principles of pharm final

Question 1

explain mechanism of rtk

Answer 1

1) hormone binds to extracellular domain = tyrosine kinase receptors dimerize
2) dimerize -> phosphorylates the C terminal tyrosine residues (active rtk)
3) intracellular signaling proteins are bound to it -> signal relayed by activated signaling proteins into the cell’s interior
4) adaptor protein attaches and has ras-activating protein attached
5) ras activating protein makes inactive ras protein + gdp -> active ras protein with gtp
6) the active ras protein continues transmitting signal
7) activates raf, mek, and erk = leads to changes in protein activity and gene expression

Question 2

what is an adaptor protein?

Answer 2

a protein which is accessory to main proteins in a signal transduction pathway
lacks intrinsic enzymatic activity, mediates specific protein-protein interaction

Question 3

? was is ras?

Answer 3

rat sarcoma protein
many tumor cells contain a mutant ras
function: activates protein kinase raf and PI3K (phosphatidylinositol 3 kinase

Question 4

? what is raf?

Answer 4

raf - rapidly accelerated fibrosarcoma
1st of the kinases that leads to activation of ERK and then transcription of specific genes

Question 5

know regulation of a Ras (a GTPase) activity

Answer 5

1) inactive ras -> GEF (guanine nucleotide exchange factor)
2) active ras -> downstream signaling
3) GAP (gtpase activating protein) induced gtp hydrolysis and ras inactivation

Question 6

cytokine superfamily receptors

Answer 6

• no catalytic domain
• interact withs non receptor protein tyrosine kinases to phosphorylate the receptor (no auto phos) ex: JAK (janus kinase)

Question 7

jak/stat pathway

Answer 7

• more immediate connection to transcription by directly affecting transcription factors
  (jak phosphorylates receptor and stat (only when stat is binded to receptor)

Question 8

know oncogene mechanism

Answer 8

reduce dependence on growth signals by: producing their own GF, overexpression of GF receptors, alterations to intracellular components of signaling pathways

Question 9

how ras mutations lead to cancer

Answer 9

-single point mutation in ras inhibits gtpase activity and prolongs active state
- mutations enhances rate of dissociation of bound gdp
= unregulated MAP cascade = inc cell proliferation

Question 10

rtks as drug targets (unsure)

Answer 10

1) growth factors (using antibodies)
2) soluble receptors
3) tyrosine kinase inhibitors
4) blockers of heat shock proteins
5) antagonists of specific signaling pathway proteins

Question 11

overall idea of rtk inhibition

Answer 11

inhibition of kinase signaling pathways will suppresses of the cell proliferation, differentation, survival, angiogenesis, stimulation of cell death = cancer treatment

Question 12

how does VEGF contribute to angiogenesis drugs

Answer 12

angiogenesis is mediated through vascular endothelial growth factor (VEGF)

Question 13

nuclear receptors are classified by location

Answer 13

1) in cytoplasm: steroid hormone receptors
2) nucleus: heterodimeric nuclear receptors

Question 14

difference between type 1 and type 2 steriod receptors

Answer 14

type 1: inactive receptor is in the CYTOPLASM w chaperone proteins, ligand activation leads to nuclear transolation, binds as homodimers to inverted repeat DNA half sites
type 2: inactive receptor is in NUCLEUS with repressor proteins, ligand LIBERATES receptor, binds as heterodimer with RXR to direct repeat

Question 15

mechanism of SHR (steroid hormone receptor)

Answer 15

when there is no ligand, SHR are bound to inhibitory (heat shock proteins) which keeps receptor in the cytoplasm
1) ligand binds -> hsps are released
2) once @ nuclear level, the ligand/receptor complex binds unique DNA sequences called hormone response elements, at the gene promotor
3) -> recruits co-activators or co-repressors = can facilitate or inhibit transcription process
mechanisms involve methylation, acetylation, or phosphorylation of histone proteins or dna

Question 16

steroid hormone receptor regulation

Answer 16

1) histone deacetylases -> represses gene expression
2) histone acetyltransferases -> inc gene expression

Question 17

classical mode moa

Answer 17

estrogen binds and
activates intracellular estrogen
receptors (ERα, ERβ) -> dimerize in the
nucleus -> bind to estrogen-response
elements in the promoters of target
genes -> regulate transcription

Question 18

indirect regulation of gene expression moa

Answer 18

interaction of ligand-bound ERs with other TF

Question 19

binding to membrane receptors ERs or GPR30

Answer 19

and activation of protein kinase cascafes or alterations via 2nd messengers -> by membrane ers: activation of transcription factors that regulate gene expression or -> by GPR30s: rapid non genomics effects (activation of specific enzymes)

Question 20

ligand- independent manner

Answer 20

ERs are activated and regulate gene expression through phosphorylation in response to GF binding to their membrance receptors

Question 21

non steroid hormone receptors

Answer 21

are located in the nucleus and under basal state are bound to DNA and are not active bc they are linked to a co-repressor RXR molecule

Question 22

mech of thyroid receptors

Answer 22

in absence of thyroid hormones, TX-RXR heterodimer associates with a corepressor complex -> binds to a promoter regions of DNA = inhibits gene expression
in presence of TH, corepressor complex dissociates from TR:RXR heterodimer -> coactivators get recruited = gene transcription occurs

Question 23

selective receptor modulators SRMS

Answer 23

nuclear receptor ligand, are compounds that exert agonistic as well as antagonistic actions in a tissue selective manner

Question 24

SERMS selective estrogen receptor modulators

Answer 24

compounds that exert estrogenic as well as anti-estrogenic actions in a tissue selective manner
unique PharmaKinetics properties bc its selective

Question 25

mech of SERMs

Answer 25

depending on serm binding, it has a unique conformation which can recruit activators or repressors (depending on what’s available in the tissue)

Question 26

know diff between pharmaceutical, pharmacokinetics, and pharmacodynamics

Answer 26

Pharmaceutical Interactions occur prior to systemic administration.
These interactions can be physical (e.g. with a visible precipitate) or chemical
with no visible sign of a problem
Pharmacokinetics involve the effect of a drug on another drug kinetic that
includes absorption, distribution, metabolism, and excretion.
Pharmacodynamics are related to the pharmacological activity of the
interacting drugs
Examples: synergism , antagonism, additive interactions

Question 27

how does gi ph contribute to DDI

Answer 27

• The non-ionized form of a drug is more lipid soluble and more readily
  absorbed from GIT than the ionized form does.
• Some drugs are absorbed from stomach (acid medium), so when this
  medium becomes neutral or alkaline, this will affect the absorption of drug

Question 28

how does altered intestinal bacterial flora contribute to DDI

Answer 28

long term abx can kill normal flora and affect drug absorption

Question 29

formulation of insoluble complexes and ddi

Answer 29

rx interact w complexation or chelation = makes complex unabsorpable

Question 30

drug induced mucosal damage and ddi

Answer 30

some drugs induce GI mucosal injuries = inhibition of absoprtion

Question 31

altered motility and di

Answer 31

some drugs inc peristalsis and dec time of absorption and absorbed amount
or it can inc gastric emptying -> inc drug absorption -> inc toxicity

Question 32

distribution interaction

Answer 32

primarily due to displacement of one drug from its binding sites on plasma proteins by another drug
The drug which is in unbound form is active while portion which is in
bound form works as temporary storage