Flashcards in Anti-Inflammatory Drugs Deck (79):
What changes occur to blood flow during acute inflammation?
increased blood flow
slowing of flow, even to stasis
also increased vascular permeability as post capillary venules leak large molecules
What aspects of inflammation can be mediated by histamine?
redness, heat, swelling, hypotension, and airway constriction
What aspects of inflammation can be mediatec by PGE2 and PGI2?
increased vascular permeability
What aspect o inflammation can be mediated by PGD2 and thromboxane?
What aspects of inflammation can be caused by TXA2?
platelet aggregation and vasoconstriction
What aspect of inflammation can be OPPOSED by PGI2?
What aspects of inflammation can be mediateed by the leukotriene LTB4?
it's a chemotatic factor for PMNs and it will reduce pain threshold
What are the two kinins we know?
bradykinin and kallidin
What aspects of inflammation cna be mediated by the kinins?
everything pretty much - just not a chemtatic factor
(super strong vasodilator which will result in hypotension)
What are the two pools of histamine in the body?
mast cell histamine
non-mast cell histamine
Where is histamine found in mast cells and basophils?
it's preformed in granules - bound by ionic bonds to a heparin protein complex
Where is non-mast cell histamine located?
in cells of the CNS (nerve endings)
cells of epidermis
in tissues undergoing rapid growth or repair (bone marrow, wounds, etc.)
enterochromaffin-like cells in the stomach - used to activate the parietal cells
What enzyme will convert histidine to histamine in mast cells and other cells that synthesize histamine?
What happens with ORAL administration of histamine? why?
nothing - because as it's absorbed it's inactivated by enzymes in the intestinal wall or liver
WHat happens with INTRACUTANEOUS administration of histamine?
itching, pain and hives
What happens with INTRANASLA administration of histamine?
intense itching, sneezing, hypersecretion and nasal blockage (vasodilation and edema)
What happens with INTRAVENOUS administration of histamine?
1. blood pressure decrease
2. tachycardia (response to drop in BP)
4. flushing of face
7. mucus secretion
8. gastric acid secretion
What's the clinical use of histamine?
pretty limited - we can inhale it to assess bronchial reactivity and use it intradermally to assess th eintegrity of sensory neurons - that's about it
What type of agonist are the antihistamines?
inverse agonists - which means they reduce receptor activity below basal levels observe in the absence of any ligand (some classify them as antagonists, but they really go beyond that)
What dtermines how a cell will respond to histamine?
the histamine receptors it has: H1, H2, H3 or H4
What do the H1 receptors mediate?
2. contraction of GI smooth muscle
3. increased capillary permeability (wheal)
6. release of catecholamines from adrenal medulla
What do the H2 receptors mediate?
gastric acid secretion!!
inhibition of IgE-mediated basophil histamine release
inhibition of T lymphocyte-mediated cytotoxicity
suppression of Th2 cells and cytokines
What do the H3 and H4 receptors mediate?
they're located on the histaminergic nerve terminals and many immune cells, so they regulate the activity of these cells - not of clinical use yet
What are the cardiac effects of the mixed H1 and H2 receptor mediated responses?
increased heart rate
icnreased force of contraction
slowed AV conduction
Both H1 and H2 will trigger vasodilation, but how do they differ in this?
H1 - rapid dilator response that's short lived
H2 - developes more slowly and is sustained
What receptors were blocked by the first generation antihistamines?
H1 receptors, but also muscarinic, alpha adrenerfic and serotonin receptors
True or false: first generation antihistamines couldn't reach the CNS.
false - they could because they aren't recognized by the P-glyc efflux pump
How were the first gen antihistamines metaoblized?
transformed to inactive metabolites in the liver and excreted in the urine
What were the side effects of the first gen antihistamines?
sedation! (and associated symptoms...like dizziness, etc.)
drying of secretions
What would acute first gen antihistamine poisoning look like?
like atropine poisoning: fixed and dilated pupils, flushed face, fever, dry mouth, excitation, hallucinations
terminally - coma and cardiorespiratory collapse
What are the two first generation antihistamines we need to know?
Of the two first gen antihistamines, which is better for daytime use and why?
chlorpheniramine - it causes less sedation than diphenhydramines
What are the three second gen antihistamines we need to know?
How do the second gens differ from the first gens in terms of side effect profile?
they have minimal anticholinergic properties, so they don't cause the sedation and drying of secretions
Why don't the second gens cause sedation?
they have affinity for the P-glyc efflus pumps so they get pumped out of the CNS
What are the therapeutic uses of the H1 antihistamines?
1. allergies (like rhinitis, urticaria and atopic dermatitis - NOT asthma)
2. motion sickness (the first gens - anticholinergic)
3. sleep aid
How are the prostanoids (thromboxanes and prostaglandins) synthesized?
PLA2 releases arachidonic acid from the phospholipid cell membrane
arachidonic acid is converted to the prostanoids by cyclooxygenase
There are two COX - which one is constitutive and which is induced?
