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Pharm 1 > Exam 1 > Flashcards

Exam 1 Flashcards

Basic Principles of Pharmacology; Receptors

1
Q

Agonist

A

Binds to Receptor & elicits response (Activator)

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2
Q

Antagonist

A

Binds to Receptor & blocks response (Inhibitor)

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3
Q

Pharmacodynamics

A

What the drug does to the body

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4
Q

Pharmacokinetics

A

What the body does to the drug

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5
Q

Pharmacogenomics

A

Genetic profile / how an individual responds to a drug

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6
Q

Chirality (stereoisomerism)

A

“Mirror Images” optical isomers

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7
Q

Orthosteric

A

Binds to active site

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8
Q

Allosteric

A

Binds outside of active site

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9
Q

EC 50

A

Concentration of drug where 50% of drug has taken affect

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10
Q

Kd

A

Drug concentration where 50% of receptors are bound

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11
Q

Toxicology

A

Study of undesirable effects of chemicals on living systems

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12
Q

Native ligand

A

Produced by body to bind to receptor to elicit response

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13
Q

Materia Medica

A

First medical textbook of pharmacology

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14
Q

Covalent bonds

A

Very strong & in many cases not reversible. Share electron bonds

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15
Q

Electrostatic

A

Charged molecules.
Weaker than covalent.

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16
Q

Hydrophobic

A

Lipid Soluble Drugs
Weakest / most numerous
Noncharged, MUST fit perfectly in receptor to elicit response.
“Phobia” to water

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17
Q

Poisons

A

drugs that have almost exclusively harmful effects.
Biologic & Nonbiologic

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18
Q

Toxins

A

Poisons of biologic origin

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19
Q

Constitutive Activity

A

Active even in absence of agonist activity

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20
Q

Racemic Mixture

A

50:50 mixture of two enantiomers, chiral molecules (mirror images)

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21
Q

Receptor

A

Target molecule that plays a regulatory role in the biologic system (Large Protein)

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22
Q

Receptor site

A

Active site on receptor to which ligand/drug binds to

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23
Q

B max

A

Point where maximum amount of receptors are bound to

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24
Q

E max

A

Point where maximum effect is seen

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25
Q

Competitive Inhibitor

A

Compete with agonist for active site binding, can be surmountable (surplus of agonist) or insurmountable (covalent bond forms)

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26
Q

Allosteric Inhibitor

A

Do not compete with agonist, binds outside of active site, can have inhibitor effects to which the agonist can not over come (Insurmountable)

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27
Q

Inverse Agonist

A

Greater affinity for Ri (Inactive form of receptor), Becomes less receptive, essentially an antagonist

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28
Q

Partial Agonist

A

Produce a reduced response at full receptor occupancy
In presence of full agonist, acts as antagonist
In absence of full agonist, acts as agonist

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29
Q

Potency

A

The concentration of drug required to produce 50% of drugs maximal effect (EC50)

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29
Q

Physiological Antagonism

A

A drug that counters the effects of another by binding to a different receptor and causes an opposite affect

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30
Q

Efficacy

A

The maximum effect a drug can produce regardless of dose (Emax)

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31
Q

Stereoisomers

A

Molecules that have the same molecular formula and differ only in how their atoms are arranged

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32
Q

Endogenous

A

Produced within the body

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33
Q

Exogenous

A

Produced outside the body

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34
Q

Imhotep

A

First recorded physician

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35
Q

Hippocrates

A

Fathers of Western Medicine

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36
Q

Caduceus

A

Symbol of peace and commerce (mistaken for rod of Asclepius) Winged staff intertwined with Two serpents

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37
Q

Asclepius

A

God of medicine staff intertwined by one serpent

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38
Q

Paracelsus

A

Father of Toxicology “The dose makes the poison”

