Part 1: NSAIDs
-COX 1, COX 2 and COX 3 genes are all present
-These genes (COX 1 and 2) essentially code for the two different enzymes/proteins. They are isoforms/isoenzymes of each other but catalyze essentially the same reaction.
Function of COX-1:
-always present in most cells throughout the body (constitutive) and catalyzes the formation of PGs involved in physiological processes
-In the stomach, COX-1 catalyzes the synthesis of PGE2, PGI2 which has cyto-protective actions and maintains the lining of the gastrointestinal mucosa.
Function of COX-2:
-Inducible (capable of being formed/activated) isoform found mainly in inflammatory and immune cells (neutrophils, macrophages, mast cells)
-Pro-inflammatory cytokines (INF) and growth factors induce COX-2.
-The making of COX-2 is triggered by exposure of inflammatory cells to certain stimuli (endotoxin, interferon, cytokines/IL-1)
-The making of COX-2 is inhibited by steroids and IL-4.
1. Thus, it may play a role in cell growth and will cause inflammation.
2. Hyperalgesic and proinflammatory prostaglandins production. COX-2 is responsible for generation of hyperalgesic and pro-inflammatory PGs (namely PGI2 and PGE2).
3. Colon Cancer.
-COX-2 is strongly expressed in human colon cancer cells
***NSAIDs are believed to delay the progress of colon tumors progression (by apoptosis)
***NSAIDs also reduces the risk of developing Alzhemier’s disease which is thought to involve an inflammatory component (chronic use of NSAIDs reduces risk)
4. Induce fever and transmission of pain.
-COX-2 are also present constitutively (always there) in the CNS (central nervous system).
-Thus it may be involved in fever and nerve transmission of pain.
5. Ovulation and Birth processes.
-Prostaglandins catalysed by COX-2 are also involved in ovulation and birth processes (Myometrial contraction)
1.1 Generations of NSAIDs
-Traditional NSAIDs include aspirin, ibuprofen (Advil, Motrin, etc.), naproxen (e.g., Aleve) and many other generic and brand name drugs. A newer NSAID is celecoxib (Celebrex), which doctors call a “COX-2 inhibitor” or a “COX-2 selective” NSAID.
1.2 Mechanisms of NSAIDs
-NSAIDs exert their actions primarily by inhibiting the production of Prostaglandins (PGs)
-Although there is no common structural motiff, the mechanism of NSAIDs would be to inhibit COX (cyclooxygenase)
1.3 Effects of NSAIDs
1. Anti-pyretic (Reduce temperature)
-Normal body temperature is regulated in the hypothalamus.
-During an inflammation, bacterial endotoxins causes the release of IL-1, IL-6 from macrophages. These cytokines are considered pyrogens which means it causes fever.
-These cytokines cause the generation of prostaglandins in the hypothalamus which causes the elevation of set-point for temperature.
***NSAIDs block the production of these prostaglandins thus normal temperature is not affected by NSAIDs.
2. Analgesic (Reduces Pain)
-When tissues are inflamed/damaged, pain is usually associated.
***NSAIDs decrease the production of prostaglandins that sensitize nociceptors to inflammatory mediators such as bradykinin.
-They are effective against pain of mild to moderate intensity in conditions such as:
Arthritis, bursitis, pain of muscular and vascular origin, toothache, dysmenorrhea, pain of post-partum states and pain of cancer metastases in bone.
Definition: Bursitis (Inflammation in one or more burses/sacs of synovial fluid in the body)
All the conditions mentioned above are associated with increase prostaglandin synthesis.
Note: Their maximum efficacy is much lower than opioids in relieving pain however, they do not cause addiction/dependence.
Note: When used in combination with the opioids, they may decresae post-operative pain while reducing the requirement for opioids by up to 1/3.
-NSAIDs affect those components of the inflammatory and immune response in which the byproducts of COX-2 play a major role.
- Oedema (by an indirect action in which vasodilation facilitates and potentiates the action of mediators such as histamine which increases permeability of post-capillary venules.
