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Pharmacology > Class > Flashcards

Class Flashcards

1
Q

Receptor

A

Regulatory role-interact with drug and initiates drug effects

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2
Q

Inert binding site

A

Drug binds without changing any function of receptor

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3
Q

Ligand

A

Binds to receptor

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4
Q

Covalent bond of ligand and receptor

A

Irreversible

Need to resynthesize

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5
Q

Non covalent ligand receptor binding

A

Reversible

Most

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6
Q

List types of bonds strongest to weakest (non covalent)

A

Ionic, hydrogen, hydrophobic interaction, van der waals

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7
Q

What are van der walls

A

Weak electrostatic interactions involving dipole moments within functional groups

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8
Q

Dose response curve

A

Drug and its effects

Linear?

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9
Q

Log of dose response curve
Drug dose log x
Y drug effect

A

Hyperbolic

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10
Q

Concentration effect curve log vs response

A

Sigmoidal curve

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11
Q

Emax

A

Max effect

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12
Q

ED50

A

Dose that produces 50% of its maximal effect

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13
Q

Graded response

A

How much
Magnitude of response varies continuously
Mean value within a population or subject

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14
Q

Quintal response

A

Yes or no
Binary response
Is there a response, if so how many

Need predefined response
Examine frequency of a large population

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15
Q

Quantal non cumulative dose response curve

A

Number or % of individuals responding at a certain dose of a drug and only at that dose

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16
Q

Cumulative quantal dose response curve

A

Number or % of individuals responding at a certain dose of a drug and at all doses lower than that dose

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17
Q

what kind of graph do you get TI from

A

Cumulative dose response curve

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18
Q

TI

A

TD50/ED50

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19
Q

Therapeutic window

A

Range at which safe and effective

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20
Q

What determines the binding and nteraction of drugs with their receptors

A

Size shape charge

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21
Q

High affinity

A

Less drug needed to produce a response

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22
Q

Low affinity

A

More drug needed to produce a responses

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23
Q

Kd

A

Parameter describing affinity

Equilibrium dissociation constant

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24
Q

What is the Kd

A

Drug concentration at which 50% of the drug receptor binding sites are occupied by the drug

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25
Q

Unit of Kd

A

Molar concentration (micromoles, nanomoles

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26
Q

Low Kd

A

Higher affinity of a drug for receptor

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27
Q

Higher Kd

A

Lower affinity of a drug for a receptor

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28
Q

Formula for Kd

A

L+R LR

Kd=(L)(R)/(LR)

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29
Q

What are L R and LR

A

Molar concentrations of ligand, receptor, and their complex

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30
Q

__ determine the quantitative relationship between a drug and its effects

A

Receptors

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31
Q

The magnitude of a drugs effects will be proportional to the degree of its interactions with a __

A

Receptor

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32
Q

Ec50=Kd or Ec50=Kd

A

Depending on the outlying of receptor occupancy and a response to a drug

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33
Q

Two graphs

A

Ok

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34
Q

Agonist have __ activity

A

Intrinsic

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35
Q

Antagonist do not have __ activity

A

Intrinsic

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36
Q

Competitive antagonist

A

Compete with endogenous chemicals or agonist drugs for binding to the receptor

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37
Q

Non competitive antagonists

A

Receptor inactivation is not surmountable

Irreversible or allow=steric antagonist

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38
Q

Irreversible antagonist

A

Irreversibly bind to and occlude the agonist site on the receptor by forming covalent bonds

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39
Q

Allosteric antagonists

A

Bind to a site other than the agonist site to prevent or reduce agonist binding or activation of the receptor

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40
Q

Competitive antagonist

A

Agonist EC50 increases, Emax does not change

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41
Q

Non competitive antagonism

A

Agonist Emax decreases

EC50 does not change

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42
Q

Potency

A

Amount of a drug required to produce a specific pharmacological effect

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43
Q

What drugs tend to be more potent

A

Higher affinity (lower Kd)

