p.115

• Sedative effect more in dogs, but licensed for both dog and cat use
• Antiemetic effects
• Mainly ant. at D2; also has ant. action at H1, alpha1, and mAch

Pharmokinetics

• Better absorption from IM than SQ sites
• Starts 30 min after IM injection (faster if IV)
• 4-6 hours sedation
• Oral dose: not as effective, so need higher dose
• Lipophilic and widely distributed
• High degree of protein binding
• Metabolized by hepatic microsomal enzymes
  • Oxidized to sulfoxides and glucuronide conjucation
  • Impaired liver → longer effect
  • Metabolites excreted in urine

Adverse effects

• CNS
  • BC dopamine, high doses can lead to extrapyramidal signs (restlessness, rigidity, tremor, catalepsy)
  • Fever, bc modify thermoregulation mechas at hypothalamus
• Cardiovascular
  • Peripheral vasodilation → drop in BP (mainly by anti-alpha1)
  • Clinical doses don't really affect HR

p.116

• Respiratory
  • Not much
• GI
  • Anti chol: Spasmolytic action on gut → reduce GI motility in dogs; reduced salivation
• Other
  • Quite mild antihistamine effect compared to other phenothiazines
  • Reduction in hematocrit: liver and spleen sequester/hog RBCs
  • Can temporarily reduce clotting activity

Contraindications

• Hypovolemia/shock
• Hx of seizures
• Reduced doses:
  • Hepatic or cardiac problems
  • Young, old, or weak
  • Bracycephalic breeds (esp. boxer)
  • Giant breeds

Known drug interactions

• CNS depressant effect makes other drugs' CNS depressant effects stronger as well, so having an opioid, even in nonpainful pt, increases sedation (need to use less)

p.130, 131

• Effects:
  • hypersensitivity to noise, startle more easily

• "Chondroprotectant"
• Inhibit serine proteinases (play role in IL-1 mediated degradation of cartilage proteoglycans and collagen)
• Reportedly inhibits some catabolic enzymes (elastase, stromelysin, metalloproteinases, cathepsin G and B1, hyaluronidases), which degrade collagen, proteoglycans, and hyaluronic acid
• Inhibit PGE synthesis, stimulates GAG synthesis
  • Inhibits aggrecanases, MMPs, NO, PGE2
• Potentiating effect on synth of hyaluronic acid by synovial membrane cells
  • Increase concentration of hyaluronan
• Within 2 hours, enters joint and starts its shit
• Best to give in early stages of osteoarthritis - once hylaine cartilage is gone, it's gone

• Adequan, Chondropotect
• "Proteolytic enz, inhibitor; chondroprotectant"
• Some studies: PSGAG much less effective in joints w/acute trauma but no degenerative enz
• Pharm
  • Acts as precursor to proteoglycan synth
  • Deposited in all layers of joint cartilage, preferentially taken up by osteoarthritic cartilage
  • IM: peak level in JOINTS @ 48 hours, lasts up to 96 hours
• No contraindication for IM use
  • Hypersensitivity - contraindicates IA use
  • But don't in place of other if infection is there
• Dose-related inhib of of coag/hemostasis in dogs
• FDA: category B for pregnancy
  • Unknown if enters milk
• Overdose difficult
  • 2% of horses getting up to 1250mg IA (normal IA dose is 250) got temporary clinical signs assoc. w/joint inflammation
• Some concern using it w/other NSAIDs or w/anticoags, since is heparin analgue
• Horses: IM, IA
• Dogs: non-infectious degenerative or traumatic arthritis or osteoarthritis: IM
• Cats: chondroprotective: IM
• Rabbits: arthritis: SQ or IM
• No human-labeled products

• Rx veterinarian
• GAG in PSGAG is mostly chondroitin sulfate w/3-4 sulfate esters per disaccharide unit
• Molec. weight of PSGAG for Adequan is 3,000-15,000 daltons
• Mechanism
  • Inhibit serine proteases (play a role in Il-L mediated degradation of proteoglycans and collagen)
  • Inhibit synth of Prostoglandin E2 (which increases loss of proteoglycan)
  • Stimulate synth of protein, collagen, proteoglycans, hyaluronic acid
• IM injection (rabbit): max concentration after 20-40 minutes
  • Drug distributed to all tissues, inc. cartilage, lungs, eyes, spinal cord, heart, and brain
• Binds ot serium proteins in blood at 30-40%
• Diffuses from synovial fluid to cartilage (relatively low molecular weight), where it's deposited into cartilage matrix
• Metabolism
  • In rabbits: liver, spleen, bone marrow, may also be in kidneys
  • If not protein bound, excreted mainly by kidneys (some in feces)
• Toxicity
  • At high concentration (50mg/kg): increased prothrombin time, decreased platelet count, increased ALT and cholesterol, increased weights of liver and kidney (latter 2 also at 15 mg/kg)
    • Microscopic lesions at liver, kidneys, lymph nodes (at 15 mg/kg and 50 mg/kg)
  • IM inflammation, hemorrhage, and degeneration dose-related; at 5mg/kg, 15, and 50
  • Normal dose is 2mg/lb (4.4mg/kg)
• Contraindications
  • Hypersensitivity to PSGAG
  • Bleeding disorders (PSGAG is synthetic heparinoid)
• Supplied in 5mL multiple dose vials, by Elanco
• UNII: 268AW7000T
• NDC: 58198-0975
• Inactive ingredients

• PSGAG: repeat chain of hexosamine and hexuronic acid
• Extracted from bovine trachea for commercial use
• Preferentially taken up by osteoathritic cartilage
• Inhibit enzymes that damage cartilage matrix
  • Also increase synovial fluid viscosity
  • Reduce inflammation by inhibiting release of prostaglandin (released at joint injury)
• Use: noninfectious degenerative/traumatic joint dysfunction/lameness in horses' carpal joints
  • And degenerative joint disorders in dogs
  • And lameness in swine
• Can use amikacin w/intraartcular injection to prevent inf

• Cartilage matrix in joints = proteoglycan complexes, collagen, water
• Proteoglycan complexes: protein core + glycosaminoglycan side chains (keratin, chondroitin sulfate)
  • Attached to a strand of hyaluronate
    • Hyaluronate works as "boundary lubricant" of soft tissue and as barrier btw blood vessels of sonival membrane and synovial cavity
  • GAG: "polyanionic", adjacent side chains are pushed away → "bottle brush" of side chains
  • Water is trapped in these complexes → can compress
  • Exchange of stuff from chondrocytes and synovial fluid due to pumping action, which results from normal movement (when moving your joints)
    • Under "mechanical load": products of metabolism of chondrocyte are pushed out into fluid
    • Pressure relieved → fluid goes back into chondrocytes, bringing substrates and shit
  • Intersperesed with collagen fibers

• Degenerative joint disease: start losing proteoglycan, which exposes collagen fibers and chrondrocytes to mechanical stress
  • Damaged matrix has increased water content, damaging normal nutrient exhange btw chondrocytes and synovial fluid
  • Which makes it harder for chondrocytes to repair what damage they can
  • And matrix continues to be lost, and cartilage loses more capacity to withstand stress
  • Collagen network collapses irreversably, and lose function of joint
  • Softening/thickening oc cartilage → cartilage bexomes thinner → cartilage fragments and thickness lost → "marginal osteophyte formation" → "sclerosis of the subchondral bone, bone lysis, and lost of joint space"
  • Quality/quantity of hyaluronate decreased
    • Lowers viscosity of synovial fluid
    • Increases friction; WBCs and enzymes enter synovial fluid and reach cartilage
  • Inflammation
    • Prostaglandin E2: longer vasodilation, increased blood vessel permeability, reduce threshold of pain receptors, negative effect on PG metabolism

• Enzymes released in response to injury destroy parts of cartilage matrix
  • inc. lysosomal elastase, cathepsin B1, cahepsin G, hyaluronidase, serine protease, neurtral metalloproteinase

• PSGAG molec weight: 10,000–12,000 daltons
  • Chemically close to glycosaminoglycans in cartilage, and related to heparin
  • Affinity for deposition into cartilage, esp. damaged cartilage

• Excreted by kidneys, only partially breaks down active drug
• LD50 over 1000 mg/kg (IV, dogs)
• Mechanism
  • PSGAG caused more chondrocytes to be synthesized
  • Decrease in chondrocyte-death caused by steroids
  • Inhibits the enzymes that are released in response to injury of joints that are listed above
    • Inhibits dissociation of PG and hyaluronate caused by lysosomal enzymes
    • Inhibits ability of cathepsin B1 as collagenase
    • Inhibits neutral proteases as proteoglycanase
    • Inhibits collagenase from being activated from inactive state
  • Inhibits loss of PGs from cartilage
  • Decrease inflammation → synovial fluid restored to normal
    • Increase viscosity and decrease protein concentration in fluid
    • Decreased infl → decreased pain (pain in degenerative joint disease very dependent on inflammation of of soft tissue)
    • Inhibits synth of prostaglandin E2
    • Inhibits complement reaction (part of infl response)
    • Inhibits clotting system (blood coag → fibrinolysis, cell lysis, contributing to local inflammation)
  • Chondroprotection

• Adequan approved for horses in US in 1984

• Australia: category D
  • Contraindicated during pregnancy and 1 month prior to conception

• US: category C
  • Only use during pregnancy if there are no alternatives and benefits outweigh risks

• Teratogencicity (embryotoxicity and skeletal malfmormations) in pregnatn rats and rabbit
• Alb and metabolites excreted into breast milk
  • But little was absorbed systemically, WHO says it's ok with breastfeeding

• [5-(Propylthio)-1H-benzimidazol-2-yl]-carbamic acid methyl ester
• Uses
  • Neurocysticercosis
    • From Cysticercus cellulosae, larval form of pork tapeworm (Taenia solium)
  • Hydatid disease
    • Of liver, lung, and peritoneum by larval form of dog tapeworm Echinococcus granulosus
    • Of alveoli by Echinococcus multilocularis in cases where can't remove surgically
  • Ascariasis
    • By Ascaris lumbricoides
  • Baylisascariasis
    • By Baylisascaris procyonis
    • Tx within 1–3 days of infection
    • Helpful to use corticosteroids as well in cases of ocular and CNS infections
  • Enterobiasis
    • Caused by pinworm Enterobius vermicularis
  • Filariasis
    • By Mansonella perstans
    • Can include antihistamines or coticosteroids to decrease allergic reactions from disintegration of microfilariae from tx
    • By Wuchereria bancrofti or Brugia malayi
      • As possible adjunct to ivermectin
      • Suppresion of microfilaremia caused by these orgs
    • Reduce microfilarmia in treating loiasis by Loa loa
      • As possible adjunct or replacement to Diethylcarbamazine when that isn't working or can't be used
  • Hookworm (cutaneous larva migrans – creeping eruption by larva)
    • By dog and cat hookworms
      • For eosinophilic entercolitis by dog hookworm Ancylostoma caninum
    • By intestinal hookworms Ancylostoma duodenale or Necator americanus
  • Toxocariasis (visceral larva migrans)
    • By 'dog or cat roundworms (Toxocara canis or Toxocara catis)
    • Can add corticosteroids in severe cases of cardiac, ocular, or CNS involvement or inflammation; might need Sx for secondary damage
  • Strongyloidiaseis
    • By threadworm Strongyloides stercoralis
    • As alternative to ivermectin
  • Trichostrongyliasis
    • By Trichostrongylus
    • As alternative to pyrantel pamoate
  • Trichuriasis
    • By whipworm Trichuris trichiura
    • As alternative to mebendazole
  • Capillariasis
    • By Capillaria philippinensis
    • As alternative to mebendazole
  • Gnathostomiasis
    • By Gnathostoma spinigerum
    • With or without Sx removal
  • Gongylonemiasis
    • By Gongylonema
  • Oesophagostomiaeis
    • By Oesophagostomum bifurcum
  • Trematode (fluke) infections
    • By Chinese liver fluke Clonorchis sinensis
  • Giardiasis
    • Alternative or adjunct to metronidazole
    • Can be especially useful in children
  • Microsporidiosis
    • By Encephalitozoon intestinalis
    • Ocular microsporidiosis by E. hellem, E. cuniculi, Vittaforma cornae
      • Conjuction with topical fumagillin for fist 2
    • Disseminated microsporidiosis by E. hellem, E. cuniculi, E. intestinalis, Pleistophora, Trachipleistophora, Branchiola vesicularum

• Cautions
  • Teratogenic effects in rats and rabbits
  • In treating neurocysticercosis
    • Can cause CNS effects such as seizures or hydrocephalus due to inflammatory rxns due to intracerebral cysts caused by tx
    • Destruction of cysticercal lesions can cause retinal damage
  • Distributed in animal milk; unknown if distributed in human milk

• Interactions
  • Cimetidine: increase concentration of albendazole in bile and cystic fluid if treating hydatid cysts
  • Dexamethasone: increase albendazole trough concentrations
  • Praziquantel: incrases plasma and AUC concentrations of albendazole
  • With extrahepatic obstruction: increased serum concentration and half-life of albendazole sulfoxide

• Pharmakokinetics
  • Low aqueous solubililty, so poor absorption from GI tract
  • Converted to active metabolite albendazole sulfoxide (which actually does antihelminthic activity) before reaching systemic circulation
    • Further metabolized to albendazole sulfone and other primary oxidative metabolites
  • Wide distribution and detected in urine, bile, liver, cyst wall, cyst fluid, and CSF
  • Detect <1% of albendazole sulfoxide in urine (also excreted in bile). Albendazole not detectable in urine

• Chemistry/mechanism
  • Benzimidazole derivative
  • Binds to beta-tubulin of parasites much better than beta-tubulin of mammals
  • Doesn't inhibit glucose uptake in mammals

• Alb sulfoxide (aka alb. oxide) also known as ricobendazole

• Side effects
  • More than 10%
    • Headache
    • Abnormal liver function
  • 1–10%
    • Abdominal pain
    • Nausea/vomiting
    • Dizziness/vertigo
    • Increased intracranial pressure
    • Meningeal signs
    • Alopecia (reversible)
    • Fever
  • Less than 1% can include:
    • Rash/hives
    • Agranulocytosis
    • Aplastic anemia
    • Bone marrow suppression
    • Granulocytopenia
    • Pancytopenia
    • Thrombocytopenia
    • Hepatitis
    • Acute liver failure
    • Acute renal failure

