dr. mahmoud h. taleb 1 بسم الله الرحمن الرحيم lecture 11 analgesics and non-...

Dr. Mahmoud H. TalebDr. Mahmoud H. Taleb 11

الرحيم الرحمن الله الرحيم بسم الرحمن الله بسم

Lecture 11Lecture 11Analgesics and Non- steroidal Analgesics and Non- steroidal

anti-inflammatory drugsanti-inflammatory drugs


PainPain Pain is essential for survival. It can serve as a warning Pain is essential for survival. It can serve as a warning

of impending or actual tissue or organ injury. of impending or actual tissue or organ injury. Humans usually do not "adapt" to pain. The sensation Humans usually do not "adapt" to pain. The sensation originates from stimulation of originates from stimulation of naked nerve endingsnaked nerve endings found in all parts of the body. The pain receptors found in all parts of the body. The pain receptors (nociceptors) can be stimulated by (nociceptors) can be stimulated by mechanicalmechanical or or chemical meanschemical means. Pain-producing substances such as . Pain-producing substances such as histamine or kinins stimulate the naked nerve endings histamine or kinins stimulate the naked nerve endings directly, while prostaglandins lower the pain directly, while prostaglandins lower the pain threshold by increasing the sensitivity of the receptors threshold by increasing the sensitivity of the receptors to the stimulus. PGE2 and PGF2α are known to cause to the stimulus. PGE2 and PGF2α are known to cause local pain at sites of injection, vascular pain, and local pain at sites of injection, vascular pain, and headache.headache.


The sensation of pain is transmitted from the The sensation of pain is transmitted from the periphery through the spinal cord to higher periphery through the spinal cord to higher integrative centers in the CNS by "fast" integrative centers in the CNS by "fast" myelinated fibers and by nonmyelinated myelinated fibers and by nonmyelinated "slow" C fibers. When first-order sensory "slow" C fibers. When first-order sensory neurons from a diseased organ and from neurons from a diseased organ and from another area of the body synapse on the same another area of the body synapse on the same second-order neurons in the spinal cordsecond-order neurons in the spinal cord


Pain actually originating in the diseased organ Pain actually originating in the diseased organ may be perceived as coming from the other may be perceived as coming from the other areaarea; this is known as "; this is known as "referred referred painpain.". .". Anxiolytics and neuroleptics may diminish Anxiolytics and neuroleptics may diminish the emotional response to pain through the emotional response to pain through action on the limbic system and action on the limbic system and hypothalamus. Morphine and other opioid hypothalamus. Morphine and other opioid analgesics act on opiate receptors in the analgesics act on opiate receptors in the gray matter around the cerebral aqueduct gray matter around the cerebral aqueduct and adjacent to the third and fourth and adjacent to the third and fourth ventricles.ventricles.


Fever Fever is the body's response to exogenous or endogenous is the body's response to exogenous or endogenous substances called pyrogens. Bacteria, molds, yeasts, and substances called pyrogens. Bacteria, molds, yeasts, and viruses elaborate high-molecular-weight viruses elaborate high-molecular-weight lipopolysaccharides capable of stimulating the release of lipopolysaccharides capable of stimulating the release of "pyrogens" such as cytokines (interleukin-1 [IL-1]) from "pyrogens" such as cytokines (interleukin-1 [IL-1]) from polymorphonuclear leukocytes and monocytes, and tumor polymorphonuclear leukocytes and monocytes, and tumor necrosis factor from other cells. necrosis factor from other cells.

These pyrogens act on the thermoreceptive region in the These pyrogens act on the thermoreceptive region in the preoptic anterior hypothalamus to release arachidonic preoptic anterior hypothalamus to release arachidonic acid, stimulate prostaglandin synthesis, and raise the set acid, stimulate prostaglandin synthesis, and raise the set point of the temperature-regulating center, which in turn point of the temperature-regulating center, which in turn will lead to vasoconstriction in the skin, decreased heat will lead to vasoconstriction in the skin, decreased heat loss, and increased body temperature. loss, and increased body temperature.

Fever arising from extensive tissue damage, autoimmune Fever arising from extensive tissue damage, autoimmune disease, neoplasia, or following thromboembolism is disease, neoplasia, or following thromboembolism is thought to be due to the release of a leukocyte-type thought to be due to the release of a leukocyte-type pyrogen from the involved tissue. Salicylates and other pyrogen from the involved tissue. Salicylates and other anti pyretic drugs appear to act by inhibiting the synthesis anti pyretic drugs appear to act by inhibiting the synthesis or release of prostaglandins in the thermoregulatory or release of prostaglandins in the thermoregulatory center.center.