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44
Q

What represents potency

A

ED50

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45
Q

Lower ED50

A

More potent

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46
Q

How determine dose

A

Potency

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47
Q

Efficacy

A

Maximal pharmacological effect that a drug can produce

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48
Q

What represented efficacy

A

Emax

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49
Q

The greater the Emax, the more ___ the drug

A

Efficacious

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50
Q

What is efficacy related to

A

Total receptors available to bind a drug

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51
Q

What does efficacy determine clinically

A

Effectiveness

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52
Q

Potency determines __ and efficacy determines ___

A

Dose

Effectiveness

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53
Q

Potency is related to __ and efficacy is related to ___

A

Affinity

Total number of receptors available to abind a drug

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54
Q

What is a drug target

A

Important regulatory proteins in the existing cell signaling pathways

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55
Q

What are the classes of drug targets

A

Membrane receptors, nuclear receptors, ion channels, transport proteins, enzymes

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56
Q

Protein kinases

A

Covalently attach phosphate group to an aa residue
-serine threonine kinases
Tyrosine kinases

Phosphorylation

500 in human genome

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57
Q

Response element

A

Specific DNA region that transcription factors bind to

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58
Q

What do transcription factors have

A

DNA binding domain

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59
Q

What do transcription factors bind to

A

Enhancer or promoter regions that are usually adjacent to the coding sequence of the regulated gene

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60
Q

GPCR makes up _% of genome

A

4

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61
Q

About _% of marketed drugs act on GPCR

A

30

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62
Q

Ligand for GPCR

A

Bio genie amines, peptides/proteins, amino acids, lipids, nucleotides

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63
Q

The N terminal (__) domain of GPCR is often __

A

Glycosylated

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64
Q

The C terminal (__) contains multiple phosphorylation sites (__/__)

A

Cytosolic

Serine/threonine residues

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65
Q

What do cytoplasmic loops of GPCR contain

A

G protein binding sites

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66
Q

The 7 transmembranes is ___

A

Hydrophobic

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67
Q

Phosphorylation of C terminal

A

Diminished G protein coupling and can promote receptor endocytosis

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68
Q

G protein cycl

A
  1. G protein receive ligand to activate
  2. Promotes release of GDP from G protein
  3. allowing entry of GTP into nucleotide binding site
  4. GTP bound state the G protein regulates activity of an effector enzyme or ion channel
  5. Signal terminated by hydrolysis of GTP
  6. Return to the basal unstimulated state
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69
Q

Rec

A

Hormone receptors

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70
Q

PDE

A

Phosphodiesterase that hydrolyze cAMP

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71
Q

Pase

A

Phosphatase

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72
Q

S

A

Protein substrates

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73
Q

So…AC turns ATP to Camp. What happens to Camp

A

Phosphodiesterase turns it to 5-AMP

Or cAMP+R2C2–> R2cAMP4+2C

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74
Q

What happens to 2C

A

With ATP turns S to SP to make ADP with Pase

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75
Q

What does SP do

A

Response

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76
Q

What happens to IP3

A

Ca enzyme and CaM—>CaM-E which causes response

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77
Q

What does DAG do

A

Activate PKC

Which with ATP turns S to SP which causes a response and releases ADP

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78
Q

What receptors have intrinsic enzyme activity

A

RTK

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79
Q

What growth factors bind to RTK

A

IGF-1, insulin, VEGF, EGF, NGF, PDGF

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80
Q

Most RTK

A

Single polypeptide chain

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81
Q

Insulin and IGF receptor RTK

A

2 chains a and b linked by disulfide bond

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82
Q

___ domain shows very little similarity between the members of the family

A

Ligand-binding

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83
Q

___ __ domain is similar between the members of the family

A

Tyrosine kinase

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84
Q

How is the EGF receptor activates

A
  1. EGF bind and conformation change (monomeric inactive, dimeric active—bound noncovalently)
  2. Cytoplasmic domains become phosphorylated on specific tyrosin residues
  3. anzymatic activities are activated , catalyzing phosphorylation of substrate proteins

Turning S into SP with ATP and releasing ADP

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85
Q

JAK

A

Receptor coupled to cytosolic protein kinases

Transmit the effect of a number of hormones and cytokines (Growth hormones, erythropoietin, leptin, interferons, interleukins 2,20,15)

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86
Q

Describe JAK STAT pathway (family of cytosolic tyrosine kinases (JAK1 to 5, TYK2) that bind to an activated receptor to start signaling cascade

A
  1. Activate and JAK(intracellular) are activated (dimerize), resulting in phosphorylation of signal transducers and activation of transcription STAT molecules
  2. STAT diners then travel to the nucleus where they regulate transcription
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87
Q

