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Flashcards in Class Deck (303):
1

Receptor

Regulatory role-interact with drug and initiates drug effects

2

Inert binding site

Drug binds without changing any function of receptor

3

Ligand

Binds to receptor

4

Covalent bond of ligand and receptor

Irreversible

Need to resynthesize

5

Non covalent ligand receptor binding

Reversible
Most

6

List types of bonds strongest to weakest (non covalent)

Ionic, hydrogen, hydrophobic interaction, van der waals

7

What are van der walls

Weak electrostatic interactions involving dipole moments within functional groups

8

Dose response curve

Drug and its effects

Linear?

9

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

Hyperbolic

10

Concentration effect curve log vs response

Sigmoidal curve

11

Emax

Max effect

12

ED50

Dose that produces 50% of its maximal effect

13

Graded response

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

14

Quintal response

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

Need predefined response
Examine frequency of a large population

15

Quantal non cumulative dose response curve

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

16

Cumulative quantal dose response curve

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

17

what kind of graph do you get TI from

Cumulative dose response curve

18

TI

TD50/ED50

19

Therapeutic window

Range at which safe and effective

20

What determines the binding and nteraction of drugs with their receptors

Size shape charge

21

High affinity

Less drug needed to produce a response

22

Low affinity

More drug needed to produce a responses

23

Kd

Parameter describing affinity

Equilibrium dissociation constant

24

What is the Kd

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

25

Unit of Kd

Molar concentration (micromoles, nanomoles

26

Low Kd

Higher affinity of a drug for receptor

27

Higher Kd

Lower affinity of a drug for a receptor

28

Formula for Kd

L+R LR

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

29

What are L R and LR

Molar concentrations of ligand, receptor, and their complex

30

__ determine the quantitative relationship between a drug and its effects

Receptors

31

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

Receptor

32

Ec50=Kd or Ec50=Kd

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

33

Two graphs

Ok

34

Agonist have __ activity

Intrinsic

35

Antagonist do not have __ activity

Intrinsic

36

Competitive antagonist

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

37

Non competitive antagonists

Receptor inactivation is not surmountable

Irreversible or allow=steric antagonist

38

Irreversible antagonist

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

39

Allosteric antagonists

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

40

Competitive antagonist

Agonist EC50 increases, Emax does not change

41

Non competitive antagonism

Agonist Emax decreases
EC50 does not change

42

Potency

Amount of a drug required to produce a specific pharmacological effect

43

What drugs tend to be more potent

Higher affinity (lower Kd)

44

What represents potency

ED50

45

Lower ED50

More potent

46

How determine dose

Potency

47

Efficacy

Maximal pharmacological effect that a drug can produce

48

What represented efficacy

Emax

49

The greater the Emax, the more ___ the drug

Efficacious

50

What is efficacy related to

Total receptors available to bind a drug

51

What does efficacy determine clinically

Effectiveness

52

Potency determines __ and efficacy determines ___

Dose
Effectiveness

53

Potency is related to __ and efficacy is related to ___

Affinity
Total number of receptors available to abind a drug

54

What is a drug target

Important regulatory proteins in the existing cell signaling pathways

55

What are the classes of drug targets

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

56

Protein kinases

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

Phosphorylation

500 in human genome

57

Response element

Specific DNA region that transcription factors bind to

58

What do transcription factors have

DNA binding domain

59

What do transcription factors bind to

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

60

GPCR makes up _% of genome

4

61

About _% of marketed drugs act on GPCR

30

62

Ligand for GPCR

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

63

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

Glycosylated

64

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

Cytosolic

Serine/threonine residues

65

What do cytoplasmic loops of GPCR contain

G protein binding sites

66

The 7 transmembranes is ___

Hydrophobic

67

Phosphorylation of C terminal

Diminished G protein coupling and can promote receptor endocytosis

68

G protein cycl

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

69

Rec

Hormone receptors

70

PDE

Phosphodiesterase that hydrolyze cAMP

71

Pase

Phosphatase

72

S

Protein substrates

73

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

Phosphodiesterase turns it to 5-AMP

Or cAMP+R2C2–> R2cAMP4+2C

74

What happens to 2C

With ATP turns S to SP to make ADP with Pase

75

What does SP do

Response

76

What happens to IP3

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

77

What does DAG do

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

78

What receptors have intrinsic enzyme activity

RTK

79

What growth factors bind to RTK

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

80

Most RTK

Single polypeptide chain

81

Insulin and IGF receptor RTK

2 chains a and b linked by disulfide bond

82

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

Ligand-binding

83

___ __ domain is similar between the members of the family

Tyrosine kinase

84

How is the EGF receptor activates

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

85

JAK

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)

