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Pharmacologic Principles
CHAPTER 5
Pharmacologic Principles JOHNNY D. HOSKINS
Improved medications, surgical techniques, and nutrition, and an apparently increased percentage of animal owners willing to care for their older dogs and cats have contributed to increased numbers of older animals being seen by veterinarians and treated. Although older dogs and cats have long been noted to have different needs than younger animals, much of our working knowledge of veterinary gerontology is extrapolated from human or laboratory animal information. This includes the changes associated with the natural aging process and its effects on drug therapies. It is clear that there are many changes occurring in the aged dog and cat that can cause multivariable effects on a drug’s pharmacokinetics and pharmacodynamics. To sort out these effects and distill them into clinical guidelines is difficult to impossible. Veterinary medicine is further hindered in managing drug therapy for the aged because of the lack of specific information on the topic and because older dogs and cats cannot complain about symptoms caused either by disease or by the drugs used for treatment.
PHARMACOKINETICS AND PHARMACODYNAMICS Absorption, distribution, biotransformation, and elimination are the parameters that are the major factors in a drug’s pharmacokinetic profile.1 Although significant changes can occur in the gastrointestinal tract of aged mammals, agerelated effects on oral absorption appear to be minimal for most drugs in older dogs and cats.
Medications administered subcutaneously may be more slowly absorbed in the aged animal. Intramuscular absorptive characteristics may be altered because of a decrease in muscle mass. Thus, the clinical significance of drug absorption and age appears to be overall quite weak. A drug’s distribution characteristics, however, may significantly change with age. As a greater percentage of the body is fat, volumes of distribution of highly lipophilic drugs, such as anesthetic agents, could be significantly increased (and initial plasma levels decreased) as compared with those in a young, adult animal. Conversely, for drugs with high water solubility but low lipid solubility (such as aminoglycoside antimicrobials), volumes of distribution could be decreased (and initial plasma levels increased). Age effects on hepatic biotransformation appear to be minimal unless severe hepatic compromise is present. Because of reduced hepatic blood flow, drugs exhibiting a high first-pass effect in the liver, such as propranolol, buspirone, diltiazem, omeprazole, chlorpromazine, clomipramine, and selegiline, could potentially require dosage adjustment in older dogs and cats. Reduced renal function is another important effect of aging with respect to pharmacokinetic alterations. Despite normal renal function tests, reduced renal function can cause clinically significant changes in drug elimination, particularly with drugs having a narrow therapeutic window, such as aminoglycoside antimicrobials, digoxin, and cisplatin. Pharmacodynamics is defined as the relationship between drug quantity and drug effect. Changes in pharmacodynamics caused by age are 43
44
Geriatrics and Gerontology of the Dog and Cat
not as well understood as pharmacokinetic alterations, and little is known with respect to older dogs and cats. Many drugs have been shown to have a reduced effect in aged animals at a given tissue concentration. It is believed that this change occurs primarily at the molecular level, with reduction in receptor density and receptor function occurring with age. Conversely, certain drugs, especially drugs that have an effect on the central nervous system, can show a particular drug effect at a lower plasma concentration than that seen in the younger animal. In humans, the incidence of adverse drug effects is higher in the elderly. Whether this is caused primarily by alterations in a drug’s pharmacokinetic profile or by some other mechanism(s) is not known.
DRUG THERAPY AND TREATMENT PLANS In an effort to bring some order to the treatment plan for older dogs and cats, it may be useful to review some basic tenets of drug therapy1: • Senior dogs and cats are not geriatric dogs and cats. There is an important difference between senior animals and geriatric animals. • Identify causative factors involved in the disease process, including ruling out drug toxicity. It should always be remembered that older dogs and cats do not have one disease process occurring at a time but have multiple disease processes occurring at the same time within one or more body systems. Also, the more aged the dog or cat is, the more likely multiple diseases are occurring at the same time. For example, chronic renal failure has been documented in an older cat, but other disease processes may be occurring at the same time—for example, hyperthyroidism, systemic hypertension, inflammatory bowel disease, and diabetes mellitus. The veterinarian needs to avoid making diagnostic as well as therapeutic decisions based on the finding of a single disease process or problem. • Consider using nondrug treatment plans. This is the least understood part of caring for older dogs and cats, but some alternative medicine approaches may be useful. • Establish a treatment plan with the owner of the older dog or cat. Because many of the diseases managed in older dogs and cats are chronic and progressive, cures are not attainable —but control, at least for a period of time, is attainable.
• Choose initial drugs based on efficacy, cost, and ease of administration; assessment of animal-at-risk profile; matching of side-effect profile to the animal profile; and treatment plan for multiple diseases with one or more drugs. • Choose initial drug dose based on the aphorism “Start low and go slow.” • Monitor drug therapy for efficacy and adverse effects. Drug therapy in older dogs and cats is often a double-edged sword. In geriatric humans, rates of adverse drug reactions are reported to be two to three times those seen in younger patients. There is no reason to believe that the same thing does not occur in older dogs and cats. Because often more than one disease is being treated and multiple drugs are being used, an increased potential for adverse drug interactions exists. Use therapeutic drug monitoring for drugs with narrow therapeutic windows. • Determining the appropriate duration of therapy is extremely difficult to impossible. There is no right answer. When in doubt as to how long to treat an animal for a particular disease or diseases, always look to the animal being treated for the answer. Many times, the duration of therapy will be for a lifetime, with no other good choices. • Avoid polypharmacy—using more drugs than are necessary—in older dogs and cats. Polypharmacy is a problem not only in human medicine but also in veterinary medicine. Polypharmacy may lead to increased morbidity and mortality secondary to drug-drug interactions, it may result in increased adverse effects, or the cost of therapy may lead to premature euthanasia.
ADVERSE DRUG EFFECTS EXPECTED The goals of any treatment plan for the older dog or cat should be to alleviate pain, suffering, and disability; improve functional capacity; promote quality of life; and prolong life. Meeting these goals starts with selected diagnostic and therapeutic choices. The drug classes for which particular caution is advised when these drugs are used in older dogs and cats include the angiotensin converting enzyme inhibitors; aminoglycosides (aminoglycosides should not be used in older dogs and cats unless other antimicrobial agents are not indicated); antiarrhythmic agents; beta-blocking agents; calcium channel blocking agents; cardiac
Chapter 5 Pharmacologic Principles glycosides (especially digoxin); central nervous system and preanesthetic agents (especially benzodiazepines and opiates); coumarin anticoagulants; histamine-2 antagonists; nonsteroidal antiinflammatory drugs; and oncologic drugs. With the use of these drug classes, an increased potential for adverse drug interactions also exists. Use therapeutic drug monitoring for drugs with narrow therapeutic windows.
GUIDELINES FOR DRUG USE IN OLDER ANIMALS Beyond the routine clinical management of a specific organ failure in the older dog and cat, the veterinarian should also be aware of specific drug use for the routine clinical management of immune-mediated diseases, acute and chronic pain, and systemic hypertension (see Chapter 10).
Immune-Mediated Disease Strategies As an animal ages, its immune system may respond by being overreactive or underreactive. When the animal’s immune system is overreactive, several different types of immune-mediated disease occur with increased frequency. The tissues and organ systems that react most dramatically in the sensitized animal are the mucous membranes of the mouth and lips, lacrimal gland, thyroid gland, parathyroid gland, esophagus, gastrointestinal tract, anus, liver, erythrocytes, leukocytes, blood platelets, muscles, joints, and nerves. Common examples of immune-mediated diseases in older dogs are keratoconjunctivitis sicca, hypothyroidism, immune-mediated hemolytic anemia, immunemediated thrombocytopenia, glomerulonephritis, acquired myasthenia gravis, polymyositis, polyneuropathy, perianal fistulas, and immune-mediated skin disease. In addition, it is not unusual for several body systems in the sensitized dog to respond simultaneously with specific or nonspecific signs of immune-mediated disease. Often, a specific body system responds more pronouncedly than another body system. General principles about immunemediated diseases in older dogs are as follows: • A general rule in clinical medicine is that any tissue or organ of a sensitized animal can be attacked by the immune system, resulting in signs of immune-mediated disease related to that tissue or organ. No tissue or organ is completely free from immune-mediated disease and its effects in the older animal.
45
• Multiple immune-mediated diseases may occur simultaneously in older dogs. Many examples exist. Immune-mediated hemolytic anemia and immune-mediated thrombocytopenia often occur simultaneously. Canine hypothyroidism and keratoconjunctivitis sicca often occur simultaneously. Canine perianal fistulas, keratoconjunctivitis sicca, and hypothyroidism often occur simultaneously. Canine hypothyroidism, hypoparathyroidism, and hypoadrenocorticism may occur simultaneously in the older dog. • When a diagnosis of an immune-mediated disease occurs, the veterinarian should investigate the possibility of a second or third immunemediated disease occurring at the same time. Medical management will never completely cure an immune-mediated disease in the dog or cat but will provide medical control and a reasonable quality of life for the animal. A treatment that seems to effect a medical cure may be causing only a brief remission from obvious signs of immune-mediated disease; relapses always occur. Therapies that may be used in the clinical management of immune-mediated diseases of older dogs and cats are presented in Table 5-1.
Infectious Agent Strategies Most antimicrobial agents currently used in veterinary medicine have wide safety margins, and changes in dosage schedule more often reflect an attempt to save money or make drug delivery more convenient, not an attempt to make drug delivery safer. Most antimicrobial efficacy is correlated with time during which concentration is above the minimum inhibitory concentration of the pathogen. Changes in disposition of most antimicrobial drugs are due to a decrease in renal function, which prolongs the action of these agents and allows a decrease in dosage frequency. If an animal is showing significant body changes consistent with aging, and renal function is unknown, it is better not to alter the antimicrobial administration schedule. Having available established serum creatinine values for the geriatric animal is very important. Veterinarians should establish baseline values for the dogs and cats before the animals are of geriatric age. A dog or cat that had a serum creatinine level of 1 mg/dl at 10 years of age and currently has a level of 2 mg/dl at 13 years of age has had a 50% reduction in glomerular filtration rate, even though a level of 2 mg/dl is within the normal range. One
46
Geriatrics and Gerontology of the Dog and Cat
TABLE 5-1. THERAPIES FOR IMMUNE-MEDIATED DISEASES THERAPY
DOSAGE
COMMENTS
Prednisone*
Dog: 2.2-6.6 mg/kg PO; Cat: 4.4-8.8 mg/kg PO; Dosage depends on severity of the disease
Glucocorticoid pulse therapy
Dog: IV methylprednisolone sodium succinate at 11 mg/kg daily in 250 ml of 5% dextrose and water during a 1-h period for 3 consecutive days Dog and cat: hydrocortisone cream; 0.1% betamethasone valerate, flucinolone acetate, or amcinonide Dog: 1.5-2.5 mg/kg every 48 h; contraindicated in cats; used in combination with glucocorticoids
Taper dose, and use alternate-day administration once active disease is resolved. Best results when used in conjunction with an additional immunosuppressive agent. Combination therapy may prolong remission and reduce side effects because of high glucocorticoid dosage. Adverse effects include secondary cutaneous and urinary tract infections, demodicosis, diabetes mellitus, gastroduodenal ulcers, leukopenia, hepatopathy, nephropathy, hypertension, electrolyte disturbances, calcinosis cutis (dogs), and skin fragility (cats). Administer for 3 days in dogs; then, intermediate to low glucocorticoid therapy ± immunosuppressive drugs. Adverse effects include cardiac arrhythmias, pancreatitis, diabetes mellitus, and gastroduodenal ulcers. Used for localized lesions and induces cutaneous atrophy.
Topical glucocorticoids Azathioprine
Gold therapy or chrysotherapy. Oral form: auranofin Injectable form: aurothioglucose Chlorambucil Cyclophosphamide
Cyclosporine
Dapsone
Tetracycline and niacinamide
Mycophenolate mofetil
Dog and cat: Auranofin: 0.12-0.2 mg/kg PO bid; aurothioglucose: 1 mg/kg IM once weekly Dog and cat: 0.1-0.2 mg/kg PO every 24 to 48 h Dog and cat: 1-2 mg/kg PO once daily
Dog and cat: 5-10 mg/kg PO bid for 2 weeks and then adjusted to maintain a therapeutic blood concentration of 400 to 600 ng/ml. Dog: 1 mg/kg PO bid-tid
Dogs >10 kg: 500 mg of each drug PO tid Dogs <10 kg: 250 mg of each drug PO tid Dogs <5 kg: 100 mg of each drug PO tid 20-30 mg/kg PO once daily
Adverse effects include anemia, leukopenia, thrombocytopenia, hemorrhagic diarrhea, pancreatitis, and hepatotoxicity. Long-term therapy is associated with recurrent skin infections and demodicosis. Used in combination with glucocorticoids. Adverse effects include bone marrow suppression, nephrotoxicity, and drug eruptions, such as erythema multiforme and toxic epidermal necrolysis. Used in combination with glucocorticoids. Adverse effects include hepatotoxicity and bone marrow suppression. Always used in combination with glucocorticoids. Stop administration if white blood cell count falls below 500 μL. Adverse effects include bone marrow suppression, teratogenicity, and increased risk of malignancies. Adverse effects include GI signs, hepatotoxicity, nephrotoxicity, gingival hyperplasia, and papillomatous dermatitis. Drugs that suppress cytochrome P-450 activity may cause potential cyclosporine toxicity. Used in combination with glucocorticoids. Do not use in cats. If agranulocytosis appears, administration should be discontinued. Adverse effects include hemolysis, methemoglobinemia, neuropathies, and hypoalbuminemia. Alternative therapy for milder cases of pemphigus foliaceus and pemphigus erythematosus. Adverse effects include vomiting, diarrhea, anorexia, and increased serum liver enzymes activity. Usually well tolerated. Adverse effects include bone marrow suppression and GI upset.
bid, Twice daily; GI, gastrointestinal; IM, intramuscular; IV, intravenous; PO, orally; tid, three times daily. *Equivalences to 5 mg prednisone: Dexamethasone, 0.5 mg; triamcinolone, 1 mg; methyl prednisone, 4 mg.
recommendation would be to change the administration interval, such as changing to twice daily from three times daily or to once daily from twice daily. Veterinarians should take more care when determining dosage for aminoglycosides. If the veterinarian is unsure of renal function, once-
daily administration at 6 to 8 mg/kg of gentamicin or 10 to 12 mg/kg of amikacin should be used. This dosage strategy is preferable both for improved efficacy and decreased renal toxicity. Aminoglycoside efficacy is correlated with a high serum concentration, and its toxicity is inversely related to frequency of administration.
