Exam 3-Paracrine Flashcards
examples of paracrines
PGs TLs and histamine
main intermediate to the eicosanoids pathway
arachidonic acid
NSAIDs inhibit
COX1 and 2, also called PGH Synthase 1 and 2
Costricosteroids inhibit
COX 1 and 2 as well as phospholipase A2 (PLA2)
eicosanoid antagonists work to block
leukotrienes
prostanoids
PGs and TXA
uses for eicosanoids and analogs
limited by kinetics, natural forms not orally available, short systemic half life
eicosanoid drugs for abortion
dinoprostone (facilitate labor) carboprost (stop hemorrhage) misoprostol (prevent ulcers)
eicosanoid drugs for ED or ductus arteriosus
alprostadil
eicosanoid drugs for pulm htn
epoprostenol, treprostinil, iloprost
eicosanoid drugs for glaucoma
lantanprost, travoprost, bimaprost, unoprostone
eicosanoid drugs for constipation
lubiprostone (activates Cl channels in the intestine to increase fluid)
prostanoid synthesis: arachidonic acid makes
PGG2 and PGH2
PGH2 makes
proaggregants and antiaggregants
proaggregants
TXA2 works at TP receptor
PGE2 works at P1-4 receptor
prostanoid for glaucoma
PGF2alpha at the FP receptor
antiaggregants
PGI2 (prostacyclin) at IP receptor
PGD2 at DP1-2 receptor
15 deoxy at DP2 receptor
Overall eicosanoids do the following
contract uterine muscle
vasoconstrict (pp hem)
decrease IOP
hypertricosis
PGF2alpha analogs for glaucoma: latanoprost, travoprost, tafluprost, bimatroprost. MOA/SE
MOA: reduce IOP by increasing aqueous humor outflow via activation of FP receptors.
SE: eye irritation, melanogenesis, hypertrichosis.
EACH should be combined with timolol
PGE2 eicosanoids in general do the following
contract uterine muscle
inhibit gastric acid
tx ED
maintain patent ductus arteriosis
PGE2 eicosanoids in general have these SE
vasoconstrict or dilate
contract GI smooth muscle
decrease pain threshold
stimulate Bicarb
These delay onset of labor because they can inhibit uterine contraction
NSAIDS
Dinoprostone (PGE2)
Prepidil gel
Prostin E2 supp
Cervidil insert
inducing abortion, facilitate labor, fetal death, hydatidiform mole
MOA: contraction of uterine smooth muscle via EP1 or EP3.
SE: NVD, change in BP
carboprost (15 PGF20)
hemabate IM
induce abortion, pp hemorrhage.
MOA: contraction of uterine smooth muscle via FP receptors
SE: NVD, change in BP
misoprostol (PGE1)
cytotec PO
induce abortion, prevent NSAID induced ulcers
MOA: EP1 or EP3 increase mucus or decrease H
SE: NVD, change in BP
alprostadil (PGE1)
for ED
MOA: relaxes corpora cavernosa sm muscle and dilates arteries via EP2 or EP4 receptors
SE: pain or priapism
[can be injected with phentolamine (alpha1/2 antagonist) or papaverine (vasodilator)]
alprostadil (PGE1) for fetal circulation
maintains patent ductus arteriosus
MOA: replaces endogenous PGI2 which keeps ductus open via IP receptors
SE: apnea, brady, hypoTN, hyperpyrexia
(indomethacin used to tx delayed closure)
PGIs effects in general
vasodilation (pulm htn), inhibit plt aggregation
PGIs SE in general
vasodilation of vasculature, contract GI, decrease pain threshold
Epropostanol (Flolan) (prostacyclin analog)
for pulm HTN, given through central line, half life minutes
MOA: vasodilation via IP receptors
SE: NV, HA, hypoTN, flushing, inj pain, inf site infections
interaction: anti-hypertensives and anticoags
Treprostinil (Remodulin) (prostacyclin analog)
for pulm HTN, given through central line or SQ, half life hours.
MOA: vasodilation via IP receptors
SE: NV, HA, hypoTN, flushing, inj pain, inf site infections
interaction: anti-hypertensives and anticoags
Iloprost (ventavis TM) (prostacyclin analog)
for pulm HTN inhaled, half life 20-30min.
