+ is reabsorbed prior to the distal tubule, the peak diuresis caused by thiazides is moderate Ritter, 2020  7) Thiazides Pharmacokinetic absorbed slowly and incompletely from the GI tract highly protein bound and undergo renal excretion (chlorothiazide and hydrochlorothiazide, eventually with some biliary route) gain access to the tubular lumen via OATs, secretion in the proximal tubule for teaching purposes only  for teaching purposes only 7) Thiazides Clinical uses edema of cardiac, hepatic or renal origin (furosemide is more used – more effective) Typical oral dosages in the dog and cat are 20–40 mg/kg q12 hours (chlorothiazide) and 2–4 mg/kg q12 hours (hydrochlorothiazide) cattle: udder edema with hydrochlorothiazide- diurizone (125–250 mg IV or IM SID or BID) may also be used in the prevention of calcium oxalate urolithiasis Management of hypertension Use in CHF may lead to cardiac deterioration  for teaching purposes only 7) Thiazides Adverse effects fluid and electrolyte abnormalities ↓ K, Na, Cl, and volume hypercalcemia Potassium loss may increase arrhytmias hyperglycemia CNS and gastrointestinal effects may occur but are not common Patients with severe renal disease, hypovolemia, diabetes or electrolyte disturbances are poor candidates for thiazides  for teaching purposes only 8) K+-sparing diuretics triamterene (Dyrenium®) and amiloride (Midamor®), belong to the class of cyclic amidine diuretic organic bases – secreted into proximal tubule by OCT family not much used in vet, more triamterene only PO preparations Lüllmann, 2018  for teaching purposes only 8) K+-sparing diuretics Mechanism of action inhibits the sodium channel in the luminal membrane of the collecting tubule (ENAc) reducing sodium influx ENAc cause a mild increase in excretion of NaCl and a retention of K+ (K+-sparing) slightly augment diuresis and can used in combination with loop diuretics or thiazides to decrease K+ excretion Ritter, 2020  for teaching purposes only 8) K+-sparing diuretics Pharmacokinetic Oral administration few data on animals amiloride is renally excreted triamterene is converted in the liver to an active metabolite (4-hydroxytriamterene sulfate), actively secreted into the renal tubules  for teaching purposes only 8) K+-sparing diuretics Clinical uses due to relative weak diuretic properties they are clinically important for the K- sparing property, in combination with other diuretics treatment of edema and ascites due to liver or heart failure (i.e. associated with CHF, liver cirrhosis), and nephrotic syndrome, steroid-induced edema, and idiopathic edema Adverse effects most important potential adverse effect – hyperkalemia may predispose to GFR ↓ and renal dysfunction  for teaching purposes only 9) Aldosterone antagonists as saw before, aldosterone help the ENaC channels to be activated and so to help to reabsorb NA+ Spironolactone (Prilactone, Aldactone; can be formulated with other drugs as benazepril - Cardalis, eplerenone and carenone - aldosterone antagonists available as oral tablets (chewable) Also K-sparing drugs  for teaching purposes only 9) Aldosterone antagonists amboss.com Aldosterone antagonism (e.g., spironolactone) which blocks the action of aldosterone, a hormone that normally increases sodium reabsorption and potassium excretion It works by increasing sodium reabsorption in the kidneys and potassium excretion, which leads to water retention, as water follows sodium to maintain a balanced concentration. When aldosterone levels are high (a condition known as hyperaldosteronism), this leads to more sodium and water retention, which can cause edema Mechanism of action Competitively bind to aldosterone receptors (cytoplasm) in late DCT and collecting duct → inhibit effects of aldosterone (that normally causes the influx of Na through the Enac channel → decreased Na+ reabsorption and K+ excretion → diuresis  for teaching purposes only 9) Aldosterone antagonists Pharmacokinetic 60% oral bioavailability in dogs – increase when given with food Peak diuresis occurs as late as 2–3 days after initiation of therapy Aldosterone antagonists do not require secretion into the renal tubule to induce Ritter, 2020 diuresis  9) Aldosterone antagonists In conditions where RAAS (Renin-Angiotensin-Aldosterone