General Pharmacology

Non Steroidal Anti-inflammatory Drugs (NSAIDs)

Done By : Mu'ad Al-Zou'bi

This lecture is about the most common type of analgesics prescribed by doctors and dentists and they are considered as OTC drugs (over-the-counter drugs) in which they can be got from pharmacies without a doctor's prescription. Some of their advantages that they're cheap (some of them), available, and don't need a doctor's prescription. They're non-narcotic analgesics, non-opioid analgesics, they are known as COX inhibitors because of their mechanism of action, and they're known as the non steroidal anti-inflammatory drugs (NSAIDs). Examples of the NSAIDs include aspirin, ibuprofen,ketoprofen ,sulindac, piroxicam, naproxen, diclofenac (Votrex or Voltaren), paracetamol (it's considered as a non steroidal anti-inflammatory although it has no anti-inflammatory effect),Ponstan or mefenamic acid, they don't have a specific suffix for their names. The NSAIDs are named like that because they have an anti-inflammatory effect although they are not steroids, comparing them with corticosteroids (they have cholesterol nucleus or synthesized from cholesterol) in which they are steroids and have an antiinflammatory effect, so the NSAIDs can be differentiated from corticosteroids that they have an anti-inflammatory effect but they are non-steroidal, they don't contain the cholesterol nucleus in their structure. - Anti-inflammatory: The main thee actions of the NSAIDs that they have an anti-inflammatory, analgesic and suppress inflammation. antipyretic effects, they are effective in the management of fever. - Analgesic effect: produce analgesia or suppress Inflammation may become a physiological response once there is a cell injury in which it's a pain sensation. way of protection to repair the tissue damage by the migration of inflammatory cells and - Antipyretic effect: synthesis and release of inflammatory mediators (the cascade that occurs during reduce elevated body inflammation). temperature (treatment of fever). There's a process of inflammation that occurs once there is cell injury, or to fight an infection that will lead to cell damage and in such situations, this process i.e. inflammation is done by the body in order to protect against or to correct and treat this damage, this process involves the release of inflammatory mediators by the leukocytes, examples of those mediators are cytokines and eicosanoids (arachidonic acid metabolites), this lecture will focus on eicosanoids, namely the prostaglandins, leukotrienes and thromboxanes. Eicosanoids are synthesized peripherally in the presence of inflammation and once they are formed, they will increase the inflammatory process that's characterized by redness, swelling, pain due to the activation of the sensory nerve fibers that will lead to pain sensation, some processes in inflammation and infection are accompanied by fever (pyrexia) in which there's an increase in the synthesis of prostaglandins in the thalamus where the thermoregulatory centre in the CNS is.
The external manifestations of inflammation, often called its cardinal signs, result from the vascular changes and cell recruitment: heat (calor), redness (rubor), and swelling (tumor). The two additional cardinal features of acute inflammation, pain (dolor) and loss of function (functio laesa) , occur as consequences of mediator elaboration and leukocyte-mediated damage. As the injurious agent is eliminated and anti -inflammatory mechanisms become active, the process subsides and the host returns to a normal state of health. If the injurious agent cannot be quickly eliminated, the result may be chronic inflammation. Robbins Basic Pathology, 8th edition.

How does the inflammatory process activate the synthesis of the inflammatory mediators?
Activation of phospholipase A2 in the cell membrane

Phospholipids

Inflammation

Arachidonic acid

5-lipooxygenase

Cyclooxygenase (COX) Endoperoxides

Leukotrienes

Prostaglandins

Thromboxane A2

Thromboxane A2 (TxA2) is mainly present in the platelets, and its formation will enhance platelet aggregation and that's important to prevent and control injury and to stop bleeding (by clotting). Prostaglandins are important not only in case of inflammation but also to maintain the normal body homeostasis, this means that in some cases we should not prevent prostaglandins synthesis, there are different types of prostaglandins, for example PGI2 (prostacyclin), PGE2, PGD2, PGF2 alpha and each type has a different certain function. Leukotrienes include different types such as LTC4, LTD4, one of the most important adverse effects of leukotriens that they induce bronchoconstirction and by that they will worsen the bronchial asthma. In the platelets, the action of COX will lead to the synthesis of two types of eicosanoids which are TxA 2 that will increase or stimulate platelet aggregation and PGI2 (prostacyclin) that will inhibit platelet aggregation (opposite actions). Cyclooxygenase enzymes will convert the arachidonic acid into prostaglandins and thromboxane A 2, there are mainly three isoforms of COX which are: - COX-1: it's considered as a constitutive enzyme (permanent enzyme), and its action is very important to maintain the normal body homeostasis (a housekeeping enzyme), in another way, the prostaglandins that are formed by COX-1 are very important and beneficial to the body. Under a physiologic stimulus, COX-1 is important in the stomach to reduce gastric acid secretion, in the kidney to maintain the renal blood flow, and in the platelets to enhance platelet aggregation (physiologic functions). - COX-2: it's an inducible enzyme, in which its activity will increase in the presence of inflammation, this means that COX-2 will synthesize the prostaglandins that will lead to an inflammatory response (inflammation), i.e. swelling, redness, pain, etc. and other inflammatory problems. - COX-3: it's mainly present in the CNS, and it's mainly inhibited by paracetamol (acetaminophen). Arachidonic acid