• Pregnancy category C
• Lactation: unknown
• Mechanism
  • Degenerates microtubules in cytoplasm of intestinal and tegmental cells of helminths

• Pharmacokinetics
  • Absorption: less than 5%, can increase up to 4–5 times w/fatty meal
  • Distribution: Well inside hydatic cysts & CSG
  • Protein bound: 70%
  • Metabolism: hepatic (rapid sulfoxidation [major], hydrolysis, oxidation]
  • Half-life: 8–12 hours
  • Peak plasma time: 2–5 hrs
  • Excretion urine (less than 1% as active metabolite), feces

• Forms
  • 200mg tablet (brand name Albenza)

• Contraindications
  • Grapefruit (can increase chance of side effects)
  • Limit alcohol (since can cause liver problems)

• Store
  • Keep away from light and moisture

• Side effects: abdominal pain, diarrhea, nausea, dizziness, headache
• Has been used for cryptosporidiosis, isosporiasis, microsporidiosis
• Interactions
  • Antiepileptics phenytoin, carbamazepine, and phenobarbital all made alb be oxidized, so that reduce concentration of albendazole sulfoxide in plsamsa

• CYP3A4 converts to inactive metabolite albendazole sulfone
  • Diff species produce diff enantiomers; humans mostly produce R(+) enantiomer

R(+) by microsomal flavin monooxidase

• S(-) by cytochrome P450 CYP3A and in the gut epithelium
• Enzymes (mainly CYP3A4) convert alb sulfoxide to alb sulfone
• In pts with neurocyst., albendazole R(+) sulfoxide accumulates more in CSF than S(-)
• R(+) more active agasint Taenia solium than S(-)
• Pharmakokinetics differ a bit btw men and woman
  • Oral clearance and volume of distribution lower in women
  • Serum peak concentration lower in men

• Food enhances oral bioavailability
  • (Presumably) stimulates gastric acid secretion, and alb, absorption is pH-dependent

• Alb. sulf crosses BBB and is in CSF at 43% of plasma levels (though differs btw indivs)
  • Can penetrate CNS, so can treat neurocyst.

• Side effects
  • Most common: transient liver fxn abnormalities (less than 20%) and alopecia (5%)
  • Bone marrow toxicity is rare but irreversible

• Cimetidine: inhibits absorption bc reduces gastric acicidity
  • But also inhibits metabolism of alb. sulfoxide by interfering with CYP3A4 enz, so prolongs elmination half-life from 7.4 hours to 19 hours

• Grapefruit: inhibits metabolism of albendazole in intestinal mucosa
• Long-term admin of ritonavir (CYP3A4 inhibitor) decreased AUC and Cmax of alb.

• Most species have more (+) alb sulfoide than (-)
  • (-) is depleted at faster rate

• Alb sulfoxide has an oxidized sulfur that makes the chemical more water-soluble
• Alb sulfoxide crosses BBB and placenta in humans
• alb sulfoxide is more water soluble due to oxidized sulfur atom
• alb → alb sulfoxide
  • Cytochrome P450 and flavin-monooxygenase
  • FMO mainly produce +, while cytochrome P450 isoenzymes 2C6 and 2A1 mainly produce - (rat liver)

• Ruminants: metabolism on GI tract due to gut microflora
  • Liver; oxidative metabolism
  • GI: reduction of foreign compounds, especially those w/nitro and sulfoxide groups (so alb sulfoxide → alb)
  • (+) version was used up more

• (-) alb sulfoxide has lower pharmacological activity, leaves blood faster

• Britain approved for cattle and sheep
• Oral absorption: 20–30% in rats, 1–5% in humans, 50% in cattle
• Very rapid 1st pass metabolism in all species, so that can't reliably detect unchanged drug in plasma
• Eat with fatty food: alb dissolved better in lipids
• Metabolism of albendazole by cytochrome P450 oxidases and other flavin-containing oxidases
  • P450 1A1 and 3A4
  • P450 enzymes make (-), while flavin enzymes (flavine-adenine-dinucleodtide monooxygenase) make (+)
  • P450 isozymes then make alb sulfone

• First approved for human use in 1982
• Not recommended in kids under 6
• Approved in Britain for cattle and sheep, inc. pregnant animals and their young
• Oral absorption
  • Rats: 20–30%
  • Cattle: ~50%
  • Humans: 1–5%

• Very fast 1st pass metabolism in all species, so can't reliably detect unchanged drug in plasma
  • Plasma levels of sulfoxide and sulfone are much higher

• Peak levels of albendazole and of alb sulfoxide is 2–3 hours (in humans, rats, and sheep)
• Half life of alb sulfoxide
  • 8–12 hours in humans

• Only the metabolites are excreted (since drug is very extensively metabolized); largely in bile
• Alb sulfoxide has a chiral center
  • Cytochrome P450 oxidases makes (-), flavin-containing oxidases (+)
  • (+) is the main one in human plasma and dogs
    • Humans: 80:20 ratio of +:-
    • Dogs: 70:30
    • Rats is around the same: 59:41

• The + is make by oxidation by a flavine-adenine-dinucleotide monooxygenase
  • The - is makde by P450 enzyme

• P450 isoenzymes convert alb sulfoxide to alb sulfone
• P450 1A1 also involved in alb → alb sulfoxide

• Drug interactions
  • Carbamazepine: decrease (+)-alb. sulf AUC by 49% and Cmax by 50–63%
  • Phenobarbitol: decrease (+)-alb sulf AUC by 61% and Cmax by 50–63%
  • Phenytoin: decrease (+)-alb sulf AUC by 66% and Cmax by 50–63%
  • Cimetidine: increase plasma concentration of alb sulf, and t_(1/2 beta) from 7.4 h to 19 h
  • Dexamethasone: increase alb suf plasma concentration by 50%
  • Levamisole: decrease alb sulf AUC by 75%

• Pharmakokin
  • Better oral absorption than other benzimidazole carbamates

• Used for
  • Alternative therapy to Ocular larvea migrans p685
  • Single dose to eliminate most Ascaris p844
  • Highly effective vs. T. trichiura when given with ivermectin

• Bind to microtubules: interfere w/nutrient uptake and cell division (microtubules needed to form spindles for nuclear division in parasites)
• Microsporidia
  • Only place where microtubules are made is in intranuclear spindles. No spindles → no chromosome segregation → clumped chromatin
  • Alb changed sporogeny; also resulted in spores w/o developed inner concent, polar tubules extruding from parasitoporous vacuoles

• Pharmacokin
  • Main factors for absorption: gastric pH, intestinal degradation
  • Gastric pH
    • On empty stomach, absorption varies a lot from person to person (diff gastric pHs)
  • Intestinal degradation
    • Degraded in small intestine lumen by cytochrome P-450 enzymes in the vili

• As one one of the first treatments
  • A. lumbricoides (roundworm)
  • E. vernicularis (pinworm/threadworm)
  • A. duodenale
  • Cysticercosis (pork tapeworm larval stage)
  • E. muiltilocularis (hydatid disease)

• As alternative
  • Trichuris trichiura (whipworm) alt to mebendazole
  • Strongyloides stercoralis (alt to thiabendazole)
  • A. braziliense: alt to thiabendazole)
  • Beef & pork tapeworms: alt to niclosamide or praziquantel

• Structures of alb → alb sulfoxide → alb sulfone
• Microtubule destruction: vesicles can't transport, intestinal cells can't take up glucose (parasite starves)
• Pharmacokinetics
  • alb → alb sulfoxide → alb sulfone and 6 other inactive metabolites
  • 2 pathways of alb → alb sulfoxide (sulfoxidation)
    • Flavin-containing mono-oxygenase system (oxidized alb via NADPH-dependent reaction)
    • Cytocrome P450 oxidizes alb sulfoxide to alb sulfone
  • given albendazole: AUC ratio of (+) to (-) alb sulfoixide is 80:20
    • Higher levels of (+) in plasma
  • alb is 89–91% protein bound; alb sulfoxide is 63–65%
    • High protein binding of alb doesn't mean much, since converted to alb sulfoxide so quickly
  • Find alb sulfoxide in CSF after oral alb]

• Interactions
  • Dexamethasone: presumably impaired elimination of albso, so albso levels in plasma increased by 50%
  • Praziquantel: AUC of albso incraseased 4.5-fold

• High therapeutic index
  • Possibly bc low solubility, so can't absorb enough to be toxic
  • 6–11% patients get headache, nausea, vomiting (most common SEs), due to acute inflammation to to sudden destruction of cysticerci
  • High doses of over longer periods of time (1 mo): elevated liver enzymes, headache, hair loss, neutropenia, fever, rash, acute renal failure
  • Possibly hepatoxicity, independent of albso levels

• Forms
  • 1996 OK'd by FDA against parenchymal NC
  • Oral suspension or 200mg or 400mg tablets
  • Common brand names: Zentel, Eskazole, Albenza

• In worms, blocking microtubules disrupts uptake of glucose
• So energy blocked, and worms are paralyzed and die or are expelled
• Also disturb cell division, so worm egg production and development also blocked (i.e. have ovicidal effect)
• Blocks fumarate reductase, enz in helminths that works in energy management
• Overdose signs/symptoms
  • Most effects on liver, testicles, and GI tract
  • Lethargy, loss of appetite, intestinal cramps, nausea, diarrhea, vomiting
  • Also dizziness, convulsions, sleepiness
  • No specific antidote

• Warnings
  • Pregnant dogs: reduce weight of puppies and cause cleft palate
  • Birds: reduce egg-laying and hatching

• Pharmacokinetics
  • Metabolized into sulfoxide derivative, which is also sold as ricobendazole
  • Ruminants: part of sulfoxide produced released back into rumen, where microbial flora reduces it to albendazole; increasese bioavailability
  • Ruminants: 60–70% excreted as metabolites in urine
  • Sheep: 14% excreted as bile as active metabolites, so helps work in bile ducts as well
  • Cats, dogs, birds: no rumen reservoir, so greatly shortens residual effect; might need higher dose or more frequent treatment
    • Dogs: alb. sulfoxide detectable in plasma for less than 12 hours
    • Sheep and goat: alb. sulfoxide detectable in plasma for ~3 days

• Completely ineffective vs. external parasites
• The only benzimidazole than can be injected and also is available for drenching
• Used a lot in ruminants in some countries (those in Latin America) but not elsewhere
• All benzimidazoles have no residual effect (unless: kill within a few hours, but don't protect much against reinfestation
• Dogs, cats, cattle, sheep, goats
• Oral LD50: 2400 mg/kg (rats)
• Dermal LD50: not found
• Can be teratogenic

• Developed in 1973
• Not actually approved for use in cats and dogs
• Broadest spectrum of the benzimidazoles
• Dogs and cats
  • Filaroides hirthi (nematode)
  • Paragonimus westermani, P. ohirai, P. kellcotti (trematode)
  • Pneumocystis carinii (w/trimethoprim)
  • Encephalitozoan cuniculi
  • Toxacara canis, catis
  • Trichinella apiralis

• "Valbazen"
• Anti-parasitic
  • Benzimidazole

• Inhibits glucose uptake in parasites
• For:
  • Intestinal helminths
    • Capillaria aerophilia, Paragonimus kellicotti, Aelurostrongylus abstrusus, Filaroides sp., Osterus osteri
  • Parasites in respiratory system
  • Giardia in small animals
  • Horses: Dictyocaulus amfieldi, Strongylus vulgaris
  • Cattle and sheep as antiparasitic

• Associated w/bone marrow suppression/toxicity in dogs and cats at high doses
  • Other species have high margin of safety

• Side effects: anorexia, lethargy, bone marrow toxicity
  • More likely when longer than 5 days

• 113.6 mg/mL suspension and 300 mg/mL paste
• Don't use in 1st 45 days of pregnancy
• 27 days cattle withdrawal time for meat

• "Albenza", "Valbluzen"
• aka albendazolum
• Non-lactating cattle:
  • Osteragia ostertagi
  • Haemonchus spp
  • Trichostrongylus sp
  • Nematodus sp
  • Cooperice sp
  • Bunostomum phlebotomum
  • Oesphagostum
  • Dictacaulus vivaparous (adult and stage 4 larva)
  • Fasciola hepatica (adult)
  • Moniezia

• Sheep
  • Ostertagia circumcinta
  • Marshallagia marshalli
  • Haemonchus contortus
  • Trichostrongylus
  • Nematodus
  • Cooperice
  • Oesphagostomum
  • Chibertia ovina
  • Dictacaulus filaria
  • Fasciola hepatica
  • Fascioides magra
  • Moniezoa expanse
  • Thysanosoma actinoides

• Cats
  • Paragonimus kellicotti
  • Capillariasis
  • Platynosum
  • opisthorchidoe

• Dogs
  • Filaroides
  • Capillariasis
  • Leishmaniases

• Rabbits
  • Encephalitozoon phacoclastic uveitis
  • E. cumiculi

• Chinchilla
  • Giardia

• Birds (ratites): flagellate parasites and tapeworms
• Extra-label in small mammals, goats, pigs for endoparasites
• Mech
  • Bind to tubulin and damage, prevent tubulilne polymerization, inhibit microtubule formation
    • Total: disrcupt intracellular microtubule transport systems
  • At higher concentrations:
    • Disrupt metab paths in helminths
    • Inhibit metabolic enzymes (inc. malate dehydrogenase and fumarate reductase)

• Pharmacokin
  • Better oral absorption than other benzimidazole

• Side effects
  • Dogs: anorexia
  • Cats: lethargy, depression, anorexia

• FDA cat C for pregnancy
• Doses @30x normal → cattle dies
• Doses @20x normal → sheep dies
• Drug interactions
  • Cimetidine (increase alb in bile and cystic fluid)
  • Dexamthasone (increase alb in serum)
  • Praziquantel (increase alb in serum)

• Have alb oral 200mg tablets for humans (Rx)
  • Albendazole suspension/paste both OTC

• (In humans:)
• Alb → alb sulfoxide
  • Flavin-containing monoxygenase and CYP3A4

