Veterinary Drug Handbook (VDH) is the reference veterinarians turn to when they want an independent source of information on the drugs that are used in veterinary medicine today.


DOXYCYCLINE CALCIUM, DOXYCYCLINE HYCLATE, DOXYCYCLINE MONOHYDRATE

Chemistry - A semi-synthetic tetracycline that is derived from oxytetracycline, doxycycline isavailable as hyclate, calcium and monohydrate salts. The hyclate salt is used in the injectable dosageform and in oral tablets and capsules. It occurs as a yellow, crystalline powder that is soluble inwater and slightly soluble in alcohol. After reconstitution with sterile water, the hyclate injection hasa pH of 1.8-3.3. Doxycycline hyclate may also be known as doxycycline hydrochloride.
The monohydrate salt is found in the oral powder for reconstitution. It occurs as a yellow, crystalline powder that is very slightly soluble in water and sparingly soluble in alcohol. The calcium salt is formed in situ during manufacturing. It is found in the commercially available oral syrup.

Storage, Stability, Compatibility

Doxycycline hyclate tablets and capsules should be stored in tight, light resistant containers at temperatures less than 30°C, and preferably at room temperature (15-30°C). After reconstituting with water, the monohydrate oral suspension is stable for 14 days when stored at room temperature.
The hyclate injection when reconstituted with a suitable diluent (e.g., D5W, Ringer's injection,
Sodium Chloride 0.9%, or Plasma-Lyte 56 in D5W) to a concentration of 0.1 to 1 mg/ml may bestored for 72 hours if refrigerated. Frozen reconstituted solutions (10 mg/ml in sterile water) arestable for at least 8 weeks if kept at -20°C, but should not be refrozen once thawed. If solutions arestored at room temperature, different manufacturers give different recommendations regardingstability, ranging from 12-48 hours. Infusions should generally be completed within 12 hours ofadministration.
Doxycycline hyclate for injection is reportedly compatible with the following IV infusion solutions and drugs: D5W, Ringer's injection, sodium chloride 0.9%, or Plasma-Lyte 56 in D5W,
Plasma-Lyte 148 in D5W, Normosol M in D5W, Normosol R in D5W, invert sugar 10%, acyclovir sodium, hydromorphone HCl, magnesium sulfate, meperidine HCl, morphine sulfate, perphenazine and ranitidine HCl. Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used. It is suggested to consult specialized references for more specific information (e.g., Handbook on Injectable Drugs by Trissel; see bibliography).

Pharmacology - DOXYCYCLINE CALCIUM, DOXYCYCLINE HYCLATE, DOXYCYCLINE MONOHYDRATE

Tetracyclines generally act as bacteriostatic antibiotics and inhibit protein synthesis by reversibly binding to 30S ribosomal subunits of susceptible organisms, thereby preventing binding to those ribosomes of aminoacyl transfer-RNA. Tetracyclines also are believed to reversibly bind to 50S ribosomes and additionally alter cytoplasmic membrane permeability insusceptible organisms. In high concentrations, tetracyclines can also inhibit protein synthesis bymammalian cells.
As a class, the tetracyclines have activity against most mycoplasma, spirochetes (including the
Lyme disease organism), Chlamydia and Rickettsia. Against gram positive bacteria, the tetracyclineshave activity against some strains of staphylococcus and streptococci, but resistance of theseorganisms is increasing. Gram positive bacteria that are usually covered by tetracyclines, include
Actinomyces sp., Bacillus anthracis, Clostridium perfringens and tetani, Listeria monocytogenesand Nocardia. Among gram negative bacteria that tetracyclines usually have in vitro and in vivoactivity against, include Bordetella sp., Brucella, Bartonella, Haemophilus sp., Pasturellamultocida, Shigella, and Yersinia pestis. Many or most strains of E. coli, Klebsiella, Bacteroides,
Enterobacter, Proteus and Pseudomonas aeruginosa are resistant to the tetracyclines.
Doxycycline generally has very similar activity as other tetracyclines against susceptible organisms, but some strains of bacteria may be more susceptible to doxycycline or minocycline and additional in vitro testing may be required.

Uses, Indications

Although there are no veterinary-approved doxycycline products available, itsfavorable pharmacokinetic parameters (longer half-life, higher CNS penetration) when compared toeither tetracycline HCl or oxytetracycline HCl make it a reasonable choice to use in small animalswhen a tetracycline is indicated, particularly when a tetracycline is indicated in an azotemic patient.
Because there is apparently less clinical experience with this agent in small animals than with eithertetracycline or oxytetracycline, some caution should be employed before routinely using.
In avian species, some clinicians feel that doxycycline is the drug of choice in the oral treatment ofpsittacosis, particularly when treating only a few birds.

