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P&T Exam 1 > Dr. Walsh Lectures > Flashcards

Dr. Walsh Lectures Flashcards

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1
Q

What is an agonist?

A

Molecule that binds to receptor and has a direct or indirect effect

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2
Q

What are competitive inhibitors?

A

Compete with agonist for receptor unless concentration of agonist is high enough. Emax is the same

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3
Q

What is an allosteric activator?

A

Binds to different site on receptor but increases efficacy of drug or binding affinity

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4
Q

What is an allosteric inhibitor?

A

Binds to different site on receptor but decreases efficacy of drug or binding affinity

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5
Q

Describe the dose response curve for all agonist + inhibitor/activator interactions

A

Agonist plus activator creates the largest line, agonist alone is just below, agonist plus competitive inhibitor makes a sigmoidal curve, agonist plus inhibitor makes a flatter curve

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6
Q

What is a partial agonist?

A

Equal affinity for Ri and Ra, they may prevent binding of the full agonist. Emax decreases

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7
Q

What is an inverse agonist?

A

Has affinity for Ri and reduces basal activity, may produce contrasting result to agonist

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8
Q

Describe the log dose response curve for agonists, partial agonists, antagonists, and inverse agonists

A

The full agonist will produce the largest curve, partial agonist is below, antagonist produces a horizontal line, inverse agonist is lower than antagonist

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9
Q

Describe aqueous diffision

A

Molecules move from high to low concentration, plasma proteins affect distribution of molecules

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10
Q

Describe diffusion across the blood-brain barrier

A

Absence of pores for aq diffusion, has several drug export pumps

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11
Q

Describe lipid diffusion

A

Lipid:aq partition coefficient determines how readily molecules move between two media. The higher the partition coefficient the more lipid soluble

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12
Q

Describe drug transporters

A

High abundancy at physiological barriers, are selective, saturable, and inhibitable

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13
Q

What are the two classes of drug transporters?

A

ATP binding cassette which is active transport, and solute carriers which is facilitated diffusion

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14
Q

Describe endo and exocytosis

A

endo- drugs bind to cell surface receptor and are engulfed into membrane
exo- vesicles are secreted out of the cell

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15
Q

Describe Ficks Law of Passive Flux

A

Flux(mol/utime)= (C1-C2)((areapermeability coefficient)/thickness)

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16
Q

What is the permeability coefficient

A

The measure of mobility of drugs in a medium

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17
Q

What is a weak acidic drug and when is it most lipid soluble?

A

A drug that can reversibly dissociate into an anion and proton, it is most lipid soluble in acidic environments

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18
Q

What is weak basic drug and when is it most lipid soluble?

A

A drug that can reversible form a cation by combining with a proton, it is most lipid soluble in alkaline environments

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19
Q

Describe ion trapping

A

Only neutral forms of weak acids/bases can cross nephron cells, if the pH of urine is acidic, weak bases will be ionized and expelled. The reverse is true for weak acids

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20
Q

What are the four criteria of Lipinski’s Rule?

A

No more than 500Da, no more than 5 H bond donors, no more than 5 H bond acceptors, a logP that does not exceed 5

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21
Q

Describe the graph of [drug] versus drug effect(E)

A

Hyperbolic curve that plateaus at Emax, EC50 is where [drug] is 50% efficient

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22
Q

Describe the graph of [drug] versus receptor-bound drug

A

Hyperbolic curve that plateaus at Bmax, Kd is the dissociation constant and marks where 50% of the receptors are bound

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23
Q

Describe the graph of [drug] versus effect for agonist alone and agonist + increase [antagonist]

A

Sigmoidal curve that shifts right the higher the [antagonist], will eventually reach a point where Emax decreases(not enough agonist can bind to produce Emax)

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24
Q

Describe spare receptors and their relationship to Emax

A

Spare receptors are the number of receptors that remain unbound after [agonist] allows for Emax. Even if some irreversible antagonist is present, can still get Emax