• Alb sulfoxide → alb sulfone
  • CYP

• Also have alb sulfone → 2-aminosulfone, gamma-hydroxysulfone, and beta-hydroxysulfone

• Mech
  • All microtubule functions are inhibited: cell division, maintaining cell shape, cell motility, nutrient absorption, intracellular transport
  • Binds much better to parasite tubulin than mammalian tubulin (so wide safety margin in mammals(

• In ruminants, sulfoxide can be turned back to normal albendazole in GI tract
  • Preference for turning (+) back over turning (-) back

• Absorption depends on lipid solubility and degree of ionization at GI pH levels, since mucus surface of GI tracts acts as lipid barrier agasint absorption
• (+) sulfoxide, compared to (-):
  • Longer in bloodstream
  • Higher concentration in tissues/fluids where parasites are
  • Higher concentration within parasites
  • Higher nemotidicidal activity

• Drug of choice
  • A. lumbricoides (single dose)
  • E. vermicularis
  • Necator americanus,A. duodenale (single dose)
  • S. stercoralis
    • Can be given with diethylcarbamine to lower microfilaremia level
  • T. trichiura (once)
  • Trichinella spiralis
  • E. granulosis (hydatid cysts), E. multilocularis, hepatid hydatid disease
    • Possible adjunct to sx
• Alternative
  • Loa loa
    • Slowly reduce microfilarial level by having embryotoxic effect on adult worms

• One of drugs of choice
  • A. lumbricoides
  • Hookworms:A. duodenale, Necator americanos
  • Pinworm (E. vermicularis)
  • Trichinella spiralis
  • Neurocysticercosis
  • Hydatid disease (E. granulosus, E. multiocularis)

• Alternative
  • S. stercoralis (alt to ivermectin)
  • Whipworm T. trichiura: alt to mebendazole
  • Filaria by W. bancrofit and B. malayi
  • T. saginata and solium (alts to praziquantel for solium, praziquantel or niclosamide for saginata)

• Originally made as veterinary antihelmintic
• Registered for humans in 1982
• Insoluble in water, so haven't developed parenteral preparations
• Antimicrobial activity
  • Very broad spectrum
  • Works against most human nematode and cestodes species; less against trematode species

• Mechanism
  • Beta tublin
  • Loss of cytoplasmic microtubules prevents eggs from hatching

• Pharmacokin
  • Drug absorption not needed for intestinal infections
  • Systemic parasites: albendazole acts as the prodrug, and albendazole sulfoxide is the active drug
  • A bit of alb sulfoxide (0.09–0.88%) excreted in urine in humans (minor elimination pathway)
    • Mostly excreted in bile
  • Liver: flavin monooxygenase and cytochromes P450 (mainly CYP3A4) to S(-)
  • R(+) by microsomal flavin mixed function oxidases
  • Some production of S(-) in gut epithelium
  • Alb sulfoxide oxidized to alb sulfone mainly by CYP2C (in rat livers, but thought to be the same as in humans)
  • 5 major metabolites excreted by humans;
    • methyl [5-(propylsulfonyl-1H-benzimidazol-2-yl)] carbamate
    • methyl [6-hydroxy 5-(n-propylsulfonyl)-1H-benzimidazole-2-yl)] carbamate
    • methyl [5-(n-propylsulfinyl)-1H-benzimidazole-2-yl)] carbamate
    • 5-(n-propylsulfonyl)-1H-benzimidazole-2-yl amine
    • 5-(n-propysulfinyl)-1H-benzimidazole-2-yl amine
  • And some minor hydroxylated sulfated or glucuronidated derivatives

• Interaction with cimetidine
  • Previously thought to increase bioavailability
  • Now know that doesn't
  • Does inhibit albendazole sulfoxide breakdown

• Uses
  • "Generally considered to be the tx of choice for single and mixed infections with the common intestinal nematodes"
  • Systemic infections: need longer dose regimen
  • Alveolar echinococcosis
    • Most cases, is just parasitostatic; some suggest that tx should be lifelong if no toxicity (same for cystic echinococcis)
    • Used w/surgery
  • Capillariasis
  • Gnathostomiasis
    • Similar effectiveness to ivermectin, but ivermectin dosing is easier (2 days versus 21 days)
  • Trichinosis
    • Eliminates intestinsal adults and migrating larva that were responsible for symptoms
    • T. spiralis and T. pseudospiralis
    • Similar efficacy to thiabendazole, but lower side effect rate
  • Toxocariasis
    • Better at reducing eosinophilia than thiabendazole
  • Loaiasis
    • Loa loa (eye worm)
  • Monsenellosis
    • M. perstans
    • Works agasint adult worms but not agasint microfilariae

• Drug interactions
  • Dexamethasone: Trough concentrations of alb. sulfoxide increase by 56%
  • Praziquantel: increase max plasma concentration of alb. sulfoxide by 50%
  • Cimetidine: in patients being treated for hydatid cysts, increase alb. sulfoxide concentrations in bile and cystic fluids by 2-fold
  • Theophylline: Al. induces cyotochrome P450 1A in human hepatoma cells; monitor theophylline plasma concentrations

• Warning/precaution
  • Bone marrow supression
    • Granulocytopenia or pancyotpenia by alb, can cause bone marrow supression, aplastic anemia, and agranulocytosis
      • Can be fatal
      • Increased risk in those with liver disease and those w/hepatic echinococcosis
  • Teratogenic
  • In treating neurocysticercosis, can cause neuro symptoms
    • Should receive steroids and anticonvulsants together w/alb. to prevent things like seizures, increased intracranial pressure, focal signs caused by inflammatory reaction of parasitic death in brain
  • In treating retina neurocystocercosis, can cause retinal damage
  • Hepatic effects
    • Increase hepatic enzyme concentrations in 16% in patients (return to normal when tx is stopped)
    • Pts w/elevated liver enzymes at increased risk for hepatotoxicity and bone marrow supression
  • Can unmask undiagnosed neurocysticercosis when treating hydatid patients

• Adverse reactions
  • Can differ in those being treated for hydatid diseae vs. neurocysticercosis

• Mechanism
  • Binds to colchicine-sensitive site of beta-tubulin, inhibiting polymerization
  • Parasite resistance due to changing amino acids that make up beta-tubuling, decreasing bindinf of alb.

• Adult liver flukes
  • Fasciola hepatica (cattle, sheep, goats)
  • Fascioloides magna (sheep)

• Tapeworms
  • Moniezia benedini (cattle), M. expansa (cattle and sheep), Thysanosoma actinioides (sheep)

• Stomach worms
  • Ostertagia ostertagi (cattle), O. circumcincta (sheep)
  • Barber pole worm (Haemonchus contortus in both, H. placei in cattle)
  • Small stomach worm: Trichostrongylus axei

• Intestinal worms
  • Thread-necked Intestinal Worm: Nematodirus spathiger (both), N. helvetianus (cattle), N. filicollis (sheep)
  • Small intestinal worm/Cooper's worm: Cooperia punctata, (cattle), C. oncophora (both)
  • Bankrupt worm: Trichostrongylus colubriformis (both),
  • Nodular worm: Oesophagostomum columbianum (sheep), Oesophagostomum radiatum (cattle)
  • Large-mouth bowel worm: Chabertia ovina (sheep)
  • Hookworm: Bunostomum phlebotomum (cattle)

• Lungworm
  • Dictyocaulus viviparus (cattle), Dictyocaulus filaria (sheep)

• Humans: tablets (220mg)
• Vet: oral paste, oral suspension
• Can penetrate CNS and cystic fluid, so choice for infections of these areas
• Dogs
  • Capillaria plica
  • P. kellicotti
  • F. hirth/Oslerus olseri
  • Giardia

• Cats
  • P. kellicotti
  • Platynosum/Opisthorchiidae

• SE
  • More than 10%: anorexia/depression in cats and dogs
  • 1-10%: elevated liver enz, nausea, vomiting, diarrhea in cats and dogs
  • less than 1%" neutropenia and aplastic anemia w/use longer than 5 days in cats and dogs

• Alb sulfoxide is excreted into milk (1.5% of maternal dose). Poor oral absorption, so inlukely to have effect on nursing animals

• Approved for neurocystocercosis and hydatid disease
• Off-label uses galore
  • Inf by A. lumbricoids,Trichuris trichiura, Enterobius vernicualris, Ancylostoma duodenale, Necator americanus, Taenia sp., Strongyloides stercoralis, Giardia
  • Crusted scabies (when combined w/topical crotamiton and salicylic acid)
  • In inf of Pediculus humanus capitis, but ivermectin is much better
  • Balamuthia mandrillaris (cutaneous diseae and granulomatous amebic encephalitis): combo of miltefosine, fluconazole, albendazole
  • Bancroftian filariasis: in combo with ivermectin
  • Taenia crassiceps
• Induces CYP1A2, so monitor theophylline levels

• Alb → albendazole sulfoxide
  • Established as CYP3A4 and flavin-containing monooxygenase (FMO)
  • 2010 study study said recombinant CYP2J2 played a bigger role (yes, sulfoxidation) (???)
• Alb → hydroxyalbendazole
  • Mainly CYP2J2
• Possibly causes infantile eczema when given during pregnancy

• Originally introduced in 1977 in Australia for sheep
• Licensed for humans in early 1980s
• Usually only needs 1 administration for intestinal nematode infections
• Not licensed in US to treat intestinal nematode infection
• Uses
  • Nematodes
    • Ascaris lumbricoides (roundworm) (single dose)
    • Trichuris trichiura
  • Hookworm
    • N. americanus and A. duodenale (single dose)
    • Cutaneous larva migrans
  • Taenis solium, T. saginata (beef tapeworm): praziquantel is better, but albendazole used more in endemic countries bc cheaper and broader spectrum
  • Enterobius vericularis
  • Capillaria philippensis
  • Toxocara canis
  • Trichinella spiralis
    • Works best when given early; acts on adult worms in intestinal mucosa before they make larva that penetrate the muscle
    • Give corticosteroids as well to inhibit infl caused by dying larvae
  • Trichostrongylus (single dose)
  • Gnathostoma spinigerum
  • Filarial nematodes (in combo with DEC or ivermectin)
    • Lymphatic filariasis (W. bancrofti, B. malayi, B. timori)
    • Loa Loa
    • Mansonella perstans

• In neurocysticercosis
  • Works best in pts w/viable cysts in cerebral paenchyma OR when cysticercosis is rapidly progressing
  • Old cysts not affected
  • Check for ocular cysticeri, since then albendazole can cause changes to existing lesions that can cause permanent blindness

• Pharmakocin.
  • Quickly changed to albendazole sulfoxide in liver, which is metabolized more slowly
  • Albendazole sulfoxide metabolized to albendazole sulfone (and other oxidative metabolites0

• Pediatric
  • Teratogenic in rats and rabbit, but found that OK in people in 2nd and 3rd timester

• Drug interactions
  • Cimetidine: reduces gastric acid production or inhibits cytochrome P450-mediated metabolism of albendazole to active metabolite, resuling in lower oral bioavailability
  • Cortcosteroids: increase steady-state plasma concentration of albendazole sulfoxide
  • Praziquantel
  • Theophylline: theophylline induces activity of CYP 1A in hepatoma cells, since also a substrate

• Side effects
  • Most common: abdominal pain, nausea, vomiting headache
  • Much less common: hypersensitiviy (rash, hives), reversible alopecia, leukopenia
  • Rare: agranulocytosis
    • If using for a long time (ex. to treat hydatid disease), can increase hepatic enzymes (stops when med stops)

In liver, is acetylated to acetyl.sulfadimethoxine, and excreted like that in bile

• Dogs don't metabolize it in liver: filtered out by kidneys
• Has good reabsorption in the renal tubules → longer half-lives
• Dobermans susceptible to sulfonamide-induced poly-systemic immune complex disease (contraindicated)
• Sulfadimethoxine/ormetoprin
  • FDA-approved for skin and soft tissue infections in dogs caused by S. aureus or E. coli
  • Sulfadimethoxine alone would be bacteriostatic; together with ormetoprin is bacteriocidal

p836

• Also spelled sulphadimethoxine

p845

• Long-acting sulfonamide, alone or w/ormetroprim (as ormetoprim-sulfadimethoxine)
• In cattle, pigs, horses, poultry, fish, dogs, and other vert/inverts
• 1/2 life of 13.1 hours in dogs

p857

• Combined with ormetoprim for better antimicrobial activity
  • "Rofenaid", to give to chickens and turkeys for food – prevent coccidioisis by Eimeria and fowl cholera
  • "Romet" for furunculosis in salmon and trout (food animals)
  • "Primor" for dogs for skin/soft tissue inf, urinary tract inf, and intestinal coccidia inf
  • Nothing commercially available for cattle, though still used to treat pneumonia

1169

• Only FDA-approved drug for intesinal coccidioisis in dogs and cats

• Sulfadimethoxine is one of the sulfonamides that last longer (elimintated more slowly), so can be given fewer times a day
• Ormetroprim is diaminopyrimidine: inhibit dihydrofolate reductase in bact quite well (further in in pathway to make folic acid)
  • "Potentiated" sulfonamide
  • Optimal ratio is usually 1:20 (20 being sulf.), but is sold pharmaceutically as 5:1

• Like all sulfonamides, is most effective at early stages when lots of multiplying, since has more of a bacteriostatic than bacteriocidal effect
• Can sometimes be given IM (sodium sulfadimethoxine)
• Relies on the patient still being able to produce an immune response
• Like all sulfanimides, diffuses easily and reaches a lot of places
• Crystallization in urine can be prevented by adding diaminopyrimidine
  • Not actually common in vet med

• Is one of the three sulfonamides actually allowed in lactating dairy cattle (others are sulfabromethazine and sulfathoxypyridazine)

