Before a drug gets to market, it undergoes preclinical and clinical testing. Students will learn what regimens and endpoints are used to evaluate efficacy and safety, and what safety information is available and what safety information is not available when a drug comes on the market. The role of the market in drug development will be discussed. Students will prepare written answers to questions from in-class material.
- Compare major types of testing and species involved before proposed therapeutic agents can be used in patients.
- Identify the purposes of preclinical and clinical testing.
- Discuss the purpose of FDA review before drugs are put on the market.
- Provide reasons for the success or failure of drugs once they reach the marketplace.
Food and Drug Administration (FDA) clinical testing preclinical testing Phase I trials acute toxicity testing Phase II trials multiple dose testing Phase III trials safety Good Laboratory Practices (GLP) toxicity Quality Assurance (QA) efficacy legend drug No Observable Adverse Effect Level (NOAEL) unapproved drug LD50 drug label Good Manufacturing Practices drug withdrawal Investigational New Drug Application (IND) Dietary Supplement Health and Education Act New Drug Application (NDA) proprietary drug (over-the-counter), OTC nutraceutical extralabel use post-market surveillance
Each drug label can be expected to contain the following: (1) description (ingredients, class, chemistry); (2) clinical pharmacology (pharmacokinetic information, therapeutic concentrations); (3) indications of usage; (4) contraindications; (5) warnings; (6) precautions (drug interactions, information for patients); (7) adverse reactions; (8) drug abuse and dependence information; (9) overdose effects and treatment; (10) dosage and administration (ranges, intervals, duration, modifications for special populations); (11) how supplied; (12) optional toxicity data; (13) information on withdrawal for drugs used in food animals.
Students will view veterinary prescription drugs and human prescription drugs used in veterinary medicine along with their label information. Examples will be from major therapeutic categories discussed in the Fundamentals of Veterinary Pharmacology course. Each student will choose a product, read the label information and answer a series of questions related to the label information (e.g., what is the drug used for? does the label suggest it is a relatively safe or a relatively toxic drug? is the drug relatively stable? will the drug interfere with any diagnostic procedure? is the drug formulated so it could be used for both very small and very large animals?). Oral and written answers will be prepared for discussion.(10 points).
- Describe and compare information included on the drug label for human and veterinary preparations.
- Discuss the clinical usefulness of drug label information when drugs are used as specified and when they are used in an extralabel manner.
- Identify information that provides information on drug toxicities as presented on drug labels.
drug label drug safety drug toxicity adverse effects indications contraindications extralabel use
bioavailablity
species differences
Using routes of administration as an example of animal variability associated with drug administration, students will compare quantitative and quantal (yes/no) results. Delineation of reasons for the observations, including the variability, will be included in a written laboratory report (10 points).
- Compare and contrast time to peak effect, intensity of peak effect, and duration of action when drugs are given by oral and parenteral routes.
- Discuss variability associated with response to drug administration and how it can be indicated.
- Discuss differences between quantal (yes/no) and quantitative responses to drug adminstration.
- Evaulate the differences between two groups of patients given drugs by different routes of administration.
oral intramuscular intraperitoneal intravenous subcutaneous efficacy duration of effect
bioequivalence
quantal (yes/no) data
quantitative datespecies differences
CNS depression that progresses from sedation to hypnosis to anesthesia can be provided by drugs given by injection or by inhalation. Dose-response curves can be steep and margins of safety narrow or wide. Opioids, barbiturates, dissociative anesthetics, and inhalant halogens will be compared. The comparison table will be turned in as a written report (10 points).
- Identify therapeutic goals associated with the use of CNS depressants.
- Compare and contrast inhalant and injectable anesthetics, including mechanism of action, pharmacokinetics, and adverse effects.
- Discuss advantages and disadvantages of the use of dissociatives and opioids.