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39
Q

Controlled drug trial

A

Compares drug to placebo to monitor for actual effects

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40
Q

Molecular Weight of most drugs

A

100-1000 Daltons

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41
Q

ADME

A

Absorption, Distribution, Metabolism, Excretion

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42
Q

Low Kd

A

High drug/receptor affinity

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43
Q

High Kd

A

Low drug/receptor affinity

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44
Q

Agonist “mimic” or Indirect agonist

A

Works inside the cell to inhibit the molecules responsible for terminating the action of an agonist

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45
Q

A drug must have the proper ___ to interact with a receptor

A

Shape, Size, Electrical Charge, or Atomic Composition

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46
Q

Van der Waals forces

A

Weak electrostatic forces that attract neutral molecules

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47
Q

Bond strength and specificity have an __ relationship

A

Inverse

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48
Q

What is nonspecific binding

A

when a drug binds somewhere else
Ex. albumin

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49
Q

What makes a compound organic?

A

Having Carbohydrates, Lipids, Proteins

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50
Q

Desensitization

A

cell shuts down signaling process; “protective mechanism”

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51
Q

Good Receptor Properties

A

selective - bind only to certain receptors
alteration - binds to ligand & causes change

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52
Q

Bound (albumin) drugs

A

can not cross barriers

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53
Q

Unbound Free form Drugs

A

can cross barriers

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54
Q

Bad Receptor Properties

A
  • binds but cause no change (drug carriers)
  • not specific
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55
Q

Albumin mostly bind to

A

Acidic drugs

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56
Q

Displacement of drugs is

A

when two drugs compete to bind to albumin (more free form drug)

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57
Q

Albumin has how many binding sites?

A

2

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58
Q

Maximal Efficacy

A

maximal effect; might see side effects at this point

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59
Q

Clinical effectiveness of a drug depends on

A

maximal efficacy

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60
Q

Therapeutic Index is

A

The distance between ED50 & TD50; Established safety margins

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61
Q

TD50 is

A

median toxic dose; point where 50% of toxic affects seen

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62
Q

ED50 is

A

Median effective dose; point where 50% of dose sees desired affects

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63
Q

Narrow Therapeutic Index

A

dangerous; closely monitored (ex. digoxin)

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64
Q

Wide Therapeutic Index

A

relatively safe; larger margin for error; OTC meds (acetaminophen)

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65
Q

Variations in drug responsiveness

A

Tolerance; Tachyphylaxis (quick tolerance); Chemical agonist (drug); Physiologic antagonism (body blocks or heightens response)

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66
Q

Four causes of drug responsiveness variations

A
  • Alteration in concentration of drug that reaches receptor;
  • Variation in concentration of endogenous receptor or ligand;
  • Alteration in number of functioning receptors;
  • Changes in downstream effect post-receptor
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67
Q

In order to cross barriers

A

drugs need to be uncharged

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68
Q

Most drugs are ___ or ___

A

“weak acids” or “weak bases”

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69
Q

pKa relates to what?

A

pH

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70
Q

If pH < pKa it

A

favors protonated form (H+ attached)

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71
Q

If pH > pKa it

A

favors unprotonated form (no H+)

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72
Q

Acids tend to ___ __ into solution

A

release H+

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73
Q

Bases tend to ___ __ from solution

A

absorb H+

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74
Q

Acids are ___ when protonated (H+ attached)

A

uncharged

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75
Q

Acids are __ when unprotonated (No H+)

A

charged

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76
Q

Bases are __ when protonated (H+)

A

charged

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77
Q

Bases are __ when unprotonated (No H+)

A

uncharged

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78
Q

“Weak acids” in acidic environment

A

protonated/uncharged

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79
Q

“Weak acids” in basic environment

A

unprotonated/charged

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80
Q

An example of a weak acid?

A

Aspirin

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81
Q

“Weak bases” in acidic environment

A

protonated/charged

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82
Q

“Weak bases” in basic environment

A

unprotonated/uncharged

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83
Q

An example of a weak base?

A

Morphine

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84
Q

Monoclonal Antibodies are created by

A

biologic organisms; clones of a single parent cell

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85
Q

monoclonal antibody suffix

A
  • mab
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86
Q

Benefit of monoclonal antibodies?

