NSAIDs Flashcards
The inflammatory process is the response to __________ evoked by a wide variety of noxious agents (e.g., infections, antibodies, or physical injuries).
an injurious stimulus
The ability to mount an inflammatory response is essential for survival in the face of environmental pathogens and injury
T/F
T
For eicosanoid synthesis to occur, ________ must first be released or mobilized from ___________ by one or more lipases of the _________ (PLA2) type
arachidonate
membrane phospholipids
phospholipase A2
At least ____ phospholipases mediate arachidonate release from membrane lipids
List them
three
cytosolic (c) PLA2, secretory (s) PLA2, and calcium-independent (i) PLA2.
Common Pharmacological Effects of NSAIDs to be covered below
______
Anti________
Anti- __________
Some are ____________
Analgesic
pyretic
inflammatory
Uricosuric
Common Pharmacological Effects of NSAIDs to be covered below
Analgesic (______________ effect)
Antipyretic (_____ effect)
Anti-inflammatory (except __________)
CNS and peripheral
CNS
acetaminophen
Common Pharmacological Effects of NSAIDs to be covered below
Analgesic : may involve _____ related effects
Anti-inflammatory : due mainly to _________
non-PG
PG inhibition.
Pharmacological Effects of NSAIDs
Diverse group of chemicals, but all inhibit ___________.
Resultant inhibition of ____ synthesis is largely responsible for their therapeutic effects.
But, inhibition of ________ in _____ mucosa leads to GIT damage (_______,________).
cyclooxygenase
PG
PG synthase; gastric
dyspepsia, gastritis
Common Adverse Effects of NSAIDs
________ Dysfunction
_____________ and ________ ulceration with bleeding
___________ Failure in susceptible
__________ retention and _____
Platelet
Gastritis and peptic
Acute Renal
Sodium+ water; edema
Common Adverse Effects of NSAIDs
________ nephropathy
Prolongation of _______ and ________
____________
GIT _______ and _______
Analgesic
gestation and inhibition of labor.
Hypersenstivity
bleeding and perforation
Hypersenstivity resulting from use of NSAIDs is immunologic
T/F
F
not immunologic but due to PG inhibition
COX
Exists in the tissue as ______ isoform (COX-__).
At site of inflammation, cytokines stimulate the induction of the ____ isoform (COX-____).
constitutive ; 1
2nd; 2
COX
Inhibition of COX-2 is thought to be due to the ___________ actions of NSAIDs.
Inhibition of COX-___ is responsible for their GIT toxicity.
anti-inflammatory
1
COX
Most currently used NSAIDs are somewhat selective for COX-___, but selective COX-___ inhibitors are available.
1
2
COX
________,________,_________– selective COX-2 inhibitors.
Celecoxib, etoricoxib, valdecoxib
COX
selective COX-2 inhibitors.
Have similar efficacies to that of the non- selective inhibitors, but ________________________________
And
no _________ and there is actually increased ———-
the GIT side effects are decr by ~50%.
cardioprotection
MI.
The Salicylates - Aspirin
Effect on Respiration: triphasic
•Low doses: ___________→____ CO2 →______ respiration.
•Direct stimulation of respiratory center → ______ventilation → resp._______ → ____ compensation
•Depression of respiratory center and cardiovascular center →____ BP, respiratory ________ , ______ compensation + metabolic ________ also
uncoupling phosphorylation ; ↑; stimulates
Hyper; alkalosis; renal
↓; acidosis; no; acidosis
The Salicylates - Aspirin
Duration of action ~_____.
______ taken.
4 hr
Orally
The Salicylates - Aspirin
Weak (acid or base?) (pKa ~____)
So it is non-ionized in _________ and easily absorbed.
It is also ______ by _______ in tissues and blood to ______ (active) and acetic acid.
Acid ; 3.5
stomach
Hydrolyzed ; esterases
salicylate
The Salicylates - Aspirin
Most salicylate is converted in _____ to H2O-soluble conjugates that are rapidly excreted by _____
liver
kidney
Effect of Aspirin
On GI System
Dose dependent _______
______ syndrome
hepatitis
Reye’s
Effect of Aspirin
Metabolic
___________ of _______
_______glycemia and depletion of ______ and ______ ———-
Uncoupling of Oxidative Phosphorylation
Hyper
muscle and hepatic glycogen
Effect of Aspirin
Endocrine: corticosteroids, thyroid
Okay?
