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92 Cards in this Set
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theraputic index
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TD or lethal dose 50/ED50
low TD -> bcare with the dose can killl |
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Types of dose response
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quantal - you wither have reposne or not
graded: graded respons |
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how to dtermine potency?
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look at 50% of man efficacy
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three different clases of antagosts
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competitive: can achieve max efficay with more agonist
noncompetive anatgonist: dec in max resposne irreversible antagonists: found out about spare receptors |
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Kd
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dissociation constant: measure of affinity of drug binding to recpetor
lower Kd -> greater the affinity |
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two main theories of receptor activation
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receptor occuapncy theroy: receptor only activated when agonist bound
two state model: recetors spont shifts bac and forth form inactive and active when receptor in activated state -> constitutive activity |
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agonist, antagonist, inverse agonist - preference for binding to active or inactive receptors
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agonist and partial agonis - only active
antagonist - equal preference for activte and inactive inverse agonist: pref for inactive state |
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cont or repeated use of antogonist
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receptor desensitizaton or tachyphyxis
get decrease in agonist affinity transient decrese in cell surface receptors - internalization of memebrane recptors or phosphorylation you see tolerance |
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long term adminstartio of agonist
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receptor down regulation
decarese in receptor number |
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long term effect of anragonists
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increase in receptor number - receptor upregulation
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receptor senssitization
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same dose gives you greter effect without a change in recpt number
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partition coefficient
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distributionof drug between lipid (oil) phase and an aqueous phase
increase partition coefficnet -> increase rate of entry into brain |
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What determines absoprtion of drugs?
bioavailability |
routes of administartaion
membrane penetartaoin |
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routes of administartaion
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parenteral
enteral - see 1st pass effect |
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membrane penetartion
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diffusion, facilitated diffucion(carrier mediated), active transport (carrier mediated), pinocytosis
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what deermines distribtuion to tissue
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protin binding
ion traping tissue barriers (BBB tight cellular junctions at the capillary-brain intersurface p-glycoprotein (ATP dependent) |
volume of distibtuion
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what dtermines elimination?
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metabolism, excretion
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half life is the concept
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Phase 1 metavolism enzymes
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CYP P450 (also to lesser degreee 3A4, 2C9, 1A2)
alcohol deydrogenase monoamine oxidasen esterase activity: esters to carboxylic acids jmj |
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bioavailabulity depends on
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route of administratin
metabolism (first pass effect) tissue barriers (absorption) |
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what does the first order kinetics lok like
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curbe with an alpha (distribution phase) and beta ohase (elimination phase- due to half life)d
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half life
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only for first order = .693/Ke
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when thinking about giving a dose to patient consider these 4 things
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clearence, volume of distribution, elimination half-life, bioavailability
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hyperplasia
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increased prliferation, cells still look how they are supposed to and reversible
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dysplasia
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after hyperplasia
morphological abnormalities - loss of normal architecture - but no invasion reversilbe |
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neoplsia
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point of no return: benigng (no invasion) - like carcinoma in situ- and malignant
but gorwing out of control remember mor emuttaions have to occur for it to metastize |
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carcinoma
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tumor of epithelial
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hallmarks of malignancy
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metasis and invasion
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what are the predicotrs of metastasis
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size, grade, mitotic rate
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grade
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diff vs undiff - histologically: more undiff it is -> cells look the same -> worst cancer
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what dtermines prognosis of cnacer/
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grade: histology
stage: how far it has spread - location - sentinel lymoh node the closest one |
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how do carcinmas spred by?
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lymphs
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sarcoma and how does it spread?
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mucle cells - blood vessels
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by knowing invasion and metastics what can you do?
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diagnosis, therapy and prognosis
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how can tumors spread?
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via direct seedinh
lymphatic spread hematogenous spread |
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steps for invasion or ebginnig of metastasis?
