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82 Cards in this Set

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Histamine is formed from which amino acid?
from the decarboxylation of L-histidine
Where is histamine sequestered?
mainly in the mast cells and basophils, the brain, and the enterochromaffin-like (ECL) cells of the fundus of the stomach
True or False

Histamine is only active in the bound form.
FALSE

Histamine is biologically INACTIVE in the bound form.
List the histamine receptors and where they are located.
H1 - sm.m., endothelium, brain

H2 - gastric mucosa, cardiac m., mast cells, brain

H3 - presynaptic: brain, myenteric plexus

H4 - eosinophils, neutrophils, CD4 T-cells
respiratory effect of histamine.
bronchoconstriction due to H1 stimulation
CV effect of histamine
increased contractility
increased HR due to H2 stim. and reflex tachycardia from H1 stim resulting in vasodilator effects on arterioles
GI effects of histamine
smooth muscle contraction due to H1 stim

increased secretions due to H2 stim
What is the "triple response" of a histamine reaction.
sm.m in microcirc --> dilation

endothelial cells of cap. and veins --> extravasation of fluid

sensory nerve endings --> pain stim. and flare
char. of 1st generation antihistamines
strong sedative effect related to CNS distribution

duration of action varies due to CNS distribution
char. of 2nd generation antihistamines
metabolized by CYP3A4 system

duration of action varies due to metabolization by CYP3A4
Where are prostaglandins produced?
in virtually all tissues and in minute quantities
What is the precursor to prostaglandin synthesis?
arachidonic acid

(20 carbon fatty acid)
Why are prostaglandins referred to as eicosanoids?
'eicosa' refers to the 20 carbon atoms
List the groups of eicosanoids with ring structures.
prostaglandins
thromboxanes
prostaglandins

these are all synthesized by the cyclooxygenase pathway
What is COX-1 responsible for synthesizing?
the physiologic production of prostaglandins, ie our everyday prostanoids such as those that regulate normal cell function (gastric cytoprotection, vascular homeostasis, platelet aggregation)
What is COX-2 responsible for synthesizing?
prostaglandins that occur in sites of disease and inflammation
Which has a larger substrate binding site, cox-1 or cox-2?
cox-2

the larger binding site permitted the development of cox-2 selective inhibitors
Which is inhibited by glucocorticoids, cox-1 or cox-2?
cox-2
What is the lipoxygenase pathway?
the action of lipoxygenase on arachidonic acid to form 5-HPETE, 12-HPETE and 15-HPETE, which are unstable and converted into the hydroxylated derivatives known as the HETES
What are the unstable prostaglandins in prostaglandin synthesis and into what are they transformed?
PGG2 & PGH2

transformed into PGE2, PGI2, PGD2, PGF2 AND TXA2
Which prostaglandin is more predominant in platelets?
TXA2
Which prostaglandin is more predominant in vascular endothelium?
PGI2
What is the significance of PGE3 in fish oils?
if ingested in significant amounts, it diminished the proinflammatory production of PGE2 and the generation of TXA2 resulting in an anti-inflammatory and CV benefit
What is the half-life of prostaglandins?
one minute

except for PGI2 (5 minutes) and TXA2 (30 seconds)
What kind of receptors are associated with prostaglandins?
G protein coupled receptors
List the prostaglandin receptors.
DP, FP, IP, EP and TP

they correlate with the prostaglandin it associates with. i.e. DP to PGD2; FP to PGF2
Actions of PGD2.
vasodilation
inhibition of platelet aggregation
relaxation of GI and uterine muscle
bronchoconstrictor
Actions of PGF2.
myometrial contraction
some bronchoconstriction
Actions of PGI2
vasodilation
inhibition of platelet aggregation
renin release & natriuresis
Actions of PGE2
on EP1 receptors - contraction of bronchial & GI smooth muscle

on EP2 receptors - bronchodilation, vasodilation, increased intestinal fluid secretion, relaxes GI smooth muscle

on EP3 receptors - GI smooth muscle contraction, inhibits gastric acid secretion, increased gastric mucous secretion, inhibits ANS neurotransmitter release
Actions of TXA2
vasoconstriction
platelet aggregation
bronchoconstriction
Which prostaglandins are released in an acute inflammatory response?
PGE2 (predominates) & PGI2 are released by local tissues/blood vessels while mast cells release PGD2.
What do mast cells release?
PGD2
True or False

Prostaglandins directly increase the permeability of postcapillary venules resulting in the redness and swelling associated with an acute inflammatory response.
FALSE

They potentiate the effects of histamine and bradykinin.
True or False

The release of prostaglandins during an acute inflammatory response results in pain as a result of the redness and swelling.
FALSE

They potentiate the effect of bradykinin by sensitizing the afferent C fibers to the effects of the noxious stimuli.
What drug is used to maintain the patency of the ductus arteriosus until surgical correction.
alprostadil (via PGE1)
Which prostaglandin agonist is used to treat open-angle glaucoma?
latanoprost
Which enzyme is responsible for producing leukotrienes?
5-lipoxygenase
char. of LTB4
chemotactic agent for neutrophils and macrophages
The anti-inflammatory effects of NSAIDS is related to the inhibition of (cox-1/cox-2) _______.
cox-2
The unwanted effects of NSAIDS, especially GI, are related to the inhibition of cox-1/cox-2) _______.
cox-1
True or False

NSAIDS can effect normal body temperature.
FALSE

The antipyretic effects of NSAIDS are a result of inhibition of prostaglandin production in the hypothalamus.
How does the analgesic effect of NSAIDS work?
1. they decrease PG production that sensitizes nociceptors to inflammatory mediators like bradykinin

