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