Nonsteroidal Antiinflammatory Drugs NSAIDs and Analgesics Dr Alia

Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and Analgesics Dr. Alia Shatanawi 4 -3 -2013

There are steroidal anti inflamatory drugs : mainly glucocoticoid cortisone. Q: Why do we use such drugs ? (common charectaristics of these drug): 1) To reduce inflamation. 2) Pain Relief. 3)To reduce fever.

• Recall that : Inflammation : is the body response to a foreign body/microorganism , it does not mean infection(microorganism). it’s the body response to any stimuli whatever is it.

Inflammatory pathways • Cyclooxygenase (COX) pathway of arachidonate metabolism produces prostaglandins • Effects on blood vessels, on nerve endings, and on cells involved in inflammation. (Different kinds of prostaglandins with different effects on different tissues : for example >prostaglandin 1 has dilatory effect on bronchi , another has constrictory effect on them. also in different conditions >in pregnancy it has retraction effect on utetrine muscles ) • The lipoxygenase pathway of arachidonate metabolism yields leukotrienes (intermediate in inflamatory rxn specially allergic rxn [histamine release] so leukotriene inhibitor pathway used to treat certain conditions such as asthma • have a powerful chemotactic effect on eosinophils, neutrophils, and macrophages and promote bronchoconstriction (initiating asthma )and alterations in vascular permeability.

` Leukotrien antagonists , lipooxygenase inhibitors used to treat asthmatic conditions. ASA: aspirin acetylsalicylic acid sometimes considered NSAID Or considered out of this group Prostaglandin modulates the action of leukotriens in asthmatic condition mainly

• Zileuton: (trade name ZYFLO) is an orally active inhibitor of 5 -lipoxygenase, and thus inhibits leukotriens (LTB 4, LTC 4, LTD 4, and LTE 4) formation. Zileuton is used for the maintenance treatment of asthma[ from wikipedia ]. • Colchicine : inhibiting the phagocytosis , how does it work ? Actin gets polymerized forming long actin tubules to help in phagocytosis process by macrophages so by inhibiting polymerization of actin in the macrophages we can inhibit their action so inhibiting inflamatory mediating action in inflamatory site.

Notes … • Uses of aspirin >> used mainly as pain killer to releive the pain & inflamation. • Thrombaxane >>needed for platelet aggregation , aspirin works to inhibit platelet aggregation. • It is also used as prophylactic treatment to decrease the risk of myocardiac infarction but the dose is lower than that used to treat the pain : 1 mlg -> myocardiac infarction 325 mlg -> as pain killer

Corticosteroid : part of endocrine system

We’ve 2 different COX enzymes >> COX 1 & COX 2 These anti inflammatory drugs used mainly to treat rheumatoid arthritis(RA) >>very important

Notes about the previous figure … ØConstitutive >>available under physiological condition. ØInducible >>it doesn’t act unless there is stimulus. ØSynoviocytes >>cells surrounding synovial fluid. ØPhysiologic functions >>to maintain homeostasis and integrity of the immune system.

Ø W e concern that there are cox 1 & cox 2, , coz of making drug , , sometimes you want to target specific isoform of the enzyme coz sometimes the isoform can be associated with many side effects thus when you target another isoform that is not present in the body , you can inhibit the side effects associated with present cox 1. Ø cox 1 Prostaglandin, in the stomach PG acts to inhibit acid secretion, increase mucus secretion, thus inhibition cox 1 by aspirin will lead to peptic ulcer so the major side effect of NSAID is : Peptic Ulcer and increasing stomach acidity. Ø We give Cox 2 inhibitors to decrease side effects associated with cox 1 inhibitors

Cyclo-oxygenase (COX) • Exists in the tissue as constitutive isoform (COX-1). • At site of inflammation, cytokines stimulates the induction of the 2 nd isoform (COX-2). • Inhibition of COX-2 is thought to be due to the antiinflammatory actions of NSAIDs. • Inhibition of COX-1 is responsible for their GIT toxicity. • Most currently used NSAIDs are somewhat selective for COX-1, but selective COX-2 inhibitors are available.

