Antihistamines and NSAIDs Flashcards
As a class of drugs, disease modifying anti-rheumatic agents target what 2 cytokines?
TNF alpha
IL-1
What is infliximab? How does it work? what 2 diseases is it used for?
Humanized anti-TNF-alpha
Works by binding up free TNF alpha
Used for RA and Crohns
What is adalimumab? How does it work? what 2 diseases is it used for?
Human antibody to TNF-alpha.
Works by binding up free TNF alpha
Used for RA and Crohns
What is Etanercept? How does it work? what 2 diseases is it used for?
Fusion protein containing the TNF alpha receptor
Works by binding up free TNF alpha
Used for RA and Crohns
What is Anakinra? What is it used for? What makes it unique among its class of drugs?
Antagonist at IL-1 receptor
Used for RA, other anti-inflammatories
Short half life requires daily injections
Proinflammatory lipid mediators are produced by what major enzyme at the plasma membrane? What is its main substrate and main product?
Phospholipase A2
Phosphatidyl choline
Arachidonic acid
How do annexins affect PLA2? What notable drug increases synthesis of annexins?
Anexins inhibit PLA2.
Their production is induced by glucocorticoids
What is the substrate for the production of prostaglandins and leukotrienes by their respective enzymes?
Arachidonic acid
What is the enzyme target of NSAIDs? What about Zileuton?
NSAIDs - Cyclo-oxygenase
Zileuton - Lipoxygenase
What is the major enzyme involved in the release of stored mediators like histamine? What are 2 drugs that block this enzyme?
PLC (Phospholipase C)
Cromolyn and nedocromil
Glucocorticoids inhibit the production of prostaglandins, leukotrienes and PAF by _
Inhibiting Phospholipase A2
Glucocorticoids inhibit the recruitment of leukocytes by _
Inhibiting the production of chemotactic factors
By inhibiting COX, NSAIDs reduce the production of _
Prostaglandins
By inhibiting lipoxygenase, zileuton inhibits the production of _
Leukotrienes
What is the mechanism of action of cromolyn? What is the net effect?
Inhibits degranulation, therefore decreases release of histamines and granular proteins
What is the effect of glucocorticoids on COX, PLA2 and Nitric oxide synthase?
Inhibits all of them, block their down stream mediators
What is the enzyme responsible for the production of histamine? What is the precursor? Histamine is preformed / induced when needed?
Histidine decarboxylase
Histidine
Preformed
What is the major enzyme involved in the break down of histamine? If this enzyme is absent or non-functional, what can result?
Diamine Oxidase
Histamine intolerance
How is histamine related to morphine?
It is stored with sulfated polysaccharides, can be displaced by morphine, therefore morphine can increase circulating histamine (itching side effect)
What is complexed with histamine in mast cells / basophils? What about fibroblasts?
Mast cells - Heparin
Fibroblasts - Chondroitin sulfate
What is the major antibody type associated with histamine release from mast cells? What is the type of hypersensitivity reaction?
IgE
Type 1
Within the CNS, where are histamine neurons located? What is its major function in the CNS?
Posterior hypothalamus
Mediates arousal
What type of histamine receptor is associated with vascular endothelium? What is the associated G protein, what is the effect of activation?
H1 receptor
Gq
Increased Nitric Oxide production, secondary to IP3 and DAG
How many different types of histamine receptors are there?
4, H1 - H4
What is the main receptor that mediates histamine’s inflammatory effects? Where is it located? (5)
H1
Smooth muscle, endothelium, cardiac muscle, sensory nerve terminals, CNS neurons
In most places, histamine release promotes smooth muscle constriction. Where is the exception and how does this happen?
Exception is vascular smooth muscle
Indirect vasodilation, because histamine releases NO with then causes the relaxation
What is the effect of H1 receptor activation in endothelial cells?
Increased NO release, separation of endothelial cells, therefore hypotension and edema
What are 3 smooth muscle beds where histamine works and what are its effects there?
Constriction for all
bronchioles - Increased difficulty breathing,
uterine smooth muscle - premature labor
gastric smooth muscle - diarrhea
What is the effect of H1 receptor activation in sensory nerves, hypothalamus and emetic center?
Sensory nerves - pain, itching
CNS - hypothalamus - increased wakefulness
CNS - emetic center - Nausea and vomiting
What is the effect of H2 receptor activation on gastric secretions?
Increased acid, pepsin and intrinsic factor secretion
What is the histamine triple response?
Wheal and flare reaction
Edema, reddening, swelling
What is the major compound used as an antagonist of histamine? What type of an antagonist is it?
Epinephrine
Physiological antagonist
What are 2 major histamine release inhibitors discussed? What disease are they used for?
Cromolyn and nedocromil
Asthma
The major effect of H1 receptor antagonists is _. What are they used for clinically (4)?