Ligand for nuclear receptors

A

Steroid hormones, thyroid hormones, vit D, vit A, FFA and their products

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88
Q

Steroid receptor families

A 
Androgen receptor
Estrogen receptor
Progesterone receptors
Glucocorticoid receptors
Mineralocorticoid receptors
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89
Q

When do we see effects of nuclear receptors

A

Lag period

And the effects can persist after the agonist concentration has bee reduced to zero

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90
Q

Mechanism of a steroid hormone action

A

Nuclear receptor polypeptide is depicted as a protein with three distinct domains.
Heat shock protein, hsp90, binds to the receptor in the absence of hormone and prevents folding into he active conformation of the receptor. Binding of a hormone ligand causes dissociation of the hsp90 stabilizer and permits conversion to the active configuration

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91
Q

What do ion channels do

A

Change the cell membranepotential

Change concentration of ions in cytosolic

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92
Q

Voltage gated channels

A

About 300 genes code for subunits of coltage gated channels
Conductance is induced by membrane potential changes
Na Ca K channels are targets of drug action

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93
Q

Ligand gated channels

A

Multimeric channels span the cell membrane and have a binding site for a neurotransmitter inducing the current, and an ion conducting pore

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94
Q

How are voltage gated ion channels controlled

A

Not by binding a ligand

Controlled by membrane potential

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95
Q

Voltage gated Na channels

A

A and b subunits

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96
Q

What drugs inhibit voltage gated Na channels

A

Local anesthetics
Antiarrhythmic drugs
Drugs used for the treatment of epilepsy

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97
Q

Voltage gated ca channel

A

L type channels are located on cardiac and smooth muscle cells

Blockers and antagonists

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98
Q

Direct gated ion channels

A

Receptors for neurotransmitters that have an ion conducting pore

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99
Q

Excitatory neurotransmitters

A

Open cation channels, depolarize the cella nd induce generation of action potential in excitable cells

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100
Q

Examples of excitatory NT

A

Acetylcholine and glutamate

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101
Q

Inhibitory neurotransmitters

A

Open anion channel causing inward anion flux and hyperpolarization, prevent generation of action potentials

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102
Q

Examples of inhibitory neurotransmitters

A

GABA and glycine

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103
Q

Activation of nicotonic acetylcholine receptors

A

Induces inward Na fluxes and membrane depolarization

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104
Q

What and where are nicotonic acetylcholine receptors

A

Pentameric receptors with two major locations

  • skeletal muscle, responsible for depolarization of skeletal muscle fibers
  • neuronal cells
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105
Q

What is a nicotonic acetylcholine receptor

A

Ligand gated ion channel

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106
Q

The nicotonic acetylcholine receptor is in the ___

A

Membrane

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107
Q

The extracellular part of the nicotonic acetylcholine receptor has _ subunits. What are they

A

Five

2a, b, y, and delta

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108
Q

What does the nicotonic acetylcholine receptor do

A

Opens a central transmembrane ion channel when ACH binds to sites on the extracellular domains of its a subunits

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109
Q

GABA receptors

A

Anionic channels causing inward Cl influx and hyperpolarization

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110
Q

What does GABA mediate

A

Synaptic inhibition in CNS via these channels

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111
Q

Structure of GABA receptos

A

Pentameric structure

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112
Q

What is the GABA receptor a target for

A

Inhalation general anesthesia drugs

Intravenous general anesthesia drugs

Ethanol

Hypnotic and anti anxiety benzodiazepine drugs

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113
Q

Binding sites on GABA receptor

A

Binding site and allosteric

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114
Q

Biotransformation

A

Enzymatically driven process whereby a substance is changed from one chemical to another in an organism

Usually xenobiotics

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115
Q

What compounds are not readily excreted

A

Lipophilic, unionized, large compounds

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116
Q

What it’s he body’s main method of elimating substances

A

Biotransformation of xenobiotics into more polar (and sometimes larger ) derivatives

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117
Q

Consequences of Biotransformation

A

May lead to products still biologically active or more active

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118
Q

L dopa biotransformation

A

Dopamine

Prodrug into active compound

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119
Q

What is l dopa

A

Pro drug

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120
Q

Example of active compound becoming an active compound

A

Diazempam—>oxazepam

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121
Q

Example of inactivation

A

Acetylsalicylic acid(asprin)-> acetic acid+ salicylate

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122
Q

What is a prodrug

A

Inactive drug that undergoes biotransformation to become an active drug
*sum drugs designed as inactive so not active until absorption

123
Q

Where does biotransformation happen

A

Liver (main), GI, lung, skin, kidneyER mitochondria cytosolic lysosomes nuclear envelope or plasma membrane

124
Q

First pass

A

Oral drugs are absorbed in the small intestine and transported to the liver via the hepatic portal system, where they undergo extensive metabolism (drugs given via parent earl routes of administration do not undergo first pass)

125
Q

First pass limits drugs?

