Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

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FACTORS THAT INFLUENCE TYPE A ADVERSE DRUG REACTIONS Table 3.3 Drugs which are therapeutically useful in cats but which may have different toxicity/activity profiles than in dogs Aspirin Chloramphenicol Digoxin Doxorubicin Enrofloxacin Furosemide Griseofulvin Ketoconazole Lidocaine Megestrol acetate Methimazole Metronidazole Opioids Morphine derivatives (excluding meperidine [pethidine], butorphanol and buprenorphine) Organophosphates Tetracyclines Thiacetarsamide Hyperpnea Hypersensitivity Hyperthermia Anemia Vomiting Anorexia Bradycardia Arrhythmias Renal failure Blindness Dehydration Hypokalemia Leukopenia and thrombocytopenia Nonreversible ataxia Dry hair coat Weight loss Myocardial and CNS depression Mammary hypertrophy and neoplasia Cystic endometritis Diabetes mellitus Anorexia Vomiting Self-induced facial excoriation Bleeding diathesis Hepatopathy Serious hematological side effects Disorientation Ataxia Seizures Blindness Inconsistent sedation Increased risk of excitation Acute toxicity – hypersalivation, vomiting, diarrhea, muscle tremors Chronic or delayed toxicity – paresis or paralysis which may or may not be reversible Hepatic lipidosis Increased ALT activity Ptyalism Anorexia Drug fever Respiratory distress Fulminant pulmonary edema Body size and percentage fat Metabolic rate (estimated by O 2 consumption) is more closely related to body surface area than bodyweight so it has been suggested that small animals within a species may require a higher dose per kg than larger animals, when scaling is more closely linked to metabolic rate. This is particularly relevant to dogs where the body size within the species covers such a large range. Where there is a narrow therapeutic range for the drug, this factor can become very important. The dose of a drug with a narrow therapeutic ratio (e.g. digoxin, cytotoxic drugs) is usually calculated on body surface area rather than bodyweight. There can be a large difference in the calculated dose for dogs of extreme size (small or large) when weight or body surface areas are used. For drugs with a wide margin of safety such accurate dosing may not be clinically important. However, for drugs with a narrow margin of safety, failure to calculate the dose appropriately can result in toxicity or reduced therapeutic efficacy. Another consideration when adjusting dosages for body size is the fat component of the bodyweight. Drug dosages are usually expressed per unit weight within a particular species. One should attempt to estimate the appropriate lean bodyweight and use this to calculate 49
CHAPTER 3 ADVERSE DRUG REACTIONS an appropriate dosage for nonlipid-soluble drugs even if using body surface area. Drugs which have a narrow margin of safety and are not lipid soluble include digoxin and the aminoglycoside antibiotics. For lipid-soluble drugs, increased body fat can act as a sink and reservoir, leading to protracted drug elimination if metabolism to a more water-soluble form is not involved. Age Neonates have a reduced capability for drug biotransformation and have underdeveloped hepatic and renal excretory mechanisms. Hence the increased sensitivity to, and prolonged recovery from, barbiturate anesthetics that may be observed in dogs and cats younger than 4 months. Other factors that influence drug disposition in the pediatric patient include increased gastrointestinal permeability, differences in body water and protein binding (greater percentage of body water, less extensive protein binding) and increased blood–brain barrier permeability. Older animals may have reduced hepatic or renal function, less body water and reduced lean body mass and therefore often require lower doses of drugs compared to younger animals. However, it is important to be aware that the aging process varies greatly between individuals. Patient-specific physiological and functional characteristics are probably more important than age per se in predicting the predisposition to ADRs in patients. Sex During pregnancy or lactation, caution should be observed in administration of drugs that might affect the fetus or neonate. Drugs that should be avoided or used with caution in pregnant animals include corticosteroids, cytotoxic drugs, griseofulvin, ketoconazole, prostaglandins, salicylates, sex hormones, tetracyclines and live vaccines. Drugs which may adversely affect lactation, causing agalactia, include atropine, bromocriptine and furosemide. Adverse drug reactions occur more commonly in female humans but it is not known if this phenomenon occurs in domestic animals. Pathology Dosage recommendations are usually based on pharmacokinetic data obtained from healthy animals under controlled conditions even though many drugs will be given to diseased animals. Drug absorption, distribution, metabolism and excretion may be adversely affected by pathology of various organs, in particular the gastrointestinal tract, liver and kidney. Adjustment in dosage may be required, depending on changes in volume of distribution and clearance as influenced by the site of metabolism and route of elimination of the particular drug. Drugs and the liver The liver is the major site of metabolism of many drugs and thus the clinician is rightly concerned about the safety of administering drugs to patients with hepatic disease. Hepatocellular dysfunction can alter the bioavailability and disposition of a drug as well as influencing its pharmacological effects. In addition, the impact of hepatic pathology on drug disposition can relate to the effect of the clinical consequences of liver disease