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96 Cards in this Set
- Front
- Back
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Best predictor of adverse drug event
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absolute number of drugs prescribed
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Critical number of drugs associated with adverse drug event in elderly
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5 or more
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age range of "young old"
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65-75
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3 characteristics of data obtained on pharmacology in eldery
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cross-sectional rather than longitudinal studies
most data obtained in healthy elderly provide information about age differences rather than changes with aging |
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5 characteristics associated with frail elderly
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reduction in lean body mass
sarcopenia chronic undernourishment decreased mobility poor endurance associated with exhaustion |
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3 factors underlying variability of drug response in elderly
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age-associated changes in organ function and body composition
declining homeostatic reserve comorbid diseases |
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Are changes in GI function in elderly relatively important to pharmacological function?
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NO
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In the elderly, there is a decrease in what 4 components of GI function?
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GI absorptive cells and gastric acid secretion
motility and sphincter activity GI blood flow active transport |
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5 factors that alter drug distribution in elderly
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albumin decreases15-20%
lean body water decreases 25-30% adipose tissue increases (higher percentage in females than males) lean body mass decreases cardiac output decreases or remains normal |
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Ethyl alcohol is a water-soluble drug. How would aging affect its volume of distribution?
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??
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How would the volume of distribution of long-acting, highly lipid-soluble benzodiazepines be affected?
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??
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What happens to phase I hepatic reactions as people age?
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no change or decrease
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what happens to phase II hepatic reactions as people age?
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no change
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Examples of effects of phase I metabolism decreases involving CYP3A
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Decreased clearance of midazolam and triazolam -->
increased sedation and impaired task performance with triazolam |
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Examples of effects of phase I metabolism decreases involving CYP2C activity
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Decreased clearance of warfarin (2C9) and phenytoin (2C19)
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Drugs with decreased clearance in elderly
due to CYP3A decrease (7) |
alprazolam,
midazolam, triazolam, verapamil, diltiazem, dihydropyridine calcium entry blockers, lidocaine |
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Drugs with decreased clearance in elderly
due to CYP2C decrease (3) |
diazepam,
phenytoin, celecoxib |
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Drugs with decreased clearance in elderly
due to CYP1A2 decrease (1) |
theophylline
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Drugs with decreased clearance in elderly
due to multiple phase I metabolic pathway decreases |
imipramine,
trazodone, flurazepam |
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Drugs that *may* show altered clearance in elderly due to
glucoronidation |
lorazepam, oxazepam
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Drugs that *may* show altered clearance in elderly due to
sulfation |
acetaminophen
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Drugs that *may* show altered clearance in elderly due to
acetylation |
Isoniazid
Procainamide |
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Three renal functions that decrease in elderly
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GFR
tubular function renal plasma flow |
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Cockroft-Gault Formula to estimate creatinine clearance
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creatinine clearance = [(140 – age)(weight in kg)]/[ 72 (serum Cr in mg/dL)]
For women, multiply by 0.85 |
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3 things to know about long-acting benzodiazepines in elderly
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Long-acting benzodiazepines such as diazepam or flurazepam are metabolized oxidatively by P450 enzymes.
Their use in elderly is associated with an increased risk of falls and hip fractures. toxicity is due primarily to decreased metabolic clearance and resultant higher plasma levels. |
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4 altered responses to NSAIDS in elderly
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Azotemia,
reduced GFR, sodium retention hyperkalemia |
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azotemia
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accumulation of nitrogen compounds (e.g.: creatinine and urea) in the body
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hyperkalemia in elderly is more likely to result from treatment with what drug class?
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ACE inhibitors
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hypokalemia in elderly is more likely to result from treatment with what drug class
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thiazide diuretics (use of lower doses largely avoids adverse effects)
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pH of neonatal small intestine lumen relative to adult
why? |
elevated
b/c of reductions in basal acid output and total volume of gastric secretions |
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effect of neonatal intestinal pH on acid-labile compounds, e.g.: penicillin G
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oral administration produces GREATER bioavailability in neonates
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effect of neonatal intestinal pH on weak acid compounds, e.g.: phenobarbitol
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oral administration produces LESS bioavailability in neonates and young children
(require greater administration dose to produce therapeutic levels) |
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general absorption rate in neonates and young children compared to adults
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SLOWER
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relative systemic exposure to topically applied medicine in young children compared to adults
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potentially much greater (can lead to toxicity)
b/c of greater vascularization |
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i.m. absorption is _____ efficient in infants than in older children
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i.m. absorption is MORE efficient in infants than in older children
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Are developmental changes in drug metabolizing enzymes general or isoform specific?
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isoform specific
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When does last hepatic CYP enzyme appear?
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1-3 months after birth
CYP1A1 |
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at what age are adult GFR values reached?
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8-12 months of life
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Affinity
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the ease and duration with which a specific drug binds with a specific receptor
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Another word for binding
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association
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reverse of binding
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disassociation
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ACh binds with similar affinity to which 2 types of receptors?
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nicotinic
muscarinic |
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BCh is structurally similar to ACh. How do its binding affinities compare?
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BCh has high affinity for muscarinic cholinergic receptor
low affinity for nicotinic cholinergic receptor |
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Does chemical structure predict binding affinity for a specific receptor?
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No
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Examples of chemicals with different chemical structures but similar binding affinities for certain receptors
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ACh and muscarine for mAChR
ACh and nicotine for nAChR |
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How is affinity measured?