- Pain (analgesic effects-Refer to (b))
NSAIDs may have complex inflammatory effects that may be deterimental:
1. NSAIDs may enhance the production of pro-inflammatory cytokines such as TNF by preventing the negative feedback of prostaglandin E. TNF causes sudden onset of shock and organ failure.
2. Impair oxygen dependent killing activities of neutrophils. This is associated with the use of ibuprofen but not flurbiprofen or indomethacin.
3. NSAIDs could exacerbate tissue damage in the long term.
-Some prostaglandins (PGI and PGE) reduce the generation of oxygen radicals, decrease lysosomal enzyme release and inhibit lymphocyte activation.
-Using NSAIDs to inhibit production of these prostaglandins will have opposite effects.
-This is found in Osteoarthritis patients prescribed with a strong COX inhibitor (indomethacin) as compared to a weaker inhibitor (azapropazone).
4. Platelet inhibitory effects
-Platelet function is affected because Thromboxane A2 production is prevented.
-This effect can be used to prevent vascular occlusion or platelet aggregation.
*Low dose Aspirin is the drug of the choice.
5. Prolongation of gestation and labour
-Prostaglandin synthesis (esp. PGF2) by the uterus increases substantially in the hours before parturition (childbirth).
*Inhibition of prostaglandin synthesis (e.g. by indomethacin) prolongs labour or prevents pre-mature labour.
1.4 Side effects of NSAIDs
1. Gastrointestinal disturbances.
*Massive GI bleeding (due to inhibition of prostacyclins which has protective gastrointestinal effect), Stomach Ulcers
-Mucosal prostaglandins inhibit acid secretion and has a cytoprotective effect by promoting the secretion of mucus.
-Inhibition of prostaglandin synthesis by inhibition of COX-1 is believed to account for erosions, ulcerations due to NSAIDs.
–Toxicity is relative to anti-inflammatory effect (thus the least toxic NSAID is paracetamol) (most toxic drugs being azapropazone and piroxicam)
Note: Prophylatic use of a prostaglandin analogue such as misoprostol is advisable.
2. Skin Reactions (2nd most common side effect)
–Mild Rashes, Urticaria (hives) and photosensitivity reactions. More serious and potentially fatal diseases occur but are rare.
*Occurs especially with Mefenamic acid (10-15%)and Sulindac (5-10%).
3. Severe rhinitis and asthma
-In some susceptible patients exposed to NSAIDs (particularly aspirin)
***4. Acute Renal failure
Three types of effects of NSAIDs on renal function.
(a) Renal Blood Flow (Perfusion decreases)
*Synthesis of PGI2 and PGE2 inhibited (which functions as vasodilators)
-Insignificant in healthy individuals but can be severe in those already with renal disease affecting blood flow and Glomerular filtration.
(Elderly, pre-existing renal conditions, hepatic cirrhosis, cardiac failure, diuretic therapy)
-Acute Renal Impairment occurs upon starting the drug, however effects are reversible if treatment discontinued promptly.
(b) Allergic type interstitial nephritis
-Rare but Severe
-Manifests itself as acute renal failure accompanied by proteinuremia (loss of proteins in urine)
-Frank Nephrotic Syndrome may occur (Heavy Proteinuria, Hypoalbuminia, Edema)
Note: Fenoprofen is likely to cause such renal damage!
(c) Analgesic nephropathy
-Mixtures of NSAIDs taken repeatedly cause severe and irreversible renal damage (esp. chronic interstitial nephritis, renal papillary necrosis and acute renal failure)
-Effects due partially to -Ischemia through inhibition of locally produced prostaglandins which as vasodilators.
-People who take high doses tend to exhibit analgesic nephropathy.
Note: Phenacetin likely to cause analgesic nephropathy (Paracetamol and NSAIDs also found to do so)
*** When NSAIDs are used in joint diseases (requires fairly large doses and prolonged use), there is a high incidence of side effects.