Chapter 5 Pharmacologic Principles
Antiinflammatory Strategies As a group, nonsteroidal antiinflammatory drugs are used more often and for longer periods of time in the elderly than in any other age group. These drugs have a high incidence of undesirable side effects, including gastrointestinal upset, ulceration, and prolonged bleeding. Their use in animals with decreased renal function may be associated with worsening of renal function. This association is due to the increased role of prostaglandins in maintaining renal blood flow in the compromised kidney. Nonsteroidal antiinflammatory drugs should be started at the lowest possible dose and dosage regimen. Gradually increase first the frequency and then the amount over weeks. Loss of appetite is a clinical sign of gastrointestinal upset and indicates that treatment should be stopped for 1 day and resumed at one-half the previous dose. An alternative is to combine the nonsteroidal antiinflammatory drugs with misoprostol at 2 to 4 μg/kg twice daily or three times daily as a protectorate. It does not provide any gastrointestinal protection in human patients with chronic renal disease. Therefore, dosing frequency should be reduced in dogs with suspected renal dysfunction. Although many nonsteroidal antiinflammatory drugs do not show alterations in elimination in the elderly, their dynamic effects seem more pronounced. Do not use a cytoprotectorant such as sucralfate in combination with nonsteroidal antiinflammatory drugs, as absorption is greatly impaired and efficacy reduced.
Anesthesia and Analgesic Strategies Pain is significant in older dogs and cats.2 Management directed toward pain management should be addressed in each animal requiring medical or surgical care (Tables 5-2 and 5-3).3 The use of opioid agonists-antagonists or opioid agonists is more commonly done now (Table 5-4). The sedative effects of analgesic drugs may be enhanced in the geriatric animal as a function of age-related changes in pharmacodynamics and alteration of cognitive pathways. It is better to use a smaller amount of a drug more frequently than to try to prolong the action by increasing the dose. Optimizing a dose for oxymorphone involves administering 0.01 mg/kg every 5 to 10 minutes until the animal is quiet and comfortable. The total dose used is determined, and this amount can then be given every 3 to 4 hours as
47
needed. No drugs require as much individualization as pain relievers. There are no standard doses, only standard dose ranges. The more pronounced sedative effect of these agents in the elderly should not deter the veterinarian from using these agents; instead, they should be used with care.
CHRONIC MEDICATION AND INFORMATION CHART All animals receiving chronic medication should have a physical examination at least annually before any medication prescriptions are refilled (Table 5-5).
TRANSFUSION MEDICINE Transfusion medicine is another important component in the management of clinical diseases in older dogs and cats.4
Individual Components Fresh whole blood should be administered within 6 hours for maximal effect of coagulation proteins and platelets. Stored whole blood is refrigerated at 4° to 6° C after collection. Packed red blood cells are red blood cells that are separated from plasma using centrifugation, sedimentation, or plasma extraction, and stored at 4° to 6° C. Packed red blood cells should be resuspended with 100 ml 0.9% saline solution prior to administration to prevent sludging. Currently, most blood banks add a red cell nutrient solution to prolong storage and shelf life up to 42 days for most commercially available red cell products. This can also be accomplished in the hospital with use of special collection bags containing this solution. These prepared red blood cells do not need to be resuspended with any additional fluid. Fresh plasma is plasma extracted from red blood cells within 6 hours and used within 24 hours of collection. Plasma is best extracted using special collection systems and blood bank centrifuge. Gravity sedimentation of red blood cells also allows plasma to be extracted if needed. Fresh frozen plasma is plasma extracted from red blood cells within 6 hours and frozen at −20º C or below (ideal is −70º C) for up to 1 year. After 1 year of storage this product should be relabeled as frozen plasma. Frozen plasma is plasma extracted from red blood cells more than 6 hours after collection
48
Geriatrics and Gerontology of the Dog and Cat
TABLE 5-2. PAIN ASSESSMENT SCALE FOR OLDER DOGS AND CATS SCORE
ANIMAL BEHAVIOR AND SIGNS
ACTION—RECORD PAIN SCORE AND NOTIFY VETERINARIAN IF 3 OR ABOVE
0 No pain 1 Probably no pain 2 Mild discomfort
Bright, bouncy, responsive, self-grooming; normal mobility; dreaming sleep Appears normal; not as clear-cut as above; possible increased heart rate Eats and sleeps but may not dream; may limp or resist palpation of affected area; increased heart rate and respiration rate may be present Limps or guards affected area (e.g., tenses abdomen); slightly depressed; restlessness with or without trembling; increased heart rate, respiration rate; cats may still purr; dogs may wag tail
None
3 Mild pain or discomfort
4 Mild to moderate pain
Resists touch of affected area; may look or chew at area; abnormal body position; may not move for hours, with or without trembling, appetite change, increased and shallow respiration rate, and increased heart rate; may give occasional whimper or cry; pupils may be dilated
5 Moderate pain
Depressed, trembling, head down, inappetent; may cry or bite if approached or moved or if affected area is touched; marked splinting or prayer position if abdomen is affected; possibly increased heart and respiration rate; animal does not sleep Animal may cry or whine frequently without provocation; cats may still purr; dogs may wag tail
6 As above
7 Moderate to severe pain 8 Severe pain
As above. Animal is very depressed; will urinate and defecate without moving; will cry if moved, may continually whimper As above, but with more vocalizing; animal is more depressed and unaware of surroundings; may thrash about intermittently; with traumatic or neurologic pain may scream (especially cats) if approached; usually there is an increased heart rate and increased respiratory rate with increased abdominal effort even if opioids were previously given 9 As above, but animal is hyperesthetic, trembles Severe to involuntarily if touched close to affected area; excruciating pain neurologic pain or severe inflammation anywhere; this degree of pain can cause death 10 As above, but animal is screaming or almost Excruciating pain comatose; animal is hyperesthetic or hyperalgesic; whole body trembles and animal reacts in pain wherever you touch it; this degree of pain can cause death
None Reassess hourly; if worse give analgesic Needs analgesic— 1. NSAID and/or butorphanol (0.1 ml/kg every 6 to 12 h) OR 2. Repeat morphine if wearing off from previous use; do not give butorphanol and morphine 1. Morphine—dogs, 0.3 mg/kg; cats, 0.1 mg/kg IM or SC 2. Butorphanol (0.15 ml per 5 kg every 4 to 12 h) OR 3. NSAID OR 4. NSAID plus morphine if opioid has already been given 1. Morphine—dogs, 0.3 to 0.5 mg/kg 2. Butorphanol (0.2 ml per 5 kg every 4 to 8 h; cats, 0.15 mg/kg every 3 to 6 h) 3. NSAID 4. Opioid plus NSAID 1. Morphine—dogs, 0.5 mg/kg; cats, 0.2 mg/kg; every 3 to 6 h OR 2. NSAID as appropriate OR 3. Both As above, but higher doses of opioid 1. High dose morphine 2. Plus NSAID as appropriate
1. High dose morphine plus NSAID 2. Plus epidural or local analgesic 3. Anesthetic while treating inciting cause Very high doses of opioids do not relieve this pain, but give the following: 1. Morphine—dogs, 1 mg/kg; cats, 0.2 mg/kg or until effective 2. Plus NSAID 3. Plus epidural or nerve blocks OR 4. General anesthesia to treat cause
IM, Intramuscular; NSAID, nonsteroidal antiinflammatory drug; SC, subcutaneous. NSAIDs are excellent for treatment of musculoskeletal pain and soft-tissue inflammation. Do not give if animal is bleeding, dehydrated, or hypotensive, or has signs of gastrointestinal tract disease or ulceration or severe pulmonary disease.
Chapter 5 Pharmacologic Principles
49
TABLE 5-3. SUGGESTED DOSES FOR ANESTHETIC AND ANALGESIC AGENTS AGENT
DOSAGE
COMMENTS
Anticholinergics Atropine
0.02 to 0.04 mg/kg IV, IM, SC
Glycopyrrolate
0.01 mg/kg IV, IM
Recommended to offset dominant parasympathetic effects and maintain heart rate, cardiac output, and blood pressure. Also decreases airway secretions. Glycopyrrolate does not cross the blood-brain barrier, takes longer to onset of action, and has increased duration compared with atropine.
Tranquilizers and Sedatives Diazepam 0.2 to 0.4 mg/kg IV, IM Midazolam
0.1 to 0.2 mg/kg IV, IM, SC
Acepromazine
0.025 to 0.05 mg/kg IM, SC
␣2 Agonists Xylazine
1 to 2 mg/kg IM
Medetomidine
20 to 30 g/kg IM
Opioids Meperidine Morphine Oxymorphone
Fentanyl
Buprenorphine Butorphanol
1 to 2 mg/kg IM Epidural: 0.5-1.5 mg/kg 0.2 to 1 mg/kg IM, SC Epidural: 0.1 mg/kg in 1 ml per 10-lb volume of saline solution 0.05 to 0.2 mg/kg IV, IM, SC Epidural: 0.1 mg/kg in 1 ml per 10-lb volume of saline solution 2 to 4 g/kg IV CRI: 2 to 4 g/kg/h IV Transdermal patch: 2.5 to 10 kg—use 25-g patch (all or part) 10 to 20 kg—use 50-g patch 20 to 30 kg—use 75-g patch Epidural: 1-10 μg/kg in 1 ml per 10-lb volume of saline solution 0.01 to 0.02 mg/kg IV, IM, SC 0.2 to 0.4 mg/kg IV, IM, SC CRI: 0.2 to 0.4 mg/kg/h IV
Intravenous Anesthetics Thiopental 4 to 6 mg/kg IV, until effective
Methohexital
4 to 6 mg/kg IV, until effective
Propofol
2 to 6 mg/kg IV, until effective CRI: 10 to 12 mg/kg/h IV
Propylene glycol carrier makes uptake unpredictable from IM site. Will not mix in same syringe with any drug, except ketamine. Water-soluble. More potent and shorter acting than diazepam. Mixes with other agents. May cause excitement on recovery in some cats. 2 mg maximum. Requires hepatic degradation. Potentiates hypotension and hypothermia. Does not provide analgesia and is not reversible. Best to dilute to 1 mg/ml solution. Requires hepatic degradation and causes marked bradycardia and decreased cardiac output. Reversible. May cause vomiting. Always use with an anticholinergic agent. Medetomidine is more potent and longer acting than xylazine. Mild analgesia. May cause histamine release if injected IV. Reversible. Analgesia with sedation and cardiopulmonary depression. Administer with an anticholinergic. Potentiates hypothermia. Most common agent used for epidural analgesia. Reversible. 4 mg maximum. Analgesia with sedation. Causes panting. Administer with an anticholinergic agent. Commonly combined with acepromazine in animals older than 12 weeks of age for neuroleptanalgesia. Can be used for epidural analgesia. Reversible. Very potent analgesic. Rapid onset and short duration of action. Minimal cardiopulmonary effects. Can be delivered by a variety of routes, including epidural. Reversible.