• Available as: inhaler (oral inhalation aerosol), oral nebulization solution, tablets, extended-release tablets, oral solution
• Contraindications
  • Known hypersensitivity to albuterol (dugh)
  • Hypersensitivity to...
    • soya lectin or related foods (soybeans, peanutes)
    • Atropine and derivatives
  • Caution if have cardio disorder or hypertension
  • Caution with seizures or sensitivity to sympathomimetic
  • Caution w/diabetes mellitus or hyperthyroidism
  • Renal impairment (higher risk of toxicity)
• Adverse effects
  • Acute/worsening asthma
  • Fatality (excessive dose)
  • Acure bronchospasm
  • Cardiovascular effects (atrial fib,., supraventricular tachycardia, extrasystoles), BP changes
  • Hyperesnsitivity reactions (hives, angioedema, rash, bronchospasm, anaphylaxis, oropharyngeal edema)
  • Hypokalemia → cardiovascular effects
• Lactation
  • Unknown if distributed in milk, but does cross across placenta
• Geriatric use
  • No differences, as long as don't have contraindicated disorders
• Interactions
  • B-adrenergic blocking agent → severe bronchospasm in asthmatic patients
  • Digoxin → decrease in digoxin levels in serum
  • Diuretics (nonpotassiuim-sparing) → decreased serum potassium
  • MAOIs → vascular system side effects
  • Sympathomimetics → cardiovascular system side effects
• Metabolism
  • Metabolized by intestinal wall and liver to inactive metabolites
  • But most is excreted by kidneys unchanged (over 70% oral dose within 24 hours)

• Overdose s/s: exaggerated common adverse reactions, esp. angina, hypertention, hypokalemia
  • Can get seizures or cardiac arrest
  • Mild/moderate overdose: tachycardia, hypertension, tachypnea, tremor, agitation, nausea, vomiting, hypokalemia, hyperglycemia
  • Severe overdose: hypotension, dusrhythmias, seizures, acidoses
• Most frequently reported side effect: tremor
• Still, poisoning is uncommon and "rarely results in serious morbitity or death"
• Pharmacokinetics
  • Volume of distribution: 2L/kg

• Can cause maternal and fecal tachycardia
• Major decreases in maternal BP (dropping by 30)
• Maternal adverse effects inc. acute congestive heart failure, pulmonary edema, death
• Can cause temporary hyperglycemia, then increase in serum insulin in both mother and fetus (like all B-mimetics)
  • Insulin in cord blood are 2x if get albuterol
  • More pronounced in diabetes pts
• Again, like all B-mimetics, increases chance of neonatal respiratory distress syndrome
• Long term in utero exposure assoc. w increased chance of: autism, psychiatric disorders, poor cognitive function, poor motor function, poor performance in school, elevated HR, hypertension
  • "Genetic predisposition for toxicity"

• Toxic via inappropriate dosing or pets biting into inhalers or vials for nebulizers
• Brand names: Proventil, Ventolin, Combivent (when combined with ipratropium)
• Dogs more common in overdosing (again, inhaler chewing)
  • Greyhounds possibly more susceptible to severe cardia arrhytmias
• Acute onset of panting, vomiting, anxiety, tremor, weakness, leghargy
• At overdose levels, not very selective for beta-2, so has excessive beta-1 and beta-2 actividy
  • Beta-2 toxic effects: "hypotension, reflex sinus tachycardia, arrhythmias; tremors from stimulation of receptors in skeletal muscles; vomiting; intracellular shifting of Ka and P secondary to increased ATP enzymes, and respiratory alkalosis from panting
  • Beta-1 toxic effects: "positive inotropic effects on the heart, tachychardia, hypertension, restlessness, anxiety"
  • Secondary myocardial damage and hypokalemia can also → arrhythmia
  • Aerosilized inhalers often have hydrocarbons as propellant → sensitive myocardium and increase risk for arrhythmias
  • Weakness due to hypokalemia and prolonged tachycardia
• Treatment
  • Beta blockers for tachycardia
  • Possibly K, but can have rebound hyperkalemia if give too much
  • Benzos for tremors/stimulation
  • Can't have induced emesis or activated charcoal if in liquid or syrup form (or inhaled), bc absorbed too fast (can still do for tablets)
• Muscle weakness → collapse in dogs after a few hours, due to severe hypokalemia
• Excellent prognosis for recovery

• "Torpex"
• Aeorsol or oral tablets in dogs, cats, and horses as bronchodilator and to alleviate bronchospasm or cough
• Pharmacokinetics
  • pKa of 9.3; so mostly in ionized form at physiological pH
  • Absorption from oral form is limited; is faster and absorbs completely from inhaled form
  • Inhalation lasts 1–7 hours; oral lasts up to 12 hours (half life of oral is 3–5 hours)
  • Metabolized in liver to 4'-O-sulfate, which is excreted in urine

• "Ventolin"
• Relaxes uterine and vascular smooth muscles
• Potassium effect by stimulating Na-K-ATPase
• For cats and dogs: bronchospasm relief; for horses: bronchodilation
• Crosses placenta
• Can enter CNS, with 5% concentration in brain as of that in plasma
• Metabolized in liver to inactive 4'-O-sulfate
• Contraindicated by hypersensitivity to albuterol.
  • Use caution with inhalatant anesthetics, during pregnancy, and in ps w/diabetes, hypertheyroidism, and heart disorders
• Drug interactions
  • Can develop tolerance, so bronchodilation effects can be increased by giving methylxanthine such as aminophylline
  • Antagonizes dinoprost and oxytocin
  • Use with other sympathomimetic drugs → more likely to have cardiovascular side effects
  • Betra-adrenergic blockers inhibit action of albuterol
  • MAOIs and tricyclic antideprresants can incraese pressor effects
  • Use w/digitalis can cause cardiac arrthymia
  • Use with inhaled anesthesia (that's halogenated hydrocarbon) can increase cardiac arrhythmia

• Short-acting B2 agonists are main med used for acute bronchoconstriction (work quickly)
• Control symptoms, but not inflammation
• Safe for animals - low toxicity
• "Medication of choice in all species for inhalation therapy of acute airway obstruction"
  • Minutes to take effect, last 3-6 hours
• S-albuterol has slower metabolism than R-albutero
  • (applies to ppl as well)
  • So accumulates in lung
    • So assoc. w/increased airway hyperreactivity and pro-inflammatory effects

• Althesin (alfaxalone + alfadone, human version) removed from market in 1984; Saffan (for cats) stayed until alfaxalone
• Saffan
  • Vasodilation → lower BP
  • Kept "cardiac index"
  • histamine release lead to the death of some cats, but Saffan was still less mortal than other anesth, most likely bc less cardiac depression
  • Was used in cats and other domestics and exotics (just not dogs)
• Alfaxalone
  • Smooth and rapid
  • Recovery better when premedicated
  • Pre-med certain med + alfaxalone, then anesthesia via CRI alfaxalone:
    • Buprenorphine + Acepromazine
    • Buprenorphine + Dexmedetomidine
    • 2nd required much less alfaxan as CRI
  • Alf can use IM: was done routinely w/cats
  • Used in exotics: red-eared turtles, axolotl, green iguana, marmosets
  • Larger animals: horses, sheep

• Alfaxalone doesn't provide analgesia, so required additional stuff to be on board (usually opioids, NSAIDs, nerve blocks, and/or NMDAR-antagonist)
• Sx less than 30 min can use only injectable anesth
• Common anesth combos for general anesth in cats:
  • Premed: acepromazine + opioid, induce: alfaxalone + diazepam, maintain: iso or sevo
  • Premed: medetomidine or dexmedetomidine + opioid, induce: alfaxalone, maintain: iso or sevo
  • Premed: ace + opioid, induce: alfaxalone, maintain: alfaxalone
• Saffan caused histamine release, but was still 3 times less likely to kil cat than any other anesth method at the time
• Need less alfaxalone for induction if dilute with sterile water, possibly by being able to administer more slowly

• Advantages of alfaxalone over other induction agents
  • Safe (was shown to be safe when given to dogs at 5xdose IV)
  • Doesn't accumulate bc metabolized and cleared so fast
  • Recovery quickly
  • Doesn't have much respiratory depression
  • Good muscle relaxation
• Derived from progesterone
• Human females recover faster than human males

• Injectable anesth
• By itself is not very soluble in water, so combined with alphadolone initially
• Mech
  • Lower concentrations: affects ion currents through GABAR
  • High concentration: acts as GABA agonist
• Pharmacokin (at 2mg/kg for dogs and 5mg/kg for cats, 1mg/kg for horses)
  • Vol. distriution: 2.4L/kg dogs, 1.8L/kg cats, 1.6 in horses
  • 1/2 life: 25 min in dogs, 45 min in cats, 33 min in hores
  • Plasma clearance (rate): 60 mL/kg/min in dogs, 25 mL/kg/min in cats, 37 mL/kg/min in horses
  • Metabolism
    • Hepatic; both cyochrome P450-dpendent and conjucation-dependent (Phases I and II)
    • Phase I metabolites: same in cats and dogs
    • Phase II metabolites: alfaxalone sulfate and alfaxalone glucuronide in cats, alfaxalone glucuronide only in dogs
    • Metabolites leave via hepatic/fecal and renal routes
• Pharmacodyn
  • CNS
    • Reduce EEG activity
    • Decrease cerebral blood flow, intracranial pressure, cerebral O2 demands
  • Carduivasc
    • At normal levels: quite stable
  • Resp
    • Respiraty depression; apnea most common side effect
    • Cats and dogs: decreased RR, minute volume, spO2
  • Hepatic/renal/GI
    • In Greyhounds, decreased liver blood flow and O2 supply
• Species-specific effects
  • Dogs
    • Increase intraocular pressure
    • CRIs as anesthesia for Sx: worked as anesth, but "significant respiratory depression"
    • Longer recovery than propofol; stuff like paddling, rigidity, vocalizing
    • OK for puppies
  • Cats
    • OK for kitties
  • Horses
    • Induce and maintain anesthesia; CRIs as general anesthesia
    • Shorter induction and same anesthesia time as ketamine, but much longer recovery
  • Ruminant
    • Myosis in sheep
  • Swine
• Recovery: leave in quiet, dark area
  • Can decrease stuff like paddling/hyperreactivity with sedative agents

• Neuroactive steroids
  • Target different GABA A receptors than benzodiazepenes
  • Low concentrations: bind to M3/M4 in alpha subunit - allosteric modification of current
  • High concentrations: "direct gating of GabaA currents", binds to alpha/beta interface near GABA binding site
  • Possibly affect expression levels of GABAa
    • Enhance tonic current but have little effect on phasic currents even after prolonged exposure
    • Research suggests that neuroactive steroids increase GABAa receptors (so harder to build a tolerance, unlike w/benzos)
• Every since progesterone and 5beta-pregnance-3,2-dione reported to have depressant effect on CNS in rodents in 1941, multiple groups searched for synthetic to use as anasthetic
  • Mainly focused on increasing water solubility
  • 1971: Althesin (withdrawn from market in 1984 bc anaphylactic reactions)
  • Phaxan being developed for use in ppl (alfaxalone in cyclodextrin)

• Originally introduced in 70s mixed w/alfadolone (Althesin for ppl, Saffan for animals)
  • Withdrawn bc of severe side effects (histamine release → anaphylactic rxns) caused most likely by solubilizing agent Cremophor EL
• Alfaxalone molecule bound to cyclodextrine to make it water soluble
• Quickly metabolized by liver
• Doesn't cause histamine release
• Rapid onset, short duraction, few side effects
  • Compare use/properties to propofol: alfaxalone doesn't affect cardiovasc
• OK to combine with common premedications
• Europe: registered IV
• Can be given IM though (Aus is IM for cats)
  • IM, unlike propofol
• Controversy: is it an analgesic? Not a signifcant one
• Side effects
  • Give IV slowly, can cause apnea (still less likely than with propofol)
  • Agitated when recover if no pre-meds use
    • Esp. cats; do best when recovering in quiet, dark room
• Dose
  • IV dose "to effect": give enough so you can intubate
  • Dose is lower if use dexmedetomidine as premed; lower still if use opioid
  • Effects peak in 5 minutes
• Used for cesareans: had little to no effect on babies
• Can replace etomidate as induction agent for high risk pts
• Good anesthesia for sighthounds
• No preservantives
  • NZ/AUS labeling says to use contents of vial within 24 hours (or can refridgerate for up to 7 days)
  • UK says use discard any extra at once

• Steroid, but no glucocorticoid or mineralocorticoid action
• Make GABA A receptors in CNS more sensitive to GABA, enhance transport of Cl-, hyperpolarize neuron cell memb
• Rapid metabolism, so few cumulative effects
  • And can use in anesthesia without making recovery longer
• Cardio vasc effects less than that of propofol
  • Increased HR, decreased vascular resistance, decresased myocardial contractility
• Most common use: IV induction of anesthesia before maintaining anesthesia where gas is used
  • Or can use as maintenance agent if want IV anesthesia for entire procedure (ex. bronchoscopy, tracheal laceration, intracranial disease)
• 60s onset
  • Normal dose in dogs give about 10 min anesthesia
  • In cats, normal dise gives around 25
• Cats take longer than dogs to recover
• Not licensed for IM or SQ use in US
  • Both cause longer recoveries, w/agitation and hypesensitive to stimuli
• Excitement in esp. cats when recovering
  • Agitation, paddling, "muscle fasciculations", exag reactions to external stimuli
• Drug interactions
  • OK to use with all normal sedatives used
• More expensive than other induction agents

• Animal use only (in US)
• Administer over 60 seconds or until showing that they're anesthetized – give too fast and increase risk of apnea
• Can give less if also gave premed
• Drug interactions:
  • OK to use with benzos, opioids, alpha2-agonists, phenothiazines, antibiotics, anticholinergics, vaccines, steroids, dewormers
• Contraindicated if sensitive to alfax or anesthesia/sedation
• Anesthetic overdose or if give bolus
  • Can get low BP, apnea, hypoxia, or death
  • Arrhythmia due to apnea and hypoxia
  • Treat cardiovasc depression with plasma expanders, pressor agents, anti-arrhythmic agents, etc.
• Abuse potential similar to other Schedule 4 drugs
• Physical dependence: no data, but mechanism similar to benzos, so assume that dependence and withdrawal same as benzos
• Precautions
  • If use benzo as only premed and then give alfaxan, higher chance of excitation in recovery
  • Decrease body temp
• Pharmakocinetic (5 mg/kg for cats, 2 mg/kg for dogs), in 8 animals each
  • Steady state volume of distribution:: 1.3 L/kg (cats), 2 L/kg (dogs)
  • Half-life: 43 min (cats), 34 min (dogs)
  • Clearance rate: 24 mL/min/kg (cat), 59.4 mL/min/kg
  • Dogs and cats that got only midazolam as premed needed MORE alfax than normal for induction