Part 2: Salicylates and Aspirin
Properties of these drugs:
-Aspirin (acetylsalicylic acid) and Salicylic Acid
-Aspirin itself is relatively insoluble but its calcium and sodium salts are readily soluble. Methylsalicylate is used topically in liniments.
Drug 1: Aspirin
(a) Mechanism of action of aspirin:
***Aspirin is unique among NSAIDs because it irreversibly inhibits COX by acylating the active site of the enzyme.
-By inhibiting COX, it prevents the formation of products including thromboxane, prostacyclin and other prostaglandins.
-Highly protein bound (95%)
Thus, the duration of action is not directly related to plasma concentration because of its irreversible nature of action.
(b) Therapeutic Effects
1. Anti-platelet effects
-Platelets (no nucleus) cannot regenerate the COX enzyme as nucleated cells can. This means that thromboxane production will only resume after new platelets are made and released into circulation (life-span around 8 days)
***Therapeutically: This means that anti-platelet effect can be readily achieved with low doses.
Indications: It is used primarily to decrease the risk of arterial thrombosis in patients who had suffered myocardial infarction or severe artherosclerosis.
It is also used post-coronary artery bypass, angioplasty or stenting (life time use) and in patients with a tendency to suffer thrombotic stroke.
2. Colon Cancer
-Sustained use of aspirin reduces the risk of colon cancer.
(c) Side Effects
- Local effects
1. Gastrointestinal effect (Focal erosive gastritis-gastric mucosal erosion caused by damage to mucosal defenses).
-Bleedings also occur which is worsened by anti-platelet effects.
- Systemic effects
2. Salicylism (Aspirin poisoning) can occur due to repeated ingestion of large doses. This syndrome consists of tinnitus, vertigo, decreased hearing and sometimes nausea and vomitting.
3. Skin rashes
4. Worsening of asthma in aspirin-sensitive individuals (inhibition of vasodilating prostaglandins)
5. Reye’s Syndrome
-Aspirin is contraindicated in children below 12 years of age.
-Brain (severe encephalitis occurs) and liver (fatty liver) affected.
-Usually occurs after a viral infection (Influenza) and has a mortality of 20% to 40%.
6. Altered Acid-Base and Electrolyte balance
-Lead to compensated respiratory alkalosis, uncompensated respiratory acidosis and metabolic acidosis (aspirin dessociates in blood to release H+)
Metabolic acidosis: occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body
Respiratory alkalosis: increased respiration (hyperventilation) elevates the blood pH
Compensation: Drop in Bicarbonate ion concentration due to the need to neutralise excess H+
(d) Drug interactions
*Potentially hazardous increase in effect of warfarin. Aspirin displaces it from plasma proteins and partly because of its anti-platelet effect.
-Aspirin on its own reduces urate secretion. It interferes with uricosuric agents such as probenacid.
*Should not be used in gout.
Drug 2: Paracetamol
-Its analgesic efficacy is equal to that of aspirin but only has mild anti-inflammatory effects (at therapeutic doses).
(a) Mechanism of action: Inhibits prostaglandin synthesis in the brain (COX-3) but hardly at all in the periphery. Does not affect platelet function.
(b) Metabolism of paracetamol (Normally and Overdose)
Step 1: Normally inactivated in the liver by conjugation as glucuronide (Phase II) and sulphate. However, with higher doses, the enzymes for these pathways are exhausted.
Step 2: The mixed function oxidases take over and convert paracetamol to the toxic metabolite N-acetyl-b-benzoquinone imime.
Step 3: With higher doses of paracetamol, glutathione is depleted and toxic intermediate accumulates
Step 4: This toxic intermediate binds to macromolecules in the cells causing death. Liver failure occurs.
Note: Agents which stimulate glutathione production (e.g. acetylcysteine or methionine) can prevent liver damage if given early.
(c) Side effects:
-Fatal liver and renal damage at toxic doses (2-3x maximum therapeutic dose) can cause serious, potentially damages.