MOA: vasodilation via IP receptors
SE: NV, HA, hypoTN, flushing, inj pain, inf site infections
interaction: anti-hypertensives and anticoags
TXA2s in general
no useful effects for analog drugs but physiological effects include: vasoconstrict, contract bronch sm muscle, contract GI, contract non preg uterine muscle. NSAIDs and ASA help with decreased pain threshold and the plt aggregation
Leuko pathway: Zafirlukast and Montelukast inhibits
CysLT2 and CysLT1/2
Leuko pathway: zileuteon inhibits
5LOX
Leuko LTC4 and LTD4 (cysteinyl leuks) MOA
act at receptor CysLT1/2 and signal Gq pathway to increase Ca and cause airway smooth muscle contraction
Leuko LTB4
act at BLT1 receptor through Gi an G16 second messenger to increase Ca and stimulate immune cell attraction
reversal of bronchospasm
epi or short beta 2 agonists (albuterol and levalbuterol)
prevent bronchospasm
slow/long act beta 2
agonists (salmeterol and formoterol)
prevent bronchospasm anticholinergic
ipratropium bromide, ipratropium and albuterol
prevent bronchospasm xanthines
theophylline, dyphylline
prevent inflammation in asthma
corticosteriods: beclomethasone, fluticasone, budesonide
prevent of inflammation and bronchospasm in asthma: mast cell stabilizer
cromolyn, neocromodil
prevention of inflam and bronchospasm in asthma: LTC4/D4 blockers
zileuton, zafirlukast, montelukast
prevention of inflam and bronchospasm in asthma: IgE neutralizer
omalizumab
high camp
low Ca and relaxation
low camp
high Ca and contraction
Xanthines: theophylline, dyphylline
bronchospasm prophylaxis
MOA: inhibition of PDE
SE:anx, HA, NV, low bp, tachy, seiz, arrythmia-death.
interactions-(p450 inducers) dilantin and barbs increase clearance. (p450 inhibitors) cimetidine and erythromycin decrease clearance.
Mast Cell stabilizers: cromolyn anything
generally preferred in kids with asthma over corticosteroids.
MOA: blocks histamine and eicosanoid release by mast and basophils.
SE: bad taste, then very rare: bronchospasm, cough, edema, pain, HA, Nausea
Zileuton (zyflo)
leuk blocker for asthma prophylaxis. reversible inhibition of 5 lox.
SE: mild heptox
Interaction: theophylline and warfarin
Zarfirlukast (accolate)
leuk blocker for asthma prophylaxis. competitve antagonist of CysLT1 receptor.
Interaction: warfarin
Montelukast
comp antag of cystLT1 receptor. leuk blocker for asthma prophylaxis
Omalizumab (xolair)
for asthma prophylaxis. dose based on IgE levels-prevent from binding to its receptor. SE: rash, bleeding, GI events
COX
converts arachidonic acid to PGH2
COX 1 locations
GI, plt, kidney, CNS
COX 1 has what function
cytoprotection, aggregation, blood flow, pain and pyrexia
inhibit COX 1 would help with
ulcers, chemoprevention, drug interactions, analgesia, decrease fever
COX 2 locations
uterus, kidney, vasculature, inducible, CNS
COX 2 functions
contraction, increase blood flow, decrease aggregation (PGI2), pain, inflamm, pyrexia
COX 2 effects of inhibition
delay labor, MI or stroke, analgesia, decrease fever or decrease inflamm
COX 1 versus 2: NSAIDS
both
COX 1 versus 2: ASA
1
COX 1 versus 2: celcoxib
2
general NSAID interactions
protein bound
slowed elim by probenecid
slow elim of MTX and Li
lasix and thiazides decreased effects
ASA
chemoprevention. alone or with dipyridamole.
MOA: irreversible inhibition of COX1, also some COX2
interact: uriosurics
contraindications: sx, kids, hemophilia, heptox
Salicylates: sulfasalazine, olsalazine, mesalamine
for inflamm bowel disease
diflunisal (dolobid)
a salicylate for musculoskeletal strains and sprains or OA. SE: less GI and less anti plt than ASA
Propionic acids: ibuprofem naproxen, flurbiprofen, ketoprofen, fenoprofen, oxaprozin
NSAIDs
Indole and Indene Acetic Acids: indomethacin, sulindac
NSAID. most potent so higher risk for ulcers. Tx for delayed closure of ductus arteriosus, stop pre-term labor and symptoms of gout
Heteroaryl Acetic Acids: Tometin, Ketorlac, Diclofenac
NSAIDS. many formulations of diclofenac. anthrotec (diclofenac and misoprostol) a PGE1 drug and is antiulcer
Fenamates: Mefenamic acid and meclofenamate
NSAIDS. SE: diarrhea and hemolytic anemia, visual disturbance
Enolic acids: Meloxicam and piroxicam
mel-COX2 selective (antiulcer)
Alkanone: nabumetone(relafen)
NSAID
Pyranocarbox acid: etodolac
NSAID. COX2 selective (antiulcer)
Celecoxib
COX2 selective inhibitor. for arthritis or uncontrolled pain or FAP. MOA: inhibit COX2
SE: NSAID renal effects, risk of CV events
Interaction: same as NSAIDS plus metab by 2C9
contraindicated: NSAID or sulfa hypersensitivity, cardiac disease or CV risks
block COX2 and CV risk
increase risk for clot formation
Tylenol
analgesia, NO INFLAMM BENEFIT.
MOA:?
SE: heptox d/t cyp2E1 and 1A2 convertion to NAPQI
interact: etoh, imatinib, isoniazid and rifampin upreg liver enz, tobacco.
