Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

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DIGITALIS GLYCOSIDES In one study, digitalis increased sodium excretion 284% above baseline in experimental dogs with heart failure. This would translate into percentage of filtered sodium load increasing from 1% to approximately 4%, making digoxin a slightly better diuretic than spironolactone. Formulations and dose rates Digoxin is available as tablets (preferred), capsules, suspension, elixir and as an injectable formulation. Tablets are better tolerated than the alcohol-based elixir. In the authors’ opinion use of the injectable formulation has no place in clinical veterinary medicine. The therapeutic range for digoxin is based on evaluation of serum trough concentration (6–8 h after a dose) in patients at presumed steady state (i.e. 3–7 d after initiation or any change in dose). However, if a patient presents with signs of possible toxicity a serum level can be obtained immediately. The reported target therapeutic serum concentration is 1–2 ng/mL, where
CHAPTER 17 DRUGS USED IN THE MANAGEMENT OF HEART DISEASE AND CARDIAC ARRHYTHMIAS become electrically unstable, resulting in ectopic tachyarrhythmias. ● The administration of other drugs concurrently with digitalis may affect the serum concentration of digoxin. – Quinidine is the classic example. It displaces digoxin from skeletal muscle binding sites and reduces its renal clearance, resulting in an increased serum digoxin concentration. Quinidine probably also displaces digoxin from myocardial binding sites. This may lessen the direct cardiac toxicity of digoxin and decrease its positive inotropic effect. In general, the combination of digoxin and quinidine should be avoided. If both drugs must be used together, the rule of thumb in human medicine is to reduce the digoxin dosage by 50%. Since serum digoxin concentration approximately doubles following quinidine administration in dogs, this recommendation appears to be valid in veterinary patients. – In humans, there are reports of numerous other drugs that increase the serum concentration of digoxin, including oral aminoglycosides (neomycin), amiodarone, anticholinergics, captopril, diltiazem, esmolol, flecainide, ibuprofen, indomethacin, nifedipine, tetracycline and verapamil. ● Digoxin pharmacokinetics are not significantly altered in cats with compensated heart failure receiving furosemide and aspirin. This is despite increases in serum urea and creatinine concentrations. Dosing strategy In general, patients should be evaluated carefully before digoxin is administered. Factors that alter the dosage should be noted and an initial dose chosen. The patient should be monitored during the initial course of therapy for signs of toxicity or improvement. A decrease in heart rate or resolution of an arrhythmia are measurable benefits in patients with tachycardia or arrhythmia. <strong>Clinical</strong> responsiveness due to improved hemodynamics in patients with heart failure is the desired endpoint of digitalis administration but can be difficult to identify, for several reasons. First, other drugs are generally administered with digoxin, so it may be impossible to identify the beneficial drug. Second, many dogs do not respond to digoxin, so clinical resolution may never occur. The dosage in the latter case should not be increased unless the serum concentration has been measured and documented to be subtherapeutic (i.e. less than 0.5 ng/mL). Each case should have a serum digoxin concentration measured 3–7 d after initiating therapy and 6–8 h after the last dose (trough concentration) or immediately any time toxicity is suspected. The therapeutic range for serum digoxin concentration is somewhat controversial, although it is generally considered to be between 0.5 and 2.0 ng/mL. However, some dogs will demonstrate toxicity at serum concentrations of 2 ng/mL. A serum concentration above 2.5 ng/mL should be regarded as toxic. If such an elevation is identified in a patient, digoxin administration should be discontinued until the serum concentration is below 1.5 ng/mL. The dosage should be reduced accordingly several days later. Pharmacokinetics Approximately 60% of digoxin tablet formulations is absorbed, while about 75% of the elixir is absorbed. There is very little hepatic metabolism, so that almost all of the absorbed drug reaches the vascular system. In serum, an average of 27% of digoxin is bound to albumin. The volume of distribution is 12–15 L/kg. In normal young dogs, serum half-life of digoxin is 23–39 h although much interpatient variability exists. Theoretically, it takes about five half-lives to reach steady state, so it is commonly thought that five halflives are required to achieve serum concentrations of between 1.0 and 2.0 ng/mL (which is generally considered to be the therapeutic range). However, this is not the case. The canine maintenance dose of digoxin generally achieves a serum concentration of 1.5–2.0 ng/mL. The serum concentration after two half-lives (75% of steady state) should be 1.1–1.5 ng/mL and after three half-lives (87.5% of steady state) 1.3–1.75 ng/mL. Consequently, maintenance doses should theoretically achieve a therapeutic serum concentration within 2–4 d. In one study of dogs given 0.022 mg/kg digoxin every 24 h, the serum concentration was within therapeutic range by the second day. On the basis of these data, maintenance doses of digoxin in dogs should be used to achieve a therapeutic serum concentration in almost all situations. Loading doses designed to achieve a therapeutic concentration within a shorter period are not recommended in dogs and cats. Digoxin is primarily excreted via glomerular filtration and renal secretion. About 15% is metabolized in the liver. Bile duct ligation increases the half-life of digoxin from an average of 26 h to 35 h in experimental dogs. The half-life is extremely variable from cat to cat, ranging from 25 h to 50 h in one study and from 39 h to 79 h in another report. In a more recent study, the half-life in a group of six normal cats ranged from 30 h to 173 h with a mean half-life of 82 h. The half-life of digoxin increases dramatically with prolonged oral administration. The elixir form results in serum concentrations approximately 50% higher than those achieved with the tablet. However, cats generally dislike the taste 448
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An imprint of Elsevier Limited © E
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CONTRIBUTORS Matthias J Kleinz Depa
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Dedication To Tom, Rosalind and Jim
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CHAPTER 1 PRINCIPLES OF CLINICAL PH
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CHAPTER 2 CLINICAL PHARMACOKINETICS
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CHAPTER 3 ADVERSE DRUG REACTIONS Un
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CHAPTER 3 ADVERSE DRUG REACTIONS
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CHAPTER 4 THE PHARMACOLOGY OF THE A
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CHAPTER 5 ANESTHETIC AGENTS However
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CHAPTER 5 ANESTHETIC AGENTS Table 5
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CHAPTER 5 ANESTHETIC AGENTS doses.
