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Pharmacology- Test 4 > NSAIDs and COX inhibitors > Flashcards

NSAIDs and COX inhibitors Flashcards

1
Q

Most of the actions of the NSAIDs can be attributed to what enzyme? What does this enzyme do?

A
  • Cyclo-oxygenase (COX)
  • This enzyme metabolizes arachidonic acid (fatty acid component of membranes) to the endoperoxide intermediates and ultimately to the formation of prostanoids (PGD2, PGE2, PGF2alpha, PGI2, and TXA2)
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2
Q

What is COX-1, COX-2?

A
  • COX-1 is a constitutive enzyme found in a variety of tissues including stomach and colon, kidney, vascular smooth muscle, and platelets (involved in many “housekeeping” functions of prostanoids)
  • COX-2 is involved in inflammatory responses, fever, and algesia (typically induced). Also expressed in blood vessels, kidney, heart, and brain
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3
Q

Prostanoids: What is the major cell or tissue structures for each of these? (5)

A

(1) PGD2- mast cells, dendritic cells and lymphocytes (brain, airways)
(2) PGE2- made by a variety of cells and tissues (brain, kidneys, VSNCs, platelets)
(3) PGI2- vascular cells including endothelial cells, vascular smooth muscle and endothelial progenitor cells
(4) PGF2alpha- female reproductive organs, elevated in arthritis
(5) TxA2- platelets and macrophages

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4
Q

What are the anti-inflammatory properties NSAIDs? (5)

A

(1) They are mainly due to inhibition of COX-2
(2) They reduce vasodilation, edema, and pain associated with inflammation in acute phases
(3) The anti-inflammatory effects of NSAIDS require significantly higher doses (~2x compared to analgesic or antipyretic)
(4) Low pH inflammatory milieu leads to increased local intracellular concentrations of NSAIDS (ion trapping of an acidic drug)
(5) By inhibiting COS, arachidonate may be diverted to lipoxygenase pathway (increased production of leukotrienes); relevant in asthma

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5
Q

T/F NSAIDs reduce inflammation with acute phase of inflammation while corticosteroids inhibit all stages of inflammation.

A

TRUE

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6
Q

T/F NSAIDs produce anti-inflammatory, analgesic, and antipyretic effects at the same dosage.

A

FALSE; NSAIDS require significantly higher doses (~2x) to produce anti-inflammatory effects

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7
Q

What are the analgesic properties of NSAIDs?

A

(1) Inhibition of COX-2 prevents formation of prostaglandins (PGE2) at peripheral sites
(2) Prostaglandins sensitize nocioceptive receptors to algesic mediators. PGE2 can potentiate the action of transient receptor potential (TRP) ion channels on sensory neurons.

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8
Q

What are mild analgesics effective at treating? (5) What is the dosage?

A

Very effective at treating certain types of pain

(1) chronic post-operative pain
(2) pain from inflammation
(3) integumental pain
(4) premenstrual syndrome headache
(5) myalgia
- achieved with “ordinary” doses of NSAIDs (e.g. 650mg aspirin, 400mg ibuprofen)

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9
Q

T/F NSAIDs do not alter sensory perceptions.

A

TRUE

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10
Q

T/F NSAIDS are not used in combination with opioids because of the drug interactions they have with each other.

A

FALSE; they are commonly used in combination in order to achieve a greater analgesic effect. It allows you to use a slightly lower dose of the opioid to get rid of the side effects with those types of drugs.

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11
Q

T/F NSAIDs are effective against all types of pain.

A

FALSE; ineffective against certain types of pain

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12
Q

What are the anti-pyretic properties of NSAIDs?

A

(1) Centrally mediated effect via resetting of the temperature control center in the hypothalamus (IL-1 (Interleukin-1) mediated stimulation of prostaglandin (PGE2) production)
(2) NSAIDs inhibit COX-2 and ultimate production of prostaglandins in the brain.

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13
Q

What is the dosage to effectively reduce elevated body temperature (fever) by NSAIDs?

A

“ordinary” doses (650mg aspirin, 400mg ibuprofen)

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14
Q

What is the difference of COX-1 and COX-2 in platelet aggregation? What is the name of the Cox-2 specific drug?

