Exam 1 Flashcards
Lecture 1
Clinical Pharmacology
-How to use a drug safely (indication)
-How to use the drug in a species-specifc manner
-How to plan the most appropriate therapy
Pharmacokinetics
What the body does to the drug
Changes in any of the following parameters affects relative plasma drug concentrations.
-Absorption
-Bioavailability
-Clearance
-Biotransformation
-Distribution
How elimination half-life and dosing frequency determine steady-state concentrations
Understand how plasma concentrations of a drug will tend to change if changes are made to the regimen
-Route
-Dose
-Frequency
-Duration
Pharmacodynamics
What the drug does to the body
Compare and contrast
-Agonists
-Partial Agonist
-Antagonist
-Potency
-Efficacy
-Effect
-Therapeutic index (margin of safety)
-Toxicity
Drug and Regimen Selection
-Safely and accurate determine doses, convey dosing information, select formulations (given patients weight, concentration units, strength, route of administration, etc from information provided in the labels) and the variability in units given for dosing recommendations
-Interconvert English and metric weight units, weight/volume, weight percent, dilution volumes for desired concentrations, calculate volume or weight of drug to administer based on dose.
-Use results from antimicrobial susceptibility testing to select and antimicrobial drug and regimen
Drug dispensing, regulations, and ethics
-Know that controlled stricter storage, record keeping, and prescription writing characteristics
-Know how to find information on how different jurisdictions have different requirements
What is a drug?
-Medicine, xenobiotic, pharmaceutical…
-Drug product: Active + Inactive components (excipients)
-Pharmaceutical form: tablets, capsules, injectable, solution, suspension, trandermal, etc…
Excipients
-Can affect PK and PD
-Can affect drug absorption: sustained vs. immediate release. Generic vs. brand names
-This can impact the concentration effect relationship: increase or decrease
Pharmacokinetics
-Explores how a drug moves in the body
-How drug concentration in plasma changes with time after dosing
-Affects onset, intensity, and duration of effect
-Explores how a drug behaves in the body: how it effect changes as the drug exposure changes
-MOA: what the drug does to the body. beneficial and toxic effects. From molecular action to clinical effect.
Clinical Pharmacokinetics
-The application of pharmacokinetic principles to the safe and effective therapeutic management of drugs in individual patients
-Primary goals of clinical pharmacokinetics include enhancing efficacy and decreasing toxicity of a patient’s drug therapy and understanding the factors that contribute to interindividual variability
Therapeutic Window & Therapeutic Index
-The range of a drug’s serum (or plasma, or other matrix) concentration at which a desired effect occurs, below which there is little effect, above which toxicity occurs.
Therapeutic Index
-Calculated by dividing the 50% value of toxicity by the 50% value of efficacy
Example: Phenobarbital
Efficay = Peak
Toxicity = trough
-Too high: potential renal toxicity
-Also AUC (area under the curve) can contribute to toxicity
Therapeutic Drug Monitoring
-Conditions where TDM is not usually needed: wide therapeutic window, undefined active metabolites (unsure what to measure), idiopathic toxicities = any exposure will lead to adverse effects.
-Downfalls of TDM: Cost, Sampling time, Calculations
Potency vs. Efficacy
Which drug has a higher potency?
Are they both equally efficient?
-Minimum effective concentration: a certain amount of drug that must be present in the body to produce an effect
-Efficacy: how well a drug produces its desired effect EC50.
-EC50: concentration required to achieve 50% of maximum effect
When comparing similar drugs Lower EC50 = higher potency
-Drug A has higher potency
-Both drugs reach 100% efficacy so they are of equally efficacies
Potency Examples
-Fentanyl: 1 ug/kg = higher potency
-Morphine: 1mg/kg
Potency vs. Efficacy
More potent drugs
-Need lower concentrations to reach a given % of maximum effect
More efficacious drugs
-Higher maximal effect
Clinician should generally favor efficacy rather than potency, unless safety is a concern
-Ex: Butorphanol more potent, but less efficacious than morphine
-Ex: Salbutamol EC50 5.6nM, Terbutaline 13.8 nM, Clenbuterol 2.1 nM (most potent). All same max effect
Agonists vs. Antagonists
-Agonists: Drugs that occupy receptors and activate them
-Antagonists: drugs that occupy receptors but DO NOT ACTIVE them. Antagonists block receptor activation by agonists.
