med chem part 7 Flashcards
what is capsaicin
in cayenne peppers (0.02%)
another name for cayenne pepper = capsicum
as an analgesic effect in RA patients
how is capsaicin used as an analgesic in RA patients
topical application reduces neuropeptide SUBSTANCE P from local sensory (C-type) nerve fibers
reduces transmission of pain to the CNS by inhibiting nociceptor
____ is an extremely pungent phenol
capsaicin
Osteoarthritis is characterized by the erosion of….
articular cartilage
the conventional treatment of RA consists of what 3 classes of drugs
NSAIDS
corticosteroids
SYSADOA (Symptomatic slow acting drugs for osteoarthritis)
what are osteophytes
bony spurs on the edge of bone that grow in osteoarthritis patients
what is an important component that maintains cartilage strength
prostaglandins
name 2 osteoarthritis treatments that work by increasing the production of prostaglandins
glucosamine sulfate
chondroitin sulfate
what is hyaluronate sodium used to treat
osteoarthritis
what is the structural distinction between chondroitin sulfate and hylauronate sodium
it is a glycosaminoglycan, but NON-SULFATED
name some MOAs of hyaluronate sodium that make it useful to treat osteoarthritis
increases flow of joint fluid
inhibits hyaluronate degredation
reduce joint pain and improve function
normalize endogenous hyaluronate synthesis
restores elasticity of synovial fluid
what is atopic dermatitis?
it is predominantly mediated by what?
chronic inflammatory skin disease
primarily mediated by helper T cells
what is another name for atopic dermatitis
eczema
explain what the skin looks like in a patient with atopic dermatitis
dry with red scaly patches and very itchy
what is a virulence factor for atopic dermatitis
staph aureus
what is treatment for atopic dermatitis aimed at?
limiting itchiness, inflammation, further skin thickening
remove the scaly lesions, prevent/control skin infection
in AD, there is increased ________ production
cytokine
the increased cytokine production in AD causes what 3 things to happen?
what do all these 3 things ultimately lead to?
loss of skin barrier
itch-scratch cycle
increased chance of skin infection
ultimately leads to skin lesions
explain the pathogenesis of atopic dermatitis
allergens get into the skin due to mechanical injury
dendritic cells recognize the allergen as foreign and present to helper T cells
they then activate B cells (who came to site of infection by chemokines and cytokines), who produce IGE antibodies to the allergen, resulting in allergic dermal and epidermal inflammation
the impaired barrier opnes the door for antimicrobial peptides and staph aureues
what is first line treatment for pruritis (itching) in atopic dermatitis
1st generation antihistamine
what is the treatment to treat INFLAMMATION in atopic dermatitis
systemic and topical corticosteroids
name 4 classes of drugs used in atopic dermatitis that are used to prevent flare ups and help the skin repair
TCIs (topical calcineurin inhibitors)
Topical PDE4 inhibitor
IL-4 receptor a targeted monoclonal antibody
JAK inhibitors
as mentioned, TCIS (topical calcineurin inhibitors) are used to prevent flare ups and help the skin repair
name 2 of them
tacrolimus
pimecrolimus
as mentioned, topical PDE4 inhibitors can be used to prevent flare ups and help the skin repair
give an example
crisaborole
as mentioned, there is an IL-4 receptor monocolonal antibody that can be used to prevent flare ups and help the skin repair
what is the name
dupilumab
name 3 JAK inhibitors used to prevent flare ups and help the skin repair in AD
Abrocitinib
Upadacitinib
Baricitinib
name the 5 minium requirements for glucocorticoid receptor binding
double bond between carbons 4 and 5
ketone at 3
beta hydroxy at 11
alpha hydroxy at 17
hydroxy at 21
what is the LEAST potent topical steroid
hydrocortisone
is mineralocorticoid activity desirable?
NO - lot of unwanted side effects like sodium and water retention
what is the name for a 21 carbon steroid?
name a 21 carbon steroid
pregnane
hydrocortisone
what are the rings in a steroid
3 6-membered rings and 1 5-membered ring
____ isomers project above the plane of the steroid nucleus
BETA
Name 4 changes that can be done to hydrocortisone to change the activity, and the results of each
- adding = at C1 increases gluco. activity and decreases mineral. activity and inc metabolic stability
- adding hydroxyl at C16 increaes GC activity, and decreased MC activity
ISSUE - too hydrophilic and wont penetrate skin well (triamcinolone) change to methyl to fix this (dexamethasone and betamethasone) - Halogen (Cl or F) at C6 inc metabolic stability, dec MC inc GC
- Halogen at C9 inc Metabolic stability, dec mc inc gc
hydrocortisone is class ____ corticosteroid
7, meaning its not very potent
adding a halogen at C21 does what?
increased GC activity
esterification at C17 or C21 hydroxyl does what?