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CHAPTER 5 ANESTHETIC AGENTS concent
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CHAPTER 5 ANESTHETIC AGENTS X R 3 C
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CHAPTER 5 ANESTHETIC AGENTS Emergen
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CHAPTER 5 ANESTHETIC AGENTS inhalat
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CHAPTER 5 ANESTHETIC AGENTS ● Exc
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CHAPTER 5 ANESTHETIC AGENTS Pharmac
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CHAPTER 5 ANESTHETIC AGENTS Central
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CHAPTER 5 ANESTHETIC AGENTS Table 5
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CHAPTER 5 ANESTHETIC AGENTS FURTHER
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CHAPTER 6 SEDATIVES ● noradrenali
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CHAPTER 6 SEDATIVES treatment, with
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CHAPTER 6 SEDATIVES Benzodiazepines
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CHAPTER 6 SEDATIVES It is not misci
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CHAPTER 6 SEDATIVES respectively. H
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CHAPTER 6 SEDATIVES Table 6.1 Sugge
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7 Behavior-modifying drugs Kersti S
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CHAPTER 7 BEHAVIOR-MODIFYING DRUGS
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8 Antibacterial drugs Jill E Maddis
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CHAPTER 8 ANTIBACTERIAL DRUGS phary
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CHAPTER 8 ANTIBACTERIAL DRUGS dose
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CHAPTER 8 ANTIBACTERIAL DRUGS Table
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CHAPTER 8 ANTIBACTERIAL DRUGS Bacte
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CHAPTER 8 ANTIBACTERIAL DRUGS lacta
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CHAPTER 8 ANTIBACTERIAL DRUGS Antis
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CHAPTER 8 ANTIBACTERIAL DRUGS RIFAM
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9 Systemic antifungal therapy Josep
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CHAPTER 9 SYSTEMIC ANTIFUNGAL THERA
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10 Antiparasitic drugs Stephen W Pa
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CHAPTER 10 ANTIPARASITIC DRUGS ●
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CHAPTER 10 ANTIPARASITIC DRUGS Para
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CHAPTER 11 GLUCOCORTICOSTEROIDS AND
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12 Immunomodulatory therapy Michael
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CHAPTER 12 IMMUNOMODULATORY THERAPY
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CHAPTER 13 NONSTEROIDAL ANTI-INFLAM
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CHAPTER 14 OPIOID ANALGESICS inflam
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A Agonist opioid (morphine) B Parti
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CHAPTER 14 OPIOID ANALGESICS Small
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CHAPTER 14 OPIOID ANALGESICS Clinic
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CHAPTER 14 OPIOID ANALGESICS Contra
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CHAPTER 14 OPIOID ANALGESICS Advers
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15 Cancer chemotherapy Jane M Dobso
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CHAPTER 15 CANCER CHEMOTHERAPY to m
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CHAPTER 15 CANCER CHEMOTHERAPY curr
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CHAPTER 15 CANCER CHEMOTHERAPY Tabl
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CHAPTER 15 CANCER CHEMOTHERAPY Clin
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CHAPTER 15 CANCER CHEMOTHERAPY best
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CHAPTER 15 CANCER CHEMOTHERAPY D-MA
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CHAPTER 16 ANTICONVULSANT DRUGS sei
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17 Drugs used in the management of
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CHAPTER 17 DRUGS USED IN THE MANAGE
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20 Drugs used in the management of
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CHAPTER 21 DRUGS USED IN THE TREATM
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23 Drugs and reproduction Philip G
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CHAPTER 23 DRUGS AND REPRODUCTION I
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CHAPTER 23 DRUGS AND REPRODUCTION F
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CHAPTER 23 DRUGS AND REPRODUCTION C
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CHAPTER 23 DRUGS AND REPRODUCTION M
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CHAPTER 23 DRUGS AND REPRODUCTION n
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CHAPTER 23 DRUGS AND REPRODUCTION E
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24 Topical dermatological therapy R
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CHAPTER 24 TOPICAL DERMATOLOGICAL T
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CHAPTER 25 OCULAR CLINICAL PHARMACO
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Index A α-adrenergic receptors 70,
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INDEX Antiplatelet drugs 456-457 pi
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INDEX Ceftazidime 168 Ceftiofur 166
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INDEX Drug receptors 4-8 Drug-drug
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INDEX Hepatic excretion 33 Hepatic
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INDEX Metabolism dogs vs cats 47 an
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INDEX Pentazocine 319, 327 Pentobar
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INDEX Semicarbazone 230 Septic arth
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Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

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