Cardiovascular effects of Aspirin
• Platelets: Inhibition of platelet COX-1-derived _____ with the net effect of increasing ______ (inhibition of _________)
• Endothelial COX-2 derived _____ can inhibit platelet _______ (inhibition ______ ———— by ______).
TxA2; bleeding time; platelet aggregation
PGI2; aggregation; augments aggregation by TxA2
Cardiovascular effects of aspirin
Aspirin (__________________) (covalently or non-covalently?) modifies and, (reversibly or irreversibly?) inhibits platelet COX.
The enzyme is inhibited for the _____ of the platelet (~____-___days).
Effect achieved at very (low or high?) dose.
acetylsalicylic acid
Covalently; irreversibily
lifetime; 8 -11
Low
Cardiovascular effects of aspirin
PLATELTS:
• Basis of therapeutic efficacy in _____ and ——— (reduces mortality and prevents recurrent events).
stroke and MI
Additional Cardiovascular effects of aspirin
• Blood vessels/smooth muscle
COX-2 derived PGI2 can antagonize ________ and _________ induced vaso_______ (NSAIDs can ______ bp).
catecholamine- and angiotensin II-
constriction
elevate
Additional Cardiovascular effects of aspirin
• Atherosclerosis
Inhibition of COX-____ can destabilize atherosclerotic plaques (due to its ________________ actions)
2
anti- inflammatory
NSAIDs can elevate Blood pressure
T/F
T
Renal effects of nsaidS
COX-1 and COX-2 – generated PGs (TxA2, PGF2 , PGI2 (_____), PGE2 (______), powerful vaso______) can both increase and decrease Na+ retention (_________ predominates), usually in response to changes in _____________, extracellular tonicity or (low or high?) bp.
Glomerular; medulla
dilators; natriuresis
tubular Cl-; low
Renal
NSAIDs tend to promote Na+ ________ and can therefore _____ease bp.
L
retention; incr
Renal
PGs have (minimal or maximal?) impact on normal renal blood flow, but become important in ____________ kidney.
Minimal
the compromised
Renal
Patients (particularly ________ and _________ ) are at risk of renal ischemia with NSAIDs.
elderly and volume depleted
Gastrointestinal effects of NSAIDs
PGs (generated via COX-1)
1)inhibit ________ secretion,
2) stimulate _____________ secretion, vaso_________ and therefore,
3) are _________ for the gastric mucosa.
stomach acid
mucus and HCO3-
dilation; cytoprotective
NSAIDs Can counteract effects of many anti-hypertensives like diuretics, ACE inhibitors and -AR antagonists
T/F
T
Gastrointestinal effects of NSAIDs
Therefore, NSAIDs with COX-1 inhibitory activity will produce opposite effects, leading to:
Gastric ______ , gastric ______, sudden ___________ (effects are dose-dependent)
distress
bleeding
acute hemorrhage
Gestation
PGs (generated from COX-___) are involved in the initiation and progression of labor and delivery. Therefore, inhibition of their production by NSAIDs can _____________
2
prolong gestation.
Respiratory system
(Low or High?) doses (salicylates) cause _____________________ with ___eased CO2 production (COX-______ effects).
Low
partial uncoupling of oxidative phosphorylation
incr; independent
Respiratory system
Increase in plasma CO2 leads to _______. Even higher doses cause ________ of respiration.
hyperventilation; depression
Other uses of NSAIDs (mechanisms less understood) - Decreased risk of fatal ____________
colon carcinoma
Aspirin - Therapeutic Uses
_______,_______
_______________ due to platelet aggregation (CAD, post-op DVT)
Antipyretic, analgesic
Prophylaxis of diseases
Aspirin - Therapeutic Uses
Anti-inflammatory: ____________,____________, other rheumatological diseases.
(Low or High?) dose needed (5-8 g/day).
But many patients cannot tolerate these doses (GIT); so, ________ derivatives, ______,_______ tried first.
rheumatic fever, rheumatoid arthritis (joint dis)
High; proprionic acid
ibuprofen, naproxen
Aspirin - Therapeutic Uses
__________ and ________ of pregnancy (?excess TXA2)
Pre-eclampsia and hypertension
Paracetemol (______) has significant anti- inflammatory effect
T/F
Tylenol
F
no significant anti- inflammatory effect,
Paracetemol (tylenol) – used for its ______ ———- effect.
