Pain Pharmacology II - QG PDF

Pain Pharmacology: Part-2 Non-Opioids Farzana Alam, PhD Learning Objectives Pharmacology of Aspirin Ibuprofen Acetaminophen Names of different types of NSAIDs Infections or tissue damage results in inflammation, permeability, redness, heat….and pain Types of no...

Pain Pharmacology: Part-2 Non-Opioids Farzana Alam, PhD Learning Objectives Pharmacology of Aspirin Ibuprofen Acetaminophen Names of different types of NSAIDs Infections or tissue damage results in inflammation, permeability, redness, heat….and pain Types of nocireceptors Pain can be acute or visceral  Physiology of pain staglandinintram adylaminstrongvasodilator b p strongvasodilator Molecular signaling is key to pain perception  Afferent fibers are key to pain percpetion river of pain erception evvatibers yetinsheathlipidbilayer nsulation ofnervefibers asterconductiondueto niviation Small and large fibers are necessary to produce pain  Key signaling molecules in transmission of pain i frombradykinin come vasodilation kprostaglandinson bradykinins asubp Non-opioids Salicylates Non-salicylates Propionic acid derivatives Phenylacetic acid derivatives Indole and Indene derivatives Pyrrole derivatives Selective COX-2 inhibitor: Celecoxib Drug names NSAIDs Effect of dose on the half-life of aspirin. aspirinirreversible ibuprofenreversible higherbindingat tinity manaspirin COX-1 and COX-2 have different functions Which pathway are we looking at, COX-1 or COX-2? stress activationofCox2 CoxI alwaysactiveforhomeostasis Mechanism p of action fun nee process Salicylates: Drug names Aspirin lDiflunisal  iusedasananticoagulant adveresea fleetbleeding Aspirin causeactivation Actions: ofCoxenzyme Antipyretic actions Analgesic actions Antipyretic so actions intiam Therapeutic uses: Anti-inflammatory and Aspirin irreversibly analgesics inhibits platelet Anti-pyretic uses cyclooxygenase-1. Cardiovascular effects External applications a foracne satisylicaid Metabolism of aspirin and acetylation of cyclooxygenase by aspirin. Which type of inhibition if more permanent? covalent bindsw highattinity irreversible noncovalent competitiveinhibitor  neonaspirinmoreacidicblood ascon.qoesr.youcann.it lethal dosesshowninbreeding hyperventilation Pharmacokinetics Effect of dose on the half-life of aspirin. Dose-dependent effects of salicylate.  Adverse effects and Drug-drug interactions O verycarefulgivingkidsaspirin Propionic acid derivatives: Drug Names we generallyinteract coxtaz Ibuprofen mainlyin interact peripheralafferent Naproxen Ketoprofen  ibumorepotentthan aspirin Adverse effects Non-NSAIDs  coxI 22havedietactive sitesinencymes y peroxidase pah z NSAIDsinhibitoxygenperoxidase Acetaminophen freerad ironneededbegoodfor oxireduxreins Mechanism of Action of Acetaminophen Pharmawiki Acetaminophen can produce other molecules through it’s reactivity  Therapeutic uses: 1. Fever and the relief of pain. 2. It is useful in patients with gastric complaints/risks with NSAIDs and those who do not Therapeutics require the anti-inflammatory action of NSAIDs. effects 3. Acetaminophen is the analgesic/antipyretic of choice for children with viral infections or chickenpox (due to the risk of Reye syndrome with aspirin). Pharmacokinetics Metabolism Adverse effects At normal therapeutic doses, acetaminophen has few significant adverse effects. With large doses of acetaminophen, the available glutathione in the liver becomes depleted, and NAPQI reacts with the sulfhydryl groups of hepatic proteins. Hepatic necrosis, a serious and potentially life-threatening condition, can result. Patients with hepatic disease, viral hepatitis, chronic malnutrition, or a history of alcoholism are at higher risk of acetaminophen-induced hepatotoxicity. Note: N-acetylcysteine is an antidote in cases of overdose. Acetaminophen should be avoided in patients with severe hepatic impairment. Drug-drug interactions Dental implications Recommended Dosing schedule Combination therapy  Dental implication **Have mentioned in detail in the last part of the supplemental slides Supplement slides Aspirin mechanism of action Anti-inflammatory actions: Inhibition of cyclooxygenase diminishes the formation of prostaglandins and, thus, modulates aspects of inflammation mediated by prostaglandins. NSAIDs inhibit inflammation in arthritis, but they neither arrest the progression of the disease nor induce remission. Analgesic action: PGE2 is thought to sensitize nerve endings to the action of bradykinin, histamine, and other chemical mediators released locally by the inflammatory process. Thus, by decreasing PGE2 synthesis, the sensation of pain can be decreased. As COX-2 is expressed during times of inflammation and injury, it is thought that inhibition of this enzyme is responsible for the analgesic activity of NSAIDs. No single NSAID has demonstrated superior efficacy over another, and they are generally considered to have equivalent analgesic efficacy. The NSAIDs are used mainly for the management of mild to moderate pain arising from musculoskeletal disorders. One exception is ketorolac, which can be used for more severe pain, but for only a short duration.  