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Pharmacology > NSAIDS > Flashcards

NSAIDS Flashcards

1
Q

DRUG LIST

A

Aspirin and friends
– Aspirin
– Salicylate

NSAID’s
– Ibuprofen
– Naproxen
– Acetaminophen 
– Celecoxib

GI protective Drugs
– Omeprazole
– Misoprostol

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2
Q

NSAID Excretion

A

RENAL

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3
Q

NSAID pharmacokinetics

A

Competitive inhibitors of COX enzymes via reversible active site inhibition (note: aspirin is IRREVERSIBLE)

Major biological effect is related to inhibition of prostaglandin synthesis

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4
Q

NSAID’s‐ Therapeutic Effects

A

At lower doses:
• Analgesia (can be additive with opioids)
• Antipyretic

At HIGHER doses
• Anti‐inflammatory
– Musculoskeletal disorders: Arthritis
– Symptomatic relief

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5
Q

Arachidonic Acid Pathway

A 
Stimulus (chemical/physical stress) >>
Phospholipase A2 >>
Phospholipids >>
Arachidonic acid >>
EICOSANOIDS
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6
Q

Eicosanoids

A

Oxygenated polyunsaturated fatty acids

Act in paracrine/autocrine manner

Bind to specific receptors on cell membranes
– Arachidonic acid (precursor)
• Prostaglandins
• Thromboxanes
• Leukotrienes (Dr. Ceryak)
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7
Q

Prostanoid pathway

A 
Cyclooxygenase (COX) >>
prostaglandins
prostacyclin
thromboxane
(all prostanoids)
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8
Q

Prostanoids: Prostacyclin

A

PGI2: (Prostacyclin)
• Synthesized by vascular endothelium
• Vasodilation
• Inhibits platelet aggregation (counteracts TXA2)

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9
Q

Prostanoids: Thromboxane

A

TXA2: (Thromboxane)
• Platelet aggregation (made from platelet COX‐1)
• Vasoconstriction/Bronchoconstriction

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10
Q

Prostanoids: PGE1

A

PGE1:
• Misoprostol: PGE1 analog, prevents peptic ulcer by preventing acid secretion, termination of early pregnancy (in combo with mifepristone)

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11
Q

Prostanoids: PGE2

A

PGE2:
• Increases body temperature (produced by COX‐2 after interleukin‐ 1 stimulation)

• Inflammation (via  blood flow, vasodilation/leukocyte infiltration, edema)
– Suppresses humoral antibody response

• Protective against peptic ulcers

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12
Q

Eicosanoid Receptors

A

Increase cAMP or cytosolic Ca++

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13
Q

Cyclooxygenase (COX)

A

Two isoforms:
• COX‐1 (PGH synthase‐1)
– Constitutive expression in most tissues (ALWAYS)
• Inhibition leads to GI‐related side effects

• COX‐2 (PGH synthase‐2)
– Expression is induced by ‘stress’, growth factors, cytokines and inflammatory mediators .
• Major source of prostanoids at sites of inflammation (cancer)

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14
Q

NSAIDS and COX inhibition

A

All NSAIDS are nonselective, EXCEPT celecoxib (note: blackbox warning for CV risk)

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15
Q

NSAID use

A

Analgesic

• Particularly effective when pain is due to an inflammatory process

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16
Q

NSAID use

A

Antipyretic‐ lowers fever
**PGE2 is elevated by cytokine release in and adjacent to the pre optic hypothalamus triggering an elevation of body temp and decrease in heat lost (NSAIDs inhibit prostaglandin synthesis)

17
Q

NSAID use

A

Anti‐inflammatory
• Generally need larger doses
• ONLY SYMPTOMATIC RELIEF

18
Q

NSAIDS and Cancer

A

Increasingly apparent relationship between chronic inflammation and cancer

19
Q

Common Adverse Effects for NSAID’s: GI

A

Pain, nausea, diarrhea, gastric ulcers/erosions, GI hemorrhage, perforation (other NSAIDs less than aspirin)

20
Q

Common Adverse Effects for NSAID’s: Renal

A
  • Renal insufficiency, renal failure, hyperkalemia, proteinuria
  • decrease effectiveness of antihypertensive meds
  • Analgesic nephropathy: slowly progressive renal failure, decreased concentrating capacity; associated with high doses of combinations of NSAID’s and frequent urinary tract infections – Decreased PGE2 = less renal blood flow?

Recall PGE2 is involved in blood flow.

