PS400 exam 3 Flashcards
for ph profile, when is the max stability of a drug?
at pka, drug segregation rate is lowest
formulate ate aka or a little above
what is best selling drugs for the years:
2012-2020
2021-23
23-24
24
humira (anti TNF a antibody)
cominrnaty (covide 19 mrna)
keytrude (anti PD1)
ozemspic & Wegovy
what are features of small molecule drugs?
low MW
organic or chemical synthhesis
fewer steps
well characterized
known structure
homogenous
not immunogenic
what are properties of biologics?
high MW
made w/ live cells or organisms
critical steps
less easily characterized
may or may not be defined
heterogenous
immunogenic
what can cause precipitation in plasma products?
ethanol, salt, pH, temp, centrifuge
what are peptide products?
calcitonin
oxytocin
vasopressin
what is the general mechanism of peptide production?
deprotection of chains
coupling of growing chain with new aa
cleavage of peptide chain
on a large scale, produced by recombinant DNA technology
why are protein therapeutics more complicated than small molecule therapeutics??
large and more complex
how are protein therapeutics produced?
recombinant by living organisms
challenging to characterize, require many analytical methods
what is affect of protein therapeutics for immunogenicity and why?
potential for immunogenicity, due to endotoxins
what happened during hGh testing??
developing fevers due to endotoxins
they must be removed by methods including ion-exchange chromatography
what is primary, secondary, and tertiary and quaternary structure?
primary: sequence of a chain
secondary: local folding of polypeptide into helices or sheets
tertiary: 3d folding pattern of protein
quaternary: protein consisting more than one amino acid
what is the process of endotoxin removal?
ion exchange chromatography
mix aa–>
binding of negative aa with cations to immobilize–>
separation of negative charged aa
how are protein therapies produced??
isolate gene of interest
introduce gene into an expression vector
transform/ transfect vector into host cells
grow cells
isolation and purify protein from cells
formulate protein product
what is the general structure of antibodies?
4 polypeptide chains connected by disulfide bonds between cysteine residues
2 heavy: Fab
2 light: fc
how do Herceptin antibodies work?
immune cells targeting cancerous cells bound by Herceptin
dimersed HER2 receptors signal tumor cells to proliferate
what does Herceptin do?
binds to HER2 tumor cells and flag them for destruction by immune system
blods downstream HER2 signaling to inhibit proliferation
how does neonatal Fc receptor recycling work?
FcRn binds IgG in acidified endosome
sorting of complexes
some are recycled and IgG disassociate at physiological pH
OR
non receptor proteins are degraded in lysosome
how does ADCC and CDC work?
ADCC:
-antibodies bind antigens
-NK cells recognize cell bound antibodies
-cross linking degranulation into lytic synapse
-die via apoptosis
CDC:
same process except for step 2
recruits complementary proteins that form membrane attack complex
what are the 5 classes of antibodies?
IgM
igA
igD
igG
igE
what is the most common subclass of IgG?
IgG1 and IgG2 & 4 r common
what is fucosylations?
what does it do?
adding focose sugar units to a molecule
on Fc domain of antibody adds bulk–> weakens binding to Fc-y receptors for ADCC
what is deamination degradation pathways?
what is rate affected by?
Asn & Gln
faster for Asn than Gln
N+1 residue (asn-gly is fastest)
reduces potency and leads to aggregation
what is the process for oxidation?
what is it caused by?
what happens to trp?
when does it occur faster?
met, trp, cys
caused by chemical reagents (excitants,surfactant ) UV light
oxidation of trp by light can become yellow
reduces potency and less to aggregation
occurs faster at higher temp
what are two other protein degradation pathways?
peptide bonde hydrolysis (asp-pro)
glycation (lys)
what is disulfide reshuffling:
between what residues
occurs at what ph
what is it faster than
between cys residues
occurs at high pH
faster than formation or reduction of disulfide
when is aggregation favored and when can it occur?
at pH near isoelectir point of protein & when protein is shake a lot
during freezing
stressors : what happens to water in cyro concentration? to protein? what happens to osmolarity?
what causes unfolding?
water freezes first and interacts with itself bc of hydrophobic interactions
protein concentrating and can aggregate due to increased interactions
increase osm
interacts between ice surface & protein can lead to unfolding
freeze drying proteins:
what is lyophilization?
freezing a protein solution to form ice
then by sublimation from solid phase to gas phase
lyophilize products are more stable
what are barriers to protein and peptide delivery?
poor bioavailability due to acidic environment in the stomach & presence of protein degrading enzymes
rapid elimination in circulation due to protein degrading enzymes in blood & renal elimination
immogenicity due to immune system developing anti drug (ADA) against drug, which eliminate drug from circulation
what was developed to tackle immongenicity, rapid elimination and poor bioavailability?
nanomedicne, but not always effective
peptide delivery: lipidatioin
what is chain covalently & non covalently attached to?
how does it increase half life?
what does it form?
lipid chain is covalently attached to to peptide
noncovalently with albumin
statically hindering proteolytic enzymes from interacting with the peptide by binding to albumin & enabling FcRN recycling
increases size–> reducing kidney filtration
micelles at injection site sustaining release & slowing absorption
peptide delivery strategies:
PLGA formulation
what can be altered to control drug release?
what does it do in the kidney?
size, porosity, polydispesity, shape, surface,
increases size–> reducing kidney filtration
peptide delivery strategy:
PEGylation
what Chains attach to peptide
how does it increase half life and reduce kidney filtration?
hydrophilic polymer attaches (inc solubility)
sterilely hindering protelyic enzymes from interaticing w peptide
increase size, red kidney filtration
peptide delivery strategies:
fusion proteins
what does Fc & albumin fusion attach to ?
how does it inc half life and reduct kidney filtration?
attach FC domain to peptide,
albumin fusions attach albumin
steriacally hinders proteolytic enzymes from intreating w the peptide & enables FcRN recycling
increase size red kidney filtration
what does PEGylation and fusion proteins affect?
pharmacokinets and pharmacodynamics
what is GLP1?
why is it rapidly eliminated?
involved in triggering insulin secretion
for type 2 diabetes
renal clearance and metabolism by dipeptidyl peptidase 4
what are strategies to extend half life of GLP1?
change aa sequence to reduce Dpp4 cleavage
lipid attachment: lira & semaglutide
albumin
Fc fusion
PLGA
implant
oral
inhaled
what can acid drug formulated as?
delayed release
hard gelatin capsule
methcrylic acid copolymer C coated
what increase the rate of drug dissolution?
increase SA
increase conc gradient
increase drug solubeining
increase volume of dissolution media
what will increase rate constant of bimolecular elementary reaction?
increasing ionic strength when reacts are similarity charged
increasing temp
increasing dielectric constant when reactant are similar charged
ln (a) vs t plot for first order reaction aAND 1/(a) for a second order reaction have what type of lines?
straight line plots
the half life of firs oder reaction is ind of?
initial concentration of reactant
the time taken for 10% of the reactant to be consumed in first order reaction is given by?
.105/k, where k is rate constant
