Drug dose adjustments for disease (Proceedings)

There is considerable evidence to support the adjustment of drug dosages in human patients with heart failure, hepatic failure, or renal insufficiency. In contrast, similar studies are lacking in dogs and cats. This presentation will discuss veterinary situations in which drug dose adjustments may be warranted.

Heart failure

Decreased cardiac output

          1. Leads to preferential shunting of blood to brain and heart

          2. May enhance cardiac toxicity (arrhythmias) and central nervous system toxicity (nausea) from digoxin

      Prerenal azotemia

          1. Requires lower doses of enalapril, digoxin, furosemide

          2. Benazepril clearance is not affected by azotemia in dogs and cats, and is a good option for patients with significant azotemia

      Gastrointestinal edema

          1. May lead to erratic oral absorption of some drugs in fulminant heart failure

      Many potential drug interactions

          1. Furosemide and digoxin:

                a) Hypokalemia and dehydration from furosemide can enhance digoxin toxicity

          2. Furosemide and angiotensin converting enzyme (ACE) inhibitors

                a) ACE inhibitors will impair the patient's ability to respond to dehydration from furosemide

          3. Furosemide and lidocaine

                a) Hypokalemia, which can be caused by furosemide, impairs the efficacy of lidocaine

          4. Spironolactone and ACE inhibitors

                a) Possible hyperkalemia when used in combination

                b) Important to monitor serum electrolytes in patients taking spironolactone

          5. Diltiazem, and beta blockers (propranolol or atenolol)

                a) Enhanced risk of atrioventricular block with combination

                b) Do not use diltiazem and beta blockers together

Hepatic insufficiency

Decreased metabolism of some drugs, but only with severe disease

          1. In humans with inflammatory liver disease without cirrhosis, most hepatic drug metabolism is fairly well conserved.

          2. With cirrhosis, drugs that are normally extensively metabolized are not cleared as readily

               a) Veterinary diseases with comparable hepatic dysfunction:

                     (1) Severe hepatic lipidosis

                     (2) Acute hepatic necrosis

                     (3) Cirrhosis in dogs

                     (4) Large portosystemic shunts

          3. Based on human data, dosages of the following drugs should probably be reduced in dogs and cats with severe hepatic dysfunction:

                a) Propranolol (decrease dose by 50% or more)

                b) Chloramphenicol (use 25% of regular dose, or choose another drug)

                c) Metronidazole (use 25-50% of antimicrobial dose)

                    (1) Or substitute:

                          (a) Lactulose or neomycin (for encephalopathy)

                          (b) Amoxicillin/clavulanate (for systemic anaerobic therapy)

                d) Diazepam or midazolam (use 25-50% of regular dose and use sparingly if treating encephalopathic seizures)

      Hypoalbuminemia

          1. Possibility of increased acute effects from highly protein drugs such as NSAIDs and benzodiazepines

      Ascites

          1. Use the total body weight (including ascites fluid) to calculate dosage of relatively water-soluble drugs:

                a) Aminoglycosides

                b) Fluoroquinolones

                c) Morphine

                     (1) Relatively polar opioid with polar active glucuronide metabolites in dogs

                    (2) Leads to decreased efficacy in humans if dosed on non-ascitic body weight.

          2. Lipid soluble drugs will not distribute to ascites fluid

               a) Use the normal body weight (minus estimated ascites fluid weight) to calculate dosage of lipid soluble drugs such as:

                     (1) Propofol

                     (2) Vitamin K1

      Increased sensitivity to CNS depressants

          1. Opioids: reduce dosage or use reversible agents

          2. Benzodiazepines, acepromazine: avoid or use reduced dosages

          3. Barbiturates: avoid or use reduced dosages

                a) For encephalopathic seizures, use phenobarbital at 20-30% of standard doses and titrate upwards

      Hepatic encephalopathy

          1. Avoid stored whole blood and packed red blood cell transfusions (can contain high ammonia levels)

          2. Avoid non-steroidal anti-inflammatory drugs (NSAID's)

                a) Risk of GI bleeding

                     (1) GI bleeding can worsen encephalopathy

          3. Avoid furosemide

                a) Hypokalemia, dehydration, azotemia, and alkalosis from furosemide can all exacerbate encephalopathy

                b) Consider spironolactone / hydrochlorthiazide instead for ascites (1 mg/kg twice daily) in dogs with portal hypertension