A

specificity - bind to a specific site, can target certain protein; can cause apoptosis (cell death - cancer cells)

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87
Q

The variable region

A

region that binds to specific protein

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88
Q

The constant region

A

region that does not change (mediates immune response after binding)

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89
Q

4 ways a drug action ceases

A
  1. Drugs stops binding to receptor
  2. Downstream effectors go away/run out
  3. Receptor degradation (covalent bond)
  4. Desensitization
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90
Q

Malnourished patients and dosing

A

Require lower dose of medication; less albumin available = more free/unbound drugs

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91
Q

a1 glycoproteins mostly bind to

A

basic drugs

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92
Q

Lipoproteins most bind to

A

neutral drugs

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93
Q

Therapeutic Index can be determined by which equation

A

TI = TD50/ED50 (human)
TI = LD50/ED50 (animal studies)

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94
Q

Unusual/unsuspected response to a drug is termed

A

idiosyncratic (don’t know why it happened)

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95
Q

Idiosyncratic responses are often attributed to

A

genetic factors

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96
Q

The largest and most important cause in drug response variation is

A

changes in components of response (downstream effectors)

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97
Q

pKa

A

dissociation constant

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98
Q

Endogenous antibodies have 2 major functions

A
  1. recognize and bind to antigen
  2. Induce immune response after binding
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99
Q

Monoclonal antibodies do not

A

elicit immune response

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100
Q

Spleen cells fused with myeloma cells are

A

Immortal; cloned; utilized in monoclonal antibody production

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101
Q

Food and Drug Administration (FDA)

A

federal agency responsible for regulating food and drug products

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102
Q

For drugs to be approved by FDA they must be proven to be

A

“Safe & Effective”

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103
Q

FDA regulates the way drugs can be

A

marketed (what claims can be made by drug/product)

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104
Q

FDA famously denied approval for ___ in the 1950s

A

Thalidomide - teratogenic medication; utilized for morning sickness in Europe

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105
Q

In Vitro studies are looking for new drugs identified as

A

Lead compounds

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106
Q

Prior to conducting human studies drugs researchers must first

A

Ensure safety in animals & be approved for IND (Investigational New Drug)

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107
Q

Phase 1 clinical trials

A

Testing a new drug on small drug of healthy individuals to find out how the body reacts to the drug

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108
Q

Phase 2 clinical trials

A

Drug is tested on target population to determine if is more beneficial than placebo (double blind)

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109
Q

Phase 3 clinical trials

A

Drug is tested on large target population (second double study)

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110
Q

Prior to phase 4 drug studies a __ is required

A

NDA (New Drug Application)

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111
Q

Phase 4 clinical trials

A

Approved and gone into market; after 20 years patent expires and generic meds can be made

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112
Q

Receptor

A

component that interacts with drug/ligand and initiates chain of events

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113
Q

Receptors are

A

Proteins

114
Q

Orphan receptors

A

receptors whose natural ligands are unknown

115
Q

G-protein coupled receptors (GPCRs)

A

a signal receptor protein in the plasma membrane that responds to the binding of a signal molecule by activating a G-protein

116
Q

Ligand-gated ion channel

A

act as “gate”; open channel when something binds to them

117
Q

Ion channels

A

open because of change in charge on membrane

118
Q

Signaling molecule

A

drug or endogenous ligand that binds to receptor of GPCR

119
Q

Second messenger

A

molecule that is activated byeffector proteins

120
Q

Effector proteins

A

have an effect on the behavior of a cell

121
Q

Most common second messenger

A

cyclic AMP (cAMP)

122
Q

Lag period

A

delay in gene expression related to the requirement for transcription/translation

123
Q

Drugs with a greater persistence require ___ dosing

A

less frequent (they last longer)

124
Q

Conformational change

A

The receptor binds to a drug & changes in some form

125
Q

Dose response is related to

A

number of receptors bound (linear) or strength of signal transduction cascade (multiple responses)

