Pharmacogenetics (Nerissa Dando, MD) Flashcards
1
Q
What is the goal for non-responders? Toxic responders?
A
Drug efficacy; drug safety
2
Q
What are the three possible effects of drug administration?
A
Therapeutic effect
Adverse effect
Lethal effect
3
Q
Describe: Succinylcholine
A
Anesthetic agent (muscle relaxant) ADR: overparalysis
4
Q
What type of drug is primaquine?
A
Antimalarial
5
Q
What type of drug is isoniazid (INH)?
A
Anti-tuberculosis
6
Q
Intake of primaquine causes ADRs among African-Americans where they develop (1) which leads to (2).
A
(1) G6PD deficiency
(2) hemolytic anemia
7
Q
Who developed the concept of chemical sensitivity?
A
Archibald Garrod
8
Q
Define: Alcaptonuria
A
Excretion of homogenateisic acid in urine due to congenital absence of homogentisate 1,2 dioxygenase.
No breakdown of phenylalanine and tyrosine.
Urine is dark.
9
Q
Enumerate Mendel’s Four Principles of Inheritance
A
- Genes come in pairs.
- Dominance and recessiveness
- Principle of segregation
- Principle of independent assortment
10
Q
How many possible codons are there?
A
64
11
Q
What is the sequence of the start codon? Stop codons?
A
Start codon - AUG
Stop codons - UAA, UAG, UGA
12
Q
Enumerate the basic patterns of inheritance
A
Autosomal Dominant
Autosomal Recessive
X-linked
Mitochondrial Inheritance
13
Q
Give examples of X-linked diseases
A
G6PD deficiency
Pyridoxine sensitive anemia
Vasopressin resistance
14
Q
T/F: Mitochondrial inheritance is secondary to exposure to aminoglycosides like streptomycin, gentamycin and amikacin.
A
True
i.e. aminoglycoside-induced deafness
15
Q
What are the factors affecting drug sensitivity?
A
Genetics
Disease
Age
Drug related factors
16
Q
Which groups of patients are most sensitive to the effects of drugs?
A
Geriatric
Preterm
Chronically Ill
17
Q
What drug related factors affect drug sensitivity?
A
Pharmaceutical formulation
Route of administration
Drug interaction
Environmental factors
18
Q
Enumerate extrinsic factors affecting drug sensitivity
A
Drug-food interaction (grapefruit juice, alcohol & histamine cause sedation)
Environmental chemicals
Vices
19
Q
Enumerate intrinsic factors affecting drug sensitivity
A
Physiological and pathophysiological attributes of a person (age, gender, weight, etc.)
Patient characteristics
20
Q
Define: Gene
A
Unit of heredity on a chromosome
21
Q
Define: Alleles
A
Alternative forms of genes that occur in pairs
22
Q
It includes all alleles present in the cell whether dominant or recessive, expressed or not.
A
Genotype
23
Q
Physical manifestation of a trait
A
Phenotype
24
Q
What method can predict whether an individual is a candidate for polymerphic metabolism?
A
Molecular Genotyping
25
What methods are commonly employed in molecular genotyping?
Polymerase chain reaction (PCR)
| Restriction fragment length polymorphism mapping (RFLM)
26
Method accomplished by administering a probe to an individual followed by analysis of metabolites in blood or urine
Phenotyping
27
What anti-hypertensive drug is used to identify the activity of CYP450?
Drebisoquine
28
Enumerate the three potential applications of molecular genotyping in drug development
1. Determine safety and efficacy of investigational new drug prior to approval
2. Protect patients against ADRs by identifying poor metabolisers
3. Establish an individual's genetic predisposition to disease
29
Define: Monogenic
Due to allelic variation at a single gene
30
Define: Polygenic
Due to variations at two or more genes
31
What describes frequently occurring monogenic variants occurring at a frequency > 1%?
Polymorphic
32
What are the most common polymorphisms?
Single nucleotide polymorphisms (SNPs)
| Copy number variations (CNVs)
33
What are less common polymorphisms?
Insertions
| Deletions
34
What are the two types of gross rearrangements?
Inversions
| Translocations
35
These are implicated in human diseases (i.e. cancer and Alzheimer's) but most have no known clinical effects.
Single Nucleotide Polymorphisms
36
What are the different types of SNPs?
Missense
Nonsense
Frameshift by addition
Frameshift by deletion
37
How many SNPs have been identified in the human genome?
2 million
38
T/F: A polymorphic distribution follows a normal distribution.
False
70 - 90% of them are found in extremes.
39
Enumerate the project goals of the Human Genome Project
1. Identify all 30,000 genes in human DNA
2. Determine sequences of 3 billion base pairs
3. Store the information
4. Improve tools for data analysis
5. Transfer technologies to private sector
6. Address ELSI (ethical, legal and social issues) that may arise
40
When was a working draft of the human genome completed?
June 2000
41
When were analysis of the working draft published?
February 2001
42
T/F: To be important, SNPs must affect either function or amount of a protein.
True
43
What are the possible effects of genetic polymorphisms?
