Anti-inflammatory Agents Flashcards
Inflammation: _____ > _____ > ______
Injury –> Mediators –> Inflammation
Inflammation: redness swelling heat pain
Autacoids:
array of substances normally present in then body brief lifetime act near sites of synthesis lcoal hormaones inflammatory mediators
Acute Inflammation physiology:
Changes in blood vessel caber and flow
Increased vascular permeability
Leuocytic infiltration
Which mediators COULD cause vasodilatation, increased permeability, migration of WBC?
histamine PGs LTs PAF platelet activiating facotor kinis products of complement system activation cytokines chemokines interleukins adehsions molecules etc.
Histamine major activities
Redness
Heat
Swelling
Airway constriction
NOT CHEMOTAXIS
Prostaglandin and thromboxane major activities
opposing effects often
See individual: PGE, PGI, PGD, thromboxane, TXA, PGI
Leukotriene major activities
LTB4 is chemotactic (PMNs)
Reduces pain threshold
Peptido LTs:
Bronchoconstriction
Increased vascular permeability
Chemotaxis (eosinophils)
Kinis (bradykinin and kallidin) major activities
everything
Very STRONG VASODILATOR
–> hypotension
NOT chemotactic
Redness/vasodilation
Histamine
PGE2
PGI2
Kinins
Swelling/increased vascular permeability
Histamine
Peptide leukotrienes (LTC4, LTD4, LTE4)
Kinins
Pain/reduces pain threshold or causes pain
PGE
PGI
LTB4
Kinins
Chemotactic/directic migration of WBCs
LTB4 (neutrophis) Peptido leukotrienes (eosinophils)
Fever
PGEs
Airway constriciton/broncoconstriction
Histamine
Peptido leukotrienes
Kinins
PGD2
Hypotension
Kinins*
Histamine
Intracutaneous histamine “triple response”
itching
pain
urticaria/hives
IV histamine
decreased BP tachycardia (response to dec BP) bronchoconstriction HA flushing of false urticaria (wheal and flare) mucus secretion gastric acid secretion
Antihistamines mech
inverse agonists
shift agonist dose-response curve to the right = look like a competitive antagonist
H1 receptor
histamine-induced…
Bronchoconstriction Contraction of GI smooth muscle Increased capillary permeability (wheal) Pruritis (itch) and pain Release of catecholamines from adrenal medulla
H2 receptor
histamine-induced…
GASTRIC ACID SECRETION
Inhibition of IgE-mediated basophilic histamine release
Inhibition of T lymphocyte mediated cytotoxicity
Suppression of Th2 cells and cytokines
H3 receptor
histamine-induced…
Present on histaminergic nerve terminals
H4 receptor
histamine-induced…
Present on many immune cells (eosinophils, DCs, T cell, neutrophils)
Mixed H1 and H2 receptor mediated responses
Cardiac effects (H1 and H2): increased HR, arr
Vasodilator effects (H1 at low dose hist, 1 and 2 at high hist): H1 rapid dilation short lived, H2 develops slowly dilation sustained
Triple response: vasodiation (H1 and H2), flare and wheal (H1 primarily), pain and itching (primarily H1)
Nasal symptoms: H2 –> itching, sneezing, hypersecretions, nasal bloakage,
H2 mucus production
Older anti-histamines pearls
Diphenhydramine (Benadryl)
Chlorpheniramine (Chlor-tabs)
and others
- BLOCK H1, muscarinic, alpha adrenergic, AND 5HT receptors
- Cross BBB, no efflux
- sedating and dry secretions
- CARDIOTOXIC
Newer anti-histamines pearls
