Diuretics Outline 1 Sites of drug action 2
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Diuretics
Outline 1. Sites of drug action 2. Osmotic diuretics 3. Carbonic anhydrase inhibitors 4. Thiazide diuretics 5. Loop diuretics 6. Potassium-sparing diuretics
Definitions Diuretics: substance that promotes the excretion of urine • caffeine, yerba mate, nettles, cranberry juice, alcohol Natriuretic: substance that promotes the renal excretion of Na+
Renal Physiology renal epithelial transport tubular reabsorption proximal tubule loop of Henle thick ascending limb distal convoluted tubule collecting tubule • tubular secretion • collecting tubules
Summary: Sites of Action
Osmotic Diuretics Do not interact with receptors or directly block renal transport activity dependent on development of osmotic pressure Mannitol (prototype) Urea Glycerol Isosorbide
Mechanism of Action osmotic diuretics are not reabsorbed increases osmotic pressure specifically in the proximal tubule and loop of Henle prevents passive reabsorption of H 2 O osmotic force solute in lumen > osmotic force of reabsorbed Na+ increased H 2 O and Na+ excretion
Therapeutic Uses Mannitol drug of choice: non-toxic, freely filtered, non-reabsorbable and non-metabolized administered prophylatically for acute renal failure secondary to trauma, CVS disease, surgery or nephrotoxic drugs short-term treatment of acute glaucoma infused to lower intracranial pressure Urea, glycerol and isosorbide are less efficient can penetrate cell membranes
Side Effects increased extracellular fluid volume cardiac failure pulmonary edema hypernatremia hyperkalemia secondary to diabetes or impaired renal function headache, nausea, vomiting
Carbonic Anhydrase Inhibitors limited uses as diuretics Acetazolamide • prototype carbonic anhydrase inhibitor • developed from sulfanilamide (caused metabolic acidosis and alkaline urine)
Mechanism of Action inhibits carbonic anhydrase in renal proximal tubule cells carbonic anhydrase catalyzes formation of HCO 3 - and H+ from H 2 O and CO 2 inhibition of carbonic anhydrase decreases [H+] in tubule lumen less H+ for Na+/H+ exchange increased lumen Na+, increased H 2 O retention
Therapeutic Uses used to treat chronic open-angle glaucoma aqueous humor has high [HCO 3 -] acute mountain sickness prevention and treatment metabolic alkalosis sometimes epilepsy mostly used in combination with other diuretics in resistant patients
Side Effects rapid tolerance increased HCO 3 - excretion causes metabolic acidosis drowsiness fatigue CNS depression paresthesia (pins and needles under skin) nephrolithiasis (renal stones) K+ wasting
Thiazide Diuretics active in distal convoluted tubule Chlorothiazide (prototype) Hydrochlorothiazide Chlorthalidone Metolazone
Mechanism of Action inhibit Na+ and Cl- transporter in distal convoluted tubules increased Na+ and Cl- excretion weak inhibitors of carbonic anhydrase, increased HCO 3 - excretion increased K+/Mg 2+ excretion decrease Ca 2+ excretion
Therapeutic Uses hypertension congestive heart failure hypercalciuria: prevent excess Ca 2+ excretion to form stones in ducts osteoperosis nephrogenic diabetes insipidus treatment of Li+ toxicity
Pharmacokinetics orally administered poor absorption onset of action in ~ 1 hour wide range of T 1/2 amongst different thiazides, longer then loop diuretics free drug enters tubules by filtration and by organic acid secretion
Side Effects hypokalemia increased Na+ exchange in CCD volume-contraction induced aldosterone release hyponatremia hyperglycemia diminished insulin secretion elevated plasma lipids hyperuricemia hypercalcemia
Loop Diuretics active in “loop” of Henle Furosemide (prototype) Bumetanide Torsemide Ethacrynic acid
