Non-steroidal Antiinflammatory Drugs and Antipyretic-Analgesics Notes / Classification of Antipyretic-Analgesics drugs / What Is Aspirin

 Nonsteroidal Antiinflammatory Drugs and Antipyretic-Analgesics :

The nonsteroidal antiinflammatory drugs (NSAIDs) and antipyretic analgesics are a class of drugs that have analgesic, antipyretic and antiinflammatory actions in different measures. In contrast to morphine they do not depress CNS, do not produce physical dependence, have no abuse liability and are particularly effective in inflammatory pain. They are also called nonnarcotic, nonopioid or aspirin-like analgesics. They act primarily on peripheral pain mechanisms, but also in the CNS to raise pain threshold. 

They are more commonly employed and many are over-the-counter or nonprescription drugs.

Willow bark (Salix alba) had been used as a medicine for many centuries. Salicylic acid was prepared by hydrolysis of the bitter glycoside obtained from this plant. Sodium salicylate was used for fever and pain in 1875. Its great success led to the introduction of acetylsalicylic acid (aspirin) in 1899. Phenacetin and antipyrine were also produced at that time. The next major advance was the development of phenylbutazone in 1949 having antiinflammatory activity almost comparable to corticosteroids. The term Nonsteroidal Antiinflammatory Drugs (NSAIDs) was coined to designate such drugs. Indomethacin was introduced in 1963. A host of compounds heralded by the propionic acid derivative ibuprofen have been added since then, and cyclooxygenase (COX) inhibition is recognised to be their most important mechanism of action. Subsequently some selective COX‑2 inhibitors (celecoxib, etc.) have been added.

The NSAIDs are chemically diverse, but all are weak organic acids or their active metabolites are organic acids.

Nsaids and prostaglandin (pg) synthesis inhibition :

In 1971 Vane and coworkers made the landmark observation that aspirin and some NSAIDs blocked prostaglandin (PG) generation. This is now considered to be the major mechanism of action of NSAIDs. Prostaglandins, prostacyclin (PG I2 ) and thromboxane A2 (TXA2 ) are produced from arachidonic acid by the enzyme cyclooxygenase (see p. 198) which exists in a constitutive (COX-1) and an inducible (COX-2) isoforms; the former serves physiological ‘house keeping’ functions, while the latter, normally present in minute quantities, is induced by cytokines and other signal molecules at the site of inflammation. This leads to generation of PGs locally which mediate many of the inflammatory changes. However, COX-2 is constitutively present at some sites in brain, in juxtaglomerular cells and in the foetus; it may serve physiological role at these sites. Most NSAIDs inhibit COX-1 and COX-2 nonselectively, but now some selective COX-2 inhibitors have been produced. Features of nonselective COX-1/ COX-2 inhibitors (traditional NSAIDs) and selective COX-2 inhibitors are compared in Table 14.1

Aspirin inhibits COX irreversibly by acetylating one of its serine residues; return of COX activity depends on synthesis of fresh enzyme. 

Other NSAIDs are competitive and reversible inhibitors of COX; return of activity depends on their dissociation from the enzyme which in turn is governed by the pharmacokinetic characteristics of the compound.

Analgesia :

PGs induce hyperalgesia (see p. 203) by affecting the transducing property of free nerve endings so that stimuli that normally do not elicit pain are able to do so. NSAIDs do not affect the tenderness induced by direct application of PGs, but block the pain sensitizing mechanism induced by bradykinin, TNFα, interleukins (ILs) and other algesic substances primarily by inhibiting COX-2. This constitutes the peripheral component of the analgesic action of NSAIDs. They are, therefore, more effective against inflammation associated pain.

Lately the central component of analgesic action of NSAIDs has also been shown to involve inhibition of PG synthesis in the spinal dorsal horn neurones as well as in brain, so that PG mediated amplification of pain impulses does not occur. 

Antipyresis :

NSAIDs lower body temperature in fever, but do not cause hypothermia in normothermic individuals. Fever during infection and tissue injury is produced through the generation of pyrogens including, ILs, TNFα, interferons which induce PGE2 production in hypothalamus—raise its temperature set point. NSAIDs block the action of pyrogens but not that of PGE2 injected into the hypothalamus. The isoform dominant at this site appears to be COX-2 (possibly COX‑3, a splice variant of COX-1 that is inhibited by paracetamol as well). However, fever can occur through non-PG mediated mechanisms as well.

