ANALGESICS AND ANTI-INFLAMMATORY DRUGS

Acetaminophen (paracetamol)

This is the active metabolite of phenacetin and is responsible for its analgesic effects. It is a weak cox – 1
and cox – 2 inhibitor, in peripheral tissues and possesses no significant anti – inflammatory effects.

It is administered orally. Absorption is related to the rate of gastric emptying, and peak blood
concentrations are usually reached in 30 – 60 minutes. It is slightly bound to plasma proteins and is
partially metabolized by hepatic microsomal enzymes and converted to acetaminophen sulfate and
glucuronide, which are pharmacologically inactive.

Less than 5% is excreted unchanged. A minor but highly active metabolite (N - acetyl – p –
benzoquinone) is important in large doses because it is toxic to both liver and kidney. The half-life of
acetaminophen is 2 – 3 hours and is relatively unaffected by renal function. With toxic doses or liver
disease, the half-life may be increases two fold or more.

Indications:

Although equivalent to aspirin as an effective analgesic and antipyretic agent, acetaminophen differs in
that it lacks anti- inflammatory properties. It doesn’t affect uric acid levels and lacks platelet-inhibition
properties. The drug is useful in mild to moderate pain such as headache, myalgia, postpartum pain and
other circumstances in which aspirin is an effective analgesic.

Acetaminophen alone is inadequate therapy for inflammatory conditions such as RA, although it may be
used as an analgesic adjunct to anti – inflammatory therapy. For mild analgesia, acetaminophen is the
preferred drug in patients allergic to aspirin or when salicylates are poorly tolerated.

It is preferable to aspirin in patients with hemophilia or a history of peptic ulcers and in those in whom
bronchospasm is precipitated by aspirin. Unlike aspirin, acetaminophen does note antagonize the effects
of uricosuric agents; it may be used concomitantly with probenecid in treatment of gout. It is preferred
to aspirin in children with viral infections

Adverse effects;

In therapeutic doses, a mild increase in hepatic enzyme may occasionally occur in the absence of
jaundice, this is reversible when the drug is withdrawn. With larger doses, dizziness, excitement and
disorientation are seen.

Ingestion of 15 g of acetaminophen may be fatal, death being caused by severe hepatotoxicity with
centrilobular necrosis, sometimes associated with acute renal tubular necrosis.

Doses greater than 4g/day are not recommended and a history of alcoholism contraindicates even this
dose.

Early symptoms of hepatic damage include nausea, vomiting, diarrhea and abdominal pain.
Cases of renal damage without hepatic damage have occurred, even after usual doses of
acetaminophen. Therapy is much less satisfactory than for aspirin overdose. In addition to supportive
therapy, the measure that has proved most useful is the provision of sulfhydryl groups in the form on
acetyl cysteine to neutralize the toxic metabolites.

Hemolytic anemia and methemoglobinemia are very rare. Caution is necessary in patients with any type
of liver disease.

Dosage:

Acute pain and fever may be effectively treated with 325 – 500 mg four times daily and proportionately
less for children.

Phenacetin:

No longer prescribed in USA, but still in common use in many parts of the world. The association
between excessive use of analgesic combination, especially those that contain phenacetin and the
development of renal failures has been recognized for almost 30 years.

Non-steroidal anti-inflammatory drugs, Disease modifying anti-rheumatic drugs and Non-