-Agonist+Antagonist: Less activation
Examples
Fentanyl - mu-agonist (pure, 100x potent as morphine)
Morphine - Agonist of mu-receptors. mu agonist (some delta and kappa affinity)
Naloxone - Antagonist of mu-receptors. Pure mu antagonist; affinity but no activity at mu and kappa receptors.
Butorphanol - Agonist-Antagonist. Kappa agonist; partial mu agonist/antagonist. Not same level of anesthesia as full agonist.
Buprenorphine - Partial agonist of mu-receptors; Kappa antagonists.
Inhibition
Competitive Inhibition
-Inhibition of a pathway due to one substance competing with another substance
Example
-Isoproterenol: non-selective Beta receptor agonist for treatment of bradycardia
-Propanolol: Beta receptor antagonist for the treatment of tachycardia
Loss of potency
Inhibition Non-Competitive
-Either irreversible binding of antagonist at the receptor
-Or interaction of the antagonist at the site away from the receptor (but to which the agonist doesn’t bind) that prevents initiation of effect.
Example:
-Norepinephrine (NorEpi) catecholamine that can increase blood pressure
-Phenoxybenzamine - reduces vasoconstriction
-Maximal effect cut in half
Competitive
Action: same site
Maximum dose effect: 100%
Affect of increasing agonist: Increase Dose effect up to 100%
Non-Competitive
Action: different site
Maximum dose effect: <100%
Affect of Increasing Agonist: No effect.
Irreversible
-Reduces activity
-Slow process
Reversible
-Reduce activity
-Rapid process
Categories
- Competitive and non-competitive
- Competitive that can be reversed by increasing concentration of drug
Agonists vs. Antagonists
Agonist
-Receptor activity = activation
-“Full agonist” maximal effect (ex: fentanyl pure mu receptor)
-Partial agonists = submaximal effect (Ex: buprenorphine)
Antagonists
-receptor activity = inactivation
-Lacks intrinsic efficacy
-“Blocks” the receptor
-Ex: Naloxone on opioid receptors
Mixed agonist/antagonists
-Butorphanol - activity on Kappa and mu receptors
Pharmacodynamic Tolerance
-Response to a given concentration is progressively reduced
-Concentration needs to keep increasing to maintain effect. Body becomes more efficient at metabolizing the drug
-Ex: morphine, phenobarbital.
Several mechanisms
-Decreased receptor affinity/response
-Changes in signaling pathways
-Decreases in receptor density
-Engaging compensatory mechanisms
Lecture 2
Regulatory Consideration 1
Regulatory Framework
-Pure food and Drug Acts
-Federal Food, Drug, and Cosmetic Act
-AMDUCA details
-Drug Compounding
What is an FDA-approved animal drug?
-One that has a New Animal Drug Application number, or for generic animal drugs (NADA)
-Abbreviated New Animal Drug Application (ANADA)
Pure Food and Drugs Act
-1906 set up for the modern FDA
-“Truthful” labeling required
-Meet purity and product strength
-Shortcomings: no way to remove dangerous drugs from the market. No authority was designated. Loopholes in the legislation, unsafe products.
-Lead toys, but package was accurately labelled.
-Dr. Hess’s poultry tablets
-Bowman’s Abortion Remedy: potential zoonotic disease. FDA won court case, but company overcame this by moving claims from label to advertising
1. No authority over consmetics (ex: obesity drugs) and 2. Very high standard, had to prove intent to deceive
Elixer Sulfonilamide Disaster 1937
-Over 100 people died in 15 states
-Investigation: toxicity of ethylene glycol not widely known
-Animal safety studies were not required
-Led to Food, Drug and Cosmetic Act
Food, Drug, and Cosmetic Act 1938, 1954, 1958
-FDA had authority to regulate medical devices and cosmetics
-FDA could set the standards for foods
-Provide adequate directions for use, misbranding was illegal, misbranding did not require intent to defraud, drugs and devices that endangered health were illegal, new drugs had to be proven safe.
Essentially made it illegal to put something harmful into the food/medicine/cosmetics supply
Differentiated between drug FDA and pesticide EPA
Delaney Clause
-Forbids the addition to food of any additives shown to be dangerous in any species of animal or in humans
What is not covered by the act?
