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phar24 > week 7 > Flashcards

week 7 Flashcards

1
Q

factors affecting individual drug response

A
  1. disease state
  2. genetic factor
  3. environment
  4. drug interaction
  5. diet
  6. weight
  7. gender
  8. age
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2
Q

define mutation

A

occur when the number or order of bases in a gene is disrupted

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3
Q

define polymorphism

A

a DNA sequence variation that is common more than 1% in the population

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4
Q

where does polymorphism begin from

A

an inherited mutation

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5
Q

4 types of mutations

A
  1. insertion
  2. deletion
  3. duplication
  4. inversion
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6
Q

define single nucleotide polymorphism

A

DNA sequence variation that occurs when a single nucleotide in the genome sequence is altered

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7
Q

two types of SNP classifications

A
  1. synonymous = results in same protein

2. non-synonymous = results in different protein

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8
Q

define wild protein

A

a protein that has the sequence that is found in the majority of the pop

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9
Q

4 types of individual variation in drug response = drug given based on genetic makeup = pharmacogenomics

A
  1. optimal responders = full benefits of the drug
  2. sub-optimal responders = adverse affect but still respond to drug
  3. non-responders = no response or adverse affect
  4. adverse reactions = only toxic/adverse affect
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10
Q

define pharmacogenomics

A

the study of how an individuals genetic inheritance affect the body’s response to drugs

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11
Q

goal of pharmacogenomics

A

right dose, right drug, for the right patient

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12
Q

define pharmacogenetics

A
  • subset of pharmacogenomics
  • targeted gene

= the study of how inherited variation affects drug response

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13
Q

polymorphism at receptor level: A118 opioid receptor & what it leads to

A
  • A to G substitution at nucleotide 118 = Asparagine –> aspartic acid amino acid change in the N-terminal domain of the mu-opioid receptor
  • leads to drug addiction, stress responsivity & in treatment responses, including dependence & pain reduction
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14
Q

polymorphism at enzyme target: VK epoxide reductase

A

warfin inhibits VKOR = reduce the synthesis of active clotting factors

the mutation - VKORC1 causes warfin resistance = carriers of this mutation require exceptionally high warfin dose to achieve effective anticoagulation = too much coagulation due to mutation

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15
Q

what is a highly polymorphic enzyme

A

CYP2D6 - from the cytochrome P450 enzyme family

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16
Q

drug example metabolised by CYP2D6

A

Nortriptyline - A tricyclic antidepressant

tamoxifen = selective estrogen receptor modulator for breast cancer

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17
Q

polymorphism in P-glycoprotein & example

A

affect the drug responses = affects drug disposition

example: 3435T polymorphism affects digoxin disposition = for treating various heart conditions

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18
Q

role of p-glycoprotein

A

a transporter that controls some drug absorption and entry into compartments (e.g. brain) or cells

SNPs identified:

  • gut, liver, kidney = pumps drugs out
  • brain endothelium = pumps drugs back into blood
  • large protein
19
Q

define biological drugs & example

A

= contain active substance derived from or extracted from biological system (often administrated as injection or infusion)

examples: protein, antibodies, oligonucleotides used as drugs

20
Q

define first-generation drugs

A

similar to hormones, not as new

21
Q

define second-generation drugs

A

modified

22
Q

application of biological drugs

A
  • therapeutic monoclonal antibodies
  • recombinant hormones
  • controlling gene expression
23
Q

what is the old way insulin & growth hormones (1st generation) were synthesised & the issues with it

A

purifying extracts to treat protein hormone deficiency

  • use to cause issues because body identifies it to not be theirs
  • transmission of diseases
24
Q

what is the new way insulin & growth hormones are synthesised

A

“genetic engineering” techniques

  1. insert human gene into suitable expression system
  2. harvest & purify the recombinant protein
25
Q

define plasmid

A

small, circular, double-stranded DNA molecule

26
Q

define protein expression system

A

refers to the type of living organism that is used to grow the desired protein

27
Q

example of common expression systems for recombinant biopharmaceuticals & the most used

