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96 Cards in this Set
- Front
- Back
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Define "Bioequivalence"
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2 drugs that have both the same
-bioavailability -rate of absorption |
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2 drugs that are Bioequivalent will have these 3 things that are the same
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1. Peak height concentrations (Cmax)
2. Peak times (Tmax) 3. Area under curves (AUC) |
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List the 3 equations for the Concentration at the Steady State
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-
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In Steady-state parameters, how many half-lives does it take to attain the Plateau state?
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4-5
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In steady-state parameters, is TIME to plateau dependent or independent of dose?
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independent
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In steady-state parameters, is the LEVEL of plateau proportional or unproportional to the dose?
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proportional
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In steady-state parameters, when are there no fluctuations?
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with a continuous I.V. infusion
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What blunts fluctuations in steady state parameters?
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Slow absorption
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What are fluctuations proportional to in steady-state parameters?
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Dosage interval / half-life
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What 3 things is Plateau concentration proportional to?
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1. Dose / dose interval
2. half-life 3. F / Cl (availability fraction / clearance) |
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What 2 things is Plateau concentration inversely related to?
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1. Kel (elimination constant)
2. Vd (volume of distribution) *High Elimination rate constant = Low Plateau Conc. *High Vd = Low Plateau Conc. |
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Definition: the maximum concentration attained after a given dose
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Peak
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Definition: the minimum concentration obtained prior to giving the next dose
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Trough
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What does Maintenance Dose depend on?
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Clearance
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What is another term for Dosing rate?
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Maintenance dose
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List 3 equations for calculating the Dosing Rate
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1. (Css . Cl) / F
2. (Css . Kel . Vd) / F 3. (.693 . Css . Vd) / Half-life |
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What does the Loading Dose depend on?
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Volume of Distribution
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What is the Equation for Loading dose?
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(1.44 . Css . Vd) / F
*the higher the Vd = the higher the LD needs to be *the lower the Availability Fraction = the higher the LD needs to be |
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How do you calculate the Rate of Infusion for IV infusion?
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Ro = Css . Kel . Vd
*Rate of Infusion does determine the plasma level at the STEADY STATE *Double the Infusion Rate = Plasma Level of the drug at the Steady State is doubled |
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How do you calculate the Loading Dose for IV infusion?
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LD = Css . Vd
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Why are loading doses given?
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A loading dose may be desirable if the time required to attain steady state by the administration of drug at a constant rate (four elimination half-lives) is long relative to the temporal demands of the condition being treated
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What is the equation for "Renal Disease Dose Adjustment"?
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-
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Definition: Study of the biochemical and physiological effects of drugs and mechanisms of actions
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Pharmacodynamics
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In dose-response relationships, what is the intensity of the response proportional to?
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the number of receptors occupied or the concentration of drug-receptor complexes
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What is INVERSELY related to the AFFINITY of drug for the receptor?
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Dissociation constant (Kd)
- higher the affinity = lower the dissociation constant = less the drug will dissociate with the receptor |
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What shapes do Log-dose response (LDR)curves typically have?
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S-shaped or sigmoidal
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Define "Graded Responses"
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measures an increase in response in an individual as dose is increased
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Define "All-or-None (Quantal)" responses
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Number of individuals within group responding to a given dose; endpoint is set and an individual is either a responder or non-responder
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For an All-or-None response, a normal histogram is usually this shape
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Bell-shaped
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Definition: in All-or-none responses, this is the dose to which 50% of subjects respond
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Median effective dose (ED50)
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What is the Therapeutic Index?
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the ratio betwen the toxic dose and the therapeutic dose, used as a measure of the relative safety of the drug for a particular treatment
*Large ratio = High TI |
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What is the equation for Therapeutic Index?
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TI = LD50/ED50
= Lethal dose / Effective dose |
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T or F: the higher the Therapeutic Index, the safer the drug
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True
- TI = LD50/ED50 - means the LD and ED are far from eachother |
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What is the equation for Margin of Safety?
