Marine Mammal Therapeutics

Question 1

Acute negative side effects with the use of what analgesic class in marine mammals?

Answer 1

NSAIDs (F8, West)

Question 2

Which anti-parasitic med causes CNS side effects in cetaceans and should be avoided?

Answer 2

Levamisole (F8)

Question 3

Drugs that have caused fatal adverse reactions in cetaceans

Answer 3

Sulfamethoxazole, phenothiazines, haloperidol, levamisole (F8)

Question 4

What are the primary routes of administering drugs to marine mammals?

Describe the considerations for each.

Answer 4

• Routes for Administering Drugs to Marine Mammals
  
  • PO administration
    
    • often preferred route if animal eating or being tube-fed
    • considerations - food interactions, factors that affect absorption (physiochemical properties of drug, stomach pH, GI microflora, anatomy), palatability
  • SC administration
    
    • technically difficult because of blubber layer in some phocids, walrus, and most cetaceans
    • effective in sea otters and otariids
    • young pinnipeds, especially neonates, can adequately absorb even lipophilic medications delivered SC, avoids muscle trauma or necrosis
    • cetaceans – although difficult can give higher volumes of fluids SC by ensuring fluids given between blubber and muscle layers
    • abscesses reported in pinnipeds, in particular with long-acting drugs such as extended-release buprenorphine
  • IM administration
    
    • frequently utilized in marine mammals that are difficult to restrain and inappetent
    • avoid superficial injection into extensive SC blubber - dramatically different vascularization and drug-partitioning properties
      
      • can result in failure to achieve systemic distribution of highly lipid-soluble medications
    • some drugs have inconsistent absorption IM
      
      • diazepam
    • irritation caused by some injectable drugs - local effect
      
      • due to irritating nature of drug or injection volume
      • recommended total volume injected per site does not increase in scale with mass of animal
    • injection sites should be as dry as possible, free of any gross contamination, and always using sterile needles
  • IV administration
    
    • Injection nearly perpendicular to vessel and deep - complicates catheterization
    • wire-reinforced epidural catheters used to catheterize epidural sinus in phocids
    • needles with side ports for directing catheter at right angles help avoid perivascular leakage of irritating drugs
    • administration of IV drugs into peri-arterial venous rete of peduncle in cetacean risks injection into surrounding arteries - IV medications should be diluted and administered slowly
    • nausea reported with IV drug administration - often resolves after slowing rate of administration
  • IP administration
    
    • Non-irritating drugs
    • difficulties depends on size of patient and availability of needles suitable to penetrate abdominal wall
    • placing flexible catheter through cannula for IP administration minimizes risk of accidental organ laceration with a rigid needle. In species like otariids for which vascular access and IV catheter maintenance is a challenge,
    • IP administration of medications like dextrose is viable option for species where vascular access if challenging – ex) otariids
    • sterility important to avoid introducing microorganisms into peritoneal cavity
  • IT (intratracheal) and IH (inhalation) administration
    
    • primarily for induction of anesthesia and targeted delivery of medications to lungs
    • nebulization and aerosolization used by either by holding mask on restrained animal or placing in a nebulization chamber
    • efficacy of aerosol absorption in lungs depends largely on droplet size
  • Topical
    
    • major challenge in marine mammals - achieve appropriate contact time for drug efficacy in aquatic environment
    • baths and dips possible for some smaller species
    • behavioral modification can augment dipping body parts into smaller containers for large species
    • most desirable application in some cases would be an ointment or salve that would remain in place
      
      • often specially compounded
      • use of human dental bases has had some success but expensive
      • lipid bases such as lanolin and petroleum gels have been used – less expensive

Question 5

What drugs are contraindicated for use in marine mammals?

Answer 5

• Drug interactions and adverse effects
  
  • Life threatening reactions
    
    • TMS, carprofen, cefovecin, and iohexol - associated with sudden death within close temporal association of drug administration
      
      • TMS - anaphylaxis in bottlenose dolphin and fatal bone marrow suppression and pancytopenia in bottlenose dolphins and killer whale
      • Carprofen - bottlenose dolphin died within 15 minutes of parenteral administration
      • Cefovecin - white-beaked dolphin died shortly after IM administration, lesions consistent with shock on necropsy, also associated with anaphylaxis in terrestrial species
      • Iohexol - CA sea lion cardiorespiratory arrest immediately following administration
    • Haloperidol associated with fatal neuroleptic malignant seizures in harbor seal, walrus, and Pacific white-sided dolphin
    • Levamisole -2 fatalities in belugas after IM administration, toxicity in sea otters
    • dichlorvos - organophosphate toxicity reported
    • bithionol - potent photosensitization effects reported

Question 6

What drugs have hepatic side effects in marine mammals?

