Block 8 Flashcards by Kate Ball

what is a SNP?

a common (1% or more) substitution of 1 nucleotide in a DNA sequence; the most common type of mutation that causes PGx responses

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Which penicillin is the “anti-pseudomonal” penicillin?

Piperacillin (carbenicillin and ticarcillin aren’t available in the US anymore)

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A repeat of a gene sequence or, in some cases, the whole gene

duplication

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A mutation that results in the insertion of a different amino acid in the peptide chain

missense

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What is the result of salt formation with inorganic bases (KOH) with penicillin?

Enhances water solubility (used for IV injections)

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Identify whether the following would decrease efficacy or increase toxicity.

Increased activity of efflux transporters

Decrease efficacy

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the organization that publishes guidelines that enable a translation of genetic laboratory results into actionable prescribing decisions for specific drugs.

CPIC

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Interindividual variation in drug response is due to a difference in genetic makeup of the individual who is taking the drug

Pharmacogenomic response

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What are the clinical uses of Penicillin G?

LAST MAN

L - Leptospira

A - Actinomyces

S - Streptococcus/Staphylococcus (not MRSA)

T - Treponema

MAN - Meningitis

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Identify whether the following would decrease efficacy or increase toxicity.

Increased activity of drug targets

Increase toxicity

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Which penicillins have broad-spectrum activity? How was that achieved?

Hydrophilic groups in the side chain increase G- activity, so NH₂, OH, and COOH can be placed on the alpha-carbon next to the carbonyl to provide the greatest G- activity

PCAT

P - Piperacillin

C - Carbenicillin

A - Amoxicillin & Ampicillin

T - Ticarcillin

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Identify whether the following would decrease efficacy or increase toxicity.

Reduced activity of enzymes that activate prodrugs

Decreased efficacy

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rs stands for ________. The numbers are generated by ________ along with ________.

Reference Sequence

the numbers are generated by NCBI (national center for biotechnology information) along with NHGRI (National human genome research institute)

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A genetic change that is “common”, defined as being observed in 1% of the population or more

Polymorphism

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A unique identification number given to a reported mutation

rs number

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Which drugs are broad-spectrum penicillins? What generations are they?

2nd - Ampicillin, Amoxicillin

3rd - Carbenicililn, Ticarcillin

4th - Piperacillin

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Which penicillins are orally active and how were they made that way?

The R group of the aryl side chain is modified with an electron withdrawing group

VODKA

V - Penicillin V

O - Oxacillin

D - Dicloxacillin

K - Cloxacillin

A - Amoxicillin/Ampicillin

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How can penicillins be made beta-lactamase resistant? Which ones ARE resistant?

insertion of a bulky group to the aryl side chain provides steric hindrance, preventing the drug from fitting into the active site

CONDEMN

C - Cloxacillin

O - Oxacillin

N - Nafcillin

D - Dicloxacillin

M - Methicillin

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Identify whether the following would decrease efficacy or increase toxicity.

Decreased activity of influx transporters.

Decrease efficacy

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a state of heterozygosity at 2 or more different mutation sites

Complex Heterozygote

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Compare and contrast ampicillin and amoxicillin. What is their spectrum of activity?

Amp - oral or IV; oral availability is 40-50%; used in shigella infections, has a higher risk of causing diarrhea

Amox - only oral; 80% orally available; not used in shigella infections

HELPS Slaughter Enterococcus
H. influenza, E. coli, Listeria, P mirabilis, Salmonella, Shigella, Enterococcus

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a ______ influence means that the genetic variant is the single cause of the variation in response.

causative

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Salt formation at the C2 carboxyl of penicillins (with organic bases) results in what?

Insoluble drugs with long durations of action (used for IM injections)

An association whose mission is to catalyze and lead research in precision medicine for the discovery and translation of genomic variation influencing therapeutic and adverse drug effects

PGRN

What variation leads to different penicillin analogs?

Variation of the acyl side chain

Identify whether the following would decrease efficacy or increase toxicity. Increased activity of influx transporters

Increase toxicity

a mutation that results in the insertion of a stop codon in the peptide chain

nonsense

The study of genetic influences on interindividual variation in drug response

Pharmacogenomics

What are the limitations of penicillin G?

- orally inactive - short duration of action due to rapid renal excretion - narrow spectrum of activity (G+ only) - sensitive to beta-lactamase

The study of the entire set of gene transcripts in an organism

Transcriptomics

a small insertion or deletion of a single or a few nucleotides (usually -5)

indel

Nomenclature for variants of CYP450 genes was established by

Human Cytochrome P450 Allele Nomenclature Committee

The general term for a permanent change in a DNA sequence in a population

mutation

Identify whether the following would decrease efficacy or increase toxicity. Reduced activity of enzymes that metabolize or clear drugs.

increase toxicity

Which drugs are included in beta-lactam antibiotics?

Penicillins Cephalosporins Carbapenems Monobactams Clavams

The percentage of people with a mutation who express the associated outcome

penetrance

A kind of study that examines millions of mutation sites across an entire genome looking for differences in cases and controls

GWAS

Define the MOA of beta-lactam antibiotics.

The penicillins and cephalosporins fit into the active site of transpeptidase because they mimic the enzyme's substrate (D-ala-D-ala)

Identify whether the following would decrease efficacy or increase toxicity. Reduced activity of drug targets.

Decrease efficacy

What is the most common cause of resistance to beta-lactam antibiotics?

Beta-Lactamase enzyme (cleaves the ring and inactivates it)

a type of duplication or deletion mutation in which the variation is a difference in the normal number of times a DNA sequence is repeated and this difference is associated with diseases, disorders, or PGx responses

CNV (copy number variation)

the study of the entire set of DNA in an organism

Genomics

The cross linking in bacterial cell walls is catalyzed by which enzyme?

bacterial transpeptidase aka penicillin binding protein (PBP) (it is a serine protease)

A pharmacogenomics knowledge base that encompasses clinical information including dosing guidelines and drug labels, potentially clinically actionable gene-drug associations, and genotype-phenotype relationships.

PharmGKB

a mutation that does not change the amino acid sequence in the peptide chain

synonymous

a ______ influence means there is another cause for the variable response, but the mutation adds to the response.

modifying altering factors such as severity, time to onset, and duration of the response are examples

a mutation that changes the amino acid sequence in a peptide chain, either by insertion of a different amino acid or insertion of a stop codon

non-synonymous

Define the mechanism of MRSA resistance.

The presence of the "mec" gene is responsible for resistance - the mec gene encodes for an altered PBP (to PBP2a). PBP2a has lower affinity for beta-lactamase antibiotics

list some beta-lactamase inhibitors.

CAST C - clavulanic acid A - Avibactam S - Salbactam T - Tazobactam

An uncommon (\<1%) substitution of 1 nucleotide in a DNA sequence

SNV (single nucleotide variation)

Which penicillins are anti-staphylococcal?

COND C - Cloxacillin O - Oxacillin N - Nafcillin D - Dicloxacillin

Identify whether the following would decrease efficacy or increase toxicity. Decreased activity of efflux transporters.

Increase toxicity

Gene names are established by the

HGNC - HUGO Gene Nomenclature Committee HUGE = Human Genome Orgnization

What is the purpose of beta-lactamase inhibitors and when are they used?

- have no antibacterial activity themselves, but they possess a beta-lactam ring when used in combination with antibiotics, beta-lactamase will target the inhibitors instead so that broad-spectrum beta-lactams will be able to overcome plasmid mediated beta-lactamase resistance

PGx responses are categorized as affecting _____ or \_\_\_\_\_

efficacy or toxicity