126
Q

Kinase

A

any enzyme that attaches a phosphate group to another protein

127
Q

a phosphorylated protein is

A

active

128
Q

Steps in Phosphorylation Cascade

A
  1. Drug bind to receptor
  2. Drug invokes conformational change
  3. Protein Kinase is activated
  4. Chain reaction of protein phosphorylation (phosphate attahed)
  5. Effector is reached & activated
129
Q

To activate intracellular receptor drug must be

A

Lipid soluble or uncharged (must cross cell membrane)

130
Q

A Catalytic receptor

A

activates an enzyme

131
Q

2/3 of all non-antibiotic drugs are activated by

A

GPCRs

132
Q

G-Protein trimeric (3 subunits); the alpha subunit is

A

the most important; it initiates a response of an effector protein

133
Q

When inactive, the alpha subunit of the G-protein is bound to

A

GDP (guanine diphosphate)

134
Q

When active, the alpha subunit of G-protein is bound to

A

GTP (Guanine triphosphate)

135
Q

G-protein

A

A GTP binding protein that relays signal from plasma membrane signal receptor (G protein coupled receptor), to signal other transduction proteins inside the cell

136
Q

GPCRs structure:

A

seven transmembrane a-helices

137
Q

GPCRs are a

A

seven transmembrane spanning receptor region

138
Q

Desensitization is

A

utilized when covalent bonds form on receptor by drug/ligand to stop constant signaling

139
Q

What are the two possible outcomes that may occur with desensitization

A
  1. The covalent bond breaks between drug & receptor to which receptor is recycled
  2. The covalent bond does not break and a lysosome breaks down receptor
140
Q

What is beta arrestin?

A

it is a protein that binds to OH groups on receptors to stop them from signaling

141
Q

What is a clathrin pit?

A

a protein involved in endocytosis (engulfs receptor with beta-arrestin attached and brings it into cell)

142
Q

Phosphatase

A

strips phosphate group from protein

143
Q

With RTKs you have _____ that join to form a ___

A

two monomers; dimer

143
Q

How many ATPs are utilized during phosphorylation of RTKs

A

6

143
Q

Receptor Tyrosine Kinase ligands typically are

A

Growth factors or Adhesion factors

143
Q

Ligand binding stimulates what on RTKs

A

Dimerization & Phosphorylation of tyrosine (makes it act like a kinase)

143
Q

Four types of Catalytic Cell Surface Receptors

A
  • Tyrosine Kinase
  • Tyrosine Phosphatase
  • Serine/Threonine Kinase
  • Guanylate Cyclase
143
Q

Steps in the RTK process

A
  1. Two RTK are bound by ligands (requires 2)
  2. Both monomers join to form Dimer
  3. The dimer becomes phosphorylated utilizing 6 ATPs
  4. The receptor begins to interact with effector protein
144
Q

Ion channels

A

pores that allow charged molecules to go from one side of membrane to the other

145
Q

Ion channels can be opened by

A

A ligand or voltage

146
Q

Voltage gated channels are found in

A

Excitable cells (Neuron, muscles, endocrine cells)

147
Q

Membrane potential is called

A

Threshold

148
Q

Inotropic-gated Ion channel

A

Ligand binds to it & opens channel on same protein

149
Q

Describe GPCR activating Ion channel

A
  1. Ligand binds to GPCR
  2. G protein is activated
  3. G protein activates effector protein
  4. Effector protein produces 2nd messenger
  5. 2nd messenger binds to ion channel & Ion channel opens
149
Q

Ligands that bind to receptors inside the cell

A
  • Gases (nitric-oxide)
  • Lipid soluble (steroid hormone)
149
Q

Metabotropic-gated Ion channel

A

Ligand activates GPCR & second messenger activity opens channel

149
Q

Four ways a drug can cross a membrane

A
  • aqueous diffusion
  • lipid diffusion
  • special carriers
  • Endocytosis & exocytosis
150
Q

water channels are

A

Aquaporin channels; pores that allow water into cell

151
Q

Aquaporin channels allow drugs into cell if they are ___ ___ by process of ___

A

water soluble; simple diffusion (high concentration to low)