The The inflammatory inflammatory processprocess can be initiated by invading can be initiated by invading microorganisms, immunological reactions and, tissue microorganisms, immunological reactions and, tissue necrosis. Mediators of inflammation are thought to cause necrosis. Mediators of inflammation are thought to cause increased release of fatty acid precursors of increased release of fatty acid precursors of prostaglandins and to increase the rate of prostaglandin prostaglandins and to increase the rate of prostaglandin synthesis. Endogenous mediators of inflammation may synthesis. Endogenous mediators of inflammation may originate from the plasma (such as bradykinin, C3 and originate from the plasma (such as bradykinin, C3 and C5 fragments, C567 complex, fibrinopeptides, fibrin C5 fragments, C567 complex, fibrinopeptides, fibrin degradation products) and from tissues (such as degradation products) and from tissues (such as histamine, serotonin, leukotrienes [SRS-A], histamine, serotonin, leukotrienes [SRS-A], prostaglandins, lysosomal proteases, migration inhibitory prostaglandins, lysosomal proteases, migration inhibitory factor, chemotactic factors, lymphotoxin, skin reactive factor, chemotactic factors, lymphotoxin, skin reactive factors, mitogenic factors, lymph node permeability factors, mitogenic factors, lymph node permeability factor, interleukin-1, platelet activating factor [PAF]). factor, interleukin-1, platelet activating factor [PAF]). Most prostaglandins are known to cause peripheral Most prostaglandins are known to cause peripheral vasodilatation with local redness and edema formation vasodilatation with local redness and edema formation and to synergistically increase the effect of bradykinin. and to synergistically increase the effect of bradykinin. Practically every part of the body may suffer damage as Practically every part of the body may suffer damage as the result of an inflammatory process. the result of an inflammatory process.


Nonsteroidal Anti-Inflammatory Drugs

The NSAIDs are a group of chemically dissimilar agents that differ in their antipyretic, analgesic, and anti-inflammatory activities. They act primarily by inhibiting the cyclooxygenase enzymes that catalyze the first step in prostanoid biosynthesis. This leads to decreased prostaglandin synthesis with both beneficial and unwanted effcts. Detection of serious cardiovascular events associated with COX-2 inhibitors have led to withdrawal of rofecoxib and valdecoxib from the market (celecoxib is still available for use in patients with RA). a notice that there is increased risk of serious gastrointestinal (GI) adverse events, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious GI events.


Non-steroidal anti-inflammatory Non-steroidal anti-inflammatory drugsdrugs

1- SALICYLATES1- SALICYLATESThe analgesic, antipyretic, and anti-inflammatory actions of salicylates are The analgesic, antipyretic, and anti-inflammatory actions of salicylates are

attributed primarily to their ability to inhibit cyclooxygenase, the enzyme attributed primarily to their ability to inhibit cyclooxygenase, the enzyme

responsible for the conversion of arachidonic acid to prostaglandin responsible for the conversion of arachidonic acid to prostaglandin

peroxides. This action of the drugs is exerted both in the periphery and at peroxides. This action of the drugs is exerted both in the periphery and at

the hypothalamic thermoregulatory center. ASA acetylates the serine the hypothalamic thermoregulatory center. ASA acetylates the serine

moiety at or near the active center of the enzyme; the inhibition is moiety at or near the active center of the enzyme; the inhibition is

irreversible, and restoration of prostaglandin production requires bio irreversible, and restoration of prostaglandin production requires bio

synthesis of new enzyme. In addition, salicylates may inhibit formation of synthesis of new enzyme. In addition, salicylates may inhibit formation of

plasmin, and thereby of bradykinin. They also block the production of pain plasmin, and thereby of bradykinin. They also block the production of pain

by kinins acting on chemoreceptors.by kinins acting on chemoreceptors.


