Zinc salts

Overview

Zinc salts are mineral supplements used in dogs and cats primarily for the treatment of zinc-responsive dermatoses and for reduction of copper accumulation in hepatic disorders.

Zinc plays an important role in DNA and RNA synthesis, essential fatty acid metabolism, white blood cell function, and multiple intermediary metabolic reactions. In addition to its nutritional functions, oral zinc administration can reduce gastrointestinal absorption and hepatic uptake of copper.

Multiple zinc formulations are available with differing oral bioavailability and gastrointestinal tolerance. Zinc salts differ in how much elemental zinc they contain and in how well they are tolerated, so the salt and the elemental-zinc dose have to be matched to each other.

Mechanism of Action (MOA): Zinc participates in numerous enzymatic and metabolic pathways and induces metallothionein in intestinal cells, which binds dietary copper and prevents its transfer into the blood, thereby lowering hepatic copper accumulation.

Indications

Zinc salts are used in dogs and cats for dermatologic and hepatic disorders associated with zinc deficiency or abnormal copper accumulation.

• Zinc-responsive dermatoses: Used for treatment of dermatologic disorders associated with zinc deficiency or impaired zinc metabolism.
• Copper storage disease: Used to reduce copper absorption and hepatic copper accumulation in dogs with copper-associated hepatopathy.
• Chronic hepatitis: Used in dogs to prevent copper accumulation in chronic hepatitis and for antioxidant and antifibrotic effects; the response is slow and may take as long as three months for full effect.
• Hepatic encephalopathy: Supportive therapy may be considered in hepatic encephalopathy when low zinc is documented; two urea-cycle enzymes require zinc, although the evidence that portosystemic shunting depletes zinc reserves comes from people.
• Hepatic fibrosis: Used in dogs in the treatment of hepatic fibrosis, where zinc competes with iron to inhibit fibrosis and collagen formation.
• Superficial necrolytic dermatitis: Adjunctive therapy for superficial necrolytic dermatitis, also called metabolic epidermal necrosis or hepatocutaneous syndrome, in dogs and cats.
• Severe hepatic lipidosis in cats: Adjunctive therapy of severe hepatic lipidosis in cats.

Dosage (Reference)

Dog

In dogs, zinc salts are given orally for dermatologic disorders and for hepatic conditions associated with copper accumulation; a parenteral zinc sulphate regimen is reserved for dermatosis cases that do not respond to oral treatment.

Cat

In cats, zinc is given orally, but the feline protocols are not the same as the canine ones: specific doses are described for severe hepatic lipidosis and for primary copper hepatopathy, while doses for superficial necrolytic dermatitis are not well described and are extrapolated from dogs.

Warnings & Precautions

Zinc salts should be used carefully in dogs and cats because excessive supplementation or altered mineral balance may result in gastrointestinal or hematologic adverse effects.

• Contraindications: Do not use in patients with copper deficiency.
• Gastrointestinal tolerance: Oral zinc may cause nausea, vomiting or diarrhea. Gastrointestinal tolerance differs between salts, and sources disagree whether gluconate or acetate and methionine is least irritating.
• Dermatologic therapy: Concurrent supplementation with essential fatty acids is advised for treatment of skin disorders.
• Concurrent copper: Do not give zinc and copper together: co-administration negates the effect of both. Where copper cannot be avoided, separate the doses by at least 2 hours.
• Injectable products: Parenteral use is formulation-specific. Commercial zinc sulphate injection is an additive for parenteral nutrition solutions and must not be given undiluted or by direct intravenous infusion; it contains aluminum, and prolonged administration may cause aluminum toxicity in animals with renal insufficiency. Separate slow intravenous or intramuscular regimens using sterile zinc sulphate solutions have been described. Do not treat these injectable preparations as interchangeable.
• Salt versus elemental zinc: Do not confuse the dose of a zinc salt with the dose of elemental zinc. The two differ several-fold – 1 mg of elemental zinc is supplied by 2.8 mg of zinc acetate or 7.14 mg of zinc gluconate – and the error is a dosing hazard in both directions.
• Pregnancy and lactation: Zinc requirements increase during pregnancy. In people, zinc deficiency is very rare and routine supplementation during pregnancy is not recommended; no impaired fertility or fetal harm was observed in laboratory animals at up to six times the recommended human dose. Zinc is excreted in milk, so use cautiously during lactation.
• Choice of salt: Avoid zinc methionine in patients with hepatic encephalopathy.