A

Yea look at other routes of administration

126
Q

Digestive enzymes and intestinal bacteria

A

May metabolically activate or inactivate drugs

127
Q

How can normal GI flora increase bioavailability of certain drugs, ugh as estrogen in contraception

A

By increasing enterohepatic cycling of metabolites (antimicrobial drugs may reduce estrogen efficacy)

128
Q

Morphine

A

Extensive first pass

129
Q

Clinical significance of morphine undergoing extensive first pass biosynthesis

A

Oral 35% absorbed

So need to give IV

130
Q

Phase I

A

Oxidation, reduction, or hydrolysis reactions

Biological inactivation

131
Q

Phase II reactions

A

Conjugate the substrate

Make more water soluble and increased molecular weight which facilitates elimination

132
Q

Phase I

A

Catabolic
Enzymes that convert the parent drug to a more polar metabolite by introducing or unmasking a functional group (OH, NH2, SH, COOH, O)

Mainly oxidation

133
Q

Common reactions phase I

A

Oxidation, reduction, and hydrolysis

134
Q

Less common reactions phase I

A

Hydroxylation, epoxidation, dealkylation, deamination, desulfurization, decholrination

135
Q

Phase I enzymes

A

MFO (mixed function oxidase) MFO or monooxygenases

  • CYP P450
  • flavin containing monoxygenases (FMO
  • epoxied hydrolysis (mEH, sEH)
136
Q

Phase II

A

Anabolic,
Enzymes that form a conjugate of the substrate
Make more polar, higher molecular weight, and often inactive

137
Q

Conjugation in phase II

A

Conjugation dependent upon endogenous substrates such as glucoronic acid, sulfuric acid, acetic acid, or an aa

138
Q

Phase I or phase II faster

A

Phase II conjugation

139
Q

Where does most conjugation take place

A

Liver

140
Q

Are some drugs not metabolized phase I or II

A

Yup

141
Q

Many phase I reactions occur ___

A

Concurrently

142
Q

Before phase I

A

Phenytoin highly liophilic

143
Q

After phase I

A

4-hydroxy phentoin

Slightl soluble in water

144
Q

After phase II

A

4-hydroxy-penytoin-glucuronide

Very soluble in water

145
Q

Cytochrome p450

A

Superfamily of enzymes that carry out phase I biotransformation

146
Q

Most common p450s

A

CYP1A2, CYP2A6, CYP2D6, CYP2E1, and CYP3A4

147
Q

What is the most abundantly expressed p450 and involved in the metabolism of about 50% of clinically used drugs

A

CYP3A4

148
Q

All p450 contain a molecule of __ that is __ bound to the polypeptide chain

A

Heme

Noncovalently

149
Q

P450 use molecular _ and _ derived from the cofactor-reduced NADPH to carry out the oxidation of substrates

A

O2 H

150
Q

P450 cycle

A

One molecule of oxygen is reduced per drug molecule with one oxygen atom added to the drug (the drug is oxidized) and the other oxygen in the byproduct water RH, parent drug; ROH, oxidized metabolite; e_ electron.

151
Q

What does NADPH do

A

Turns flavinprotein(oxidized) to flavinprotein reduced with P450 reductase

152
Q

What does a reduced flavinprotein do

A

Give 2 electrons to p450-RH

153
Q

Succinylcholine

A

Depolarizing neuromuscular blocking drug

154
Q

Genetic defect in ___ can metabolize can metabolize succinylcholine at 50% the rate as normal individuals

A

Pseudocholinesterase

155
Q

What is slow acetylator phenotype

A

Autosomal recessive trait have a decrease in N-acetyltransferase levels, rather than a mutated form of the enzyme , in the liver

156
Q

Result of slow acetylator phenotype

A

Isoniazid (used to treat TB), hydralazine(used to treat hypertension), caffeine, and other similar amines are metabolized at slower rates, which can lead to hepatotoxicity (hepatitis)