Antiinflammatory :

The most important mechanism of antiinflammatory action of NSAIDs is considered to be inhibition of COX-2 mediated enhanced PG synthesis at the site of injury. However, there is some evidence that inhibition of the constitutive COX-1 also contributes to suppression of inflammation, especially in the initial stages. The antiinflammatory potency of different compounds roughly corresponds with their potency to inhibit COX. However, nimesulide is a potent antiinflammatory but relatively weak COX inhibitor. PGs are only one of the mediators of inflammation, and inhibition of COX does not depress the production of other mediators like LTs, PAF, cytokines, etc. Inflammation is the result of concerted participation of a large number of vasoactive, chemotactic and proliferative factors at different stages, and there are many targets for antiinflammatory action.

Activated endothelial cells express adhesion molecules (ELAM-1, ICAM-1) on their surface and play a key role in directing circulating leucocytes to the site of inflammation (chemotaxis). Similarly, inflammatory cells express selectins and integrins. Certain NSAIDs may act by additional mechanisms including inhibition of expression/activity of some of these molecules and generation of superoxide/other free radicals. Growth factors like GM-CSF, IL-6 as well as lymphocyte transformation factors and TNFα may also be affected. Stabilization of lysosomal membrane of leukocytes and antagonism of certain actions of kinins may be contributing to antiinflammatory action of NSAIDs.

Dysmenorrhoea :

Involvement of PGs in dysmenorrhoea has been clearly demonstrated: level of PGs in menstrual flow, endometrial biopsy and that of PGF2α metabolite in circulation are raised in dysmenorrhoeic women. Intermittent ischaemia of the myometrium is probably responsible for menstrual cramps. NSAIDs lower uterine PG levels—afford excellent relief in 60–70% and partial relief in the remaining. Ancillary symptoms of headache, muscle ache and nausea are also relieved. Excess flow may be normalized.

Antiplatelet aggregatory :

NSAIDs inhibit synthesis of both proaggregatory (TXA2 ) and antiaggregatory (PGI2 ) prostanoids, but effect on platelet TXA2 (COX-1 generated) predominates. Therapeutic doses of most NSAIDs inhibit platelet aggregation and prolong bleeding time. Aspirin is highly active, because it acetylates platelet COX irreversibly in the portal circulation before getting deacetylated by first pass metabolism in liver. Small doses of aspirin are therefore able to exert antithrombotic effect for several days. Risk of surgical and anticoagulant associated bleeding is enhanced .

Ductus arteriosus closure :

During foetal circulation ductus arteriosus is kept patent by local elaboration of PGE2 by COX-2. Unknown mechanisms switch off this synthesis at birth and the ductus closes. When this fails to occur, small doses of indomethacin or aspirin bring about closure in majority of cases within a few hours by inhibiting PG production. Administration of NSAIDs in late pregnancy has been found to promote premature closure of ductus in some cases. Risk of post-partum haemorrhage is increased. Prescribing of NSAIDs near term should be avoided.

Parturition :

Sudden spurt of PG synthesis by uterus occurs just before labour begins. This is believed to trigger labour as well as facilitate its progression. Accordingly, NSAIDs have the potential to delay and retard labour. However, labour can occur in the absence of PGs.

Gastric mucosal damage :

Gastric pain, mucosal erosion/ulceration and blood loss are caused by all NSAIDs to varying extents: relative gastric toxicity is a major consideration in the choice of NSAIDs. Inhibition of COX‑1 mediated synthesis of gastroprotective PGs (PGE2 , PGI2 ) is clearly involved, though local action inducing back diffusion of H+ ions in gastric mucosa also plays a role. Deficiency of PGs reduces mucus and HCO3 ¯ secretion, tends to enhance acid secretion and may promote mucosal ischaemia. Thus, NSAIDs enhance aggressive factors and contain defensive factors in gastric mucosa; are therefore ulcerogenic. Paracetamol, a very weak inhibitor of COX is practically free of gastric toxicity and selective COX-2 inhibitors are relatively safer. Stable PG analogues (misoprostol) administered concurrently with NSAIDs counteract their gastric toxicity .

Renal effects :

Conditions leading to hypovolaemia, decreased renal perfusion and Na+ loss induce renal PG synthesis which brings about intrarenal adjustments by promoting vasodilatation, inhibiting tubular Cl¯ reabsorption (Na+ and water accompany) and opposing ADH action. NSAIDs produce renal effects by at least 3 mechanisms:

• COX-1 dependent impairment of renal blood flow and reduction of g.f.r., which can worsen renal insufficiency. 