Mechanism of Action enter proximal tubule via organic acid transporter inhibits apical Na-K-2 Cl transporter in thick ascending loop of henle competes with Cl- binding site enhances passive Mg 2+ and Ca 2+ excretion increased K+ and H+ excretion in CCD inhibits reabsorption of ~25% of glomerular filtrate
Therapeutic Uses edema: cardiac, pulmonary or renal chronic renal failure or nephrosis hypertension hypercalcemia acute and chronic hyperkalemia
Pharmacokinetics orally administered, rapid absorption rapid onset of action bound to plasma proteins: displaced by warfarin, and clofibrate increase toxicity of cephalosporin antibiotics and lithium additive toxicity with other ototoxic drugs inhibitors of organic acid ion transport decrease potency (i. e. probenecid, NSAID’s)
Side Effects hypokalemia hyperuricemia metabolic alkalosis hyponatremia ototoxicity Mg 2+ depletion
K+ sparing diuretics three groups steroid aldosterone antagonists spironolactone, eplerenone Pteridines triamterene Pyrazinoylguanidines amiloride
Mechanism of Action K+ sparing diuretics function in CCD decrease Na+ transport in collecting tubule Spironolactone competitive antagonist for mineralocorticoid receptor prevents aldosterone stimulated increases in Na+ transporter expression Triamterene/Amiloride organic bases secreted into lumen by proximal tubule cells inhibit apical Na+ channel
Therapeutic Uses primary hyperaldosteronism (adrenal adenoma, bilateral adrenal hyperplasia) congestive heart failure cirrhosis nephrotic syndrome in conjunction with K+ wasting diuretics
Pharmacokinetics Spironolactone orally administered aldactazide: spironolactone/thiazide combo Amiloride • oral administration, 50% effective • not metabolized • not bound to plasma proteins • Triamterine • oral administration, 50% effective • 60% bound to plasma proteins • liver metabolism, active metabolites
Side Effects hyperkalemia: monitor plasma [K+] spironolactone: gynecomastia triamterene: megaloblastic anemia in cirrhosis patients amiloride: increase in blood urea nitrogen, glucose intolerance in diabetes mellitus
Antibiotics
Antibiotics Sulfonamides Penicillins Cephalosporins Tetracyclines Aminoglycosides Quinolones Macrolides
What are Antibiotics? Antibiotics = “against life” Antibiotics are molecules that stop microbes, both bacteria and fungi, from growing or kill them outright. Antibiotics can be either natural products or synthetic chemicals.
Antibiotics Medications used to treat bacterial infections Ideally, before beginning antibiotic therapy, the suspected areas of infection should be cultured to identify the causative organism and potential antibiotic susceptibilities.
Antibiotics 1. Empiric therapy: treatment of an infection before specific culture information has been reported or obtained 2. Prophylactic therapy: treatment with antibiotics to prevent an infection, as in intra-abdominal surgery
Antibiotics Bactericidal: kill bacteria Bacteriostatic: bacteria. inhibit growth of susceptible
Antibiotics can be categorized based on their target specificity: 1. narrow-spectrum" antibiotics target particular types of bacteria, such as Gram-negative or Gram-positive bacteria. 2. broad-spectrum antibiotics affect a wide range of bacteria.
Primary Modes of Action
Bacteriocidal A bacteriocide is a substance that kills the bacteria of choice and, preferably, nothing else. Microbe death is usually achieved by disruption of the bacterial cell membrane leading to lysis.
Bacterial Antibiotics were created at a time when previously untreatable infections such as tuberculosis, gonorrhea, and syphilis could be almost incredibly treated. Bacteria have been successful because they are capable of adapting to changes in their environment. Penicillin is the best-known antibiotic, which is used to treat bacterial infections, such as syphilis, gonorrhea, meningitis, and anthrax.