• Saffan (alfaxalone + alfadolone)
  • Cremphor EL as carrier agent
  • Cats: histamine release → edema and hyperemia in ears and paws; sometimes laryngeal or pulmonary edema'
  • Dogs: absolutely contraindicated (HUGE histamine release)
• "Alfaxan", 'Vetoquinol"
  • Allfadolone not included, since much weaker hypnotic effect than alfaxalone
  • Use: induce/maintain general anesthesia, CRI for longer sedation
  • Side effects: mild cariovasc and resp depression, muscle twitching
  • Contraindications: "inability to secure airway"

• Released for cats and dogs in AUS in 2000, UK in 2007, Central Europe in 2008, Canada in 2011
• Synthetic neuroactive steroid
• IM sedation, IV induction, IV anesth maintenace
• Doesn't inhibit pain, but does muscle relaxation
• Safe; lowered RR and BP when given too much, but not as much as with propofol, iso, or sevo
• Can use in pediatric (under 3 months)
• US says can keep for 6 hours after opening

• Warnings
  • Don't know if safe to use for more than 14 days - potential ototoxicity and nephrotoxicity
  • Neurotoxicity (vestibular and permanebt bilateral auditory ototoxicity) if p had renal damage or if p received higher/longer dose than recommended
    • Renal damage increased risk of aminoglycoside-induced ototoxicity
    • High frequency deafness possible at first
    • Vertigo possible
    • Numbness, skin tingling, muscle twitching, seizures
    • Risk of hearing loss (increases w/increasing peak concentration)
      • No symptom of cochlear damage (due to 8th nerve toxicity) during treatment
      • So can be partially or fully deaf after finish drug
  • Neuromuscular blockade and respiratory paralysis (inc. acute muscular paralysis and apnea) from topical or oral use of aminoglycosides
    • Ca salts can reverse neuromusc blockade
    • Increased risk for pts getting anesthetics or neuromuscular blocking agents (ex. tubocurarine, succinylcholine) or getting large transfusions of citrated-anticoagulated blood
  • Don't use with or sequentally with other neurotoxic/nephrotoxic drugs
    • Dehydration and being old increase risk of tox
  • Avoid using w/potent diuretics bc diuretics can cause ototox, and can change aminoglycoside concentrations, which would also enhance tox
• Aminoglycoside derived from kanamycin
• Uses:
  • Bone and joint infections (serious inf by susceptible gram -)
  • Intra-abdominal infections (serious inf by susceptible gram -)
    • Inc. peritonitis
    • Use as adjunct to clindamycin, metronidazole, piperacillin + tazobactam, ampicillin + sulbactam
  • Meningitis (by gram - bact) as adjunct in initial treatment
    • With ampicillin for neonatal S. agalactiae or Listeria monocytogenes
    • With 3rd generation cephalosporin for neonatal gram- bact meningitis, inc. by E. coli
    • With imipenem in adults for menin by E. coli
    • With meropenem in menin by Pseudomonas
    • With impimenem or colistin for menin by Acinetobacter
  • Resp tract inf (serious, by gram -)
    • As adjunct ot Beta-lactam or carbapenem for treating nosocomial pneumonia
  • Septicemia (by gram -)
    • As adjunct to betalactam or carbapenem
  • Skin and skin suture infections (serious inf, by susc. gram -)
  • UTIs (serious, complicated by susc. gram-)
    • Inc. by Enterobacteriaceae or Pseudomonas aeruginosa
    • Possibly as adjunct to another tx
    • Only use if causing organism is resistant to less toxic drugs
  • Mycobacterial
    • 2nd line agent in multiple-drug regiments for treating active TB (if have relapse or tx failure) or TB resistant to isoniazid and/or rifampin or when 1st-line drugs can't be tolerated
    • Use as alernative in multiple-drug regiments for treating M. avium
    • Use for nonpulmonary M. abscessus, M. chelonae, M. fortiuitum
  • Infections by Nocardia
    • (Usually) As adjunct to sulfonamide if inf is severe or disseminated
    • If can't use sufonamide, use amikacin + carbapenem or 3rd gen cephalosporin or tetraxycline or amoxiclav or clarithromycin or cycloserine or linezolid
  • Inf by Rhodococcus equi
  • Inf in febrile neutropenic patients
    • (Empiric therapy)
    • Use w/anti-psuedomonal cephalosporin or extended-spectrum penicillin or carbapenem
• Administration
  • IV or IM
  • Can be given intrathecally or intraventricularly for meningitit or other CNS infection
  • If giving IV with a beta-lactam, don't admix them; administer separately
  • IV and IM dosage is the same
• Special populations
  • Old people: age-related decrease in kidney fxn
  • PPl w/muscular disorder like myasthenia gravis or parkinsons since amikacin has strong curare-like effect on neuromusc junctions and can make muscle weakness worse
  • Pregnancy category D
    • Possible harm to fetus
    • W/comcurrent aminoglycoside, can cause bilateral congentical deafness
    • Low concentration in lactated milk
  • Pediatric: immature renal system (→ prolonged serum half-lif)
• Contraindications
  • Sensitivity to aminoglycosides (cross-allergenic)
  • Sensitivity to sulfite, since amikacin has sodium metabisulfite and can cause allergic-type reactions
  • Possibility of additive toxicity, so avoid concurrent or sequential use of other neurotoxic/nephrotoxic drugs, esp. bacitration ,cisplatin, ampotericin B, cephaloridine, paromomycin, viomycin, polymyxin B, colistin, vancomycin, or other aminoglyc.
  • Potent diuretic
  • Neuromuscular blocking agents (tubocurarine, succinylcholine, decamethonium)
  • Topical use (small or large fields) → irriversible deafness, renal failure, death
• Drug interactions (specific)
  • Acyclovir, amphotericin B, bacitracin, capreomycin, cisplatin, colistimethate/colistin, polymyxin B, vancomycin → can increase neurotox, ototox, or nephrotox effects
  • Penicillins: additive antibact effect against Enterobacteriaceae or P. aeruginosa
  • Cephalosporin: possible increase in nephrotox; randomly elevate creatnine levels
  • Amikacion can be inactivated beta-lactams, though not as much as other aminoglyocosides
  • Carbapenem: additive/synergistic effect agasint some gram + bact
  • Chloramphenicol, clindamycin, tetracycline: possibly antagonism w/aminoglycos.
  • Diuretics: increased risk of ototox (since diuretics can cause them); increase SE of aminoglycosides, since can change their concentration in serum or tissue
  • Nuromuscular blocking agents (see above)
  • Indomethacin: possibly increase serum aminoglycosides in premature babies
• Pharmacokin
  • Not absorbed orally
  • Peak serum concentration within 0.5–2 hours after IM
  • Distributed into:
    • Bone, heart, gallbladder, lung tissue, bile, sputum, bronchial secretions, interstitial fluids, pleural fluids, synovial fluids
    • Low concentration in CSF from IM or IV; high concentration in CSF from intraventricular
    • Crosses placenta
  • Less than or equal to 11% plasma protein binding
  • 94-96% of a single IM or IV dose secreted unchanged by glomerular filtration within 24 hours
  • 2-3h hour half-life
• Preparations
  • 50mg/mL inj
  • 250mg/mL inj

• Ototox w/amikacin: 14% of patients
  • Needs long duration of tdx and repeated courses or high cumulative dose
  • Cause high-frequency hearing loss (beyond range of normal speech)
• Hearing loss of 15 decible at 2 or more frequencies, or 20 decibels at at least 1 freuency: 18%
• Nephrotox w/amikacin: 8.5%

• Expanded-spectrum aminoglyc
• Resistance by bact enzymes
  • Amikacin is more resistant to enzymatic hydrolysis than kanamycin
• Half-life: 60 min (dogs), 45 min (horses), 115 min (sheep)
• Volume of distribution (mL/kg): 300 (dogs), 207 (horses), 200 (sheep)
• Clearance (mL/kg/min): 3.5 (dogs), 0.75 (horses), 0.7 (sheep)
• Half-life
  • Dogs: 60 min
  • Horses: 45 min
  • Sheep: 115 min

• Treating MDR tuberculosis, use several different drugs
  • Regimen includes capreomycin; if that doesn't work, trade out for kanamycin; if that doesn't work, trade out for amikacin
    • Although capreomycin is often skipped out on - not available everywhere, and more expensive than kanamycin
• Cross-resistance
  • Resistance to streptomycin usually still susc to amikacin
  • Resistance to capreomycin usually still susc to amikacin
  • Resistance to amikacin also resistant to kanamcin and capreomycin
  • Resistant to kanamycin: diff levels of resistance to amikacin
  • Never use amikacin 1st, bc will confer cross-resistance to other drugs

• Causes vestibular toxicity at 7.4%
  • (Most likely) By creating excessive oxidative free radicals (time-dependent, but not dose-dependent)
  • Reduce risk by minimizing duration of exposure
• Electrolyte imbalance (aminoglyc in general)
  • Change renal tubular function → changes in fluid/electrolyte/acid-base → hypokalemia and acidosis or alkalosis
• UTI (aminoglyc in general): nephrotox more common in those w/glomerular filtration rate under 60mL/min/1,73 m3, diabetes mellitus, treatment with other nephrotox drugs or iodinated contrast agents, hypotension
• Amikacin damages vestibular organ in infants more often than damages the cochlea
• Amikacin attributed to Type 5 Barter-like syndrome w/severe hypocalcemia
• Susceptibility factors
  • Correlation btw lower gestational age and/or birth weight percentile and lower amikacin clearance

• Nocardiosis: sulfonamides are drugs of choice; might end up needeing amikacin or imipenem

• Amikacin stx makes it immune to aminogly-inactivating enzymes
  • Only one location on stx makes it vulnerable – ginteamicin and tobramycin have 6
• Aminogly w/"greatest degree" of activity against P. aeruginosa and the one least likely to cause resistance
• Mostly against aeribic gram- bacilli
• Rarely used as monotherapy
• Pharmacokin
  • Plasma protein binding: less than 5%
  • 95% excreted unchanged
  • 2 hr serum half life normally; 50 hrs in end-stage renal disease
  • volume of distribution 0.25 L/kg
  • Single daily dose "virtually eliminates" nephrotox/ototox potential
  • CSF penetation: 15% (w/inflamed meninges, is 20%)
• Traditional uses
  • Combo therapy for P. aeruginosa and aerobic G- bacilli
• Increased/new uses; combo therapy for:
  • MDR P. aeruginosa
  • MDR Klebsiella pneumoniae
  • MDR Acenitobacter baumannii
  • MDR M. tuberculosis

• Amikin (human), Amiglyde (vet)
• Aminocyclitol
• Sparingly soluble in water; works best in alkaline environment; heat resistant
• Rapidly bacateriocidal to most G-
• Resistant to aminoglyc-inactivating enzymes
• Binds to 30S and 50S subunits
  • Abnormal initiation complexes accumulate
  • Misread mRNA and add incorrect amino acid
• Uses
  • Treating aerobic G- resistant to gentamicin and tobramycin
  • Treating G- eye infections (esp. by P. aeuroginosa)
• Uterine absorption poor
• Ocular absorption has been found (when have conjunctivitis(
• Bioavilability: >90% from IM or SQ injections
• Distribution
  • Sequestered in the inner ear and kidneys
  • Vd = 0.27 L/kg in humans (lower in obesity, higher in newborns)
  • 0.15–0.3 in cats and dogs
  • 0.26–0.58 in horses
• Clearance higher in those w/cystic fibrosis
• Interactions; indomethacin, enflurane, and methoxyflurane increase tox potential

• Choices in animals p594
  • Alt choice for respiratory tract infection (1st are clavamox, fluoroquinolones, cephalosporins)
  • Alt choice for septicemia (1st are csame as above)
• Active agasint kennel cough p595
• Aminoglyc nephrotox in dogs and cats p1976
  • Not metabolizes, low molecular weight, high water solubililty →all factors that make it excreted almost completely via urine
  • Easily ionize to cationic complexes and bind to anionic sites on epithelial cells of proximal tubule
  • Internalized by pinocytosis
  • Renal cortical concentrations 10x of plasma concentration → renal tubular damage
  • Factors that increase risk of tox: prolonged use (more than 5 days), high trough levels (>5 microg/mL), pre-existing renal disease, dehydration, hypokalemia, hypocalcemia, hypomagnesemia, metabolic acidosis, age, concurrent nephrotox drug admin, diureitcs, antiprostaglandins
  • Tox can be reduced by less frequent dosing
• Efficacy of aminoglycs is assessed by peak concentrations, but toxicity correlated more to trough concentrations (so dosing every 24 hrs instead of every 8 hours)
• Severe, unstable bacterial pneumonia p1103
  • As pat of combo therapy w/a beta-lactam
• Avoid in neonates p523
• 2nd line tx for Mycobacteriam avium-intracellular complex and non-TB mycobacteria in dogs and cats p879
• Pus and necrotic debris bind and inactivate vancomycin and aminoglycs → they become ineffective p591

• FDA for dog and intra-uterine for horse
• Amikacin and gentamicin most common aminoglycs in vet medicine
• Dogs and cats
  • • Topical otic for bact infections in ear (dogs and cat) (most common P. aeruginosa)
  • Poor activity in presence of pus and cellular debris, so clean ear first
  • Corneal ulcer (most common P. aeruginosa)
• Horses
  • Freq. w/IV penicillins
  • Opthalmic preparations, regional limb perfusion, joint lavage, intraarticular injections
• Side effects
  • Ototox: cats are more sensitive to vestibular damage by aminoglycs
  • Inj site reactions w/IM injections
  • Nephrotox, ototox
  • Neuromusc. blockade, facial edema, peripheral neuropathy
• Overdose
  • "Hemodialysis, peritoneal dialysis, and complexation using of the penicillins"

• Amikacin: large side chains attached onto kanamycin; block access of various enzymes that converge resistance
• AAC = aminoglycoside acetyltransferase
• AAD = aminoglycoside adenylyltransferase
• Resistance
  • In P. aeruginosa, enzyme = AAC(6')-IV (also confers resistance to kanamycin, gentamicin, aand tobramycin)
  • In S. epidermidis, and S. aureus, enzime - AAD(4',4) (also confers resistance to kanamycin, apramycin, and tobramycin)
• Susceptibility in E. coli w./enzyme AAD(2) (but confers RESISTANCE to kanamycin and gentamycin)