          4. Avoid 0.9% saline IV

                a) Often leads to edema, worsens ascites

               b) Consider 1/2 strength saline with 2.5% dextrose, and added potassium, for patients with liver disease accompanied by hypoalbuminemia

                c) Use Hetastarch for volume expansion

          5. Avoid glucocorticoids

                a) Catabolic

                     (1) Enhance deamination of proteins and release of NH3

          6. Consider lactulose and neomycin over metronidazole

               a) Less likely to cause neurologic signs

Renal failure

Leads to:

          1. Decreased filtration of renally eliminated drugs and active metabolites

          2. Decreased tubular secretion of some drugs

                a) Digoxin, cimetidine, trimethoprim, quinidine

          3. Decreased renal P450 and conjugative metabolism of some drugs

          4. Decreased binding of acidic drugs to albumin

                a) Furosemide, sulfamethoxazole, aspirin

          5. Reduced tissue binding of some drugs

                a) Digoxin

      Few good studies regarding dose adjustments for renal failure in dogs or cats

          1. Creatinine clearance is used to make rational dosage adjustments in azotemic humans, but is almost never known for veterinary patients

          2. Drug dosage adjustments are often made in humans with creatinine clearances less than around 0.7-1.2 ml/min/kg (depending on the drug)

               a) Corresponds to a serum creatinine of about 2.5 to 3.5 mg/dl in cats

      For many drugs, a crude dose reduction can be made by adjusting the amount given based on the serum creatinine

          1. Multiply the standard dose by a normal serum creatinine, divided by the patient's serum creatinine (i.e. less drug given at same intervals)

          2. Roughly accurate for serum creatinine concentrations up to 4 mg/dl

          3. Exception is aminoglycosides (and probably fluoroquinolones), for which the dose interval should be extended instead (see below)

      Drugs that merit dose reductions in renal failure:

          1. Penicillins

                a) Toxicity unlikely, but dose reduction is appropriate and will also decrease the cost of using more expensive beta lactams and related drugs (such as ticarcillin, aztreonem, meropenem) in patients with azotemia

          2. Cephalosporins

                a) Cephalothin can be nephrotoxic at very high doses in humans, so dose reduction of these two drugs in renal failure may be important in dogs and cats

                b) Cephalothin can also be nephrotoxic in combination with gentamicin to elderly humans; avoid this combination in older dogs and cats

          3. Fluoroquinolones

               a) Most fluoroquinolones are renally cleared.

               b) Given the risk of retinal toxicity in cats, always think twice about fluoroquinolone dosing in cats with renal insufficiency.

                c) Although the optimal method is not established, consider extending the dosing interval of enrofloxacin

                     (1) New interval for dosing = normal dosing interval x (patient creatinine / normal creatinine)

                         (a) e.g. enrofloxacin 5 mg/kg every 48 hours instead of every 24 hours

                d) Or choose less retinotoxic fluoroquinolones

                     (1) Retinotoxic potential in cats is marbofloxacin < orbifloxacin << enrofloxacin

          4. Aminoglycosides

                a) Use other agents whenever possible (fluoroquinolones, ticarcillin, cefotetan, aztreonem, meropenem)

               b) When necessary for use in patients with pre-existing renal failure:

                     (1) Always rehydrate first

                     (2) Always use concurrent fluid therapy (IV or SC)

                     (3) Consider possibly less nephrotoxic forms of aminoglycosides

                         (a) Amikacin 15 mg/kg SC q. 24h

                         (b) Netilmicin 6-8 mg/kg SC q. 24h

                    (4) Monitor for tubular damage by examining daily fresh urine sediments for granular casts

                     (5) Reduce the dose by multiplying the dose interval by the serum creatinine

                          (a) New interval for dosing = normal dosing interval x (patient creatinine / normal creatinine)

                         (b) e.g. for a serum creatinine of 2.0 mg/dl, dose every 48 hours instead of every 24 hours

