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 H2O osmotic force solute in lumen > osmotic force of reabsorbed Na+ increased H2O 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 HCO3- and H+ from H2O and CO2 inhibition of carbonic anhydrase decreases [H+] in tubule lumen less H+ for for Na+/H+ exchange increased lumen Na+, increased H2O retention

Therapeutic Uses

used to treat chronic open-angle glaucoma aqueous humor has high [HCO3-] 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 HCO3- 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 HCO3- excretion increased K+/Mg2+ excretion decrease Ca2+ excretion

Therapeutic Uses

hypertension congestive heart failure hypercalciuria: prevent excess Ca2+ 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-2Cl transporter in thick ascending loop of henle competes with Cl- binding site enhances passive Mg2+ and Ca2+ 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 Mg2+ 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.

2.

Empiric therapy: treatment of an infection before specific culture information has been reported or obtained Prophylactic therapy: treatment with antibiotics to prevent an infection, as in intra-abdominal surgery

Antibiotics  Bactericidal: kill bacteria  Bacteriostatic: inhibit growth of susceptible bacteria.

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  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 1940s  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 blockade  Dizziness  Vertigo  Skin rash  Fever  Superinfections

Antibiotics: Quinolones  ciprofloxacin (Cipro)  enoxacin (Penetrex)  lomefloxacin (Maxaquin)  norfloxacin (Noroxin)  ofloxacin (Floxin)

Quinolones: Side Effects Body System CNS GI Effects headache, dizziness, fatigue, depression, restlessness nausea, vomiting, diarrhea, constipation, thrush, increased liver function studies

Quinolones: Side Effects Body System Integumentary urticaria, photosensitivity lomefloxacin) Other vision, Effects rash, pruritus, flushing, (with 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 mL 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

Question?