1. Pharmacokinetic (enzymes, transporters and binding proteins)
2. Pharmacodynamic (target proteins, receptors and ion channels)
3. Idiosyncratic Responses (no explanation)
44
Refers to genetic loci in which variants occur with a frequency of 1 - 2%
Genetic Polymorphism
45
Twin and family studies enable discrimination of?
Various modes of genetic transmission
| Dominance-recessivity relationships
46
T/F: Pharmacogenomics is a subset of pharmacogenetics.
False
It's the other way around.
47
Define: Pharmacogenomics
Study of variations of DNA AND RNA characteristics related to drug response
48
Define: Pharmacogenetics
Study of genetically controlled variations in DNA sequence related to drug response
49
According to pharmacogenomics, what is the key to creating personalised drugs with greater efficacy and safety?
Understanding an individual's genetic make-up
50
Define: Poor Metabolizers
Slower-than-usual metabolism leading to toxicity
| May be due to liver or kidney failure
51
Define: Ultra-rapid Metabolizers
Observed therapeutic failure
| Variability in drug target genes
52
T/F: There is poor efficacy of prodrugs in slow metabolizers and ADR risk in ultra-rapid metabolizers.
True
53
Give examples of prodrugs.
Codeine
Tamoxifen
Clopidogrel
54
What is seen in CYP2D6 poor metabolises of debrisoquine?
Marked hypotension
Note: This is not an ADR.
55
What group has the largest incidence of G6PD deficiency?
Indians-Parsees
56
T/F: Newborn screening cannot detect G6PD deficiency.
False
57
Enumerate the drugs demonstrated to precipitate haemolytic anemia in G6PD deficients
```
Acetanilide
Methylene blue
Nalidixic acid
Naphthalene
Sulfapyridine
Sulfanilamide
Sulfamethixazole
Primaquine
Sulfacetamide
Nitrofurantoin
Nitrates
```
58
Example of an unusual drug response is malignant hyperthermia following the use of what?
Halothane (anaesthetic agent)
59
What is the classic presentation of malignant hyperthermia?
```
Rapid rise in body temperature
Muscle rigidity
Tachycardia
Rhabdomyolysis
Severe acidosis
Hyperkalemia
```
60
What is the antidote for malignant hyperthermia?
L.V. dantrolene
61
What causes malignant hyperthermia?
Mutations in the ryanodine receptor
62
In cases of Warfarin resistance, by how much does the dose need to be increased?
7 - 20 times recommended therapeutic dose
63
In cases of folate resistance, by how much does the dose need to be increased?
40 - 1000 times daily recommended dose
64
T/F: Fast acetylators are susceptible to phenytoin toxicity when phenytoin and isoniazid are given together.
False
Slow acetylators!
65
T/F: Individualizing therapy is important for drugs with a wide therapeutic range.
False
Narrow!
66
Increased risk of cancer is associated with polymorphisms in what genes?
CYP (2A1, 1A2 and 2E1)
Glutathione transferases (GSMT1, GSTT1)
Epoxide hydrolase
NAT2 - N-acetyl transferase 2
67
T/F: Drug clearance typically removes drugs via enzymatic transformation into more hydrophobic metabolites.
False
Hydrophilic!
68
T/F: Cytochrome P450 enzymes are responsible for Phase II oxidative metabolism of steroid hormones, xenobiotics and carcinogens.
False
Phase I oxidative metabolism!
69
What CYPs are important for Phase I?
CYP3A4, CYP2C19 and CYP2D6
70
What enzymes are important for Phase II?
TPMT, NAT1 & NAT2
71
What are the mechanisms of variation in drug response?
1. Modification of absorption of xenobiotic
2. Modified metabolism resulting in modification of rate, pattern of elimination, detoxification or activation of a given xenobiotic
3. Modification in the abundance, affinity or function of a target enzyme or receptor
72
What factors influence absorption of the xenobiotic?
1. Rapid metabolizer
2. Decreased abundance of transport protein
3. Enhanced excretion by multi-drug resistance protein
73
T/F: When the main metabolic pathway leading to a harmless metabolite is blocked, parent drug could accumulate and cause toxicity.
True
74
T/F: Deficiency of methemoglobin reductase is inherited as an autosomal recessive trait.
True
75
T/F: Methemoglobin reductase homozygotes are predisposed to develop methemoglobinemia when exposed to nitrates and other stress.
False
Heterozygotes!
76
Give an example of a modification in the abundance, affinity or function of a target enzyme or receptor.
1. Silent variants of serum cholinesterase associated with succinylcholine
2. Poor metaboliser variants of CYP2D6 and CYP2C19
77
Describe the metabolism of ethanol by the body
Ethanol -> acetaldehyde (by ADH) -> acetate (by ALDH)
78
T/F: The rate of ethanol metabolism of genetically controlled.
True
79
T/F: Atypical ADH exhibits higher catalytic activity and typically contains a variant alpha 2 subunit.
False
Variant beta 2 subunit!
80
What ethnic group has the largest distribution of atypical ADH?
Swiss (20%)
81
How does the atypical B2 subunit of alcohol dehydrogenase differ from the typical?