2. decrease PG production in the spinal cord, decreasing transmission from afferent pain fibers.
What components of inflammation do NSAIDS reduce?
vasodilation
edema
pain
3 main desired effects of NSAIDS
anti-inflammatory

analgesic

antipyretic
cox-1 or cox-2

NSAIDS inhibiting this pathway result in a rapid and reversible inhibition.
COX-1
NSAIDS inhibiting this pathway result in an irreversible reaction.
COX-2
List some unwanted side effects of NSAIDS use.
GI - dyspepsia, N/V, ulcers
skin rashes
reversible renal insufficiency
liver disorders
bone marrow suppression
analgesic associated nephropathy
ASA is more selective for cox-1 or cox-2?
cox-1
characteristics of ASA.
cox-1 selective
inhibits thromboxane production in platelets
irreversible inhibition of cox-1
changes ratio of prostacyclin to thromboxane
What percent of platelets is renewed every 24 hrs? Why is this significant for ASA dosing?
1/7 or 14% of platelets are renewed every 24hrs.

This is significant in ASA dosing due to the irreversible inhibition of TXA2 prod in platelets requiring DAILY dosing for effectiveness rather that QOD dosing.
True or False

NSAIDS can be taken as a preventative measure to reduce CV risk.
FALSE

ASA has been shown to reduce CV risk by 30% whereas NSAIDS show no reduction in CV risk.
If we have to admin both ASA and NSAIDS, which do we give first and why?
ASA first, then NSAIDS at least 30 min. later b/c NSAIDS block the cox-1 pathway where ASA works.

In the event the ASA is enteric coated, this does not apply.
What are the 3 main risks with taking NSAIDS?
CV - increase risk of bleeding due to inhibition of platelet aggregation
GI - ulcers, bleeding obstructuve strictures
renal - sodium and fluid retention, hyperkalemia, ARF, HTN
When do we use a cox-2 inhibitor?
pts at high risk for GI bleed
use lowest effective dose (200mg for OA; 200-400mg for RA; 400mg for pain)

avoid in pts with CV disease
What are the 2 main prostaglandins synthesized in the kidney?
PGE2
PGI2
How do NSAIDS adversely effect the kidney?
via the cox-2 pathway, inhibits the beneficial effects of PGE2 and PGI2 in the kidney

inhibiting PGE2 results in sodium retention, fluid retention, HTN, vasoconstriction
inhibiting PGI2 results in hyperkalemia and ARF
Which of the following is/are prodrug(s)?

a. diclofenac
b. sulindac
c. naproxen
d. ibuprofen
b. sulindac

its metabolized in the liver to its active metabolite
True or False

It's acceptable to substitute a different NSAID for one which a pt has had a reaction.
FALSE

There is cross reactivity between ASA and NSAIDS due to a redirection of arachidonic acid metabolism resulting in increased leukotrienes.
The majority of NSAIDS are weak acids or weak bases?
weak acids
What does it mean when the therapeutic index of a drug is high?
The higher the TI, the more safe the drug.
Which NSAID is labeled renal-sparing?
sulindac
What is the significance of ketorolac?
It's the first injectable NSAID for analgesia. Enhanced efficacy due to its injectability.
If used with an opioid, it decreases the required amt of opioid needed for pain relief.
Which NSAID requires taking it on an empty stomach?
fenoprofen

due to absorption problems with the drug
What should we be aware of when admin oxicams?
high incidence of GI toxicity and phototoxic cutaneous eruptions

no longe used in Europe; FDA still approves use for menstrual cramps and short term pain relief in US
Name the pyrazoles. What is the problem with pyrazole administration?
phenylbutazone
oxyphenbutazone

SE of aplastic anemia with a 50% mortality rate

administration can not exceed 1 week.
Indications for celebrex admin.
osteoarthritis
RA
FAP (familial adenomatous polyps)
Why is celebrex effective in treating FAP?
FAP (familial adenomatous polyps) has been shown to express Cox-2, which celebrex blocks as a cox-2 inhibitor
What is salicylism?
high dose ASA admin resulting in tinnitus, decreased hearing and vertigo
List salicylates. How do the others differ from ASA?
magnesium choline salicylate
sodium salicylate
salicylsalicylate

they are less efficacious
slower onset
no ASA hypersensitivity
no drug interactions
less GI side effects
What effects does acetaminophen have?
antipyretic
analgesic

little anti-inflammatory effect
What is the active metabolite of acetaminophen and what is its significance?
N-acetyl-benzoiminoquinone

it is hepatic and renal toxic

treated with N-acetylcysteine
characteristics of acetaminophen
very little protein bound
very little drug interactions
mild adverse effects (except with OD)
What is gout?
deposition of monosodium urate crystals in joints and soft tissue
What is 'usually' the first body part affected by gout?
the big toe
what is the enzyme responsible for uric acid production?
xanthine oxidase
Uric acid is made from what compound(s)?
purines, which is converted to hypoxanthine
normal plasma urate level
4-6 mg/dl
types of gout patients
overproducers and underexcretors

90% of pts are underexcretors
What drug(s) are used for acute gouty attacks?
colchicine - it reduces leukocyte migration into joints

NSAIDS
What drug(s) are used for chronic gouty attacks?
probenecid

sulfinpyrazone
What drug(s) are used to prevent gouty attacks? How do they work?
allopurinol - competitive inhibition of xanthine oxidase