30 to 45 minutes to onset of action; long duration due to slow rate of dissociation from receptor; unpredictable reversal with opioid antagonists. Agonist-antagonist. Minimal cardiopulmonary depression. Good visceral analgesia. Used to reverse agonist adverse effects and preserve analgesia. Ultra–short-acting thiobarbiturate. Termination of action depends on redistribution and hepatic degradation. May cause dysrythmia. Respiratory depression is common, be prepared to intubate and ventilate. Ultra–short-acting oxybarbiturate. Terminated by redistribution with minimal hepatic metabolism. May cause excitement on induction and recovery. Be prepared to intubate and ventilate. Alkyl phenol. Do not bolus; give slowly, over several minutes. Ultra–short-acting; rapid onset, rapid recovery. Noncumulative, can be used as CRI without prolonged recovery. Be prepared to intubate and ventilate. Continued
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Geriatrics and Gerontology of the Dog and Cat
TABLE 5-3. SUGGESTED DOSES FOR ANESTHETIC AND ANALGESIC AGENTS—cont’d AGENT
DOSAGE
COMMENTS
Intravenous Anesthetics—cont’d Etomidate 1 to 2 mg/kg IV CRI: 2 to 4 mg/kg/h IV Ketamine
1 to 2 mg/kg IV 11 to 22 mg/kg IM
Telazol
1 to 2 mg/kg IV 5 to 13 mg/kg IM
Nonbarbiturate. No cardiopulmonary effects. May cause nausea, vomiting, myoclonus, excitement on induction and recovery. Noncumulative, can be used as constant rate infusion. Dissociative anesthetic. Excessive salivation controlled with anticholinergic agents. Increases intracranial and intraocular pressures. May cause seizures. Elimination depends on renal and hepatic function. Contains 1:1 tiletamine, a dissociative anesthetic, and zolazepam, a benzodiazepine. Tiletamine is more potent and longer lasting than ketamine. Zolazepam effects may be prolonged in some cats and cause rough recovery.
IV, Intravenous administration; IM, intramuscular administration; SC, subcutaneous administration; CRI, constant rate infusion.
TABLE 5-4. SUGGESTED DOSES FOR TRANQUILIZER AND SEDATIVE ANTAGONIST AGENTS AGENT
ANTAGONISTIC EFFECTS
DOSE
COMMENTS
Flumazenil
Benzodiazepines
0.1 mg/kg IV to effect
Yohimbine
α2 receptors
Atipamazole Tolazoline Naloxone
α2 receptors α1 and α2 receptors Pure narcotic antagonist
0.25 to 0.5 mg/kg IM; 0.15 mg/kg IV until effective 0.2 to 0.4 mg/kg IM 0.3 mg/kg IV until effective 0.04 to 0.4 mg IV until effective
Duration short—1 h in adults; may have agonist effects at high dose May cause excitement after IV administration Most effective reversal agent
Naltrexone
Pure narcotic antagonist
0.04 mg/kg IV
Nalmefene Butorphanol
Pure narcotic antagonist Narcotic agonist-antagonist
0.1 to 0.2 mg/kg IV or IM 0.2 mg/kg IV, IM, SC
Nalbuphine
Narcotic agonist-antagonist
0.5 to 2 mg/kg IV, IM, SC
Short duration—0.5 to 1.5 h ; animals may renarcotize 8 to 12 h duration; most effective for reversal of central effects related to epidural opioid administration 8 to 10 h duration Used to reverse bradycardia and respiratory depression of agonists while maintaining analgesia Lasts 2 to 4 h; less potent analgesic than butorphanol
IM, Intramuscular administration; IV, intravenous administration; SC, subcutaneous administration.
and frozen, or fresh frozen plasma that has been stored longer than 1 year or at temperatures greater than −20º C. Platelet rich plasma and platelet concentrate are concentrated platelet products that are manufactured from successive centrifugation of fresh plasma. The process is complex and requires a blood banking centrifuge. Cryoprecipitate is a concentrated clotting factor product rich in factor VIII and von Willebrand factor, fibrinogen, and fibronectin. It is manufactured by thawing fresh frozen plasma at 1º to 6º C until slushy or until approximately 90% of volume is liquid, then centrifuging at 5 g for 5 minutes or using gravity to extract liquid plasma. Both components (cryoprecipitate and supernatant cryoprecipitate) can be refrozen at −20º C or below (ideal −70º C) for
up until 1 year after collection of plasma. If vasopressin is administered to the blood donor at 0.6 μg/kg diluted in 10 ml of sterile saline solution intravenously over 10 minutes approximately 30 minutes before collection, the yield of factor VIII and von Willebrand factor can be improved.
Canine Red Blood Cells Typing the recipient is strongly encouraged, so that DEA 1.1- and 1.2-positive donors can be used in transfusion programs and so that the blood is correctly directed to positive recipients. Commercial typing cards check only for DEA 1.1. Dogs who are autoagglutinating should always receive negative blood, because the typing cards (Text continued on p. 56)
Behavioral evaluation Every 3 months
CBC
Serum chemistry profile
Amitriptyline
Aspirin
Atenolol
No
No
No
No
No
Monitor for gradual or sudden behavioral changes Ocular pressures and Every 4-6 months May not be working properly; Schirmer tear tests may cause eye irritation; may cause increase in serum liver enzymes
No
Yes
No eyedrops for last 3-4 h
No
No
No
No
Yes
Yes
No
Yes
No
No
Yes
No
No
No
No Yes
No
No
No
No
Continued
Vomiting, diarrhea, weakness, decreased appetite, increased lethargy, sudden loss of stamina, seizures, skin eruptions May cause transient depression and atropine-like signs Sedation, dryness of mouth, rapid heart rate, poor grooming Owner should avoid contact with medication; medication has to be used regularly as prescribed
Give on an empty stomach; vomiting, diarrhea, weakness, decreased appetite, increased lethargy, coughing, sudden loss of stamina
Aggression, poor grooming
Give on an empty stomach; vomiting, diarrhea, weakness, decreased appetite, increased lethargy, coughing, sudden loss of stamina
Can cause hypotension, especially in animals with preexisting cardiac disease; can cause excessive sedation, seizures Sedation, dryness of mouth, rapid heart rate, poor grooming Vomiting, diarrhea, weakness, decreased appetite, increased lethargy, sudden loss of stamina Changes in behavior, weakness
SPECIAL TIMING FOR SPECIAL INFORMATION/ TESTS OWNER SHOULD CALL IF:
Yes
Yes
No
Yes
FAST FOR 8 HOURS BEFORE TESTING
May cause changes in the liver
CBC, Complete blood count; ECG, electrocardiogram.
Cyclosporine
Monitor for gradual or sudden behavioral changes Check for anemia
Check for liver dysfunction via serum liver enzymes
REASON FOR TESTING
Monitor for liver and kidney dysfunction and electrolyte disorders Lead II ECG Every 6 months Monitor progression of heart disease and arrhythmias Serum chemistry Every 6 months Check for azotemia and electrolyte profile disorder; should use in advancing kidney disease and can cause sodium loss CBC Every 12 months Check for anemia or hemoconcentration Lead II ECG Every 6 months Monitor progression of heart disease Behavioral evaluation Every 3 months Monitor for gradual or sudden behavioral changes Serum chemistry Every 6 months Check for azotemia and profile electrolyte disorder; should use in advancing kidney disease and can cause sodium loss CBC Every 12 months Check for anemia or hemoconcentration Lead II ECG Every 6 months Monitor progression of heart disease Serum chemistry Every 3-6 months Monitor for liver and kidney profile dysfunction
Every 6 months
Every 6 months
Chlorpheniramine CBC and serum Every 12 months chemistry profile Clomipramine Behavioral evaluation Every 3 months
Carprofen
Captopril
Buspirone
Benazepril
Serum chemistry profile
Acepromazine
Every 12 months
TESTS NEEDED
DRUG NAME
TESTING FREQUENCY
TABLE 5-5. CHRONIC MEDICATION AND INFORMATION CHART
Chapter 5 Pharmacologic Principles 51
Furosemide
Fluoxetine
Fludrocortisone
Enalapril
Diltiazam
Digoxin
Every 6 months
Lead II ECG
CBC
Lead II ECG Serum chemistry profile Serum chemistry profile Serum chemistry profile
CBC
Lead II ECG Serum chemistry profile
Monitor progression of heart disease and check for ECG signs of toxicity Check for liver dysfunction
Check for liver or kidney dysfunction Check for liver and kidney dysfunction and electrolyte disorder Check for anemia or hemoconcentration Ensure adequate dosage
Check for liver and kidney dysfunction; contraindicated in liver and kidney disease Check for adequate therapeutic levels
REASON FOR TESTING
Check for anemia or hemoconcentration Every 6 months Monitor progression of heart disease Every 6 months Check for azotemia and electrolyte disorder; should use in advancing kidney disease and can cause sodium loss Every 12 months Check for anemia or hemoconcentration Every 6 months Monitor progression of heart disease Every 3-4 months Monitor sodium and potassium levels and for liver dysfunction Every 3 months Monitor for liver and kidney dysfunction Every 6 months Check for liver and kidney dysfunction and electrolyte disorder; can cause potassium loss Every 12 months Check for anemia, hemoconcentration, and leukopenia
Every 12 months
Every 6 months
Every 6 months
Digoxin serum level
Serum chemistry profile CBC
Every 6 months
CBC
Every 6 months
Every 6 months
Diazepam serum levels
Serum chemistry profile Serum chemistry profile
Every 6 months
Serum chemistry profile
Diazepam
Diethylstilbestrol
Every 6 months
TESTS NEEDED
DRUG NAME
TESTING FREQUENCY
TABLE 5-5. CHRONIC MEDICATION AND INFORMATION CHART—cont’d
Yes
Yes
Yes
No Yes
Yes
No Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
FAST FOR 8 HOURS BEFORE TESTING
No
No
No
No No
No
No No
No
No
8 h after last dose No
No
No
4-6 hours after pilling No
No
Vomiting, diarrhea, decreased appetite, increased lethargy, polyuria-polydipsia, dehydration
Vomiting, diarrhea, decreased appetite, increased lethargy Restlessness, insomnia, weight loss
Vomiting, diarrhea, weakness, decreased appetite, increased lethargy, coughing, sudden loss of stamina
Decreased appetite, weakness, increased lethargy, coughing, sudden loss of stamina
May cause vomiting, diarrhea, lethargy, abnormal bruising or bleeding, polyuria-polydipsia Give on an empty stomach; vomiting, diarrhea, weakness, decreased appetite, increased lethargy, coughing, sudden loss of stamina
Scheduled drug—login required; may cause too much sedation and increased appetite; may cause hyperexcitation
SPECIAL TIMING FOR SPECIAL INFORMATION/ TESTS OWNER SHOULD CALL IF:
52 Geriatrics and Gerontology of the Dog and Cat
Serum chemistry profile CBC Urinalysis CBC
D-Penicillamine
ACTH, Adrenocorticotropic hormone.