• Can give SQ at home for pyoderma
• Nephrotox: renal proximal tubular necrosis
  • Still might be less nephrotox than other aminoglycs, inc. gentamicin
  • Signs: decreased specific gravity, cats, proteinuria, glycoosuria, finally azotemia
  • Renal tox is usually reversible with early drug withdrawal
• Ototox
  • Causes apoptosis in inner ear hair cells

• For subcutis infections in horses (cellulitis, ulcerative lymphangitis), usually caused by Staphylococcus
  • In combo with cephalosporin
• Inf of synovial stx (joint, tendon sheath, bursa), either traumatic or surgical
  • Cephalosporin + amikacin; add metronidazole for wounds on distal limb or anywhere likely to have fecal contamination
• Staphylococcus infections
  • Amikacin more likely than gentamicin to work, but susceptibility to amikacin in equine MRSA is variable
• Less effective agasint Streptococcus than gentamicin
• Enterobacter: better than gentamicin
• E. coli and other enterobacteria: amikacin better than gentamicin
• Pasteurella: gentamicin better than amikacin
• Choice abx against Pseudomonas

• "Amiglyde-V" (vet version)
• More active than gentamicin against many Gram-
• 1/2 life short in most animals (1-2 hours)
• Horses;
  • Local administration as an intrauterine lavage to treat metritis
  • Regional limb perfusion
• Dogs, cats, horses, cattle

• IA injection in foals for G- septic arthritis
• Mechanism
  • Irriversible binding to 30S
  • Concentration-dependent Abx
• Covers
  • Many G- and some G+
  • Including most species of E. coli, Klebsiella, Proteus, Pseudomonas, Salmonella, Enterobacter, Serratia, Shigella, Mycoplasma, Staphylococus
• Better action in alkaline environment
• Pharmacokin
  • Topically absorbed if used in irrigation during sx
  • Orally absorbed only if pt has hemorrhagic or necrotic enteritis
  • IM dogs and cats: peak level is after 1/2-1 hr
    • SQ injections: peak is slightly later, more variable
  • IM or SQ has bioavailability greater than 90%
  • Distribution
    • Mainly in extracellular fluid, inc. ascitic, pleural, pericardial, peritoneal, synovial, and abscess
      • High levels in sputusm, bronchial secretions, and bile
    • Don't easily cross BBB or penetrate ocular tissue
    • CSF levels range from 0–50% (unpredictable)
    • AGs tend to accumulate in kidneys and inner ear, possibly explaining their toxicity
    • Volume of dist: 0.15–0.3 L/kg in dogs and cats, 0.26–0.58 in horses
      • May be a lot larger in newborns and young animals bc more extracellular fluid fraction
    • Cross placenta; 15–50% of serum concentration reaches fetus
  • Mostly glomerular filtratoin
  • Half-life: 5 hrs in foals, 1.14–2.3 hrs in adult horses, 2.2–2.7 hrs in calves, 1–3 hours in cows, 1.5 hours in sheep, 0.5–2 hours in dogs and cats
• Contraindication
  • Hypersensitive to AGs
  • No other absolute contraindications, bc these drugs are often the only effective agents in severe G- infections
  • Extreme caution in those w/renal disease
  • Risk for tox: age (young or old), fever, sepsis, dehydration
  • Reduced dosage for sighthounds bc have smaller volumes of distribution
  • Generally considered contraindicated in rabbits/hares bc harm GI floral balance
• Adverse effects
  • Nephrotox
    • Tubular necrosis
    • Thought to be interference w/phospholipid metabolism in lysosomes of proximal renal tubular cells → proteolytic enzymes leak into cytoplasm
    • Manifested by increases in BUN, creatinine, nonprot nitrogen in serum; decreases in urine specific gravity and creatinine clearance
    • Possible proteinuria and cells/casts seen in urine
    • Usually reversible when abx discontinued
    • Slightly less nephrotox than gentamicin
  • Ototox (tox of 8th cranial nerve)
    • Manifested as vestibular or auditory signs
    • Auditory signs more common w/amikacin
    • Cats sensitive to vestibular effects of AGs
  • Neuromusc blockade
  • Facial edema
  • Pain/infl at injection site
  • Peripheral neuropath
  • Hypersensitivity reactions
  • Rare: GI clinical signs, hematologic and hepatic effects
• Pregnant/nursing
  • Rare, but can cause ototox or nephrotox in fetuses
  • Excreted in milk, but unlikely to be of significant concern after baby is at least a few days old
• Overdose
  • Hemodialysis: reduce serum concentrations well, but not viable for most vet pts
  • Peritoneal dialysis: reduces serum concentrations, but not as well as above
  • Complexation of drug w/either carbenicillin or ticarcillin (humans) almost as effective as hemodial
• Drug interactions
  • Beta-lactams: synergistic effect vs. bact
    • Cephalosporins: use together is controversial; potentially add on to nephrotox
  • Loop diuretics (furosemide, torsemide) or osmotic diuretics (mannitol): can increase nephrotox or ototox
  • NSAIDs: also can cause nephrotox, so some say avoid
  • Other nephrotox drugs: cisplatin, ampohotericin B, polymyxin B, vancomycin
• Dose 1x a day in most mammals
  • AGs have a "post-antibiotic effect" where surviving bact don't replicate as well even when abx below MIC concentration
• Dogs and cats: IM, IV, SQ
• Ferrets, rabbits, guinea pigs, chinchillas, hamsters, rats, mice, prairie dogs, cattle, horses, birds, crocodilians, fish (WTF)
• Birds
  • Sunken eyes/sinusitis in macaws (by susc bact)
• Snakes: common for resp infections; use lower dose for Python curtus
• Turtles: bacterial shell disease, used often with beta-lactam
• aka amikacin sulfphate, amikacini sulfas

• 50 mg/mL injectible (Amikin, Amiglyde) and 250 mg/mL intrauterine solution for horses
• Bioavilability: 90% IM and 100% SQ in cats
• Dogs, calves
• Snakes, tortoises

• Pharmacokin
  • Volume of distribution: 24 liters
  • Excreted via glomerular filtration
  • Spinal fluids in infants: 10-20% (can reach 50% in meningitis)
  • Crosses placenta at 16% peak maternal serum concentration
  • 1/2 life in mom is 2 hours, 1/3 life in fetus is 3.7 hours
• Mechanism
  • Binds to prokaryotic ribosome and inhibits protein synth
  • Vs. gram+ and gram-
• Resistance
  • Salmonella, Shigella
  • Some aminoglycoside inactivating enzymes that work against gentamicin, tobramycin, or kanamycin don't work agasint amikacin
• Activity
  • Lower activity against Gram+ other than Straphylococcus
  • Gram-
    • Pseudominas
    • E. coli
    • Proteus
    • Klebsiella
    • Enterobacter
    • Serratia
    • Acinetobacter
    • Citrobacter freundii (in vitro)
• Uses
  • Short-term of serious infections by susceptible gram-, inc. Pseudomonas, E. coli, Proteus, Klebsiella, Enterobacter, Serratia, Acinetobacter
  • Effective against: Bacterial septicemia (inc. neonatal), serious inf of repiratory tract, bones and joints, CNS, skin and soft tissue, intra-abdominal, burns, post-op infections, complicated UTIs
    • Some severe inf (ex. neonatal sepsis), use w/penicillin-type to cover any Gram+ bact
• Pregnancy
  • Aminoglyc.: deafness to fetuses (no serious effect by other aminogl.)
  • No harm to fetuses in rat/mice studies
• Sulfite sensitivity (seen more in people w/asthma)
• Can lead to C. difficile-associated diarrhea
• Adverse effects
  • Neurotox-ototox
    • Toxic effect on 8th cranial nerve → hearing loss, loss or balance
    • Cochlear damage (inc. losing high frequency hearing) happens before clinical hearing loss can be detected
  • Neurotox-neuromuscular blockade
  • Nephrotox
    • Increases serum creatinine, albuminuria, RBCs, WBCs, azotemia, oliguria
    • Renal function changes are reversible when end drug
  • Rare side effects: skin rash, drug fever, headache, paresthesia, tremor, nausea/vomiting, eosinophilia, arthralgia, anemia, hypotension, hypomagnesemia
    • Macular infarction tat can lead to permenent vision loss after inj into the eye (intravitreous)
• Overdose
  • Peritoneal dialysis or hemodyalisis to remove amikacin from blood
  • Can use exchange transfusion for newborns
• Usually treat for 7–10 days
• At normal dose, uncomplicated inf by amikacin-sensitive bact should respond within 24-4 8 hours
• Supplied as amikacin sulfate injection (colorles solution, sometimes can become very pale yellow)
  • Inactive ingredients: sodium metabisulfite, sulfuric acid, water, sodium citrate

• Uses
  • Hospital-acquired pneumonia w/beta-lactam or carbapenem
  • Mycobacterium infections
    • Inhaled liposomal amikacin
    • Can use for non-TB mycobacteria
  • P. aerugionosa lung infections or bronchopulmonary P. aeruginosa in pts w/cystic fibrosis
    • Inhaled liposomal amikacin
  • Bronchiectasis in pts w/P. aeruginosa infections or non-TB mycobacteria or other susc bacteria
• Interactions/contraindications
  • SEVERE
    • Amphotericin B: both increase nephrotox and/or ototox
    • Cidofovir: same
    • Neomycin PO: same
  • Serious (use alternative)
    • abobotulinumtoxina (and other shit from botox bact) effect increased, risk of apnea
    • atracurium: effect increased, risk of apnea
    • BCG vaccine live: amikacin decreases effect by pharmacodynamic antagonism. Wait until done w/amikacin tx
    • Cholera vaccine: pharm. antagonism. Systemic abx can work against cholera vax
    • Ioversol (contrast medium): both increase nephrotox and/or ototox
    • Quinidine: increases level of amikacin by P-glycoprotein (MDR1) efflux transporter
    • Typhoid vax live: effect decreased by pharm. antagonism.
  • Use caution/monitor
    • amiodarone: increase level or effect of amikacin by P-glycoprotein efflux transporter
    • conjugated estrogens (oral forms): effect decreased bc intestinal flora altered. Low risk of contraceptive failure
    • Clarithromycin: MDR1 efflux transporter
    • Clotrimazole: same
    • Cyclosporine: same
    • deferasirox: reports of acute renal failure
    • dienogest/estradiol valerate (oral): decreased bc amikacin changes intestinal flora
    • a lot more, I'm not doing this
• Side effects
  • 1-10%: neurotox, nephrotox, ototox
  • Less than 1%: hypotension, headache, drug fever, rash, nausea/vomiting, eosiniphilia, paresthesia, tremor, arthralgia, weakness, allergic rxn

• As adjuvant in human and pet vaccines
• Powder is most popular form
• Cheap, OTC
• Doesn't accumulate in body, so no toxicity
• No serious side effects (some constipation in small animals)
• OTHER USES
  • Horses with chronic renal failure
  • Adjuvant for vax for livestock

• Reduce hyper-P in pts w/renal failure
  • Binding to dietary P, reducing amount that's absorbed from intestines
• Kidneys normally filter excess P out, but P accumulates if kidneys failing
• High P → lethargy, poor appetite
• Al. hydroxide used when dietary restriction/renal diet not enough
• Powder that you mix into food, or capsules or liquid
• Most likely side effect in small animals is constipation

• "Amphogel"
• Oral antacid/phosphate binder
• Decreases hyperphosphatemia in patients w/renal failure if diet changes don't work
• Al salts bind to dietary P, reducing amount of P absorbed from intestine
• Small animals; can cause constipation
• Class A for pregnancy
• Hard to OD orally
• Dogs & foals: also used as adj. therapy for gastric ulcers

• Can combined with other drugs when treating hypertension
• Contraindication:
  • Pt sensitive to dihydropyridines
  • Don't use in cardiogenic shock, severe aortic stenosis, unstable angina (excluding variant angina) or severe hypotension
• Warning
  • Amlodipine can cause pulmonary edema in pts with heart failure
  • If pt has impaired liver function, drug will have longer half-life
• Pregnancy: haven't established safety; reproductive toxicity at high does
• Unknown if excreted in breast milk

• Ca-channel blockers preferred for high BP in patients with certain preexisting conditions (ex. ischemic heart disease) and old people, and black people (respond better)
• Don't use for acute crises
• Amlodopine-associated edema risk can go down if add ACE inhibitor or angiotensin II
• Combo therapy (NOT in order of strength)
  • Amlodopine/atorvastatin for hypertension (former) and dyslipidemias and preventing cardiovascular events (latter)
  • Or for CAD (former) and same for latter
  • Amlodopine/aliskiren if need more than one agent for BP control (can give individually or as combo)
  • Amlodopine/aliskiren/hydrochlorothiazide combo tablet if BP still not decreasing
  • Amlodopine/benazepril combo if either has failed indivi
    • Or if amlodopine alone gave edema
  • Amlodopine/olmesartan for ppl who need more for BP
  • Amlodopine/olmesartan/hydrohclorothiazide
  • Amlodipine/Perindopril
    • Or if amlodipine alone gave edema
  • Amlodipine/telmisartan
  • Amdlodipine/valsartan
  • Amlodipine/valsartan/hydrochlorothiazide
• Use for Prinzmetal variant angina and chronic stable angina pectoris
• Can be taken orally
• Side effects: edema, dizziness, flushing, palpitations, fatigue, nausea, abd pain (flushing, palpitations, and sleepiness more common in women)
• Interactions
  • Increased amlodipine levels
    • CYP3A inhibitor
    • Antifungals (maybe)
    • Diltiazem
    • Clarithromycin
  • Statins (HMG-CoA reductase inhibitors): increases simvastatin levels (not all statins though)
  • Increases cyclosporine levels and tracrolimus levels
• Bioavailability
  • Highest level 6-12 hours after oral
  • 64-90%
• Works for at least 24 hours
• around 93% plasma protein binding
• Mostly (90%) metabolized to inactive metabolites by liver
  • Excreted either as metabolite or unchanged in urine
• Half-life is 30-50 hours
• Mechanism
  • Prevents passing of Ca ions into myocardial and vasc. smooth muscle cells
  • Peripheral arterial vasodilator
  • Acts on vascular smooth muscle to reduce peripheral vascular resistance and BP
  • Reduces total peripheral resistance
  • Blocks constriction in coronary arteries
• oral tablets or capsules