- Identify means for reducing adverse effects when CNS depressants are used.
anesthesia CNS depression analgesia inducation medullary paralysis hypoxia muscle relaxation preanesthetic medications respiratory failure stages of anesthesia neuroleptanalgesia immobilization controlled drug euthanasia dissociative cataleptic barbiturates pentobarbital
phenobarbitalthiopental intravenous inhalation halothane ketamine nitrous oxide morphine opioid oxymorphone neuroleptanalgesia redistributuion opioid receptor biotransformation naloxone agonist antagonist mixed agonist/antagonist anticonvulsant diazepam analeptic
Clinicians are using a variety of drugs to reduce anxiety, counteract depression, and induce changes in behavior in their patients. Evaluation is often based on subjective outcomes that are more easily assessed in human than in veterinary patients. Drugs used include phenothiazines, benzodiazepines, serotonin and catecholamine enhancers, alpha-2 agonists, and herbal remedies. Mechanisms responsible for effects and side effects will be included in the discussion. Students will turn in a comparison report (10 points).
- Discuss the pharmacology of agents used for behavioral modification, identifying properties that could contribute to their usefulness and to potential side effects.
- Discuss expectations associated with use of pharmacological behavior modification.
- Differentiate between pharmacological effects of drugs used for chemical restraint and drugs approved for veterinary use in treatment of separation anxiety and/or cognitive dysfunction.
tranquilizer phenothiazine acepromazine barbiturate phenobarbital opioid benzodiazepines diazepam (Valium®) alpha 2 agonist alpha 2 antagonist xylazine monamine monoamine oxidase MAO-B monamine reuptake inhibitors norepinephrine dopamine serotonin (5-HT) St. John's Wort selegiline (deprenyl, Anipryl®) tricyclic antidepressants clomipramine (Clomicalm®) fluoxetine (Reconcile®, Prozac®)
Students will be provided with data from anesthetized animals given therapeutic doses of sympathomimetics, sympatholytics, parasympathomimetics, and parasympatholytics. Cardiac function, blood pressure, and respiratory effects will be assessed. Homeostatic mechanisms used by the animals to counteract pertubations of the autonomic nervous will be considered in the responses observed. A written report will be prepared (10 points).
- Compare effects of alpha and beta adrenergic stimulation and alpha and beta adrenergic blockade on heart rate, respiration, and blood pressure. Provide explanations for the effects seen.
- Compare effects of acetylcholine, cholinesterase inhibition, and muscarinic blockade on heart rate, respiration, and blood pressure. Provide explanations for the effects seen.
- Explain the effects ganglionic blockade has on heart rate, respiration, and blood pressure.
- Evaluate the contribution of anesthesia to heart rate, respiration rate, and blood pressure in the absence and presence of ANS pertubations.
Autonomic Nervous System alpha-1 stimulation alpha-2 stimulation alpha-1 blockade alpha-2 blockade beta stimulation beta blockade muscarinic stimulation muscarinic blockade ganglionic stimulation ganglionic blockade epinephrine norepinephrine isoproterenol propranolol acetylcholine neostigmine atropine nicotine
Topic 7: REVIEW AND QUIZ
Discussion of major concepts associated with bringing a drug to market, animal variability associated with physiological responses, CNS drugs, and the autonomic nervous system.
Quiz, 25 points.
Autacoid drugs (hormones, antihormones, antiinflammatory drugs) come in many pharmaceutical variants, with the same pharmacological entity available as different salts and in different vehicles depending on solubility, desired use, and desired duration of action. Therapeutic agents used to alter the endocrine system and antiinflammatory drugs and their package inserts will be provided for viewing. In addition to drug labels as the source of drug information, students will have opportunity to view other references that provide information on each individual therapeutic agent separately, and general references that provide information on drug classes with comparison information on drugs in that class. Case scenarios involving endocrine and/or antiinflammatory drugs will be presented, and written answers to questions on a clinical case will be prepared (10 points).
- Prepare a written discussion of a clinical case in which pharmaceutical preparation can affect how a drug is used.
- Inspect pharmaceutical preparations of endocrine and antiinflammatory drugs, noting that some exist as free drugs, some as salts, and that various routes of administration may be used. Contrast for peptide and steroid hormones.
- Identify references of value in pharmacology and therapeutics.
- Review endocrine and antiinflammatory drug pharmacology, and define the relationship between physiology and the use of therapuetic agents (why and how they work).
pharmaceutical preparation pharmacokinetics peptide hormone steroid hormone thyroid regular insulin Lente insulin hydrocortisone prednisone prednisolone dexamethasone soluble salt insoluble salt duration of action absorption aspirin phenylbutazone flunixin (Banamine®) H-1 blocker
antihistamineDMSO, dimethyl sulfoxide
anti-inflammatory agent
Discussion of regulatory and medical aspects of drug residues. Calculation of depletion curves with extralabel use of medicinal agents in food animals. Written answers for questions will be prepared (10 points).