Fasting and postprandial bile acids
Serum chemistry profile CBC Phenobarbital serum level
ACTH response test
Mitotane
Phenobarbital
Serum chemistry profile CBC
Every 6 months
Urinalysis
Every 12 months Every 12 months or more often if seizures are not adequately controlled Every 12 months
Every 6 months
Every 12 months Every 6 months Every 6 months
Every 6 months
Monitor for liver dysfunction
Check for liver and kidney dysfunction Check for anemia Ensure safe but adequate blood levels being obtained; serum levels should be 15-40 μg/ml
Monitor for liver and kidney dysfunction Monitor bone marrow function Check for urinary tract infection Check for anemia and leukopenia
Every 3-6 months Monitor for anemia, leukopenia, and thrombocytopenia Every 6 months Monitor for proper dosage and adrenal gland function
Check for glucose and ketones and for urinary tract infection Every 3-6 months Monitor for liver dysfunction
Every 6 months Every 6 months
Methimazole
Insulin
Check for anemia, monitor bone marrow function (may cause depression) Monitor progression of heart disease Monitor for liver and kidney dysfunction Monitor for liver and kidney dysfunction Monitor insulin metabolism and effects
Every 12 months Every 6 months Every 6 months
Check for kidney dysfunction
REASON FOR TESTING
Every 6 months
TESTING FREQUENCY
Lead II ECG Serum chemistry profile Serum chemistry profile Blood glucose curve
Serum chemistry profile CBC
Hydralazine
Hydrocodone
TESTS NEEDED
DRUG NAME
TABLE 5-5. CHRONIC MEDICATION AND INFORMATION CHART—cont’d
Yes
No Yes
Yes
Yes No Yes
Yes
No
Yes
Yes
No
No
Yes
No Yes
Yes
Yes
FAST FOR 8 HOURS BEFORE TESTING
Scheduled drug—login required; sedation, constipation, vomiting, increased coughing Weakness, lethargy, vomiting, incoordination, disorientation, polyuria-polydipsia
Give with food; vomiting, diarrhea, decreased appetite, increased lethargy
Vomiting, diarrhea, decreased appetite, lethargy, weight loss
No
No Before first tablet in morning
No
No No No
Continued
Vomiting, weakness, decreased appetite, increased lethargy, loss of stamina Scheduled drug—login required; anxiety or depression, increased appetite, polyuria-polydipsia
Must stay Use with caution in animals with liver or kidney in hospital disease; vomiting, diarrhea, decreased appetite, at least increased lethargy, incoordination, 3 hours polyuria-polydipsia No
No
No
Give insulin at usual time No
No
No No
No
No
SPECIAL TIMING FOR SPECIAL INFORMATION/ TESTS OWNER SHOULD CALL IF:
Chapter 5 Pharmacologic Principles 53
Serum chemistry profile
Prednisolone or prednisone
Primidone
Serum chemistry profile Potassium bromide serum level
Potassium bromide
Fasting and postprandial bile acids
Serum chemistry profile CBC Phenobarbital serum level
CBC
CBC
Every 12 months Every 12 months or more often if seizures are not adequately controlled Every 12 months
Every 6 months
Every 12 months
6 weeks after initiation of therapy and then every 6 months Every 12 months
Every 6 months
Every month
Every 12 months
Urinalysis
Piroxicam
Every 12 months
CBC
Serum chemistry profile
Every 6 months
Serum chemistry profile
Phenylbutazone
Phenylpropanolamine
Every 6 months
TESTS NEEDED
DRUG NAME
TESTING FREQUENCY
Monitor for altered white blood cell levels Check for liver and kidney dysfunction Check for anemia Ensure safe but adequate blood levels being obtained; phenobarbital serum levels should be measured to estimate anticonvulsant effect Monitor for liver dysfunction
Monitor for liver dysfunction and electrolyte disorders
Monitor for liver and kidney dysfunction Check adequate or toxic levels of potassium bromide; serum levels should be 1-2 mg/ml (100-200 mg/dl)
Check for liver and kidney dysfunction; can cause toxic changes Can cause changes in the bone marrow Check blood glucose (can cause problems in diabetics) and for liver dysfunction Monitor for ability to concentrate urine and check for urinary tract infection Monitor for anemia
REASON FOR TESTING
TABLE 5-5. CHRONIC MEDICATION AND INFORMATION CHART—cont’d
Yes
No Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
FAST FOR 8 HOURS BEFORE TESTING
Give with food; vomiting, diarrhea, weakness, decreased appetite, increased lethargy, sudden loss of stamina Give with food; can cause sedation, weakness; can take up to 4 months to achieve therapeutic levels
Restlessness, anxiousness, decreased appetite, urinary incontinence
Give with food; vomiting, diarrhea, weakness, unusual bleeding or bruising
Scheduled drug—login required; anxiety or depression, increased appetite, polyuria-polydipsia
Give with food; increased polyuria-polydipsia, hair loss, weakness, significant changes in body weight, panting, behavioral change
No
No Before first tablet in morning
No
No
No
Before first dose in the morning
No
No
No
No
No
No
SPECIAL TIMING FOR SPECIAL INFORMATION/ TESTS OWNER SHOULD CALL IF:
54 Geriatrics and Gerontology of the Dog and Cat
Every 3 months
Ocular pressures and Schirmer tear tests Serum electrolytes
Serum chemistry profile CBC
Tylosin
L-Thyroxine
Serum chemistry profile Serum T4
Theophylline
Lead II ECG
Every 6 months
CBC
Terbutaline
Every 6 months
Serum chemistry profile
Sulfasalazine
Every 12 months
Every month for the first 3 months and then every 12 months Every 12 months
Every 12 months
Every month for first 3 months and then every 6 months Every 6 months
Every 3 months
Every 3 months
Lead II ECG
Serum chemistry profile CBC
Every 6 months
Serum chemistry profile
Propranolol
Selegiline (Deprenyl)
Every 6 months
TESTS NEEDED
DRUG NAME
TESTING FREQUENCY
Monitor red blood cell and white blood cell levels
Monitor for liver dysfunction
Monitor for heart disease and arrhythmias Monitor for liver and kidney dysfunction Monitor serum T4 levels for adequate dosing; requirement may change as animal ages
Check for anemia, white blood cell changes, and thrombocytopenia Check the eyes for normal intraocular pressures and normal tear production Can cause potassium loss
Monitor for liver and kidney dysfunction and electrolyte disorders Monitor progression of heart disease and arrhythmias Check for liver and kidney dysfunction Check for anemia, white blood cell changes, and thrombocytopenia Check for liver and kidney dysfunction
REASON FOR TESTING
TABLE 5-5. CHRONIC MEDICATION AND INFORMATION CHART—cont’d
Yes
Yes
Yes
Yes
No
Yes
No
Yes
Yes
Yes
Yes
No
Yes
FAST FOR 8 HOURS BEFORE TESTING
Vomiting, diarrhea, excitement, increased coughing
Weakness, depression, decreased appetite
Eyes are especially sensitive; causes redness or chronic gummy discharge; weakness, depression, decreased appetite
Vomiting, diarrhea, weakness, depression, decreased appetite
Changes in behavior, weakness
No
No
Vomiting, diarrhea, loss of appetite
6-8 h after Weight gain, extreme weight loss, excitement, medication restlessness, constant panting given
No
No
No
No
No
No
No
No
No
No
SPECIAL TIMING FOR SPECIAL INFORMATION/ TESTS OWNER SHOULD CALL IF:
Chapter 5 Pharmacologic Principles 55
56
Geriatrics and Gerontology of the Dog and Cat
are difficult to interpret when autoagglutination is present. Bitches that have whelped and any dog that that has received a transfusion more than 7 days previously should have a cross-match performed prior to transfusion.
Feline Red Blood Cells Typing felines prior to transfusion is mandatory. Type B blood is rarely stored, but ideally cat type B blood from such breeds as the rex, British shorthair, and Maine coon should be available to the veterinary practice to donate as needed. If type A red cells are given to a type B cat, the results are catastrophic. If autoagglutination is present in the recipient, and interpretation of the card typing results is not clear, then crossmatching is mandatory to attempt to identify incompatibility.
ADMINISTRATION OF RED CELL PRODUCTS Packed red blood cells that have not been stored in nutrient solutions should be resuspended with sterile saline or non–calcium-containing crystalloid fluids. All red cell products should be administered through a blood administration filter (170 μm) using a nonrotary fluid administration pump (peristaltic flow pumps are acceptable). Before a transfusion is begun, measurements of baseline rectal temperature, pulse rate, respiratory rate, packed cell volume (PCV), and total solids should be obtained. Initial rate of administration should be slow (0.25 ml/kg hourly) for 15 to 20 minutes to monitor for transfusion reaction. Animals should be monitored carefully during transfusion. The calculated dose of red blood cell product should be administered within 4 hours of puncturing the donation bag. The dose of red blood cells to administer to an anemic animal should be calculated as follows: Dose (ml) = 80 (Dogs) or 70 (Cats) × Desired change in PCV Body weight (kg) × PCV transfused blood Total daily doses of red blood cell products should not exceed 22 ml/kg/day, unless severe ongoing losses are occurring (do not exceed 22 ml/ kg hourly except in the case of massive hemorrhage). If risk of volume overload is present, then maximum administration rate should be 4 ml/kg hourly. In animals with congestive heart failure
and anemia the maximum administration rate should be 5 ml/kg/day. Animals that are experiencing severe and rapid blood loss should receive red blood cell products as rapidly as needed to maintain adequate circulating volumes. Slow initial rates of transfusion are usually not used in emergency situations. The packed cell volume and total solids should always be performed within 60 to 90 minutes after completion of the transfusion to determine response.
ADMINISTRATION OF PLASMA PRODUCTS Typing and cross-matching as discussed above is not relevant to plasma transfusion for either dogs or cats. All plasma products should be thawed at a constant temperature (37° C) and administered through a blood administration filter (170 μm) using a fluid administration pump (peristaltic flow and rotary type pumps are acceptable). The animal’s baseline rectal temperature, pulse rate, respiratory rate, PCV, and total solids should be measured before a transfusion is begun. Initial rate of administration should be slow (0.25 ml/kg hourly) for 15 to 20 minutes to monitor for transfusion reaction. Animals should be monitored carefully during transfusion. The calculated dose of plasma product should be administered within 4 hours of puncturing the donation bag. The dose of plasma product to administer should be 6 to 8 ml/kg two to three times per day as required. Cryoprecipitate should be administered at 1 unit per 10 to 20 kg, and the animal should be monitored hourly after transfusion to detect ongoing bleeding or serum activated PTT concentration. Additional transfusions are administered as required to control hemorrhage.
COMPLICATIONS Acute Intravascular Hemolysis Acute intravascular hemolysis is the most severe type of transfusion reaction and results in hemoglobinemia and hemoglobinuria. Signs may include restlessness, anxiety, nausea, muscle tremors, urticaria, fever, tachycardia, tachypnea, and seizures. Acute death, thromboembolic disease, or acute renal failure are possible sequelae. The most common situations in which this would occur include those in which type A
Chapter 5 Pharmacologic Principles blood is given to a type B cat, or DEA 1.1/1.2 blood is given to a negative dog previously sensitized to DEA 1.1/1.2-positive blood through previous transfusion or breeding (negative female dog bred to positive male with exposure to positive fetal blood during whelping). Transfusion should be discontinued immediately. Supportive care includes renal diuresis and corticosteroids. Urinary alkalization may assist in removing erythrocytic membrane stroma. Plasmapheresis would be ideal but is not readily available.
Acute Nonhemolytic Reaction This transfusion reaction is manifested by urticaria, pruritus, fever, or anaphylaxis. Most of the time, the reaction is directed against an incompatible antigen located on the platelet or white blood cell remnants or some plasma protein component. Anaphylaxis should be treated with aggressive fluid resuscitation, corticosteroids, and antihistamines if severe. Epinephrine (0.1 ml/kg or 1:100000 concentration intravenously) may also be necessary if severe bronchoconstriction and cardiovascular collapse are present. Restarting the transfusion is not recommended in this case. If urticaria or fever is the only manifestation, the transfusion should be stopped temporarily, corticosteroids or antihistamines administered, and the transfusion reattempted after 20 to 30 minutes.
57
reflect rapid transfused erythrocytic destruction and extravascular hemolysis. Occasionally a pyogenic substance from the plastic bag or tubing can cause a febrile response. Administration of erythrocytes or plasma products with calciumcontaining crystalloid solutions can cause microembolization within the intravenous tubing. Inappropriate plasma product storage or administration can result in poor viability of plasma or clotting proteins and ineffective response. Massive transfusion in severe hemorrhage can result in hypocalcemia or anticoagulant toxicity. Disease transmission can also occur if donors have not been carefully chosen and screened.
AUTOTRANSFUSION Autotransfusion requires a simple apparatus (metal teat cannula, three-way stopcock, catheter injection port, and blood collection bag) and should be easy to perform. Blood is collected by gravity flow into a collection bag from hemorrhage into the abdomen or thoracic cavity. This technique is indicated in animals with trauma if no ready access to blood supply is available. Its use in other causes of hemoabdomen or hemothorax is not advised because of the potential risk of infusing neoplastic cells or bacteria into the animal. Autotransfused blood does not contain adequate clotting factors or platelets to be helpful in controlling hemorrhage and should be used only as a source of red blood cells and albumin to maintain oxygen-carrying capacity and volume.
Delayed Destruction of Erythrocytes Typically, DEA 3/5/7 antigen antibody reactions are involved as a result of previous sensitization or naturally occurring antibodies. Rapid drop in PCV within 3 to 7 days and evidence of extravascular hemolysis are the typical signs.
Nonimmunologic Reactions The most common problems include vascular overload (cough, pulmonary edema, vomiting, urticaria, and serous nasal discharge). In addition, poor component handling can result in hemolysis (physical trauma to red cells during collection or administration, prolonged or inadequate storage, freezing, overheating, and mixing with nonisotonic fluids). If erythrocytic damage is severe, then signs may be similar to acute severe intravascular hemolysis, but more commonly they
RED BLOOD CELL ALTERNATIVES Oxyglobin solution (Biopure Corporation, Cambridge, Mass.), a hemoglobin glutamer-200 (bovine), is the only commercially available red blood cell substitute available to veterinarians.5,6 It is expensive, but potential advantages include immediate oxygen unloading capability, ready accessibility and easy storage, and oxygencarrying capacity that is provided without contributing red cell stroma to animals with immune-mediated hemolysis. In extravascular immune-mediated hemolytic anemia cases, there exists a low risk of contributing to further activation of the immune system as well as suppressing bone marrow response. In intravascular hemolysis, the risk of acute renal failure and thromboembolization is potentially reduced by providing oxygen-carrying capacity without erythrocytic
58
Geriatrics and Gerontology of the Dog and Cat
stroma using Oxyglobin instead of using red blood cell products. Some speculate that Oxyglobin can act as a nitric oxide scavenger in the vasculature and can cause or exacerbate pulmonary hypertension. The dose recommended by the manufacturer is 30 ml/kg given no faster than 10 ml/kg hourly (perhaps even more cautiously in normovolemic animals at risk of volume overload). The duration of effect of the product is approximately 24 hours, with 90% elimination by 7 to 10 days. Administration of Oxyglobin does cause tissue discoloration and can interfere with serum chemistry profile and coagulation (depending on instrument type) testing results.
References 1. Plumb DC: Drug considerations in the geriatric patient, Proc Vet Med Forum 17:429, 1999. 2. Robertson SA: What is pain? J Am Vet Med Assoc 221:202, 2002. 3. Hellyer PW: Treatment of pain in dogs and cats, J Am Vet Med Assoc 221:212, 2002. 4. Kristensen AT, Feldman BF: Canine and feline transfusion medicine, Philadelphia, 1995, WB Saunders. 5. Rentko VT, Kelly N, Niggemeir A et al: Effects of oxyglobin and packed red blood cells (PRBC) on the erythropoietic response to acute anemia, J Vet Intern Med 12:227, 1998. 6. Muir WW, Wellman ML: Hemoglobin solutions and tissue oxygenation, J Vet Intern Med 17:127, 2003.