opioid analgesics
The Immune response
The immune response occurs when immunologically competent cells are activated in response to
foreign organisms or antigenic substances liberated during the acute or chronic inflammatory
response.
The outcome of the immune response for the host may be beneficial as when it causes invading
organisms to be phagocytosed or neutralized. On the other hand, the outcome may be deleterious
if it leads to chronic inflammation without resolution of the underlying injurious process.
Chronic inflammation involves the release of a number of mediators that are not prominent in the
acute response. One of the most important conditions involving the mediators in rheumatoid
arthritis (RA) in which chronic inflammation results is pain and destruction of bone and cartilage
that can lead to severe disability and in which systemic changes can result in shortening of life.
The cell damage associated with inflammation acts on cell membranes to cause leucocytes to
release lysosomal enzymes; arachidonic acid is then liberated from precursor compounds and
various eicosanoids are synthesized. The COX pathway of arachidonate metabolism produces
prostaglandins, which have a variety of effects on blood vessels, nerve endings and on cells
involved in inflammation.
The discovery of COX isoforms (COX-1 and COX-2) led to the concepts that constitutive COX-
1 isoforms tends to be homeostatic in function while COX-2 is induced during inflammation and
tends to facilitate the inflammatory response.
Hence, highly selective COX-2 inhibitors have been developed and marketed on assumption that
such selective inhibitors would be safer than non-selective COX-1 inhibitors, but without loss of
efficacy.
The LOX pathway of arachidonate metabolism yields leukotrienes, which have a powerful
chemotactic effect on eosinophils, neutrophils and macrophages, and promote bronchospasm and
alterations in vascular permeability.
Kinins, neuropeptides and histamine are also released at the site of tissue injury, as are
complement components, cytokines and other products of leukocytes and platelets.
Stimulation of the neutrophil membranes produces oxygen-derived free radicals. Superoxide
anions formed by reduction of molecular oxygen which may stimulate the production of other
reactive molecules e.g. hydrogen peroxide and hydroxyl radicals.
The interaction of these substances with arachidonic acid results in the generation of chemotactic
substances, thus perpetuating the inflammatory process.
Therapeutic strategies
The treatment of patients with inflammation involves 2 primary goals:
i. The relief of pain, which is often the presenting symptom and the major continuing complaint
of the patient.
ii. The slowing or in the theory, the arrest of tissue damaging process.
In RA, response to therapy can be quantitated by means of the American College of
Rheumatology (ACR) scoring system values ACR 20, ACR 50 and ACR 70, which denote the %
of patients showing an improvement of 20%, 50% or 70% in global assessment of signs and
symptoms. Reduction of inflammation with NSAIDs often results in relief of pain for significant
periods.
In addition, most of the non-opioid analgesics also have anti-inflammation effects and are
appropriate for the treatment of both acute and chronic inflammatory conditions.
The glucocorticoids also have powerful anti- inflammatory effects and when they were first
introduced, were considered to be the ultimate answer to the treatment of inflammatory arthritis,
but the toxicity associated with chronic corticosteroid therapy usually limits their use except in
the control of acute flare –ups of joint disease.
The NSAIDS continue to have significant role in the long-term treatment of arthritis.
Disease modifying anti-rheumatic drugs (DMARDs) slow bone damage associated with R.A and
are thought to affect more basic inflammatory mechanisms than do the NSAIDS. They may also
be more toxic than the NSAIDS.
Non-Steroidal anti- inflammatory drugs
Introduction
Salicylates and other similar agents used to treat rheumatic diseases share the capacity to
suppress the signs and symptoms of inflammation. These drugs also exert antipyretic and
analgesic effects but their anti- inflammatory properties make them most useful in the
management of disorders in which pain is related to the intensity of the inflammatory process.
NSAIDs are effective in RA, seronegative spondyloarthropathies e.g. psoriatic arthritis, arthritis
associated inflammatory bowel disease, osteoarthritis, localized syndrome e.g. sprains and
musculoskeletal low back pain and gout (except tolmentin).
Aspirin the original NSAID has a number of adverse effects and may other NSAIDs have been
developed in attempt to improve upon aspirin’s efficacy and decrease its toxicity.