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LD1 / ED99 = dose to which it is lethal to 1% / dose to which it is 99% effective
*the higher the MS, the safer the drug |
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A and B = full agonists
C = partial agonist |
Define A, B, and C as partial or full agonists
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Definition: the propensity of a drug to bind with a given receptor and is inversely related to Kd
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Affinity
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Which has a higher affinity, a drug with a Kd of 10^-7 M for a receptor or one with a Kd of 10^-6?
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10^-7
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Definition: comparative expression relating the dose required to produce a particular effect of given intensity relative to a standard reference
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Potency
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Which is more potent, a drug that exerts 50% of its maximal response at 10^-7 M or 10^-6 M?
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10^-7
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Definition: Measure of how well a drug produces a response
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Efficacy
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Synonym for Efficacy
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Intrinsic value
*max efficacy is assigned 100% *Intrinsic value is assigned 1.0 |
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Definition of an Agonist
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stimulates a receptor, provoking a biological response
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Definition of a Partial Agonist
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provokes a maximal response somewhat less than a full agonist
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Describe an "Inverse Agonist"
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based on the concept that there is ongoing basal signal transduction occurring which is reduced by the inverse agonist
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Define a Competitive Antagonist
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Interaction of an Antagonist with a receptor does not result in stimulus for biological response, but will block the effect of agonist binding at same receptor site
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How does one overcome the effects of Competitive Antagonist?
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increase the dose of the agonist
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As the concentration of the antagonist increases, does the Emax (max effect) change?
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NO
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What is the Efficacy (Intrinsic activity) of a Competitive Antagonist?
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0
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What will be the effect of a fixed dose of a Competitive Antagonist in a dose-response curve
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cause a parallel shift for an agonist to the right
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With Noncompetitive Antagonists, can the effect be completely overcome by increasing the agonist concentration?
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No
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What is decreased in the presence of Noncompetitive Antagonists?
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number of functional receptors
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What happens to Emax as the concentration of noncompetitive antagonists increases?
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decreases because of fewer functional receptors available
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What happens to the Dose-response curve with the presence of Noncompetitive Antagonists?
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nonparallel, downward shift for the agonist to the right
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Give 2 examples of when partial agonists act as inhibitors to a full agonist
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1. Acebutolol is a partial agonist at the B1-adrenoreceptor
2. Selective Estrogen receptor Modulators - Tamoxifen - Clomifene - Raloxifene *As the partial agonist displaces the full agonist from the receptor, the response is reduced - the partial agonist is acting as an ANTAGONIST |
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Define Potentiation
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the effect of 2 drugs is greater than predicted from individual effects
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Give 2 examples of Potentiation
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1. Physostigmine (an AChEI) potentiates the response to ACh
2. Cocaine (uptake I blocker) potentiates the effects of NE and Epi |
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What effect does Potentiation have on the Dose-response curve?
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shifts the agonist to the left
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Time it takes for steroids to cause a response
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Hours
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Time it takes for Insulin and Growth Factors to cause a response
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Minutes
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Time it takes for IL-2 and Cytokines to cause a response
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Minutes
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Time it takes for Nicotine to cause a response
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Milliseconds
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Time it takes for Epinephrine to cause a response
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Seconds
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Nicotinic/ACh receptors are this kind of receptor
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Ionotropic --> Sodium channel
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GABA--Benzodiazepine receptors are this kind of receptor
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Ionotropic -> Chloride channel
-Hyperpolarization - Inhibitory |
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Glutamate/AMPA receptors are this kind of receptor
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Sodium channel
-Depolarization -Excitatory |
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Glutamate/NMDA receptors are this kind of receptor
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Ionotropic = Calcium channel
-Depolarization -Toxicity -Excitotoxicity |
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What do G proteins bind to and what do they couple with?
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Bind to GTP
Couple with "7-TM receptors" or "Serpentine receptors" |
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In G protein-coupled receptors, agonists promote the release of what?
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GDP which allows for the attachment of GTP to nucleotide-binding site
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In G-protein couple receptors, when GTP is bound what is the G protein capable of?
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regulating an enzyme or ion channel
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In G Protein-Coupled receptors, how is the signal terminated?