COX-1
Non-selective NSAIDs COX-2 selective NSAIDs Prostaglandins that are essential or functional in the body including prostaglandins that cause: - Gastrointestinal cytoprotection. - Platelet activity (TxA2)

COX-2

Prostaglandins that will lead to: - inflammation - Pain - Fever

Most of the NSAIDs such as aspirin, diclofenac, ibuprofen, ketoprofen, sulindac, piroxicam, naproxen, are non selective in which they inhibit both COX-1 and COX-2. By the inhibition of COX-2, the therapeutic purpose or response is produced (analgesic effect, inflammation suppression and fever treatment) while the inhibition of COX-1 produces the adverse effects of the NSAIDs. Once the NSAIDs are needed to be prescribed, some of the most important questions that should be asked during taking history from the patient are if the patient has a history of peptic ulcer or gastritis (GIT problems), if the patient has a history of bronchial asthma and if the patient has gout. Once the patient has one of those problems, the NSAIDs are contraindicated. Also if the patient has heart failure or renal problems, it's better to avoid the NSAIDs. The most important thing to concern about is the peptic ulcer, one of the advices that's given to the patient to reduce the risk of ulcer development is to take the NSAIDs after a meal, it's a minor pathway to reduce the ulcer development in which the contact between the stomach or the gastric lining and the drug is reduced, although their mechanism i.e. the NSAIDs to induce peptic ulcer is a systemic effect. Some NSAIDs are selective COX-2 inhibitors, they inhibit only the synthesis of the inflammatory mediators (inflammatory prostaglandins). The selective COX-2 inhibitors are more expensive because they have fewer side effects and low risk of GI tract adverse effects, although some of them are withdrawn from the market.

NSAIDs are either: - Non-selective (COX-1 and COX-2) inhibitors. - Selective COX-2 inhibitors. - Selective COX-3 inhibitors, by that they only produce the analgesic and the antipyretic effects (COX-3 is mainly present in the CNS). The most important example of COX-3 inhibitors is paracetamol (acetaminophine), (some brand names are, dolomol, panadol, panda, dolocet, revanin). The anti-inflammatory, the analgesic and the antipyretic effects are produced by the inhibition of COX-2, while the adverse effects are produced by the inhibition of COX-1. The beneficial actions (or therapeutic uses) of the NSAIDs due to prostanoid synthesis inhibition are: 1- Analgesia. 2- Antipyretic effect. 3- Anti-inflammatory action. 4- Antithrombotic action, aspirin has an antithrombotic action in a low dose, in a low dose it can inhibit platelet aggregation by the inhibition of TxA2 synthesis, it can be used prophylactically, and it can be used in the essential management of the emergency MI, in acute MI, aspirin is taken in a high dose, about 300 mg, just crushed by the patient to treat thromboembolic disorder or thrombosis including MI and stroke. In patient with history of cardiovascular thrombotic disorders and in patients who have risk factors to develop cardiovascular disorders e.g. old patients, heavy smokers, obese patients, hypertensive patients or diabetic patients, those patients have a risk to develop MI or stroke due to platelet aggregation, as a prophylactic in order to prevent these manifestations, a low dose of aspirin (known as baby aspirin), about 75-100 mg, some books say 75-150 mg of aspirin (aspirin in a low dose has an antiplatelet effect). 5- Closure of ductus arteriosus, indomethacin is mainly used for closing patent ductus arteriosus that's an opening between the pulmonary artery and the aortic arch, this opening is patent while the fetus is in the uterus, after labor (delivery), this opening should be closed within 12-24 hours and completely sealed within weeks, if it stays patent (isn't closed), it will lead to cardiovascular-respiratory problems characterized by dyspnea, respiratory problems, tachycardia and it may lead to the development of heart failure in the baby, indomethacin enhances the closure of this patent ductus arteriosus in which it will inhibit prostaglandin synthesis, if not, it's treated by surgery. The shared toxicities (or adverse effects) of the NSAIDs due to prostanoid synthesis inhibition are: 1- Gastric mucosal damage, that will lead to GI tract bleeding and peptic ulcer formation, because they inhibit the formation of good prostaglandins. In the stomach, prostaglandins will reduce gastric acid secretion and they will increase mucus and bicarbonate (HCO3-) secretion, this will protect the stomach as well as the duodenum from hyperacidity, if the synthesis of those good or beneficial prostaglandins is inhibited, the risk of peptic ulcer development will be increased (induction of gastropathy). 2- Bleeding. 3- Limitation of renal blood flow due to the continuous use of the NSAIDs for a prolonged period time, because the prostaglandins PGI2 and PGE2 will induce vasodilation and this will increase the renal blood flow (maintain renal glomerular filtration), by inhibition of prostaglandin synthesis, the renal blood flow will be reduced (by the induction of renal vasoconstriction) and this may alter the kidney function. 4- Sodium and water retention and edema formation, this means that the use of the NSAIDs should be avoided in patients with fluid overload like in case of heart failure. 5- Analgesic nephropathy (a kidney disease known as papillary renal necrosis) because of chronic use of the NSAIDs for a prolonged period of time. 6- Delaying or prolongation of labor, but in some case this may be a beneficial or therapeutic effect like in case of premature or preterm labor, as in a female that she doesn't reach the full term for delivery for example between 20 weeks to 37 weeks of

