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145 Cards in this Set
- Front
- Back
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pharmacology
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a study of natural and synthetic drugs and how they act in the body
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drug
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agent for prevention, cure, txt, diagnosis of disease
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approved drug
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meets FDA requirements for safety and efficacy
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unapproved drug
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health claim but no approval by FDA
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food supplement, nutraceutical
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no health claim, no FDA oversight
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food additive
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meets FDA requirement for safety
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disease
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- acute or chornic condition, deviation from normal physiology
- drugs are indicated or contraindicated |
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pharmacokinetics
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absorption, disctribution, elimination of drugs
SPECIES DIFFERENCES |
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absorption
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into bloodstream
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distribution
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from blood to tissue
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elimination
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metabolism to inactive drug and excretion
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what does clearance relate to?
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fluid processed over time as drugs are eliminated
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pharmacodynamics
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- mechanisms of drug action
- action at the cellular or receptor level - dose response NO SPECIES DIFFERENCES |
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therapeutics
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applied use of drugs in disease states
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clinical pharmacology
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individualized drug therapy
- dosage choice- effective but not toxic - choice btw a min and max value |
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chemotherapy
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specific drug for specific disease
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toxicology
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adverse effects
-toxic, side and adverse effects - safety indicated by safety margin that compares LD and EF or therapeutic index which compare toxic and effective doses |
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safety margin equation
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LD01/ED99 = certain safety factor
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therapeutic index equation
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LD50/ED50
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toxic effect
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overdose effect
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side effect
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action an undesirable and/or nonselective site
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adverse effects
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toxic effects and side effects
- may also involve dependence or immune-mediated effects - not all side effects are adverse |
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pharmacy
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standarization and dispensing of drugs
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biopharmaceutics
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science of formulating drugs
- dosage form, vehicle, drug "salt" |
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pharmacognosy
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drugs from plant sources
- alkaloids and glycosides |
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drug classifications
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drugs are classified by:
- chemical structure - mechanism of action - indication and/or system they affect |
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appropriate use of drugs by licensed professionsals includes...
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- drugs themselves
- patient - professional responsibilities |
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appropriate use of drugs- drugs themselves (chemistry)
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- chemistry can affect drug pharmacodynamics- structure affects drug effectiveness, potency, dosages, toxicities
- chemistry can affect drug pharmacokinetics- absorption, distribution, metabolism, excretion (acid/base properties, molecular wt, lipophilic/hydrophilic characteristics, functional groups) |
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appropriate use of drugs- drugs themselves (pharmaceutical preparations)
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- can affect drug pharmacology
- physical poperties of the drug perparation contribute to route of administration and drug absorption (pharmaceutics) 1. "salts" of drugs affect water solubility- determien route of administration 2. vehicle- contributes to absorption and route given |
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apprpriate use of drugs- patient
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1. general physiological/pathological factors can alter drug effectiveness
- dz itself influences drug action - use of multiple drugs can result in interactions- addition, synergism/potentiation, antagonism 2. individualized pt factors can alter drug effectiveness 3. client must comply |
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appropriate use of drugs- professional responsibilities
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1. medical-ethical responsibilities
- proper diagnosis - knowledge of drug actions, correct ordering - relationship - proper supervision - consideration of the client for recommended regiment and cose - adverse drug rxn reporting 2. legal-ethical responsibiliteies - defined by law and AVMA guidelines - what is Rx, OTC - obtaining, storing, prescribing, and labeling drugs - extralabel use |
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The Federal Food, Drug, and Cosmetic Act (FFDCA)- 1938
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1. Durham-Humphrey Amendment (1952)- req drugs to be designated as Rx or OTC
2. Kefauver Harris Amendment (1962)- each drug be safe and effective, have unique generic name, testing for efficacy adn safety required 3. Poison Prevention Amendment (1970)- req use of safety closeures for human-use drugs |
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laws specifically for veterinarians (amendments to the FFDCA)
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1. Animal Drugs Amendment (1972)- drugs used in animals are to be safe, effective, and no human hazard (shorter time to market)
2. Animal Drug Availability Act (1996)- shorter time to market, licensed feed mills can manufacture medicated feeds under a veterinary feed directive 3. Animal Medicinal Drug Use Clarification Act (1994)- extra-label use as long as no violative residues occur in food-producing animals |
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Comprehensive Drug Abuse Prevention and Control Act (1970)
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ranks drugs with potential for abuse and provides restrictions on use, orders, and storage that pply to all clinicians
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Schedule I (C-I) drugs
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have no therapeutic usefulness
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Schedule II (C-II) drugs
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require triplicate orders, locked storage, strict prescribing, and inventory
- high potential for abuse |
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Schedules III-IV (C-III,IV) drugs
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have restrictions on prescribing and req inventory
- refillable 5x or 6mo |
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Schedule V (C-V) drugs
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used for drug combinations that include one with potential for abuse
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Schedule VI drugs
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used in VA for other legend drugs
- made so all rx are considered controled/scheduled so there are tougher consequences for stealing/abusing them |
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DEA is responsible for...
