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175 Cards in this Set
- Front
- Back
Pharmacodynamics
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actions of drug on the body
(what the drug does to the body) |
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Pharmacokinetics
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actions of the body on the drug
(ADME) |
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What is needed for pharmacodynamics to occur?
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drug binding to receptor
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drug product
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preparations and formulations of drugs
(pills, tablets, capsules) |
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drug substance
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active ingredient
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excipients
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inactive substances used as a carrier for the active ingredient
-accurate dosage -stabilize the drug |
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3 Names of a drug
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chemical, generic, trade
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Name of drug assigned by the FDA and is public property
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generic name
-first letter lower case with same endings in same pharmacological class |
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Name of drug assigned by company, aka brand name
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trade name
-first letter is capitalized -able to have a lot of trade names for one generic |
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Prescription Drugs
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deemed unsafe without medical supervision
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Orphan Drugs
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target rare disease or conditions affecting fewer than 200,000 people
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Controlled Drugs
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classification depends on schedule
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Drugs scheduled according to:
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-medical use
-abuse liability -tendency to develop physical and psychological dependence |
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Dietary Supplement
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NOT intended to diagnose, treat, prevent, or cure disease
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Investigational New Drug (IND) Application
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FDA has 30 days to review
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Duties of the Institutional Review Board (IRB)
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-scientific merit
-ethical acceptabiltiy -protection of patient rights -proper consent process |
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Basic Elements of Informed Consent
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-explanation of purpose and procedures of the research
-description of foreseeable risks and expected benifits -statement of available alternative procedures or course treatment -statement on confidentiality of records -explanation of compenstaion and available medical treatments if injury occurs -Participation is voluntary -who to contact |
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4 Phases of Clinical Trials
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Phase I - safety and pharmacokinetics
Phase II - safety and efficacy Phase III - safety and efficacy Phase IV - postmarketing studies |
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Describe Phase I Clinical Trials
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-1st time in patients
-6 mo to 1 yr -20 to 100 HEALTHY volunteers -evaluating: safety and tolerability; pharmacokinetics and dose range |
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Describe Phase II Clinical Trials
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-assess efficacy and safety
(optimal dose selection and dose schedule) -100-200 pts with disease or condition |
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Describe Phase II Clinical Trials
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-1000 - 6000 patients
-PROVE safety and efficacy |
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Describe Phase IV Clinical Trials
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-detect rare or long term adverse effects
-larger pt population and longer timescales |
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Receptors are responsible for drug _________
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selectivity
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Receptor determine relationship between drug dose and ________ _______
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pharmacological effect
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What do receptors mediate?
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action of agonist and antagonist
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Main affect of antagonist binding
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prevent agonist from binding and activating
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How does the degree of inhibition increase with competitive antagonist?
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increase the concentration of competitive antagonist
[Increase conc. of agonist can overcome effect of antagonist] |
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What does a non-competitive antagonist do to receptor efficacy?
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decreases efficacy
-its potency is independent of the agonist dose |
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Action of an irreversible antagonist
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covalently (irreversibly) binds the receptor
-duration of effect is dependent on the turnover rate of receptors |
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Antagonism
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2 drugs produce opposite effects by interacting with two separate receptor systems
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What distinguishes an agonist from an antagonist?
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intrinsic activity = activates a receptor
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Describe the difference between affinity and intrinsic activity
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affinity - how well it binds
intrinsic activity - able to produce a measurable effect ~ do not always go hand in hand, ex. antagonist |
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Axises of Michaelis-Menton graph
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X -> substrate concentration
Y -> reaction velocity |
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Km of Michaelis-Menton kinetics
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Km = concentration of substrate needed to reach 1/2 Vmax
-measure of the affinity of the substrate for the enzyme |
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What does Potency relate to?
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drug binding affinity
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What does efficacy relate to?
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rate and extent of receptor activation after drug binding
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What does EC(50) represent?
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concentration that produces 50% of the maximal effect
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What does the Law of Mass Action represent?
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drugs reversible interaction with a receptor
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Occupational Theory of drug binding
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magnitude of response is directly proportional to the # of receptors occupied or filled up
-potency is related to affinity for the receptor |
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Kd
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concentration of drug required to bind 50% of receptor
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If Kd is low, binding affinity is _____
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high
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What is the difference between a full agonist and partial agonist
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full agonist - drug that produces full effect in a system
partial agonist - drug that interacts with receptor but is unable to produce full effect *all relative |
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Emax represents?
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efficacy
-maximum response achieved by an agonist |
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ED50 represents?
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potency
-drug concentration at which 50% of Emax is achieved |
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What is the graphical representation of potency
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further to the Left -> more potent
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Chemical Antagonist
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-chemical interaction of two substances
-does not require receptor |
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Pharmacological Antagonist
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-binds to receptors, but does not activate signal transduction
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What happens to the potency and efficacy when a competitive antagonist is added to an agonist?