Antipyretic action: Fever occurs when the set-point of the anterior hypothalamic thermoregulatory center is elevated. This can be caused by PGE2 synthesis, which is stimulated when endogenous fever- producing agents (pyrogens), such as cytokines, are released from WBCs that are activated by infection, hypersensitivity, malignancy, or inflammation. The NSAIDs lower body temperature in patients with fever by impeding PGE2 synthesis and release, resetting the “thermostat” back toward normal. This rapidly lowers the body temperature of febrile patients by increasing heat dissipation through peripheral vasodilation and sweating. NSAIDs have no effect on normal body temperature.  herapeutic uses a.Anti-inflammatory and analgesic uses: NSAIDs are used in the treatment of osteoarthritis, gout, RA, and common conditions requiring analgesia (for example, headache, arthralgia, myalgia, and dysmenorrhea). Combinations of opioids and NSAIDs may be effective in treating pain caused by malignancy. Furthermore, the addition of NSAIDs may lead to an opioid-sparing effect, allowing for lower doses of opioids to be utilized. The salicylates exhibit analgesic activity at lower doses. Only at higher doses do these drugs show anti-inflammatory activity (Figure 40.10). For example, two 325-mg aspirin tablets administered four times daily produce analgesia, whereas 12 to 20 tablets per day produce both analgesic and anti-inflammatory activity. b.Antipyretic uses: Aspirin, ibuprofen, and naproxen may be used to treat fever. [Note: Aspirin should be avoided in patients less than 19 years old with viral infections, such as varicella (chickenpox) or influenza, to prevent Reye syndrome—a syndrome that can cause fulminating hepatitis with cerebral edema, often leading to death.]  Cardiovascular applications: Aspirin irreversibly inhibits COX-1–mediated production of TXA2, thereby reducing TXA2-mediated vasoconstriction and platelet aggregation and the subsequent risk of cardiovascular events (Figure 40.11). The antiplatelet effects persist for the life of the platelet. Low doses of aspirin (75-162 mg—commonly 81 mg) are used prophylactically to reduce the risk of recurrent cardiovascular events, transient ischemic attacks (TIAs), stroke, and death in patients with a history of previous MI, TIA, or stroke. Chronic use of aspirin allows for continued inhibition as new platelets are generated. Aspirin is also used acutely to reduce the risk of death in acute MI and in patients undergoing certain revascularization procedures. d.External applications: Salicylic acid is used topically to treat acne, corns, calluses, and warts. Methyl salicylate (“oil of wintergreen”) is used externally as a cutaneous counterirritant in liniments, such as arthritis creams and sports rubs. Diclofenac is available in topical formulations (gel or solution) for treatment of osteoarthritis in the knees or hands. In addition, ocular formulations of ketorolac are approved for management of seasonal allergic conjunctivitis and inflammation and pain related to ocular surgery. Aspirin: PK Aspirin: After oral administration, aspirin is rapidly deacetylated by esterases in the body to produce salicylate. Unionized salicylates are passively absorbed mainly from the upper small intestine. Salicylates (except for diflunisal) cross both the blood–brain barrier and the placenta and are absorbed through intact skin (especially methyl salicylate). Salicylate is converted by the liver to water-soluble conjugates that are rapidly cleared by the kidney, resulting in first-order elimination and a serum half-life of 3.5 hours. At anti-inflammatory dosages of aspirin (more than 4 g/d), the hepatic metabolic pathway becomes saturated, and zero- order kinetics are observed, leading to a half-life of 12 hours or more (Figure 40.12). Salicylate is secreted into the urine and can decrease uric acid excretion at low doses. Therefore, aspirin should be avoided in gout, if possible, or in patients taking probenecid. Phenylacetic Acid Derivatives Diclofenac sodium, a phenylacetic acid derivative, is also highly protein bound at 99% and has a plasma half-life of 2 hours. Its analgesic and antiinflammatory effects are similar to those of aspirin, but it has minimal to no antipyretic effects. It is indicated for RA, osteoarthritis, and ankylosing spondylitis. Diclofenac is available in oral, extended-release, and topical 1% gel preparations. Side effects and adverse reactions are similar to those of other NSAIDs, with far fewer detrimental