Introduction
The fundamental goal of veterinary clinical pharmacology is to optimize therapy for a particular patient (individual, herd, flock, etc.) based on pathophysiology and pharmacology. Veterinary therapeutics are made more interesting by limited knowledge such as:
- Financial constraints
- Limit diagnostic detail
- Limit therapeutic selection
- Limit therapeutic monitoring (all techniques used to evaluate therapy).
- Limited clinical trials in animal patients
- Limited outcome assessment information from clinical records
- Limited current susceptibility information (antimicrobial therapy)
| Therapeutic Decision Making |
| Empirical
| vs
| Analytical
|
- Therapeutic guidelines
- "Drugs of Choice"
- Personal experience
|
- Detailed Therapeutic Objectives
- Pharmacodynamics
- Pharmacokinetics
- Clinical trials results
|
| Advantages |
Advantages |
- Efficient
- Often listed in references
|
- Therapy tailored to specific patient circumstances
- New therapies incorporated into a trusted analysis
|
| Disadvantages |
Disadvantages |
- Hard to evaluate new therapies
- Subject to "operant conditioning"
- May ignore individual patient variables
|
- Time consuming
- Missing vairables
|
Prescribe empirically and:
- know when to take a closer look
- re-assess empirical when new therapies emerge
- maintain an awareness that it is possible to improve therapeutic perfomance
|
Structured decision analysis1
Therapeutic Objective: Provide effective antimicrobial
therapy for bovine respiratory disease complex (calves)
Historical susceptibility profile
- Probability that the organism is susceptible to penicillin = 70%
Translation: Out of 100 calves with BRDC, 70 will have an infection susceptible to penicillin.
- Probability that the organism is susceptible to ampicillin = 90%
Translation: Out of 100 calves with BRDC, 90 will have an infection susceptible to ampicillin. (Likely 70 will have an organism susceptible to both penicillin and ampicillin, 20 will have an organism suceptible to only ampicillin).
Historical estimate of efficacy (epidemiology)
- Probability of a cure if correct active antimicrobial is chosen = 90%
Translation: A few will not respond even if you do everything right.
- Probability of a cure if an inactive antimicrobial is chosen = 30%
Translation: You will have SOME success even if you choose wrong.
Costs and values:
- Ampicillin costs $25 / head for a full treatment.
- Penicillin costs $7 / head for a full treatment.
- A cured calf is worth $75, a dead calf is worth $0.00
Conclusions based on selected (hypothetical) values:
1. If you treat 100 calves with penicillin the value of treatment is:
- 72 calves respond (90% of 70 calves + 30% of 30 calves)
- ($75 x 72 calves) - (100 calves x $7 / calf) = $4700
2. If you treat 100 calves with ampicillin:
- 84 calves respond (90% of 90 calves + 30% of 10 calves)
- ($75 x 84 calves) - (100 calves x $25 / calf) = $3800
3. Even though ampicillin cures more calves it is not economically viable to do so because of the increased drug costs involved. What specific variables might change and make ampicillin a more attractive therapeutic alternative?
1 Weinstein MC and Fineberg HV (eds): Clinical Decision Analysis. Philadelphia: W.B. Saunders Co. 1980.
Sources of drug information
"Quick" References
- Veterinary Drug Handbook - Plumb If you're only going to own one book with pharmacology in it, this is probably it. Upside, it's comprehensive in a practical way and includes human drugs. Downside, don't expect single consistent dosing recommendations, that's why there are also formularies.
- Compendium of Veterinary Products, most current edition., North American Compendiums, 942 Military Street, Port Huron MI, 48060 (www.compasnac.com). Generally given away by a drug company, this is the best reference if you need to answer questions like: "What's available? For what is it approved?"
- USP Drug Information for the HealthCare Provider, Micromedex, P.O. Box 564, Wiilliston, VT 05495-0564. The quality of this reference is the result of the team of experts that review its content. Although an excellent reference, this one is probably too expensive. You should take a look at one if you have an opportunity. There are veterinary monographs available (special editions of the Journal of Veterinary Pharmacology and Therapeutics) for antimicrobials and non-steroidal anti-inflammatories.
- Physicians Desk Reference, P.O. Box 10689, Des Moines IA, 50336 Keep this one around if you intend to write prescriptions to a human pharmacy AND for the pictures of human medications to help you sort out small animal poisonings.
