Physicians are known for their oath of “first, do no harm” to their patients. Though this is not in the veterinary oath, these words should be taken to heart, especially regarding the administration of drugs.
Using unapproved routes of administration in food animals can lead to ineffectiveness of the drug, residue violations, injection site reactions, food safety and quality issues and illness or death in the animal.
During drug approval the FDA identifies a specific target organ to determine drug residues following administration by the approved route. “If an unapproved route is used, the residue profile becomes completely unpredictable,” explains Hans Coetzee, BVSc, Cert CHP, PhD, Dipl. ACVCP, Kansas State University. “This will greatly increase the risk for violative residues.” Coetzee gives the example of intramuscular (IM) administration of flunixin. “This is only approved for intravenous (IV) administration. If given IM, this will greatly increase the risk of a violative residue at the site of injection.”
In addition to drug residues at the injection site, certain compounds, such as the macrolide class of antibiotics, will result in significant tissue reactions at the site of injection. “If these are given IM instead of subcutaneously (SQ), there will be a much greater risk for significant bruising and swelling at the injection site,” adds Coetzee. Not only does this cause pain and discomfort to the animal but resolution of these lesions reduces meat quality and violates beef quality assurance regulations. Certain drugs given IV or parentally instead of IM can be fatal to food animals.
Some drugs will not work very effectively if given by an alternative route of administration. “For example, oral neomycin is not absorbed systemically following oral administration, so it will not be very effective if you are trying to treat a systemic infection with oral neomycin,” says Coetzee.
Beef quality issues are also an important factor. Beef Quality Assurance guidelines indicate the neck should be used for all SQ or IM injections to reduce the prevalence of injection site blemishes in whole-muscle cuts of beef, such as the round, sirloin and chuck. The prevalence of injection-site lesions in outside round muscles of market dairy cows was reported in one study as approximately 49%, resulting in producer losses of nearly $70 per cull cow due to product defects such as bruises, injection-site lesions and condemnations.
Route of administration
Drug distribution is based on gaining access to the blood stream and then to the body.
There have been some veterinarians who believe injecting reproductive hormone products in the top butt of the cow will enable the drug to more quickly reach the ovaries located nearby, but Mike Apley, DVM, PhD, Dipl. ACVCP, Kansas State University, says this isn’t how it works. “For tissues such as the ovaries, about anywhere you would inject would end up in the heart prior to getting to the ovaries. Both the circulatory system and the lymphatic system head to the heart first.”
It’s important to remember physiology and pharmacology when making choices about route of administration. A drug administered anywhere besides directly into the bloodstream (IV or intra-arterially) must reach the heart before it can circulate to the site of action, agrees Virginia Fajt, DVM, PhD, Dipl. ACVCP, Texas A&M University. “A drug must enter the arterial blood supply to move to the site of action. Since it is the arterial blood supply to the site of action that will deliver drug to that site, physical proximity to the desired site of action does not guarantee rapid drug movement to that site; more important is rate of drug absorption.”
Rate of absorption from the site of administration influences onset of action; absorption can be influenced by vascularity, muscle to connective tissue ratio (a drug is likely to move more slowly through non-vascularized tissue, since drug movement will depend only on diffusion), and activity of muscles, as well as drug formulation, Fajt explains. “A drug has to get into the bloodstream to move to the site of action, so anything that hinders absorption will delay onset of action.”
“Even with intratracheal administration, there is work to show that much of this will be absorbed into the blood stream and come back to the lung through the general circulation,” Apley adds. “Some ways veterinarians have tried to achieve higher local concentrations are through transdermal administration, regional IV perfusion using tourniquets, intra-articular administration, and intraosseous injection.”
Apley says prostaglandins are metabolized primarily in the lungs, which would receive 100% of cardiac output. “It is true that for a prostaglandin you get 100% pass through the primary organ of metabolism each time. But, wherever you put it, that is going to happen.”
A first-pass liver effect for some drugs would comprise the major concern for oral administration (100% for the gut through the liver first pass), notes Apley.
About the only site of administration that causes a little quirk in exposure to organ of metabolism is administration of suppositories. “In many mammal species the rectal mucosa is plumbed to the heart through the caudal vena cava rather than through the portal vein (straight to the liver) as is the rest of the colon and small intestines,” Apley says. “So, suppositories avoid 100% first pass through the liver just like an injection, but unlike the rest of the digestive tract.”
AMDUCA does not clearly state that liability for adverse effects are the responsibility of the prescribing veterinarian, except in the case of a violative residue. Animal health companies are not permitted to advertise or promote extralabel use. “One might surmise that use of a drug in an extralabel manner would not have the full force of animal health company support in the event of an adverse effect, since the label with its concomitant safety and efficacy studies would not be completely applicable,” Fajt says. “Remember that adverse effects can include lack of efficacy as well as toxicities and unexpected residues.”
Veterinarians can find themselves liable if they administer drugs or direct their producers to administer drugs in an unapproved fashion. “If a violative residue arises following off-label admin-istration of the drug — including site of administration — then the veterinarian will be liable,” cautions Coetzee.
Adhering to the label
Virginia Fajt, DVM, PhD, Dipl. ACVCP, says adhering to the label directions when using drugs in cattle is important for several reasons:
A labeled dose and route of administration have been shown to be effective for the claim on the label. Using a different route or dose may result in decreased efficacy.
Withdrawal data are based on the approved dose and route. Alterations in dose and route may result in differences in drug disposition (e.g., changes in absorption) that change the amount of drug left in tissues at the end of the labeled withdrawal period.
Adverse drug effects may occur at unlabeled doses or routes of administration. Adverse drug effects may include toxicity, damage to edible tissues, violative residues, and decreased efficacy. Veterinarians have the training to evaluate the potential adverse effects of using a drug in an extralabel manner and therefore make a decision to use a drug extralabel. However, not all adverse effects are predictable, and the veterinarian is responsible for adverse effects that occur due to extralabel use.
In the case of production drugs, AMDUCA explicitly prohibits extralabel use. Extralabel use of drugs is only permitted when the health of an animal is threatened or suffering or death may result from failure to treat.