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muttaion in tumor suppressor gene that doesn't allow for apoptosis
detachment of tumor cells from one another orients cell in basal direction - Epithelial to Mesenchmal transition proteases to dossilve basement membrane and less protease in hibitors move thru ECM - active chemotaxis |
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active chemotaxis
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you secret something (autocrine dervied chemoatactic factors) and move towards it
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what are the reast of the steps for metastasis
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intravasation:entry into blood vessel or lymp
circulate via emboli - evade imune system attachement to endothelium at distant site: recognize specific adhesion molecues in endothelium extravasate - paget's seed hypothesis - attach at a distant site angiogenesis VEGF |
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what detemines metastassi?
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drainage and orgna specific homing
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dominant oncogenes
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autonomous function and cn drive the cell into division
thy are genes in a celll cycle that are always on |
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tumor suppresor gene or recessigve oncogen
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loss of function -> cancer
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what have RNA tumor virsuse identified for us?
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dominant oncognes - they hav to dow ith the cel cycle
they come form ceullar genes - btut when virus captured it -> ability to be cance rnow tells you what genes are good candiates for cancer |
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what are the celluar genes that viruss captured called?
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proto-oncogenes
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function of V-src
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encodes a pp60 protein - increased protein tyrosine kinase activity
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mechanism of RB
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mitogen stimualtes -> phosphorylaitn of restriction boundary ortiein -> disosciated from E2F-> transcrobed genes you need for G1/S trnasition
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v-erb
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similar to EGF but now it is a ligand-indenepnt tyrosine kinase
gain of fucntion - a domiannt oncogene |
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WHat is so speical of PDGF protein?
v-sis PDGF |
when ectopically expresed from an RN tumor -> dominant oncogene :
autocrine loop- coexpression of gorwh factor and its receptor |
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mechnism of epidermal gorwth factr
V- erb (EGFR) |
stimulates v-fos and v-jun downstream
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what is the mechanism of gorwth factor receptor?
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stimulted -> Ras -> v-fos jun
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how to activate PKA?
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stimulation -> G beta and agamma come and bind and then G alpha comes with GDP -> takes up GDP -> goes o andeunylates cyclease -> makes cAMP -> this goes and binds to regulatory subinuts and relases the catalytic subunit that goes to nuckeus and turns on transcription
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what is the Ras pahway?
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GF receptor stimulated -> dimerize -> tyrosine resideus phosphoryaked -> Grb2 binds with GNEF attached -> now Ras+GDP come sin -> GDP relased and GTP taken up -> goes to Ras and activates it -> rAs phosphoryates MAPKK -> phosphorlayes MAPK -> that goes to nuclues and phopshoylates tagregt transcription factors
GAP cleaves GTP and makes it inot GDP - turns it off |
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what is the problem with oncogenic RAS?
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can't bind GAP - so always turned on
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what does Ras simulate?
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RAF
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Adenylate cycles mediate pathway
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the cAMP -> relasd catalytic subunit -> goes and phopshoryales CREB
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what does Iressa do?
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EGFR tyrosine kinase inhibitor
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how to get melanoma?
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muttaion in bRAF
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what are some thng that contribute to cancer?
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single nucleotide/base pair mutations in
EGFR RAs Raf Gapha subnuit |
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significance of myc?
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dominant oncogen
causes burketts lymphoma translocation places an Ig promoter contorlling myc |
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what so special about cyclin D?
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overproduction via Ig promoter -> cancer
always phosportlating Rb -> E2F transcribes genes needed for cell cycle clyclin D on top of CDK4 |
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Philadepphia chromonse
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chr 9 and 22
CMLukemia -> BCR-ABL: BCR promoter is driving a chimeric protein with part of BCR and all of ABL |
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what does gleevac do?
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inhibits BCR_ABL tyrosine kinase
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how are oncognes acivatein human cancers?
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point mutattions, ranslocations (c-myc, BCR-ABLE) and aplification (HER2 - breast, myc)
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what hapens with loss of Rb control?
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target of Cdc4/cyclin D1 kinase -> loss of restrcition boundary growth control
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what does p53 do?
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it is a tumor suppressor
if you have damaged DNA -> stop diving and start reparing turns on CDKI -> now can't go through cell cycle |
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how can CDK e inactivated?
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via phosphorylaion on active site
via absecne of cyclin via CDKI |
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how to get colon cancer?
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either both MSH2 defective or both MLH1 defectivem
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significance of PTEN? mechanism?