DMARDS
slow damage, more toxic than NSAID, slow onset
alternative therapies for arthritis
lovaza, capsaicin, sativex, glucosamine and chondroitin
DMARD immunosupp: MTX, lefludomide, azathioprine, cellcept, cyclosporine
MOA: inhibit enz to DNA synthesis or Tcell function, suppress DNA synthesis. SE: immunosupp, GI, heptox, CA. cyclosporin is nephrotox, hirsutism
contraind:ID, hep impairment, cyclo-inhibitos of 3A4
MTX (DMARD)
folate analog, inhibits AICA transformylase and thymidylate synthase. stops making DNA
Lefluomide (DMARD)
inhibits DHODH
Azathioprine (DMARD)
purine antagonist, converted to 6 thioguanine.
Cellcept (DMARD)
inhibits IMPDH/GMP/GDP/GTP production. more cell use alt pathway but T and B cells cannot
Anti-malarial DMARD: hydroxychloroquine (plaquenil)
MOA:? may involve inhibition of DNA/RNA synthesis.
SE: visual dist, allergic rxn, psoriasis, heme, CNS
Contraind: hypersensitive of ocular disease***
interact: inhibits 2D6, antacids, reduces MTX clearance.
Gold DMARD: aruanofin, aurothiomalate
MOA:?
SE:stomatitis, proteinuria, heme, aplastic anemia. auranofin-less efficatious and GI worse.
CAUTION-black box-heme or renal issues, stomatitis.
Penicillamine DMARD: cuprimine, depen
MOA?
SE: bone marrow supp, lung/hep/renal tox, skin rxn, GI, stomatitis
contraind:preg, breast feeding, renal
caution: bone marrow supp ***
interaction: gold, cytotoxic drugs, Al or Mg antacids or Fe supp.
Sulfasalazine DMARD
MOA: metab mesalamine and sulfapyridine by colon bacteria
SE:rash, GI, NV, heptox, orange yellow skin and urine, decreased male fertility
TNF blockers DMARDs: etanercept, infliximab, adalimumab, golimumab, certolizumab
MOA: antagonize TNF activity by binding TNF alpha
SE: inj site rxn, immunosupp, increase Ab form, HA, GI, rash, fatigue.
Caution: CA***
interact: immunosupp, vaccines and TNF/IL blockers
Interleukin blockers DMARDs:anakinra (kineret), tocilizumab (actemra)-IL6R, canakinumab (iaris)-IL1Beta
MOA: antagonize IL1R or IL6R receptors or binds IL1beta preventing interleuk mediated immune activation.
SE: inj site rxn, inf, decreased WBC/plt, GI.
Contraind:anakinra-ecoli or latex allergy
Caution: BB for toxilizumab (infection)***
interact:TNF/IL blockers, rituximab, abatacept
Tofacitib (xeljanz) DMARD
nib means its a signal transduction inhibitpr (STI) or kinase inhibitor. MOA: inhibits Janus kinase (JAK) proteins.
SE: myelosupp, URI, HA, diarrhea.
caution: don’t use with other biologic DMARDs
Rituximab (rituxan) DMARD
human/mouse Ab to CD20 protein, Ca channel reg cell cycle, diff in B cells
MOA: binds CD20, kills B cells.
SE: 1st inf rxn, pulm and CV efx, myelosupp
cautions: exfoliative derm **BB.
Abatacept (orencia) DMARD
used for failure of other DMARDs like MTX and anti-TNF drugs.
MOA: binds CD80/86 receptor preventing full act of T cells which are central in RA path.
SE: inf rxn, URI
interaction: TNF or IL blockers or other immunosupp, live virus vaccines
Glucocorticoids DMARDs:prednisone, prednisolone
MOA: decrease PLA2 and COX2 expression, decrease WBC count.
SE: limit long term use, frax, cataracts, cushing, DM, htn.
can give intraarticular
Capsaicin DMARD
mediator of hot sensation from chili peppers. MOA: depletes substance P and act TRPV1 channels. SE: burn, sting.
Gout drugs: colchicine
alkaloid from autumn crocus.
MOA: prevent polymerization of tubulin, inhibit cell migration and phagocyt of crystals.
SE:diarrhea, VN, alopecia, immunosupp, neuritis, myopathy.
OD tox: burning throat, bloody diarrhea, shoc, fatal ascending CNS depression
Uricosurics:probenecid and sulfinpyrazone
Gout drugs. MOA: inhibit reabs of uric acid in prox tube of kidney SE: GI irritation, rash, kidney stones Contraind:kidney stones interact: NSAIDs may decrease effects
Xanthine Oxidase Inhibitors: allopurinol and febuxostat
used in pts with very high urate, prior kidney stones, renal impairment***
MOA: competitively inhibits xanthine oxidase
SE:initial increase in attachs, rash, CV events with febux
interact:inhibits metab of probenecid, meraptopurine and azathioprine
pegloticase (krystexxa)
use for refractory gout.
MOA: enzymatic degredation of uric acid to allantoin.
SE: inf rxn, anaphylaxis, initial increase in attacks, NVD
Contraind:G6PD def-causes hemolysis and malig hyperthermia***
caution in preg/breastfeeding. must have special caregiver to administer