Pharmacologic Principles JOHNNY D. HOSKINS
Improved medications, surgical techniques, and nutrition, and an apparently increased percentage of animal owners willing to care for their older dogs and cats have contributed to increased numbers of older animals being seen by veterinarians and treated. Although older dogs and cats have long been noted to have different needs than younger animals, much of our working knowledge of veterinary gerontology is extrapolated from human or laboratory animal information. This includes the changes associated with the natural aging process and its effects on drug therapies. It is clear that there are many changes occurring in the aged dog and cat that can cause multivariable effects on a drug’s pharmacokinetics and pharmacodynamics. To sort out these effects and distill them into clinical guidelines is difficult to impossible. Veterinary medicine is further hindered in managing drug therapy for the aged because of the lack of specific information on the topic and because older dogs and cats cannot complain about symptoms caused either by disease or by the drugs used for treatment.
PHARMACOKINETICS AND PHARMACODYNAMICS Absorption, distribution, biotransformation, and elimination are the parameters that are the major factors in a drug’s pharmacokinetic profile.1 Although significant changes can occur in the gastrointestinal tract of aged mammals, agerelated effects on oral absorption appear to be minimal for most drugs in older dogs and cats.
Medications administered subcutaneously may be more slowly absorbed in the aged animal. Intramuscular absorptive characteristics may be altered because of a decrease in muscle mass. Thus, the clinical significance of drug absorption and age appears to be overall quite weak. A drug’s distribution characteristics, however, may significantly change with age. As a greater percentage of the body is fat, volumes of distribution of highly lipophilic drugs, such as anesthetic agents, could be significantly increased (and initial plasma levels decreased) as compared with those in a young, adult animal. Conversely, for drugs with high water solubility but low lipid solubility (such as aminoglycoside antimicrobials), volumes of distribution could be decreased (and initial plasma levels increased). Age effects on hepatic biotransformation appear to be minimal unless severe hepatic compromise is present. Because of reduced hepatic blood flow, drugs exhibiting a high first-pass effect in the liver, such as propranolol, buspirone, diltiazem, omeprazole, chlorpromazine, clomipramine, and selegiline, could potentially require dosage adjustment in older dogs and cats. Reduced renal function is another important effect of aging with respect to pharmacokinetic alterations. Despite normal renal function tests, reduced renal function can cause clinically significant changes in drug elimination, particularly with drugs having a narrow therapeutic window, such as aminoglycoside antimicrobials, digoxin, and cisplatin. Pharmacodynamics is defined as the relationship between drug quantity and drug effect. Changes in pharmacodynamics caused by age are 43
44
Geriatrics and Gerontology of the Dog and Cat
not as well understood as pharmacokinetic alterations, and little is known with respect to older dogs and cats. Many drugs have been shown to have a reduced effect in aged animals at a given tissue concentration. It is believed that this change occurs primarily at the molecular level, with reduction in receptor density and receptor function occurring with age. Conversely, certain drugs, especially drugs that have an effect on the central nervous system, can show a particular drug effect at a lower plasma concentration than that seen in the younger animal. In humans, the incidence of adverse drug effects is higher in the elderly. Whether this is caused primarily by alterations in a drug’s pharmacokinetic profile or by some other mechanism(s) is not known.
DRUG THERAPY AND TREATMENT PLANS In an effort to bring some order to the treatment plan for older dogs and cats, it may be useful to review some basic tenets of drug therapy1: • Senior dogs and cats are not geriatric dogs and cats. There is an important difference between senior animals and geriatric animals. • Identify causative factors involved in the disease process, including ruling out drug toxicity. It should always be remembered that older dogs and cats do not have one disease process occurring at a time but have multiple disease processes occurring at the same time within one or more body systems. Also, the more aged the dog or cat is, the more likely multiple diseases are occurring at the same time. For example, chronic renal failure has been documented in an older cat, but other disease processes may be occurring at the same time—for example, hyperthyroidism, systemic hypertension, inflammatory bowel disease, and diabetes mellitus. The veterinarian needs to avoid making diagnostic as well as therapeutic decisions based on the finding of a single disease process or problem. • Consider using nondrug treatment plans. This is the least understood part of caring for older dogs and cats, but some alternative medicine approaches may be useful. • Establish a treatment plan with the owner of the older dog or cat. Because many of the diseases managed in older dogs and cats are chronic and progressive, cures are not attainable —but control, at least for a period of time, is attainable.
• Choose initial drugs based on efficacy, cost, and ease of administration; assessment of animal-at-risk profile; matching of side-effect profile to the animal profile; and treatment plan for multiple diseases with one or more drugs. • Choose initial drug dose based on the aphorism “Start low and go slow.” • Monitor drug therapy for efficacy and adverse effects. Drug therapy in older dogs and cats is often a double-edged sword. In geriatric humans, rates of adverse drug reactions are reported to be two to three times those seen in younger patients. There is no reason to believe that the same thing does not occur in older dogs and cats. Because often more than one disease is being treated and multiple drugs are being used, an increased potential for adverse drug interactions exists. Use therapeutic drug monitoring for drugs with narrow therapeutic windows. • Determining the appropriate duration of therapy is extremely difficult to impossible. There is no right answer. When in doubt as to how long to treat an animal for a particular disease or diseases, always look to the animal being treated for the answer. Many times, the duration of therapy will be for a lifetime, with no other good choices. • Avoid polypharmacy—using more drugs than are necessary—in older dogs and cats. Polypharmacy is a problem not only in human medicine but also in veterinary medicine. Polypharmacy may lead to increased morbidity and mortality secondary to drug-drug interactions, it may result in increased adverse effects, or the cost of therapy may lead to premature euthanasia.
ADVERSE DRUG EFFECTS EXPECTED The goals of any treatment plan for the older dog or cat should be to alleviate pain, suffering, and disability; improve functional capacity; promote quality of life; and prolong life. Meeting these goals starts with selected diagnostic and therapeutic choices. The drug classes for which particular caution is advised when these drugs are used in older dogs and cats include the angiotensin converting enzyme inhibitors; aminoglycosides (aminoglycosides should not be used in older dogs and cats unless other antimicrobial agents are not indicated); antiarrhythmic agents; beta-blocking agents; calcium channel blocking agents; cardiac
Chapter 5 Pharmacologic Principles glycosides (especially digoxin); central nervous system and preanesthetic agents (especially benzodiazepines and opiates); coumarin anticoagulants; histamine-2 antagonists; nonsteroidal antiinflammatory drugs; and oncologic drugs. With the use of these drug classes, an increased potential for adverse drug interactions also exists. Use therapeutic drug monitoring for drugs with narrow therapeutic windows.
GUIDELINES FOR DRUG USE IN OLDER ANIMALS Beyond the routine clinical management of a specific organ failure in the older dog and cat, the veterinarian should also be aware of specific drug use for the routine clinical management of immune-mediated diseases, acute and chronic pain, and systemic hypertension (see Chapter 10).
Immune-Mediated Disease Strategies As an animal ages, its immune system may respond by being overreactive or underreactive. When the animal’s immune system is overreactive, several different types of immune-mediated disease occur with increased frequency. The tissues and organ systems that react most dramatically in the sensitized animal are the mucous membranes of the mouth and lips, lacrimal gland, thyroid gland, parathyroid gland, esophagus, gastrointestinal tract, anus, liver, erythrocytes, leukocytes, blood platelets, muscles, joints, and nerves. Common examples of immune-mediated diseases in older dogs are keratoconjunctivitis sicca, hypothyroidism, immune-mediated hemolytic anemia, immunemediated thrombocytopenia, glomerulonephritis, acquired myasthenia gravis, polymyositis, polyneuropathy, perianal fistulas, and immune-mediated skin disease. In addition, it is not unusual for several body systems in the sensitized dog to respond simultaneously with specific or nonspecific signs of immune-mediated disease. Often, a specific body system responds more pronouncedly than another body system. General principles about immunemediated diseases in older dogs are as follows: • A general rule in clinical medicine is that any tissue or organ of a sensitized animal can be attacked by the immune system, resulting in signs of immune-mediated disease related to that tissue or organ. No tissue or organ is completely free from immune-mediated disease and its effects in the older animal.
45
• Multiple immune-mediated diseases may occur simultaneously in older dogs. Many examples exist. Immune-mediated hemolytic anemia and immune-mediated thrombocytopenia often occur simultaneously. Canine hypothyroidism and keratoconjunctivitis sicca often occur simultaneously. Canine perianal fistulas, keratoconjunctivitis sicca, and hypothyroidism often occur simultaneously. Canine hypothyroidism, hypoparathyroidism, and hypoadrenocorticism may occur simultaneously in the older dog. • When a diagnosis of an immune-mediated disease occurs, the veterinarian should investigate the possibility of a second or third immunemediated disease occurring at the same time. Medical management will never completely cure an immune-mediated disease in the dog or cat but will provide medical control and a reasonable quality of life for the animal. A treatment that seems to effect a medical cure may be causing only a brief remission from obvious signs of immune-mediated disease; relapses always occur. Therapies that may be used in the clinical management of immune-mediated diseases of older dogs and cats are presented in Table 5-1.
Infectious Agent Strategies Most antimicrobial agents currently used in veterinary medicine have wide safety margins, and changes in dosage schedule more often reflect an attempt to save money or make drug delivery more convenient, not an attempt to make drug delivery safer. Most antimicrobial efficacy is correlated with time during which concentration is above the minimum inhibitory concentration of the pathogen. Changes in disposition of most antimicrobial drugs are due to a decrease in renal function, which prolongs the action of these agents and allows a decrease in dosage frequency. If an animal is showing significant body changes consistent with aging, and renal function is unknown, it is better not to alter the antimicrobial administration schedule. Having available established serum creatinine values for the geriatric animal is very important. Veterinarians should establish baseline values for the dogs and cats before the animals are of geriatric age. A dog or cat that had a serum creatinine level of 1 mg/dl at 10 years of age and currently has a level of 2 mg/dl at 13 years of age has had a 50% reduction in glomerular filtration rate, even though a level of 2 mg/dl is within the normal range. One
46
Geriatrics and Gerontology of the Dog and Cat
TABLE 5-1. THERAPIES FOR IMMUNE-MEDIATED DISEASES THERAPY
DOSAGE
COMMENTS
Prednisone*
Dog: 2.2-6.6 mg/kg PO; Cat: 4.4-8.8 mg/kg PO; Dosage depends on severity of the disease
Glucocorticoid pulse therapy
Dog: IV methylprednisolone sodium succinate at 11 mg/kg daily in 250 ml of 5% dextrose and water during a 1-h period for 3 consecutive days Dog and cat: hydrocortisone cream; 0.1% betamethasone valerate, flucinolone acetate, or amcinonide Dog: 1.5-2.5 mg/kg every 48 h; contraindicated in cats; used in combination with glucocorticoids
Taper dose, and use alternate-day administration once active disease is resolved. Best results when used in conjunction with an additional immunosuppressive agent. Combination therapy may prolong remission and reduce side effects because of high glucocorticoid dosage. Adverse effects include secondary cutaneous and urinary tract infections, demodicosis, diabetes mellitus, gastroduodenal ulcers, leukopenia, hepatopathy, nephropathy, hypertension, electrolyte disturbances, calcinosis cutis (dogs), and skin fragility (cats). Administer for 3 days in dogs; then, intermediate to low glucocorticoid therapy ± immunosuppressive drugs. Adverse effects include cardiac arrhythmias, pancreatitis, diabetes mellitus, and gastroduodenal ulcers. Used for localized lesions and induces cutaneous atrophy.
Topical glucocorticoids Azathioprine
Gold therapy or chrysotherapy. Oral form: auranofin Injectable form: aurothioglucose Chlorambucil Cyclophosphamide
Cyclosporine
Dapsone
Tetracycline and niacinamide
Mycophenolate mofetil
Dog and cat: Auranofin: 0.12-0.2 mg/kg PO bid; aurothioglucose: 1 mg/kg IM once weekly Dog and cat: 0.1-0.2 mg/kg PO every 24 to 48 h Dog and cat: 1-2 mg/kg PO once daily
Dog and cat: 5-10 mg/kg PO bid for 2 weeks and then adjusted to maintain a therapeutic blood concentration of 400 to 600 ng/ml. Dog: 1 mg/kg PO bid-tid
Dogs >10 kg: 500 mg of each drug PO tid Dogs <10 kg: 250 mg of each drug PO tid Dogs <5 kg: 100 mg of each drug PO tid 20-30 mg/kg PO once daily
Adverse effects include anemia, leukopenia, thrombocytopenia, hemorrhagic diarrhea, pancreatitis, and hepatotoxicity. Long-term therapy is associated with recurrent skin infections and demodicosis. Used in combination with glucocorticoids. Adverse effects include bone marrow suppression, nephrotoxicity, and drug eruptions, such as erythema multiforme and toxic epidermal necrolysis. Used in combination with glucocorticoids. Adverse effects include hepatotoxicity and bone marrow suppression. Always used in combination with glucocorticoids. Stop administration if white blood cell count falls below 500 μL. Adverse effects include bone marrow suppression, teratogenicity, and increased risk of malignancies. Adverse effects include GI signs, hepatotoxicity, nephrotoxicity, gingival hyperplasia, and papillomatous dermatitis. Drugs that suppress cytochrome P-450 activity may cause potential cyclosporine toxicity. Used in combination with glucocorticoids. Do not use in cats. If agranulocytosis appears, administration should be discontinued. Adverse effects include hemolysis, methemoglobinemia, neuropathies, and hypoalbuminemia. Alternative therapy for milder cases of pemphigus foliaceus and pemphigus erythematosus. Adverse effects include vomiting, diarrhea, anorexia, and increased serum liver enzymes activity. Usually well tolerated. Adverse effects include bone marrow suppression and GI upset.
bid, Twice daily; GI, gastrointestinal; IM, intramuscular; IV, intravenous; PO, orally; tid, three times daily. *Equivalences to 5 mg prednisone: Dexamethasone, 0.5 mg; triamcinolone, 1 mg; methyl prednisone, 4 mg.
recommendation would be to change the administration interval, such as changing to twice daily from three times daily or to once daily from twice daily. Veterinarians should take more care when determining dosage for aminoglycosides. If the veterinarian is unsure of renal function, once-
daily administration at 6 to 8 mg/kg of gentamicin or 10 to 12 mg/kg of amikacin should be used. This dosage strategy is preferable both for improved efficacy and decreased renal toxicity. Aminoglycoside efficacy is correlated with a high serum concentration, and its toxicity is inversely related to frequency of administration.