• Juxtaglomerular COX-2 (probably COX-1 also) inhibition dependent Na+ and water retention. 

• Ability to cause papillary necrosis on habitual intake. 

Renal effects of NSAIDs are not marked in normal individuals, but become significant in those with CHF, hypovolaemia, hepatic cirrhosis, renal disease and in patients receiving diuretics or antihypertensives. In them Na+ retention and edema can occur; diuretic and antihypertensive drug effects are blunted.

Involvement of PG synthesis inhibition in analgesic nephropathy is uncertain.

Analgesic nephropathy occurs after years of heavy ingestion of analgesics. Such individuals probably have some personality defect. Regular use of combinations of NSAIDs and chronic/repeated urinary tract infections increase the risk of analgesic nephropathy. Pathological lesions are papillary necrosis, tubular atrophy followed by renal fibrosis. Urine concentrating ability is lost and the kidneys shrink. Because phenacetin was first implicated, it went into disrepute, though other analgesics are also liable to produce similar effects. 

Anaphylactoid reactions :

Aspirin precipitates asthma, angioneurotic swellings, urticaria or rhinitis in certain susceptible individuals. These subjects react similarly to chemically diverse NSAIDs, ruling out immunological basis for the reaction. Inhibition of COX with consequent diversion of arachidonic acid to LTs and other products of lipoxygenase pathway may be instrumental, but there is no proof.

SALICYLATES :

Aspirin :

Aspirin is acetylsalicylic acid. It is rapidly converted in the body to salicylic acid which is responsible for most of the actions. Other actions are the result of acetylation of certain macromolecules including COX. It is one of the oldest analgesic-antiinflammatory drugs and has diverse uses. 

Pharmacological  Actions :

1. Analgesic, antipyretic, antiinflammatory actions :

Aspirin is a weaker analgesic (has lower maximal efficacy) than morphine type drugs: aspirin 600 mg ~ codeine 60 mg. However, it effectively relieves inflammatory, tissue injury related, connective tissue and integumental pain, but is relatively ineffective in severe visceral and ischaemic pain. The analgesic action is mainly due to obtunding of peripheral pain receptors and prevention of PG-mediated sensitization of nerve endings. A central subcortical action raising threshold to pain perception also contributes to analgesia, but the morphine-like action on psychic processing or reaction component of the pain is missing. No sedation, subjective effects, tolerance or dependence is produced.

Aspirin resets the hypothalamic thermostat and rapidly reduces fever by promoting heat loss (sweating, cutaneous vasodilatation), but does not decrease heat production.

Antiinflammatory action is exerted at high doses (3–6 g/day or 100 mg/kg/ day). Signs of inflammation like pain, tenderness, swelling, vasodilatation and leucocyte infiltration are suppressed. In addition to COX inhibition, quenching of free radicals may contribute to its antiinflammatory action. However, progression of the underlying disease in rheumatoid arthritis, osteoarthritis and rheumatic fever, etc. is not affected.

2. GIT :

Aspirin, as well as salicylic acid released from it irritate gastric mucosa, cause epigastric distress, nausea and vomiting. At high doses, it stimulates CTZ. Vomiting caused by aspirin has a central component as well. 

Aspirin (pKa 3.5) remains unionized and diffusible in the acid gastric juice, but on entering the mucosal cell (pH 7.1) it ionizes and becomes indiffusible. This ‘ion trapping’ (see p. 17) in the gastric mucosal cell enhances gastric toxicity. Further, aspirin particle coming in contact with gastric mucosa promotes local back diffusion of acid. This causes focal necrosis of mucosal cells and capillaries → acute ulcers, erosive gastritis, congestion and microscopic haemorrhages. The occult blood loss in stools is increased by even a single tablet of aspirin. Blood loss averages 5 ml/day at antiinflammatory doses. Haematemesis occurs occasionally: may be an idiosyncratic reaction.

Soluble aspirin tablets containing calcium carbonate + citric acid and other buffered preparations are less liable to cause gastric irritation, but incidence of ulceration and bleeding is not significantly lowered.

3. Blood :

Aspirin, even in small doses, irreversibly inhibits TXA2 synthesis by platelets. Thus, it interferes with platelet aggregation and bleeding time is prolonged to nearly twice the normal value. This effect lasts for about a week (turnover time of platelets).

Long-term intake of large dose decreases synthesis of clotting factors in liver and predisposes to bleeding. This can be prevented by prophylactic vit K therapy.