CHEMISTRY AND PHARMACOKINETICS

NSAIDS are grouped in several classes:
1. Propionic acid derivatives e.g. ibuprofen.
2. Indole derivatives e.g. indomethacin.
3. Pyrrolealkanoic acid e.g. tolmetin
4. Phenylalkanoic acid e.g. flurbiprofen
5. Pyralozone derivatives e.g. phenylbutazone
6. Phenylacetic acid derivatives e.g. diclofenac
7. Fenamates e.g. .meclofenamic acid
8. Oxicams e.g. piroxicam
9. Naphthylacetic acid pro drug e.g. nabumetone
The chemical diversity yields a broad range of pharmacokinetic characteristics. Although the
kinetics of NSAIDs are different, some general properties are common.
All but one of the NSAIDs are weak organic acids, except nabumetone which is ketone pro drug
metabolized to the acidic active drug. Most of the drugs are well absorbed and food does not
substantially change their bioavailability.
Most of the NSAIDS are highly metabolized, some by phase -1 followed by phase-2
mechanisms. Others by direct glucuronidation (phase-2) alone. NSAID metabolism proceeds in
large part by way of CYP3A or CYP2C families of P450 enzymes in the liver.
Renal excretion is the most important route of excretion and nearly all undergo varying degrees
of biliary excretion and reabsorption (enterohepatic circulation). In fact, the degree of the lower
GIT irritation correlates with the amount of enterohepatic circulation.
Most of the NSAIDS are highly protein-bound approx.98% usually to the albumin.
Some of the NSAIDS e.g. Ibuprofen are racemic mixtures, while naproxen is provided as a
single enantiomer and a few have no chiral center e.g. diclofenac
All NSAIDs can be found in the synovial fluid after repeated dosing.
Drugs with short half-life remain in the joints longer than would be predicted from their half-life,
while drugs with longer half-life disappear from the synovial fluid at a rate proportionate to their
half-lives.
Pharmacodynamics
The anti-inflammatory activity of the NSAIDs is mediated chiefly through inhibition of
biosynthesis of prostaglandins.
Various NSAIDS have additional possible mechanisms of action including:
i. Inhibition of chemotaxis
ii. Down regulation of Interlukin-1 production.
iii. Decreased production of free radicals and superoxide.
iv. Interference with calcium-mediated intracellular events.
Aspirin irreversibly acetylates and blocks platelet COX, while most non-COX selective NSAIDs
are reversible inhibitors. Selectivity for COX-1 versus COX-2 is variable and incomplete for the
older members, but the highly selective COX-2 inhibitors is currently available and other highly
selective Coxibs are being developed.
At the usual doses, the highly selective cox-2 inhibitors do not affect platelet function.
In testing using human blood, aspirin, indomethacin, piroxicam and sulindac were more effective
in inhibiting COX-1.
Ibuprofen and meclofenamate inhibited the two isoenzymes about equally.
The efficacy of the COX-2 selective drugs equals that of the older NSAIDs, while the GIT safety
is improved.
On the other hand, highly selective COX -2 inhibitors may increase the incidence of edema and
hypertension. Currently, celecoxib is the only inhibitor marketed in USA.
Rofecoxib and valdecoxib, highly selective COX-2 inhibitors have been withdrawn from the
market due to their association with increased cardiovascular thrombotic events.
NSAIDs decrease the sensitivity of vessels to bradykinin and histamine, affect lymphokine
production from T-lymphocytes and reverse the vasodilation of the inflammation.
All newer NSAIDs are analgesics, anti-inflammatory and ant-pyretic, and all except the COX-2
selective agents and non- acetylated salicylates inhibit platelet aggregation.
NSAIDs are all gastric irritants as well, although the newer agents tend to cause less gastric
irritation than aspirin.
Nephrotoxicity and hepatotoxicity can occur with any NSAID. Nephrotoxicity is due in part to
the interference with auto -regulation of renal blood flow which is mediated by prostaglandins.
Although these drugs effectively inhibit inflammation in contrast to drugs like Methotrexate and
gold, there is no evidence that they alter the course of an arthritic disorder.
Several NSAIDs (including aspirin) appear to reduce the incidence of colon cancer when taken
chronically. Several epidemiologic studies have shown a 50% reduction in relating risk when
these drugs are taken for ≥ 5years. The mechanism of this protective effect is unclear.
Aspirin
Introduction:
Aspirin is rarely used as an anti-inflammatory medication .It has been replaced by ibuprofen and
naproxen, which are effective and are available as the over the counter medication (OTC) and
have good to excellent safety records.
PHARMACOKINETICS
Sodium salicylate and aspirin are equally effective anti-inflammatory drugs, though aspirin may
be more effective as an analgesic.
 Structure and metabolism of the salicylates

Salicylates are rapidly absorbed from the stomach and the upper small-intestines yielding peak
plasma salicylate level within 1-2hours. Aspirin is absorbed as such, and is rapidly hydrolyzed.
(Serum half -life 15minutes) to acetic acid and salicylate by esterases in tissue and blood.
Salicylate is bound to plasma albumin, but the binding and metabolism of salicylates are
saturable so that the unbound fraction increases as total concentration increases. As doses of
aspirin increases from 3-5 hours (for 600mg/d dosage) to 12-16 hours (dosage >3.6g/d).
Alkalinization of the urine increases the rate of excretion of free salicylate and its water soluble
conjugates.
Mechanism of action
A. Anti-inflammatory effect
Aspirin is a non-selective inhibitor of both COX isoforms, but salicylate is much less effective in
inhibiting either isoforms. Non-acetylated salicylates may work as oxygen radical scavengers.
Aspirin irreversibly inhibits COX and inhibits platelet aggregation, while non –acetylated
salicylates do not.
B. Analgesics effects
Aspirin is the most effective in reducing pain of mild to moderate intensity through its effects on
inflammation and because it probably inhibits pain stimuli at sub-cortical site.
C. Antipyretic effects
Aspirin’s antipyretic effects is probably mediated by both COX inhibition in the CNS and
inhibition of interlukin-1 (which is released from macrophages during episodes of inflammation).
D. Antiplatelet effects
Aspirin irreversibly inhibits platelet COX, so that its antiplatelet effect lasts 8-10 days (the life of
the platelet).
Clinical uses
Analgesia, antipyretic and anti-inflammatory effects. Aspirin is employed for mild to moderate
pain of varied origin, but is not effective for severe visceral pain. Aspirin and other NSAIDs have
been combined with opioid analgesics for treatment of cancer pain, where their anti-
inflammatory effects act synergistically with the opioids to enhance analgesia.
High dose salicylates are effective for treatment of rheumatic fever, RA and other inflammatory
joint conditions.
Other effects
Aspirin decreases the incidence of transient ischemic attacks, unstable angina, coronary artery
thrombosis with myocardial infarction, and thrombosis after coronary artery bypass grafting.
Epidemiology studies suggest that long-term use of aspirin at low dosage is associated with a
lower incidence of colon cancer, possibly related to COX inhibiting effects.
Dosage
The optimal analgesic or antipyretic dose of aspirin is less than 0.6-0.65 g oral dose.
The anti-inflammatory dose for children is 50-75mg/kg/day in divided doses. The average
starting dose anti-inflammatory dose foe adult is 45mg/kg/day in divided doses.

