Anti-Inflammatory Drugs Flashcards by Emily Prazak

What changes occur to blood flow during acute inflammation?

arteriolar dilation
increased blood flow
slowing of flow, even to stasis

also increased vascular permeability as post capillary venules leak large molecules

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What aspects of inflammation can be mediated by histamine?

redness, heat, swelling, hypotension, and airway constriction
NOT chemotaxis

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What aspects of inflammation can be mediatec by PGE2 and PGI2?

vasodilation
increased vascular permeability
pain

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What aspect o inflammation can be mediated by PGD2 and thromboxane?

bronchoconstriction

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What aspects of inflammation can be caused by TXA2?

platelet aggregation and vasoconstriction

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What aspect of inflammation can be OPPOSED by PGI2?

platelet aggregation

causes vasodilation

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What aspects of inflammation can be mediateed by the leukotriene LTB4?

it’s a chemotatic factor for PMNs and it will reduce pain threshold

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What are the two kinins we know?

bradykinin and kallidin

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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

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What are the two pools of histamine in the body?

mast cell histamine

non-mast cell histamine

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Where is histamine found in mast cells and basophils?

it’s preformed in granules - bound by ionic bonds to a heparin protein complex

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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

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What enzyme will convert histidine to histamine in mast cells and other cells that synthesize histamine?

L=histidine decarboxylase

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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

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WHat happens with INTRACUTANEOUS administration of histamine?

itching, pain and hives

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What happens with INTRANASLA administration of histamine?

intense itching, sneezing, hypersecretion and nasal blockage (vasodilation and edema)

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What happens with INTRAVENOUS administration of histamine?

blood pressure decrease
tachycardia (response to drop in BP)
braonchoconstriction
flushing of face
headache
urticaria/hives
mucus secretion
gastric acid secretion

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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

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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)

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What dtermines how a cell will respond to histamine?

the histamine receptors it has: H1, H2, H3 or H4

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What do the H1 receptors mediate?

bronchoconstriciton
contraction of GI smooth muscle
increased capillary permeability (wheal)
pruritis
pain
release of catecholamines from adrenal medulla

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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

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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

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What are the cardiac effects of the mixed H1 and H2 receptor mediated responses?

increased heart rate
icnreased force of contraction
increased arrhythmias
slowed AV conduction

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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 GI disturbances

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?

diphenhydramine | chlorpheniramine

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?

cetirizine fexofenadine loratadine

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 not colds

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?

COX2

Which COX is in platelets?

only COX1

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?

PGE

What are the three things a drug has to be able to do to be considered an NSAID?

analgesic antipyretic anti-inflammatory

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?

aspirin

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?

indomethacin

What NSAID is administered once a day and can cause dose-related serious GI bleeding?

piroxicam

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?

celecoxib (celebrex)

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?

liver

What are the adverse effects of drugs that inhibit COX?

gastric/intestinal ulceration 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?

the leukotrienes

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 leukocyte adhesion ROS production hyperalgesia = reduced pain threshold

What will LTC4, LTD4 and LTE4 cuase by binding to the cys LTR1 receptor?

BRONCHOCONSTRICTION 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 | fibrosis

What will HETEs trigger?

chemokinetic and chemotactic - movement of WBCs

What is the clinical relevance of LTC4 and LTD4? | LTB4?

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?

zileuton zafirlukast montelukast

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 release prostaglandins

What do the kinins due via the B1 receptor?

have chronic inflammatory efffects they're INDUCED after trauma hypotension pain