Inflammatory Mediators Flashcards
storage of histamine
- mast cells
- basophils
synthesis and release of histamine
- in epidermal cells
- gastric mucosa
- CNS
- regenerating or rapidly growing tissues
synthesis of histamine from
histidine
function of endogenous histamine
- allergic hypersensitivity response
- gastic acid secretion (by H2 receptors on gastric parietal cells)
- gastric carcinoid tumors (proliferation of mast cells and basophils)
- CNS neurotransmitter
- myenteric plexus
endogenous histamine inhibited by
- cromolyn sodium
- nedocromil
- moderated by beta-2 agonists
what non-immune compounds can release histamine
- organic bases
- venoms
- several drugs
metabolism of histamine
can occur by 2 different pathways:
- N-methyltransferase
- diamine oxidase
pharmacologic effect of H1 receptor
- vascular/extravascular smooth muscle
- nerves
- glands
- some CNS
pharmacologic effect of H2 receptor
- vascular/smooth muscle
- gastric parietal cell
- cardiac
- some CNS
pharmacologic effect of H3 receptor
- CNS
- dampening
- negative feedback
pharmacologic effect of H4 receptor
WBC
effects of histamine on the cardiovascular system
- vasodilation
- increased “capillary” permeability
- cardiac stimulation; arrhythmias
what is the “triple response” of Lewis (wheal and flare)
- Localized red spot
- Brighter red flush/flare
- Wheal that is noticeable in 1-2 mins that occupies the original red spot
extravascular effect of histamine
- bronchoconstriction
- intestinal smooth muscle contraction
- cause nerve ending pain or itch
Histamine Antagonists (ie. Antihistamines) are available as
drug block H1 and H2 receptors
how are H1 blockers divided
- older (1st) generation
- newer (2nd) generation agents
2nd generation H1 receptors
- penetrate CNS poorly
- are non sedating
H2 blockers (OTC) used to deccrease
gastric acid secretion
what are H1- Receptor Antagonists
-REVERSIBLE, competitive inhibitors of the H1 receptor (act like an inverse agonist)
1st generation H1 receptors are
- sedative
- anticholinergic
2nd generation H1 recptors are
-less or no sedation
what are the properties of H1 receptors
- sedation (varies)
- anticholinergic; some with alpha and 5-HT blocking action
- central antinausea and antiemetic effects (some agents irritate GI)
- mild antiparkinsonian effects (anticholinergic)
- local anesthetic effects (structural features of local anesthetics)
- drug allergy from topical administration
clinical uses of H1 Antagonists
- allergies
- allergic reactions
- pruritus
- itching
- motion sickness
- vestibular disturbances
- OTC sleep aid
function of H2 Receptor Antagonists
block histamine - induced gastric acid secretion
H2 receptor antagonists have a larger effect on
nocturnal acid secretion
all drugs in H2 receptor antagonists are available OTC to reduce
gastric acid secretion
name 4 H2 receptor antagonists
- cimetidine
- ranitidine
- famotidine
- nizatidine
function of cimetidine
inhibits p450 and may cause confusion in ELDERLY patient receiving larger doses
what are kinins
are peptide autocoids that act locally to produce pain, vasodilation, increased vascular permeability
-synthesize vasoactive substances (ie. prostaglandins)
kinins are activated by
- tissue damage
- allergic rxns
- viral infection
- inflammatory events
kinins are cleaved from
alpha 2 globulins (kininogens)
bradykinin and kallidin are cleaved by
plasma or tissue kallikrein
plasma killikrein activated by
factor XII
kinins are inactivated by
- ACE (kininase II)
- inactivated by conversion to active Des-Arg metabolites by other peptidases
bradykinin and kallidin are cleaved from
- HMW or LMW kininogens by plasma
- tissue kallikrein
B1 (kinin receptor) binds to
des-Arg metabolites
B1 (kinin receptors) are present in what cells
normal vascular smooth m.
B1 (kinin receptors) are unregulated during
inflammation by cytokines, GF and endotoxins
function B2 (kinin receptors)
- mediate the effects of bradykinin in the absence of inflammation
- activate proinflammatory transcription factors, NO synthesis, prostaglandin synthesis
pharmacological function of kinins
- pain
- inflammation - increase permeability
- respiratory disease - provokes bronchospasms
- kidney function - regulate urine volume and composition
drugs affecting kinins
- ACE inhibitors
- investigational bradykinin agonists and antagonisists
- kallikrein inhibitors
what are eicosanoids
- prostaglandins
- leukotrienes
eicosanoids are derived from
20-C essential F/A that contain 3,4 or 5 double bonds
where are eicosanoids found
in almost every tissue and body fluid
eicosanoid production increases in response to
diverse stimuli
what are the 2 routes of metabolism of arachidonic acid
- lipoxygenase
2. cyclooxygenase
lipoxygenase pathway leads to
HPETEs
HETEs
leukotrienes
cyclooxygenase pahtway leads to
- cyclic endoperoxides (PGG and PGH)
- metabolic products
how many active sittes does cyclooxygenase have
2
expression of cyclooxygenase-1 (COX-1)
constitutively expressed
where is COX-2 expressed
- endothelial cells
- kidney
- brain
COX-2 induced by
- cytokines
- GF
- endotoxin
- an effect that is blocked by glucocorticoids
- laminar shear force
function of eicosanoids
- inflammation
- smooth muscle tone
- hemostasis/thrombosis
- paturation (labor delivery)
- gastrointestinal secretion
- renal function
what blocks Eicosanoids
NSAIDs
what drugs decrease the effect of leukotrienes
Leukotriene receptor antagonists
5-Lipoxygenase inhibitor
Name the Leukotriene receptor antagonists
- Zafirlukast
2. Montelukast
name the 5-Lipoxygenase inhibitor
zileuton
what is zileuton used to treat
- asthma
- block leuoktriene derivatives
what are the effects of Eicosanoids on the Cardiovascular system
- vasodilate (PGI2, PGE2, PGD2)
- hypotension (LRC4, LTD4)
- vasoconstrict (TXAs, PGF2; endoperoxides)
- increase C.O (PGE2m PGF2)
- increase capillary permeability (LTC4, LTD4)
what are the effects of Eicosanoids on Blood Elements
- platelet aggregation (PGI2 inhibits; TXA2 promotes)
- chemotaxis (LTB4)
- inhibit lymphocyte function (PGE2)
postaglandins contract or relax what type of muscle
extravascular smooth muscle
leukotrines contract what kind of muscle
smooth muscle
broncoconstriciton caused by
LTC4
LTD4
PGF2
PGD2
uterine contraction caused by
PGE2
PGF2
gastrointestinal smooth muscle contraction caused by
LTC4
LTD4
PGE2
PGF2
effect of prostaglandins on GI
- decrease gastric secretion
- increase mucus
- promote local blood flow
- stimulate epithelial growth (PGE2 PGI2)
effect of prostaglandins on kidney and urine formation
- increase renal blood flow
- decrease chloride reabsorption
- increase renin secretion
affects of prostaglandins on afferent nerves
- direct pain producer
- hyperalgesia
effect of prostaglandins on CNS
- elevate body temp
- modulate NT
effect of prostaglandins on eye
PGF decrease intraocular pressure
what are the therapeutic uses of prostaglandins
- cervical ripening (PGE2)
- therapeutic abortion - stimulate uterine contraction)
- gastric cytoprotection (Misoprostol; PGE1 analog)
- maintenance of patent ductus arterioles
- primary pulmonary hypertension