157
Q

How many people are slow acetylator phenotype

A

This phenotype occurs in roughly 50% of the US population, 83% French, and is less common in Asian populations

158
Q

Page 43 katzung

A

Ok

159
Q

CYP2E1

A

Is endured by chronic ethanol

160
Q

Tobacco smoke(benzo a pyrene

A

Inducer

161
Q

Rifampin

A

For TB

Inducer

162
Q

Rats pretreated with phenobarbital

A

Significantly faster half life of chloramphenicol in comparison to control rats

163
Q

Grapefruit juice effect

A

Irreversibly inhibit CYP3A4
Alters oral bioavailability of drugs, including antihypertensive, immunosuppressant, antidepressants, antihistamines, and statins

164
Q

Allopurinol and mercaptopurine

A

Allopurinol used to treat excess uric acid (gout) and acts by inhibiting xanthine oxidase

Xanthine oxidase is a key enzyme in the biotransformation pathway of the immunosuppressive agent mercaptopurine (used during cancer)

Coadministration of allopurinol with mercaptopurine prolongs the duration of mercaptopurine action and enhances its chemotherapeutic and toxic effects

Doses of mercaptopurine must be reduced in patients receiving allopurinol

165
Q

Neonate biotransformation

A

Low hepatic enzymes actively involved in drug biotransformation

166
Q

Biotransformation in postnatal period and elderly

A

Hepatic enzymes increase rapidly in postnatal period and are heterogenous in elderly population

167
Q

Premature infants

A

Decreased conjugating activity

168
Q

Hyperbilirubinemia in new born

A

During metabolism of fetal hemoglobin , bilirubin levels accumulate int he blood

Due to the immature hepatic metabolic pathways, newborns are unable to conjugate bilirubin with UDP glucuronic acid (UDP glucuronosyl-transferase levels are low) and bilirubin is unable to be excreted

Bilirubin induced encephalopathy is a concern when levels become dangerously high

169
Q

Why are fetus and neonate highly susceptible to drug toxicity

A

A poorly developed bbb, weak biotransforming activity, and immature excretion mechanisms

170
Q

Does metabolism for drugs decrease with age

A

Sometimes not really

Bc drug half-life is more dependent on the drug itself

171
Q

Liver and kidney disease

A

In elderly

Important factor accounting for decreased drug metabolism

172
Q

Age related variables that affect pharmacokinetics

A

Body water, lean body mass, body fat, serum albumin, kidney weight, hepatic blood flow

173
Q

Young or old people have more body water

A

Young

174
Q

Young or old people have more lean body mass

A

Young

175
Q

Young or old people have more body fate

A

Old

176
Q

Young or old people have more serum albumin

A

Young

177
Q

Young or old people have more kidney weight

A

Young

178
Q

Young or old people have more hepatic blood flow

A

Young

179
Q

Liver disease

A

Hepatic drug metabolizing enzymes (p450) may be compromised and drug elimination rates could be reduced

180
Q

Disease states that could decrease metabolism

A

Alcoholic hepatitis, cirrhosis, acute viral or drug induced hepatitis, biliary cirrhosis, hemochromatosis, chronic active hepatitis

181
Q

Flow limited biotransformation drugs

A

Rate of elimination is dependent upon the rate of blood flow supplying the drug to the liver

182
Q

Cardiac disease may cause specific drug levels to rise

A

Atenolol, propranolol, isoniazid, lidocaine, morphine, verapamil (calcium channel blocker)

183
Q

What happens when endogenous detoxifying cosubstrates are limited

A

The toxic pathways may prevail resulting in organ toxicity or carinogenesis

184
Q

What may cause cosubstrate limitation

A

Dietary insuffiency or an alternative underlying defiency

185
Q

Example of biotransformation to more toxic product

A

Acetaminophen-induced hepatotxicity

186
Q

For a normal adult 1.2 g/day, how is acetaminophen metabolized

A

95% undergoes glucuronidation and sulfation with 5% biotransformed via P450 pathways

187
Q

What happens when acetaminophen intake exceeds therapeutic dose

A

Hepatic GSH is depleted faster than it is regenerated and toxic metabolites accumulate resulting in hepatotoxicity

