med chem part 7 Flashcards by amanda kastel

what is capsaicin

in cayenne peppers (0.02%)

another name for cayenne pepper = capsicum

as an analgesic effect in RA patients

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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

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____ is an extremely pungent phenol

capsaicin

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Osteoarthritis is characterized by the erosion of….

articular cartilage

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the conventional treatment of RA consists of what 3 classes of drugs

NSAIDS
corticosteroids
SYSADOA (Symptomatic slow acting drugs for osteoarthritis)

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what are osteophytes

bony spurs on the edge of bone that grow in osteoarthritis patients

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what is an important component that maintains cartilage strength

prostaglandins

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name 2 osteoarthritis treatments that work by increasing the production of prostaglandins

glucosamine sulfate
chondroitin sulfate

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what is hyaluronate sodium used to treat

osteoarthritis

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what is the structural distinction between chondroitin sulfate and hylauronate sodium

it is a glycosaminoglycan, but NON-SULFATED

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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

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what is atopic dermatitis?

it is predominantly mediated by what?

chronic inflammatory skin disease

primarily mediated by helper T cells

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what is another name for atopic dermatitis

eczema

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explain what the skin looks like in a patient with atopic dermatitis

dry with red scaly patches and very itchy

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what is a virulence factor for atopic dermatitis

staph aureus

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what is treatment for atopic dermatitis aimed at?

limiting itchiness, inflammation, further skin thickening

remove the scaly lesions, prevent/control skin infection

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in AD, there is increased ________ production

cytokine

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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

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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

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what is first line treatment for pruritis (itching) in atopic dermatitis

1st generation antihistamine

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what is the treatment to treat INFLAMMATION in atopic dermatitis

systemic and topical corticosteroids

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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

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as mentioned, TCIS (topical calcineurin inhibitors) are used to prevent flare ups and help the skin repair

name 2 of them

tacrolimus
pimecrolimus

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as mentioned, topical PDE4 inhibitors can be used to prevent flare ups and help the skin repair

give an example

crisaborole

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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

1. adding = at C1 increases gluco. activity and decreases mineral. activity and inc metabolic stability 2. 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) 3. Halogen (Cl or F) at C6 inc metabolic stability, dec MC inc GC 4. 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