Non -steroidal Anti-Inflammatory Drugs • • Analgesic pain. Antipyretic Anticoagulant platelet aggregation. Anti-inflammatory (at higher doses)

Opiods are strong analgesics that work on CNS May lead to addiction. Comparison of Analgesics Feature Narcotic (Opioids) Nonnarcotic (nonopioid) Efficacy Strong Weak Prototype Morphine Aspirin Pain Relieved Any Type Musculoskeletal Site of Action Central Peripheral and Central Mechanism Specific Receptors [in PG Synthesis the brain] inhibition Danger Tolerance & Dependence G. I irritation Anti-inflammatory No Yes Antipyretic No Yes Antiplatelets No Yes 14

In this table the dr said that you already know : ibuprofen [propionic acid ] Aspirin [salicylate. And it’s important to focus on selective cox 2 inhibitors.

Notes about the previous figure …. üDiclofenac : voltarine. üThey work by the same mechanism of action but they classified as they differ in : potency , efficacy , duration of action. üIndomethacin: the most drug causes adverse effect on GIT , then there is ibuprofen with less severity. ü Also Aspirin has high GI side effect. üSelective Cox-2 inhibitors (Rofecoxib) where heavily prescribed in inflammatory conditions such as RA and GI irritation, then Rofecoxib drug was no more present in the market coz of its association with adverse effects : myocardiac infarction , stroke (cerebrospinal attack ).

ü Mechanism of action of cox -2 inhibitors is not clear but they are mainly responsible to decrease platelet aggregation so they supposed to have beneficial effect on myocardic infarction but this promising effect was not detected so they stop selling this drug [Rofecoxib] in the markets. ü Celecoxib is still present in market however it’s not advised to use for those who complain from heart diseases.

Common Pharmacological Effects • Analgesic (CNS and peripheral effect) may involve non-PG related effects • Antipyretic (CNS effect) -> associated with hypothalmic pathway in controlling body temperature • Anti-inflammatory due mainly to PG inhibitionexcept acetaminophen is same as paracitamol >>inhibiting Cox 2, but it does not have much anti-inflammatory action , it’s mainly analgesic &antipyretic }. Some shown to inhibit activation, aggregation, adhesion of neutrophils & release of lysosomal enzymes • Some are Uricosuric [related to excretion of uric acid , , we’ll talk about them in Gout ]

Mechanisms of Action • Antipyretic actions – Fever, heat stroke, incr T° are hypothalamic problems. - So, NSAIDs do not decr body T°. - Fever release of endog pyrogens (e. g. , interleukin-1) released from leucocytes acts directly on thermoregulatory centers in hypothalamus incr body T°. - This is assoc with incr in brain PGs (pyrogenic). - Aspirin prevents the T°-rising effects of interleukin-1 by preventing the incr in brain PGs.

Pharmacological Effects (cont’d) • Diverse group of chemicals, but all inhibit cyclooxygenase. • Resultant inhibition of PG synthesis is largely responsible for their therapeutic effects. • But, inhibition of PG synthase in gastric mucosa GIT damage (dyspepsia, gastritis).

NSAID Mechanism of Action: • Inhibition of PG synthesis – Cyclooxygenase (COX) Enzyme: • COX-1 or Constitutional form of COX. • COX-2 or Induced form of COX. 21

Ø Cardiovascular Ø • Platelets: Inhibition of platelet COX-1 -derived Tx. A 2 with the net effect of increasing bleeding time (inhibition of platelet aggregation) mainly cox 1 enzyme is responsible to thrombaxane production Ø • Endothelial COX-2 derived PGI 2 can inhibit platelet aggregation (inhibition augments aggregation by Tx. A 2). The process of inhibition cox 2 platelet aggregation maybe more powerful than cox 1. Ø Aspirin (acetylsalicylic acid) covalently modifies and, irreversibly inhibits platelet COX[v. imp in the exam]. The enzyme is inhibited for the lifetime of the platelet (~8 -11 days). Effect achieved at very low dose. Ø • Basis of therapeutic efficacy in stroke and MI (reduces mortality and prevents recurrent events).