188
Q

Glucuronidation of acetaminophen

A

to nontoxic glucuronide

189
Q

Sulfation of acetaminophen

A

Nontoxic sulfate

190
Q

CYP2E1 and CYP3A4 of acetaminophen

A

To reactive toxic intermediate

191
Q

What happens to reactive toxic intermediate of aceteminophen

A

GSH conjugation
To mercapturic acid conjugate
Or

Nucleophillic cell macromolecules to cause liver cell death

192
Q

Pharmacogenomics/pharmacogenetics

A

Study of genetic factors that underlie variation ind rug response

193
Q

Genome wide association studies

A

Hundreds of thousands of genetic variants across the genome are tested for association with drug response led to discovery of many other important polymorphism in genes that encode transporters , HLA, cytokines, and other proteins

194
Q

Precision/stratified personal medicine

A

Genetic information is used to guide drug and dosing

195
Q

Clinical pharmacogenetics implementation consortium (CPIC)

A

Series of guidelines for using genetic information in selecting medications and in dosing

196
Q

Allele

A

One of two or more alternative forms of a gene that arise by mutation and are found at the same genetic locus.
CYP2D6 is a variant allele for a drug metabolizing variant of CYP2D6

197
Q

CSNP

A

Snp in coding region

198
Q

HaplotypE

A

Series of alleles found in a linked locus on a chromosome

199
Q

Hardy Weinberg

A

Allele frequencies will remain constant from generation to generation in absence of evolution

200
Q

Linkage disequilibrium

A

Nonrandom association of alleles at two or more loci that descend from a single ancestral chromosome

201
Q

Nonsynonymous snp (nsSNP)

A

Single base pair substitution in the coding regions hat results in an aa change

202
Q

PM, IM, EM, UM

A

Poor, intermediate, extensive, or ultra rapid metabolized phenotype

203
Q

Synonymous SNP

A

Base pair substitutions int he coding regions hat do not result in an aa change

204
Q

Extensive metabolized

A

Individuals metabolic rate of a particular drug that is a known substrate of a specific enzyme, were used to describe genetic effects on drug etabolism

205
Q

*

A

Specific sequence variant

206
Q

*1xN

A

N number of copies

207
Q

Enzyme activity is ___ or _-

A

Co dominant

Additive

208
Q

If an individual has one normal and one functional allele

A

Have intermediate

209
Q

0, .5, 1-2, >2

A

PM, IM, EM, UM

210
Q

CYP2D6

A

1/4 of all rugs

B blockers, antidepressants, antipsychotics, opoid analgesics

211
Q

CYP2D6*4

A

20% of Europeans and absent in Asians

212
Q

CYP@D^ alleles

A

*1, *2 functional
10, 17, 41 reduced function
3, 4, 5, 6 nonfunctional

213
Q

LPM CYP2D6

A

3, 4, 5, 6 more in Europe’s

214
Q

*5 deletion CPY 2D6

A

Similar frequencies European and Asian

Hardy Weinberg

215
Q

Ethnicity specific@

A

Look at ethnicity of patient you are treating

216
Q

Codeine active metabolite

A

Morphine

217
Q

What do codeine and morphine bind to

A

Mu-opoid receptor in CND

218
Q

Why is conversion of codeine to morphine essential for it to work

A

Morphine 200 times more potent

219
Q

What enzyme converts codeine to nomrphine

A

O-demethylation -a CYP2D6

220
Q

EM CYP2D6

A

Convert sufficient (5-10% of codein0 to get analgesic

221
Q

PM IM CYP2D6

A

Insufficient pain relief

222
Q

UM CYP2D6

A

Side effects of codeine

Drowsy, respiratory depression, due to high morphine

223
Q

CYP 2C19

A

Metabolizes acidic drugs including proton pump inhibitors, antidepressants, antiepileptics, and antiplatelet drugs

224
Q

CYP2C19 alleles

A

2 3 are nonfunctional
1 fully functional
17 increased function

225
Q

CYP2C19*17

A

Increased function allele is unable to fully compensate for nonfunctional alleles and in combination with a nonfunctional allele could be considered IM

226
Q

PM CYP2C19

A

Asians

227
Q

CYP2C19*2

A

Asians

228
Q

CYP2C19*17

A

Not Asians

In Europeans and Africans

229
Q

Clopidogrel

A

Thienopyridine antiplatelet prodrug indicated for prevention fo atherothrombic events

230
Q

How does clopidogrel work

A

Active metabolites selectively and irreversibly inhibit adenosine diphosphate induced platelet aggregation