Cetirizine (Zyrtec)
Fexofenadine (Allegra)
Loratadine (Claritin)
- BLOCK H1 receptors, minimal anticholinergic properties
- Do not cause sedation and drying of secretions
- Cross BBB, BUT EFFLUXED OUT
- NOT cardiotoxic
Anti-histamine TU
Allergy (uricaria, poison ivy, etc., not asthma)
Motion sickness
Sleep aid (diphenhydramine)
May reduce rhinorrhea of common cold
H2 anti-histamines (for next year)
Cimetidine
Ranitidine
Famotidine
Nizatidine
Prostainoid synthesis
Phospholipis in cellmembrane (phospholipase A2) –> arachidonic acid –> (COX) > Prostaglandins and Thromboxanes OR (LOX) > Leukotrienes
COX-1
constitutive
constitutively expressed in most cells
protects gastric mucosa (because allows mucosal secretion fro certain PG)
found in platelets
COX-2
induced
constitutively expressed in brain and kidney
induced by certain serum factors, cytokines, GFs in tissues and site of inflammation*
NOT found in platelets
Cyclooxygenase produces
Inflammation (redness, swelling, heat, pain)
Fever
Cardiovascular disease (PGs and TXA important in balance of platelet aggregation)
Action of cyclooxygenase product depends on…
which prostanoid receptor is in that tissue
Receptors for prostaglandins
Seven transmembrane G protein coupled receptors with various 2nd messengers
DP (PGD) FP (PGF) IP (PGI2) TP (TXA2) EP (PGE) EP1-4
Characteristics of PG receptors (platelet aggregation, smooth muscle tone, natural agonist, G protein, second messenger)
DP (-, +/-, PGD2, Gs, cAMP) FP (-, +, PGF2a, Gq, IP3/DAG/Ca2+) IP (-, -, PGI2 (PGE1), Gs, cAMP) TP (+, +, TXA2, PGH2, Gq, IP3/DAG/Ca2+) EP1 (-, +, PGE2, Gq, IP3/DAG/Ca2+) EP2 (-, -, PGE2, Gs, cAMP) EP3 (-, +, PGE2) Gi Gs Gq, cAMP, IP3/DAG/Ca2+) EP4 (-, -, PGE2, Gs, cAMP)
DP
(-, +/-, PGD2, Gs, cAMP)
FP
(-, +, PGF2a, Gq, IP3/DAG/Ca2+)
IP
(-, -, PGI2 (PGE1), Gs, cAMP)
TP
(+, +, TXA2, PGH2, Gq, IP3/DAG/Ca2+)
EP1, 2, 3, 4
EP1 (-, +, PGE2, Gq, IP3/DAG/Ca2+)
EP2 (-, -, PGE2, Gs, cAMP)
EP3 (-, +, PGE2) Gi Gs Gq, cAMP, IP3/DAG/Ca2+)
EP4 (-, -, PGE2, Gs, cAMP)
Inflammatory effects of PGs:
Fever (PGEs)
Vasodilation (PGEs and PGIs)
Increased vascular permeability (PGEs and PGIs)
Pain (PGEs cause pain, PGEs and PGI2 sensitize pain receptors)
Shared therapeutics of COX1/2 inhibitors
analgesia
antipyretics
anti-inflammatory
Aspirin
Irreversibly binds/acetylated COX
Ibuprofen
(-) COX1/2
fewer GI SE
Naproxen
(-) COX1/2
Ketorolac
(-) COX1/2
promoted primarily for analgesia, also anti-inflammatory
Ketoprofen
(-) COX1/2
Indomethacin
(-) COX1/2
Most potent NSAID
SEVERE FRONTAL HA and BLOOD DISORDERS
Sulindac
(-) COX1/2
Piroxicam
(-) COX1/2
only QD admin
cause SERIOUS GI BLEED
Celecoxib
Celebrex
(-) COX 2***
Acetaminophen
NOT A NSAID analgesic antipyretic NOT ANTI-INFLAMMATORY effectively inhibits COX in brain, but not at sites of inflammation
SE (-) COX
Gastric or intestinal ulcertain Prolongation of gestation Renal dysfunction Hepatic dysfunction Increased bleeding time (inhibition of COX1 in platelet prevents platelet aggregation and TXA formation) Aspirin hypersensitivity
Aspiring hypersensitivity
3-10% of asthmatics
Atopic individuals
No antibody to aspirin, so hypersensitivity reaction
Sx: rhinitis, urticaria, asthma, laryngeal edema