Additional Cardiovascular Considerations • Blood vessels/smooth muscle COX-2 derived PGI 2 can antagonize catecholamine- and angiotensin II-induced vasoconstriction (NSAIDs can elevate bp). • Atherosclerosis Inhibition of COX-2 can destabilize atherosclerotic plaques (due to its antiinflammatory actions)

Notes about atherosclerosis plaques … Using cox 2 inhibitor drugs leads to mobilizing of the atherosclerosis plaques this may help in myocardiac infarction, these plaques will be ruptured to smaller ones that may go to small artery[in the brain] leading to stroke or coronary artery leading to myocardiac infarction. Atherosclerosis plaques : Those who suffer from Angina pectoris usually have predisposing factors mainly high concentration of cholesterol , lipoprotein in the blood stream , this cholesterol will adhere [deposit] to the internal wall of artery this will lead to initiating the inflammatory process >>macrophages will come forming atherosclerosis plaques that composed of fibroblasts, inflammatory cells , the core of it formed by lipid finally constriction of the blood vesseles

• also hypertension considered as predisposing factor, constriction of blood vesseles , different factors related to collagen and thickening of smooth muscles will increase.

Renal PG important in controlling the blood flow in the kidney ( Dilation afferent Arterioles , so if we block production we will impair the kidney circulation ) • COX-1 and COX-2 – generated PGs (Tx. A 2, PGF 2 , PGI 2 (glom), PGE 2 (medulla), powerful vasodilators) can both incr and decr Na+ retention (natriuresis predominates), usually in response to changes in tubular Cl-, extracellular tonicity or low bp. • NSAIDs tend to promote Na+ retention and can therefore increase bp. Can counteract effects of many antihypertensives (diuretics, ACE inhibitors and -AR antagonists ). • PGs have minimal impact on normal renal blood flow, but become important in the compromised kidney. Patients (particularly elderly and volume depleted) are at risk of renal ischemia with NSAIDs.

It’s important to notice …… q. Cox 1 cox 2 produce pg powerful vasodilator Na+ retention & H 2 O retention thus regulates BP. q. If we inhibit pg. . constriction of afferent arterioles we will have Na+ retention & H 2 O retention thus BP.

Gastrointestinal • PGs (generated via COX-1) 1) inhibit stomach acid secretion, 2) stimulate mucus and HCO 3 - secretion, vasodilation and therefore, 3) are cytoprotective for the gastric mucosa. • Therefore, NSAIDs with COX-1 inhibitory activity will produce opposite effects, leading to: • Gastric distress, gastric bleeding, sudden acute hemorrhage {it’s developed also due to the fact that these drugs are antiplatelet } (effects are dosedependent)

Gestation PGs (generated from COX-2) are involved in the initiation and progression of labor and delivery. Therefore, inhibition of their production by NSAIDs can prolong gestation. {these drugs not recommended to be taken in the 3 rd trimester of pregnancy coz of their association with early closure of ductus artreosum: an open btn right & left ventricles , it’s closed when the baby born}. They noticed that aspirin may associate with abortion coz it’ll cause platelet dysfunction(dysaggregation) specially in the early months of pregnancy. Respiratory system High doses (salicylates) cause partial uncoupling of oxidative phosphorylation with increased CO 2 production (COX-independent effects). Increase in plasma CO 2 hyperventilation. Even higher doses cause depression of respiration. Other uses of NSAIDs (mechanisms less understood) - Decreased risk of fatal colon carcinoma

Common Adverse Effects • Platelet Dysfunction • Gastritis and peptic ulceration with bleeding (inhibition of PG + other effects) • Acute Renal Failure in susceptible • Sodium+ water retention and edema • Analgesic nephropathy • Prolongation of gestation and inhibition of labor. • Hypersenstivity (not immunologic but due to PG inhibition) • GIT bleeding and perforation