Chapter 5 Pharmacologic Principles
Antiinflammatory Strategies As a group, nonsteroidal antiinflammatory drugs are used more often and for longer periods of time in the elderly than in any other age group. These drugs have a high incidence of undesirable side effects, including gastrointestinal upset, ulceration, and prolonged bleeding. Their use in animals with decreased renal function may be associated with worsening of renal function. This association is due to the increased role of prostaglandins in maintaining renal blood flow in the compromised kidney. Nonsteroidal antiinflammatory drugs should be started at the lowest possible dose and dosage regimen. Gradually increase first the frequency and then the amount over weeks. Loss of appetite is a clinical sign of gastrointestinal upset and indicates that treatment should be stopped for 1 day and resumed at one-half the previous dose. An alternative is to combine the nonsteroidal antiinflammatory drugs with misoprostol at 2 to 4 μg/kg twice daily or three times daily as a protectorate. It does not provide any gastrointestinal protection in human patients with chronic renal disease. Therefore, dosing frequency should be reduced in dogs with suspected renal dysfunction. Although many nonsteroidal antiinflammatory drugs do not show alterations in elimination in the elderly, their dynamic effects seem more pronounced. Do not use a cytoprotectorant such as sucralfate in combination with nonsteroidal antiinflammatory drugs, as absorption is greatly impaired and efficacy reduced.
Anesthesia and Analgesic Strategies Pain is significant in older dogs and cats.2 Management directed toward pain management should be addressed in each animal requiring medical or surgical care (Tables 5-2 and 5-3).3 The use of opioid agonists-antagonists or opioid agonists is more commonly done now (Table 5-4). The sedative effects of analgesic drugs may be enhanced in the geriatric animal as a function of age-related changes in pharmacodynamics and alteration of cognitive pathways. It is better to use a smaller amount of a drug more frequently than to try to prolong the action by increasing the dose. Optimizing a dose for oxymorphone involves administering 0.01 mg/kg every 5 to 10 minutes until the animal is quiet and comfortable. The total dose used is determined, and this amount can then be given every 3 to 4 hours as
47
needed. No drugs require as much individualization as pain relievers. There are no standard doses, only standard dose ranges. The more pronounced sedative effect of these agents in the elderly should not deter the veterinarian from using these agents; instead, they should be used with care.
CHRONIC MEDICATION AND INFORMATION CHART All animals receiving chronic medication should have a physical examination at least annually before any medication prescriptions are refilled (Table 5-5).
TRANSFUSION MEDICINE Transfusion medicine is another important component in the management of clinical diseases in older dogs and cats.4
Individual Components Fresh whole blood should be administered within 6 hours for maximal effect of coagulation proteins and platelets. Stored whole blood is refrigerated at 4° to 6° C after collection. Packed red blood cells are red blood cells that are separated from plasma using centrifugation, sedimentation, or plasma extraction, and stored at 4° to 6° C. Packed red blood cells should be resuspended with 100 ml 0.9% saline solution prior to administration to prevent sludging. Currently, most blood banks add a red cell nutrient solution to prolong storage and shelf life up to 42 days for most commercially available red cell products. This can also be accomplished in the hospital with use of special collection bags containing this solution. These prepared red blood cells do not need to be resuspended with any additional fluid. Fresh plasma is plasma extracted from red blood cells within 6 hours and used within 24 hours of collection. Plasma is best extracted using special collection systems and blood bank centrifuge. Gravity sedimentation of red blood cells also allows plasma to be extracted if needed. Fresh frozen plasma is plasma extracted from red blood cells within 6 hours and frozen at −20º C or below (ideal is −70º C) for up to 1 year. After 1 year of storage this product should be relabeled as frozen plasma. Frozen plasma is plasma extracted from red blood cells more than 6 hours after collection
48
Geriatrics and Gerontology of the Dog and Cat
TABLE 5-2. PAIN ASSESSMENT SCALE FOR OLDER DOGS AND CATS SCORE
ANIMAL BEHAVIOR AND SIGNS
ACTION—RECORD PAIN SCORE AND NOTIFY VETERINARIAN IF 3 OR ABOVE
0 No pain 1 Probably no pain 2 Mild discomfort
Bright, bouncy, responsive, self-grooming; normal mobility; dreaming sleep Appears normal; not as clear-cut as above; possible increased heart rate Eats and sleeps but may not dream; may limp or resist palpation of affected area; increased heart rate and respiration rate may be present Limps or guards affected area (e.g., tenses abdomen); slightly depressed; restlessness with or without trembling; increased heart rate, respiration rate; cats may still purr; dogs may wag tail
None
3 Mild pain or discomfort
4 Mild to moderate pain
Resists touch of affected area; may look or chew at area; abnormal body position; may not move for hours, with or without trembling, appetite change, increased and shallow respiration rate, and increased heart rate; may give occasional whimper or cry; pupils may be dilated
5 Moderate pain
Depressed, trembling, head down, inappetent; may cry or bite if approached or moved or if affected area is touched; marked splinting or prayer position if abdomen is affected; possibly increased heart and respiration rate; animal does not sleep Animal may cry or whine frequently without provocation; cats may still purr; dogs may wag tail
6 As above
7 Moderate to severe pain 8 Severe pain
As above. Animal is very depressed; will urinate and defecate without moving; will cry if moved, may continually whimper As above, but with more vocalizing; animal is more depressed and unaware of surroundings; may thrash about intermittently; with traumatic or neurologic pain may scream (especially cats) if approached; usually there is an increased heart rate and increased respiratory rate with increased abdominal effort even if opioids were previously given 9 As above, but animal is hyperesthetic, trembles Severe to involuntarily if touched close to affected area; excruciating pain neurologic pain or severe inflammation anywhere; this degree of pain can cause death 10 As above, but animal is screaming or almost Excruciating pain comatose; animal is hyperesthetic or hyperalgesic; whole body trembles and animal reacts in pain wherever you touch it; this degree of pain can cause death
None Reassess hourly; if worse give analgesic Needs analgesic— 1. NSAID and/or butorphanol (0.1 ml/kg every 6 to 12 h) OR 2. Repeat morphine if wearing off from previous use; do not give butorphanol and morphine 1. Morphine—dogs, 0.3 mg/kg; cats, 0.1 mg/kg IM or SC 2. Butorphanol (0.15 ml per 5 kg every 4 to 12 h) OR 3. NSAID OR 4. NSAID plus morphine if opioid has already been given 1. Morphine—dogs, 0.3 to 0.5 mg/kg 2. Butorphanol (0.2 ml per 5 kg every 4 to 8 h; cats, 0.15 mg/kg every 3 to 6 h) 3. NSAID 4. Opioid plus NSAID 1. Morphine—dogs, 0.5 mg/kg; cats, 0.2 mg/kg; every 3 to 6 h OR 2. NSAID as appropriate OR 3. Both As above, but higher doses of opioid 1. High dose morphine 2. Plus NSAID as appropriate
1. High dose morphine plus NSAID 2. Plus epidural or local analgesic 3. Anesthetic while treating inciting cause Very high doses of opioids do not relieve this pain, but give the following: 1. Morphine—dogs, 1 mg/kg; cats, 0.2 mg/kg or until effective 2. Plus NSAID 3. Plus epidural or nerve blocks OR 4. General anesthesia to treat cause
IM, Intramuscular; NSAID, nonsteroidal antiinflammatory drug; SC, subcutaneous. NSAIDs are excellent for treatment of musculoskeletal pain and soft-tissue inflammation. Do not give if animal is bleeding, dehydrated, or hypotensive, or has signs of gastrointestinal tract disease or ulceration or severe pulmonary disease.
Chapter 5 Pharmacologic Principles
49
TABLE 5-3. SUGGESTED DOSES FOR ANESTHETIC AND ANALGESIC AGENTS AGENT
DOSAGE
COMMENTS
Anticholinergics Atropine
0.02 to 0.04 mg/kg IV, IM, SC
Glycopyrrolate
0.01 mg/kg IV, IM
Recommended to offset dominant parasympathetic effects and maintain heart rate, cardiac output, and blood pressure. Also decreases airway secretions. Glycopyrrolate does not cross the blood-brain barrier, takes longer to onset of action, and has increased duration compared with atropine.
Tranquilizers and Sedatives Diazepam 0.2 to 0.4 mg/kg IV, IM Midazolam
0.1 to 0.2 mg/kg IV, IM, SC
Acepromazine
0.025 to 0.05 mg/kg IM, SC
␣2 Agonists Xylazine
1 to 2 mg/kg IM
Medetomidine
20 to 30 g/kg IM
Opioids Meperidine Morphine Oxymorphone
Fentanyl
Buprenorphine Butorphanol
1 to 2 mg/kg IM Epidural: 0.5-1.5 mg/kg 0.2 to 1 mg/kg IM, SC Epidural: 0.1 mg/kg in 1 ml per 10-lb volume of saline solution 0.05 to 0.2 mg/kg IV, IM, SC Epidural: 0.1 mg/kg in 1 ml per 10-lb volume of saline solution 2 to 4 g/kg IV CRI: 2 to 4 g/kg/h IV Transdermal patch: 2.5 to 10 kg—use 25-g patch (all or part) 10 to 20 kg—use 50-g patch 20 to 30 kg—use 75-g patch Epidural: 1-10 μg/kg in 1 ml per 10-lb volume of saline solution 0.01 to 0.02 mg/kg IV, IM, SC 0.2 to 0.4 mg/kg IV, IM, SC CRI: 0.2 to 0.4 mg/kg/h IV
Intravenous Anesthetics Thiopental 4 to 6 mg/kg IV, until effective
Methohexital
4 to 6 mg/kg IV, until effective
Propofol
2 to 6 mg/kg IV, until effective CRI: 10 to 12 mg/kg/h IV
Propylene glycol carrier makes uptake unpredictable from IM site. Will not mix in same syringe with any drug, except ketamine. Water-soluble. More potent and shorter acting than diazepam. Mixes with other agents. May cause excitement on recovery in some cats. 2 mg maximum. Requires hepatic degradation. Potentiates hypotension and hypothermia. Does not provide analgesia and is not reversible. Best to dilute to 1 mg/ml solution. Requires hepatic degradation and causes marked bradycardia and decreased cardiac output. Reversible. May cause vomiting. Always use with an anticholinergic agent. Medetomidine is more potent and longer acting than xylazine. Mild analgesia. May cause histamine release if injected IV. Reversible. Analgesia with sedation and cardiopulmonary depression. Administer with an anticholinergic. Potentiates hypothermia. Most common agent used for epidural analgesia. Reversible. 4 mg maximum. Analgesia with sedation. Causes panting. Administer with an anticholinergic agent. Commonly combined with acepromazine in animals older than 12 weeks of age for neuroleptanalgesia. Can be used for epidural analgesia. Reversible. Very potent analgesic. Rapid onset and short duration of action. Minimal cardiopulmonary effects. Can be delivered by a variety of routes, including epidural. Reversible.