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hydrolysis of GTP to GDP
*slow hydrolysis of GTP allows signal to persist long after the ligand has dissociated from the receptor |
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What does Gs stimulate?
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Adenylyl Cyclase
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What does Gi do?
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inhibits Adenylyl Cyclase and opens K+ channels
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What does Gq do?
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stimulates phospholipase C
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What does Go do?
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closes Ca+ channel
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Explain the Adenylyl Cyclase system
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Gs
- agonist binds receptor, couples the G-protein GTP binds causing alpha subunit to dissociate with Beta/gamma - alpha/GTP stimulate Adenylyl Cyclase which converts ATP to cAMP - cAMP activates PKA Gi = inhibits AC |
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List 7 stimulatory agonists for the Adenylyl Cyclase system
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1. ACTH
2. Beta-agonists (isoproterenol) 3. Glucagon 4. FSH 5. PGE2 6. Thyrotropin 7. Dopamine D1 agonists |
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List 3 inhibitory agonists of the Adenylyl Cyclase system
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1. Alpha-2 agonists = Clonidine
2. Muscarinic M2 agonists 3. Dopamine D2, D3, and D4 agonists **MAD 2's** |
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Explain the model of desensitization
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-Beta arrestin kinase phosphorylates the internal domain of the receptor when agonist binds
-When it's P'ed, beta arrestin binds and blocks coupling to Gs protein |
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Explain the Polyphosphoinositide Signaling system
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1. agonist binds to receptor and activates Gq protein
2. Gq activates Phospholipase C 3. PLC cleaves PIP2 into DAG and IP3 -DAG activates PKC -IP3 releases Ca+ -> Calmodulin-Ca+ |
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List 5 receptors that activate the Polyphosphoinositide signaling system
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1. Muscarinic receptors M1 and M3
2. alpha-1 adrenoceptors 3. Vasopressin receptors (V1) 4. Angiotensin receptors (AT1) 5. Serotonin receptors (5-HT2) |
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What do muscarinic receptors bind?
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ACh and muscarine
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What do Alpha-1 adrenoceptors bind?
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Norepinephrine
Phenylephrine *PIP2 signaling system |
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What do Growth Factors signal through?
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Protein Tyrosine Kinase Signaling
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Examples of agonists that signal through Tyrosine Kinase receptors
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1. PDGF
2. Insulin 3. Epidermal Growth Factor **Insulin and Growth Factors |
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Explain the Receptor Tyrosine Kinase signaling system
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1. agonist binds
2. semi-distant receptors dimerize and autophosphorylate 3. Phosphorylation of downstream substrates |
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What do Cytokines signal through?
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Receptor Tyrosine Kinases linked to the JAK/STAT pathway -> dimerized STAT goes to nucleus
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List 6 ligand responsive Transcrtiption Factors (Nuclear Receptors)
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1. Glucocorticoids
2. Mineralcorticoids 3. Sex steroid hormones 4. Vitamin D 5. Thyroid hormone 6. Retinoid acid |
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Explain the mechanism of Glucorticoid signaling
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1. Steroid binds to Ligand-binding domain
2. Regulator protein is released 3. Tsc-activating domain and DNA-binding domain are exposed 4. Modification of gene expression |
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Describe 2 ways in which Glucocorticoids are anti-inflammatory
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1. induce synthesis of Lipocortin, an inhibitor of Phospholipase A2 (cleaves off Arachidonic acid)
2. decrease the up-regulation of COX-2 driven cytokines |
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Where is Nitric Oxide formed?
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Endothelial cells
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What is NO's mode of action?
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it diffuses through plasma membrane of Smooth Muscle cells activating Guanylyl Cyclase, converting GTP to cGMP
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What does NO activate?
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Guanylyl cyclase
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What does cGMP activate?
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Protein kinase G -> vasodilation
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Where is iNOS found?
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Professional killer cells
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What is the substrate for NO?
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Arginine
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How can NO be toxic?
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it reacts with Superoxide, forming the toxin Peroxynitrite
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