Antibiotics: Penicillins First introduced in the 1940 s Bactericidal: inhibit cell wall synthesis Kill a wide variety of bacteria Also called “beta-lactams”
Penicillins: Side Effects Common side effects: nausea, vomiting, diarrhea, abdominal pain Other side effects are less common
Antibiotics: Cephalosporins Semisynthetic derivatives from a fungus Structurally and pharmacologically related to penicillins Bactericidal action Broad spectrum Divided into groups according to their antimicrobial activity
Cephalosporins: Side Effects similar to penicillins
Antibiotics: Tetracyclines Natural and semi-synthetic Obtained from cultures of Streptomyces Bacteriostatic—inhibit bacterial growth Inhibit protein synthesis Stop many essential functions of the bacteria
Tetracyclines: Therapeutic Uses Wide spectrum: gram-negative, gram-positive, protozoa, Mycoplasma, Rickettsia, Chlamydia, syphilis, Lyme disease Demeclocycline is also used to treat SIADH, and pleural and pericardial effusions
Tetracyclines: Side Effects May also cause: Vaginal moniliasis Gastric upset Enterocolitis Maculopapular rash
Antibiotics: Aminoglycosides gentamicin (Garamycin) kanamycin neomycin streptomycin tobramycin amikacin (Amikin) netilmicin
Aminoglycosides Natural and semi-synthetic Produced from Streptomyces Poor oral absorption; no PO forms Very potent antibiotics with serious toxicities Bactericidal Kill mostly gram-negative; some gram-positive also
Aminoglycosides: Side Effects Ototoxicity and nephrotoxicity are the most significant Headache Paresthesia Neuromuscular Dizziness Vertigo Skin rash Fever Superinfections blockade
Antibiotics: Quinolones ciprofloxacin (Cipro) enoxacin (Penetrex) lomefloxacin (Maxaquin) norfloxacin (Noroxin) ofloxacin (Floxin)
Quinolones: Side Effects Body System Effects CNS headache, dizziness, fatigue, depression, restlessness GI nausea, vomiting, diarrhea, constipation, thrush, increased studies liver function
Quinolones: Side Effects Body System Effects Integumentary urticaria, photosensitivity rash, pruritus, flushing, (with lomefloxacin) Other vision, fever, chills, blurred tinnitus
Antibiotics: Nursing Implications Before beginning therapy, assess drug allergies; hepatic, liver, and cardiac function; and other lab studies. Be sure to obtain thorough patient health history, including immune status. Assess for conditions that may be contraindications to antibiotic use, or that may indicate cautious use. Assess for potential drug interactions.
Antibiotics: Nursing Implications It is ESSENTIAL to obtain cultures from appropriate sites BEFORE beginning antibiotic therapay Patients should be instructed to take antibiotics exactly as prescribed and for the length of time prescribed; they should not stop taking the medication early when they feel better. Assess for signs and symptoms of superinfection: fever, perineal itching, cough, lethargy, or any unusual discharge.
Antibiotics: Nursing Implications Each class of antibiotics has specific side effects and drug interactions that must be carefully assessed and monitored. The most common side effects of antibiotics are nausea, vomiting, and diarrhea. All oral antibiotics are absorbed better if taken with at least 6 to 8 ounces of water.
Antibiotics: Nursing Implications Sulfonamides Should be taken with at least 2400 m. L of fluid per day, unless contraindicated. Due to photosensitivity, avoid sunlight and tanning beds. These agents reduce the effectiveness of oral contraceptives.
Antibiotics: Nursing Implications Penicillins Any patient taking a penicillin should be carefully monitored for an allergic reaction for at least 30 minutes after its administration. The effectiveness of oral penicillins is decreased when taken with caffeine, citrus fruit, cola beverages, fruit juices, or tomato juice.
Antibiotics: Nursing Implications Cephalosporins Orally administered forms should be given with food to decrease GI upset, even though this will delay absorption. Some of these agents may cause an Antabuse-like reaction when taken with alcohol.
Antibiotics: Nursing Implications Tetracyclines Milk products, iron preparations, antacids, and other dairy products should be avoided because of the chelation and drug-binding that occurs. All medications should be taken with 6 to 8 ounces of fluid, preferably water. Due to photosensitivity, avoid sunlight and tanning beds.
Antibiotics: Nursing Implications Aminoglycosides Monitor peak and trough blood levels of these agents to prevent nephrotoxicity and ototoxicity. Symptoms of ototoxicity include dizziness, tinnitus, and hearing loss. Symptoms of nephrotoxicity include urinary casts, proteinuria, and increased BUN and serum creatinine levels.
Antibiotics: Nursing Implications Quinolones Should be taken with at least 3 L of fluid per day, unless otherwise specified
Antibiotics: Nursing Implications Macrolides These agents are highly protein-bound and will cause severe interactions with other protein-bound drugs. The absorption of oral erythromycin is enhanced when taken on an empty stomach, but because of the high incidence of GI upset, many agents are taken after a meal or snack.
Antibiotics: Nursing Implications Monitor for therapeutic effects: Disappearance of fever, lethargy, drainage, and redness
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