reactions when using a topical preparation. Ketorolac, another phenylacetic acid derivative, is the first injectable NSAID. Like other NSAIDs, it inhibits prostaglandin synthesis, but it has greater analgesic properties than other antiinflammatory agents. Ketorolac is recommended for short- term management of pain. For postsurgical pain, it has shown analgesic efficacy equal or superior to that of opioid analgesics. It is administered intramuscularly in doses of 30 to 60 mg every 6 hours for adults. Ketorolac is also available in oral, intravenous (IV), and intranasal preparations. Adverse-effects: Ibuprofen The incidence of adverse events with some propionic acid derivatives may be less than with aspirin, but various gastrointestinal disturbances (epigastric pain, nausea, vomiting, gastric bleeding, and constipation or diarrhea) can occur, and these drugs should be used with caution in patients with a history of peptic or duodenal ulcer. Long- term, high-dose administration for arthritic conditions is far more likely to produce serious adverse events than short-term administration for acute pain. In fact, meta-analyses of OTC doses of ibuprofen (800 to 1200 mg/day) or naproxen sodium (440 to 880 mg/day) taken for 10 or fewer days have a side-effect profile no worse than placebo. Propionic acid derivatives can, however, injure the gastric mucosa by suppressing COX-1 activity and therefore decrease the cytoprotection afforded by PGI2 and PGE2. CNS effects may include headache, dizziness, drowsiness, vertigo, and visual and auditory disturbances including tinnitus. Skin rashes are somewhat common, and immediate allergic reactions have been reported. All the NSAIDs can lead to anaphylactoid-like reactions in aspirin-intolerant patients (i.e., those susceptible to aspirin- induced asthma). These agents decrease platelet aggregation and adhesiveness and increase bleeding time, although to a lesser degree than aspirin; they should be avoided in patients with bleeding disorders and used with caution in patients receiving anticoagulants. These drugs may promote Na+ retention, and their use may lead to the formation of edema in susceptible persons. They can interfere with the antihypertensive effects of β-adrenergic blockers, ACE inhibitors, and diuretics if they are administered for more than 1 week. In elderly patients, especially during long-term therapy, the dosage of the propionic acid NSAIDs may have to be reduced by up to 50%. Of recent concern are epidemiologic reports indicating an increased risk of gastrointestinal bleeding when these drugs and other NSAIDs are taken concomitantly with antidepressants of the selective serotonin reuptake inhibitor (SSRI) class such as fluoxetine (Prozac) and paroxe- tine (Paxil). It appears that SSRIs block the reuptake of serotonin in the platelet as they do in neurons in the CNS. Like the COX-1 arachidonic acid product thromboxane A2, serotonin stimulates platelet aggregation. Thus the combined intake of SSRIs and NSAIDs can result in an additive or supra-additive antiplatelet effect. Another recent concern has been the reported ability of NSAIDs like ibuprofen to inhibit the antiplatelet and cardioprotective effects of low-dose aspirin. Because NSAIDs such as ibuprofen and naproxen can compete with aspirin for COX-1 bind- ing sites in the platelet, less aspirin will be bound. Unlike aspirin, the antiplatelet effects of the bound NSAIDs would only be temporary plus a large proportion of unbound aspirin would then be converted to sal- icylic acid. Warnings of this potential interaction now appear on both OTC and prescription formulations of NSAIDs. Because all NSAIDS reduce prostaglandins in the kidney, they present a risk of renal toxicity as explained above. This is due in part to decreased perfusion of glomeruli. This risk is especially pertinent for those with pre-existing kidney disease. M/A: Acetaminophen Acetaminophen has both analgesic and antipyretic activity that is essentially equivalent to that of aspirin. The drug’s mechanism of action also appears to stem from an inhibition of PG synthesis, although there may be some differences in the spectrum of COX enzymes that are inhibited. It has been suggested that acetaminophen may be more active than aspirin as an inhibitor of CNS COX and less active in the periphery, based largely on the differences in the therapeutic and toxic effects of aspirin and acetaminophen rather than on direct experimen- tal evidence. For example, acetaminophen has very weak antiinflam- matory effects compared with aspirin, but it may be a more selective inhibitor of neuronal PG synthesis. More recent evidence suggests that a peripheral mechanism of acetaminophen may indeed be partially responsible for its analgesic effects. However, the presence of peroxides from leukocytes in inflamed tissues leads to inhibition of acetamino- phen, which may severely limit any effect of acetaminophen on inflam- mation. Other proposed mechanisms of action for acetaminophen do not involve PGs and include the activation of spinal serotonergic path- ways and the inhibition of nitric oxide synthase.  