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Pharmacology for Anaesthetists > NSAIDS > Flashcards

NSAIDS Flashcards

1
Q

What is the most important pharmacokinetic aspect of NSAIDS and what are the implications of this

A

All are highly protein bound: 90 - 99%

  1. Overdose: binding sites all quickly saturated –> increase free fraction
    - -> total drug levels are not meaningful (? free vs bound)
    - -> More free drug to cause toxic effects
    - -> More free drug for removal by dialysis
  2. May displace other protein bound drugs changing the free concentration of those
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2
Q

What is the overall oral bioavailability for NSAIDS

A

Sluggish hepatic metabolism means excellent oral bioavailability 80 - 100 %

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3
Q

How are NSAIDS metabolised and excreted. What are the exceptions.

A

Hepatic metabolism (CYP3A and CYP2C) –> water soluble conjugates –> renal excretion.

Exceptions:

  1. Diclofenac
    - -> 70% hepatic metabolism then renal excretion
    - -> 30% cleared by biliary clearance: enterohepatic circulation (gut bacteria break down glucoronides –> liberating original drug molecule for reabsorption.
  2. Paracoxib (Pro-drug) rapidly metabolized by liver into Valdecoxib (20 seconds). Valdecoxib is then metabolized like other NSAIDS.
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4
Q

Why is the fact that NSAIDS are weak acids important

A

Alkalinizing the urine can trap the NSAID in the tubule (ionized) and enhance excretion of free drug in the context of toxicity

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5
Q

Why is the enterohepatic recirculation of diclofenac relevant

A

In the context of toxicity, multi-dose activated charcoal administration is indicated

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6
Q

Name and describe the function of the two most important isoforms of cycloxygenase

A

COX -1 = ‘Constitutive’ present in all tissues has a housekeeping funciton –> maintain various homeostatic baselines

GIT
E2 –> HCO3- mucus secretion in gastric mucosa
I2 –> HCO3- mucus secretion in gastric mucosa

PLATELETS
A2 –> Increase Platelet aggregation
I2 –> Decrease Platelet aggregation + Vasodilation

RENAL
E2 - Increase RBF (Vasodilation)
I2 - Increase RBF (Vasodilation)

COX-2 = Inducible enzyme (by IL-1, TNF alpha)

INFLAMED TISSUE
E2 –> Incr: vasc. permeability, oedema, nociception
I2 –> Incr: vasc. permeability, oedema, nociception

HYPOTHALAMUS
E2 –> Increase Tb set point (fever)

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7
Q

How do NSAIDS bring about analgaesia

A

Prostaglandins bind to nociceptor nerve endings (via G protein couple receptors) –> INCREASING the SENSITIVITY of the nociceptors to inflammatory stimuli: bradykinin and histamine.

NSAIDS decrease PG synthesis decreasing the sensitivity of nociceptors

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8
Q

List the adverse effects of NSAIDS

A

BOTH Selective COX 2 and Non-selective COX inhibitors

  1. Cardiovascular Event (MI/Stroke)
    - MI/Stroke
    - Increase BP
    - Accelerate atherosclerosis
    - Decrease cardioprotection of statins
  2. Nephrotoxicity
    - Excessive vasoconstriction –> reduced GFR –> AKI
  3. Exacerbation CCF
    - Reduced GFR –> Activation RAAS —> fluid retention + HPT (angiotensin)
    - NSAIDS double risk of hospitalization for CCF

Non-selective COX inhibitors only

  1. Gastric ulceration
    - Chronic NSAID = 4 - 5 x higher risk of GI bleeding
    - Enteric administration = even higher risk (ion trapping)
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9
Q

What is the difference between eicosanoids and prostanoids

A

Eicosanoids = Prostaglandins + Leukotrienes

Prostanoids = Prostaglandins

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10
Q

Differentiate COX 1, COX 2 and COX 3

A

COX 1
- Constitutively expressed in most tissues
- Housekeeping functions: GIT, Plts, RBF
(can be induced during cell differentiation and angiogenesis)

COX 2
- Induced by inflammation (interferon, IL1, TNF), hormones, hypoxia

COX 3
- No prostaglandin producing activity

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11
Q

How do NSAIDS bring about:

  1. Anti-inflammatory
  2. Analgaesic
  3. Antipyretic effects
A
  1. Anti-inflammatory - Block PGE2 and PGI2 synthesis (reduced VD and oedema)
  2. Analgaesia - Reduced PGE2, PGI2 –> reduced sensitization of nociceptors to inflammatory stimuli (bradykinin and histamine)
  3. Antipyretic - Blocks PGE2 mediated change in set point body temperature in the hypothalamus
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12
Q

What are the important pharmacokinetic properties of NSAIDS

A

Lipid soluble weak acids
Completely absorbed GIT
Highly protein bound (90 - 99%)
Half life varies 2 - 8 hours

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13
Q

What % of patients on chronic NSAIDS develop GIT bleeding

A

1 - 3%

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14
Q

How do NSAIDS elicit GIT erosion, ulceration and bleeding

A

PGI2 and E2 promote HCO3- rich mucus production i the GIT mucosa.

PGI2 and E2 also inhibit H+ secretion.

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15
Q

How does the risk of GIT ulceration change if patients are on concomitant aspirin

A

Increases

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16
Q

How does the risk of cardiovascular event differ for patients on long term COX 2 inhibitors.

State the mechanism for this

A

1.5 - 5 x increased risk of MI/CVA/Thromboemboli

COX 2 inhibit PGI2 (prostacyclin) release from endothelial cells.
- Vasodilator the prevents platelet aggregation

COX 1 containing platelets produce TXA2
- Vasoconstrictor and platelet aggregator

Overall –> prothrombotic effect with increased risk of CVE.

Avoid NSAIDS in patients with increase CVS risk factors

17
Q

Are NSAIDS arhythmogenic?

A

COX 2 produced prostacyclin = acts as an endogenous antiarrhythmic agentby inhibiting epicardial SNS activity

NSAIDS elicit proarrhythmic effects by inhibiting PGI2, fluid retention and electrolyte abnormalities

18
Q

How do NSAIDs cause heart failure

A 
Fluid retention (GFR down and activation of RAAS)
--> angiotensin --> increased BP

2 x risk of heart failure

19
Q

Describe the effects of NSAIDS in the kidneys

A

COX 1 controls: RBF

COX 2 controls: diuresis and electrolyte balance

COX 2 inhibition is associated with increased K levels

20
Q

Hod do NSAIDS affect bleeding

A

Inhibit TXA2 –> reduced platelet aggregation, VC and clot formation –> increased bleeding risk if used in combination with other anticoagulants.

Aspirin binds to platelets irreversibly. The anticoagulant effect of other NSAIDS is usually reversible and of much shorter duration.

21
Q

Should NSAIDS be omitted in patients with fractures

A

Evidence to support NSAID related delayed fracture healing is largely opinion based. Potential mechanisms have not been described.

Avoid in elderly, diabetics, malnourished where delayed fracture healing is already a concern

22
Q

Are NSAIDS used in malignancy?

A

Inhibition of PGE2 associated with apoptosis in cancer cells

Pharmacology for Anaesthetists (37 decks)

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