231
Q

How is clopidogrel metabolized

A

85% rapidly hydrolyzed by hepatic esterases to its inactive carboxylic acid derivative,
15% converted cia two sequential CYP mediated oxidation reactions (CYP2C19) to the active thiol metabolite responsible for antiplatelet activity

232
Q

CYP2C19*2 and clopidogrel

A

Increased risk for serious adverse CV events, coronary syndrome and stent thrombosis, and percutaneous coronary intervention

233
Q

CPIC recommendations clopidogrel

A

Standard starting dose for EM, UM

Give antiplatelet agent to PM and IM

FDA says alternative antiplatelet for poor metabolizes

234
Q

Recommendation CPIC for CYP2D6 and codeine

A

Standard starting dose for EM, IM (close monitoring IM

Don’t use in PM and UM

235
Q

Dihydropyrmiidine dehydrogenase (DPD)

A

First rate limiting step in pyramiding catabolism and major elimation route for fluoropyridime chemotherapy agents

236
Q

Three nonfunctional alleles of DPD

A

DPYD*2A, *13, and rs67376798

237
Q

DPYD*2A

A

Common in Swedish populations

Lower in European, African and Asian

238
Q

Fluoropyridime 5-FU

A

Treat solid tumours (colorectal cancer, breast cancer, must be given IV

239
Q

DPYD*2A and fluoropyridime

A

If treat with 50% of normal dose the adverse effects decreases

240
Q

What do phase 2 enzymes do

A

Biotransformation reactions typically conjugate endogenous molecules into things to eliminate

241
Q

Polymorphic phase 2 enzymes

A

Diminish drug elimation and increase toxicities

242
Q

Uridine 5-diphosphoglucuronosyl transferase 1 (UGT1A1)

A

Enzymes conjugate glucuronic acid into small lipophilic molecules so readily excreted in bile

243
Q

UGT1A1 *28

A

Common all ethnic groups

244
Q

Gilbert syndrome

A

UGT1A1 *28/28

245
Q

28 allele Gilbert’s

A

Extra TA in proximal promoter

246
Q

Gilberts syndrome

A

Increased unconjugated bilirubin and increased risk for adverse drug reactions due t recused biliary elimination

247
Q

Irinotecan

A

Topoisomerase inhibitor prodrug for chemo

248
Q

Irinotecan metabolized to ___

A

An-38, toxic and inhibits topoisomerase leading to DNA termination or rep and cell death

249
Q

How in SN-38 inactivated

A

UGT1A1

250
Q

Irinotecan SN38 and UGT1A1*38

A

Severe life threatening toxicities (neutropenia, diarrhea, due to decrease SN38 clearance)

251
Q

Thiopurine S-methyltransferase (TPMT)

A

Covalently attaches a methyl group into aromatic and heterocyclic sulfhydryl compounds and is responsible for the pharmacological deactivation fo thiopurine drugs

252
Q

Phenotypes of TPMT

A

High intermediate and low activity

253
Q

Who has most high one nonfunctional TPMT

A

Europeans and Africans

254
Q

What percent of Europeans have two defective TPMT

A

.3

255
Q

TMPT*2, 3A, 3B, 3C

A

Non functional alleles

256
Q

Thiopurine drugs and TPMT

A

Treat immunologic disorders

TPMT is major determinant of thiopurine metabolism and exposure to cytokines dosing strategies

257
Q

G6PD

A

Rate limiting step in PPP and supplies NADPH and reduced glutathione which prevent oxidative damage
G6PD normally in RBC to detoxify unstable oxygen species while working at 2% of its capacity

258
Q

Exposed to ROS

A

G^PD activity in RBS increases proportionately to meet NADPH demands

259
Q

G6DP defiency

A

Risk for abnormal RBC destruction hemolysis due to antioxidant capacity under oxidative pressures

260
Q

What chromosome is G6PD on

A

X chromosome

261
Q

How many people have G6PD decent

A

400 million

262
Q

G6PD defiency associated with

A 
High malaria prevelance 
AFRICA 
Mediterranean 
Asia 
East Asia
263
Q

Rasburicase

A

Recombinant rate oxidase enzyme for initial management of high uric acid levels in cancer patients receiving chemo

264
Q

Rasburicase

A

Alleviates the uric aid burden that often accompanies tumor losing treatments by converting uric acid into allantoin, a more soluble and easily excreted molecule