A
  • Inhibition of platelet COX-1 derived TxA2 with the net effect of inhibiting platelet aggregation
  • Endothelial COX-2 derived PGI2 inhibits platelet aggregation (therefore, inhibition augments aggregation by TxA2) - Coxibs
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15
Q

T/F Aspirin (acetylsalicylic acid) covalently modifies, and reversibly inihibits platelet cyclo-oxygenase.

A

FALSE; it irreversibly inhibits platelet cyclo-oxygenase. The enzyme is inhibited for the lifetime of the platelet (~8-11 days)

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16
Q

What is the therapeutic efficacy of Aspirin good in treating?

A

Stroke and myocardial infarction

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17
Q

What happens when you take Aspirin and Ibuprofen at the same time? (when you take a COX-1 inhibitor with acetylsalicylic acid)

A

You’re going to get an antagonism because it’s going to block the actions of the aspirin (therapeutic thing to think about because a lot of people take low dose aspirin)

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18
Q

What is the dose for Aspirin regarding platelet modification?

A

Achieved at very low dose. Selective inhibition of COX-1 due to impact on platelets in portal circulation

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19
Q

What are 2 additional cardiovascular considerations regarding NSAIDs?

A

(1) Blood vessels/smooth muscle: COX-2 derived PGI2 can antagonize catecholamine and angiotensin II induced vasoconstriction
(2) Atherosclerosis: COX-2 is upregulated in atherosclerotic plaques. Role in atherosclerosis is unclear.

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20
Q

T/F NSAIDS can elevate blood pressure.

A

TRUE

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21
Q

T/F COX-2 has an anti-atherogenic property.

A

FALSE; it is unclear whether it is pro- or anti-atherogenic.

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22
Q

Do COX-1 and COX-2 generate prostanoids (PGE2, PGI2, PGF2alpha, TxA1) that “increase or decrease” sodium retention? What is this usually in response to?

A

BOTH increase AND decrease (natriuresis predominates); usually in response to changes in tubular chloride, extracellular tonicity or low BP.

23
Q

T/F NSAIDs tend to promote sodium retention and can therefore increase BP.

A

TRUE; can counteract effects of many anti-hypertensives (diuretics, ACE inhibitors, and B-AR antagonists)

24
Q

Why are prostaglandins important in the compromised kidney? (They have minimal impact on normal renal blood flow)

A
  • In renal failure, prostaglandins facilitate renal perfusion by promoting vasodilation of afferent arterioles
  • Patients (particularly elderly and volume depleted) are at risk of renal ischemia with NSAIDs
25
Q

What do prostaglandins (PGE2) generated by COX-1 do in the GI tract? (3)

A

(1) Inhibit stomach acid secretion
(2) Enhance mucosal blood flow
(3) Promote intestinal secretion of cytoprotective mucus

26
Q

NSAIDs with COX-1 inhibitory activity will produce opposite effects in the GI tract, leading to what things? (3)

A

(1) Gastric distress (dyspepsia, heartburn)
(2) Gastric bleeding/ulcers
(3) Sudden acute hemorrhage
- these effects are dose dependent-

27
Q

What do NSAIDS do in regards to gestation?

A

Prostaglandins are involved in the initiation and progression of labor and delivery. Therefore, the inhibition of their production by NSAIDs can prolong gestation.

28
Q

What do NSAIDS do in regards to the respiratory system? Is this COX dependent or independent?

A

high doses of salicylates cause partial uncoupling of oxidative phosphorylation with increased CO2 production (COX independent effects). Increase in plasma CO2 results in hyperventilation. Even higher doses cause depression of respiration

29
Q

What are the Salicylates? What type of NSAID is this?

A

(1) Acetylsalicylic acid (aspirin)

- prototype non-selective NSAID

30
Q

Salicylates: Mechanism of action

A

Irreversible inhibition of COX via acetylation of active site serine

31
Q

What is the duration of effect of Salicylates?

A

Duration of effect depends upon the turnover of the cyclo-ocygenase in the particular tissue

32
Q

T/F Acetylsalicylic acid has a first order metabolism of salicylate.

A

FALSE; zero order; aspirin is rapidly converted to salicylate

33
Q

What is the distribution of ASA?