(Poorly or Well?) -absorbed and (with or without?) GIT irritation.
Mild analgesic
Well
Without
Paracetemol (tylenol)
Serious disadvantage: at high doses, _______________ results.
severe hepatotoxicity
Mechanism of action of NSAIDs
Analgesia
– works (centrally or peripherally?)
-associated with ___________ actions that results from ______ of ________ in inflamed tissues.
Works both centrally and peripherally.
anti-inflammatory
inhibition of PG synthesis
Mechanism of action of NSAIDs
PGs cause little pain relief themselves
T/F
T
But
potentiate the pain caused by other mediators of inflammation (e.g., histamine, bradykinin).
Mechanism of action of NSAIDs
Anti-inflammatory action –
Normally, PGs in inflammation leads to vaso______ and ____eased vascular permeability.
- Inhibition of PGs by NSAIDs _______, not ________, inflammation
- Very _________ from pain, stiffness, swelling for RA often prescribed for their anti-inflammatory actions.
dilation; incr
attenuates, not abolish
modest relief
NSAIDs inhibit mediators of inflammation
T/F
F
NSAIDs do not inhibit mediators of inflammation
Mechanisms of Action of NSAIDs
Antipyretic actions – Fever, heat stroke, increased T° are _________ problems.
- So, NSAIDs _________ body T°.
hypothalamic
do not decr
Mechanisms of Action of NSAIDs
Antipyretic actions
- Fever occurs due to release of _______ (e.g., interleukin-1) released from ______ and acts directly on the ________ in _________ , leading to an increase in body T°.
- This is associated with increase in brain ____ (pyrogenic).
- Aspirin prevents the T°-rising effects of interleukin-1 by ____________
endogenous pyrogens
leucocytes; thermoregulatory centers
hypothalamus; PGs
preventing the incr in brain PGs
Mechanisms of Action
Aspirin prevents the T°-rising effects of interleukin-___ by _______________
1
preventing the incr in brain PGs
Mechanism of Action on the Active Site of COX
Possess a (short or long?) channel
Non-selective NSAIDs enter channel (but not ______).
_____ channels by _____________________ half of the way in.
This (reversibly or irreversibly ?) inhibits the COX by preventing ______________
Long ; aspirin
Block; binding with H- bonds to an arg
reversibly; arachidonic acid from gaining access.
Whose Channel is wider
COX-1 or COX-2
COX-2 channel is wider than in COX-1
Mechanism of Action on the Active Site of COX
Aspirin ______ COX (at _____) and is, therefore, irreversible.
acetylates
ser530
Selective COX-2 inhibitors generally (more or less?) bulky molecules
More
Selective COX-2 inhibitors can enter and block the channel of COX-2, but not that of COX-1.
T/F
With reason
T
Because Selective COX-2 inhibitors are generally more bulky molecules - can enter and block the channel of COX-2, but not that of COX-1.
Paracetamol – reduces _______________:
Recall: _______ is necessary to activate _____ enzyme to the ____.
.
cytoplasmic peroxide
peroxide
heme; Fe
Paracetamol –
Acute inflammation: paracetamol is not very effective because _________________________________, which overcome the actions of the drug.
neutrophiles and monocytes produce much H2O2 and lipid peroxide
Selective COX-2 Inhibitors
Anti-inflammatory with (more or less?) adverse effects, especially ___ events.
Potential toxicities: ______ and _______ , leading to increased risk of ______ events.
Less; GI
kidney and platelets
thrombotic
Selective COX-2 Inhibitors
Associated with MI and stroke because _________________.
Thus,.. should not be given to patients with ____ disease
they do not inhibit platelet aggregation
CV
Selective COX-2 Inhibitors
Has a Role in ______ prevention
Has a Role in ________ disease
Cancer
Alzheimer’s
Lipoxins – (Anti or Pro?) -inflammatory Mediators
During inflammation, cells die by ______.
Anti-
apoptosis
Lipoxins signal _______ to clean up.