Pharmacologic effects: Compared with aspirin, acetaminophen exerts relatively few important effects on specific organs or systems. The potency and efficacy of acetaminophen as an antipyretic are similar to those of aspirin. At therapeutic doses, acetaminophen has little if any effect on the car- diovascular or respiratory systems. Acetaminophen does not inhibit platelet aggregation, cause occult bleeding or gastric irritation, affect uric acid excretion, or have as many drug interactions as aspirin. In overdose, the organ most affected is the liver. Acute renal toxicity may also occur. With long-term use, analgesic nephropathy is a possi- bility, but the risk is low.  **Broad explanation Dental Implication Aspirin and other NSAIDs The major use of aspirin and other NSAIDs in dentistry is to relieve acute pain associated with pathologic processes (e.g., pulpitis, dentoalveolar abscesses) or after surgical procedures. In both situations, the anti-inflammatory actions of the NSAID may contribute significantly to the therapeutic effect sought. Aspirin at doses between 650 and 1000mg is an acceptable drug for mild to moderate dental pain. However, for more traumatic surgical procedures such as the removal of impacted third molars, the newer NSAIDs at dosages that approach their analgesic ceiling are more efficacious and sometimes better tolerated than aspirin. In fact, postsurgical dental pain studies that have used ceiling analgesic doses of NSAIDs, such as ibuprofen at 400mg and naproxen sodium at 440mg, have displayed efficacy at least equal to that obtained with opioid combination drugs In addition, the NSAIDs produce far fewer side effects of drowsiness, dizziness, nausea, and vomiting than do opioid-containing analgesics.  **Broad explanation There are very few instances where the use of the highly selective COX-2 inhibitor celecoxib can be recommended, considering that in most instances NSAIDs are only used for a few days in the dental setting, thus negating any gastrointestinal benefit with the long-term use of the drug, the relatively high cost of the drug compared to traditional prescription and OTC NSAIDs, and concerns about cardiovascular risk of highly selective COX-2 inhibitors as a whole. One possible exception would be in the treatment of temporomandibular joint (TMJ) pain where the duration of NSAID therapy is measured in weeks and significant GI toxicity of NSAIDs becomes a greater concern. Still, it would behoove the clinician not to prescribe celecoxib to patients with cardio- vascular risk factors including previous MI or stroke, unstable angina, or poorly controlled hypertension. Finally, naproxen has demonstrated better efficacy in TMJ pain overall than celecoxib.  **Broad explanation Contraindications to the NSAIDs must be heeded. For instance, salicylates must be avoided in children or teenagers with viral or suspected viral infections. The antiplatelet effect of NSAIDs, especially aspirin and ketorolac, must be considered if the patient is at risk from a bleeding abnormality or anticoagulant therapy. Hypersensitivity to aspirin may indicate a risk to NSAIDs in general, including COX-2 inhibitors. The elimination of methotrexate and lithium is reduced with NSAIDs; other drug interactions may occur because of the ability of NSAIDs to displace drugs from plasma albumin and otherwise alter their pharmacokinetic properties. The common adverse effects for NSAIDs on the gastrointestinal tract and CNS should be considered, especially when the patient is taking drugs with overlapping toxicity. The NSAIDs can reduce the therapeutic effects of several antihypertensive drugs, most prominently β-adrenoreceptor blockers, ACE inhibitors, and diuretics.  **Broad explanation Acetaminophen The wide attention given to the adverse effects of aspirin has caused increasing numbers of dentists to substitute acetaminophen for aspirin in the treatment of postoperative dental pain, even though the antiinflammatory effects of acetaminophen are poor. In clinical studies, aspirin and acetaminophen are similar in their effectiveness in relieving pain after the extraction of third molars. Acetaminophen has a positive dose–effect curve for analgesia up to 1000 mg. On the basis of this finding, some clinicians recommend the use of 1000mg of acetaminophen rather than the customary 650-mg dose, but that pushes the limit for staying under the 3 g daily limit of the drug. For postsurgical dental pain, acetaminophen is most often used in combination with an opioid analgesic agent (see later).