COX 1 is constitutive in most cells
COX2 is constitutive in the brain and kidney, but is induced in other cells
Which COX is more important for the production of prostaglandins and thromboxanes in inflammation?
Which COX is in platelets?
In general, the COX products have short half lives - how are they broken down?
spontaneous chemical hydrolysis or uptake into cells by transport protein with subsequent enzymatic degradation
What are the 5 COX products receptors and what are they sensitive to?
DP - prostaglandin D
FP - prostaglandin F
IP - Prostaglandin I2
TP - thromboxane A2
EP - prostaglanding E
Which prostaglandin is the most potent fever inducer?
What are the three things a drug has to be able to do to be considered an NSAID?
Why do NSAIDs work for pain?
because they block the production of prostaglandins, which reduce the pain threshold
Which NSAID is an irreversible inhibitor of COX?
What does ibuprofen do better than aspirin?
It has fewer GI side effects
What's the most potent NSAID, used for severe frontal headache and blood disorders?
What NSAID is administered once a day and can cause dose-related serious GI bleeding?
What are the four other NAIDS we didn't just mention?
naproxen, ketorolac, ketoprofen and suldinac
What's the only selective COX2 inhibitor still on the market?
Why isn't acetaminophen (tylenol) considered an NSAID?
It is analgesic and antipyretic, but NOT anti-inflammatory
Where does acetaminiophen effectively inhibit COX if not at the site of inflammation?
in the brain
Acetaminophen OD can cause serious damage to what organ?
What are the adverse effects of drugs that inhibit COX?
prolongation of gestation
renal function issues
decreased hepatic function
What COX inhibitor is the most common culprit in hypersensitivity reactions?
aspirin - usually in atopic individuals
What are the symptoms of an aspirin hypersensitivity?
rhinitis, urticaria, asthma and laryngeal edema
What side effects of the nonselective COX inhibitors aren't an issue for celecoxib?
gastric SEs are less common
doesn't inhibit platelet function, soyou don't need to worry about bleeding
Why does long-term treatment with COX2 inhibitors result in higher risk of thrombotic cardiovascular events?
1 . platelets don't have COX2, so they'll continue to make thromboxane - a platelet aggregatory
2. COX2 will inhibit the production of prostacyclin (an aggregation inhibitor) by endothelial cells
Why don't we give aspirin to kids with viral infections?
Reye syndrome - encephalopathy and fatty liver
What are the products of lipoxygenase?
Leukoctrienes are predominantly generated in what cells?
leukocytes - especially PMNs, eosinophils, basophils, monocytes, macrophages and mast cells
Some cells that lack 5-lipoxygenase (like endothelial and platelets) can still generate leukotrienes. How?
Through transcellular megabolism
LTA4 is synthesized elswehre and can travel to cell types where it can be converted to LTC4 or LTB4
`What can LTB4 cause by binding its receptor?
CHEMOTAXIS of white blood cells
hyperalgesia = reduced pain threshold
What will LTC4, LTD4 and LTE4 cuase by binding to the cys LTR1 receptor?
also eosinophil chemotaxis, increased vascular permeability, increased mucous production, dendritic cell maturation, smooth muscle proliferation
What will LTC4, LTD4 and LTE4 cause by binding to the cyx LTR2 receptor?
endothelial cell and macrophage activation
What will HETEs trigger?
chemokinetic and chemotactic - movement of WBCs
What is the clinical relevance of LTC4 and LTD4?
C and D = asthma
B = rheumatoid arthritis and gout
What type of asthma are the leukotriene inhibitors best for?
chronic asthma - not recommended for acute asthma attacks
What are the 3 leukotriene inhibitors we know?
How does zileuton work?
It inhibits 5-lipoxygenase and thus prevents the synthesis of LTB4 and others
How is zileuton metabolized and why doe sit require monitoring?
cytochrom p450 (so watch for drug interactions)
monitor for hepatic toxicity
How do zafirlukast and montelukast work?
They are leukotriene receptor antagonists - specifically cys LTR1
Which one is prescribed more? why?
montelukast - because it's only administered once daily and zafirlukast inhibits cytochrome p450, so you have to worry about it more
Where are the kinins synthesized in the body?
extracellularly! - in blood or interstitial fluid, not in cells
What two moleculs degrade kinins?
1. kininase 1 (carboxypeptidase N or anaphylatoxin inactivator)
2. kininase 2 (Angiotensin converting enzyme or dipeptide hydrolase)
Kininase 1 removes an arginine from bradykinin and kallidin. DOes this make them more or less active? On what receptors?
B1: without the arg are more active
B2: with the arg are more active
What do the kinins due via the B2 receptor?
potent vasodilators, so hypotension
increased capillary permeability and edema
algesic agents - stimualtes nerve endings
contract gut smoth muscle slowly
contract airway smooth muscle
release catecholamines from adrenal medulla