During the acute inflammatory process, cytokines (e.g., IFN-γ and IL-1β) can induce the expression of anti-inflammatory mediators (_______ and _______), which promote the _______ phase of inflammation.
macrophages
lipoxins and IL-4
resolution
Aspirin Toxicity - Salicylism
________-________-________– ____ impairment – ____ vision
Confusion and drowziness
________ and _____ventilation
Nausea, vomiting
Headache - timmitus - dizziness
Hearing ; dim
Sweating and hyper
Aspirin Toxicity - Salicylism
Marked _____ disturbances
Hyper______
Dehydration
_________ and _________ collapse, coma convulsions and death
acid-base
pyrexia
Cardiovascular and respiratory
Aspirin Toxicity - Treatment
Decrease absorption - _______,_______,______
Enhance excretion – ion trapping (_________ urine), forced ______, _______
Supportive measures - fluids, decrease temperature, bicarbonate, electrolytes, glucose, etc…
activated charcoal, emetics, gastric lavage
alkalinize; diuresis; hemodialysis
Other NSAIDs
Phenylbutazone: additional _____ effect. Can cause ________ anemia.
uricosuric
Aplastic
Other NSAIDs
_______________: has additional uricosuric effect. Aplastic anemia.
.
Phenylbutazone
Other NSAIDs
Indomethacin: Common adverse rxns: ______,__________, CNS most common: hallucinations, depression, seizures, headaches, dizziness.
gastric bleeding, ulceration
Other NSAIDs
___________: Common adverse rxns: gastric bleeding, ulceration, CNS most common: hallucinations, depression, seizures, headaches, dizziness.
Indomethacin
Other NSAIDs
Proprionic acids: (better or worse?) tolerated. Differ in pharmacokinetics; ________,________,_______ widely used for inflammatory joint disease and (few or plenty?) side-effects.
better
ibuprofen, fenbufen, naproxen
Few
Other NSAIDs
__________ : better tolerated. Differ in pharmacokinetics; ibuprofen, fenbufen, naproxen widely used for inflammatory joint disease and few side-effects.
Proprionic acids
Other NSAIDs
Acetaminophen: differs in effects and adverse reaction from rest. Main toxicity: ________ due to toxic intermediate which ________ ————-.
Treat with _____________
hepatitis
depletes glutathione
N-acetylcysteine.
Other NSAIDs
___________ : differs in effects and adverse rxn from rest. Main toxicity: hepatitis due to toxic intermediate which depletes glutathione. Treat with N-acetylcysteine.
Acetaminophen
Other NSAIDs
_________
___________
__________
____________
Proprionic acids
Acetaminophen
Phenylbutazone
Indomethacin
Drug reaction between NSAIDs and Lithium
The effect on lithium
NSAIDs inhibits renal elimination of lithium
Elevated serum lithium levels
Drug reaction between NSAIDs and anti hypertensives
Effect on the anti hypertensives
NSAIDs may cause fluid retention and edema
Decreased antihypertensive effect
Drug reaction between NSAIDs and anticoagulants
Effect on the anti coagulants
Displacement/additive effect
Increased anticoagulant activity
Gout Characterized by deposition of _______ in the joint leading to painful ______.
Na urate crystals; arthritis
Gout
Acute attacks treated with _______, ________, or other _______, but not with _________ because it ___________________________ by ________________ in the renal tubules
indomethecin; naproxen; NSAIDs
aspirin
increases plasma urate levels at low doses
inhibiting uric acid secretion
Gout
Colchicine – bonds ________ in leukocytes that prevents ___________ In _________ which inhibits the ____________ and __________ of leukocytes to the area of _____________ thereby decreasing _________
tubulin
polymerization in microtubules
phagocytic activity and migration
uric acid deposition; inflammatory repsonse.
Prophylactic treatment of Gout
Allopurinol lowers plasma urate by ________________
Uricosuric drugs inhibit ____________ thereby increasing ________.
Should drink plenty of _____ to prevent _________________
But These drugs (more or less?) effective and (more or less?) toxic than allopurinol.
inhibiting xanthine oxidase
renal tubular reabsorption of uric acid ; excretion
H2O; crystallization of urate in the urine.
Less; more
Uricosuric drugs (_________,_________)
sulfinpyrazone, probenicid
Period purr
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