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Drug Abuse and Control Act
- does not differentiate human and veterinary products |
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FDA is responsible for...
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Food, Drug, and Cosmetic Act and amendments
- CVM regulates and monitors premarket testing of drug products, drug labeling, post-market adverse reactions, and public protection |
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US EPA is responsible for...
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premarket testing and labeling of insecticides
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USDA is responsible for...
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drug residues found in food products
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do drugs create new body functions?
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no
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pharmacological effects are due to...
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drug-receptor interactions
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receptor
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initial site for drug action
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affinity
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if a drug/ligand binds to a receptor, it has affinity for that receptor
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agonist drugs
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- initiates the prpagation of a msg in the cells
- causes a biological response (intrinsic activity) |
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antagonist drugs
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- can bind to a receptor (have affinity)
- do not initiate a biological response (do not have intrinsic activity) |
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structure-activity relationships
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- the steric arrangement of the drug molecule with the receptor (how well a drug "fits" in a receptor) contributes to specificity of drug action
- may differentiate drugs within a class |
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drug pharmacodynamics that occur outside cells are...
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physico-chemical actions that do not require specific molecular receptors
(laxatives, antacids, absorbants, osmotic diuretics) |
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drug pharmacodynamics can occur in or on cells without specific molecular recptors but rather cause...
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a whole organelle or whole cell effect
(antiseptics, some volatile general anesthetics) |
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where can receptors be?
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receptors may be located on cell membrane or within the cell
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what do receptors do?
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as the initial site for drug action, they bind the drug/ligand
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what does activation of a receptor initiate?
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propagation of a msg via 2nd messenger cascades
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properties of receptors
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- specific or not
- expected to bind some normal body component(s)- hormones, NT - may have subtypes that can be exploited in therapeutics- ANS has B1 for heart, B2 for bronchi - can be desensitized- tolerance, tachyphylaxis |
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covalent bonds
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- irreversible
- rare for drugs and receptors |
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noncovalent bonds
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- reversible
- likely for drugs and receptors |
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what are the 3 types of noncovalent bonds?
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1. ionic bonds- electrostatic bonds for weak acids and bases
2. hydrogen bonds- proton/electron bonds 3. hydrophobic (Van der Waals) bonds- dipole bonds to stabilize drugs in receptor |
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dose-response curves- general principles
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- receptors bound is proportional to drug concentration (up to a max)
- drug-receptor interaction is reversible - dose relationship is logarithmic- curve on a semi-log scale has a straight portion in the middle but bends at both ends |
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what is the X axis on a dose-response curve?
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dose
(independent) |
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what is the Y axis on a dose-response curve?
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% response
(dependent) |
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affinity
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ability to bind to receptor
(both agonist and antagonist have affinity) |
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what 2 things identify an agonist?
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1. intrinsic activity
2. efficacy |
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efficacy
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- response obtained from combination of drug and receptor
- no benefit to giving a higher dose than max efficacy - maximal efficacy can be used to compare agonists - those not causing a maximal response are partial agonists |
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threshold
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concentration of drug needed at receptor to initiate a response
(below there is no response) |
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range of effective doses
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doses resulting in response
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potency
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comparative term to describe position of 2 or more agonists on a dose-response graph
- less potency has curves move to right (takes more drug to have same effect) |
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when can summation and potentiation/synergism be determined?