151
Q

Aqueous diffusion will not be allowed if drug is

A

Highly charged or Bound to large proteins (carriers)

152
Q

Lipid Diffusion allows ___ ___ drugs to cross membrane

A

lipid soluble

152
Q

Special carriers

A

Bind to drug & move it across barriers (by active transport or facilitated diffusion)

153
Q

Endocytosis

A

membrane engulfment

154
Q

Exocytosis

A

releasement out of membrane

155
Q

Volume distribution (Vd)

A

relates amount of drug in body to concentration in blood (how much we gave vs. how much is in the blood)

155
Q

Clearance is

A

ability of body to eliminate drug; given in percentage of how much drug is eliminated/hr

156
Q

Elimination does not equal

A

clearance

157
Q

Elimination changes based on

A

clearance (in first order)

158
Q

The higher the volume distribution

A

the less amount there is in the blood

159
Q

Equation for volume distribution (Vd)

A

dose/drug concentration = Vd
ex. (10mg/Kg / 125mg/L = 0.08L/kg)

160
Q

Target concentration can be calculated from

A

volume distribution

161
Q

Clearance predicts

A

the rate of elimination in relation to drug concentration

162
Q

Equation for clearance

A

CL = rate of elimination/C

163
Q

Clearance for almost every drug will remain

A

constant

164
Q

Equation for Rate of Elimination

A

ROE = CL x C

165
Q

First order elimination is

A

Clearance is constant; rate of elimination varies with concentration

166
Q

Zero order elimination is

A

Rate of elimination is constant; clearance varies with concentration (so much drug in body, elimination mechanism saturated)
Ex. Ethanol, phenytoin, ASA

167
Q

Vmax

A

Maximum rate you can eliminate drug

168
Q

Three main drugs Zero order applies to

A

Ethanol; Phenytoin; Aspirin

169
Q

Sodium channels are considered to be

A

Fast

170
Q

Calcium channels are considered to be

A

Slow

171
Q

Four stages of gated channels

A
  1. Channel closed; internal gate 1st closed & 2nd (innermost) gate open
  2. Channel activated & both gates open
  3. Channel is inactivated; 2nd gate closes to prevent too many ions; 1st gate remains open
  4. Channel is deactivated & both gates closed
172
Q

Rational Dosing

A

goal is to achieve desired beneficial effect with minimal adverse effects

173
Q

Whole blood constant is

A

0.08 L/Kg

174
Q

Plasma volume constant is

A

0.04 L/Kg

175
Q

How many nanograms in a mg

A

1,000,000

176
Q

How to calculate dose given Vd

A

Vd x Target conc. = dose

177
Q

To get dose, divide ___ by ___

A

Target concentration; percent in blood

178
Q

Rate of elimination is

A

Mass of drug eliminated per unit time. (mg/hr)

179
Q

What is half life (T 1/2)?

A

Time it takes for the body to get rid of half the concentration of drug

180
Q

What is the formula for half life?

A

T 1/2 = (0.7 x Vd)/CL

181
Q

High extraction drugs are

A

Drugs that are eliminated in large portions during “first pass effect”

182
Q

Extraction ratio categories & percentages

A
  • High extraction ratio > 70%
  • Intermediate extraction ratio 30-70%
  • Low extraction ratio < 30%
183
Q

The only time we have a high clearance is when we have both

A

A high extraction ratio & high (normal) blood flow

184
Q

How many half lives does it take to reach steady state (No bolus)?

A

4 half lives

185
Q

How many half lives does it take to eliminate the drug from the body when the dose is stopped?

A

4 half lives

186
Q

If dosing interval is shorter than four half lives __ will develop

A

Accumulation (toxic levels can be reached)

187
Q

What is Bioavailability?