Sedation, mainly with first generation drugs
Allergy, uticaria, motion sickness, emesis
Four non-H1 mediated side effects of H1 receptor antagonists are _
Anticholinergic effects- Atropine like
Adrenoreceptor blockade
Serotonin receptor blockade
Local anesthesia (via sodium channel block)
What effects do 1st generation antihistamines elicit by acting at adrenoreceptors? Serotonin receptors?
Adrenoreceptors - orthstatic hypotension
Serotonin receptors - Increased appetite
What are the 4 first generation antihistamines that we are responsible for?
Diphenhydramine
Dimenhydrinate
Cyclizine
Promethazine
What is a main commonality of the first generation antihistamines?
All cause sedation
Beyond allergy and uticaria, 3 other uses of the first generation antihistamines are _
Motion sickness
Sleep aids
Antiemetics
Second generation antihistamines bind poorly to the cholinergic receptors, true or false? What is their intended receptor target?
True, poor binding
H1, high receptor selectivity
What are the three second generation antihistamines? What are their improvements?
Loratidine
Certirizine
Fexofenadine
Poor CNS penetration, therefore low sedation
What is the precursor of both prostanoids and leukotrienes? What enzyme makes prostanoids? Leukotrienes?
C-20:4 fatty acid
COX
Lipoxygenase
What are the 4 prostanoids with biologic activity? What is their precursor?
PGE - alpha PGF-alpha PGI2 TXA2 PGH is the precursor
How are protanoids stored? How are they released?
They aren’t stored. They are passively released following synthesis. This makes their activity entirely synthesis dependent
What is another name for TXA2? PGI2? Where are they found?
TXA1 - Thromboxane - endothelium (vasculature)
PGI2 - Prostacyclin - Platelets and macrophages
All of the biologically active prostanoids have a half life of 30 seconds, except for one with a half life of 3 mins. Which is this?
Prostacyclin
What is the enzyme responsible for the synthesis of the common prostanoid precursor? What is this common precursor? What are the 2 components of the synthesizing enzyme?
COX enxymes
PGH2
Cyclooxygenase and peroxidase
How do the prostanoids affect blood vessels?
PGE and PGI dilates
TXA constrict
How do prostanoids affect smooth muscle?
PGE and PGI dilates
TXA constrict
** PGE does both based on g-protein associated with**
What prostanoids inhibit platelet aggregation? Promote?
Inhibit - PGI2
Promote - TXA2
Which 2 prostanoids are associated with hyperalgesia?
PGE and PGI
There are types 1, 2 and 3 prostanoids, based on the number of double bonds. Which one is usually most effective? What is the precursor for type 2 prostanoids?
Type 2
Arachidonic Acid
PGH is the common precursor for the biologically active prostanoids. What enzymes make it? Where are they found?
COX1 - All cells except RBC
COX2 - All cells except RBC and platelets
Which of COX1 and COX2 is constitutively expressed? Which is inducible? Which can be blocked by corticosteroid and cytokines?
COX 1 - Constitutive
COX 2- Inducible
COX 2, blocked by corticosteroids and cytokines
At baseline, which COX isotype produces most of the prostanoids found In most tissues? What major tissue is an exception?
COX 1 makes most baseline prostanoids
Kidney is exception, where COX 2 plays role
Most prostanoids associated with inflammation are produced by what enzyme?
COX 2
How are the COX enzymes associated with pain? What class of drugs can interfere with this process?
During inflammatory injury, COX 2 is made in sensory terminals. They produce PGE and PGI.
NSAIDs block the COX enxymes
How are the COX enzymes associated with fever? What class of drugs can interfere with this process?
COX 2 (mediated by IL1 and TNF-alpha) and PGE in the vascular organ of the lamina terminalis cause increase in core body temp. Blocked by NSAIDs
What is the only COX isotype found in platelets? What is the main product? What is its effect?
COX 1
TXA (from arachidonate and PGH)
Stimulates platelet aggregation
How do NSAIDs and aspirin differ in their interactions with COX 1?
NSAIDs reversibly inhibit while aspirin permanently inhibits COX 1 (approx 1 week platelet lifespan)
Regarding platelets, how does PGI affect TXA activity? In what context does COX 2 contribute to PGI synthesis? What is the net effect of COX 2 inhibition?
PGI counters TXA, reduces platelet aggregation
COX 2 involved in PGI synthesis in endothelial cells
Inhibit COX 2, reduce PGI, increase clotting
What is the major COX isotype in the GI tract? What are the major prostanoids and their locations? What are their net effects?
COX 1
PGE - epithelium
PGI - Blood vessels
Decrease acid, increase mucus
What is the effect of COX 1 inhibition on the epithelium? What drug is protective against this? How does it work?
Causes lysis of epithelium - ulcers
Misoprostol is protective, a PGE analogue
Under what circumstances is COX 2 induced in the GI?
Following GI infections
What major organ expresses both COX 1 and 2 constitutively? What are their functions?
Kidney
Maintain renal blood flow
What COX isotype is expressed in the uterus? Which prostanoids contract the uterine smooth muscle? Which relaxes it?
