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96 Cards in this Set

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Define "Bioequivalence"
2 drugs that have both the same
-bioavailability
-rate of absorption
2 drugs that are Bioequivalent will have these 3 things that are the same
1. Peak height concentrations (Cmax)
2. Peak times (Tmax)
3. Area under curves (AUC)
List the 3 equations for the Concentration at the Steady State
-
In Steady-state parameters, how many half-lives does it take to attain the Plateau state?
4-5
In steady-state parameters, is TIME to plateau dependent or independent of dose?
independent
In steady-state parameters, is the LEVEL of plateau proportional or unproportional to the dose?
proportional
In steady-state parameters, when are there no fluctuations?
with a continuous I.V. infusion
What blunts fluctuations in steady state parameters?
Slow absorption
What are fluctuations proportional to in steady-state parameters?
Dosage interval / half-life
What 3 things is Plateau concentration proportional to?
1. Dose / dose interval

2. half-life

3. F / Cl (availability fraction / clearance)
What 2 things is Plateau concentration inversely related to?
1. Kel (elimination constant)

2. Vd (volume of distribution)

*High Elimination rate constant = Low Plateau Conc.
*High Vd = Low Plateau Conc.
Definition: the maximum concentration attained after a given dose
Peak
Definition: the minimum concentration obtained prior to giving the next dose
Trough
What does Maintenance Dose depend on?
Clearance
What is another term for Dosing rate?
Maintenance dose
List 3 equations for calculating the Dosing Rate
1. (Css . Cl) / F

2. (Css . Kel . Vd) / F

3. (.693 . Css . Vd) / Half-life
What does the Loading Dose depend on?
Volume of Distribution
What is the Equation for Loading dose?
(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
How do you calculate the Rate of Infusion for IV infusion?
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
How do you calculate the Loading Dose for IV infusion?
LD = Css . Vd
Why are loading doses given?
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
What is the equation for "Renal Disease Dose Adjustment"?
-
Definition: Study of the biochemical and physiological effects of drugs and mechanisms of actions
Pharmacodynamics
In dose-response relationships, what is the intensity of the response proportional to?
the number of receptors occupied or the concentration of drug-receptor complexes
What is INVERSELY related to the AFFINITY of drug for the receptor?
Dissociation constant (Kd)
- higher the affinity = lower the dissociation constant = less the drug will dissociate with the receptor
What shapes do Log-dose response (LDR)curves typically have?
S-shaped or sigmoidal
Define "Graded Responses"
measures an increase in response in an individual as dose is increased
Define "All-or-None (Quantal)" responses
Number of individuals within group responding to a given dose; endpoint is set and an individual is either a responder or non-responder
For an All-or-None response, a normal histogram is usually this shape
Bell-shaped
Definition: in All-or-none responses, this is the dose to which 50% of subjects respond
Median effective dose (ED50)
What is the Therapeutic Index?
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
What is the equation for Therapeutic Index?
TI = LD50/ED50

= Lethal dose / Effective dose
T or F: the higher the Therapeutic Index, the safer the drug
True
- TI = LD50/ED50
- means the LD and ED are far from eachother
What is the equation for Margin of Safety?
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
A and B = full agonists

C = partial agonist
Define A, B, and C as partial or full agonists
Definition: the propensity of a drug to bind with a given receptor and is inversely related to Kd
Affinity
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?
10^-7
Definition: comparative expression relating the dose required to produce a particular effect of given intensity relative to a standard reference
Potency
Which is more potent, a drug that exerts 50% of its maximal response at 10^-7 M or 10^-6 M?
10^-7
Definition: Measure of how well a drug produces a response
Efficacy
Synonym for Efficacy
Intrinsic value

*max efficacy is assigned 100%
*Intrinsic value is assigned 1.0
Definition of an Agonist
stimulates a receptor, provoking a biological response
Definition of a Partial Agonist
provokes a maximal response somewhat less than a full agonist
Describe an "Inverse Agonist"
based on the concept that there is ongoing basal signal transduction occurring which is reduced by the inverse agonist
Define a Competitive Antagonist
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
How does one overcome the effects of Competitive Antagonist?
increase the dose of the agonist
As the concentration of the antagonist increases, does the Emax (max effect) change?
NO
What is the Efficacy (Intrinsic activity) of a Competitive Antagonist?
0
What will be the effect of a fixed dose of a Competitive Antagonist in a dose-response curve
cause a parallel shift for an agonist to the right
With Noncompetitive Antagonists, can the effect be completely overcome by increasing the agonist concentration?
No
What is decreased in the presence of Noncompetitive Antagonists?
number of functional receptors
What happens to Emax as the concentration of noncompetitive antagonists increases?
decreases because of fewer functional receptors available
What happens to the Dose-response curve with the presence of Noncompetitive Antagonists?
nonparallel, downward shift for the agonist to the right
Give 2 examples of when partial agonists act as inhibitors to a full agonist
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
Define Potentiation
the effect of 2 drugs is greater than predicted from individual effects
Give 2 examples of Potentiation
1. Physostigmine (an AChEI) potentiates the response to ACh