                     (6) Do not use aminoglycosides in patients with urinary obstruction

                     (7) Do not use furosemide or NSAID's concurrently /

                     (8) Limit aminoglycoside therapy to 5 days or less whenever possible

          5. Tetracyclines

                a) Use doxycycline, not tetracycline

                    (1) No adjustment needed with renal insufficiency

                b) Tetracyclines can increase BUN, independent of any renal damage, due to protein catabolism (increase is reversible)

                c) Never use outdated tetracyclines (breakdown products are nephrotoxic)

          6. Chloramphenicol

                a) In cats, 25% or more is excreted unchanged in the urine

                b) Avoid use in cats with renal insufficiency

                     (1) Or monitor CBC for dose-dependent leukopenia

          7. Potentiated sulfonamides

                a) Decreased renal clearance and decreased protein binding in renal failure

                     (1) Reduce dose in renal failure

                b) Rehydrate first

                c) Dose accurately

                d) Avoid sulfadiazine (in Tribrissen) in renal failure

                     (1) Sulfadiazine forms drug crystals in the renal tubules and can lead to hematuria in humans

                e) Avoid use with methotrexate (combination can precipitate in urine and cause tubular damage)

                f) Avoid urinary acidifiers

          8. Digoxin

                a) Decreased renal filtration, tubular secretion, and skeletal muscle binding leads to increased serum concentrations in uremia

                b) Reduce dose in azotemia

                c) Measure serum digoxin concentrations

                     (1) Steady state after about 1 week in dogs

                     (2) Draw level 6 to 8 hours after dosing

                    (3) Therapeutic level: 0.8 – 1.2 ng/ml

          9. Furosemide

                a) Can lead to dehydration, hypokalemia, even acute renal failure

                b) Use conservative dosages and monitor carefully

                     (1) Serial BUN, creatinine, potassium, packed cell volume (PCV), and total protein (TP)

          10. Cimetidine / ranitidine / famotidine

                a) CNS disturbances reported in elderly humans with decreased GFR when given H2 blockers without appropriate dose reductions

                b) Reduce dosage in renal failure

                c) Either decrease dose or extend dosing interval (either method used in people)

          11. Metoclopramide

                a) Standard CRI dosages (1-2 mg/kg/day) may cause tremor and ataxia in azotemic patients

               b) Consider 0.25-0.50 mg/kg/day in renal failure, and titrate to dosage that controls emesis without tremor

                c) Or substitute maropitant as antiemetic (but this lacks prokinetic effects)

          12. Atenolol

                a) Renally cleared (unlike propranolol)

                b) Given at 25-50% of standard dosages in humans with moderate to severe renal insufficiency

          13. Angiotensin converting enzyme inhibitors (ACEi)

                a) Benazepril is preferred over enalapril in azotemic patients

                     (1) Benazepril undergoes some hepatic clearance, and does not accumulate in azotemia in dogs or cats

                b) All ACE inhibitors have potential adverse effects on glomerular filtration rate (GFR)

                     (1) Efferent arteriolar dilation can drop GFR

                    (2) May lead to worsened azotemia, particularly with:

                          (a) Concurrent NSAIDs

                          (b) Concurrent furosemide

                          (c) High ACEi dosages

               c) Monitor BUN, creatinine, and electrolytes in patients on ACE inhibitors, especially those with pre-existing azotemia

          14. NSAID's

                a) Decreased renal clearance, decreased protein binding, and adverse effects on GFR

               b) Use alternatives to NSAIDs in azotemic patients with osteoarthritis:

                     (1) Tramadol, buprenorphine

                     (2) Glucosamine/chondroitin

                     (3) Acupuncture

                     (4) S-adenosylmethionine (SAMe)

                          (a) Some efficacy for osteoarthritis in humans

               c) If NSAID is required for pain control and quality of life, use conservative NSAID dosages, and monitor frequently for:

                     (1) Dehydration, inappetance, or increases in BUN and creatinine

                d) Coxibs have same potential to adversely affect GFR

                     (1) COX-2 is constituitively expressed in the kidney

                e) Coxibs are not safer than classical NSAIDs in renal insufficiency

Table 1: Conditions that may require drug dosage adjustment in dogs and cats