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reduce potency but does not effect efficacy
(need more of drug to produce the same effect) |
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What happens to the efficacy and ED50 when in irreversible antagonist is added to an agonist?
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decrease Emax => decrease efficacy
- does not affect ED50 |
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What happens to the potency and efficacy when a non-competitive antagonist is added to an agonist?
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still have maximum potency but reduced efficacy
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Physiological antagonist
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-opposing effects by 2 agonists that act on different receptors
(both have intrinsic activity) |
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Sensitivity of a cell to an agonist depends on ______ ______ and ______ _______ _______
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receptor affinity and total receptor concentration
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What is the role of spare receptors?
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increase sensitivity of target cells to activation by low levels of ligand
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What happens in the values of ED50 and Kd with spare receptors?
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a greater difference between the 2
(normally they are equal) -due to greater sensitivity created by the spare receptors |
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How do spare receptors affect the curve of a non-competitive antagonist?
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normally just decrease in the maximal response (decrease in efficacy)
->but see a shift to the Right due to spare receptors |
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ED50
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=drug dose effective in 50% of population
Effective Dose (ED) |
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LD50
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=lethal dose for 50% of the population
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Eq for Therapeutic Index
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TI = LD50/ED50
-margin of drug's safety -higher ratio -> more safe/less toxic |
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Eq for Certain Safety Factor
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CSF = LD1/ED99
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Concentration of a drug has a _______ effect on the intensity of the effect.
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direct
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What is required for passive diffusion
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concentration gradient
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First order process
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proportional to the magnitude of the drug concentration across a membrane
-rate dependent on concentration |
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Eq for partition coefficient
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PC = ([drug] in lipid phase)/([drug] in aqueous phase)
-larger the # the greater the rate of transfer across a membrane (more lipid soluble) |
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Weak acids become highly ionized as pH ________
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increases
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Weak bases become highly ionized as pH _____
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decreases
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In general what pH is more conducive to weak acid passage across a membrane?
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lower pH
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In general what pH is more conducive to weak base passage across a membrane?
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higher pH
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Henderson-Hasselbalch eq. for a weak acid
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pH = pKa + log (ionized/non-ionized)
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Henderson-Hasselbalch eq. for a weak base
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pH = pKa + log (non-ionized/ionized)
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First Pass Effect
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metabolism of drug before it reaches systemic circulation
-enzymes of intestinal bacteria -enzymes of intestinal cells -liver enzymes on the way to systemic circulation |
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Why aren't absorption and bioavailability always equal?
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first pass effect
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Eq for oral absorption extraction ratio
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ER = (Ci - Co)/Ci
Ci = conc. in Co = conc. out |
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Do transport proteins require ATP?
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Yes
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P-glycoprotein
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aka. MDR1
-best known ATP binding cassette (ABC) protein |
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Locations of P-glycoprotein
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-luminal surface of intestinal cells
-hepatocyte biliary canalicular membrane -luminal surface of the renal proximal tubular cells -luminal surface of brain endothelial cells |
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2 transporters for uptake into hepatocytes (first pass metabolism)
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organic anion transporting polypeptide (OATP)
organic cation transporter (OCT) |
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family of transporters responsible fro renal secretion
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organic anion transporter (OAT)
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Eq for Bioavailability
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Foral = AUC(PO)/AUC(IV)
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Issue with chemically equivalent preparations
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contain same amount of active ingredient but may not be therapeutically equivalent
-differ in bioavailability -> can not be used as generic substitute |
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4 areas a generic drug is identical, or bioequivalent to a band name drug
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-dosage form
-safety, strength -route of administration -quality, performance characteristics and intended use |
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2 transporters for uptake into hepatocytes (first pass metabolism)
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organic anion transporting polypeptide (OATP)
organic cation transporter (OCT) |
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family of transporters responsible fro renal secretion
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organic anion transporter (OAT)
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Eq for Bioavailability
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Foral = AUC(PO)/AUC(IV)
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Issue with chemically equivalent preparations
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contain same amount of active ingredient but may not be therapeutically equivalent
-differ in bioavailability -> can not be used as generic substitute |
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4 areas a generic drug is identical, or bioequivalent to a band name drug
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-dosage form
-safety, strength -route of administration -quality, performance characteristics and intended use |
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Volume of Distribution (Vd)
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conceptual description of drug distribution
-volume into which the total amount of drug would be uniformly distributed to give the observed plasma concentration |
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Eq for Volume of Distribution
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Vd = dose (D)/ measured plasma conc. (Cp)
-does not represent a real volume |
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volume of drug limited to plasma water
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3L
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volume of drug limited to plasma water and interstitial water (extracellular water)
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12L
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volume of drug limited to intracellular water
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28L
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volume of drug found in total body water
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40L
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What does a very large Vd indicate?