A

Fraction of unchanged drug reaching systemic circulation

188
Q

Giving a drug IV will make the bioavailability

A

100%

189
Q

Factors that affect bioavailability (6)

A
  • Physical properties (pKa, Hydrophilicity, solubility)
  • Formulation/route
  • GI - diet, gastric emptying
  • Overall heath/disease state
  • Interactions with other drugs
  • Circadian
190
Q

Absorption does not equal concentration because

A

once absorbed in gut medication must undergo “First pass effect” in liver

191
Q

Routes that bypass First Pass Effect

A
  • IV, IM, SC
  • Inhalation (has own metabolism/first pass effect)
  • Sublingual or transdermal
  • Rectal suppositories
192
Q

Target concentration

A

concentration that will produce desired effect without adverse effects

193
Q

Target concentration is ____

A

Therapeutically determined (what is the end goal?)
Ex. Digoxin
- 2ng/mL: controls a fib
- 1ng/mL: manages HF

194
Q

Formula for Dosing rate

A

Dosing rate = CL x TC

195
Q

Formula for Dosing rate with less than 100% Bioavailability

A

Dosing rate = (CL x TC) / Foral (bioavailability)

196
Q

Maintenance dose formula

A

Dosing rate/ Foral (bioavailability) x Dosing interval

197
Q

Why is a loading dose given?

A

To reach steady state quickly

198
Q

Formula for Loading dose?

A

LD= Vd x TC

199
Q

A loading dose must be given

A

Slowly, needs time to distribute

200
Q

The most important factor in Therapeutic drug monitoring is?

A

Clearance

201
Q

Drugs that do not penetrate fat (stay in bloodstream) utilize ___ when drug dosing

A

Ideal Body Weight (IBW)

202
Q

Creatine clearance give us

A

overall idea of health/function of kidneys

203
Q

Where does Biotransformation primarily occur?

A

Liver

204
Q

What is Biotransformation?

A

changing or bio modifying a drug to make it more or less active

205
Q

First pass effect is

A

passing through the liver prior to reaching systemic circulation

206
Q

Oral Hepatic portal system of drug

A

GI –> Local veins –> Hepatic portal Vein –> Sinusoids (Leaky capillaries) –> Hepatic vein –> Vena Cava –> Systemic circulation

207
Q

Biotransformation takes place in liver by which cells?

A

Hepatocytes

208
Q

Where is a drug bio-transformed?

A

Sinusoids

209
Q

Hepatic Artery route (all IV drugs take)

A

Systemic circulation –> Hepatic artery –> Sinusoids –> Hepatic Vein –> Vena Cava –> Systemic circulation

210
Q

Phase 1 Reactions

A

utilization of an enzyme to add or unmask a functional group (convert drug to more polar metabolite)

211
Q

Phase 1 reaction types:

A
  • Oxidation (most important) (Lose electrons)
  • Reduction (Gain electrons)
  • Dehydrogenation (Remove OH group)
  • Hydrolysis (add OH group)
212
Q

Most drugs are modified by which oxidation reaction in phase 1

A

Cytochrome P450

213
Q

Cytochrome P450 enzymes have

A
  • low substrate specificity (Bind to multiple drugs)
  • Multiple different types (CYP-***)
  • Mixed-function oxidases (oxidizes & makes drug hydrophilic)
214
Q

CYP3A4

A

cytochrome P450 subtype that metabolisms 50% of drugs undergoing phase 1 reactions

215
Q

The Cytochrome P450 that occurs most often in blood types is (wild type)

A

CYP3A4*1

216
Q

P450 Induction

A

Enhance synthesis or inhibit degradation (increased levels of P450)

217
Q

P450 Inhibition

A

Decrease or irreversibly inhibit P450

218
Q

Competitive inhibition is

A

co-administration of drugs metabolized by same P450 (cant metabolize 2 drugs at once)

219
Q

The effects of inhibition or induction of CYP450 depend on

A

if metabolism by P450 activates or deactivates the drug

220
Q

Three CYP subtypes & percentages of phase 1 reactions they are involved in

A
  • CYP2B6 (8%)
  • CYP2D6 (20%)
  • CYP3A4 (50%)
221
Q

Phase 2 reactions

A

Conjugation reactions - attaches a molecule making it larger & more hydrophilic (less likely to cross barrier)

222
Q

Types of phase 2 conjugations (7):

