Class Flashcards
1
Q
Receptor
A
Regulatory role-interact with drug and initiates drug effects
2
Q
Inert binding site
A
Drug binds without changing any function of receptor
3
Q
Ligand
A
Binds to receptor
4
Q
Covalent bond of ligand and receptor
A
Irreversible
Need to resynthesize
5
Q
Non covalent ligand receptor binding
A
Reversible
Most
6
Q
List types of bonds strongest to weakest (non covalent)
A
Ionic, hydrogen, hydrophobic interaction, van der waals
7
Q
What are van der walls
A
Weak electrostatic interactions involving dipole moments within functional groups
8
Q
Dose response curve
A
Drug and its effects
Linear?
9
Q
Log of dose response curve
Drug dose log x
Y drug effect
A
Hyperbolic
10
Q
Concentration effect curve log vs response
A
Sigmoidal curve
11
Q
Emax
A
Max effect
12
Q
ED50
A
Dose that produces 50% of its maximal effect
13
Q
Graded response
A
How much
Magnitude of response varies continuously
Mean value within a population or subject
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
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
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
17
Q
what kind of graph do you get TI from
A
Cumulative dose response curve
18
Q
TI
A
TD50/ED50
19
Q
Therapeutic window
A
Range at which safe and effective
20
Q
What determines the binding and nteraction of drugs with their receptors
A
Size shape charge
21
Q
High affinity
A
Less drug needed to produce a response
22
Q
Low affinity
A
More drug needed to produce a responses
23
Q
Kd
A
Parameter describing affinity
Equilibrium dissociation constant
24
Q
What is the Kd
A
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