265
Q

During the conversion fo uric acid to allantoin, __ is formed

A

H2O2

266
Q

Rasburicase and G6PD

A

Can’t reduce H2O2

Risk for hemolytic anemia and methemoglobinemia

267
Q

Recommendation

A

Rasburicase no use in people with G6PD defiency

268
Q

Organic anion transporter (OAT1B1) from SLOC)1B1

A

Sinusoidal membrane of hepatocytes and is responsible for the hepatic uptake of mainly weakly acidic drugs and endogenous compounds like statins, methotrexate and bilirubin

269
Q

Reduced function OAT1B1

A

Rs4149056

  • 5
  • 15 17-reduced function
270
Q

Statins

A

HMG-coenzyme A reductase inhibitors

271
Q

Statin and SLCO1B1 5, 17

A

Myopathy

Recommend alternative

272
Q

Breast cancer resistance protein (BCRP, ABCG2)

A

An effluvia transporter in the ATP binding cassette superfamily on epithelial cells of the kidney, liver, and intestine and on endothelial cells of BBB

273
Q

BCRP issue

A

East Asians (Chinese Japanese)

274
Q

Allopurinol and BCRP, statin,

A

Problem

275
Q

Drug induced hypersensitivity reactions

A

Stevens Johnson, necrosis, liver injury,

276
Q

Drug classes associated with hypersensitivity

A

Antibiotics, NSAIDS< aanti-epileptic, methotrexate

277
Q

Carbamazepine induced skin toxicities

A

East Asian

278
Q

HLA B, , DQ, DR

A

Drug induced hypersensitivity reactions to allopurinol, carbamazepine, abacavir, and flucloxallin

279
Q

HLA-B and abacavir

A

Nucleoside reverse transcriptase inhibitor used in HIC associated with hypersensitivity reactions in the skin , SJS, TEN

280
Q

Ethnic group for abacavir and HLAB57:)1

A

Ligand bound peptide onthe cell surface in a structurally different configuration which is recognized by CD8 cells

281
Q

Increase testing genetic variants of HLAB5701

A

For chemo

282
Q

Flucloxacillin

A

Hypersensitivity reaction HLAB5701 liver toxicity

283
Q

HLAB5701 and flucloxallin

A

Liver injury

284
Q

Interferon lambda-3 (IFN-gamma3)

IFNL3 (IL-28B)

A

Encdedn by IFNL3
Directly induced by viruses and act through JAK STAT final transduction pathways to produce antiviral activity inc Ellis
HepC

285
Q

Genetic variants IFNL3 and HCV treatment

A

Ribavirin-greater cure in patients with favorable

286
Q

IFNL3 is considered what

A

Strongest baseline predictor variant, is inherited most frequently in Asians

287
Q

Peggy lasted interferon with ribavirin

A

Chronic HCV want a sustained virologist response (SVR)

Europeans homozygous favorable
More likely to achieve SVR

288
Q

Unfavorably IFNLE

A

Lesss SVR with ribavirin

289
Q

Warfarin

A

CYP2C9 and VKORC1

290
Q

CYP2C9

A

Phase I drug metabolizing enzyme that acts primarily on acidic drugs including warfarin, phenytoin, and NSADIS

291
Q

CYP2CP *2, 3,

A

Reduced metabolism of warfarin common European

292
Q

Why warfarin variability in Africans

A

High CYP2C9, *5, 6, 8, 11

293
Q

VKORC1

A

Vitamin K epoxied reductase complex subunit 1

294
Q

VKORC1

A

Target of warfarin and key enzyme in VK recycling

295
Q

VK dependent cofactors

A

II, VII, IX, X, C, S

296
Q

Variation in VKORC1

A

Bleeding , like multicoagulation factor defiency type 2A or warfarin resistance

297
Q

VKORC1-1639>A

A

Reduced expression of VKORC1 in the liver
Increased sensitivity to warfarin
Asians

298
Q

Warfarin

A

VK antagonist, widely prescribed oral anticoagulatnt

299
Q

Why do dose variation cause problems with warfarin

A

Narrow therapeutic range

300
Q

What polymorphism are important for warfarin

A

CPY2C9 and VKORC1

301
Q

S- R- warfarin entantimer

A

How its administered. Increased risk for bleeding if CYP92C9 and VKORC1

302
Q

Epigenomics

A

Epigenomics

303
Q

Can regulate genes involved in pharmacokinetics or drug targets include DNA methylation and histone modification

A

Ok

Pharmacology (52 decks)

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