30 to 45 minutes to onset of action; long duration due to slow rate of dissociation from receptor; unpredictable reversal with opioid antagonists. Agonist-antagonist. Minimal cardiopulmonary depression. Good visceral analgesia. Used to reverse agonist adverse effects and preserve analgesia. Ultra–short-acting thiobarbiturate. Termination of action depends on redistribution and hepatic degradation. May cause dysrythmia. Respiratory depression is common, be prepared to intubate and ventilate. Ultra–short-acting oxybarbiturate. Terminated by redistribution with minimal hepatic metabolism. May cause excitement on induction and recovery. Be prepared to intubate and ventilate. Alkyl phenol. Do not bolus; give slowly, over several minutes. Ultra–short-acting; rapid onset, rapid recovery. Noncumulative, can be used as CRI without prolonged recovery. Be prepared to intubate and ventilate. Continued
50
Geriatrics and Gerontology of the Dog and Cat
TABLE 5-3. SUGGESTED DOSES FOR ANESTHETIC AND ANALGESIC AGENTS—cont’d AGENT
DOSAGE
COMMENTS
Intravenous Anesthetics—cont’d Etomidate 1 to 2 mg/kg IV CRI: 2 to 4 mg/kg/h IV Ketamine
1 to 2 mg/kg IV 11 to 22 mg/kg IM
Telazol
1 to 2 mg/kg IV 5 to 13 mg/kg IM
Nonbarbiturate. No cardiopulmonary effects. May cause nausea, vomiting, myoclonus, excitement on induction and recovery. Noncumulative, can be used as constant rate infusion. Dissociative anesthetic. Excessive salivation controlled with anticholinergic agents. Increases intracranial and intraocular pressures. May cause seizures. Elimination depends on renal and hepatic function. Contains 1:1 tiletamine, a dissociative anesthetic, and zolazepam, a benzodiazepine. Tiletamine is more potent and longer lasting than ketamine. Zolazepam effects may be prolonged in some cats and cause rough recovery.
IV, Intravenous administration; IM, intramuscular administration; SC, subcutaneous administration; CRI, constant rate infusion.
TABLE 5-4. SUGGESTED DOSES FOR TRANQUILIZER AND SEDATIVE ANTAGONIST AGENTS AGENT
ANTAGONISTIC EFFECTS
DOSE
COMMENTS
Flumazenil
Benzodiazepines
0.1 mg/kg IV to effect
Yohimbine
α2 receptors
Atipamazole Tolazoline Naloxone
α2 receptors α1 and α2 receptors Pure narcotic antagonist
0.25 to 0.5 mg/kg IM; 0.15 mg/kg IV until effective 0.2 to 0.4 mg/kg IM 0.3 mg/kg IV until effective 0.04 to 0.4 mg IV until effective
Duration short—1 h in adults; may have agonist effects at high dose May cause excitement after IV administration Most effective reversal agent
Naltrexone
Pure narcotic antagonist
0.04 mg/kg IV
Nalmefene Butorphanol
Pure narcotic antagonist Narcotic agonist-antagonist
0.1 to 0.2 mg/kg IV or IM 0.2 mg/kg IV, IM, SC
Nalbuphine
Narcotic agonist-antagonist
0.5 to 2 mg/kg IV, IM, SC
Short duration—0.5 to 1.5 h ; animals may renarcotize 8 to 12 h duration; most effective for reversal of central effects related to epidural opioid administration 8 to 10 h duration Used to reverse bradycardia and respiratory depression of agonists while maintaining analgesia Lasts 2 to 4 h; less potent analgesic than butorphanol
IM, Intramuscular administration; IV, intravenous administration; SC, subcutaneous administration.
and frozen, or fresh frozen plasma that has been stored longer than 1 year or at temperatures greater than −20º C. Platelet rich plasma and platelet concentrate are concentrated platelet products that are manufactured from successive centrifugation of fresh plasma. The process is complex and requires a blood banking centrifuge. Cryoprecipitate is a concentrated clotting factor product rich in factor VIII and von Willebrand factor, fibrinogen, and fibronectin. It is manufactured by thawing fresh frozen plasma at 1º to 6º C until slushy or until approximately 90% of volume is liquid, then centrifuging at 5 g for 5 minutes or using gravity to extract liquid plasma. Both components (cryoprecipitate and supernatant cryoprecipitate) can be refrozen at −20º C or below (ideal −70º C) for
up until 1 year after collection of plasma. If vasopressin is administered to the blood donor at 0.6 μg/kg diluted in 10 ml of sterile saline solution intravenously over 10 minutes approximately 30 minutes before collection, the yield of factor VIII and von Willebrand factor can be improved.
Canine Red Blood Cells Typing the recipient is strongly encouraged, so that DEA 1.1- and 1.2-positive donors can be used in transfusion programs and so that the blood is correctly directed to positive recipients. Commercial typing cards check only for DEA 1.1. Dogs who are autoagglutinating should always receive negative blood, because the typing cards (Text continued on p. 56)
Behavioral evaluation Every 3 months
CBC
Serum chemistry profile
Amitriptyline
Aspirin
Atenolol
No
No
No
No
No
Monitor for gradual or sudden behavioral changes Ocular pressures and Every 4-6 months May not be working properly; Schirmer tear tests may cause eye irritation; may cause increase in serum liver enzymes
No
Yes
No eyedrops for last 3-4 h
No
No
No
No
Yes
Yes
No
Yes
No
No
Yes
No
No
No
No Yes
No
No
No
No
Continued
Vomiting, diarrhea, weakness, decreased appetite, increased lethargy, sudden loss of stamina, seizures, skin eruptions May cause transient depression and atropine-like signs Sedation, dryness of mouth, rapid heart rate, poor grooming Owner should avoid contact with medication; medication has to be used regularly as prescribed
Give on an empty stomach; vomiting, diarrhea, weakness, decreased appetite, increased lethargy, coughing, sudden loss of stamina
Aggression, poor grooming
Give on an empty stomach; vomiting, diarrhea, weakness, decreased appetite, increased lethargy, coughing, sudden loss of stamina
Can cause hypotension, especially in animals with preexisting cardiac disease; can cause excessive sedation, seizures Sedation, dryness of mouth, rapid heart rate, poor grooming Vomiting, diarrhea, weakness, decreased appetite, increased lethargy, sudden loss of stamina Changes in behavior, weakness
SPECIAL TIMING FOR SPECIAL INFORMATION/ TESTS OWNER SHOULD CALL IF:
Yes
Yes
No
Yes
FAST FOR 8 HOURS BEFORE TESTING
May cause changes in the liver
CBC, Complete blood count; ECG, electrocardiogram.
Cyclosporine
Monitor for gradual or sudden behavioral changes Check for anemia
Check for liver dysfunction via serum liver enzymes
REASON FOR TESTING
Monitor for liver and kidney dysfunction and electrolyte disorders Lead II ECG Every 6 months Monitor progression of heart disease and arrhythmias Serum chemistry Every 6 months Check for azotemia and electrolyte profile disorder; should use in advancing kidney disease and can cause sodium loss CBC Every 12 months Check for anemia or hemoconcentration Lead II ECG Every 6 months Monitor progression of heart disease Behavioral evaluation Every 3 months Monitor for gradual or sudden behavioral changes Serum chemistry Every 6 months Check for azotemia and profile electrolyte disorder; should use in advancing kidney disease and can cause sodium loss CBC Every 12 months Check for anemia or hemoconcentration Lead II ECG Every 6 months Monitor progression of heart disease Serum chemistry Every 3-6 months Monitor for liver and kidney profile dysfunction
Every 6 months
Every 6 months
Chlorpheniramine CBC and serum Every 12 months chemistry profile Clomipramine Behavioral evaluation Every 3 months
Carprofen
Captopril
Buspirone
Benazepril
Serum chemistry profile
Acepromazine
Every 12 months
TESTS NEEDED
DRUG NAME
TESTING FREQUENCY
TABLE 5-5. CHRONIC MEDICATION AND INFORMATION CHART
Chapter 5 Pharmacologic Principles 51
Furosemide
Fluoxetine
Fludrocortisone
Enalapril
Diltiazam
Digoxin
Every 6 months
Lead II ECG
CBC
Lead II ECG Serum chemistry profile Serum chemistry profile Serum chemistry profile
CBC
Lead II ECG Serum chemistry profile
Monitor progression of heart disease and check for ECG signs of toxicity Check for liver dysfunction
Check for liver or kidney dysfunction Check for liver and kidney dysfunction and electrolyte disorder Check for anemia or hemoconcentration Ensure adequate dosage
Check for liver and kidney dysfunction; contraindicated in liver and kidney disease Check for adequate therapeutic levels
REASON FOR TESTING
Check for anemia or hemoconcentration Every 6 months Monitor progression of heart disease Every 6 months Check for azotemia and electrolyte disorder; should use in advancing kidney disease and can cause sodium loss Every 12 months Check for anemia or hemoconcentration Every 6 months Monitor progression of heart disease Every 3-4 months Monitor sodium and potassium levels and for liver dysfunction Every 3 months Monitor for liver and kidney dysfunction Every 6 months Check for liver and kidney dysfunction and electrolyte disorder; can cause potassium loss Every 12 months Check for anemia, hemoconcentration, and leukopenia
Every 12 months
Every 6 months
Every 6 months
Digoxin serum level
Serum chemistry profile CBC
Every 6 months
CBC
Every 6 months
Every 6 months
Diazepam serum levels
Serum chemistry profile Serum chemistry profile
Every 6 months
Serum chemistry profile
Diazepam
Diethylstilbestrol
Every 6 months
TESTS NEEDED
DRUG NAME
TESTING FREQUENCY
TABLE 5-5. CHRONIC MEDICATION AND INFORMATION CHART—cont’d
Yes
Yes
Yes
No Yes
Yes
No Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
FAST FOR 8 HOURS BEFORE TESTING
No
No
No
No No
No
No No
No
No
8 h after last dose No
No
No
4-6 hours after pilling No
No
Vomiting, diarrhea, decreased appetite, increased lethargy, polyuria-polydipsia, dehydration
Vomiting, diarrhea, decreased appetite, increased lethargy Restlessness, insomnia, weight loss
Vomiting, diarrhea, weakness, decreased appetite, increased lethargy, coughing, sudden loss of stamina
Decreased appetite, weakness, increased lethargy, coughing, sudden loss of stamina
May cause vomiting, diarrhea, lethargy, abnormal bruising or bleeding, polyuria-polydipsia Give on an empty stomach; vomiting, diarrhea, weakness, decreased appetite, increased lethargy, coughing, sudden loss of stamina
Scheduled drug—login required; may cause too much sedation and increased appetite; may cause hyperexcitation
SPECIAL TIMING FOR SPECIAL INFORMATION/ TESTS OWNER SHOULD CALL IF:
52 Geriatrics and Gerontology of the Dog and Cat
Serum chemistry profile CBC Urinalysis CBC
D-Penicillamine
ACTH, Adrenocorticotropic hormone.