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if doses are less than maximally efficacious and receptors remain to be occupied
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surmountable antagonism
(competitive antagonism) |
- curve moves to right on X axis- decrease potency
- shape is unchanged (antagonist is binding receptor so agonist can't- have to give more agonist to get same effect) |
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insurmountable antagonism (noncompetitive antagonism)
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- curve shape changes- efficacy is decreased
- with drugs that have no agonist activity, but decrease pool of receptors - with partial agonists (don't reach full efficacy) |
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graded plots
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- response has measurable unit
- quantitative |
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plotting quantal data
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- response is yes/no
- number responding versus log dose gives bell-shaped curve (ranges from sensitive to drug at low dose to resistant/tolerant to drug at high dose) - cumulative number responding versus log dose gives straight line (except at ends)- straight btw 16-84% |
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therapeutic index
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- LD50/ED50
- TD50/ED50 |
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margin of safety
(certain safety factor) |
- TD01/ED99
- must be greater than 1 (curves have to be apart) - provides a therapeutic window - not all drugs have a "margin of safety" - bigger number = safer drug |
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advantages of dose-response curves
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- id drug properties (intrinsic activity, max efficacy, threshold, ranges of doses, risk-benefit)
- comparisons of agonists, partial agonists for efficacy and potency - studies of drug interactions (surmoutable and insurmountable antagonism) |
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disadvantages of dose-response curves
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- low-dose extrapolations (need straigtening at ends)
- only 1 response can be determined at a time - toxicity is not necessarily the same as lethality |
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absorption
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getting the drug into the bloodstream
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distribution
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movign the drug from bloodstream to tissue
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elimination
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biotransformation + excretion
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clearance
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amt of fluid processed over time to remove drug
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what are the factors for pharmacokinetics?
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- absorption
- distribution - biotransformation - excretion |
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what are factors for drug absorption?
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1. membrane composition and membrane permeability
2. drug properties and formulation of drug * both contribute to drug absorption and distribution |
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membrane composition and membrane permeability
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- contributes to drug absorption and distribution
- transport in body water also important - membranes provide a lipid/protein barrier that drugs must cross to be effective inside cells - drugs may pass thru lipids or pores |
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drug properties and formulation of drug
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- contributes to drug absorption and distribution
1. concentration gradient 2. MW 3. formulation properties- particle size, vehicle, "salt", special delivery forms 4. solubility as determined by lipid-water (oil/water) partition coefficient- drug needs lipid solubility to cross membranes, drugs need solubility in body water for extracellular distribution 5. solubility as determined by drug ionization- depends on drug pKa and tissue pH relationships [only unionized drug (nonpolar form) diffueses across membranes]- ionized drugs are "ion trapped" |
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when is a weak acid unionized?
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unionized when pH < pKa
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when is a weak base unionized?
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unionized when pH > pKa
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what is the pKa of a drug?
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pH at which drug is half ionized
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what does drug metabolism/biotransformation include?
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- change in WATER SOLUBILITY of drug results in activation adn inactivation
- contributes to intensity and druation of drug action - may contribute to side effects and/or toxicities |
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why is drug metabolism/biotransformation done?
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- alters passage of drug across membranes (translocation), esp for excretion
- increase water solubility and retained in urine |
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where does drug metabolism/biotransformation occur?
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- organs- LIVER, intestine, kidney, plasma
- cell fractions- microsomes, mitochondria, cytosol |
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who is metabolized/biotransformed?
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drugs with susceptible functional groups
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how does drug metabolism/biotransformation take place?
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drug -> PHASE I -> transformed -> PHASE II -> conjugated
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what does conjugation do to a drug?
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decreases activity
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what does transformation do to a drug?
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increase/decrease/no effect on activity
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what does phase I of biotransofmration do?
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- change structure
- increase water solubility - no large change in MW - activate, detoxify, do nothing for activity |
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what does phase II of biotransformation do?
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- usually detoxification
- decrease activity - increase MW significantly |
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what are the 3 phase I reactions?
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1. oxidation
2. reduction 3. hydrolytic reactions NOT MANY SPECIES DIFFERENCES |
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what is oxidation (phase I rxn)?
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- C, N, S
- addition of O or addition of -OH (hydroxylation) - removal of -H - removal then replacement of large group with -H - MOST COMMON RXN |
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what is reduction (phase I rxn)?
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- add H
- in oxygen-reduced environment- NOT in liver - happens in gingiva, colon, rumen |
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what are hydrolytic rxn (phase I rxn)?