A

widely, bound to plasma protein (~80%)

34
Q

What is the absorption of ASA?

A

rapid, partly in the stomach, mostly from upper small intestine

35
Q

What is the excretion of ASA?

A

metabolites and as free salicylate (excretion enhanced by alkalinization)

36
Q

Salicylates: Side effects/toxicity (4)

A

(1) GI distress and bleeding
(2) Prolongation of bleeding time: important for those with coagulation problems (contraindicated in patients taking Warfarin)
(3) Contraindicated in children with chicken pox of influenza (Reye’s syndrome)
(4) Salicylism (dose dependent)

37
Q

What is Salicylism?

A

Side effect of ASA

  • Mild: headache, dizziness, sweating, and tinnitus
  • Severe: CNS disturbances, skin eruptions, fever, nausea, acid-base disturbances (respiratory alkalosis followed by respiratory and metabolic acidosis)
38
Q

What are the non-selective/non-salicylate drugs? What are they derived from?

A

(1) Ibuprofen
(2) Naproxen
- all proprionic acid derivatives

39
Q

Which non-selective/non-salicylate drug has a relatively long plasma half-life?

A

Naproxen

40
Q

What is the COX-2 selective inhibitor? What do they lack and what are they approved for?

A

(1) Celecoxib (8-10 fold selective for COX-2)
- they lack the COX-1 side effects (GI, platelet)
- they are approved for rheumatoid arthritis, osteoarthritis, acute pain

41
Q

What are the CV risks of COX-2 inhibitors? (5)

A

(1) inhibition of anti-thrombogenic prostaglandins (i.e. PGI2)
(2) increase blood pressure
(3) increase oxidative stress
(4) decrease lipoxins
(5) inhibition of vascular remodeling

42
Q

What is the anti-pyretic, analgesic drug that does NOT have anti-inflammatory effects?

A

Acetaminophen

43
Q

Acetaminophen- Mechanism of action

A

(1) COX- independent effects (e.g. cannabinoids, transient receptor potential cation channel (TRPA1))
(2) COX- dependent effects

44
Q

When is Acetaminophen a poor inhibitor of cyclo-oxygenase?

A

In the presence of peroxides, which are found in high levels at inflammatory sites

45
Q

T/F Acetaminophen is well tolerated and typically does not cause GI distress and also does not effect platelet function.

A

TRUE

46
Q

Where is acetaminophen metabolized? What does this mean in regards to high doses? How does this happen?

A

Metabolized in the liver; high doses cause hepatotoxicity
- after depletion of glutathione, it metabolites form protein adducts, leading to increased oxidative stress, mitochondrial dysfunction, DNA damage, and subsequently cell death.

47
Q

What can treat an overdose of acetaminophen? How does this happen?

A

Sulfhydryl reagent (Acetylcysteine) which replenishes glutathione levels.

48
Q

What is the effect of combination therapy in NSAIDs and Opioids?

A

Additive at low opioid doses (not recommended for chronic pain)

49
Q

NSAIDs are the first line therapy for what rheumatoid condition? Which ones are most used?

A

Rheumatoid arthritis; high dose non-selective COX or COX-2 selective inhibitors

50
Q

What are the two therapeutic strategies in treating gout? What drugs are used for this?

A

(1) Acute targets the pain and inflammation (Colchicine, Ibuprofen, Naproxen)
(2) Chronic therapy is designed to either increase excretion or decrease production of uric acid (Allopurinol, Probenicid)

51
Q

T/F Aspirin is typically used as acute therapy for gout.

A

FALSE; you do NOT use aspirin because low dose acetylsalicylic acid inhibits uric acid secretion

52
Q

Colchicine- Mechanism of action; therapeutic uses

A
  • Inhibits microtubule polymerization, mitosis, and cytokinesis
  • use to relieve acute attacks and prophylactically to minimize frequency and severity of occurences
53
Q

What does Allopurinol do?

A

(1) inhibitor of enzymatic production of uric acid

(2) inhibits the enzyme xanthine oxidase

54
Q

What does Probenicid do?

A

(1) inhibits renal tubular reabsorption of uric acid thereby promoting excretion (uricosuric)

Pharmacology- Test 4 (11 decks)

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