Renal Pharma PDF

Drugs that modify salt excretion Proximal Convulated Tubules -→ Carbonic anhydrase inhibitors Thick Ascending Loop -→ loop diuretics Distal Convulted Tubules -→ Thiazides - Corticl collecting duct -→ K- Sparing diuretics Drugs that modify w...

Drugs that modify salt excretion Proximal Convulated Tubules -→ Carbonic anhydrase inhibitors Thick Ascending Loop -→ loop diuretics Distal Convulted Tubules -→ Thiazides - Corticl collecting duct -→ K- Sparing diuretics Drugs that modify water excretion Osmotic diuretics ADH agonist ADH antagonists Table 1 THIAZIDE Thiazide Act mainly in the cortical region of the Volume Depletion,Hypokalemia, most Ascending loop of Henle and the distal frequent.Predispose patient Taking digoxin, convoluted tubule. Decrease reabsorption of Hypercalcemia, hyponatremia, Metabolic sodium by inhibition of Na+/Cl- alkalosis, Other metabolic effects , cotransporter (NCC) on the luminal Hyperuricemia, Glucose/lipid effects membrane of the tubules. usually not clinically significant at standard doses Indication: HTN: Initial therapy of choice if uncomplicated. Pharmacologocal effect of thiazide Mild heart failure: (to reduce extracellular Inc Urinary NaCl excretion →hyperosmolar volume).Adjunct to loop diuretic. urine Nephrolithiasis:  urinary calcium Inc Urinary K excretion (Hypokalemia) Nephrogenic Diabetes insipidus: (decrease Inc Urinary magnesium excretion Dec blood volume and GFR) Urinary calcium excretion Loop resistance Inc Hypercalcemia →increase reabsortion of calcium →excretion. Treatment of osteoporosis Chlorothiazide Hydrochlorothiazide Most commonly used Thiazide like More potent and longer half-life than HCTZ diuretics long duration of action, Used once daily to treat hypertension Used in major clinical Chlorthalidone trials Metolazone Very potent, intermediate half-life Typically used in combination with loops Causes Na+ excretion even in advance heart failure. Indapamide Lipid soluble, non thiazide diuretics. Long duration of action. Significant anti-hypertensive with minimal diuretics. Table 2 LOOP DIURETICS LOOP DIURETICS High Filtered and secreted into lumen Pharmacokinetic Ceiling diuretics MOA (Inhibit Na+/K+/2Cl- pump in thick Given by orally or I. V.,Have fast onset of ascending limb (TAL) action (suitable for emergency),Have short duration of action., Excreted by DEC Na+ reabsorption active tubular secretion of weak acids Dec Passive Ca++ & Mg++ reabsorption by into urine , Interfere with uric acid changing electrical gradient secretion (hyperuricemia)., Increases the Ca content of urine inc Secretion of K+ and H+ in collecting duct due to high Na+ load Drug Drug interaction Adverse effect of loop diuretics NSAIDS → ↓ Diuretic Response Hypovolemia ,Hyponatraemia (↓ blood Na+)., Hypokalemia (↓ blood Digitalis → Arrhythmias K+)→hypokalemic alkalosis. Aminoglycosides →↑ Ototoxicity of Loop Hypomagnesaemia (↓ blood Mg2+), Diuretic Hypocalcaemia (↓ blood Ca2+) Metabolic alkalosis.Postural ContRaindiation hypotension, OVERDIURESIS causes NSAIDs antagonize effects and add to hypovolemia Dehydration, prerenal nephrotoxicity azotemia, hypernatremia, Allergic reactions, OTOTOXICITY: (usually (+ ACE inhibitor or ARB = increased risk) reversible, risk increased if combined with aminoglycosides) Furosemide MOA: Furosemide inhibition the sodium- potassium-2 chloride (Na+-K+-2 Cl−) co- transporter (symporter) located in the thick ascending limb of the loop of Henle in the renal tubule. Lower potency, Highly variable oral absorption Torsemide Higher potency, Oral bioavailability consistently ~80-100% Bumetanide Higher potency, Oral bioavailability consistently ~80-100% Ethacrynic Acid