Both COX 1 and 2
PGE and PGF contract
PGI relaxes
What are the 2 notable effects of COX inhibitors on uterine function?
Delay premature labor
Can reduce dysmenorrhea (menstrual cramps)
Aspirin (Acetylsalicylic acid, ASA) is metabolized to _
Salicylic acid
How do aspirin and salicylic acid differ in their activities on the COX enzymes?
ASA - Irreversible acetylation of both enzymes
Salicylic acid - Reversibly acetylates both enzymes
What does the selectivity ratio (Cox 2/ Cox1) of 4.4. tell you about aspirin?
It indicates that 4.4 times more aspirin is needed to inhibit Cox 2 than Cox 1. i.e. by the time you are inhibiting Cox 2, Cox 1 already inhibited
Among the mixed NSAIDs, what are the preferred target enzymes of ketorolac and indomethacin (Relatively)? What is each used for?
Both COX 1 selective (mainly ketotolac, 395 fold selective)
Ketorolac - post-surgical analgesic
Indomethacin - Arthritis, anti-inflammatory
Among the mixed NSAIDs, what are the preferred target enzymes of diclofenac, etodolac and meloxicam? What are they used for?
All COX 2 selective
All used for arthritis
What is the mechanism by which NSAIDs exert their anti-inflammatory effects?
Block COX production of all prostanoids
WHat is the mechanism by which NSAIDs exert their anti-pyretic effects?
Reduced IL1 and TNf- alpha induced increase in PGE2 production in the CNS
What are the major prostanoids (2) responsible for inflammatory pain targeted by NSAIDs?
PGE2 and PGI2
What is the effect of NSAIDs on platelet aggregation? What is the physilogical manifestation? Which of the NSAIDs will produce the longest lasting effect on platelets?
Blocks aggregation
Increased bleeding
Aspirin, because of irreversible inhibition
What is the effect of NSAIDs on gastric function? What are the prostanoids targeted?
Reduces protection, Increases ulcers
PGE2 and PGI2
Which NSAIDs provide cardiovascular benefits if taken daily?
Aspirin ALONE!
What is salacylism? What are the associated symptoms (5)
Hypersensitivity to aspirin.
Hyperventilation (MAJOR)
tinnitus, vertigo, emesis and sweating
What is reyes syndrome? What are to major symptoms?
Syndrome associated with giving aspirin to children with viral illnesses
Acute encephalopathy
Fatty liver degeneration
Dyspepsia, ulcers and GI bleeding can be associated with NSAID use. What class of drugs can be used to prevent the effects (3)?
Histidine (H2) receptor antagonists
Proton pump inhibitors
Misoprostol
In addition to GI effects, what other systems are associated with NSAID toxicity (2)?
Renal
Clotting
Analgesic, antipyretic and anti-inflammatory. Which of these attributes is not associated with tylenol? Why?
Anti-inflammatory
Effects blocked by peroxides, elevated at sites of peroxides
While tylenol is generally well tolerated, what organ is usually affected following overdose?
Liver
Analgesic, antipyretic and anti-inflammatory. Which of these attributes are associated with COX 2 specific NSAIDs? What organ system is at risk with chronic use?
All three
Kidneys
What is the major use of COX2 selective NSAIDs?
Osteoarthritis
Rheumatoid arthritis
What are the 4 examples of COX2 selective NSAIDs provided? Which 2 are most specific for COX2? What is their advantage?
Meloxicam, celecoxib, rofecoxib, valdecoxib
rofecoxib, valdecoxib
No GI side effects
True or false: Only the COX 2 NSAIDs are associated with adverse cardiovascular effects?
False, all NSAIDs except aspirin are associated with adverse cardiovascular effects
What is the proposed mechanism by which NSAIDs increase cardiovascular risk?
Block the COX2 dependent reduction of platelet aggregation
What enzyme is reponsible for making leukotrienes from arachidonic acid?
5-lipoxygenase
What are the leukotriene receptors antagonists that block LTD 4? (2) What are they used for?
Zafirlukast
Montelukast
Reduce broncho-constriction and edema in lungs
What is the mechanism of zileuton? What are 2 things to be aware of when using this drug?
Blocks 5-lipoxygenase
- increase liver toxicity
- CYP inhibitor, blocks other drugs metabolism
What are the side effects associated with infliximab? How must it be administered?
Increased frequency of infections (upper respiratory, urinary).
Must be administered parenterally
What is tofacitinib? What disease is it used for? How is it administered? What is its mechanism?
Jak kinase inhibitor
Rheumatoid arthritis
Administered orally (only antibody like that)
Inhibits the signalling of cytokines (IL2, IL4 and IL6) that require Jak kinases to signal
What are 2 processes that glucocorticoids directly affect? What is an inflammation related process that glucocorticoids don’t directly affect?
Directly anti inflammatory and immunosuppressive
Don’t directly affect histamine release