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that the drug is not in the plasma
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What does Vd indicate?
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if the drug resided mainly in the plasma or tissue
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Does albumin prefer acidic or basic drugs?
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acidic
-plasma binding protein |
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Does Alpha-1-acid glycoprotein (AAG) prefer acidic or basic drugs?
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basic
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Thiopental
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drug that redistributes
-transition of a drug from a rapidly perfused tissue to a slowly perfused tissue |
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What is the limiting factor in duration and intensity of a LS drug?
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rate of metabolism
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bioactivation
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activate a drug via metabolism
-prodrug |
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Describe what happens in an acetaminophen overdose
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-pathway to non-toxic metabolites via glucuronidation and sulfation become saturated
-excess drug metabolized by CYP450 -> produce toxic metabolites -> glutathione becomes depleted -> hepatotoxicity and cellular necrosis |
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Phase I metabolism
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changes drug to a more polar metabolite
-many phase I metabolites not excreted -metabolites often inactive |
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Phase II metabolism
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-conjugation
-endogenous substrate added to drug by acetylation, glucuronidation or sulfation -form highly polar, inactive metabolite that is renally excreted |
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Phase II metabolism reactions
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-glucuronidation
-acetylation -glutathione conjugation -glycine conjugation -methylation |
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2 types of phase I metabolism
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-microsomal 'mixed function oxidases'
-microsomal P450 catalyzed oxidations |
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_______ is involved in the metabolism of ~50% of clinically used drugs
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CYP3A4
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Where is CYP3A4 and what is it susceptible to?
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-found in the liver and intestine
-susceptible to induction and inhibition (inducer: St. John's Wort) |
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What does grapefruit juice inhibit?
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intestinal CYP3A4
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How do polymorphisms of CPY2D6 affect metabolism?
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creates is significant difference in effective dose due to the variation in individual metabolization
(poor to ultra-rapid metabolizers) |
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What class of medications is CPY2D6 greatly involved in?
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antipsychotic medications
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What is the most frequent phase II reaction
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glucuronidation
(addition of a glucuronic acid) |
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glucuronides
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drug that is excreted that has under-gone glucuronidation
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What is major function of glutathione conjugation
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protection of cells against toxic injury
-protects against free radicals, electrophils, reactive metabolites |
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Phenobarbital
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classic inducer
-increase enzyme level to increase rate of metabolism |
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autoinduction
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an inducer increase the rate of its own metabolism
-tolerance |
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cimetidine
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significant inhibitor of P450 enzymes
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Which is more affected by age and disease Phase I or Phase II
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Phase I
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Clearance
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quantitative measure of elimination
-typically a measure of renal excretion |
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Capacity-limited elimination
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clearance varies with concentration
-saturable -blood concentrations continue to rise with continued doesing |
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3 drugs that have capacity-limited elimination
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ethanol, phenytoin, aspirin
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Flow-dependent elimination
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drug easily cleared by elimination organ (high extraction)
-primarily dependent on rate of drug delivery to the organ |
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Elimination
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general term for removal of drug from body
-refers to all processes involved |
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Is a drug with a very large Vd readily removed by Dialysis?
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No, because a drug with a large Vd is tightly protein bound or extensively stored or distributed into a tissue
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Capacity-limited elimination
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clearance varies with concentration
-saturable -blood concentrations continue to rise with continued dosing |
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3 drugs that have capacity-limited elimination
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ethanol, phenytoin, aspirin
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Flow-dependent elimination
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drug easily cleared by elimination organ (high extraction)
-primarily dependent on rate of drug delivery to the organ |
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Elimination
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general term for removal of drug from body
-refers to all processes involved |
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Is a drug with a very large Vd readily removed by Dialysis?
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No, because a drug with a large Vd is tightly protein bound or extensively stored or distributed into a tissue
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Enterohepatic Recirculation
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phase II glucuronide conjugate is excreted via bile into the intestine -> glucuronidase regenerates the drug -> reabsorption of the drug
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Glomerular filtration rate
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100-120 ml/min
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Factors involved with Glomerular filtration
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-molecular size is the limiting factor
-protein bound drug is NOT filtered -non-selective, non-saturable -dependent on hydrostatic pressure |
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Back diffusion
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drug move from nephron to circulation
-ionization traps drug |
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In acidic urine what form is the weak acid drug in and what does that mean for reabsorption?