4. Metabolic and other effects of high (antiinflammatory/toxic) doses :

Analgesic doses of aspirin (0.3–0.6 g 6–8 hourly) employed for headache, fever, etc. produce almost no other action. However, high doses (3–5 g/day or 100 mg/kg/day) needed for antiinflammatory action in rheumatoid arthritis/rheumatic fever produce several other effects .

• Cellular metabolism is enhanced, especially in skeletal muscles, due to uncoupling of oxidative phosphorylation. Glucose utilization is increased resulting in fall in blood glucose level (especially in diabetics); liver glycogen is depleted. However, toxic doses may cause central sympathetic stimulation and rise in blood sugar.
• Respiration is stimulated by direct action on respiratory centre as well as due to increased CO2 production. Hyperventilation followed by respiratory depression occurs at toxic doses.
• Respiratory stimulation tends to washout CO2 and produce respiratory alkalosis. This is compensated by enhanced HCO3 – excretion by kidney. Most adults receiving 3–5 g/day stay in a state of compensated respiratory alkalosis. Still higher doses depress respiration while excess CO2 production continues to cause respiratory acidosis. Increased production of metabolic acids (lactic, pyruvic, acetoacetic) and dissociated salicylic acid may contribute to uncompensated metabolic acidosis, since plasma HCO3 – is already low. Dehydration occurs due to excess water loss in urine, sweating and hyperventilation. Most children menifest this phase during salicylate poisoning, while in adults it is seen only in late stages of poisoning.
• Aspirin has no direct effect on heart or circulation, but doses which enhance metabolic rate, increase cardiac output indirectly. Toxic doses depress vasomotor centre, so that blood pressure may fall. CHF may be precipitated if cardiac reserve is low.
• Aspirin interferes with urate excretion and antagonises the uricosuric effect of probenecid. However, at high doses (≥ 5 g/day) it may block urate reabsorption and increase its excretion, but aspirin is not a reliable uricosuric.

Pharmacokinetics :

Aspirin is absorbed from the stomach and small intestines. Its poor water solubility is the limiting factor in absorption: microfining the drug-particles and inclusion of an alkali (solubility is more at higher pH) enhances absorption. However, higher pH also favours ionization, thus decreasing the diffusible form.

Aspirin is rapidly deacetylated in the gut wall, liver, plasma and other tissues to release salicylic acid which is the major circulating and active form. It is ~80% bound to plasma proteins and has a volume of distribution ~0.17 L/kg. Entry into brain is slow, but aspirin freely crosses placenta. Both aspirin and salicylic acid are conjugated in liver with glycine to form salicyluric acid (major pathway). They are conjugated with glucuronic acid as well. The metabolites are excreted by glomerular filtration and tubular secretion, only 1/10th is excreted as free salicylic acid.

The plasma t½ of aspirin as such is 15–20 min, but taken together with that of released salicylic acid, it is 3–5 hours. However, metabolic processes get saturated over the therapeutic range; t½ of antiinflammatory doses may be 8–12 hours while that during poisoning may be as long as 30 hours. Thus, elimination is dose dependent.

Adverse effects :

(a) Side effects that occur at analgesic dose (0.5–2.0 g/day) are nausea, vomiting, epigastric distress, increased occult blood loss in stools. The most important adverse effect of aspirin is gastric mucosal damage and peptic ulceration. 

(b) Hypersensitivity and idiosyncrasy Though infrequent, these can be serious. Reactions include rashes, fixed drug eruption, urticaria, rhinorrhoea, angioedema, asthma and anaphylactoid reaction. Profuse gastric bleeding occurs in rare instances.  

(a) Side effects that occur at analgesic dose (0.5–2.0 g/day) are nausea, vomiting, epigastric distress, increased occult blood loss in stools. The most important adverse effect of aspirin is gastric mucosal damage and peptic ulceration. (b) Hypersensitivity and idiosyncrasy Though infrequent, these can be serious. Reactions include rashes, fixed drug eruption, urticaria, rhinorrhoea, angioedema, asthma and anaphylactoid reaction. Profuse gastric bleeding occurs in rare instances.

Aspirin therapy in children with rheumatoid arthritis has been found to raise serum transaminases, indicating liver damage. Most cases are asymptomatic but it is potentially dangerous. An association has been noted between salicylate therapy and ‘Reye’s syndrome’, a rare form of hepatic encephalopathy seen in children having viral (varicella, influenza) infection.