A
  1. bacteria = more used
  2. yeast
  3. mammalian
28
Q

what does it mean to engineer a protein

A

alter the protein prior to expression by changing the gene sequence

29
Q

reasons for changing the structure of the recombinant protein x3

A
  1. modification of pharmacokinetic properties
  2. creation of novel fusion or other proteins
  3. reducing immunogenicity (humanising proteins) = less chance of causing disease
30
Q

examples of when PEGylation is added

A
  1. size increase reduces kidney filtration
  2. reduced accessibility for proteases & antibodies
  3. hydrophilicity of PEG increases drug solubility
31
Q

when proteins are engineered what generation are they

A

second generation

32
Q

what is the suffix of monoclonal antibodies

A

-MAB e.g., infliximab, omalimuab

33
Q

defie antibodies

A

large proteins produced by activated b cells (plasma cells) which are important cells for our immune system

34
Q

what are the three effects of antibodies binding

A
  1. neutralisation
  2. aggulation
  3. precipitation

= decrease effect = improve condition

35
Q

define epitope

A

the specific part of the antigen that binds to a specific antigen receptor on the surface of B cells

36
Q

how are monoclonal antibodies made

A
  1. mousse is injected with antigen (protein want to make antibodies against)
  2. spleen cells are extracted
  3. spleen cells fused by myeloma cells (live forever)
  4. hybridomas are made and the desired antibodies are extracted from those cells
    - they can be frozen and regrown and used
37
Q

pharmacokinetics of monoclonal antibodies

  • Vd
  • absorption
  • oral availability
  • specificity
  • elimination
A
  • large so difficult to cross membranes = decrease Vd & absorption
  • very low oral bioavailability due to low absorption & because they are proteins that can be digested in the stomach
  • high specificity = less off-target effect leading to less adverse affect
  • majority broken down into peptides & amino acids (intracellular catabolism)
  • endocytosis from receptor mediated degradation –> receptors in the cell surface bind to the antibody & internalise it, monoclonal receptor complex is then degraded in a lysosome

= renal impairment does not affect elimination of monoclonal antibodies

38
Q

comparisons between biologics (B) and conventional (C) drugs

A
  1. size = B larger
  2. synthesis
    = C identical & well-characterised (easy synthesis)
    = B unique = more complex & harder to characterise = harder to be reproduced
  3. relationship between dose & effect
    = C usually predictable relationship
    = B complex mechanisms of action (high affinity binding, slow on and off rates (take while to leave), unusual shape D/R curves
  4. pharmacokinetics
    = C oral administration, variable absorption & bioavailability, 2 phases metabolism, excretion of drug in urine or faeces
    = B parenteral administration (not through digestion), bioavailability high, long half-life, atypical biodistribution (large affinity so small amount = large affect) & removal mechanisms)
  5. toxicology & adverse effects

= C variable, possible drug interactions

= B immunogenicity (allergic reaction), few drug interactions, generally few adverse effects

39
Q

what has a longer half life: antibodies or plasma proteins

A

antibodies. specifically IgG (around 21 days) compared to IgA and IgM (around 6 days)

40
Q

define gene therapy

A

= the addition of genetic material to cells to precent. alleviate or cure disease

= use of oligonucleotides

41
Q

2 applications of gene therapy

A
  • cure diseases caused by single defective gene such as CFB
  • improvement of conditions with or without a genetic component, including malignant, neurodegenerative and infectious diseases
42
Q

role of antisense oligonucleotide in gene therapy

A

= binds complementary (“sense”) mRNA sequences & block translation

43
Q

administration of antisense oligonucleotide

A

parental administration widely distributed except CNS

44
Q

issue with gene therapy

A

delivery into the cells

  • viral vectors (should be safe, efficient, selective, produce a long lasting expression of therapeutic gene)

phar24 (12 decks)

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