Answer 6

• Hepatic effects
  
  • several drugs associated with elevations in hepatic enzymes
    
    • reversible elevations in transaminases reported with azole antifungals, ceftriaxone, florfenicol, and azithromycin
      
      • azole antifungal (particular itraconazole, ketoconazole, fluconazole) in bottlenose dolphins - mild and reversible liver pathology and 2- to 25-fold increases in AST, ALT, LDH
      • itraconazole associated with hypocholesterolemia in pilot whale
    • irreversible hepatotoxicity associated with voriconazole and ketoconazole in cetaceans
      
      • voriconazole -potential for severe hepatic, cardiac, and neurological effects
    • Flucytosine should be administered in combo with an azole to prevent resistance to flucytosine, premature cessation of azole may lead to flucytosine resistance

Question 7

What drugs have been shown to be nephrotoxic in marine mammals?

What combinations of drugs have shown to be extra deleterious to marine mammals?

Answer 7

• Renal effects
  
  • Several drugs have potential to be nephrotoxic - gentamicin, amikacin, sulfonamides
    
    • amikacin associated with renal tubular necrosis in a bottlenose dolphin
    • gentamicin – significant toxicity reported in sea otters, particularly with repeated doses
    • amphotericin B and liposomal nystatin - acute renal failure reported in a bottlenose dolphin and Pacific white-sided dolphin
    • NSAIDs - may cause hemodynamically mediated renal impairment, use cautiously in dehydrated patients or those with renal dysfunction
    • drugs w/ primary route of excretion through urinary tract used with caution in patients with renal compromise or dehydration
      
      • cephalosporins or fluconazole
      • dose may need to be adjusted for reduced clearance
    • concurrent administration of aminoglycosides and cephalosporins increases risk of renal toxicity - renal effects additive
    • concurrent aminoglycosides and flunixin meglumine linked to renal papillary necrosis in pilot whale
      
      • contraindicated in cases of toxemia because both have antiprostaglandin activity
    • nephrotoxicity of gentamicin and cephalosporins exacerbated with concurrent furosemide administration
    • furosemide diuresis results in increased renal loss of thiamine and pyridoxine - important when nutrition or oral supplement marginal
    • increased potassium loss in urine caused by furosemide may be exacerbated by concurrent steroid administration, esp if sodium intake high (often in marine mammals being fed supplemental salt)

Question 8

What drugs ahve had GI side effects in marine mammals?

What is a common side effect of azole antifungals?

What drugs have been associated with constipation?

What about GI ulcerations?

Answer 8

• GI effects
  
  • exceedingly common, particularly with oral drug administration
  • anorexia and GI discomfort - most commonly reported with antibiotic use
  • aminoglycosides, cephalosporins, fluoroquinolones, macrolides, penicillins, sulfonamides, and tetracyclines have reported GI effects in marine mammals
  • azole antifungals frequently associated with GI upset and inappetence
  • aminophylline and leuprolide – GI upset
  • fluconazole considered less likely to cause inappetence than ketoconazole or itraconazole, when administered to bottlenose dolphins
    
    • appetite may return by reducing dose
  • constipation noted in both cetaceans and pinnipeds with ferrous sulfate, sucralfate, and tramadol use
  • diarrhea noted during treatment with tylosin
  • ulcers, gastritis, enteritis reported with aspirin, steroids, NSAIDs
    
    • steroids and NSAIDs should not be combined
    • associated with fatal perforation of connecting channel in several cetaceans
  • PGF2A works on smooth muscle of uterus but has GI, musculoskeletal, and cardiac effects

Question 9

Ivermectin in marine mammals has been associated with what clinical signs?

What other drugs have been associated with neurological signs?

Answer 9

• Neuro effects
  
  • Ivermectin
    
    • transient neuro signs reported in odontocetes
    • tremors noted in Guadalupe fur seals
  • seizures, visual deficits, hepatotoxicity noted in CA sea lion with voriconazole
  • enrofloxacin associated with neuro signs and muscle fasciculations in bottlenose dolphins and rough-toothed dolphins
  • chronic parenteral amikacin - tremors of flukes noted in bottlenose dolphins, killer whales, and belugas

Question 10

What marine mammals have had cutaneous reactions to drugs?

Which medications have been involved?

Answer 10

• Dermal effects
  
  • TMS - hypersensitivity reactions characterized by ulcerations of mucocutaneous junctions reported in a beluga
  • Minocycline - associated with hyperpigmentation in killer whale
  • enrofloxacin - associated with photosensitivity in bottlenose dolphins for 4–8 weeks following cessation of treatment

Question 11

Sulfonamide use has been associated with what side effects?

Answer 11

• Hematologic effects
  
  • sulfonamide use in cetaceans - hematologic effects reported
    
    • moderate reaction characterized by neutrophilia
    • severe reaction noted in belugas, killer whales, and bottlenose dolphins includeing both neutropenia and thrombocytopenia
  • linezolid in combo with sulfonamides - anemia and leukopenia noted in killer whale
  • exceptionally long half-life of some sulfonamides in cetaceans likely a contributing factor in producing adverse reactions
    
    • sulfamethoxazole - half-life of 5.3-7.2 days in killer whales
  • TMS associated with severe bone marrow suppression and death in several cetaceans
  • most cases of adverse reactions to sulfas occurred with sulfatrimethoprim combo drugs
  • folic acid should be administered to any cetaceans receiving sulfa-trimethoprim combo drugs to mitigate risk of drug-induced deficiency
  • ferrous sulfate used to treat severe anemia or low serum iron or when hand-raising neonate cetaceans
    
    • monitor for iron overload during therapy

Question 12

What drugs have been associated with painful IM injections?