Internet Resources
- http://www.fda.gov/cvm/ - FDA Center for Veterinary Medicine Home Page for all things regulatory.
- http://dil.vetmed.vt.edu/ - FDACVM Approved animal drug products database. for the most up-to-date list of approved animal drugs.
- http://www.farad.org/ - Food Animal Residue Avoidance Database (FARAD) keeps an up-to-date formulary and can provide withdrawal guidance to veterinarians considering extra-label uses of drugs.
- http://www.ncbi.nlm.nih.gov/PubMed/ - PubMed at the National Library of Medicine when trying to adapt human therapies to animals, this may be your only source of useful information.
Text Books
- Serious students of pharmacology need one of:
- The Pharmacologic Basis of Therapeutics - Goodman and Gilman (The epic)
- Essentials of Pharmacology - Smith & Reynard (A bit more digestible).
- Veterinary Pharmacology and Therapeutics - Booth and MacDonaldNo particular advantage to this veterinary text.
- Antimicrobial Therapy - Prescott, Baggott, Walker
- If your orientation is small Animal:
- Current Veterinary Therapy (VIII - XII) - Kirk This is a non-overlapping series that repeats in approximately three year cycles. (You need to own at least three eventually).
- Small Animal Clinical Pharmacology and Therapeutics - Boothe
- Other species:
- Current Therapy in Equine Medicine - Robinson
- Current Therapy in Food Animal Medicine - Morrow
Miscellaneous handbooks and formularies
- Printed formularies from veterinary schools: Minnesota CVM, Purdue, Cornell, Washington State et al.
- PDA based formularies: Saunders Handbook of Veterinary Drugs - Dr. Mark Papich ed. This is an excellent pocket reference and includes both large and small animal formularies as well as information concerning adverse effects, mechanism, interaction, etc. Includes human drugs. Available for both Palm and Pocket PC.
Quality of Information
| Anecdotal |
Personal Observation |
Worst (and most) |
| Expert agreement on personal observation |
| Retrospective |
Case Reviews |
| Meta-analyses | Best (and least) |
| Controlled Clinical |
Blinded |
| Double-Blinded |
Veterinary Access to Drugs
Society's concerns:
- Efficacy in animal populations
- Safety in animal populations
- Safety of the food supply
- Susceptibility of human vs. animal pathogens
FDA Center for Veterinary Medicine
- Determine and enforce standards of efficacy and safety. (Approves drug products)
- Oversight for distribution channels, manufacturing practices.
- Records and catelogues "clinical experience." (Adverse reactions, inefficacy complaints).
- Funds and conducts drug research related to regulatory concerns.
Definitions
New Animal Drugs (NAD): New Drug
Originally - a drug that is not generally recognized by qualified experts as safe and effective.
Now - a drug which was approved and marketed after the 1962 amendment to the FD& C act.
Drugs approved pre-1962 - reviewed by NAS/NRC Committee; specific wording for many indications (especially antimicrobial) was changed.
Extra-label drug use
any use of a pharmaceutical product in a manner inconsistent with its label (not described on the label - different species, route, dose, disease)
"Restricted Use" vs OTC
"...when adequate directions for use cannot be written for the layman to safely and effectively use the drug."
Animal drugs may be approved as "restricted", OTC or both (with different indications).
- There is a definite marketing advantage for a company to sell a product
OTC.
- Perspective has always been: all animal drugs should be OTC unless a significant reason exists to "restrict"
- Restrictions based on level of knowledge necessary for use (diagnosis
needed?, safety of the drug for the animal??, dose form difficulties??)
Labeling (restricted product)
- The only phrase that restricts a drug to veterinary "prescription": "Federal law restricts this drug to use by or on the order of a licensed veterinarian"
- "For veterinary use only", "Sales to graduate veterinarians", "Restricted drug".
These are marketing phrases that have no legal basis
.
- Only claims and/or directions for use which require the restricted legend should be listed on the restricted product.
Labeling (OTC product)
- Tradename of the OTC product cannot be the same as for the restricted product.
- The OTC product must be distinguished by a different color or style for packaging.
Regulations
Congress writes the laws, the FDA determines best how to administer them.