86

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

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

87

Ligand for nuclear receptors

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

88

Steroid receptor families

Androgen receptor
Estrogen receptor
Progesterone receptors
Glucocorticoid receptors
Mineralocorticoid receptors

89

When do we see effects of nuclear receptors

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

90

Mechanism of a steroid hormone action

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

91

What do ion channels do

Change the cell membranepotential
Change concentration of ions in cytosolic

92

Voltage gated channels

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

93

Ligand gated channels

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

94

How are voltage gated ion channels controlled

Not by binding a ligand
Controlled by membrane potential

95

Voltage gated Na channels

A and b subunits

96

What drugs inhibit voltage gated Na channels

Local anesthetics
Antiarrhythmic drugs
Drugs used for the treatment of epilepsy

97

Voltage gated ca channel

L type channels are located on cardiac and smooth muscle cells

Blockers and antagonists

98

Direct gated ion channels

Receptors for neurotransmitters that have an ion conducting pore

99

Excitatory neurotransmitters

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

100

Examples of excitatory NT

Acetylcholine and glutamate

101

Inhibitory neurotransmitters

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

102

Examples of inhibitory neurotransmitters

GABA and glycine

103

Activation of nicotonic acetylcholine receptors

Induces inward Na fluxes and membrane depolarization

104

What and where are nicotonic acetylcholine receptors

Pentameric receptors with two major locations
-skeletal muscle, responsible for depolarization of skeletal muscle fibers
-neuronal cells

105

What is a nicotonic acetylcholine receptor

Ligand gated ion channel

106

The nicotonic acetylcholine receptor is in the ___

Membrane

107

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

Five
2a, b, y, and delta

108

What does the nicotonic acetylcholine receptor do

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

109

GABA receptors

Anionic channels causing inward Cl influx and hyperpolarization

110

What does GABA mediate

Synaptic inhibition in CNS via these channels

111

Structure of GABA receptos

Pentameric structure

112

What is the GABA receptor a target for

Inhalation general anesthesia drugs

Intravenous general anesthesia drugs

Ethanol

Hypnotic and anti anxiety benzodiazepine drugs

113

Binding sites on GABA receptor

Binding site and allosteric

114

Biotransformation

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

Usually xenobiotics

115

What compounds are not readily excreted

Lipophilic, unionized, large compounds

116

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

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

117

Consequences of Biotransformation

May lead to products still biologically active or more active

118

L dopa biotransformation

Dopamine

Prodrug into active compound

119

What is l dopa

Pro drug

120

Example of active compound becoming an active compound

Diazempam—>oxazepam

121

Example of inactivation

Acetylsalicylic acid(asprin)-> acetic acid+ salicylate

122

What is a prodrug

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

123

Where does biotransformation happen

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

124

First pass

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

First pass limits drugs?

Yea look at other routes of administration

126

Digestive enzymes and intestinal bacteria

May metabolically activate or inactivate drugs

127

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

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

128

Morphine

Extensive first pass

129

Clinical significance of morphine undergoing extensive first pass biosynthesis

Oral 35% absorbed
So need to give IV

130

Phase I

Oxidation, reduction, or hydrolysis reactions

Biological inactivation

131

Phase II reactions

Conjugate the substrate

Make more water soluble and increased molecular weight which facilitates elimination

132

Phase I

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

Common reactions phase I

Oxidation, reduction, and hydrolysis

134

Less common reactions phase I

Hydroxylation, epoxidation, dealkylation, deamination, desulfurization, decholrination

135

Phase I enzymes

MFO (mixed function oxidase) MFO or monooxygenases
-CYP P450
-flavin containing monoxygenases (FMO
-epoxied hydrolysis (mEH, sEH)