**COX2 are save in aspirin hypersensitive individuals
Selective COX-2 inhibitor SE
inhibition of induction of labor
alterations in renal function
***reduce production of PROSTACYCLIN (inhibits platelet aggregation) by endothelial cells –> longterm –> increase risk of thrombotic CV events
less likely: gastric ulceration or aspirin hypersensitivity
Aspirin and Reye syndrome
encephalopathy and fatty liver following viral infection in children
(use acetaminophen)
Aspirin TI
LOW TI
anti-inflammatory doses for aspirin are close to toxic doses
borderline: anti-inflam and tinnitus
Leukotriene synthesis and limitation in pathway
AA –> 5-HPETE –> LTA –> LTB OR LTC –> D E
**AA availability is limitation in pathway
Degradation of LOX products
LTA4: short half life
LTB4: oxidized by enzymes in PMNs
LTE4: excreted in urine OR acetylated and excreted in bile
SRS-As
slow reacting substance of anaphylaxis
LTC4, LTD4, LTE4
= peptidoleukotrience or cysteinyl leukotrienes
5-lipoxygenase
5-LOX is a cytosolic enzyme that is translocated from the cytosol to membranes by binding to the protein FLAP (5-lipoxygenase activating protein)
Leukotrienes are primarily generated in…
leukocytes.
PMNs primarily make LTB4
Mast cells and basophils primarily make peptide-leukotriends
PMN
LTB4
RBC
LTB4
Platelet
LTB4
Endothelial cell, smooth muscle cell
LTC4
Mast cell, basophil
LTC4
LTD4
LTB4 receptor
LTB4 only
CysLTR1 peptidoleukotriene receptor
CysLTR1 OR LTD4 Rec
1st LTD4, 2nd LTC4/LTE4
CysLTR2 peptidoleukotriene receptor
CysLTR2 OR LTDC4 Rec
1st LTC4, 2nd LTD4/LTE4
Leukotriene inhibitors used in treatment of…
bronchial asthma
chronic asthma
Zileuton mech
Inhibits 5-LOX
Prevents synthesis of LTB4 and peptide-leukotrienes
Zileuton use and tox
cytoP450 –> drug interactions
decrease need for beta-agonstis in asthma
HEPATIC TOXICITY
Zafirlukast/Montelukast mech
Leukotriene receptor antagoneis (LTD4 receptor, CysLTR1)
Zafirlukast/Montelukast use and tox
Zafirlukast: inhibits cyto P450 –> significant drug interactions
Montelukast: QD admin**
both used in chronic asthma
Kinins
bradykinin
kallidin
redness swelling, heat, pain
Kinin synthesis
extracellular synthesis
Kininase I and II
Hfa
activated Hageman factor, part of clotting cascade
Plasmin
enzyme that digests fibrin
Kininase I
carboxypeptidase N removes carboxy terminal arginine
Kininase II
angiotensin converting enzyme (ACE) removes terminal phe and arg
bradykinin and kallidin are the ___________
mediators with inflammatory activities
Actions of kinins (kallidin and bradykinin = plasma kinins) via B2 receptor
kallidin and bradykinin: more active > bradykinin and kallidin without the terminal arg
HYPOTENSION EDEMA capillary permeabiity PAIN stimulate nerve endings contract gut smooth muscle contract airway smooth muse relaes catecholamines release prostaglandins
Actions of kinins (kallidin and bradykinin = plasma kinins) via B1 receptor
bradykinin and kallidin without the terminal arg: more active > bradykinin or kallidin
chronic inflammatory effects
INDICTED after trauma
Hypotension
pain
Interrelationship between __, __, __, and __.
kinin
complement
coagulation
fibrinolytic pathways