• Use:
  • High BP
  • Coronary artery disease
    • Chronic stable angina
    • Vasospastic angina
    • Sometimes Coronary artery disease
• Warnings/side effects
  • Unlikely to have acute high BP bc has slow onset
  • Most common: headache edema
• Has chart of % side effects vs. placebo
  • At 10 mg, most common were (increased with dose):
    • Edema 10.8% (vs. 0.6% placebo); more in women (3x)
    • Dizziness 3.4% (vs. 1.5%)
    • Flushing 2.6% (vs. 0); more in women
    • Palpitaions 4.5% (vs. 0.6%); more in women
  • Not dose related
    • Fatigue 4.5% vs. 2.8%
    • Nausea 2.9% vs. 1.9%
    • Abdominal pain 1.6% vs. 0.3%
    • Sleepiness 1.4% vs. 0.6%
• Interactions
  • Increased amlodipine levels with CYP3A4 inhibitors
• Mechanism
  • Exp data suggests that it binds to both dihydropyridine and nondihydropyridine binding sites on Ca channels
  • Inhibits more on vascular smooth muscle than cardiac muscle
  • pKa = 8.6; gradual association/dissociation with binding site
• Pharmacodynamics
  • Decreases BP, but not change HR or catecholamine levels
• Pharmacakinetics not affected by renal impairment
• Metabolism: 90% to inactive metabolite in liver, rest excreted in urine
• ~93% of circulating drug bound to plasma proteins in patients with high BP
• Steady plasma levels occur after 7-8 days of taking med

• Systemic high BP in cats; lesser extent: heart failure and high BP in dogs
• Cats
  • Considered successful 1st line of treatment
  • Renal disease cats sometimes also get ACE inhibitors to prevent potential glomerular damage
  • Decreases proteinuria in most cats with chronic renal disease
• Dogs
  • Congestive heart failure, mitral valve regurgitation, systemic hypertension due to renal disease
    • ACE inhibitors are usually 1st line for high BP; amlodipine is add-on

• Class: 1,4-dihydropyridine calcium channel blocker
• FDA approved in 1990
• 3rd gen calcium channel blocker - higher bioavailability and longer half life
• Most prescribed antihypertensive drug in world in 2003
• Stuck on calcium channel, so don't affect concentrations of Na or K
  • Specficially L-type voltage-gated calcium channels
• Dihydropyridines can aldo inhibit cyclic PDE
• Structure
  • Basic amine group (pKa 8.6) → longer half-life and high bioavailability
    • So molecule is >90% ionized at physiological pH
• Like with most other dihydropyrimidines, S isomer (-) is more active
• Oxidized by CYP450 to become inactive pyridyl metabolite (NH → N, and ring becomes phenyl group)
• Vasodilation from amlodipine can cause reduced cardiac output in ppl w/severe aortic stenosis

• "Norvasc"
• High BP in cats (often 1st choice)
• Decrease BP in dogs w/chronic renal failure, but otherwise meh
• Activates renin-angiotensin aldosterone system (RAAS) in healthy dogs at higher doses except with ACE inhibitor
• Cat: high BP often sign of other disease (renal failure, thryotoxic cardiomyopathy, etc.)
• Mech: decrease impulse formation and conduction velocity in cardiac cells
• Diuretic in dogs
• Concerns
  • Renal disease in cats with high BP
    • Local increase in RAAS activity higher pressure bc of efferent arteriolar constriction
• Infrequent, bug in cats; azotemia, lethargy, hypokalemia, reflex tachychardia, weight loss
  • Dogs: possible gingival hyperplasia with chronic use

• Uses
  • Endocarditis
    • Enterococcal endocarditis, w/aminoglycoside
    • Endo by slow-growing fastidious gram-negative bacilli (HACEK group: Haemophilus parainfluenzae, H. aphrphilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae)
      • W/gentamicin
    • By susceptible staphylococci, streptococci, E. coli, P. mirabilis, or Salmonella
    • Prevention of endocarditis in those w/cardiac conditions undergoing dental, oral, respiratory tract, or esophageal procedures, or GU and GI procedures
  • Meningitis/other CNS
    • By Neisseria mengingitisis, S. agalactiae, Listeria monocytogenes, E. coli, H. influenzae, S. pneumoniae
    • Drug of choice for neonatal S. agalactiae meningitis and L. monocytogenes; use w/aminoglycoside
    • For Haemophilus influenzae, used w/chloramphenicol
  • Respiratory tract infections
    • By S. aureus (inc strains resistant to penicillin), Streptococcus, S. pyogenes, H. influenzae (non-penicillinase strains only)
    • Don't use for strept or staph rep infections if penicillin works
  • Septicemia
    • Susc. staph, strept, enterococci, E. coli, P. mirabilis, Salmonella
  • UTIs
    • Susc. enterococci (drug of choice), E. coli, P. mirabilis
  • Infections by Eikenella corrodens (drug of choice)
  • Used to be used for gonorrhea and associated infections, but too many penicillin-resistant strains now
  • Listeria monocytogenes, alone or w/aminoglycoside
    • Drug of choice for tx during pregnancy, granulomatosis infantiseptica, sepsis, endocarditis, meningitis, foodborne infections
  • Whooping cough (prevent and treat 2ndary infections)
  • Salmonella infections, inc. typhoid fever, and inc. chronic carriers of T. typhi
    • Shigella infections
    • Previously a drug of choice before resistance strains of S. flexneri and S. sonnei started popping up more
  • Prevent early-onset neonatal group B streptococcal disease
    • Amp given to pregnant women identified as GBS carriers in prenatal screenings
  • Perioperative prophylaxis for vaginal hysterectomy or C-sections
• Administration
  • Orally
    • But not as initial treatment for severe infections; can be follow-up to IV or IM ampicillin
  • Slow IV injection/infusion
  • IM injection
• Contraindications: hypersensitivity to any penicillin
• Warning
  • Can cause C. diff-associated colitis
  • Hypersensitivity reactions
  • Higher risk of rash in patients w/mono
• Pregnancy category B
• Distributed into maternal milk
• Renal clearance delayed in young infants bc renal function not fully matured
• Common side effects: diarrhea, nausea, rash
• Interactions
  • Allopurinol: increase risk of rash, though unclear if bc allopurinol or bc of hyperuricemia in those patients
  • Aminoglycosied: synergistic effects
  • Chloramphenicol: evidence of antagonism
  • Hormonal contraceptives: possible decrease of efficacy of oral contraceptives w/estrogen and increased probability of breakthrough bleeding
  • Methotrexate: possible decrease in renal clearance of both drugs
  • Probenecid: decreased renal tubular secretoin
  • Sulbactam: synergistic bactericidal effect against bact that make beta-lactamase
  • Sulfonamides: antagonism
  • Glucose test: possible false-positives in urine glucose tests that use Clinitest, Benedict's solution, or Fehling's solution. Use glucose tests that are based on enzymatic glucose oxidase reactions instead
  • Uric acid test: possible false increased serum concentration of uric acid if use copper-chelate method; use phosphotungstate or uricase method
• Pharmacokinetics
  • Bioavailability
    • 30–55% oral dose absorbed in GI tract of fasting adults
    • Peak concentration in serum in 1–2 hours
    • IM: peak concentrations faster and higher
    • IV: peak concentrations immediately after infusion
    • Food decreased rate and extent of absorption
  • Distribution
    • Ascitic, synovial, pleural fluids, and liver, bile, lungs, gallbladder, prostate, muscle, middle ear effusions, bronchial secretions, sputum, maxillary sinus secretions, tonsils, saliva, sweat, tears
    • Into CSF at 11–65% serum concentrations
    • Crosses placenta
    • Into milk at low concentrations
  • 15–25% protein binding
    • Lower in neonates (8–12%)
  • Metabolism
    • Hydrolysis of beta-lactam ring to penicilloic acid ("microbiologically inactive")
    • Eliminated in urine: mostly renal tubular secretion, also glomerular filtration
      • A bit in bile and feces
    • 20–64% of an oral dose excreted unchanged in urine in 6–8 hours; and 60–70% IM dose, 73–90% IV dose
  • Half-life: 0.7–1.5 hours
• Take w/full glass of water 1 hour before or 2 hours after meal

• Typhoid vaccine (same interaction as cholera vaccine)
• Esp. bc amp is used to treat Salmonella, and typhoid vax is vs, Salmonella typhi (so can't mount an immune response)

• Broad-spectrum, semisynth
• Destroyed by beta-lactamase
• Aminopenicillin (amoxicillin is also)
• Susceptible genera include Staph, Strept, Trueperella, Clostridium, Eschericia, Klebsiella, Shigella, Salmonella, Proteus, Pasteurella
• Sulbactam given w/ampicilin to protext agasint beta-lactamase
• Food impairs absorption of ampicillin

• aka aminobenzylpenicillin
• Inhibits transpeptidase enzyme, blocking synth of peptidoglycan
• Can go intra mammary in animals
• Well-absorbed from GI tract
• Bioavailability: 62% (plus-minus 17%) in humans
• Distribution: through most tissues, concentrated in liver and kidneys
  • In CSF only when meninges are inflamed, and then at 5–10%
• 15–20% plasma protein binding (lower in neonates)
• Small portion is metabolized by hydrolysis to inactive penicilloic acid
• Half-life
  • 1.3 +/- 0.2 hours in humans
  • Higher w/uremia or hepatic cirrhosis, or in neonates
  • 12 hours in animals
• Side effects
  • 10%: skin rash, diarrhea, vomiting
  • rare: Severe abdominal cramp, encephalopathy, seizure, lymphocytic leukemia
  • Can cause superinfection after oral admin
  • Overdose → neuromuscular hypersensitivity, electrolyte imbalance, renal failure

• 1/2 systemic availability of amoxicillin (20–40% vs. 60–70%)
• Hetacillin and pivampicillin are ampicillin esters developed to increase systemic availability
• Forms
  • Sodium salt
  • Trihydrate salts (less soluble and thus absorbed less intestinally, but ok in aq preparations for inj)
  • Aq forms reconstituted are unstable after several hours
  • Inj forms should be given within 6 hour intervals (bc short half-life) to maintain
• Toxicities/adverse effects
  • Don't give to small rodents or rabbis bc can produce clostridial colitis (C. dif; in rabbits, C. spiroforme)
• Uses
  • Cattle, sheep, and goats, oral ampicillin has been used to treat E. coli and Salmonella (but resistance more common so now not as effective)
  • Bovine respiratory disease (but no advantage over penicillin G)
  • Don't use much in horses bc don't have much advantage over benzyl penicilins, largely due to acquired resistance in G- bact
  • For mixed aerobic-anaerobic infections, such as from cat bites
  • Canine urinary tract infections (over 90% of S. aureus, streptococci, and P. mirabilis, almost 90% of E. coli, and 65% of Klebsiella are susceptible to ampicillin at concentrations used to treat UTIs)
  • Oral in poultry to prevent or treat salmonellosis, E. coli sepsis, S. aureus sepsis

• Resistance to ampicillin is plasma-mediated; can transfer btw different bacteria

• Additional amino group in side chains of ampicillin and amoxicillin make them more hydrophilic and lets them enter porins of outer membranes of some G– rods (ex. E. coli, P. mirabilis. S. enterica, Shigella)

• Sodium and trihydrate forms
• Ampicillin trihydrate can be given orally to foals (but in adult horses, beta-lactam antibiotics have very low bioavail)
• Used to be that some gram- nonenteric microbes, as well as E. coli, Klebsiella, and Proteus not susc to penicillin but susc to ampicillin
  • But decades of use has made ampicillin lose some effectiveness
  • Pseudomonas and many Enterobacter are resistant to penicillin and ampicillin
• One of the few abx that work against multidrug resistant Enterococcus faecalis and E. faecium

• Rapid IV admin lead to convulsive seizures
• Powder reconstituted with sterile water or bacteriostatic water
• Lasts longest with reconstituted with sterile water, saline, or LRS (8 hours in fridge, 24hrs - 72 hours in fridge depending on choice of reconstitution and concentration, with low concentration lasting longer)
  • Sterile water: 48–72 hours
  • Saline: 24–48 hours
  • LRS: 24 hours
• Can also be reconstituted in 5% dextrose, but stable for only 1 or two hours (in or out of fridge)

• Narrow spectrum, similar to that of amoxicillin
  • Streptococci, non-beta-lactamase producing staphpylococci, other gram +
  • Many staphylococci resistant due to beta-lactamase production
  • Most enteric gram- bacilli of Enterobacteriaceae are resistant
  • Susc. gram-: Proteus, Pasteurella multocida, Histophilus
    • Resistance among G- is common
• Half-life is 1–1.5 hours in most animals
• Oral absorption is less than 50% in cats and dogs, less than 4% in horses
• Adverse reaction mostly due to penicillin allergy
• Absorbed around 50% less than amoxicillin when given orally
• Storage
  • After reconstituting ampicillin sodium, stability is dependent on concentration
  • If w/sterile water at 250 mg/mL, is stable for 1 hr at room temp
  • Increase time if dilute in IV fluids (saline, LRS), if put in fridge
• Dogs, cats, horses, cattle
• Cattle withdrawal time: 6 days for meat, 48 hours for milk (at 6 mg/kg)
• Ampicillin + sulbactam
  • Sulbactam: beta lactamase inhibitor, similar activity to clavulanate not as active against clavulonate vs. some gram- beta-lactamase enzymes
  • For general bacteria infections
  • Use when resistance to ampicillin is expected
  • Can only be given by injection
  • Need more frequent/higher doses for gram- infections

• Poorly bound penicillins like amp cross placental barrier better
• Get concentration in amniotic fluid that is 0.5–1 times that of in maternal plasma; can lead to high concentration of drug in newborn
• bc increased blood volume and renal clearance, ampicillin concentrations can be reduced by up to 50% in pregnant women, so need higher doses for same abx effect
• No evidence of embryotoxic, fetotoxic, or teratogenic effects
• Cat B by FDA, like all penicillins