136

Phase II

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

137

Conjugation in phase II

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

138

Phase I or phase II faster

Phase II conjugation

139

Where does most conjugation take place

Liver

140

Are some drugs not metabolized phase I or II

Yup

141

Many phase I reactions occur ___

Concurrently

142

Before phase I

Phenytoin highly liophilic

143

After phase I

4-hydroxy phentoin
Slightl soluble in water

144

After phase II

4-hydroxy-penytoin-glucuronide
Very soluble in water

145

Cytochrome p450

Superfamily of enzymes that carry out phase I biotransformation

146

Most common p450s

CYP1A2, CYP2A6, CYP2D6, CYP2E1, and CYP3A4

147

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

CYP3A4

148

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

Heme
Noncovalently

149

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

O2 H

150

P450 cycle

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

What does NADPH do

Turns flavinprotein(oxidized) to flavinprotein reduced with P450 reductase

152

What does a reduced flavinprotein do

Give 2 electrons to p450-RH

153

Succinylcholine

Depolarizing neuromuscular blocking drug

154

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

Pseudocholinesterase

155

What is slow acetylator phenotype

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

156

Result of slow acetylator phenotype

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

How many people are slow acetylator phenotype

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

158

Page 43 katzung

Ok

159

CYP2E1

Is endured by chronic ethanol

160

Tobacco smoke(benzo a pyrene

Inducer

161

Rifampin

For TB
Inducer

162

Rats pretreated with phenobarbital

Significantly faster half life of chloramphenicol in comparison to control rats

163

Grapefruit juice effect

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

164

Allopurinol and mercaptopurine

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

Neonate biotransformation

Low hepatic enzymes actively involved in drug biotransformation

166

Biotransformation in postnatal period and elderly

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

167

Premature infants

Decreased conjugating activity

168

Hyperbilirubinemia in new born

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

Why are fetus and neonate highly susceptible to drug toxicity

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

170

Does metabolism for drugs decrease with age

Sometimes not really
Bc drug half-life is more dependent on the drug itself

171

Liver and kidney disease

In elderly
Important factor accounting for decreased drug metabolism

172

Age related variables that affect pharmacokinetics

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

173

Young or old people have more body water

Young

174

Young or old people have more lean body mass

Young

175

Young or old people have more body fate

Old

176

Young or old people have more serum albumin

Young

177

Young or old people have more kidney weight

Young

178

Young or old people have more hepatic blood flow

Young

179

Liver disease

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

180

Disease states that could decrease metabolism

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

181

Flow limited biotransformation drugs

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

182

Cardiac disease may cause specific drug levels to rise

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

183

What happens when endogenous detoxifying cosubstrates are limited

The toxic pathways may prevail resulting in organ toxicity or carinogenesis

184

What may cause cosubstrate limitation

Dietary insuffiency or an alternative underlying defiency

185

Example of biotransformation to more toxic product

Acetaminophen-induced hepatotxicity

186

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

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

187

What happens when acetaminophen intake exceeds therapeutic dose

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

188

Glucuronidation of acetaminophen

to nontoxic glucuronide

189

Sulfation of acetaminophen

Nontoxic sulfate

190

CYP2E1 and CYP3A4 of acetaminophen

To reactive toxic intermediate

191

What happens to reactive toxic intermediate of aceteminophen

GSH conjugation
To mercapturic acid conjugate
Or

Nucleophillic cell macromolecules to cause liver cell death

192

Pharmacogenomics/pharmacogenetics

Study of genetic factors that underlie variation ind rug response

193

Genome wide association studies

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

Precision/stratified personal medicine

Genetic information is used to guide drug and dosing

195

Clinical pharmacogenetics implementation consortium (CPIC)

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

196

Allele

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

CSNP

Snp in coding region

198

HaplotypE

Series of alleles found in a linked locus on a chromosome

199

Hardy Weinberg

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

200

Linkage disequilibrium

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

201

Nonsynonymous snp (nsSNP)

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

202

PM, IM, EM, UM

Poor, intermediate, extensive, or ultra rapid metabolized phenotype

203

Synonymous SNP

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

204

Extensive metabolized

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

*

Specific sequence variant

206

*1xN

N number of copies

207

Enzyme activity is ___ or _-

Co dominant
Additive

208

If an individual has one normal and one functional allele

Have intermediate

209

0, .5, 1-2, >2

PM, IM, EM, UM

210

CYP2D6

1/4 of all rugs
B blockers, antidepressants, antipsychotics, opoid analgesics

211

CYP2D6*4

20% of Europeans and absent in Asians

212

CYP@D^ alleles

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

213

LPM CYP2D6

3, 4, 5, 6 more in Europe’s

214

*5 deletion CPY 2D6

Similar frequencies European and Asian
Hardy Weinberg

215

Ethnicity specific@

Look at ethnicity of patient you are treating

216

Codeine active metabolite

Morphine

217

What do codeine and morphine bind to

Mu-opoid receptor in CND

218

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

Morphine 200 times more potent

219

What enzyme converts codeine to nomrphine

O-demethylation -a CYP2D6

220

EM CYP2D6

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

221

PM IM CYP2D6

Insufficient pain relief

222

UM CYP2D6

Side effects of codeine
Drowsy, respiratory depression, due to high morphine

223

CYP 2C19

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

224

CYP2C19 alleles

2 3 are nonfunctional
1 fully functional
17 increased function

225

CYP2C19*17

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

226

PM CYP2C19

Asians

227

CYP2C19*2

Asians

228

CYP2C19*17

Not Asians
In Europeans and Africans

229

Clopidogrel

Thienopyridine antiplatelet prodrug indicated for prevention fo atherothrombic events

230

How does clopidogrel work

Active metabolites selectively and irreversibly inhibit adenosine diphosphate induced platelet aggregation

