3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.3. Pharmacology
                  3.1.3.6. NSAIDs
 3.1.3.6.2. Nonspecific NSAIDs 

Nonspecific NSAIDs

Classifications of nonspecific NSAIDs

  • Carboxylic acids
    * Acetylated = aspirin
    * Nonacetylated = sodium salicylate, salicylamide, diflunisal
  • Acetic acid
    * Indomethacin, sulindac, tolmetin
  • Propionic acid
    * Ibuprofen, naproxen, fenoprofen, ketoprofen
  • Enolic acid
    * Phenylbutazone, piroxicam
  • Pyrrolopyrrole
    * Ketorolac

 

 

Pharmacokinetics of nonspecific NSAIDs in general

Absorption

  • Well absorbed from GIT
  • Low first-pass hepatic extraction
  • Only parecoxib is available for IV/IM administration

Distribution

  • Highly protein bound (>95%) to plasma albumin
  • Small Vd

Physicochemical properties

  • Weak acids
  • pK = 3-5

NB:

  • Acidic NSAIDs becomes sequestered preferentially in the synovial tissue of inflamed joints

Selected examples of nonspecific NSAIDs by classification

Carboxylic acid

Acetylated carboxylic acid

See Aspirin

Nonacetylated carboxylic acid

Diflunisal
  • Analgesic, antipyretic, and antiinflammatory
  • Mostly antiarthritic
    * Not very antipyretic
  • Also affect platelet function and bleeding time
    * But reversible, unlike aspirin

Acetic acid

Indomethacin

  • Methylated indole derivative
  • Analgesic, antipyretic, antiinflammatory
    * Comparable to salicylates
    * One of the most potent COX inhibitors
    * Comparable to colchicine in antiinflammatory potency in acute gout
  • Drug of choice in ankylosing spondylitis
  • Also used for closing patent ductus arteriosus
  • Could be used as initial treatment of Reiter's syndrome
  • More effective than aspirin in treatment of dysmenorrhoea
  • Side effects
    * GIT disturbance and severe frontal headaches are common
    * Inhibition of platelet aggregation
    * Renal and hepatic toxicity possible
    * Neutropenia, thrombocytopenia, and aplastic anaemia are rare

Sulindac

  • Substituted analogue of indomethacin
  • A prodrug
    --> Reduced to the sulfide form (active metabolite)
  • Similar analgesic, antipyretic, and antiinflammatory effects
  • Active metabolite is cleared slowly from plasma
    * Elimination half-time = 16 hours
  • Side effects:
    * GIT disturbane
    * Renal dysfunction
    * Altered liver function test
    * Inhibition of platelet aggregation

Tolmetin

  • More potent than salicylates, but less potent than indomethacin
  • Rapid oral absorption
  • Extensive protein-binding (99%)
  • Inactivated by decarboxylation

Propionic acid derivatives

Include:
* Ibuprofen
* Naproxen
* Diclofenac

Prominent analgesic, antipyretic, and antiinflammatory effects

  • Naproxen
    * Unique in its long elimination half-life
    * Twice daily dosing
    * Metabolised by dealkylation by CYP450
    * <10% excreted unchanged in urine
  • Ibuprofen
    * Primarily eliminated by metabolism to hydroxyl or carboxyl conjugates
    * <1% excreted unchanged in urine
  • Diclofenac
    * Metabolised to glucuronide, hydroxy, and sulphate conjugates
    * 90% of clearance within 3 to 4 hours

Side effects

  • GIT irritation and mucosal ulceration
    * But less severe than salicylates
  • Some inhibition of platelet function
  • May exacerbate renal dysfunction
  • Cross-reaction with hypersensitivity to salicylates

Drug interaction

  • Increased warfarin effect
    * Due to extensive plasma protein binding
    * Ibuprofen does NOT increase warfarin effect, possibly because it only occupies a small number of binding sites on albumin
  • Haematopoietic suppression occurs with chronic use of ibuprofen
    --> Agranulocytosis, bone marrow granulocytic aplasia

 

Diclofenac

[MCQ:Q248]

  • 99% protein bound (mosting albumin)
  • 50% first pass metabolism
  • Peak concentration = 10 - 30 min
  • Metabolised by hydroxylation and conjugation
  • Elimination halflife = 1.5 hours
  • Clearance = 3 mL/kg/min

 

Enolic acid

Phenylbutazone

  • Effective antiinflammatory
  • Useful in treatment of acute gout and rheumatoid arthritis
    * An effective alternative to colchicine (control in 85% of patients within 24-36 hours)
  • Toxicity (see "Side effects")
    * Not be used for longer than 7 days
    * Not to be used for analgesic and antipyretic (better alternatives available)
  • Rapid oral absorption
  • 98% protein binding
  • Oxyphenbutazone
    * A metabolite with antiinflammatory action similar to the parent drug
  • Slow excretion
    * Elimination half-time = 50-100 hours
    * Significant concentration in synovial spaces for up to 3 weeks after discontiuation

NB:

[MCQ:Q258]