• [Vet version]
• Pharmacology
  • Peak serum levels in cats and dogs in 30 min. after SQ or IM injections; 1-2 hours in cattle after IM injections
• Uses
  • Upper resp infections, tonsilitis, and bronchopneumonia by hemolytic streptococci, S. aureus, E. coli, P. mirabilis, Pasteurella
  • UTIs due to P. mirabilis, E. coli, Staph, hemolytic streptococci, Enterococcus
  • GI inf due to Enterococc, Staph, E. coli
  • Abscesses, pustular dermatitis, cellulitis, anal gland infections due to E. coli, P. mirabilis, hemolytic strept, Staph, Pasteurella
  • Cattle resp tract infections: bacterial penumonia (shipping fever, calf pneumonia, bovine pneumonia) by Aerobacter, Klebsiella, Staph, Strept, Pasteurella multocida, E. coli

• Pharmacology
  • Into CSF and brain only when meninges are inflamed
  • Excreted largely unchanged in urine; can be delayed if also getting probenecid at same time
  • Active form more in bile than in serum
  • Is least serum-bound of all the penicillins (average of 20% vs. 60–90%)
  • Well-tolerated by most patients
• Use
  • Resp tract infections by: S. pneumoniae, S. aureus, H. influenzae, Group A beta-hemolytic streptococci
  • Meningitis by: E. coli, Group B streptococci, other Gram - (ex. Listeria monocytogenes, N. meningitidis)
    • Add aminolgycoside for more effectiveness vs. Gram-
  • Septicemia and endocarditis by Streptococcus, susc. Staphylococcus, enterococci
    • Gram- sepsis by E. coli, Proteus mirabilis, Salmonella
    • Endocarditis by enterococcal strains
      • Add aminoglycoside for better effectiveness vs. streptococcal endocarditis
  • UTIs by: E. coli and P. mirabilis
  • GI infections by: Salmonella (inc. typhoid fever)
• Contraindications: hypersensitivity to any penicillin (can → fatal anaphylactoid reactions; more common in parenteral therapy, though also happens w/oral admin)
• Warnings
  • C. diff diarrhea (from mild diarrhea to fatal colitis)
  • 43–100% of pts w/mononucleosis get skin rash w/apmicillin (7 to 10 days after oral amp is started; goes away a few days to a week after ended)
    • Usually maculopapular, pruritic, and generalized
• Interactions:
  • Transient elevation of transaminase in serum after ampicillin
  • Skin rashes more common if given w/allopurinol
  • High concentrations of ampicillin: false positive for glucose reaction tests
• Side effects
  • More likely in those w/sensitivity to penicillins and those w/history of allergy, asthma, hay fever, or hives
  • GI (most often w/oral form): glossitis, stomatitis, black "hairy" tongue, nausea, vomiting, entercolitis, pseudomembraneous colitis, diarrhea
  • Hypersens.
    • Frequent: skin rashes and hives
    • Some: exfoliative dermatitis and erythema multiforme
  • Liver: moderate rise in serum glutamic oxaloacetic transaminase (esp. in infants)
  • Hemic/lymphatic: anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, agranylocytis (all reversible and thought to be caused by hypersens.)

• Broad-spectrum penicillin
• Antagonists include chloramphenicol, erythromycin, tetracyclines, cephalosporidines
• IM injections of ampicillin/sulbactam can be painful; IV injection can cause thrombophlebitis
• "Principen" for humans; "Polyflex" for animals
• Ampicillin/sulbactam: Unasyn (human only)

• Off-label use as endocarditis prophylaxis
  • IV or IM before procedure in pts who can't take oral amoxicillin
• Forms: capsules, oral suspension, powder for injection
• Metabolized in liver

• Overdose inc. behavioral changes, confusion, black outs, convulsions

• One of most commonly used drugs in pregnancy
• Reduces risk of post-op fever in c-section
• Pregnancy increases clearance
• Ampicillin/sulbactam prolongs period of time btw water breaking to delivery in women where water breaks before 37 weeks
• No evidence of birth defects in humans or rodents
• Some amounts (minimal) secreted in breast milk; considered OK

• PONV = postoperative nausea and vomiting (159)
• 5HT3 receptor antagonists (160)
  • ex. ondansetron, dolasetron, ganisetron, palonosetron
  • Fewer side effects than other antiemetics
• Dopamine antagonists
  • 3 types of dopamine antagonists used:
    • Phenothiazines
      • ex. perphenazine, promethazine, prochlorperazine
      • perphenazine given preop enhances effects of ondansetron and dolasetron
    • Butyrophenones
      • ex. droperidol (most effective when used with other antiemetics)
      • haloperidol (161)
    • Benzamides
      • ex. metoclopramide inhibits DA receptors in CTZ and increases gastric motiligy
• Corticosteroids
  • ex. dexamethasone, methylprednisolone
  • Not completely understood how they are antiemetics
• Histamine blockers (H1)
  • Inhibits H1 receptros in vestibular system
  • Most of the drugs in this category are also weak anticholinergics (also inhibit M1 [muscarinic] receptors that are in vestibular system)
  • When used with dopamine antagonists, can decrease risk of extrapyramidal side effects
  • ex. diphenhydramine, dimenydrinate, hydroxyzine, meclizine
• Anticholinergic
  • ex. scopolamine (most common anticholinergic for PONV)
• Neurokinin 1 receptor antagonists
  • NK1 receptor antagonists inhibit signals that the nucleus tractus solitarius (NTS) receives from CTZ
  • Also inhibits substance P (which binds to area postrema and in GI tract to casue nausea)
  • ex. aprepitant; most effective when used with corticosteroids and 5HT3 receptor blockers

Antiemetics decrease nausea → reduce urge to vomit (262) Antihistamines

• ex. Buclizine, cyclizine, himenhydrinate, diphenhydramine, hydroxyzine, meclizine, trimethobenzamide
• Method of action unclear
• Used for nausea/vomiting caused by inner ear stimulation → motion sickness
  • Except trimethobenzamide

Phenothiazines

• ex. chlorpromazine, perphenazine, prochlorperazine, promethazine
• Block dopamine receptors in "chemoreceptor trigger zone of brain"/may "directly depress vomiting center"
• For severe nausea and vomiting
• Used for chemo or radiotherapy

Serotonin-receptor antagonists

• ex. Dolasteron, ganisteron, ondansetron
• Block serotonin receptors in "chemoreceptor trigger zone" and vagal nerve terminals (so work in both CNS and peripheral nervous system)
• Used for chemo or radiotherapy

Uses: chemo and radiation patients

Classes of antiemetics

• Serotonin receptor antagonists
  • ex. Dolasetron (Anzemet), Granisetron (Kytril), Ondansetron (Zofran), Tropisetron (Navoban)
  • These are the 4 agents that are commercially available in many countries
  • Antagonis of 5-HT3 receptor, highly selective and high affinity
  • Low side effects
  • Conflicting efficacy for delayed (after >24 hours) emesis, but definitely useful for acute emesis
• Corticosteroids
  • ex. Dexamethasone, methylprednisolone (some also use prednisone)
  • Among most frequently-used
  • Most useful category for delayed emesis (vomiting more than 24 hours after chemo session)
• Ones with lower therapeutic index/more side effects
  • Dopamine receptor antagonists
    • DA2 antagonists
    • ex. Metoclopramide, prochlorperazine
  • Butyrophenones (also anti DA)
    • ex. haloperidol and droperidol
  • Phenothiaines (also anti DA)
    • ex. prochlorperazine and thiethylperazine
  • Cannabinoids
    • Dronabinol (plant extract), nabilone and levontradol (both synthetic)
    • Dronabinol less effective than metoclropamide
    • Inhalant marijuana found not to be effective (study with chemotherapy)
• Adjuncts (not recommended as single agents)
  • Benzodiazepines
    • esp. Lorazepam
    • Mostly given bc anxiolytic effects is useful for antiemetic
  • Antihistamines
    • Can be given as antiemetic or to prevent dystonic reactions with dopamine antagonists
    • ex. Diphenhydramine, hydroxyzine, benztropine (studies haven't shown antiemetic activity for these drugs)
• Combining serotonin antagonists with corticosteroids
  • Together, work better than when alone for chemotherapy

For radiation therapy, the one recommended for both full-body and hemi-body is serotonin receptor antagonist

• Lifespan in captivity: 50 years
• 7ft tall (inc. hump)
• Weigh 1800 lbs
• When give birth, is usually to 1 calf after 12–14 mo. gestation
• When fat depleted, humps → floppy and flabby
• Live in Central and e. Asia rocky deserts
  • Very hot in summer (38º+), very cold in winter (-29º)
  • Bactrian camel can survive in both (change coats)
• Only real wild camels still existing are Bactrian
  • Gobi Desert, less than 1000 left

Origins and Distribution p. 1–10

• Genus Camelus has 2 species: dromedary (C. dromedarius) and Bactrian (C. bactrianus)
• Origin traced to Protylopus (1)
  • Was in N. America in Eocene (1)
  • Camelidae disappeared from N. America (unknown why)
• Camelidae Migrated across Bering Straits to Asia (late Pliocene/early Glacial epochs" (1)
• Camels and llama evolved over 1mya from common N. American ancestor
• Dromadary evolved from 2-humped version
• Domesticated Bactrian earlier than 2500 BC
• Domesticated dromedary around 3000 BC in s. Arabia (3)
• Somalia
  • Has largest herd in world
• Sudan
  • 2nd largest in world – almost 3 million

Reproductive Performance p. 11–32 [DROMEDARY]

• Anatomy
  • Male
    • Testes look similar to that of horse (11)
    • Right testicle is often a bit smaller than left one (11)
    • Diameter of seminiferous tubules smallest in summer and largest in winter (12)
    • Breeding season: larger testes, more spermatogenesis (12)
    • Has prostate gland, no seminal vesicles (12)
    • Point of penile sheath points posteriorly, so when camels pee, urine goes backwards (13)
    • Large casing: non-erect penis is hidden inside (like horse) (13)
    • Average length of camel penis is 60cm (13)
  • Female
    • Reproductive tract is like that of a horse (13)
    • Size and weights of gonads vary with ovarian activiy (14)
    • Gonads = "Fairly flattened with numerous ovisacs, giving them the appearance of a bunch of grapes (14)
    • Left ovary's Graffian follicles usually slightly larger than those of the right (14)
    • Follicular activity decreases when get farther into pregnancy (14)
    • More ovulation from left ovary than right
    • Ovulation needs copulation to occur (15) ("induced ovulator")
• Castration
  • Domestic males not reserved for breeding often castrated (18)
    • Camels become more maneagable
• Mating
  • From behind (20)
  • Single mating session → ejaculate 3 or 4 times (21)

Production and Utilization 59–80

• Camel slaughter for meat: Kenya, Ethiopia, Sudan, Somalia (65)
• Average carcass weight: 300–400 kg for dromedary male, 250–300 kg for dromedary female, 650 kg (estimate) for Bactrian male (67)
• Best time for meat is 2.5 years: as get older, meat → tougher and less tasty (68)
• Some nomads consume camel blood (68)

• Thick hair to keep warm at night
• Thick hair around/in ear: protect from sand
  • Also coated with thick wax to stave off sand
• Feet are wide; get wider when step with them
  • Easier to walk long distances
• Eyes: raised ridge above eye + thick, long lashes to keep sand out
  • And protect from sun
• Long legs away from ground, which is hotter
• Pads on knees to protect when kneeling

• Bactrian named after Baktria region of Persia
• Can carry twice as much in weight as dromedary camels can
  • Can carry up to 1000 lbs
• Racing (dromedary) camels can run up to 100mi in a day
• 1- and 2-humped camels can interbreed
  • Child has 2 humps, called "tulu"
• Has 3rd eyelid (transparent) that dislodges sand from eye
• Mouth has thick, leathery lining
  • Can eat thorny plants

• In UAE
• Rama, male born 1998
• Kamilah, female, born February 2002
• Camels and llamas don't mate in wild, but have same number of chromosomes
• Camelids only ovulate in intercourse, so have to inject female llamas with gonadotorphin to start ovulation
• Then inseminate llama with "fresh camel semen" collected with artifical vagina
• Gestation: 11 mo.
• Have also had male llama and female camel
• Camas like mules: sterile
• Cama project funded by Dubai's crown prince

• Camas:
  • No hump
  • Llama coat
  • Ears are 1/2-way in length btw camel's and llamas
  • "Strong, desert-ready legs of a camel"
  • Partially cloven feet (like mix of camel's foot pad and llama's cloven feet)
  • This source says no male llamas and female camels

• Hybrids of dromedary and Bactrian have one hump, but is asymmetrical and has indentation (4–12cm deep) dividing back from front
  • Or can look flat
• Animal is 2.32m tall at hump; 2.15m tall at shoulder
• Legs are long
• Weight average is 650kg
• Can carry ~400–450kg, more than dromedary or Bactrian
• "Indeed Herodotus says that camels carried provisions for the advancing Persians, marvelling that Xerxes' camel train was attacked by lions while marching between Acanthus and Therma, even though the lions had never seen that beast before, nor had any experience of it. We do not know whether these were dromedaries, like those used by Cyrus against Croesus of Lydia."

• "A camel's poop is so dry you can use it immediately to start a fire"
• Don't actually spit - vomit (so don't waste water)
• Babies born without hump
• Bactrians
  • Hump are ~75lbs each
  • Long shaggy coat in winter, shed in spring
• Camels sometimes cluster to keep cool - when body temp is lower than env temp
• 3rd eyelid moves sideways like windshield wiper
  • Can still see if that eyelid is closed, so can travel in sandstorms
• Nose traps moisture from exhalations
• Normally herbivore, but becomes omnivore when food is scarce (will eat owners' tents)
• Drink brackish water
• Sharp teeth
• Camel can be fully trained and be able to carry full load by age 5

p. 54

• Protolypus of N. America around size of rabbit
• Beginning of Pleistocene (3mya), Isthmus of Panama formed and Protolypus migrated to S. America

p. 55

• Camel gained water-storing abilities in Arabia