(Regulatory discretion)
Food, Drug and Cosmetic Act - 1938
No new drug could be introduced without evidence of safety
Durham - Humphrey Amendment to FDC Act - 1951
Created classed for drugs: Prescription / OTC / Animal Drugs
Harrison - Kefauver Amendment to FDC Act - 1962
FDA must certify new drugs safe and effective (substantial evidence)
Close control over experimental drugs (distribution and use)
Drug surveillance after marketing
Regulation of manufacturing practices
AMDUCA (Animal Medicinal Drug Use Clarification Act) 1994
will now officially permit veterinarians, like physicians, to prescribe extralabel uses
key constraints:
- any extralabel use must not result in violative residues in food-producing
animals
- the use must be by or on the order of a veterinarian within a veterinary-client-patient
relationship
- non-DVMs may not legally use drugs in an extra-label manner on their own accord.
- FDA may restrict extralabel use in certain circumstances:
- FDA may establish a safe level for a residue for such extralabel uses
- if extralabel animal drug use presents a risk to public health or that
no analytical method has been developed and submitted, the Agency may
prohibit such extralabel use.
Extra-label use of the following drugs is PROHIBITED:
Chloramphenicol
Clenbuterol
Diethylstilbestrol (DES)
Dimetridazole
Ipronidazole
Other nitroimidazoles
Furazolidone
Nitrofurazone
Sulfonamide drugs in lactating dairy cattle (except approved use of sulfadimethoxine, sulfabromomethazine, and sulfaethoxypyridazine)
Fluoroquinolones
Glycopeptides
Phenylbutazone in female dairy cattle 20 months of age or older.
For additional details concerning AMDUCA. Click on the AMDUCA button on the web site menu or use the following URLs:
View the AVMA Extra-label Drug Use (ELDU) Brochure at: http://cpharm.vetmed.vt.edu/ELU/intro.htm
View an interactive Algorithm (Created from the AVMA Extra-label Use Brochure) at: http://cpharm.vetmed.vt.edu/ELU/algorithm/introduction.htm.
Animal Drug Availability Act 1996
- increased FDA flexibility for claims (reduces requirements in some cases)
- provides for greater direct interaction between animal drug sponsors and
the reviewers at FDA
- creates a new category of drugs -"Veterinary Feed Directive Drugs" (prescriptions
for feeds)
- supports "flexible labeling"
State Board of Pharmacy
According to the laws of the state of Virginia, a veterinary practice is a pharmacy as concerns sale and distribution of pharmaceuticals.
- Oversees sales to the public.
- (Sets standards for dispensing , ie. child-proof packaging)
- Enforces Controlled Substances requirements.
- Contact Virginia State Board of Pharmacy for Regulations
The Pharmaceutical Industry
Some factors considered during drug development (in relative order of importance).
- Number of doses used by the animal industry.
- Cost to produce each dose.
- Likely acceptance of dose regime (SID >>> BID > TID >>>QID etc.)
- Product "performance" (can you squeeze an automatic syringe full of the
stuff in Feb. in Iowa?)
- Withdrawal period (this may be higher on the list for some drugs)
- Need for a product like this (there is no therapeutic equivalent)
Organized Veterinary Medicine
AVMA Legislative initiatives
Practice Formulary
Stocking a practice
Prescription writing
Topic Summary
- Clinical pharmacology integrates pharmacology, pathophysiology and clinical medicine. Mastery requires the vocabulary and basic knowledge of all three.
- Finances constrain our diagnostic capabilities and our choice of therapeutic agents.
- Few, if any, therapeutic interventions are successful in 100% of patients. It is not possible to predict the outcome of drug treatment for a single animal. (It is possible to give odds, however).
- It follows from 3 that it is not possible to evaluate the efficacy of a particular therapy in a single patient. Decisions should be based on the results of controlled clinical trials.
- Veterinary drugs are regulated by the same Food, Drug & Cosmetic act used to regulate human drugs. Most of the requirements for drug approval are the same.
- Extra-label drug use results any time that the label is not followed explicitly (different species, dose, route, disease).
- Doses and intervals listed on approved animal drug products are usually a compromise between efficacy, safety, and compliance. The are rarely, if ever the best or only way to use a drug.
- The FD&C act was only recently amended by congress so that the FDA's extralabel policy became "law". There were no significant changes made in existing policy.
- There is no "prescription only" animal drug class. Rather, the FDA restricts the use of some drugs to licensed veterinarians. (Based on the extra knowledge that a veterinarian is supposed to possess about diagnosis, adverse reactions, routes of administration).
