Pharm - S2B1 - General Principles 4

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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
Define A, B, and C as partial or full agonists: A and B = full agonists

C = partial agonist
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

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