System) is activated (for example, in heart failure or kidney disease), aldosterone levels tend to increase. This makes the diuretic’s ability to remove extra fluid from the body even more important. Clinical uses Effectiveness as diuretic depends on concentrations of endogenous aldosterone (↑ with RAAS) Secondary hyperaldosteronism and edema: associated with cardiac ccurs when the body overproduces aldosterone due to other conditions failure, hepatic cirrhosis, some kidney diseases (nephrotic syndrome) and severe ascites Spironolactone is used in veterinary medicine at a dose of 2–4 mg/kg/day PO to: manage refractory edema associated with these conditions used in the management of hepatic cirrhosis can be combined with benazepril (Cardalis) – chewable tablets for dogs for teaching purposes only  for teaching purposes only 9) Aldosterone antagonists Adverse effects Hyperkalemia, dehydration, and hyponatremia (+) metabolic acidosis combination of any K+-sparing diuretic, including spironolactone, with ACEI must be accomplished cautiously to avoid hyperkalemia  for teaching purposes only dose and routes of diuretics for small animals Boothe, 2011  for teaching purposes only 10) ANS pharmacology in the kidney Langfitt, 2017 Disorders of urine storage usually result in urine leakage, whereas disorders of voiding result in urine retention, incomplete voiding Most disorders of micturition can be classified and managed according to the status of urinary bladder (hypocontractile or hypercontractile) and urethral (hypotonic or hypertonic) function α1 –adrenergic contract urethral sphincter In the urine storage phase– Sympathetic predominance β–adrenergic drugs relax bladder muscle In the emptying phase of the bladder– parasympathetic predominance cholinergics (Ach) contract bladder muscle and relax urethral sphincter  10) ANS pharmacology in the kidney α: Reduces internal urethral sphincter tone (in functional urethral obstruction, Antagonists spasms) - Tx urinary retention– Phenoxybenzamine (male cats), prazosin (cats) S Tx Urinary urethral incontinence – Adrenergic Phenylpropanolamine – propalin, uristop, uriphex (female dogs) ANS Bethanecol: increase urinary bladder Cholinergic contractility: used in detrusor muscle atony in dogs and cats PS Helps promote urinary retention in Anticholinergics urge incontinence, as detrusor hyperreflexia- Propantheline, in cats and dogs for teaching purposes only Martini-Johnson, 2021  for teaching purposes only 11) Drugs for micturition disorders Martini-Johnson, 2021 Apart from ANS drugs, reproductive hormones and muscle relaxants can be effective in treating micturition disorders by enhancing urethral tone and reducing muscle spasms, respectively. These drugs help manage conditions like urethral incompetence and functional urethral obstruction  for teaching purposes only 11) Urine pH Modifiers Coelho, 2024 (dog urine)  for teaching purposes only 11) Urine pH Modifiers The pH of the urine (namely with changes due to diet, infection, obstructions) influences the formation and dissolution of these crystals Acidifying or alkalizing urine is crucial to prevent and treat urinary crystals By adjusting the pH of urine through diet or medication, it is possible to dissolve existing crystals and prevent the formation of new ones, improving the animal's urinary health “Urinary acidifiers” “Urinary Alkalizers”  for teaching purposes only 11) Urine pH Modifiers Urinary acidifiers and related Helps dissolve/prevent struvite crystals (which form in alkaline urine) In disuse with the introduction of urinary diets Agents: methionine (methigel, uropet gel), ammonium chloride Martini-Johnson, 2021  for teaching purposes only 11) Urine pH Modifiers Urinary Alkalizers and related It helps in the management of ammonium urate, calcium oxalate and cystine crystals (which tend to form in urine with low pH (acidic) Agents: Citrate - Cystopurin, Potassium citrate; 30% oral solution; Citrates complex with calcium to form salts that are more soluble than oxalate salts; enhances renal tubular resorption of calcium and promote generation of bicarbonate, that is excreted; USE: urinary alkalinization, management of calcium oxalate and urate urolithiasis; Dogs, Cats: 75 mg/kg BID Cystopurine sodium bicarbonate - increase