Pharmacokinetics - DOXYCYCLINE CALCIUM, DOXYCYCLINE HYCLATE, DOXYCYCLINE MONOHYDRATE

Doxycycline is well absorbed after oral administration. Bioavailability is 90-100% in humans. No bioavailability data was located for veterinary species, but it is thought that the drug is also readily absorbed in monogastric animals. Unlike tetracycline HCl or oxytetracycline, doxycycline absorption may only be reduced by 20% by either food or dairy products in the gut.
This is not considered to be clinically important.
Tetracyclines as a class, are widely distributed to the heart, kidney, lungs, muscle, pleural fluid, bronchial secretions, sputum, bile, saliva, synovial fluid, ascitic fluid, and aqueous and vitreoushumor. Doxycycline is more lipid soluble and penetrates body tissues and fluids better than tetracycline HCl or oxytetracycline, including to the CSF, prostate and eye. While CSF levels are generally insufficient to treat most bacterial infections, doxycycline has been shown to be efficacious in the treatment of the CNS effects associated with Lyme disease in humans. The volume ofdistribution at steady-state in dogs is approximately 1.5 L/kg. Doxycycline is bound to plasmaproteins in varying amounts dependent upon species. The drug is approximately 25-93% bound toplasma proteins in humans, 75-86% in dogs, and about 93% in cattle and pigs.
Doxycycline's elimination from the body is relatively unique. The drug is primarily excreted intothe feces via non-biliary routes in an inactive form. It is thought that the drug is partially inactivatedin the intestine by chelate formation and then excreted into the intestinal lumen. In dogs, about 75%of a given dose is handled in this manner. Renal excretion of doxycycline can only account forabout 25% of a dose in dogs, and biliary excretion less than 5%. The serum half-life of doxycyclinein dogs is approximately 10-12 hours and a clearance of about 1.7 ml/kg/min. In calves, the drughas similar pharmacokinetic values. Doxycycline does not accumulate in patients with renaldysfunction.

Contraindications, Precautions, Reproductive Safety

Doxycycline is contraindicated in patients hypersensitive to it. Because tetracyclines can retard fetal skeletal development and discolordeciduous teeth, they should only be used in the last half of pregnancy when the benefits outweighthe fetal risks. Doxycycline is considered to be less likely to cause these abnormalities than othermore water soluble tetracyclines (e.g., tetracycline, oxytetracycline). Unlike either oxytetracycline ortetracycline, doxycycline can be used in patients with renal insufficiency.
Until further studies documenting the safety of intravenous doxycycline in horses are done, theparenteral route of administering this drug in horses should be considered contraindicated.

Adverse Effects, Warnings

The most commonly reported sided effects of oral doxycyclinetherapy in dogs and cats are nausea and vomiting. To alleviate these effects, the drug could be givenwith food without clinically significant reductions in drug absorption.
Tetracycline therapy (especially long-term) may result in overgrowth (superinfections) of nonsusceptible bacteria or fungi.
In humans, doxycycline (or other tetracyclines) has also been associated with photosensitivityreactions and, rarely, hepatotoxicity or blood dyscrasias.
Intravenous injection of even relatively low doses of doxycycline has been associated with cardiacarrhythmias, collapse and death in horses.

Overdosage, Acute Toxicity

With the exception of intravenous dosing in horses (see above), doxycycline is apparently quite safe in most mild overdose situations. Oral overdoses would mostlikely be associated with GI disturbances (vomiting, anorexia, and/or diarrhea). Althoughdoxycycline is less vulnerable to chelation with cations than other tetracyclines, oral administrationof divalent or trivalent cation antacids may bind some of the drug and reduce GI distress. Shouldthe patient develop severe emesis or diarrhea, fluids and electrolytes should be monitored andreplaced if necessary.
Rapid intravenous injection of doxycycline has induced transient collapse and cardiac arrhythmiasin several species, presumably due to chelation with intravascular calcium ions. If overdosequantities are inadvertently administered, these effects may be more pronounced.

Drug Interactions

When orally administered, tetracyclines can chelate divalent or trivalentcations which can decrease the absorption of the tetracycline or the other drug if it contains thesecations. Oral antacids, saline cathartics or other GI products containing aluminum, calcium, magnesium, zinc or bismuth cations are most commonly associated with this interaction.
Doxycycline has a relatively low affinity for calcium ions, but it is recommended that all oraltetracyclines be given at least 1-2 hours before or after the cation-containing product.
Oral iron products are also associated with decreased tetracycline absorption, and administrationof iron salts should preferably be given 3 hours before or 2 hours after the tetracycline dose. Oralsodium bicarbonate, kaolin, pectin, or bismuth subsalicylate may impair tetracyclineabsorption when given together orally.
Bacteriostatic drugs like the tetracyclines, may interfere with bactericidal activity of the penicillins, cephalosporins, and aminoglycosides. There is some amount of controversy regardingthe actual clinical significance of this interaction, however.
Tetracyclines may increase the bioavailability of digoxin in a small percentage of patients(human) and lead to digoxin toxicity. These effects may persist for months after discontinuation ofthe tetracycline.
Tetracyclines may depress plasma prothrombin activity and patients on anticoagulant (e.g., warfarin) therapy may need dosage adjustment. Tetracyclines have been reported to increase thenephrotoxic effects of methoxyflurane and tetracycline HCl or Oxytetracycline are not recommended to used with methoxyflurane.
GI side effects may be increased if tetracyclines are administered concurrently with theophyllineproducts.
Tetracyclines have reportedly reduced insulin requirements in diabetic patients, but this interaction is yet to be confirmed with controlled studies.
Drug/Laboratory Interactions - Tetracyclines (not minocycline) may cause falsely elevatedvalues of urine catecholamines when using fluorometric methods of determination.
Tetracyclines reportedly can cause false-positive urine glucose results if using the cupric sulfatemethod of determination (Benedict's reagent, Clinitest®), but this may be the result of ascorbic acidwhich is found in some parenteral formulations of tetracyclines. Tetracyclines have also reportedlycaused false-negative results in determining urine glucose when using the glucose oxidase method(Clinistix®, Tes-Tape®).