gestation, she has uterine contractions associated with cervical dilatation, if it continues, she will lose her baby, to overcome this problem, some drugs are used to inhibit the uterine contractions, like 2 agonists that induce uterine relaxation and the NSAIDs that inhibit prostaglandin synthesis, because prostaglandins initiate the uterine contractions, when their formation i.e. prostaglandins is inhibited, the uterine contractions are inhibited. It's an adverse effect of the NSAIDs if this female has already reached term, but in some cases it may become a beneficial effect if a female has a condition like a preterm labor, in this case, the inhibition of the uterine contractions and delivery are desired. 7- They may induce asthma and anaphylactoid reactions. Examples of the NSAIDs: A- Non-selective NSAIDs (COX-1 and COX-2 inhibitors): 1- Aspirin or acetylsalicylic acid (ASA), it has an analgesic, antipyretic and anti-inflammatory effect, while the salicylic acid cannot be used systemically like aspirin (orally or pareterally), salicylic acid is mainly used topically in the management of corns or warts because of its keratolytic effect, it's applied locally, once it's applied to the skin, it may produce a sensation like burning, the patient is advised to use Vaseline around the wart as an isolator to reduce the contact between the salicylic acid and the normal tissue, it's only applied to the affected area, directly to the corns or to the warts. Aspirin is the only NSAID that irreversibly inhibit the COX enzymes. The uses of aspirin: 1- As anti-inflammatory for the treatment of inflammatory disorders like rheumatoid arthritis, osteoarthritis. 2- As an analgesic, it suppresses pain sensation. 3- As an antipyretic, to lower the body temperature in case of fever. 4- As an anti-platelet, only aspirin of the NSAIDs has an anti-platelet effect once it's used in a low dose. Part of the answer is that in a low dose it will inhibit prostaglandin synthesis that will initiate platelet aggregation, 75-100 mg of aspirin is taken once daily as an anti-platelet drug. 5- Uric acid is one of protein metabolites, the aspirin effect on uric acid depends on its dose, in a small dose (about 1-2 g), it will inhibit uric acid excretion, and this means that it will exacerbate the gouty attacks (gout is an inflammatory disease affects the joints and the kidneys and it's characterized by hyperuricemia, uric acid is deposited in the form of crystals, in the joints and the kidneys that will lead to pain, one of its causes is an excessive protein intake). But if aspirin is used in a high dose (about 5 g), it will inhibit uric acid renal reabsorption and this will reduce the plasma uric acid level (a uricosuric effect, it enhances uric acid renal excretion). It's found that the chronic use of 6- Aspirin reduces the percentage of the development of radiation induced diarrhea. aspirin may increase the risk of 7- Aspirin can reduce colonic and rectal cancer development. blindness in the elderly 8- Aspirin is beneficial in Alzheimer's disease. individuals. The contraindications of aspirin: 1- Peptic ulcers, it will reduce the gastric protection by the inhibition of the formation of the good prostaglandins i.e. the prostaglandins that maintain the normal body functions. 2- Bronchial asthma, (arachidonic acid is converted by COX-1 and COX-2 to prostaglandins and by 5-lipooxygenase to leukotrienes, by the use of the NSAIDs, the COX pathway is inhibited and the arachidonic acid metabolism will be shifted to the leukotrienes pathway, this will increase the formation of the leukotrienes and once they are formed, they will lead to bronchospasm, in asthmatic patients, this will worsen asthma). 3- Viral infection in children, any infection is associated with fever (pyrexia) that can be treated by the NSAIDs, if the fever is induced by infection due to virus (chickenpox, vericella, influenza, etc.), it's found that prescription and administration of aspirin by a child who's less than 12 years old will induce the development of a rare syndrome known as Reye's syndrome, this syndrome is characterized by liver damage (dysfunction) due to fatty infiltration of the liver, hepatic mitochondrial injury and metabolic encephalopathy (encephalitis). In other words, the pyrexia will not be treated, instead, serious and fatal complications will be induced. So, the better is to avoid aspirin for the treatment of fever in children, the safer drug is paracetamol, it's effective in reducing fever in children and infants, it's present in the form of suppositories and syrup (effective in the management of fever in children). 4- In gout, if it's used in a low dose.