231

How is clopidogrel metabolized

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

CYP2C19*2 and clopidogrel

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

233

CPIC recommendations clopidogrel

Standard starting dose for EM, UM

Give antiplatelet agent to PM and IM

FDA says alternative antiplatelet for poor metabolizes

234

Recommendation CPIC for CYP2D6 and codeine

Standard starting dose for EM, IM (close monitoring IM

Don’t use in PM and UM

235

Dihydropyrmiidine dehydrogenase (DPD)

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

236

Three nonfunctional alleles of DPD

DPYD*2A, *13, and rs67376798

237

DPYD*2A

Common in Swedish populations
Lower in European, African and Asian

238

Fluoropyridime 5-FU

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

239

DPYD*2A and fluoropyridime

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

240

What do phase 2 enzymes do

Biotransformation reactions typically conjugate endogenous molecules into things to eliminate

241

Polymorphic phase 2 enzymes

Diminish drug elimation and increase toxicities

242

Uridine 5-diphosphoglucuronosyl transferase 1 (UGT1A1)

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

243

UGT1A1 *28

Common all ethnic groups

244

Gilbert syndrome

UGT1A1 *28/28

245

28 allele Gilbert’s

Extra TA in proximal promoter

246

Gilberts syndrome

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

247

Irinotecan

Topoisomerase inhibitor prodrug for chemo

248

Irinotecan metabolized to ___

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

249

How in SN-38 inactivated

UGT1A1

250

Irinotecan SN38 and UGT1A1*38

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

251

Thiopurine S-methyltransferase (TPMT)

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

252

Phenotypes of TPMT

High intermediate and low activity

253

Who has most high one nonfunctional TPMT

Europeans and Africans

254

What percent of Europeans have two defective TPMT

.3

255

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

Non functional alleles

256

Thiopurine drugs and TPMT

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

257

G6PD

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

Exposed to ROS

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

259

G6DP defiency

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

260

What chromosome is G6PD on

X chromosome

261

How many people have G6PD decent

400 million

262

G6PD defiency associated with

High malaria prevelance
AFRICA
Mediterranean
Asia
East Asia

263

Rasburicase

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

264

Rasburicase

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

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

H2O2

266

Rasburicase and G6PD

Can’t reduce H2O2
Risk for hemolytic anemia and methemoglobinemia

267

Recommendation

Rasburicase no use in people with G6PD defiency

268

Organic anion transporter (OAT1B1) from SLOC)1B1

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

Reduced function OAT1B1

Rs4149056
*5
*15 17-reduced function

270

Statins

HMG-coenzyme A reductase inhibitors

271

Statin and SLCO1B1 5, 17

Myopathy
Recommend alternative

272

Breast cancer resistance protein (BCRP, ABCG2)

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

BCRP issue

East Asians (Chinese Japanese)

274

Allopurinol and BCRP, statin,

Problem

275

Drug induced hypersensitivity reactions

Stevens Johnson, necrosis, liver injury,

276

Drug classes associated with hypersensitivity

Antibiotics, NSAIDS< aanti-epileptic, methotrexate

277

Carbamazepine induced skin toxicities

East Asian

278

HLA B, , DQ, DR

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

279

HLA-B and abacavir

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

280

Ethnic group for abacavir and HLAB57:)1

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

281

Increase testing genetic variants of HLAB5701

For chemo

282

Flucloxacillin

Hypersensitivity reaction HLAB5701 liver toxicity

283

HLAB5701 and flucloxallin

Liver injury

284

Interferon lambda-3 (IFN-gamma3)
IFNL3 (IL-28B)

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

285

Genetic variants IFNL3 and HCV treatment

Ribavirin-greater cure in patients with favorable

286

IFNL3 is considered what

Strongest baseline predictor variant, is inherited most frequently in Asians

287

Peggy lasted interferon with ribavirin

Chronic HCV want a sustained virologist response (SVR)

Europeans homozygous favorable
More likely to achieve SVR

288

Unfavorably IFNLE

Lesss SVR with ribavirin

289

Warfarin

CYP2C9 and VKORC1

290

CYP2C9

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

291

CYP2CP *2, 3,

Reduced metabolism of warfarin common European

292

Why warfarin variability in Africans

High CYP2C9, *5, 6, 8, 11

293

VKORC1

Vitamin K epoxied reductase complex subunit 1

294

VKORC1

Target of warfarin and key enzyme in VK recycling

295

VK dependent cofactors

II, VII, IX, X, C, S

296

Variation in VKORC1

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

297

VKORC1-1639>A

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

298

Warfarin

VK antagonist, widely prescribed oral anticoagulatnt

299

Why do dose variation cause problems with warfarin

Narrow therapeutic range

300

What polymorphism are important for warfarin

CPY2C9 and VKORC1

301

S- R- warfarin entantimer

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

302

Epigenomics

Epigenomics

303

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

Ok