21
Q

NSAID and pregnancy

A

CONTRAINDICATED (only tylenol ok)

22
Q

Common Adverse Effects for NSAID’s: Hypersensitivity

A

Hypersensitivity reactions – not IgE‐meditaed

• Aspirin intolerance/allergy is contraindication for therapy with any other NSAID

RED FLAG for aspirin = nasal polyps

23
Q

Common Drug Interactions Associated with NSAID’s

A

1) Use of NSAID’s concomitantly with low dose aspirin (cardioprotective)
• Ibuprofen impairs aspirin’s ability to acetylate the active site of COX and therefore entire anti platelet effect goes away

2) With ACE inhibitors
• ACE inhibitors + NSAID’s = hyperkalemia, (elderly, HTN, DM, ischemic heart disease)

• May decrease EFFICACY of ACE inhibitors (due to inhibition of vasodilatory PGs?), renal toxicity (NSAIDs decrease renal EXCRETION of ACE inhibitors)

24
Q

DI: Warfarin

A

NSAIDs and aspirin all inhibit platelet function: increased bleeding

Metabolized by CYP2C9 (inhibits metabolism of warfarin)

25
Q

Aspirin MOA

A 
Analgesic
Antipyretic (lo dose)
Anti‐inflammatory‐ non‐selective irreversible inhibitor of both COX‐1 and COX‐2
– At higher doses than the analgesic/antipyretic dose
26
Q

Aspirin Metabolism

A

Acetylates Cox 1 and 2

Liver breaks down to acetic acid and salicylate (salicylate = competitive and reversible inhibitor of COX)

27
Q

Aspirin: cardiovascular use

A

Cardiovascular‐Cardioprotective (low doses)
(decreases platelet aggregation)

  • Platelet effects last 4‐7 days due to permanent inactivation of platelet COX’s; thromboxane (TXA2) synthesis prevented
  • Increased bleeding times

• Decreased MI
– 20‐25% aspirin (low dose)
– 10% naproxen
– Evidence does not support low‐dose aspirin in healthy individuals without CV risk factors (only in people with MI)

28
Q

Aspirin Adverse effects

A

Gastrointestinal Effects
• Prevents synthesis of protective PGE1/2 for GI epithelial cells in stomach lining (increase acid secretion)
• Co‐adm with PPI

Hypersensitivity (0.5‐2.5%)
• Often nasal polyps
• Reaction is not immunologically mediated
• PROVOKED BY LOW DOSES
• Probably due to diversion of AA to the
leukotriene pathways (Cox‐1)
• Mast cell and eosinophil involvement
CROSS SENSITIVITY with all NSAIDS
29
Q

Aspirin Adverse effects 2

A

Acid‐base balance
– at therapeutic dose: respiratory alkalosis (stimulation of respiratory center/medulla), increase CO2 production

– at toxic doses: get a respiratory and metabolic acidosis due to accumulation of (lactic) acid products

30
Q

Aspirin Adverse effects 3

A

Renal Effects
• Analgesic nephropathy – Slowly progressive renal failure, decreased renal perfusion

Ototoxicity
• Tinnitus, high frequency hearing loss

31
Q

Ibuprofen facts

A
  • recently approve for IV

- short 1/2 life (2 hrs)

32
Q

Naproxen

A
  • LONG 1/2 life (14 hrs)
33
Q

Celecoxib (Celebrex)

A

Preferentially inhibits COX2, therefore less GI side effects!!

Risk of thrombosis, hypertension, atherogenesis —avoid in patients prone to cardiovascular or cerebrovascular disease.

34
Q

Celecoxib (Celebrex): CV risk

A

Inhibits PG12 which is a prostacylcin, therefore inhibits macrophage activation that releases Cox 2 (decrease platelet aggregation) and increased leukotrienes

35
Q

GI Protective Agents for Use with NSAIDs

A 
Misoprostol
• PGE1 analog
• Inhibits gastric acid, prevents ulcers
• Induces labor/Uterine contractions
• Abortifacient

Omeprazole
• Better tolerated than misoprostol
• Proton pump inhibitor
• Prodrug/enteric coating

36
Q

Acetaminophen Administration

A

PO, IV

Analgesic and antipyretic activity
– NO STRONG ANTI‐INFLAMMATORY ACTIVITY

37
Q

Acetaminophen Metabolism

A

Reversible inhibitor of Cox 1/2

Gets metabolized by glucuronidation and sulfation. If you saturate the enzyme, it goes down a third pathway. Forms a reactive toxic intermediate that binds to proteins in the liver. (the enzyme CYP2E1 involved can be increased by ethanol)

38
Q

Acetaminophen‐ Hepatotoxicity

A
  • Single doses of 10‐15 g‐serious hepatotoxicity; 20‐25g are potentially fatal
  • Induction of CYP2E1 increases risk of toxicity
  • Symptoms‐ nausea, abdominal pain and anorexia
  • Plasma transaminases elevated 12‐36 h after ingestion
  • Clinical indication of hepatic damage 2‐4 d; liver enzymes peak 72‐96 h after drug
39
Q

Acetaminophen‐ Hepatotoxicity Tx

A
  • Activated charcoal to reduce absorption

* N‐acetylcysteine (Mucomyst), detoxifies NAPQI

Pharmacology (9 decks)

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