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- hydrolyses
- add HOH- to break molecule - break esters, amides, conjugates (esp glucoronides) - breaks the most labile of bonds - HAPPENS FIRST IF HAVE THESE FUNCTIONAL GROUPS |
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what are the 5 phase II rxns for biotransformation?
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1. glucuronic acid conjugation
2. sulfate conjugation 3. mercapturic acid formation 4. acetylatino 5. methylation |
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veterinarian who recognizes drug functional groups and reactions they may undergo can use this information to...
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1. increase drug effectivenss (species, age)
2. establish dosages and regimens, esp in extralabel use (biotransformation contributes to peak levels, duration) 3. avoid drug toxicities 4. consider special situations, such as species/breed sensitivities |
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what must drugs have to be absorbed and reach sites of action?
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drugs must have some ability to dissolve in water
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what must drugs have in almost all cases to move around in capillaries and cells?
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drugs must have a certain degree of lipid solubility
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T/F: solubility is a preference not an absolute
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true
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T/F: drug effects/ concentrations in the blood stream (measured in either serum or plasma) are USUALLY proportional (tho not always linear) to drug concentration at the site of action
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true
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T/F: Drug concentration in the blood stream is ALMOST ALWAYS an excellent predictor of drug action (either efficacy or toxicity) even though they may not be identical to the concentration in the target tissue
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true
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pharmacokinetics are the consequences of...
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physiologic processes (that may or may not be altered by disease)
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what is the primary difference btw veterinary pharmacology and human pharmacology?
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species differences
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what is the primary difference btw basic and clinical pharmacology?
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disease-induced differences
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what do drugs dissolve in?
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body fluid (water)
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how do drugs enter the cirulatory system?
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as fluid enters the circulatory system
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drugs must enter the circulatory system before they can...
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be distributed to sights of action
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drugs are not IN the body until they are...
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IN the bloodstream
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describe how an aqueous solution mixes with tissue fluid for rapid absorption (IM route)
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- drug is already sissolved in "water"- dissolution is tissue fluid is not rate-limiting
- entry of drug into circulatory system limited (only) by rate of blood flow to the tissue - blood flow varies by body region/muscle group, so exercise may affect absorption rate |
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shape of a bolus injection
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roughly spherical
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describe how a bolus in a lipid soluble vehicle is absorbed
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- bolus remains relatively spherical
- mixing and dissolution in tissue fluid occurs from surface of bolus - entry of drug into circulatory system limited by rate of drug "dissolution" (mvmt from "bolus" to tissue fluid) - produces tissue residues - reduces effect |
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what happens when a drug "falls" out of solution in a bolus?
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- occ, vehicle may be absorbed more rapidly than drug- drug "falls" out of solution in the tissue and dissolves slowly
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what is the volume of distribution?
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- volume of fluid that "appears" to contain the amt of drug in the body (based on plasma concentration)
- partially determines the relationship btw dose and plasma concentration - defines the volume of fluid that must be processed by organs of elimination - roughly describes "tissue penetration" - may not equal an actual physiologic space |
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what is the equation for volume of distribution?
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Vz = amt in the body/plasma concentration
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what is clearance?
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the volume of plasma water cleared of the drug during a specified time period
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what is organ clearance?
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- flow x the effciency of extraction
- requires animal to be dead to calculate |
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what is total body clearance (Clt)?
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- hepatic + renal + pulmonary
- sum of all organ clearances |
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what is the rate constant of elimination?
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- the fraction of the volume of distribution cleared per unit time OR
- the slope of the natural log plots of the drug concentration versus time profile - total clearance/volume of distribution |
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what is elimination half-life?
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the time for elimination of one half of the total amt in the body
- units- hours or minutes |
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tissue residues
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- at 5 x T1/2, 97% has been eliminated
- make sure you use the longest half-life - metabolites may be more important than the drug - extremely slow absorption from injection site may be the primary cause of residues |
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approach to stead state
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- steady state exists when defined plasma concentrations (peak, average, trough) are identical
- at 5 x T1/2 concentrations are 97% of steady state no matter what dose and interval - digoxin- max effects may appear as late as 8 days after therapy is initiated - the relationship btw dose interval and half-life determines loading dose |
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what is a loading dose?
