Terms Flashcards
Biogenic Amine Cellular Source: Mast cells, basophils Physiological response: 1. vasodilation 2. increased vascular permeability 3. pain Mechanism: Activation of GPCRs Pharmacology: Antihistamines (H1 antagonists)
Histamine
Peptide Cellular Source: Endothelial cells Physiological response: 1. vasodilation 2. increased microvessel permeability 3. pain Mechanism: activation of GPCRs Pharmacology: receptor antagonists being tested
Bradykinin
Plasma proteins
Cellular Source: synthesized by liver, circulates in blood
Physiological response:
1. Chemotaxis: recruitment of inflammatory cells to site of injury
2. promote release of mediators from neutrophil
3. increase vascular permeability
4. excessive activation may contribute to tissue injury
Mechanism: complement protein complexes cause osmotic lysis, activation of GPCRs
Pharmacology: Eculizumab, APT070
Complement
Plasma protein
Cellular Source: produced in liver in response to cytokines, adipocytes
Physiological Response:
1. “acute phase reactant”
2. activates complement cascade
3. mediates phagocytosis
4. “marker of inflammation”
Mechanism: binds to phospholipids in bacteria and damaged cells, may be specific receptors in macrophages
Pharmacology: elevated CRP may be associated with increased risk of diabetes, hypertension and cardiovascular disease, statins may help
C-Reactive Protein
Secreted proteins (IL-a, IL-B, TNF-a)
Cellular source: nearly all inflammatory cells
Physiological response:
1. TNF-a: acute phase reaction, fever, sepsis
2. IL-1: acute phase reaction, fibroblast and lymphocyte proliferation, fever
Mechanism: bind to specific receptor proteins to induce gene expression in number of proteins via activation of NFkB and AP-1 –> increase COX and lipoxygenases, increase adhesion molecule expression, induce collagenase (fibrosis)
Pharmacology: etanercept, Infliximab
Cytokines
Purine Nucleotide
Cellular source: all cells
Physiological response:
1. Increased extracellularly during injury - anti-inflammatory
2. Inhibit cytokine action
Mechanism: activation of GPCRs
Pharmacology: Adenosine A2 agonists, Methotrexate, Folic acid antagonist
Adenosine
Family of Proteins
Cellular source: endothelial cells, platelets, leukocytes
Physiological response:
1. Leukocyte adhesion to endothelium
2. Endothelial adhesion molecules recruit activated platelets
Mechanism: contact molecules, calcium dependent
Pharmacology: Abciximab
Cell Adhesion Molecule
Lipid Mediator Cellular source: virtually all cells Physiological response: 1. Vasodilation/vasoconstriction 2. pain 3. fever 4. platelet aggregation (via thromboxanes) Pharmacology: NSAIDS
Prostaglandin
Lipid Mediator
Cellular source: macrophages, neutrophils
Physiological response:
1. Increased vascular permeability
2. Bronchoconstriction
Mechanism: activation of GPCRs
Pharmacology: Zileuton - 5 lipoxygenase inhibitor
Zafirlukast - cys-leukotriene receptor antagonist
Leukotriene
Lipid Mediator Cellular source: adrenal cortex Physiological Response: 1. inhibition of cytokines 2. inhibition of phospholipase A2 3. inhibition of COX2 4. inhibition of cell adhesion molecules Mechanism: activation of nuclear receptors Pharmacology: steroids
Glucocorticoid
Physiological response:
- vasodilation
- increased vascular permeability
- pain
Histamine
Physiological response:
- vasodilation
- increased microvessel permeability
- pain
Bradykinin
Physiological response:
- Chemotaxis: recruitment of inflammatory cells to site of injury
- promote release of mediators from neutrophil
- increase vascular permeability
- excessive activation may contribute to tissue injury
Complement
Physiological Response:
- “acute phase reactant”
- activates complement cascade
- mediates phagocytosis
- “marker of inflammation”
C-Reative Protein
Physiological response:
- TNF-a: acute phase reaction, fever, sepsis
- IL-1: acute phase reaction, fibroblast and lymphocyte proliferation, fever
Cytokines
Physiological response:
- Increased extracellularly during injury - anti-inflammatory
- Inhibit cytokine action
Adenosine
Physiological response:
- Leukocyte adhesion to endothelium
- Endothelial adhesion molecules recruit activated platelets
Cell Adhesion Molecules
Physiological response:
- Vasodilation/vasoconstriction
- pain
- fever
- platelet aggregation (via thromboxanes)
Prostaglandins
Physiological response:
- Increased vascular permeability
- Bronchoconstriction
Leukotrienes
Physiological Response:
- inhibition of cytokines
- inhibition of phospholipase A2
- inhibition of COX2
- inhibition of cell adhesion molecules
Glucocorticoids
Exists as two isoforms, oxygenate and cyclize the precursor fatty acid to form cyclic endoperoxide (PGG), peroxidase activity converts PGG2 to PGH2
Inhibited by Aspirin
Cyclooxygenase
Constitutive
COX-1
Larger active site, inducible
COX-2
Most abundant precursor of eicosanoids, concentration in cells is low, Found esterified to membrane phospholipids
Arachidonic Acid
LT1 and LT2
Cysteinyl Leukotriene
PGE2
Lowers threshold of nociceptors in periphery
Activates spinal neurons and microglia that contribute to neuropathic pain
Fever
what essential amino acid is serotonin synthesized from?
