Avoiding Adverse Drug Reactions

Lauren Trepanier United States

Adverse drug reactions are defined as any undesired response to therapy and may involve either therapeutic failure or toxicity. Although the overall incidence of these reactions in veterinary patients is unknown, dogs and particularly cats are susceptible to adverse drug reactions for several reasons:

 Species differences in drug disposition or action compared to humans.

 Lack of suitable drug formulations for small patients.

 Changes in drug dose requirements because of age or disease state.

I.�������� Species differences in drug disposition or action compared to humans

A.   Pay attention to where a dose originates

B.   Whenever possible, use dosages for drugs in dogs and cats that are based on kinetic or efficacy studies in dogs and cats

C.   Monitor carefully for side effects when using a dosage extrapolated from humans

II.������� Lack of suitable drug formulations

A.   Most drugs given to dogs and cats have been formulated for humans (70 kg standard), so the dose in a single pill is often excessive, and splitting pills is inaccurate

B.   Options for more accurate dosing:

1.   Choose specially formulated veterinary products when available

2.   Use commercially available veterinary, or human pediatric, suspensions

3.   Have tablets or injectables reformulated into suspensions by your local pharmacist

a)   azathioprine, chlorambucil, metronidazole, sucralfate

b)   cyclophosphamide, hydralazine

4.   Request custom formulations (capsules or suspensions) from veterinary custom pharmacies

a)   metronidazole, phenoxybenzamine, potassium bromide, cimetidine, tetracycline, mitotane, methimazole syrup, atenolol suspension

III.����� Changes in drug disposition due to age and disease

A.   Neonates

1.   Immature renal tubular function prior to eight weeks of age

a)   Avoid digoxin, aminoglycosides, ACE inhibitors, NSAIDs

2.   Physiologic hypoalbuminemia

a)   Caution in dosing highly protein bound drugs such as diazepam or NSAIDs

3.   Decreased body fat

a)   Use lower doses of lipid soluble drugs such as anesthetics

4.   Increased target organ susceptibility

a)   Cartilage damage from enrofloxacin in puppies, but not in kittens

b)   Increased anesthetic effects due to immature blood brain barrier at < 8 weeks of age

c)   Predisposition to hypotension due to poor cardiac compliance and immature baroreceptors

B.   Geriatrics

1.   Decreased renal function due to nephron loss

a)   Increased risk of aminoglycoside, digoxin, ACE inhibitor toxicity

b)   Use lower doses of renally cleared drugs

2.   Decreased muscle mass

a)   May see increased serum digoxin concentrations, and increased toxicity, in cachectic old dogs and cats (digoxin distributes to skeletal muscle)

3.   Decreased total body water

a)   May see erratic SC absorption in older patients

b)   Consider IM or IV routes in geriatrics

4.   Decreased liver blood flow (seen in older humans)

a)   Use lower doses of drugs such as propranolol and hydralazine

C.   Obesity

1.   Reduce the dosages of polar, water-soluble drugs with poor fat distribution, when prescribing for overweight patients

a)   In obese dogs and cats, the dose of gentamicin or digoxin should be adjusted to lean body weight (i.e., dose should be reduced by 15�20%)

D.   Heart failure

1.   Decreased cardiac output

a)   Leads to preferential shunting of blood to brain and heart

b)   May enhance cardiac toxicity (arrhythmias) and CNS toxicity (nausea) from digoxin

2.   Prerenal azotemia

a)   Requires lower doses of enalapril, digoxin, furosemide

3.   Gastrointestinal edema

a)   May lead to erratic oral absorption of some drugs during acute heart failure

4.   Drug interactions

a)   Furosemide and digoxin

b)   Furosemide and enalapril

c)   Digoxin and propranolol; digoxin and diltiazem

E.   Liver disease

1.   Decreased metabolism of some drugs

a)   In humans with cirrhosis, some drugs that are normally extensively metabolized are not cleared as readily

b)   Based on human data, dosages of the following drugs should probably be reduced in dogs and cats with severe liver disease:

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

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

(3)   Metronidazole (use 25�50% of regular dose)

(a)   substitute neomycin (for gut sterilization)

(b)   substitute amoxicillin/clavulanate (for systemic anaerobic therapy)

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

2.   Hypoalbuminemia

a)   Increased toxicity from highly protein drugs such as aspirin and diazepam�

3.   Ascites

a)   Use the total body weight (including ascites fluid) to calculate dosage of aminoglycosides or other polar drugs

b)   Use the normal body weight (minus estimated ascites fluid weight) to calculate dosage of lipid soluble drugs such as anesthetics and vitamin K1

4.   Increased sensitivity to CNS depressants

a)   Opioids: reduce dose or use reversible agents

b)   Benzodiazepines, acepromazine: avoid or use reduced dosages

c)   Barbiturates: avoid or use reduced dosages

(1)   For encephalopathic seizures, use phenobarbital at 20�30% of standard doses and titrate upwards

F.   Renal failure

1.   Use drugs that are inactivated by metabolism, or drugs that are eliminated by the kidneys and make dosage adjustments

2.   Once isosthenuria appears (GFR is less than 30-40% of normal; 2/3 of functional nephrons are lost), doses of renally excreted drugs should be adjusted

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

a)   Divide the dose by the serum creatinine in mg/dl (i.e. less drug given at same intervals)

b)   Roughly accurate for serum creatinine concentrations less than or equal to 4 mg/dl

c)   Exception is aminoglycosides, for which the dose interval should be extended instead (see below)

4.   Drugs that require dose reductions in renal failure:

a)   Penicillins

(1)   Toxicity unlikely, but dose reduction is appropriate and will also decrease the cost of using more expensive penicillins (such as ticarcillin) in patients with azotemia

b)   Cephalosporins

(1)   Cephalothin and cefazolin can be nephrotoxic at very high doses in humans, so dose reduction of these two drugs in renal failure is important

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

c)   Aminoglycosides

(1)   Use other agents whenever possible (enrofloxacin, ticarcillin, cefotetan)

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

(a)   Always rehydrate first

(b)   Always use concurrent fluid therapy (preferably IV)

(c)   Consider less nephrotoxic forms of aminoglycosides

(i)   Amikacin 15 mg/kg SC q. 24h

(ii)   Netilmicin� 6�8� mg/kg SC q. 24h

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

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

(i)   E.g. for a serum creatinine of 2 mg/dl, dose every 48 hours instead of every 24 hours

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

(g)   Do not use furosemide or NSAID�s concurrently

(h)   Limit aminoglycoside therapy to five days or less whenever possible

d)   Tetracyclines

(1)   Use doxycycline instead for patients with renal insufficiency

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

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

e)   Chloramphenicol

(1)   In cats, 25% or more is excreted unchanged in the urine; therefore, avoid use in cats with renal insufficiency or reduce the dose

f)   Sulfonamides

(1)   Reduce dose in renal failure (especially sulfadiazine, which can form drug crystals in the renal tubules and lead to hematuria)

(2)   Rehydrate first

(3)   Dose accurately

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

g)   Dgoxin

(1)   Reduce dose in renal failure

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

h)   Cmetidine / ranitidine / famotidine

(1)   Reduce dose in renal failure

(2)   CNS disturbances reported in elderly humans with decreased GFR when given cimetidine without appropriate dose reductions

REFERENCES are AVAILABLE ON REQUEST