The Salicylates - Aspirin Different effects on respiratory system depending on the dose. • Effect on Respiration: triphasic 1. Low doses: uncoupling phosphorylation → ↑ CO 2 → stimulates respiration. 2. Direct stimulation of respiratory center → Hyperventilation → resp. alkalosis → renal compensation 3. Depression of respiratory center and cardiovascular center → ↓ BP, respiratory acidosis, no compensation + metabolic acidosis also

The Salicylates - Aspirin • Duration of action ~ 4 hr. • Orally taken. • Weak acid (p. Ka ~ 3. 5); so, non-ionized in stomach easily absorbed. • Hydrolyzed by esterases in tissues and blood to salicylate (active) and acetic acid. • Most salicylate is converted in liver to water soluble conjugates that are rapidly excreted by kidneys.

Reye's syndrome this is specific for aspirin in infants and children below the age of 6 yrs • Reye's syndrome is a potentially fatal disease that has numerous detrimental effects to many organs, especially the brain and liver, as well as causing a lower than usual level of blood sugar (hypoglycemia). [1] The classic features are a rash, vomiting, and liver damage. The exact cause is unknown and, while it has been associated with aspirin consumption by children with viral illness, it also occurs in the absence of aspirin use.

• Note about the Reye Syndrome : If you have a baby or a child with viral infection it’s not recommended to prescribe NSAID for him coz this condition of unknown cause but it maybe associated with aspirin consumption by a child who has viral illness , so it’s preferred to prescribe another analgesic for him like paracitamol.

Aspirin - Therapeutic Uses • Antipyretic, analgesic • Anti-inflammatory: rheumatic fever, rheumatoid arthritis (joint dis), other rheumatological diseases. High dose needed (5 -8 g/day). • But many pts cannot tolerate these doses (GIT); so, proprionic acid derivatives, ibuprofen, naproxen tried first. • Prophylaxis of diseases due to platelet aggregation (CAD, post-op DVT){ CAD >>coronary artery disease , DVT >Deep pain thrombosis}. • Pre-eclampsia and hypertension of pregnancy (? excess TXA 2) BUT It maybe associated with platelet dysaggregation or defects in fetus so aspirin not always advised to be used during pregnancy.

Aspirin Toxicity - Salicylism • Headache - timmitus - dizziness – hearing impairment – dim vision • Confusion and drowziness • Sweating and hyperventilation • Nausea, vomiting • Marked acid-base disturbances [coz it’s salicylic acid These complications mainly in pts who ]. take over dose of aspirin , or have • Hyperpyrexia hypersensitivity to it. so you should know the history of disease for the pts • Dehydration • Cardiovascular and respiratory collapse, coma convulsions and death

Aspirin Toxicity - Treatment • Decrease absorption - activated charcoal, emetics, gastric lavage • Enhance excretion – ion trapping (alkalinize urine), forced diuresis, hemodialysis • Supportive measures - fluids, decrease temperature, bicarbonate, electrolytes, glucose, etc…

Paracetamol • Paracetemol(acetaminophen) – no significant anti-inflammatory effect, but used for its mild analgesic effect. • Well-absorbed and without GIT irritation. • Serious disadvantage: at high doses, severe hepatotoxicity results [coz it will be converted to a metabolite that is usually toxic to the liver but the body has a mechanism to come over with this problem by reduction glutathione rxn , if you take over dose of it the body mechanism can't be able to tolerate it ].

Paracitamol >>If it’s considered as NSAID this is due to its mechanism of action that is based on PG inhibition , , but it maybe considered as different group coz it’s not strongly associated with anti-inflammatory response. [Be Careful >>it’s never considered as opiods ]

• Every things written in different color/style or within boxes are extra notes. Sorry for late…. Rinad Al-Sa’adi.