Drug 3: COX-2 specific inhibitors
-It was hypothesised that the undesirable side effects of NSAIDs such as gastric erosion and renal dysfunction are due to inhibition of COX-1
-The anti-inflammatory (therapeutic) effects are due to inhibition of COX-2.
-Inhibitory potency and selectivity of the 1st generation NSAIDs (refer to 1.1 for NSAID classes) for COX-1 and COX-2 vary greatly
Side note: Some NSAIDs (ketoprofen) are relatively COX-1 selective, some (ibuprofen and naproxen) are essentially non-selective, while others (diclofenac) are selectively to COX-2.
Side Note: Inhibitory effects of NSAIDs on gastric PG synthesis correlate with COX-1 inhibitory potency in blood and with COX-1 selectivity but not with COX-2 inhibitory potency (i.e COX-2 affinity does not affect gastric PG synthesis but COX-1 does)
-However. even COX-2 selective NSAIDs still had sufficient anti-COX 1 activity to cause potent inhibition of gastric PG.
-Thus, at therapeutic concentrations, none of NSAIDs spare gastric COX-1 activity.
-In general, NSAIDs have a comparable efficacy but different safety profiles due to their differences in ability to inhibit COX-1 at therapeutic doses.
∴ We can evaluate NSAID selectivity by comparing their IC50 values (i.e. drug concentration at 50% inhibition of enzyme)
Drug selectivity= (COX-2 IC-50)/ (COX-1 IC-50)
-Smaller ratio indicates that the drug is more selective towards COX-2 (because smaller value of COX-2 means higher affinity)
- Celecoxib (Highly COX-2 selective~375 times)
-Indications: Rheumatoid and osteoarthritis
-At therapeutic doses, its plasma concentration does not reach the level required for COX-1 inhibition.
-In clinical trials, celecoxib showed effective anti-inflammatory activity with virtually no gastrointestinal adverse effects (compared to placebo)
- Rofecoxib (withdraw from market)
-Prostaglandin I2 was previously shown to be main cyclooxygenase product in endothelium (inhibits platelet aggregation, causing vasodilation, preventing the proliferation of vascular smooth muscle cells (in. vitro)
-Thus, it was assumed that PGI2 was derived mainly from COX-1 which was found constitutively in endothelial cells.
–However, this assumption was incorrect. COX-2 was the dominant source and may result in cardiovascular events. Further Explained below.
∴Point to note, PGI2 comes primarily from COX-2
-Thromboxane A2 is produced from COX-1 (Recall prostaglandin pathway)
-Thromboxane A2 has prominant effects in blood and vessels (Promotes Platelet aggregation, vasoconstriction and vascular proliferation).
-The cardiovascular effects of PGI2 (in vitro) contrast with the effects of Thromboxane A2 (i.e PGI2 inhibits platelet aggregation, has vasodilation effects).
–Aspirin and traditional NSAIDs inhibit both thromboxane A2 and prostaglandin I2.
Explanation why cardiovascular risk is higher:
-COX-2 selective inhibitors prevent PGI2 production in endothelial cells (express COX-2). However, it does not affect platelet’s thromoboxane A2 production.
-However, the coxibs leave the thromboxane A2 generation unaffected due to the lack of COX-2 in the platelets.
-This reduces PGI2 levels in comparison to Thromboxane A2 (COX-1 unaffected, very minimal Cox-2 present).
-Thus the protective anti-coagulative effect of PGI2 is decreased.
-Without this protective anti-coagulative property, there is an increase risk of thrombus, myocardial infarction and ciruclatory problems.
-Thus in a single action of depressing PGI2 formation results in the,
1. elevation of blood pressure
2. acceleration of atherogenesis
3. Patients receiving coxibs are more likely to have an exaggerated thrombotic response when atherosclerotic plaque ruptures.
*Selective inhibitors of COX-2 remain a rational choice for patients at low cardiovascular risk who had serious gastrointestinal events, especially while taking traditional NSAIDs.
*Avoid Coxibs in patients who have cardiovascular disease or are at risk.