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an initial dose of drug given to shorten the time to reach steady-state concentrations
(rare, only do when drug is safe) |
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what is the absorption rate constant (ka)?
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describes the rate of drug movement (oral, IM...) from the dose to the circulatory system
- units- /hr, /min - with other factors, determines the time required to reach the peak concentration (Cmax) following a dose of drug and the peak drug concentration |
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what is the fraction of dose absorbed (F)?
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when a drug is administered by any route OTHER than IV, it is rare that the entire dose is absorbed
- oral- destroyed in GI tract, passes out in feces before it is absorbed, binds to ingesta, etc. - IM- hydrolysis of drug in tissue, drug binding to injection site, abscess formation, etc - units- % of dose or fraction of dose - determine's a drug's bioavailability |
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what is bioavailability?
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- how much gets into the bloodstream
- a common measure used to compare 2 different drug formulations or to compare prods sold by 2 different manufactors |
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what is bioequivalence?
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- two drug products are bioequivalent if the nature and extent of therapeutic and toxic effects are equal following administration
- although similar and related, equal bioavailability does nto guarantee bioquivalence |
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what are pharmacokinetic physiologic models used for?
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attempt to describe the actual events which control drug absorption, distribution, elimination
- derived from measurements of drug concentratiosn in specific fluids - deal with an organ, a tissue, or an organ system - combined to describe functions and processes - CAN'T DO ON LIVE ANIMAL |
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what ia a pharmacokinetic mathematic model used for?
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attempt to accurately predict the time course of drug concentrations in one (usually blood or plasma) or 2 (also urine) body fluids
- predictions are generally made for tissues which can be sampled from intact patients |
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modeling begins with a single does experiment...
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- a dose of drug is administered, samples are taken at timed intervals after dosing, samples are analyzed for drug concentrations
- drug concentrations are then plotted and analyzed mathematically to determine the drug's clearance, the rate constant of elimination, half-life, and the volume of distribution of the drug |
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what are the 3 body compartments?
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DO NOT ASSUME THAT ANY REAL PHYSIOLOGIC BODY SPACE IS BEING DESCRIBED BY MATHEMATICAL MODELS
1. central compartment- blood volume + organs of elimination 2. peripheral compartment- muscle, SQ, lung tissue 3. deep compartments- fat (poor blood supply, lipid soluble drugs), kidneys (aminoglycosides) |
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the number of compartments is not a pharmacological property of the drug...
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- N compartments represent the amt of detail available considering the "experimental conds"- # of samples, sample timing, obesity, starvation, dehydration...
- diff in rate of distribution into various tissues (2 volumes can't be sep if individual rate constants are similar) - N compartments may be arbitrarily reduced if the level of detail available is unnecessary - most clinical monitoring reduces "truth" to a one compartment open model |
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pharmacokinetics of certain drugs are dose-independent b/c...
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for 99% of drugs, it is assumed that the relationship btw the dose we give and the concentration that the dose produces in the body are linear
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pharmacokinetics of dose-dependent absorption is...
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if pharmacokinetics of ABSORPTION change when we increase the dose
- doubling the dose produces less than a doubling of tissue concentrations and effects |
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pharmacokinetics of dose-dependent elimination is...
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if the pharmacokinetics of ELIMINATION change when we increase the dose
- doubling the dose produces MORE than a doubling of tissue concentrations and effects |
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what is Michaelis-Menton kinetics?
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- first-order at "low" doses (most drugs at therapeutic doses)
- zero-order at "high" doses - mixed-order in btw |
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what is first-order?
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- increasing slope of graph
- pharmacokinetics of MOST drugs is 1st order at therapeutic doses - a fraction of the dose of drug is absorbed per unit time - a fraction of the amt of drug in the body is elimination per time - there will be a half-life of elimination - increasing/decreasing the dose will produce a proportional increase or decrease in the plasma concentration and in drug effect - a steady state will be achieved for ANY rate of drug administration |
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what is zero-order?
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- special dose forms, high concentrations of some drugs
- steady state on a graph - semi-log plots will have neg slope - a constant amount of drug is absorbed/eliminated per unti time - drug may accumulate indefinitely - there is no "half-life" |
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what is the peak plasma concentration?
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highest plasma concentration achieved following a single non-IV dose of a drug
- units- mg/ml or mg/l |