2. Cocaine (uptake I blocker) potentiates the effects of NE and Epi
What effect does Potentiation have on the Dose-response curve?
shifts the agonist to the left
Time it takes for steroids to cause a response
Hours
Time it takes for Insulin and Growth Factors to cause a response
Minutes
Time it takes for IL-2 and Cytokines to cause a response
Minutes
Time it takes for Nicotine to cause a response
Milliseconds
Time it takes for Epinephrine to cause a response
Seconds
Nicotinic/ACh receptors are this kind of receptor
Ionotropic --> Sodium channel
GABA--Benzodiazepine receptors are this kind of receptor
Ionotropic -> Chloride channel
-Hyperpolarization
- Inhibitory
Glutamate/AMPA receptors are this kind of receptor
Sodium channel
-Depolarization
-Excitatory
Glutamate/NMDA receptors are this kind of receptor
Ionotropic = Calcium channel
-Depolarization
-Toxicity
-Excitotoxicity
What do G proteins bind to and what do they couple with?
Bind to GTP

Couple with "7-TM receptors" or "Serpentine receptors"
In G protein-coupled receptors, agonists promote the release of what?
GDP which allows for the attachment of GTP to nucleotide-binding site
In G-protein couple receptors, when GTP is bound what is the G protein capable of?
regulating an enzyme or ion channel
In G Protein-Coupled receptors, how is the signal terminated?
hydrolysis of GTP to GDP

*slow hydrolysis of GTP allows signal to persist long after the ligand has dissociated from the receptor
What does Gs stimulate?
Adenylyl Cyclase
What does Gi do?
inhibits Adenylyl Cyclase and opens K+ channels
What does Gq do?
stimulates phospholipase C
What does Go do?
closes Ca+ channel
Explain the Adenylyl Cyclase system
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
List 7 stimulatory agonists for the Adenylyl Cyclase system
1. ACTH
2. Beta-agonists (isoproterenol)
3. Glucagon
4. FSH
5. PGE2
6. Thyrotropin
7. Dopamine D1 agonists
List 3 inhibitory agonists of the Adenylyl Cyclase system
1. Alpha-2 agonists = Clonidine

2. Muscarinic M2 agonists

3. Dopamine D2, D3, and D4 agonists

**MAD 2's**
Explain the model of desensitization
-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
Explain the Polyphosphoinositide Signaling system
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+
List 5 receptors that activate the Polyphosphoinositide signaling system
1. Muscarinic receptors M1 and M3
2. alpha-1 adrenoceptors
3. Vasopressin receptors (V1)
4. Angiotensin receptors (AT1)
5. Serotonin receptors (5-HT2)
What do muscarinic receptors bind?
ACh and muscarine
What do Alpha-1 adrenoceptors bind?
Norepinephrine

Phenylephrine

*PIP2 signaling system
What do Growth Factors signal through?
Protein Tyrosine Kinase Signaling
Examples of agonists that signal through Tyrosine Kinase receptors
1. PDGF

2. Insulin

3. Epidermal Growth Factor

**Insulin and Growth Factors
Explain the Receptor Tyrosine Kinase signaling system
1. agonist binds
2. semi-distant receptors dimerize and autophosphorylate
3. Phosphorylation of downstream substrates
What do Cytokines signal through?
Receptor Tyrosine Kinases linked to the JAK/STAT pathway -> dimerized STAT goes to nucleus
List 6 ligand responsive Transcrtiption Factors (Nuclear Receptors)
1. Glucocorticoids
2. Mineralcorticoids
3. Sex steroid hormones
4. Vitamin D
5. Thyroid hormone
6. Retinoid acid
Explain the mechanism of Glucorticoid signaling
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
Describe 2 ways in which Glucocorticoids are anti-inflammatory
1. induce synthesis of Lipocortin, an inhibitor of Phospholipase A2 (cleaves off Arachidonic acid)

2. decrease the up-regulation of COX-2 driven cytokines
Where is Nitric Oxide formed?
Endothelial cells
What is NO's mode of action?
it diffuses through plasma membrane of Smooth Muscle cells activating Guanylyl Cyclase, converting GTP to cGMP
What does NO activate?
Guanylyl cyclase
What does cGMP activate?
Protein kinase G -> vasodilation
Where is iNOS found?
Professional killer cells
What is the substrate for NO?
Arginine
How can NO be toxic?
it reacts with Superoxide, forming the toxin Peroxynitrite