NSAIDs Flashcards by Iseoluwa Ojo

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

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The ability to mount an inflammatory response is essential for survival in the face of environmental pathogens and injury

T/F

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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

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At least ____ phospholipases mediate arachidonate release from membrane lipids

List them

three

cytosolic (c) PLA2, secretory (s) PLA2, and calcium-independent (i) PLA2.

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Common Pharmacological Effects of NSAIDs to be covered below

______
Anti________
Anti- __________
Some are ____________

Analgesic

pyretic

inflammatory

Uricosuric

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Common Pharmacological Effects of NSAIDs to be covered below

Analgesic (______________ effect)

Antipyretic (_____ effect)

Anti-inflammatory (except __________)

CNS and peripheral

CNS

acetaminophen

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Common Pharmacological Effects of NSAIDs to be covered below

Analgesic : may involve _____ related effects

Anti-inflammatory : due mainly to _________

non-PG

PG inhibition.

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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 synthase; gastric

dyspepsia, gastritis

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Common Adverse Effects of NSAIDs

________ Dysfunction

_____________ and ________ ulceration with bleeding

___________ Failure in susceptible

__________ retention and _____

Platelet

Gastritis and peptic

Acute Renal

Sodium+ water; edema

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Common Adverse Effects of NSAIDs

________ nephropathy
Prolongation of _______ and ________

____________

GIT _______ and _______

Analgesic

gestation and inhibition of labor.

Hypersenstivity

bleeding and perforation

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Hypersenstivity resulting from use of NSAIDs is immunologic

T/F

not immunologic but due to PG inhibition

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COX

Exists in the tissue as ______ isoform (COX-__).

At site of inflammation, cytokines stimulate the induction of the ____ isoform (COX-____).

constitutive ; 1

2nd; 2

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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

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COX

Most currently used NSAIDs are somewhat selective for COX-___, but selective COX-___ inhibitors are available.

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COX

________,________,_________– selective COX-2 inhibitors.

Celecoxib, etoricoxib, valdecoxib

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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.

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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

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The Salicylates - Aspirin

Duration of action ~_____.

______ taken.

4 hr

Orally

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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

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The Salicylates - Aspirin

Most salicylate is converted in _____ to H2O-soluble conjugates that are rapidly excreted by _____

liver

kidney

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Effect of Aspirin

On GI System

Dose dependent _______
______ syndrome

hepatitis

Reye’s

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Effect of Aspirin

Metabolic
___________ of _______

_______glycemia and depletion of ______ and ______ ———-

Uncoupling of Oxidative Phosphorylation

Hyper

muscle and hepatic glycogen

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Effect of Aspirin

Endocrine: corticosteroids, thyroid

Okay?

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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

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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

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

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

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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