Only non-sulfa loop Ethacrynic acid most likely to cause deafness Table 3K SPARING DIURETIC Potassium-Sparing MOA: Interfere with sodium-potassium exchange in Spironolactone and eplerenone bind to Diuretics CD and CT mineralocorticoid receptors and blunt aldosterone activity. bind to aldosterone receptors by blocking the resorption of sodium and water Amiloride and triamterene do not block aldosterone Prevent potassium from being pumped into the tubule, thus preventing its secretion Hyperkalemia Competitively block the aldosterone receptors and GI: Cramps, nausea,vomiting, diarrhea inhibit its action Sodium and water are excreten CNS: Dizziness, headache Other: Urinary frequency, weakness Amiloride direct inhibitors of sodium influx in the cortical Clinical use Treatment of HF collecting tubule (CCT). Clinical use Treatment of HF Spironolactone is a spironolactone analog.greater selectivity for Clinical use of spironolactone and the mineralocorticoid receptor.hundred fold less triamterene Hyperaldosteronism, active on androgen and progesterone receptors Hypertension, Reversing the potassium than spironolactone loss caused by potassium-losing drugs. Certain cases of heart failure, Liver failure AE : Gynecomastia, Endocrine disorder, Hyperkalemia Triamterene direct inhibitors of sodium influx in the (CCT). Triamterene is metabolized in the liver has shorter half-life. given more frequently than amiloride, which is not metabolized. Table 4ADH AGONIST AND ADH ANTAGONIS ADH AGONIST Work on ascending loop and CD AE: water overload, hyponatremia ADH ADH facilitates water reabsorption from thecollecting tubule by:activation of V2 by increasing cAMP.cause insertion of additional aquaporin water channels in the membrane of tubule. DESMOPRESIN AE: water overload, hyponatremia ADH ANTAGONIST DEMECLOCYLINE AE bone and teeth abnormalities CONIVAPTAN Conivaption is inhibitor at v1a and v2 receptor Table 5CARBONIC ANHYDRASE INHIBITORs CARBONIC ANHYDRASE INHIBITORs This enzyme catalyzes the inter- conversion between CO2 and water(H2O). Carbonic acid i.e between bicarbonate and hydrogen ion (H ,HCO3). NaCl and Na HCO3 are of more relevant solutes absorbed at PCT. Carbonic anhydrase inhibitor diuretics block NaHCO3 reabsorption. It has predominant action at PCT. MOA : H ion secreted in to the lumen combines with bicarbonate (HCO3) to form carbonic acid (H2CO3). Which is rapidly dehydrated to CO2 and H2O by carbonic anhydrase. CONTINDACATED( METABOLIC CLINICAL USE ACIDOSIS, RENAL STONE ACETAZOLAMIDE Glucoma, and used as prophylaxis to prevent mountain sickness. acetazolamide also prevents dizziness,nausea ,weakness and breathlessness it is also effective and used in cerebral edema and pulmonary edema AE: DROWSINESS,PARSTHESIA,DISOREINTATION,RENAL STONE, BRINZOLAMIDE DORZOLAMIDE Table 6 osmotic diuretics OSMOTIC DIURETICS mannitol & urea are given before & after brain surgery. Prophylaxis of acute tubular necrosis due to surgery and trauma PROTOTYPE ❑ Mannitol Given iv ❑ Glycerine Given orally 80% metablized ❑ Urea GIVEN iv not metabolized ❑ Isosorbide Given orally not metabolized Table 7Nephrotoxicity and types Types of Nephrotoxicity 1. ALTERED The kidney auto regulates intra-glomerular INTRAGLOMERULAR pressure by modulating the afferent and HEMODYNAMICS efferent arterial tone to preserve GFR and urine output. Intraglomerular pressure is sustained by the action of angiotensin-II– mediated vasoconstriction of the efferent arteriole. Drugs that cause tubular cell toxicity do so by Cause Aminoglycosides, impairing mitochondrial function: Interfering Amphotericin B , Antiretrovirals, 2. TUBULAR CELL TOXICITY with tubular transport , Increasing oxidative Cidofovir, Tenofovir, Cisplatin, and stress, Forming free radicals. zoledronate. 