Fasting and postprandial bile acids
Serum chemistry profile CBC Phenobarbital serum level
ACTH response test
Mitotane
Phenobarbital
Serum chemistry profile CBC
Every 6 months
Urinalysis
Every 12 months Every 12 months or more often if seizures are not adequately controlled Every 12 months
Every 6 months
Every 12 months Every 6 months Every 6 months
Every 6 months
Monitor for liver dysfunction
Check for liver and kidney dysfunction Check for anemia Ensure safe but adequate blood levels being obtained; serum levels should be 15-40 μg/ml
Monitor for liver and kidney dysfunction Monitor bone marrow function Check for urinary tract infection Check for anemia and leukopenia
Every 3-6 months Monitor for anemia, leukopenia, and thrombocytopenia Every 6 months Monitor for proper dosage and adrenal gland function
Check for glucose and ketones and for urinary tract infection Every 3-6 months Monitor for liver dysfunction
Every 6 months Every 6 months
Methimazole
Insulin
Check for anemia, monitor bone marrow function (may cause depression) Monitor progression of heart disease Monitor for liver and kidney dysfunction Monitor for liver and kidney dysfunction Monitor insulin metabolism and effects
Every 12 months Every 6 months Every 6 months
Check for kidney dysfunction
REASON FOR TESTING
Every 6 months
TESTING FREQUENCY
Lead II ECG Serum chemistry profile Serum chemistry profile Blood glucose curve
Serum chemistry profile CBC
Hydralazine
Hydrocodone
TESTS NEEDED
DRUG NAME
TABLE 5-5. CHRONIC MEDICATION AND INFORMATION CHART—cont’d
Yes
No Yes
Yes
Yes No Yes
Yes
No
Yes
Yes
No
No
Yes
No Yes
Yes
Yes
FAST FOR 8 HOURS BEFORE TESTING
Scheduled drug—login required; sedation, constipation, vomiting, increased coughing Weakness, lethargy, vomiting, incoordination, disorientation, polyuria-polydipsia
Give with food; vomiting, diarrhea, decreased appetite, increased lethargy
Vomiting, diarrhea, decreased appetite, lethargy, weight loss
No
No Before first tablet in morning
No
No No No
Continued
Vomiting, weakness, decreased appetite, increased lethargy, loss of stamina Scheduled drug—login required; anxiety or depression, increased appetite, polyuria-polydipsia
Must stay Use with caution in animals with liver or kidney in hospital disease; vomiting, diarrhea, decreased appetite, at least increased lethargy, incoordination, 3 hours polyuria-polydipsia No
No
No
Give insulin at usual time No
No
No No
No
No
SPECIAL TIMING FOR SPECIAL INFORMATION/ TESTS OWNER SHOULD CALL IF:
Chapter 5 Pharmacologic Principles 53
Serum chemistry profile
Prednisolone or prednisone
Primidone
Serum chemistry profile Potassium bromide serum level
Potassium bromide
Fasting and postprandial bile acids
Serum chemistry profile CBC Phenobarbital serum level
CBC
CBC
Every 12 months Every 12 months or more often if seizures are not adequately controlled Every 12 months
Every 6 months
Every 12 months
6 weeks after initiation of therapy and then every 6 months Every 12 months
Every 6 months
Every month
Every 12 months
Urinalysis
Piroxicam
Every 12 months
CBC
Serum chemistry profile
Every 6 months
Serum chemistry profile
Phenylbutazone
Phenylpropanolamine
Every 6 months
TESTS NEEDED
DRUG NAME
TESTING FREQUENCY
Monitor for altered white blood cell levels Check for liver and kidney dysfunction Check for anemia Ensure safe but adequate blood levels being obtained; phenobarbital serum levels should be measured to estimate anticonvulsant effect Monitor for liver dysfunction
Monitor for liver dysfunction and electrolyte disorders
Monitor for liver and kidney dysfunction Check adequate or toxic levels of potassium bromide; serum levels should be 1-2 mg/ml (100-200 mg/dl)
Check for liver and kidney dysfunction; can cause toxic changes Can cause changes in the bone marrow Check blood glucose (can cause problems in diabetics) and for liver dysfunction Monitor for ability to concentrate urine and check for urinary tract infection Monitor for anemia
REASON FOR TESTING
TABLE 5-5. CHRONIC MEDICATION AND INFORMATION CHART—cont’d
Yes
No Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
FAST FOR 8 HOURS BEFORE TESTING
Give with food; vomiting, diarrhea, weakness, decreased appetite, increased lethargy, sudden loss of stamina Give with food; can cause sedation, weakness; can take up to 4 months to achieve therapeutic levels
Restlessness, anxiousness, decreased appetite, urinary incontinence
Give with food; vomiting, diarrhea, weakness, unusual bleeding or bruising
Scheduled drug—login required; anxiety or depression, increased appetite, polyuria-polydipsia
Give with food; increased polyuria-polydipsia, hair loss, weakness, significant changes in body weight, panting, behavioral change
No
No Before first tablet in morning
No
No
No
Before first dose in the morning
No
No
No
No
No
No
SPECIAL TIMING FOR SPECIAL INFORMATION/ TESTS OWNER SHOULD CALL IF:
54 Geriatrics and Gerontology of the Dog and Cat
Every 3 months
Ocular pressures and Schirmer tear tests Serum electrolytes
Serum chemistry profile CBC
Tylosin
L-Thyroxine
Serum chemistry profile Serum T4
Theophylline
Lead II ECG
Every 6 months
CBC
Terbutaline
Every 6 months
Serum chemistry profile
Sulfasalazine
Every 12 months
Every month for the first 3 months and then every 12 months Every 12 months
Every 12 months
Every month for first 3 months and then every 6 months Every 6 months
Every 3 months
Every 3 months
Lead II ECG
Serum chemistry profile CBC
Every 6 months
Serum chemistry profile
Propranolol
Selegiline (Deprenyl)
Every 6 months
TESTS NEEDED
DRUG NAME
TESTING FREQUENCY
Monitor red blood cell and white blood cell levels
Monitor for liver dysfunction
Monitor for heart disease and arrhythmias Monitor for liver and kidney dysfunction Monitor serum T4 levels for adequate dosing; requirement may change as animal ages
Check for anemia, white blood cell changes, and thrombocytopenia Check the eyes for normal intraocular pressures and normal tear production Can cause potassium loss
Monitor for liver and kidney dysfunction and electrolyte disorders Monitor progression of heart disease and arrhythmias Check for liver and kidney dysfunction Check for anemia, white blood cell changes, and thrombocytopenia Check for liver and kidney dysfunction
REASON FOR TESTING
TABLE 5-5. CHRONIC MEDICATION AND INFORMATION CHART—cont’d
Yes
Yes
Yes
Yes
No
Yes
No
Yes
Yes
Yes
Yes
No
Yes
FAST FOR 8 HOURS BEFORE TESTING
Vomiting, diarrhea, excitement, increased coughing
Weakness, depression, decreased appetite
Eyes are especially sensitive; causes redness or chronic gummy discharge; weakness, depression, decreased appetite
Vomiting, diarrhea, weakness, depression, decreased appetite
Changes in behavior, weakness
No
No
Vomiting, diarrhea, loss of appetite
6-8 h after Weight gain, extreme weight loss, excitement, medication restlessness, constant panting given
No
No
No
No
No
No
No
No
No
No
SPECIAL TIMING FOR SPECIAL INFORMATION/ TESTS OWNER SHOULD CALL IF:
Chapter 5 Pharmacologic Principles 55
56
Geriatrics and Gerontology of the Dog and Cat
are difficult to interpret when autoagglutination is present. Bitches that have whelped and any dog that that has received a transfusion more than 7 days previously should have a cross-match performed prior to transfusion.
Feline Red Blood Cells Typing felines prior to transfusion is mandatory. Type B blood is rarely stored, but ideally cat type B blood from such breeds as the rex, British shorthair, and Maine coon should be available to the veterinary practice to donate as needed. If type A red cells are given to a type B cat, the results are catastrophic. If autoagglutination is present in the recipient, and interpretation of the card typing results is not clear, then crossmatching is mandatory to attempt to identify incompatibility.
ADMINISTRATION OF RED CELL PRODUCTS Packed red blood cells that have not been stored in nutrient solutions should be resuspended with sterile saline or non–calcium-containing crystalloid fluids. All red cell products should be administered through a blood administration filter (170 μm) using a nonrotary fluid administration pump (peristaltic flow pumps are acceptable). Before a transfusion is begun, measurements of baseline rectal temperature, pulse rate, respiratory rate, packed cell volume (PCV), and total solids should be obtained. Initial rate of administration should be slow (0.25 ml/kg hourly) for 15 to 20 minutes to monitor for transfusion reaction. Animals should be monitored carefully during transfusion. The calculated dose of red blood cell product should be administered within 4 hours of puncturing the donation bag. The dose of red blood cells to administer to an anemic animal should be calculated as follows: Dose (ml) = 80 (Dogs) or 70 (Cats) × Desired change in PCV Body weight (kg) × PCV transfused blood Total daily doses of red blood cell products should not exceed 22 ml/kg/day, unless severe ongoing losses are occurring (do not exceed 22 ml/ kg hourly except in the case of massive hemorrhage). If risk of volume overload is present, then maximum administration rate should be 4 ml/kg hourly. In animals with congestive heart failure
and anemia the maximum administration rate should be 5 ml/kg/day. Animals that are experiencing severe and rapid blood loss should receive red blood cell products as rapidly as needed to maintain adequate circulating volumes. Slow initial rates of transfusion are usually not used in emergency situations. The packed cell volume and total solids should always be performed within 60 to 90 minutes after completion of the transfusion to determine response.
ADMINISTRATION OF PLASMA PRODUCTS Typing and cross-matching as discussed above is not relevant to plasma transfusion for either dogs or cats. All plasma products should be thawed at a constant temperature (37° C) and administered through a blood administration filter (170 μm) using a fluid administration pump (peristaltic flow and rotary type pumps are acceptable). The animal’s baseline rectal temperature, pulse rate, respiratory rate, PCV, and total solids should be measured before a transfusion is begun. Initial rate of administration should be slow (0.25 ml/kg hourly) for 15 to 20 minutes to monitor for transfusion reaction. Animals should be monitored carefully during transfusion. The calculated dose of plasma product should be administered within 4 hours of puncturing the donation bag. The dose of plasma product to administer should be 6 to 8 ml/kg two to three times per day as required. Cryoprecipitate should be administered at 1 unit per 10 to 20 kg, and the animal should be monitored hourly after transfusion to detect ongoing bleeding or serum activated PTT concentration. Additional transfusions are administered as required to control hemorrhage.
COMPLICATIONS Acute Intravascular Hemolysis Acute intravascular hemolysis is the most severe type of transfusion reaction and results in hemoglobinemia and hemoglobinuria. Signs may include restlessness, anxiety, nausea, muscle tremors, urticaria, fever, tachycardia, tachypnea, and seizures. Acute death, thromboembolic disease, or acute renal failure are possible sequelae. The most common situations in which this would occur include those in which type A
Chapter 5 Pharmacologic Principles blood is given to a type B cat, or DEA 1.1/1.2 blood is given to a negative dog previously sensitized to DEA 1.1/1.2-positive blood through previous transfusion or breeding (negative female dog bred to positive male with exposure to positive fetal blood during whelping). Transfusion should be discontinued immediately. Supportive care includes renal diuresis and corticosteroids. Urinary alkalization may assist in removing erythrocytic membrane stroma. Plasmapheresis would be ideal but is not readily available.
Acute Nonhemolytic Reaction This transfusion reaction is manifested by urticaria, pruritus, fever, or anaphylaxis. Most of the time, the reaction is directed against an incompatible antigen located on the platelet or white blood cell remnants or some plasma protein component. Anaphylaxis should be treated with aggressive fluid resuscitation, corticosteroids, and antihistamines if severe. Epinephrine (0.1 ml/kg or 1:100000 concentration intravenously) may also be necessary if severe bronchoconstriction and cardiovascular collapse are present. Restarting the transfusion is not recommended in this case. If urticaria or fever is the only manifestation, the transfusion should be stopped temporarily, corticosteroids or antihistamines administered, and the transfusion reattempted after 20 to 30 minutes.
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reflect rapid transfused erythrocytic destruction and extravascular hemolysis. Occasionally a pyogenic substance from the plastic bag or tubing can cause a febrile response. Administration of erythrocytes or plasma products with calciumcontaining crystalloid solutions can cause microembolization within the intravenous tubing. Inappropriate plasma product storage or administration can result in poor viability of plasma or clotting proteins and ineffective response. Massive transfusion in severe hemorrhage can result in hypocalcemia or anticoagulant toxicity. Disease transmission can also occur if donors have not been carefully chosen and screened.
AUTOTRANSFUSION Autotransfusion requires a simple apparatus (metal teat cannula, three-way stopcock, catheter injection port, and blood collection bag) and should be easy to perform. Blood is collected by gravity flow into a collection bag from hemorrhage into the abdomen or thoracic cavity. This technique is indicated in animals with trauma if no ready access to blood supply is available. Its use in other causes of hemoabdomen or hemothorax is not advised because of the potential risk of infusing neoplastic cells or bacteria into the animal. Autotransfused blood does not contain adequate clotting factors or platelets to be helpful in controlling hemorrhage and should be used only as a source of red blood cells and albumin to maintain oxygen-carrying capacity and volume.
Delayed Destruction of Erythrocytes Typically, DEA 3/5/7 antigen antibody reactions are involved as a result of previous sensitization or naturally occurring antibodies. Rapid drop in PCV within 3 to 7 days and evidence of extravascular hemolysis are the typical signs.
Nonimmunologic Reactions The most common problems include vascular overload (cough, pulmonary edema, vomiting, urticaria, and serous nasal discharge). In addition, poor component handling can result in hemolysis (physical trauma to red cells during collection or administration, prolonged or inadequate storage, freezing, overheating, and mixing with nonisotonic fluids). If erythrocytic damage is severe, then signs may be similar to acute severe intravascular hemolysis, but more commonly they
RED BLOOD CELL ALTERNATIVES Oxyglobin solution (Biopure Corporation, Cambridge, Mass.), a hemoglobin glutamer-200 (bovine), is the only commercially available red blood cell substitute available to veterinarians.5,6 It is expensive, but potential advantages include immediate oxygen unloading capability, ready accessibility and easy storage, and oxygencarrying capacity that is provided without contributing red cell stroma to animals with immune-mediated hemolysis. In extravascular immune-mediated hemolytic anemia cases, there exists a low risk of contributing to further activation of the immune system as well as suppressing bone marrow response. In intravascular hemolysis, the risk of acute renal failure and thromboembolization is potentially reduced by providing oxygen-carrying capacity without erythrocytic
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Geriatrics and Gerontology of the Dog and Cat
stroma using Oxyglobin instead of using red blood cell products. Some speculate that Oxyglobin can act as a nitric oxide scavenger in the vasculature and can cause or exacerbate pulmonary hypertension. The dose recommended by the manufacturer is 30 ml/kg given no faster than 10 ml/kg hourly (perhaps even more cautiously in normovolemic animals at risk of volume overload). The duration of effect of the product is approximately 24 hours, with 90% elimination by 7 to 10 days. Administration of Oxyglobin does cause tissue discoloration and can interfere with serum chemistry profile and coagulation (depending on instrument type) testing results.
References 1. Plumb DC: Drug considerations in the geriatric patient, Proc Vet Med Forum 17:429, 1999. 2. Robertson SA: What is pain? J Am Vet Med Assoc 221:202, 2002. 3. Hellyer PW: Treatment of pain in dogs and cats, J Am Vet Med Assoc 221:212, 2002. 4. Kristensen AT, Feldman BF: Canine and feline transfusion medicine, Philadelphia, 1995, WB Saunders. 5. Rentko VT, Kelly N, Niggemeir A et al: Effects of oxyglobin and packed red blood cells (PRBC) on the erythropoietic response to acute anemia, J Vet Intern Med 12:227, 1998. 6. Muir WW, Wellman ML: Hemoglobin solutions and tissue oxygenation, J Vet Intern Med 17:127, 2003.