-Nutritional supplements
-Required in label, “This product is not intended…”
Food Animal (AMDUCA) Considerations
-No approved food animal drug
-Diagnosis and evaluation of the condition required
-Establish an extended withdraw period. ELDU tolerance = Zero
Multi sample method = ~ 350 drugs per sample
-Institute procedures to assure animal’s identity is maintained
-Take appropriate measure to assure that assigned withdraw times are met and no illegal residues occur
AMDUCA: Labeling Extralabelly Used Drugs
- The name and address of the prescribing veterinarian
- The established name of the drug: Active ingredients
- Any directions for use specified by the veterinarian
- Any cautionary statements
- The veterinarian’s specified withdrawal, withholding, or discard time (s)
-For meat, eggs, milk, or any food that might be derived from the treated animal (s)
Prohibited Group 1
-Chloraphenicol
-Clenbuterol
-Diethylstybesterol
-Fluroquinolones
-Glycopeptides (ex: Vancomycin)
-Nitroimidazoles
-Nitrofurans
Restricted Extra-Label Group 2
-Neuraminidase Inhibitors: can’t use in chickens and turkeys
-Cephalosporins: 3rd generation prohibited
-Gentain Violet: can’t use in food or feed
-Indexed drugs
-Phenylbutazone: can’t use in female dairy cattle 20 mts or older
-Sulfonamide class: can’t use in lactating cattle
AMDUCA Prohibited Group III
FDA publishes a minimum standards and requirements for the production of Grade “A” milk.
**Pasteurized Milk Ordinance (Grade A PMO)
Prohibit
-Non-medical grade dimethylsulfoxide (DMSO)
-Dipyrone
-Colloidal silver
Lecture 3
What do NSAIDs do? AAA - hint
- Antiinflammatory
- Analgesic: Act mostly on periphery nociceptors
- Anti-pyretic
NSAIDs MOA
-Inhibit one or more steps in the AA cascade
-Inhibit Cox-1 and Cox-2 enzymes from binding
-Cox catalyzes first 2 steps in the conversion of Arachidonic Acid Cascade to Prostaglandins
-Variable MOA: Cox isoform targeted, non-prostaglandin effect
Effects
-Leads to reduced Eicosanoids synthesis
-Anti-aggregation, VD/VC
-anti-inflammatory
Responses
-Antipyretic
-Analgesic
-Anti-inflammatory
Glucocorticoids
-Inhibit Phospholipase A2
NSAIDs
-Inhibit Cox
Piprants
-Prostaglandin receptor antagonist
Arachidonic Acid Cascade
Eicosanoids therapeutic use
-Abortion
-Ulcer prevention
-Blood flow issues
NSAIDs Side Effects
Cox-1
Normally:
-GI mucosa
-PGE2
-Increase secretion, increase bicarbonate, increase mucosal flow
Risks/Side effects
-Peptic ulcers
-GI bleeding
Cox-1 & Cox-2
Normally:
-PGE2 and PGI2
-Vasodilation, increase GFR
Risks/side effects
-Na and water retention
-Hypertension
-Hemodynamic acute kidney injury
Cox-1 & Cox-22
-PGI2 and TXA2
-Vascular vasodilation (Cox-2 and PGI2)
-Inhibit platelet aggregation (Cox-2 and PGI2)
-Platelet aggregation and vasoconstriction (Cox-1 TXA2)
Risks/Side effects
-Stroke
-Myocardial infarction
**Aspirin inhibits platelet cox-1, binds and irreversibly inactivates COX, duration of effect depends on COX turnover rate (different than elimination). Anti-coagulant effect **
Acetaminophen: antipyretic, analgesic
Cox-1 and Cox-2
COX-1
-Tissues: ALL
-Properties: Constitutive
-Binding site: narrow
-Effect: Homeostasis, GI protection, Kidney protection
COX-2
-Tissues: Damaged, inflamed
-Properties: Inducible
-Binding site: wide
-Effect: Inflammation, thermoregulation, Pain - others
Classification of NSAIDs
Carboxylic Acids (R-COOH)
Enolic Acids (R-COH)
Coxibs: Bulky = selective “Steric Hindrance”
Pharmacokinetics
Absorption: Lipid soluble, weak acids, well absorbed
Distribution: high plasma protein biding, competition. Small volume of distribution.