Drug Interactions

Zinc salts may interfere with the absorption or metabolism of several minerals and orally administered medications.

Concomitant use is not necessarily contraindicated unless specifically stated; weigh the potential risks and perform additional monitoring when appropriate.

• Iron and copper: Significant interactions with other divalent heavy metals may occur, and prolonged zinc administration may decrease hepatic copper or iron stores.
• Penicillamine: May inhibit zinc absorption, and zinc salts may reduce the absorption of penicillamine; the combination is considered contraindicated in dogs with hepatopathy.
• Ursodeoxycholic acid: May potentially inhibit zinc absorption.
• Oral tetracyclines: Zinc salts may chelate tetracycline antibiotics and reduce their absorption; separate administration by at least 2 hours.
• Fluoroquinolone antibiotics: Zinc salts may reduce oral absorption of fluoroquinolones.
• Calcium: Oral calcium supplements may inhibit zinc absorption, and high dietary calcium or phosphorus impairs it as well.
• Other copper chelators: Trientine may not be effective if zinc is given at the same time.
• Combining zinc with a chelator: Combined use of zinc with penicillamine or trientine is controversial: it has been described in practice, but other references warn that each may reduce the other’s effectiveness, and consider zinc plus penicillamine contraindicated in dogs with hepatopathy.
• Phytate-containing foods: Dietary phytates – in bran, cereal grains and soy- or corn-based diets – chelate zinc and reduce its absorption. Where the dermatosis is caused by such a diet, supplementation may be discontinued once the diet has been corrected and clinical signs have resolved.

Side Effects & Overdose

Side Effects

Gastrointestinal adverse effects are the most commonly reported side effects associated with oral zinc supplementation.

• Gastrointestinal effects: Oral zinc may cause nausea, vomiting, inappetence, gastritis or diarrhea, particularly when given without food.
• Pancreatic enzyme changes reported in people: In people receiving zinc acetate, elevations of alkaline phosphatase, amylase and lipase suggesting pancreatitis have been reported and may persist for weeks to months.

Overdose

Excessive zinc administration or markedly elevated serum zinc concentrations may result in hematologic complications.

• Hemolysis: Hemolysis: Large doses or serum zinc concentrations above approximately 800–1,000 μg/dL may cause regenerative hemolytic anemia, particularly in animals with concurrent copper deficiency.
• Copper deficiency–associated toxicity: Risk of hemolysis may increase when concurrent copper deficiency is present.
• Clinical signs: The commonest signs in dogs and cats are vomiting, diarrhea, polydipsia and lethargy. Reported signs in mammals also include hemolytic anemia, neutropenia, hypotension, acute pancreatitis, jaundice and pulmonary edema.
• Usual source: Most zinc toxicosis follows ingestion of a zinc-containing object rather than over-supplementation; US coins minted after 1982 are the commonest source, and small-breed dogs under 30 pounds are over-represented – a small pylorus retains the object.
• Threshold intake: Toxic doses are not well defined; an unreferenced median lethal oral dose for zinc salts of 100 mg/kg is quoted. In therapeutic use, an oral intake above 200 mg per day can cause hemolytic anemia.
• Diagnosis: Serum zinc is often above 5 ppm in zinc toxicosis, compared with a normal range of approximately 0.70–2 ppm in dogs and cats.
• Management: Remove the source first: rapid endoscopic or surgical removal of the object, intravenous fluids to maintain hydration and diuresis, and transfusion for severe intravascular hemolysis. Zinc concentrations fall within days once the source is gone, so chelation is often unnecessary. Reducing stomach acidity with an H2-blocker, a proton-pump inhibitor, sucralfate or an antacid slows the release and absorption of zinc.
• Monitoring: For the first 72 hours after removing the zinc source, monitor PCV, red cell count, coagulation profile, amylase, lipase, BUN, creatinine, ALP, AST and ALT. Monitor serum zinc, and use an ECG to watch for arrhythmias and ST-segment changes.
• Drugs to avoid: During zinc toxicosis, avoid aminoglycoside antibiotics and other potentially nephrotoxic drugs; they add to the risk of acute renal failure.
• Chelation: If clinical improvement or a fall in serum zinc does not follow removal of the source, chelation may be used: penicillamine 110 mg/kg/day PO divided every 6 to 8 hours for 5 to 14 days is the safer choice, and calcium EDTA 100 mg/kg/day SC in four divided doses is potentially nephrotoxic. Succimer has also been used. Consult a 24-hour poison-control center.
• Prognosis: Rapid removal of the source may give progressive improvement over 48 to 72 hours, with complete recovery possible. Multiple organ failure, disseminated intravascular coagulation, pancreatic disease and cardiopulmonary arrest are not common but are potential outcomes.