such as anorexia, pyrexia, hypoproteinemia and jaundice. Hepatic extraction and the first-pass effect When a drug is absorbed across the gut wall, it is delivered via portal blood to the liver prior to entry into the systemic circulation. Drug metabolism most commonly occurs in the liver prior to the drug reaching the systemic circulation although it can also occur in gut wall and portal blood. The liver may also excrete the drug into bile, allowing enterohepatic recycling. The effect of first-pass elimination on bioavailability (the proportion of administered dose that reaches the systemic circulation unchanged) is expressed as the extraction ratio ER CL liver = where CL liver is clearance Q by the liver and Q is hepatic blood flow. This equation would predict that if clearance of a drug by the liver is reduced because of hepatocellular dysfunction causing reduced drug metabolism or decreased biliary excretion, then the ER will be reduced and systemic availability of the drug will rise when the drug is given orally. The equation also predicts that if hepatic blood flow is reduced then ER will also increase. Studies in horses have demonstrated that acute submaximal exercise increases the elimination half-life of bromosulfan, possibly due to decreased splanchnic and hepatic blood flow. Whether this has clinical relevance for animals that are exercised to a far greater degree than the ‘normal’ pet is unknown. Hepatic diseases that are accompanied by substantial intrahepatic or extrahepatic shunting (such as cirrhosis, congenital portacaval shunts) will result in increased bioavailability of drugs with high extraction ratios such as verapamil, pethidine, propranolol and several tricyclic antidepressants. Clearance of drugs which have intermediate extraction ratios such as aspirin, codeine and morphine may also be affected. Clearance of these drugs will also be prolonged by poor hepatic perfusion (e.g. in heart failure, in shock and with propranolol administration). Liver blood flow also tends to be reduced in older patients. In contrast, there will be little change in bioavailability of drugs that are poorly 50
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An imprint of Elsevier Limited © E
Page 3 and 4: CONTRIBUTORS Matthias J Kleinz Depa
Page 5 and 6: Dedication To Tom, Rosalind and Jim
Page 7 and 8: CHAPTER 1 PRINCIPLES OF CLINICAL PH
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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 forms
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CHAPTER 8 ANTIBACTERIAL DRUGS ● I
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CHAPTER 8 ANTIBACTERIAL DRUGS ● R
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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 Tabl
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CHAPTER 10 ANTIPARASITIC DRUGS leva
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CHAPTER 10 ANTIPARASITIC DRUGS Form
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CHAPTER 10 ANTIPARASITIC DRUGS prod
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CHAPTER 10 ANTIPARASITIC DRUGS Adve
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CHAPTER 10 ANTIPARASITIC DRUGS 62.5
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CHAPTER 10 ANTIPARASITIC DRUGS incr
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CHAPTER 10 ANTIPARASITIC DRUGS The
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CHAPTER 10 ANTIPARASITIC DRUGS In a
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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 admini
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CHAPTER 14 OPIOID ANALGESICS may ac
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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 respon
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CHAPTER 14 OPIOID ANALGESICS Advers
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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 sion
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CHAPTER 15 CANCER CHEMOTHERAPY In t
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CHAPTER 15 CANCER CHEMOTHERAPY afte
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CHAPTER 15 CANCER CHEMOTHERAPY Form
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CHAPTER 15 CANCER CHEMOTHERAPY conc
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CHAPTER 15 CANCER CHEMOTHERAPY ●
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CHAPTER 15 CANCER CHEMOTHERAPY Phar
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CHAPTER 15 CANCER CHEMOTHERAPY best
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CHAPTER 15 CANCER CHEMOTHERAPY Form
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CHAPTER 15 CANCER CHEMOTHERAPY baso
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CHAPTER 15 CANCER CHEMOTHERAPY D-MA
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CHAPTER 16 ANTICONVULSANT DRUGS sei
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CHAPTER 16 ANTICONVULSANT DRUGS bit
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CHAPTER 16 ANTICONVULSANT DRUGS Kno
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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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CHAPTER 19 GASTROINTESTINAL DRUGS C
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CHAPTER 19 GASTROINTESTINAL DRUGS
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CHAPTER 19 GASTROINTESTINAL DRUGS
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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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