- Identify sources of information about drug clearance following labeled and extralabel use.
- Discuss the role of the Animal Medicinal Drug Use Clarification Act (AMDUCA) in reducing the risk of drug residues.
- Evaluate factors that could contribute to differences in drug clearance in different species of animals.
- Discuss the importance of drug residues from the aspect of human safety.
Food and Drug Administration Animal Medicinal Drug Use Clarification Act (AMDUCA) Veterinary Feed Directive pharmacokinetics residue extralabel use FARAD species differences age differences route of administration human safety FDA tolerance level clearance half-life CVM / FDA The Green Book
Clinical scenarios involving pharmacokinetic principles, including rational regimen development when dosages and intervals are given in ranges, regimen development when clearance is impaired or volume of distribution is altered, rational regimen adjustment in cases of species differences (cats versus dogs), pulse dosing of aminoglycosides in neonates, regimen adjustment in the presence of enzyme induction, and regimen adjustment based on dosage form. A written laboratory report will be prepared (20 points).
- Using antimicrobial agents as examples, determine differences in blood levels and clearance when dosages and when routes of administration differ.
- Evaluate the effects of varying dosage regimen (dosage level and interval) on therapeutic effectiveness and safety.
- Examine the contributions made by immaturity or disease on drug pharmacokinetics.
- Using a computer model, develop regimens for treatment that are safe, effective, and provide ease for client compliance.
volume of distribution elimination rate constant clearance peak concentration trough concentration Minimal inhibitory concentration Minimal toxic concentration steady state dosage regimen dosage interval Dr. Wilcke's Clinical Pharmacology Class Notes: http://cpharm.vetmed.vt.edu, click on KinetiClass ®
Topic 12 PHARMACY TOUR
Students will have opportunity to observe how drugs are ordered, received and stored to meet state and federal requirements. A special facility for preparation of anticancer drugs will be viewed. In-hospital and outpatient orders for therapeutic agents will be observed and compared as to requirements and records. Written answers to questions will be prepared, (10 points).
- Discuss requirements for drug orders and dispensing to hospital in-patients, including dosage calculations.
- Examine outpatient prescriptions and describe the information necessary.
- Explain the need for safety procedures for preparation of compounded veterinary preparations, especially those needed for cancer patients.
- Examine patient charts for evidence of multi-drug use and potential for drug interactions.
KEY WORDS:
clinician's order drug dispensing record safety cabinet controlled substance storage prescription
dosage calculationhospital formulary
Discussion of major concepts associated with use of pharmaceutical and pharmacokinetic information in therapeutics and clinical practice. Discussion of role of VMTH Pharmacy.
Quiz, 25 points.
Students will consider therapeutic value, side effects, and interactions when drugs are used in clinical scenarios that include congestive heart failure with and without arrhythmias, hypertension, antiinflammatory drug overdose, bronchial disease, and/or renal failure. Diuretic effects on electrolytes will be calculated. A written report and answers to questions will be prepared (10 points).
- Delineate drugs that could be used alone and in combination for treatment of clinical conditions that directly or indirectly affect the cardiovascular system.
- Identify at least three major clinical conditions which are appropriate indications for the use of diuretics and indicate why these agents would be included in a therapeutic regimen.
- Examine effects of diuretics on excretion of sodium, potassium, and bicarbonate.
vasodilator cardiotonic antiarrhythmia agent diuretic antihypertensive prostaglandin potassium sodium carbonic anhydrase
creatinine clearanceangiotensin-converting enzyme inhibitor loop diureretic phosphodiesterase inhibitors thiazide diuretic
Texts and Special Teaching Aids
GM Brenner & CW Stevens: Pharmacology, 2nd Edition, WB Saunders Co., Philadelphia, 2006.
KinetiClass Program: http://cpharm.vetmed.vt.edu, click on KinetiClass ®
Other materials provided by instructors.
Questions and case preparations, 7 x 10
Quizzes, 2 x 25
Reports 5 x 10
Total = 170 points