A
  • Glucuronidation
  • Acetylation
  • Glutathione conjugation
  • Glycine conjugation
  • Sulfation
  • Methylation
  • Water conjugation
223
Q

Glucuronidation

A
  • uridine diphosphate glucuronosyltransferases (UGTs) enzyme - carrier molecules - add glucuronic acid making it easily excreted in urine
224
Q

Glutathione-S-Transferase (GST) enzymes attach

A
  • Glutathione to xenobiotic (foreign body) making it more likely to be excreted in urine
  • Ubiquitous - found everywhere (High in RBCs)
225
Q

When a patient ODs we see toxics byproducts because we have ___

A

overwhelmed normal pathways & alternative pathways that are activated can have toxic by-products

226
Q

What is the importance of pharmacogenetics?

A

The specific testing to help predict, explain, & treat

227
Q

Warfarin is a __ mixture

A

Racemic mixture (R &S)
- S is 7-10x more potent than R

228
Q

15-25% of breast cancers are caused by ___

A

HER2

229
Q

What is the drug that targets breast cancers that are HER2 positive

A

Trastuzumab (Herceptin)

230
Q

What is the Purine analogs MOA

A

blocks rapidly dividing cell from dividing

231
Q

What is the role of drug transporters in the cell?

A

To transport endogenous & xenobiotic substances across barriers (membranes)

232
Q

Role of Drug efflux transporters

A

Pump drug out of cell

233
Q

Most of drug efflux transporters are

A

ATP - binding cassette transporters (ABC)

234
Q

What are the three important ABC transporters?

A

ACBB1, ABCC, & ABCG2

235
Q

Which ABC transporter has the broadest substrate specificity?

A

ABCB1

236
Q

Which ACB transporter is the largest?

A

ABCC

237
Q

Which way do transporters typically move in the Intestine?

A

Into cell (INFLUX)

238
Q

Which way do transporters typically move in the Placenta?

A

Out of cell (EFFLUX) (alcohol can pass)

239
Q

Which way do transporters typically move in the Liver?

A

Into cell (INFLUX) ; liver metabolizes most drugs; Liver –> bile

240
Q

Which way do transporters typically move in the Kidneys?

A

Into cell (INFLUX) ; into glomerulus out through tubule excreted via urine

241
Q

Which way do transporters typically move in the Blood Brain Barrier?

A

Out of cell (EFFLUX)

242
Q

Which way do transporters typically move in the CSF?

A

Out of CSF (Efflux)

243
Q

What are the components that protect the BBB?

A
  • ABC transporters
  • Vascular epithelium cells (tight junction)
  • Cells that regulate what enters neuron (Astrocytes & Podocytes)
244
Q

Barrier properties mediated by specific transporters in BBB are

A
  • Active Efflux transporters (allows small lipophilic molecules - O2, CO2, Ethanol)
  • Carrier Protein (allows glucose, amino acid nucleotides in)
  • Receptor mediated (Insulin)
  • Adsorption endocytosis (Albumin)
245
Q

Delineate pathway of Tylenol in gut before & after bio-transformation

A

Tylenol absorbed through gut –> “First pass” goes to liver –> Phase 2 metabolism (glucuronidation adds glucose to it becomes nontoxic glucuronide) –> gets sent to bile –> Bile dumps it into intestine (ABC transporters) –> out through feces

246
Q

What are parameters Affecting Passive diffusion?

A
  • Molecular weight
  • pKa
  • Lipid solubility
  • Plasma protein binding
247
Q

Describe the pathways Acetaminophen can take upon metabolism

A

Normal pathways
- Glucuronidation –> non-toxic glucuronide (main pathway)
- Sulfation –> nontoxic sulfate
Alternative pathways
- GSH conjugation –> adds glutathione
- Nucleophilic cell macromolecules –> Liver cell death

248
Q

If Drug1 is metabolized by CYP3A4; and CYP3A4 is induced, what affect would that have on drug1?