CGC to CAC transition resulting in an Arg47His substutition
82
What does the atypical ADH subunit mutation cause?
Higher ethanol Vmax
| Higher Km for the homozygous B2B2
83
What are the three genotypes for aldehyde dehydrogenase?
1. Homozygote normal
2. Heterozygote
3. Deficient homozygote
84
What causes the "flush" and feelings of discomfort associated with ethanol intake?
Acetaldehyde accumulation
85
Describe: cyclophosphamide polymorphic biotransformation
Antineoplastic agents that cause cystitis
86
Familial pyrimidinemia and pyridinuria are associated with what?
5-fluorouracil induced toxicity
87
Major toxic manifestation of 5FU in DPD occurs in what tissue?
Bone marrow
88
What are the two phenotypes for mephenytoin hydroxylation polymorphism?
1. Poor metaboliser
| 2. Extensive metabolizer
89
Mephenytoin hydroxylation is mediated by what enzyme?
CYP2C19
90
What are the types of parathion poisoning and paraoxon polymorphism?
PON1 & PON2
91
What causes the hydrolysis of succinylcholine?
Pseudocholinesterase
92
How do you document pseudocholinesterase deficiency?
History taking
| Unexpected persistent respiratory paralysis for a prolonged period of time
93
Enumerate a few examples of choline ester compounds
Succinylcholine
Mivacarium
Cocaine
94
Atypical plasma cholinesterase causes (1) that lasts (2)
(1) paralysis
(2) 2 - 6 mins
Note: Patients deficient in the enzyme experience 1-hour long paralysis episodes.
95
How many % of succinylcholine is inactivated by normal functioning pseudocholinesterase?
90 - 95%
96
T/F: Flaccid paralysis of skeletal muscle develops within 1 minute of succinylcholine binding
True
97
What is the cause of pseudocholinesterase deficiency?
Abnormal alleles that code for the enzyme
98
Where is the gene coding for pseudocholinesterase located?
E1 locus on the long arm of chromosome 3
99
How many % of the population carries one or more of the atypical gene alleles for pseudocholinesterase gene?
4%
100
How is the dibucaine-resistant genetic variant form of pseudocholinesterase detected?
Percent inhibition of hydrolysis of benzyl choline caused by addition of dibucaine (dibucaine number)
101
What is the DN value for normal homozygotes? for the atypical dibucaine resistant genotype?
80%; 20%
102
How is the fluoride-resistant pseudocholinesterase enzyme variant detected?
Percent inhibition of benzyl choline hydrolysis when fluoride is added to assay
103
What is the FN value for normal homozygotes? for the atypical homozygotes?
60%; 36%
104
What is the most severe form of atypical pseudocholinesterase?
Silent form
105
T/F: Only 1 in 100,000 individuals are homozygous for the silent Es genotype with no detectable pseudocholinesterase enzyme activity.
True
106
What causes the silent Es genotypes?
Gene mutations by frameshift or stop codon
107
What is the cause of fish odor syndrome?
Excessive excretion of trimethylaminuria (TMA) in urine, sweat and breath
108
What is the prodrug used to check the activity of CYP2D6?
Debrisoquine
109
T/F: If you give a patient debrisoquine and there is marked hypotension, the phenotypic presentation is ultra rapid metabolism.
False
Poor metabolism!
110
What are drugs that can cause increased toxicity in ultra rapid metabolizers?
Codeine-narcotic and opioid
111
What are drugs with an extremely narrow therapeutic index?
Antiarrythmitics
Antidepressants
Antipsychotics
112
What are the two N-acetyltransferase isozymes?
NAT1 and NAT2
113
T/F: Filipinos are fast acetylators.
True
114
NAT2 allele polymorphism produces what phenotypes?
Rapid acetylator
Intermediate acetylator
Slow acetylator
115
T/F: Due to NAT2 polymorphism, there is a higher incidence and/or severity of adverse drug reactions to isoniazid, hydrazine, procainamide and sulfamethaxazole.
True
116
NAT2 activates and deactivates many of the (1) and (2) amine carcinogens.
(1) Aromatic
| (2) Heterocyclic
117
T/F: There is no association between acetylation polymorphism and urinary bladder & colorectal cancers.
False
There is!
118
Slow acetylators have an 8-fold higher risk of what compared to fast acetylators?
Cancer
119
Rapid acetylators are at increased risk of what from acetylation of heterocyclic amines found in cooked meats?
Colon cancer
120
Where has human NAT2 been localised?
Short arm of chromosome 8
121
What allele is associated with rapid acetylators?
NAT2*4
122
What alleles are associated with poor acetylators?
NAT2*5B, NAT2*6A and NAT2*14A
123
What complications does thiopurinemethyltransferase (TPMT) polymorphism cause?
Severe coma or depression after giving certain anti-cancer drugs
In AFL, patients may develop myosuppression
124
Patients with TPMT polymorphism will experience toxicity after administration of what?
6-mercaptopurine
125
T/F: TPMT is found in patients with acute lymphoblastic leukaemia.
True
126
With pharmacogenetics, we aim for (1) and (2).
(1) efficacy
| (2) safety