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tumor suppressor
gvies you prostate and glioblostama mechanism: cel receptor -> factor binds to it -. PIP2 becomes PIP3 via PI3 kinase -> PIP3 goes and activates AKT (protein kinase) -> phophoyrlates mTOR -> goes and phosphioylates stuff needed for clel cycle PTEN converts PIP3 back to PIP2 - the switch |
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what happens with rapamycin?
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blocks mTOR -> stop survial and prliferationgj
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what are initiators
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geneotxic usually require metabolic activation via phase I usualy CYP450 if not -> direct acting (they are lakylating agenst- but they react with environemtn first so not to bad ) it is the compounds that are more stable with longer half lifes you have to worry about
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promoters and exmaples
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non-genotoxic
TPA mimics DAG and activate PKC -> 1. go thru Ras/Raf pathway -> stimulate Ap-1 dependent transcirtion 2. Nf-kappaB - but TPA has a long half life |
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complete carcinogens
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have both promoters and initators otgether
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examples of initiatros
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benozy a payren -> activated cy CYP1A1 -> epoxde -> binds to guanine resideu in DNA
alflatoxin B1 -> via CYP450 -> mutagenic epoxide |
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why are promoters so dnagerous?
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mimics endogenous ligans (TPA and DAG) but have a longer half lfie
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examples of prmoters
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TPA and dioxin:
dioxin makes more CYP1A1 -> so more benzo-a-pyrene can be metabolized |
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what is the epoxide form of benzo a pyrne called
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BPDE -> binds to guanine -> promotes a G to T transversio n
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what muttaions do carcinogens form?
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G to T, G to A, CC to T
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what does cucifeous vegetables have that helps with cancer
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glucosinolates
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2010
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2010: access for uninsured patients w/preexisting conditions (for children, or adults switching
plans) Patient Center Outcome Research Institute established: review what works & what doesn’t |
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2014
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2014: access for all, individual mandates (pay or play), undocumented still won’t be covered,
health insurance exchanges (able to barter), so EVERYONE is going for insurance (or else system will not work) |
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2018
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2018: high cost excise tax (against Cadillac plans)
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tissue repair
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formation of temp barier: hemostatis with fibrin clot formation -> scab
removal of dead tissue: inflamm; neutrophils then macs resotration of parenchymal integrity: fibroblast and blood vessel ingorwth - new connective tissue matrix laid down restoration of eptihelial integrity: regenration of epithelial surface |
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hemostatic plug first 24 hrs
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barrier formation, temp matrix - via fibrin, acute inflamm repossne - to take away the dead tissue
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granlation tissue
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macrphae angiogeneis and fibrogensis
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scar
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matrix remodeling, contraction, reduced vscularity
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hemostasis
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when blood tissue that it shouldn't -> triggers clotting via protease cascade -> factor Xa -> generated thrombin from prothromin -> makes fibrinogen -> fibrin
starts bringin in fibroblasts clotting set up to start to activate growth of cells |
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inflamm
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proteins and more protease cascade -> geenrated enzymes that breaks down fibrin (this is temp) , this is to take out dead tissue
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second pahse angiogenesis and fibrogenesis
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fibroblasa, macs, lays doewn collagen connective issue and brings in blood vessel -. created granulation tissue and starts process of eptiehrlial regenrating
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angiogenesis
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come ffrom a brahcing of exsiting cpapillary that is nearby - need to atarct cells that are capable of becoming blood vessels -> sprout -> new capillary
uses HIF (hypoxia inducing factor) - if damaged area this becomes low - other clels sense this -> trigger hypoxia recognition -> turns on VEGF |
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for proliferation, migration
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PGF EGF
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collagen synthesis
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TGF beta, PDGF
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myofibroblasts
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change to be able to contract scar
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undersirable ocnsequences
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let something heal and form fibrois bridge acorss koint -> contracture limited mobility
adhesions: dense connecive tissue scars that brdge serosal surface stricutre: replace normal esophgheal tissue wtith scar keloid and hypertrophic scar - excess of scarring |
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fibrosis
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stimulated by chronic inflamm
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