Aspirin Toxicity Salicylism The side effects of aspirin are dose dependent, these are some of them: - Headache , tinnitus , dizziness , hearing impairment , dim vision. - Confusion and drowsiness. - Sweating and hyperventilation. - Nausea, vomiting. - Marked acid-base disturbances characterized by respiratory alkalosis, followed by respiratory acidosis, followed by metabolic acidosis. - Hyperpyrexia (hyperthermia) which is a paradoxical effect, by the toxic dose the body temperature will increase. - Dehydration. - Electrolytes disturbances. - Cardiovascular and respiratory collapse, coma convulsions and death (the lethal dose is about 250 mg per kg). Although aspirin is cheap and effective, it's complicated by many adverse effects. Therapeutic doses of aspirin: - In a very low dose, it has an anti-platelet effect. - In a moderate dose, it has an analgesic and antipyretic effect. - In a high dose it has an anti-inflammatory effect. - Aspirin intoxication is ranged as mild, severe and lethal. - The lethal dose is ranged from 150 to 250 mg per kg There's no specific antidote for aspirin overdose. 2- Indomethacin The uses: 1- To close ductus arteriosus in newborn. 2- Management of pretermlabour (inhibit the synthesis of prostaglandins that induce the uterine contractions). 3- It has a powerful anti-inflammatory effect. The adverse effects: 1- GI tract adverse effects. 2- CNS adverse effects (frontal headache).

The NSAIDs in general are effective in the management of somatic pain, but they can be used in some cases of visceral pain like in case of renal colic (combined with opioids), or for the treatment of dysmenorrhea (painful menses) in females because the endometrial shedding that occurs due to uterine contraction is induced by prostaglandin formation that can be inhibited by the NSAIDs (effective to treat this type of pain).

3- Iboprofen (some brand names are profen and ibogesic) It's commonly used and it has the least GI tract toxicity among the NSAIDs because of its short half-life (short duration of action). 4- Diclofenac-sodium or diclofenac-potassium Diclofenac-sodium is contraindicated in patients with hypertension, heart failure or renal disease where they require sodium restriction (low sodium intake). Diclofenac is available in many dosage forms such as tablets, injections, suppositories (the brand name is Infla-ban or Voltaren), patches (for example Voltaren patch that is used for backache), creams and eye drops. 5- Piroxicam It's highly anti-inflammatory and it has a long duration of action (long half-life) that permits once daily dosing. 6- Meloxicam It's a non-selective NSAID but preferentially inhibits COX-2 more than COX-1 (preferentially selective rather than highly selective). It has a long duration of action and can be used once daily. It has a low incidence of GI tract manifestations. The drug has been approved for the treatment of osteoarthritis and rheumatoid arthritis.

A comparison between the actions of the non-selective and the selective COX inhibitors:

By observing the preceding table, it's obvious that the main benefit of using the selective COX-2 inhibitors is that they have less GI tract complications. B- Selective COX-2 inhibitors (Coxibs): They exert an anti-inflammatory, analgesic and antipyretic action with a low ulcerogenic potential (fewer GI tract manifestations), and they act only on COX-2. They are expensive drugs. 1- Celecoxib (Celebrex) It's preferred to be used in individuals who need the NSAIDs for a prolonged period of time like in case of rheumatoid arthritis or osteoarthritis as inflammatory diseases in which the patient needs to use the NSAIDs for the remainder of his life. 2-Valdecoxib 3- Rofecoxib (VIOXX), it's out of date (withdrawn from the market and not used), one of the causes for its withdrawal is that it increases the incidence of thrombosis (cardiovascular thrombotic disease), it will increase the risk of MI and stroke development in some patients. Paracetamol (acetaminophen) The most common drug of the NSAIDs, it has different brand names, it's available in the form of tablets, suppositories, and injections (Prodafalgan). It has a powerful analgesic and antipyretic effect with a weak or no anti-inflammatory effect, it doesn't inhibit platelet function, and it has no effect on plasma uric acid level (doesn't affect uric acid excretion). This means that paracetamol can substitute the analgesic and antipyretic effects of aspirin and other NSAIDs if they're contraindicated as in a patient complaining from peptic ulcer or asthma and needs an analgesic, it's obligatory to prescribe paracetamol, or there's a child with a viral infection that induced fever, the best is to select paracetamol (in general, paracetamol is the best antipyretic agent in a febrile child to reduce the risk of the development of Reye's syndrome). But paracetamol will not substitute aspirin as an anti-inflammatory or an anti-platelet drug, for example, a patient has peptic ulcer and needs an anti-inflammatory drug, in this case aspirin is contraindicated but paracetamol cannot be used because it has already a weak or no anti-inflammatory effect, in this case aspirin and other non-selective NSAIDs should be avoided, instead, selective COX-2 inhibitors and other types of anti-inflammatory drugs like corticosteroids can be used. It's the drug of choice in children with febrile seizure. Acute paracetamol poisoning About 10 g (20 tablets) of paracetamol (taken suddenly) are lethal or 150 mg per kg (accidental or suicidal attempt). This will induce a lethal adverse effect. Paracetamol requires the liver enzymes for its metabolism, it's metabolized mainly by glucuronidation (a conjugation process), it's metabolized by the cytochrome P450 to form a toxic metabolite, this toxic metabolite which is N-acetyl-pbenzoquinoneimine (NABQI), this metabolite i.e. NABQI can be eliminated by glutathione (GSH) conjugation, GSH is a sulfur donor, this conjugation will convert NABQI to mercapturic acid conjugate which can be renally excreted. But if paracetamol is taken in a high dose (especially in alcoholic patients) where there is excessive formation or accumulation of this toxic metabolite i.e. NABQI, there will be glutathione depletion and this metabolite will interacts with proteins in the kidneys and in the liver to induce liver cells death, liver necrosis is the adverse effect of paracetamol overdose.

Treatment of paracetamol poisoning: For example in the emergency department or the emergency room (the ER), an emergency case is presented in which the patient has taken about one package of revanin (30 tablets). The main important things to assess for any poisoning are the ABCDE (airways, breathing, circulation, disability and exposure) If this drug has been taken orally (in the form of tablets), gastric lavage can be induced, or activated charcoal can be used orally to adsorb paracetamol and minimizes its systemic absorption. At the same time the antidote is used, the antidote for paracetamol overdose is N-acetylcysteine, it's an (SH) donor, the presence of (SH) group is important for the detoxification of NABQI, this drug i.e. acetylcystiene is given parenterally (I.V infusion) and it should be given within 12 hours of intoxication.

In this lecture, there was an issue to search for, it was about why aspirin is taken in a low dose as an anti-platelet or why aspirin is not taken in a high dose as anti-platelet. The following box discusses the answer.

Aspirin and Antiplatelet Medications

At lower doses, such as 75 mg/d, the antiplatelet effect of aspirin can be achieved in several days instead of minutes. Since the risk of serious bleeding from aspirin is lower at lower doses, 75 mg/d is an appropriate dose for long-term primary and secondary prevention. Even though aspirin at doses as low as 40 mg/d has been shown to have anti-platelet effects, there is insufficient and inconclusive data to show that such low doses are effective in preventing heart attacks and ischemic strokes. There also is no evidence that higher doses of aspirin, such as 1000 mg/day or higher, is more effective than lower doses. Some studies even suggest that higher doses may not be as effective as lower doses. Since the side effects of aspirin are more frequent with higher doses, doctors generally do not recommend higher doses for long-term use. The USPSTF also looked into the optimal dose of aspirin for primary preventive purposes in 2009. They concluded that the low doses of 75-100mg daily were as effective as higher doses in preventing vascular disease and less associated with bleeding complications.

If you want to read more about this, check the following link: http://www.medicinenet.com/aspirin_and_antiplatelet_medications/page5.htm

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- I apologize for any scientific, grammatical or spelling error if it's present. "Mu'ad Salahuddin Al-Zou'bi"

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