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25
How do spare receptors change sensitivity?
The more receptors, the more sensitive the cell is to a specific dose(more available binding sites, easier to get Emax)
26
How can spareness of receptors be temporary?
A secondary messenger may last longer than the agonist-receptor interaction itself
27
What is a competitive antagonist and its relationship to Emax?
Competes with agonist for binding site, but if [agonist] is high enough can still get Emax
28
What is a noncompetitive(irreversible) antagonist and its relationship to Emax?
Binds to a different site than agonist but changes morphology of receptor so that agonist cannot bind. Emax decreases
29
What is a positive allosteric modulator?
Increases receptor activity
30
What is a negative allosteric modulator?
Reduces receptor activity
31
What are allosteric modulators?
Modifies pharmacologic activity of drug-receptor without completely blocking agonist
32
What are the two classes of agonists and what do they do?
partial agonists lower response at full receptor occupancy, full agonist produces max response at full receptor occupancy
33
What are the mechanisms of transmembrane signaling?
Lipid soluble ligand, transmembrane receptor regulated by ligand that binds to extracellular domain, transmembrane receptor that activates intracellular tyrosine kinases, ion channels, and g-protein coupled receptors
34
Why do some drugs produce effects that last for extended periods of time even after drug is no longer present?
Downstream second effector activation
35
Why do responses to other drugs diminish rapidly with prolonged or repeated administration?
Receptors can become desensitized and will not produce the same effect with the same amount of drug.
36
How do cellular mechanisms for amplifying external chemical signals explain the phenomenon of spare receptors?
Not all receptors must be occupied in order to produce an effective response. Amplification of signals decreases [drug] required to hit Emax
37
What is drug potency?
The concentration of drug that is required to reach 50% max effect, is dependent on affinity of drug-receptor and efficiency of its coupled response
38
What is drug efficacy?
The ability of a drug to reach maximal response with minimal dose
39
Describe the graph of log partial agonist versus percent max binding
Binding of full agonist decreases and concentration of partial agonist increases
40
What happens when we have a constant [full agonist] and an increases [partial agonist]?
Total response decreases(reaches level of partial agonist alone)
41
What is a therapeutic windown?
How high of a dose we can give to a patient that will result in high efficacy but low toxicity
42
What can we expect if there is a wide therapeutic window versus a narrow window?
There is probably little to no toxic effect for drugs with a wide window, but there is a fine line between beneficial and toxic for drugs with a narrow window
43
What occurs during Phase I drug metabolism?
Parent drug is converted to a more polar metabolite by adding or unmasking a functional group, this allows drug to stay in blood for clearance
44
What enzymes are involved in Phase I drug metabolism?
Cytochrome P450, flavin-containing monooxygenases, epoxide hydrolases
45
What is a prodrug?
Drug that is activated by metabolism
46
What occurs during Phase II drug metabolism
Conjugate reaction which introduces an endogenous molecule, such as sulfuric acid or acetic acid, that increases aqueous solubility
47
What are the enzymes involved in Phase II drug metabolism?
Sulfotransferases, UDP-glucuronosyltransferases, Glutathione-S-transferases, N-acetyltransferases, Methyltransferases
48
Why does phase I typically proceed phase II metabolism?
Phase II requires an acceptor site for a hydrophilic moiety which phase I can reveal
49
What are the top three CYP450 isoforms involved in metabolism and their percentage of abundace?
CYP3A4(30%), CYP2C9(20%), CYP1A2(15%)
50
What do CYP450's do?
Uses a cofactor to oxidize substrates, consumes one molecule of O2 and produces oxidized substrate(drug) and 1 molecule of water
51
What is the most common combination of Phase I and Phase II enzymes involved in metabolism of drugs in use?
CYP3A4 and UDP-glucuronosyltransferases
52
What is the purpose of drug metabolism?
To reduce bioavailability and to prevent drugs from reaching systemic circulation
53
Describe First-Pass Effects and how these influence drug bioavailability(F)
Extensive metabolism before entering systemic circulation, bioavailability decreases with each pass through
54
What is bioavailability(F)?
The amount of drug which reaches systemic circulation
55
Describe hepatic clearance(CLh)
Volume of blood that perfuses liver which is cleared of drug per unit time
56