tryptophan
what is the rate-limiting enzyme in serotonin synthesis?
tryptophan hydroxylase?
most of the serotonin in the body is found where?
GI system
in the brain, cell bodies of serotonergic neurons are primarily located in?
raphe nucleus
which serotonin receptor isn’t a GPCR?
5HT3
what explains the GI complaints associated with aspirin use?
decreased production of PGs that promote mucus secretion
why does aspirin increase bleeding time?
TXA2 production in platelets decreases
general properties of NSAIDS?
anti-inflammatory, anti-pyretic, analgesic
which medicine does not have anti-inflammatory properties?
acetaminophen
which COX relates to PGs and inflammation?
COX 2
mechanism of all NSAIDS?
inhibition of COX
mechanism of acetylsalicylic acid
irreversible inhibitor of COX 1& 2, acetylation of serine moiety (covalent bonding)
effect of aspirin on platelet cells
cannot regenerate without new platelet synthesis (no nucleus)
unique effects specific to Aspirins (unrelated to COX inhibition)
uric acid excretion, CNS, respiration
uricosuric agent/effects
increases rate of excretion of uric acid via competition with urate transporter
low aspirin dose effect on uric acid (typical two 325 mg/4hrs)
decrease uric acid excretion
large aspirin dose effect on uric acid
normal uricosuric effect: block reabsorption via interaction with transporter, OAT
CNS effect of salicylates
stimulation followed by depression; tinnitus; nausea & vomiting
adverse reactions to NSAIDs
GI (block production of protective PGs): ulceration and irritation
Renal: decrease RBF, Na/H20 retention (esp in CHF, renal disease, elderly)
prostaglandins in GI
from COX-1, PGE2 and PGI2, inhibit acid secretion by stomach, promote secretion of cytoprotective mucus in intestine
inhibition of platelet aggregation
PGI2
stimulation of platelet aggregation
TXA2
effect of PGE2 and PGI2 on kidney
increase RBF, increase salt and water excretion
PGF2a (re: uterus)
pregnant uterus, contraction
PGE2 (re: uterus)
pregnant uterus, contraction
maintain PDA
PGI2 (re: uterus)
early pregnancy, dilation
NSAIDs and pregnancy (SE)
increase risk of postpartum hemorrhage (TXA2), intrauterine closure of PDA, avoid use during 3rd trimester
aspirin half-life during overdose
15-30 hours (zero order kinetics)
Reye’s Syndrome
aspirin. children; acute encephalopathy, liver degeneration; follows viral illness; mitochondrial damage?
side effects associated with all non-selective NSAIDs
GI irritation, inhibition of platelet aggregation/increased risk of bleeding, decrease in RBF in patients, hypersensitivity
what do you give to manage acetaminophen toxicity?
N-acetylcysteine (replenishes glutathione stores)
role of alcohol in acetaminophen toxicity?
EtOH induces P450 (2E1) involved in NAPIQ metabolite, also depletes glutathione
location of histamine
tissues: mast cells
blood: basophils
non-mast cells (gastric mucosa cells, epidermis, neurons)
drugs, peptides and venoms that promote histamine release
vancomycin, succinylcholine, morphine, curare
bradykinin, complement, substance P
wasp venom
mechanism of histamine release
increase in intracellular calcium
vancomycin-induced histamine reaction
red-man syndrome: follows rapid IV infusion, rash on face/neck/upper torso, hypotension, due to mast cell degranulation (not allergic rxn)
mechanism of action of omalizumab
IgG that binds Fc portion of IgE; Fc portion cannot bind to mast cell
H1 receptor G-protein coupling and 2nd messenger
Gq
Calcium
H2 receptor G-protein coupling and 2nd messenger
Gs
cAMP
H1 receptor effects on vasoconstriction and vascular permeability
acts on vascular smooth muscle
on post-capillary venules, causes endothelial cells to contract
H1 effect on bronchioles, intestinal smooth muscle, peripheral nerve endings
contraction
contraction
pain and itching
H2 effect on bronchioles, intestinal smooth muscle, peripheral nerve endings
relaxation
none
none