What drugs have resulted in abscesses?

Muscle necrosis has been found with IM injections of what drugs?

Why are fluoroquinolones contraindicated in young animals?

Answer 12

• Musculoskeletal effects
  
  • certain drugs associated with pain and irritation at injection site
    
    • ceftriaxone, ceftiofur, imipenem, leuprolide, ondansetron
  • abscesses reported with IM ampicillin/sulbactam, ceftiofur, enrofloxacin, and praziquantel use in pinnipeds
  • muscle necrosis associated with tetracycline and enrofloxacin injections in sea otters
  • florfenicol causes increase in AST and LDH due to muscle trauma at injection sites in bottlenose dolphins and belugas
  • fluoroquinolones reported to cause cartilage damage in weight-bearing joints of young, rapidly growing animals – not necessarily reported in marine mammals
    
    • inhibit cell proliferation and induce morphological changes in tendon cells
    • clinical responses often good when treating neonatal marine mammals suffering from severe infections of unknown origin
    • use caution in juvenile marine mammals

Question 13

Describe common approach to antiulcer therapy in marine mammals.

Use of antacids may affect the absorption of what drugs?

Cimetidine and ranitidine can impact drug metabolism through what mechanism?

What is a common problem of cetaceans being treated for ulcers?

Answer 13

• Antiulcer medications
  
  • use of antacids, H2 blockers, PPI, and gastroprotectants in treatment of gastric ulcers is routine
  • simultaneous administration of antacids with H2 blockers significantly decreases absorption and effectiveness of these drugs
    
    • administer either antacids or H2 blockers at least 1 hour prior to the other to allow adequate absorption
  • use of antacids may alter stomach pH – may effect absorption of drugs
    
    • steroids, azoles, tetracyclines, and iron should be administered at least 2-3 hours before or after administration of antiulcer meds
  • antacids with di- and trivalent cations decrease oral steroid absorption
  • presence of multivalent cations such as calcium, magnesium, iron, and zinc from other medications or stomach ingesta can decrease absorption of tetracyclines, fluoroquinolones, and sulfonamides
    
    • cimetidine - negative impact on tetracycline absorption in killer whales
  • cimetidine and ranitidine can impair metabolism of certain drugs such as benzodiazepines in terrestrial mammals by inhibiting cytochrome P450 pathway
  • famotidine does not inhibit cytochrome P450
  • common problem in cetaceans administered antiulcer medications is vomiting when gastric pH becomes too high to digest fish bones
    
    • bones can be seen in vomitus or via endoscopy
    • prolonged administration (weeks) in pinnipeds can cause impaction of fish bones in stomach
    • changes in pH more pronounced with PPIs – assess GI motility and emptying frequently
  • necrotizing dermatitis of unknown etiology observed in several bottlenose dolphins receiving ranitidine
  • sucralfate - commonly administered gastroprotectant in marine mammals
    
    • may decrease absorption of other drugs if given concurrently
      
      • separate out administration
    • may be inactivated by tetracyclines

Question 14

Describe the effect of steroid administration on the cetacean hematology & biochemistry.

If given concurrently with NSAIDs, where does perforation of the GI tract occur?

What are some side effects that can occur with rifampin?

Answer 14

• Steroids
  
  • complex metabolic effects on marine mammals, particularly on electrolyte balance
  • dexamethasone or prednisolone reduces calcium and phosphate absorption and increases urinary output of calcium and potassium in terrestrial animals
    
    • prolonged therapy could predispose to hypocalcemia
  • increase circulating serum glucose, triglyceride, and cholesterol
  • dexamethasone in bottlenose dolphins can cause neutrophilia, lymphopenia, eosinopenia, elevated insulin, depressed ACTH and cortisol concentrations, and enhanced appetite - changes may return to normal when steroids stopped
  • supplemental vitamin D, folate, ascorbic acid, and pyridoxine may be appropriate during prolonged steroid administration
    
    • serum content can be depleted
  • associated with fatal perforation of connecting chamber in several cetaceans when given with NSAIDs
  • gradual reduction/taper recommended to allow adrenal gland to resume normal function
  • rifampin
    
    • stimulates microsomal enzymes involved in steroid metabolism
      
      • may prevent effects of steroids
    • can have long-lasting effects even after discontinuation
    • enhances elimination of both exogenous and endogenous steroids, compromising ability to maintain metabolic homeostasis
    • documented to cause idiopathic thrombocyte dysfunction resulting in prolonged bleeding times
    • turns urine red-orange color in dolphins
  • high estrogen levels increase anti-inflammatory effects of steroids by approximately 20-fold
    
    • corticosteroids not metabolized properly in animals undergoing estrogen therapy
  • megestrol acetate associated with adrenal cortical dysfunction in bottlenose dolphins