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greater [H+] causes a shift to HA -> increase reabsorption
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What is the active transporter for organic anions and conjugated metabolites
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P-glycoprotein
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Active transporter for organic cations
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ABC transporters
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drug clearance >120 mL/min
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must involve tubular secretion
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drug clearance < 120mL/min
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must involve tubular reabsorption
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max CL
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~1500 mL/min
-equal to the liver blood flow |
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Eq. for Clearance
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Cl (L/hr) = Rate of elimination (mg/hr) / C (mg/L)
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Total systemic clearance
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-clearance is additive
CLsystem = CL renal + CL liver + CL other |
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Eq for the rate of elimination
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rate of elimination = CL x C
-First order elimination |
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Zero order elimination
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elimination of constant amount of drug per unit time, independent of concentration
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Eq. of Renal Clearance
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CLr = (UxV)/(CpxT)
U = urine concentration, V = urine volume -hypothetical -amount of plasma that would have to be 100% cleared of drug to obtain that amount in urine |
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Clearance helps determine what PK parameter
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maintenance dose rate
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Volume of distribution (Vd) helps determine which PK parameter
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loading dose (LD)
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Half-life (t1/2) helps determine which PK parameter?
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time to steady-state and dosing interval
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First Order Kinetics
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-elimination rate dependent on drug concentration
-rate of elim. = CL x Cp -clearance is fixed but rate is variable |
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Zero Order Kinetics
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-elimination rate is independent of drug concentration and constant over time
-as conc. goes up the clearance decreases -dose change will be reflected in proportional change in plasma concentration |
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In 1st order kinetics is the half-life dependent on concentration?
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No
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What occurs with the half-life in zero order kinetics?
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half-life becomes longer as the concentration increases
-hang over! |
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Which drugs display dose dependent kinetics
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ethanol, aspirin, phenytoin
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3 Eq. for clearance
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CL = Does/AUC
CL = (F x Dose)/AUC CL = (0.693 x Vd)/t1/2 |
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Eq. for half-life
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t1/2 = (0.693*Vd)/CL
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Significance of 5 t1/2
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amount of time to reach steady state and amount of time to eliminate drug
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3.3 t1/2 =
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90%
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What are 2 methods to achieve a Plateau of steady state concentrations
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-give drug at constant intervals of less than 5 t1/2
-continuous infusion |
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Eq for steady state drug concentration
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Css = infusion rate (R)/ clearance (CL)
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What does a faster rate of infusion change and not change
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change: steady-state concentration
does not change: time to steady state |
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Expanded Eq for steady state concentration
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Css = (1.44 x F x D x t1/2)/(Vd x T)
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Purpose of a loading dose
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achieves therapeutic levels with a single dose
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Eq for loading dose
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Dose(loading) = Css x Vd
For oral: Dose(loading) = (Css x Vd)/Foral |
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Eq for maintenance dose
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Dose(maintenance) = Css x CL
For oral: Dose(maintenance) = (Css x CL)/ Foral |
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Eq for intermittent dose for the maintenance dose
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Dose(maintenance) = Css x CL x Dose interval
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2 Eq for dose adjustments
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New Dose = t1/2(normal)/t1/2(disease) x maintenance dose
new dose = CL(diseased)/CL(normal) x maintenance dose |
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2Eq for dose interval adjustment
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New interval = t1/2(diseased)/t1/2(normal) x old interval
New interval = CL(normal)/CL(disease) x old interval |
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Synergistic drug-drug interactions
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observed effect of 2 drugs > than additive effect
2+3 = 20 |
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Potentiation of drug-drug interactions
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one drug does not cause a effect but combined with another produces a greater effect
0+2 = 10 |
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Idiosyncratic response
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genetically determined variable response to a drug
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Type II hypersensitivity
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immune mediated destruction of RBC
-drug modified RBC induce production of antibodies -> RBC with antibodies are more susceptible to lysis or phagocytosis |
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Pharmacokinetic Tolerance
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-metabolic in nature
(drug does not work as well as it used to -> increase dose to get the same response) -lower drug conc. at the receptor site |
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Pharmacodynamic Tolerance
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-cellular-adaptive in nature
(receptors adapt sensitivity or increase or decrease number of receptors) |
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What are the axises of a Quantal Dose Response Curve
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x - minimal effective dose
y - frequency of population responding (did they respond, yes/no) |
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What does a Graded Dose Response Curve represent
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difference in intensity of response in an individual
-info on potency, selectivity, maximal efficacy |
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What does a quantal dose response curve show
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distribution of effective doses in a GROUP or Population
-info: potency, selectivity, variability (pharmacodynamic variability in pt pop.) |
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Graded Dose effect endpoint relates dose to _______ of effect
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intensity
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Quantal dose effect endpoint relates dose to ________ of effect
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frequency
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In a quantal dose curve what does a larger standard deviation represent?
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greater variability
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