Key Notes

Practical clinical points that help optimize the use of zinc salts in dogs and cats:

• Multiple formulations available: Zinc sulphate, gluconate, acetate, methionine and chelated preparations are available and differ in elemental-zinc content and gastrointestinal tolerance: zinc acetate 30%, zinc sulphate 23%, zinc methionine 21% and zinc gluconate 14.3%.
• Elemental-zinc content: Zinc preparations differ in elemental-zinc content: zinc acetate approximately 30% (some products or references give 35%), zinc sulphate 23%, zinc methionine 21% and zinc gluconate 14.3%. Confirm the exact content from the product label.
• Copper reduction effect: Oral zinc administration can decrease gastrointestinal absorption and hepatic uptake of copper.
• Biological roles: Zinc is required by over 200 metalloenzymes, maintains the structural integrity of cell membranes and nucleic acids, and is needed for sexual maturation and reproduction, cell growth and division, vision and night vision, wound healing, immune response and taste acuity.
• Salt-to-elemental conversion: 1 mg of elemental zinc is supplied by 2.8 mg zinc acetate, 2.09 mg zinc chloride, 7.14 mg zinc gluconate or 4.4 mg zinc sulphate; 5 mg of zinc methionine supplies 1 mg of elemental zinc.
• Monitoring schedule: Measure baseline zinc and recheck during the first two to three weeks until stable. Published maintenance intervals range from monthly to every two to three months. Aim for a plasma zinc of 200 to 500 micrograms/dL and avoid concentrations of 800 micrograms/dL or more. Measure a CBC periodically for hemolytic anemia, quantify hepatic copper where possible, and follow serum ALT serially where it is not.
• Limits of serum zinc: Serum zinc correlates poorly with zinc-deficient states in dogs and does not reflect liver zinc concentration, so it is more useful for detecting toxic intake than for confirming deficiency.
• Onset of effect: In dogs, zinc is slow-acting in copper-related liver disease and may take as long as three months for full effect; it is not a substitute for chelation in dogs with high copper concentrations and active hepatitis.
• Strength of the evidence: Evidence in canine copper-associated hepatopathy is limited to a small study of six dogs, which showed reduced hepatic copper after two years. Zinc may be useful in early disease when hepatic copper is below 1,000 micrograms/g dry liver, but low-dose zinc added to a copper-restricted diet gave no additional benefit in previously chelated Labrador retrievers.
• Antifibrotic and antioxidant action: Zinc competes with iron to inhibit fibrosis and collagen formation and also acts as an antioxidant, which is the basis of its antifibrotic use in liver disease.
• Absorption and elimination: About 20 to 30% of dietary zinc is absorbed, mainly from the duodenum and ileum; it is stored mostly in red and white blood cells and eliminated mainly in the feces.
• Storage: Store zinc products in tightly sealed containers, protected from light, at room temperature; store zinc acetate crystals in tight containers and zinc sulphate products at 15 to 30 degrees C.
• Client information: Do not give more than prescribed; zinc can be very toxic, especially in dogs. Return for the recommended blood tests during treatment and do not miss follow-up visits.
• Elemental content of zinc acetate: Sources differ on the elemental-zinc content of zinc acetate: some give about 30% and another gives 35%. Where the exact amount matters, confirm it against the product label.
• Which salt is best tolerated: Sources differ on which salt is best tolerated: one reports that zinc gluconate is better tolerated than the sulphate or acetate forms, another that zinc acetate or methionine is less irritating than other salts.