  • Phenylbutazone is a useless drug which is commonly asked in exams
Side effects
  • Frequent severe side effects
    * Anaemia
    * Agranulocytosis
  • N&V, epigastric discomfort, skin rashes are common
  • Sodium retention
    * Due to reversible direct effect on renal tubules
    --> Plasma volume increases and pulmonary oedema possible
Interaction
  • Displace other drugs, and thus increasing their effects
    * Warfarin, oral hypoglycaemics, sulfonamides, thyroid hormones
  • Decreases uptake of iodine by thyroid gland

Piroxicam

  • Differ from other NSAIDs chemically
    * But similar in pharmacological actions
  • Extensive protein binding
    --> May increase the actions of other drugs such as aspirin and oral anticoagulants

Pyrrolopyrrole

Ketorolac

  • Potent analgesic effect
  • Moderate antiinflammatory effect (when given IM or IV)
  • Likely that ketorolac potentiate the antinociceptive actions of opioids
  • Ketorolac 30mg IM is equivalent to:
    * 10mg of morphine, or
    * 100mg of pethidine
  • After IM, peak plasma concentration is achieved within 45-60 minutes
  • Elimination half-time is about 5 hours
  • Protein-binding > 99%
  • Metabolised principally by glucuronic acid conjugation
Side effects
  • Side effect profile is similar to other NSAIDs
  • Inhibition of platelet aggregation
  • Life-threatening bronchospasm can occur
    * At-risk patients include asthma, aspirin sensitivity, and nasal polyposis
  • GIT irritation, N&V, sedation, peripheral oedema can occur
  • Without preexisting renal disease and dehydration, ketorolac is not likely to cause renal toxicity

Other antiarthritis drugs

Colchicine

  • Decreases inflammation and pain in acute gout
    * Only useful as treatment and prophylaxis of acute gout attacks
  • Effect within 24-48 hours of oral administration
  • Colchine is NOT an analgesic and does NOT provide relief against other types of pain or inflammation
  • Oral colchicine should be stopped when GIT symptoms appear
Mechanism of action
  • Does NOT influence renal excretion of uric acid
  • Changes fibrillar microtubules in granulocytes
    --> Inhibition of granulocytes migrating into inflammed areas
    --> Inhibition of inflammatory response evoked by sodium urate crystal deposited in joint tissues
Side effects
  • N&V, diarrhoea, and abdominal pain (in 80% of patients)
  • Enhancement of CNS depressants and sympathomimetics
  • Depression of medullary ventilatory centre
  • Severe toxicity --> Bone marrow depression with leukopenia and thrombocytopenia

Allopurinol

  • Preferred drug for primary hyperuricaemia of gout and hyperuricaemia during chemotherapy
  • Rapid absorbed orally
  • Metabolised to oxypurinol
    * Also an inhibitor of xanthine oxidase
    * Longer elimination half-time (21 hours) than parent drug (1.3 hours for allopurinol)
Mechanism of action
  • Does NOT influence renal excretion of uric acid either
  • Allopurinol interferes with the final steps of uric acid synthesis
    * By inhibiting xanthine oxidase (which converts xanthine to uric acid)
Side effects
  • Most common side effect = maculopapular rash
    * Essentially an immune complex dermatitis
    * Often preceded by pruritus
    * Pruritus is an indication to discontinue therapy
  • Fever and myalgia
  • Allopurinol can act as a hapten
    --> Nephritis, vasculitis, maculopapular rash
  • Hepatic dysfunction with elevated transaminase enzyme is common
  • Allopurinol inhibits the enzymatic inactivation of 6-mercaptopurine and azathioprine
    --> These drugs need to be reduced in dosage
  • Allopurinol also inhibits hepatic enzymes
    --> Increased effect of some drugs (e.g. oral anticoagulants)

NB:

  • Hapton = small molecule which can elicit an immune response only when attached to a large carrier such as protein

Uricosuric drugs

  • Uricosuric drugs act directly on renal tubules to increase the rate of excretion of uric acid and other organic acids (e.g. penicillin)
Probenecid
  • Completely absorbed after oral administration
  • Peak plasma concentration in 2-4 hours
  • Elimination half-time = 8 hours
  • Protein-binding = 90%
  • Probenecid 1g/day in 4 divided doses
    --> Effectively block the renal excretion of penicillin
  • Probenecid also decreases biliary excretion of rifampin
    --> Higher plasma concentration of rifampin (thus great anti-tuberculosis effect)
  • Salicylate antagonise the uricosuric action of probenecid but not its capacity to inhibit renal tubular excretion of penicillin
  • Mild allergic reactions (cutaneous rashes) occur in 2-4%
Sulfinpyrazone
  • Related to phenylbutazone
    * Lacks antiinflammatory effect
  • Potent inhibitor of renal tubular reabsorption of uric acid
    --> Antagonised by salicylates
  • Renal tubular secretion of many drugs also decreased
    --> Greater effect of oral hypoglycaemics
  • Protein-binding around 98%
  • Sulfinpyrazone undergoes proximal renal tubular secretion
  • 90% excreted unchanged in urine
  • Metabolised to parahydroxyl analogue
    --> Also has uricosuric activity
  • Side effects
    * GIT irritation in 10-15%
    * Inhibition of platelet function