Accumulate in exudate (very desirable)
Metabolism/Excrition
-Clearance and 1/2 life difference a lot between species, breed, age, and disease.
-Liver (conjugation), cats decreased/lack ability to gluthatione and metabolize certain NSAIDs
-Enterohepatic recirculation
-Urinary (GFR, tubular excretion)
Prostaglandins are Ubiquitous and serve (patho) physiological functions
Avoid in vulnerable patients
-Dehydration
-Hypovolemia
-Hypotension
-Sodium retention
-Existing condition (renal, hepatic, CV, GI)
-Receiving steroids, aminoglycosided, polymyxins (toxic)
Gastrointestinal
-Prostaglandin inhibition
-Vamiting
-GI ulcers
-Right dorsal colitis, horses
-1/2 life, heterohepatic recycling
-Gastric adaptation
-Exacerbating factors
Renal
-Prostaglandin inhibition
-Vulnerable patient
-Volume depletion, sepsis
-Sodium retention
-Pre-existing disease
-Papillary necrosis
-Interstitial nephritis
Cardiovascular
-Impaired platelet function
-TXA2/PGI2 imbalance
-Delayed clotting (Aspirin binds irreversible)
-Blood dyscrasia with long term use
-Acetaminophen in cats is FATAL
-Human CV events
vWD in dog breeds Doberman, Scott
Other Effects
-Hepatic changes
-Idiosyncratic reactions
-Healing and repair (delayed), bone, tendon, ligament, soft tissue
-Respiration: human asthma
-Skin
-Reproductive system
-Nervous system
Glucocorticoids
Steroidal anti-inflammatory drugs
Steroid base: Ester on C-21
GM, MC potency, duration of action
Mineralocoricoids MC (Aldosterone)
-Maintain electrolyte homeostasis
Glucocorticoids
-Metabolic effects
-Anti-inflammatory effects
-Effect on immune mechanism
What do steroids do?
Therapeutic effects
-Pain relief: secondary
-Anti-allergy
-Immunosuppression
-Anti-inflammatory
-Decrease blood vessel permeability
Metabolic Effects
-Gluconeogenesis
-Protein catabolism
-Lipolysis
Side Effects
-Infections
-Myopathies
-Osteoporosis, Aseptic Necrosis of Humerus
-Skin thinning
-Hyperglycemia, weight gain, fluid retention, Cushingoid appearance
-HPA insufficiency, neuropsychiatric disorders
-Cataracts, Glucoma
-Hypertension
MOA
Action
-Genomic effect
-Non-genomic effect
Effects
-Inhibit nuclear factor KB
-Trans-repression: decrease transcription inflammatory genes
-Trans-activation: increases transcription of immunosuppressive genes
-Induction of lipocortin & PLA2 inhibition
Responses
-Metabolic side effects
-Anti-inflammatory effects
-Immune effects
Metabolic Effects
-Glucose: + Gluconeogenesis
-Protein: - Catabolism
-Lipid: - Lipolysis
-Antagonizes ADH release
-GI: decreases intestinal absorption, Increases gastric acid
-Skin: atrophy
-Osteoporosis, soft tissue mineralization, decrease chondrocyte
-Decrease CRH, ACTH, TSH
Adverse Effects
Cushingoid mnemonic
C: cataracts
U: ulcers
S: skin, striae, thinning, bruising
H: hypertension, hirtuism, hyperglycemia
I: Infections
N: necrosis, avascular necrosis of the femoral head
G: glycosuria
O: osteoporosis, obesity
I: Immunosuppressive
D: diabetes
Principles of rational GC therapy
- How serious is the issue (diagnose, set goal)
- How long is therapy required
- Is the patient predisposed to complications
- What dosage is used (ideally combined with something else to decrease needed dose)
- What preparation is used
- What other treatments can decrease GC dosage and side effects
- How can the dose be tapered
GC Usage
-Physiologic replacement therapy: provide small daily amount
-Intensive short-term and shock therapy (controversial)
-Anti-inflammatory and anti-allergic therapy
-Immunosuppressive therapy: highest dose then tapered
-Chronic palliative: when NSAIDs don’t succeed, eodintermittent use