Adverse effects
 i. At the usual dosage, aspirin’s main adverse effects are gastric upset (intolerance) and
gastric and duodenal ulcers.
ii. Hepatotoxicity
iii. Asthma
iv. Renal toxicity occurs less frequently.
v. With higher doses, patients may experience salicylism – vomiting, tinnitus, decreased
hearing and vertigo. These effects are reversible by reducing dosage.
vi. Larger doses cause hyperpnoea through a direct effect on the medulla.
vii. At toxic salicylate levels, respiratory alkalosis followed by metabolic acidosis
(salicylate accumulation), respiratory depression and even cardio toxicity and glucose
intolerance can occur.
viii. The antiplatelet action of aspirin contraindicates its use by patients with hemophilia.
ix. Salicylate over dosage constitutes a medical emergency and requires hospitalization.
Non-acetylated salicylates
These drugs include choline salicylate, sodium salicylate and salicysalicylate. These drugs are
effective anti-inflammatory drugs, but less effective as analgesics compared to aspirin.
They are also much less effective than aspirin as COX inhibitors, and may be preferable when
COX inhibition is undesirable e.g. in patients with asthma, those with bleeding tendencies and
those with renal dysfunction.
COX-2 selective inhibitors
Examples are;
Celecoxib, etericoxib, meloxicam, valdecoxib.
Non-selective COX inhibitors
Examples are;
Diclofenac, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac
etc.
Ketorolac is an NSAID promoted for systemic use mainly as analgesic, not as an anti-
inflammatory drug. The drug is an effective analgesic and has been used successfully to replace
morphine in some situations involving mild to moderate post-surgical pain.
It is administered by IM or IV routes, although an oral dose is available.
When used with an opioid, it may decrease the opioid requirement by 25-50%.
An ophthalmic preparation is available for ocular inflammatory conditions.
Toxicities are similar to other NSAIDs, although renal toxicity may be more common with
chronic use.
Meclofenamate and mefenamic acid are rarely used today. They inhibit both COX-1 and PLA2.
Other NSAIDs include;
Nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tenoxicam, tiaprofen, tolmentin (also
used in gout), azapropazone and carprofen.
Clinical Pharmacology of the NSAIDs
All NSAIDs are about equally efficacious with a few exception-tolmetin, which seems to be
effective in gout.
Aspirin is less effective than other NSAIDs for ankylosing spondylitis.
Thus, NSAIDs tend to be differentiated on the basis of toxicity and cost-effectiveness.
For example, the toxicity of ketorolac limits its use.
It was noted that indomethacin, tolmentin and meclofenamate are the NSAIDs associated with
greatest toxicity.
Salicylate, aspirin and ibuprofen are less toxic.
For patients with renal insufficiency, non-acetylated salicylates may be best.
The relatively expensive COX-2 inhibitors are probably the safest for patients at high risk for
GIT bleeding, but may have a higher risk for cardiovascular toxicity.
Celecoxib or non-selective NSAIDs plus omeprazole or misoprostol may be appropriate in
patients at highest risk of GIT bleeding.
In this subpopulation of patients, they are cost-effective despite their high acquisition cost.
The choice of an NSAID thus requires a balance between efficacy, cost-effectiveness, safety and
numerous personal factors (e.g. other drugs being used, concurrently illness, compliance,
medical insurance coverage) so that there is no best NSAID for all patients.
There may be one or two best NSAID for a specific person.