urine pH thiopronin: convert cystine to more soluble compounds  for teaching purposes only 12) Other drugs used in the kidney Urinary Alkalizers and related Others: Allopurinol – Xanthine oxidase inhibitor (enzyme that forms uric acid: ↓ uric acid production → helps dissolve ammonium urate crystals (Urate Urolithiasis)  for teaching purposes only 12) Other drugs used in the kidney Desmopressin - vasopressin (ADH) analogue Action: Binds to and stimulates ADH receptors in the collecting ducts; with longer duration of action than vasopressin; Also increases von Willebrand factor, factor VIII and plasminogen concentrations Clinical use: Diagnosis and treatment of central diabetes insipidus; IV, IM, PO, intranasal or conjunctiva  for teaching purposes only 14) Drugs used in chronic kidney disease Boothe, 2011 Apart from the drugs, chronic kidney diseases also envolves the use of: dietary strategies: therapeutic diets for renal diseases dietary supplements: in particular phosphate-binding agents (intestinal)  for teaching purposes only 14) Drugs used in chronic kidney disease CKD leads to hyperphosphatemia because the kidneys lose their ability to effectively excrete phosphorus → exacerbate kidney damage and complications Aluminum antacids: oral formulations - binds to phosphate in the GIT, preventing intestinal absorption of ingested phophorus to lower serum phosphate levels (dog, cat) it can be mixed with food; aluminum hydroxide, aluminum carbonate – Alucap, Sevelamer hydrochloride with the same phosphate binder effect Ipakitine - Dietary food for dogs and cats in powder form, composed by chitosan and calcium carbonate– decreases phosphorus levels by binding and eliminating it through GIT Calcium-based products (calcium acetate, calcium carbonate) are alternative phosphorus-binding agents with additional alkalinizing effects  for teaching purposes only 14) Drugs used in chronic kidney disease Glomerular disease A common cause of proteinuria and progressive renal disease 1) Glomerulunephritis: deposition of immune complexes in glomerular capillary that triggers a local inflammatory response, linked to various systemic infectious and inflammatory conditions (dogs and cats) Treatment ACEi - reduce proteinuria and blood pressure (enalapril) Immunosupressive Tx: corticosteroids may be used in some cases, but risky thromboxane synthetase inhibitors and low-dose aspirin can help manage proteinuria and inflammation Dietary adjustments, including protein and sodium restriction, omega-3 fatty acid supplementation, are recommended. Diuretics (furosemide) if edema  for teaching purposes only 14) Drugs used in chronic kidney disease Glomerular disease A common cause of proteinuria and progressive renal disease 2) Renal amyloidosis: deposition of amyloid A, derived from the acute phase reactant serum amyloid A, triggered by chronic inflammatory disease. Tx: Dimethylsulfoxide (DMSO): enhance solubilization of amyloid fibrils, reduce serum amyloid A protein concentrations, and reduce associated interstitial inflammation and fibrosis - antifibrotic SC, 3x/week or PO, SID Colchicine: blocks the synthesis and secretion of serum amyloid A → prevent development and progression of amyloidosis effective mostly in the early stages; used in dogs (Shar Pei) oral tablets, SID Take home message for teaching purposes only Ritter, 2020  for teaching purposes only Take home message msdvetmanual.com Lecturio, 2023  References Riviere, J. E., & Papich, M. G. (Eds.). (2018). Veterinary pharmacology and therapeutics. John Wiley & Sons. Ritter, J. M., Flower, R., Henderson, G., Loke, Y. K., MacEwan, D., & Rang, H. P. (2020).Rang and Dale's Pharmacology. Philadelphia, PA: Elsevier. Lüllmann, H., Mohr, K., Hein, L., & Bieger, D. (2018). Color atlas of pharmacology. New York: Thieme Tillement, J. P. Allerton, F. (2020). BSAVA: Small Animal Formulary (Ed. 10). British Small Animal Veterinary Association Papich, M. G. (2020). Papich Handbook of Veterinary Drugs-E-Book: Papich Handbook of Veterinary Drugs-E-Book. Elsevier Health Sciences. Martini-Johnson, L. (2020). Applied Pharmacology for Veterinary Technicians, 6th edition. Elsevier Health Sciences. Eknoyan, G. (1997). A history of diuretics. In Diuretic Agents (pp. 3-28). Academic Press. Slidesgo