3. INFLAMMATION: Drugs can cause inflammatory changes in the Cause : GOLD therapy, glomerulus, renal tubular cells, and the hydralazine, interferon-alfa, surrounding interstitium leading to fibrosis and lithium, NSAIDs, propylthiouracil, renal scarring. Medications that cause acute and pamidronate have been interstitial nephritis are thought to bind to reported as causative agents antigens in the kidney act as antigens that are then deposited into the interstisium, inducing an immune reaction. 4. CRYSTAL NEPHROPATHY Drugs that produce crystals that are insoluble Cause antibiotics e.g., ampicillin, in human urine. The crystals precipitate, ciprofloxacin. usually within the distal tubular lumen antivirals e.g., acyclovir, foscarnet. obstructing urine flow and eliciting an Methotrexate, triamterene interstitial reaction 5. RHABDOMYOLYSIS a syndrome in which skeletal muscle injury Cause: cocaine, heroin, ketamine leads to lysis of the myocyte, releasing (Ketalar), methadone, and intracellular contents methamphetamine including myoglobin and creatine kinase into the plasma 6. THROMBOTIC In thrombotic microangiopathy, organ damage Cause by antiplatelet agents (e.g., MICROANGIOPATHY is caused by platelet, thrombi in the clopidogrel [Plavix], ticlopidine microcirculation, as in thrombotic [Ticlid]), cyclosporine, mitomycin- thrombocytopenic purpura. Mechanisms of C (Mutamycin), and quinine renal injury secondary to drug-induced (Qualaquin). thrombotic microangiopathy include an immune-mediated reaction or direct endothelial toxicity.  ANTIMETABOLITES ( ANTIBIOTICS ALKYLATING AGENTS MICROTUBULE INHIBITORS STEROID HORMONES Anti AND THEIR cancer ANTAGONISTS drugs MONOCLONAL Platinum ANTIBODIES coordination complexes Topoisomerase inhibitors Tyrosine kinase inhibitors Miscellaneous Table 8 DRUG FOR UTI Bacteriostatic Sulphonamides. Nitrofurantion. Cotrimoxazole. Bactericidal Aminoglycosides. Fluoroquinolones. inhibit DNA gyrase in bacteria. Nausea, vomiting, diarrhea, damage growing cartilage, arthropathy, 1GEN( NALIDIXIX ACID) Ciproflox, ofloxa are very popular because headache, light-headedness, dizziness they are highly effective. They have potent 2NDGEN activity against gram–ve bacilli. Contraindications:Moxifloxacin and (CIPROFLOXACIN,NORFLO other Fluoroquinolones may prolong XACIN, OFLOXACIN) Fluoroquinolones contraindicated in QTc interval, and thus should not be pregnancy. 3RDGEN( LEVOFLOXACIN) used in patients who are predisposed QUINOLONE(Bacteriocidal (especially to to arrthymias or taking anti 4THGEN( MOXIFLOXACIN) arrhythmic medications. gram–ve bacteria) like E. coli, Enterobacter species, shigella, proteus.) It can act as urinary anti-septic in uncomplicated UTI.Mechanism of action: Bacterial DNA replication, Transcription, repair recombination DNA gyrase and topoisomerase help DNA for replication and transcription. Urinary antiseptic Nitrofurantoin effect DNA protein synthesis. adverse effect of Methenamine treatment is gIT A) Methenamine. Methenamine producing formaldehyde which distress.hematuria,albuminuria,rashes acts locally and is toxic to most bacteria. B) Nitrofurantoin.(GIVEN orally.) Sulpha drugs (Anti- MOA: PABA: suphamethoxazole dihydrofolic SE: Nausea, vomiting, Megaloblastic microbial regime) acid →tetrahydrofolate in 1:5 ratio. anemia.,Crystal formations, Teratogenicity. Folic acid synthatase , Dihydrofolic reductase. DRUG INTERACTIONS:Prolonged prothrombin time ( increased INR) in patients receiving both sulfamethoxazole and warfarin.: The plasma half life of phenytoin may be increased due to an inhibition of its metabolism.