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measuring the amount of drug binding to a population of receptors
over a range of drug concentrations when only one type of drug and one type of receptor are present |
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2 types of binding sites on a receptor
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effector binding site
modulator binding site |
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drug that binds modulator binding site
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allosteric modulator
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allosteric modulation in binding
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binding of modulatory site changes affinity of effector site for agonist
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Under what conditions may a given receptor effect different cellular functions?
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When that receptor type is located on different cell types.
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Can a specific receptor type be coupled to more than one cellular effector mechanisms in a given cell type?
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No
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True or False: Any drug activating a particular type of receptor is assumed to have the same effect as any other drug activating those receptors.
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True.
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Graded Concentration Reponse Relationship
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response amplitude or intensity measured in increasing dosages of the drug
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Does affinity predict effect?
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No
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response
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change in some cellular activity
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0% response
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basal activity of the cell
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maximum response
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100% response
response induced when 100% of the receptors in question are fully activated |
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full agonist
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can activate the maximum response
said to have 100% Pharmacological Efficacy |
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partial agonist
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can only partially activate the receptor after binding
unable to effect 100% response even after all the receptors are bound by the drug |
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How are partial agonists used as antagonist?
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they compete with full agonist and prevent full agonist from binding to the receptors
thus, prevent 100% pharmacological efficacy |
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antagonist
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binds to the receptor, but does not activate it, thus inhibiting the cellular response produced by the agonist at that receptor
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pharmacological efficacy of an antagonist
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0% pharmacological efficacy
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intrinsic activity
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ability of a single molecule bound to a receptor to activate that receptor
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difference between pharmacological efficacy and intrinsic activity
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essentially the same, except intrinsic activity is expressed in the rang 0 - 1.
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agonist potency
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concentration of a drug necessary to produce 50% of the maximum response: EC(50)
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function of agonist potency measure
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shows how much of a full agonist drug is needed to produce an effect through activation of receptors
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A low ED(50) value reflects ____ potency
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high
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Can partial agonist potency be calculated?
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Yes, but the number is meaningless/misleading?
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Can agonist potency for an antagonist be calculated
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no (antagonist potency is a separate and distinct calculation)
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biochemical measure representing affinity
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Kd (dissociation constant)
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When can potency be predicted from affinity?
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When comparing full agonist for the same receptor type
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When are graphs of the Concentration Binding Relationship and the Graded Concentration Response Relationship superimposed for a given drug?
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when there is sufficient drug for 100% of the receptors to be bound
and when there is insufficient drug for any receptors to be bound |
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For full agonists, which measure is greater, EC(50) or Kd?
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Kd
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theory that explains why Kd is greater than EC(50) for a given drug
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spare receptor theory
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does the spare receptor theory state that there are non-functional receptors within a given receptor population?
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no - it's merely a figure of speech
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graphical response to the addition of a constant dose of antagonist over a range of agonist doses
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graph shifted to right, but maximum value and shape not changed
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2 factors influencing extent of Graded Concentration Response Relationship shift to the right when antagonist added
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concentration of antagonist
relative affinities of antaonist and full agonist for the receptor |
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one way in which antagonist potency is established
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The concentration of agonist just sufficient to produce the Maximum Response is established. Then, with this concentration of agonist present, the response (induced by the agonist) is measured over a range of concentrations of antagonist. The Pharmacological Antagonist Potency, or IC50, is measured as the concentration at which the response (induced by the agonist) is reduced to 50% of the Maximum Response.
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are there endogenous pharmacological antagonists?
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no, not that we know of
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Graded Concentration Response Relationship
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cellular response to a drug (agonist, antagonist or modulator) over a range of doses
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EC(50) equivalent for antagonists
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IC(50)
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at what dose does one normally start when titrating for effect in an individual patient?
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the "average" prescribed dose
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Quantal Dose Response Relationship
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frequency histogram showing how many people for each given dose report a complete remission (Yes/No)Cu of symptoms for which a drug is targeted
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Cumulative Quantal Dose Response Relationship
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double transformation from Quantal Dose Response Relationship:
(1) all individuals who said "Yes" at given dose AND all those who said "Yes" for lower dose included together (2) frequency expressed as percentage of total study population |
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From which relationship is clinical potency established?
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Culumative Quantal Dose Response Relationship
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Clinical potency =
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ED(50) - dose required to produce desired endpoint (e.g.: remission of headache) in 50% of the population
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Which does the clinical potency reflect, pharmacological efficacy or drug potency?
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drug potency
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What is the difference between pharmacological efficacy and clinical potency?
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pharmacological efficacy takes into account the type of drug: agonist, antagonist or modulator; clinical potency does not
clinical potency looks at clinical symptoms; pharmacological efficacy does not |
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Are side effects categorically detrimental?
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No - side effects are any effect other than the target effect; may be beneficial or detrimental
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How are toxic and lethal doses established?
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In animals (esp. for lethal doses) using Cumulative Quantal Dose Response Relationship
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TD(50)
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dose at which 50% of population experiences toxicity
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LD(50)
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dose that is lethal in 50% of the population
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therapeutic index (TI) =
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TI = LD(50)/ED(50)
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do you want a high or low TI?
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high
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decent measure of safety
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Standard Safety Margin (SSM) or Certain Safety Margin (CSM)
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SSM (or CSM) =
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SSM = LD(1)/ED (99)
or, dose at which drug is lethal in 1% of the population divided by dose at which drug is effective in 99% of the population |