MAKES IT A PRODRUG
more lipophilic so more easily absorbed into the skin
however, it will be cleaved upon hydrolysis and the original OH will be exposed at the site of action. GC activity is maintained
as mentioned, esterifying the C17 hydroxyl can increase potency
how can the duration of action be maintained for longer? what is the name of this drug?
the esterified C17 can be easily hydrolyzed by esterases
however, replacing C21 OH with Cl can prolong the action of this ester by increasing metabolic stability
an example of this is clobetasol propionate
which is a stronger glucocorticoid and why - hydrocortisone or cortisone
HYDROCORTISONE
cortisone has a keto group at position 11 rather than an alcohol
an alcohol at that position is essential for Glucocorticoid activity
true or false
cortisone and hydrocortisone are biochemically interchangeable
true
all cyclohexane rings of a steroid are in what conformation
chair
through which enzyme can cortisone and hydrocortisone be interconverted
11 beta hydroxy steroid dehydrogenase
TRUE OR FALSE
more water soluble steroids are preferred for dermatological applications
FALSE - more lipid
is absorbed better
differentiate between triamcinolone vs triamcinolone acetonide vs fluocinolone acetonide
(in terms of structure)
triamcinolone acetonide is the same as triamcinolone but with an acetonide between C16 and C17
fluocinolone acetonide is the same as triamcinolone acetonide but with an alpha fluorine at position 6
what is amcinonide and which steroid is it derived from
21-acetate with additional cyclopentane ring
derived from triamcinoline
true or false
amcinomide is a prodrug
TRUE
must undergo hydrolysis to 21-OH
just by looking at the name, how can you differentiate between dexamethasone and dexamethoasone acetate
they’re the same, dex acetate just has 21-acetate
just by looking at the name, how can you differentiate between dexamethasone and desoximetasone
same, desoxy just has 17a OH group taken off
how can you differentiate between betamethasone and betamethasone dipropionate
2 positions on betamethasone were esterified with propionic acid (17 and 21)
differentiate between betamethasone dipropionate and beclomethasone dipropionate
same, beCLO just has a chlorine added at 9 alpha
what is the purpose of adding a halogen at carbon 21? name 2 steroids that have this
increases the metabolic stability of the ester at 17 position
clobetasol propionate and halobetasol propionate
explain the structure of clobetasol propionate by looking at the name
chlorine group (at 21)
1 propionate ester (carbon 17)
purpose of chlorine 21 is to increase metabolic stability of the ester at 17
by looking at the name, explain the structure of halobetasol propionate
1 propionate ester (17)
chlorine at 21 (increased ester stability)
fluorine at 6a
which is more lipophilic and why - acetic acid esters or propionic acid esters
propionic because they have 3 carbons instead of 2
why is amcinonide more potent than triamcinolone
polar groups are hidden by acetonide/cyclopentane
enhances the skin permeability.
undergoes hydrolysis to expose OH’s again
why is fluocinolone acetonide more potent than triamcinolone acetonide
has a fluorine at position 6 to increase glucocorticoid activity
why is clobetasol propionate more potent than betamethasone dipropionate
has chlorine at position 21 to enhance the metabolic stability of the C17 ester
chlorine also adds lipophilicity and glucocorticoid activity
name 3 MOAS of corticosteroids
inhibits PLA2 VIA LIPOCORTIN
down regulate inflammatory cytokines like IL-1, IL-6, and TNFa (genomic)
produce anti inflammatory proteins in cytosol (nongenomic)
which MOA of corticosteroids happens faster - nongenomic activation or genomic activation?
nongenomic — does not have to cross nucleus and bind – happens in cytoplasm
explain the genomic mechanism of corticosteroids
steroid is highly lipophilic and easily crosses the cell membrane
in the cytoplasm, it binds to glucocorticoid receptor with the help of heat shock proteins (chaperones).
this complex is transported to the nucleus where it dimerizes and binds to a sequence on DNA, mRNA is produced, and antiinflammatory proteins are transcribed such as Lipocortin (PLA2 inhibitor)
also suppresses the transcription of genes responsible for inflammation. cytokines not produced as much
what is the kind of DNA sequence that glucocorticoid-glucocorticoid receptor bind to?
palindromic sequence
true or false
glucocorticoids cannot permeate through the membrane
false - they can
lipophilic
true or false
steroids are more potent anti inflammatories than NSAIDS
TRUE
block synthesis of both PGS and leukotrienes