A

Drug1 would be inactivated much quicker

249
Q

If a Prodrug is activated by CYP3A4; and CYP3A4 is induced, what affect would that have on the Prodrug?

A

The Prodrug would become active much quicker

250
Q

If Drug1 is metabolized by CYP3A4; and CYP3A4 is inhibited, what affect would that have on drug1?

A

Drug1 would be more active (can lead to toxic levels)

251
Q

If a Prodrug is activated by CYP3A4; and CYP3A4 is inhibited, what affect would that have on the Prodrug?

A

The Prodrug would remain inactive having no effect

252
Q

What is a Prodrug?

A

A drug that has no biologic affect until it is metabolized

253
Q

What drugs interact with ABCB1 transporters & what affect do they have on ABCB1?

A

Cyclosporine A, Quinidine, Ritonavir all inhibit ABCB1

254
Q

What is Loperamide? & what effects does it have when combined with quinidine?

A

Loperamide - opioid, antidiarrheal no CNS effect BUT when combined with quinidine; quinidine inhibits ABCB1 –> Loperamide then has CNS effects (respiratory suppression)

255
Q

Describe ABCG2 transporters

A
  • breast cancer resistance proteins (BCRP)
  • Antineoplastic, toxins, food borne carcinogens
  • folate transport
256
Q

Describe ABCB1 transporters

A
  • broadest specificity (HIV protease inhibitors, ABX, antidepressants, antiepileptics & opioids)
  • Wide distribution (GI, Kidneys, Liver & testes - Critical in BBB)
257
Q

Describe ABCC transporters

A
  • Largest class
  • Mainly antineoplastic efflux
258
Q

What is the enzyme that metabolizes Warfarin?

A

CYP2C9

259
Q

If TPMT is mutated or missing, how will this affect the metabolism of 6-MP?

A

6-Mercaptopurine (6-MP) will increase & become toxic (TMPT is the main pathway for 6-MP metabolism)

260
Q

What is an Allele?

A

alternative form of a gene which occurs at the same locus

261
Q

Purine analogs are used to treat cancers & autoimmune disease but are toxic, why?

A

They suppress immune (myelosuppression) - narrow therapeutic index

262
Q

If a patient has 2 copies of the TMPT gene, how does this affect how they take 6-MP?

A

It does not, they can take normal doses

263
Q

If a patient has 1copy of the TMPT gene, how does this affect how they take 6-MP?

A

They need to take a reduced dose of drug

264
Q

If a patient has 0 copies of the TMPT gene, how does this affect how they take 6-MP?

A

They will require another drug as they can not metabolism drug

265
Q

What is the function of Solute Carrier (SLC) proteins?

A

Transport 15-30% of all membrane proteins
- High substrate specificity (Na, Glucose, Amino acids)

266
Q

What is the function of SLC21

A
  • Organic anion transporter proteins (OATPs)
  • Primarily passive (gradients)
  • some function for drug Influx
267
Q

What affect would a poor metabolizer phenotype have on a Prodrug?

A

Prodrug would be inactive as it needs to be metabolized to work, poor efficacy –> possible accumulation of drug

268
Q

What affect would a poor metabolizer phenotype have on an Active drug?

A

Active drug would stay active longer, good efficacy, can lead to toxic effects; may require lower dose

269
Q

What affect would an Ultra-rapid metabolizer phenotype have on a Prodrug?

A

Prodrug would be active faster, good efficacy

270
Q

What affect would an Ultra-rapid metabolizer phenotype have on an Active drug?

A

Active drug would become inactive rapidly, poor efficacy, will need greater dose

271
Q

Describe the metabolism process involved in Cytochrome P450

A

Drug binds to P450 (contain iron) –> oxidation occurs –> electrons go to Flavoproteins (FMN) & becomes reduced & oxidized –> FMN is recycled by NADPH –> P450 & the drug are combined with hydrogen & oxygen to form H20 & an OH group attached to drug –> drug leaves HYDROPHILIC

272
Q

60-70% of breast cancers express which type of receptors?

A

Estrogen receptors & Progesterone Receptors

Pharm 1 (2 decks)

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