What is the relationship between extraction ratio(E) and bioavailability(F)?
After first pass extraction, F=1-E. E is a sum of absorption, gut wall metabolism and hepatic extraction
57
What is total clearance?
Total clearance is equal to renal clearance plus hepatic clearance
58
What is the well-stirred model?
Blood flow(Q) going through an organ and extraction ration(E) through the same organ
59
What is the equation for clearance in the well stirred model?
CL=(Q(arterial concentration-venous concentration)/arterial concentration)
60
What is intrinsic clearance?
Ability of liver to metabolize drug in absence of blood flow limitations
61
What is the equation for intrinsic hepatic clearance?
CLh=(Qh*fu*Cl(int(u)))/(fu*CL(int(u))+Qh)
62
What is CL(int(u)) and fu?
Unbound intrinsic clearance and fraction of drug unbound to protein
63
What is a high extraction drug?
Extraction is greater than 0.7, increase in blood flow increases drug removal (clearance=blood flow)
64
What is a low extraction drug?
Have lower CL(int(u)), less affected by blood flow, can be rewritten as CLh~fu*CL(int(u))
65
Describe renal clearance
The volume in which drug is dissolved that is removed from plasma per unit time through kidney
66
What is the equation for renal clearance
CLr= urinary drug excretion rate/plasma drug conc
67
Describe glomerular filtration
Affects all solutes less than or equal to 500Da, influenced by protein binding, unidirectional and passive, dependent on # functioning nephrons and integrity of glomeruli
68
What is the equation of glomerular filtration rate?
CLfilt=CLr=Glomerular filtration rate * drug unbound from protein
69
What is tubular secretion?
Saturable due to effects mediated by drug transporters, requires carrier protein, relatively nonspecific, glomerular filtration is always a component
70
What is the equation for tubular secretion?
CLr is greater than glomerular filtration rate * drug unbound from protein
71
Describe renal reabsorbtion
Affected by extent of ionization, occurs all along nephron, normally passive, favors lipid soluble unionized drug, is pka and pH dependent
72
When do filtration and secretion occur?
CLr is greater than glomerular filtration rate* drug unbound from protein
73
When do filtration and reabsorption occur?
CLr is less than glomerular filtration rate*drug unbound from protein
74
What happens when we only have filtration occuring?
CLr=~ glomerular filtration rate * drug unbound from protein
75
What is drug exposure?
Dose and measures of [drug] in body
76
What is drug response?
Pharmacologic effect
77
How is pharmacokinetic monitoring useful?
Can use to predict drug effects if there is a relationship between plasma drug concentration and response
78
What is the direct relationship between drug exposure for many drugs?
Plasma drug concentration versus time profile and drug response are directly related
79
What is compartment 1?
Central compartment, represents plasma and organs that see a lot of blood, reach eq quickly
80
What is compartment 2?
Organs that do not see a lot of blood OR organs that are difficult to access(like the brain)
81
What is half life?
The amount of time it takes for drug to be reduced to 50% concentration. Dependent on rate constant(k) and hours(h)
82
What is clearance?
Volume of blood that is completely cleared of drug/minute(ml/min)
83
What parameter is pk independent?
Clearance, dependent on function of organ of elimination
84
What is area under the curve in relation to drug response?
Measures total drug exposure, greater area=greater exposure
85
What is volume of distribution?
Shows extent by which drug is in extracellular tissues but not in plasma
86
What is a zero order reaction?
Drug elimination rate is independent of drug conc
87
What is a first order reaction?
Drug elimination rate is dependent on drug conc
88
What does the slope of a zero or first order graph equal?
Slope= rate constant(k)
89
What is the rate constant and its equation?
Equivalent to fraction of drug that is removed per unit time at any instant (kmetabolism+kexcretion=k)
90
What is IV Bolus administration?
One compartment open model, characterized by two pk parameters, distribution(Vss) and elimination(CL)
91
What is the equation for a one compartment open model?
k=CL/Vss (rate equals elimination over distribution)
92
What happens when liver or kidney function decrease?
rate constant(k) and half life decreases and therefore the slope of their lines decrease
93
What is loading dose?
Dependent on volume of distribution(how much drug will be in plasma versus tissue, helps us get to desired plasma drug conc
94
What PK parameter dictates maintenance dose?
Clearance rate
95
What is the maintenance phase
Helps us maintain desired plasma drug conc obtained from loading dose

P&T Exam 1 (3 decks)

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