Pharmacological EffectsPharmacological Effects

AnalgesiaAnalgesia

Low-intensity pain, such as headache, myalgia, arthralgia, and Low-intensity pain, such as headache, myalgia, arthralgia, and other pain arising from integumental structures rather than other pain arising from integumental structures rather than from viscera, is alleviated by salicylates. Part of the analgesia from viscera, is alleviated by salicylates. Part of the analgesia arises from actions on subcortical sites of the CNS, probably arises from actions on subcortical sites of the CNS, probably the hypothalamus, because at therapeutic concentrations the hypothalamus, because at therapeutic concentrations mental function or alertness is not affected. In con trast to the mental function or alertness is not affected. In con trast to the opioid analgesics, these drugs do not produce tolerance or opioid analgesics, these drugs do not produce tolerance or physical dependence during chronic administration. physical dependence during chronic administration. Paradoxically, salicylates cause headache in toxic overdose. Paradoxically, salicylates cause headache in toxic overdose. ASA is frequently combined with codeine or other opioid ASA is frequently combined with codeine or other opioid analgesics and sedatives; such combinations are claimed to analgesics and sedatives; such combinations are claimed to give more pain relief with less toxicity than any of the give more pain relief with less toxicity than any of the ingredients given alone in effective doses, although this claim ingredients given alone in effective doses, although this claim has not been clearly -proven. The analgesic dose range is has not been clearly -proven. The analgesic dose range is between 300 and 1000 mg three or four times a day. between 300 and 1000 mg three or four times a day.


AntipyresisAntipyresisSalicylates lower the body temperature in febrile Salicylates lower the body temperature in febrile

patients by direct action on the hypothalamic patients by direct action on the hypothalamic thermoreceptive region and the temperature-thermoreceptive region and the temperature-regulating center concerned with heat production and regulating center concerned with heat production and heat loss. Normal body temperature is not affected by heat loss. Normal body temperature is not affected by therapeutic doses. The increased heat loss produced therapeutic doses. The increased heat loss produced by salicylates in febrile patients is due to secondary by salicylates in febrile patients is due to secondary peripheral vasodilatation, especially in cutaneous peripheral vasodilatation, especially in cutaneous areas, and to increased sweating. Sweating is areas, and to increased sweating. Sweating is important but not essential in this process, because important but not essential in this process, because atropine (which prevents sweating) does not prevent atropine (which prevents sweating) does not prevent salicylates from lowering the elevated tem perature. salicylates from lowering the elevated tem perature. Heat production is not inhibited, and toxic doses of Heat production is not inhibited, and toxic doses of salicylates actually produce fever. The anti pyretic salicylates actually produce fever. The anti pyretic dose range is similar to the analgesic range.dose range is similar to the analgesic range.


Effects on rheumatic, inflammatory, and Effects on rheumatic, inflammatory, and immunological processesimmunological processes

Salicylates in large doses (5-8 g daily) are used for Salicylates in large doses (5-8 g daily) are used for the treatment of rheumatoid diseases and other the treatment of rheumatoid diseases and other inflammatory conditions. The increased capillary inflammatory conditions. The increased capillary permeability during inflammation is reduced by permeability during inflammation is reduced by salicylates, which thereby prevent edema salicylates, which thereby prevent edema formation, cel lular exudation, and pain. Their formation, cel lular exudation, and pain. Their ability to block cellular immune responses ability to block cellular immune responses appears to contribute to the therapeutic effect.appears to contribute to the therapeutic effect.


Uricosuric effectUricosuric effectSalicylates in doses of 500 mg inhibit both the renal tubular Salicylates in doses of 500 mg inhibit both the renal tubular

secretion of uric acid and the uricosuric effect of secretion of uric acid and the uricosuric effect of probenecid and sulfinpyrazone by competition for the probenecid and sulfinpyrazone by competition for the same proximal tubular transport systems. same proximal tubular transport systems.

In large doses of 5-10 g daily, however, the tubular In large doses of 5-10 g daily, however, the tubular reabsorption of uric acid is also inhibited by competition reabsorption of uric acid is also inhibited by competition with uric acid for more distal active transport sites in the with uric acid for more distal active transport sites in the tubule. The net effect of the larger doses is that most of tubule. The net effect of the larger doses is that most of the uric acid filtered by the glomeruli is excreted and the the uric acid filtered by the glomeruli is excreted and the uric acid concentration in the blood is lowered. When this uric acid concentration in the blood is lowered. When this happens, the urate crystals already deposited in joints (in happens, the urate crystals already deposited in joints (in cases of gout) are slowly eliminated.cases of gout) are slowly eliminated.


Respiratory actions: At therapeutic doses, aspirin increases alveolar ventilation. [Note: Salicylates

uncouple oxidative phosphorylation, which leads to elevated CO2 and increased respiration.] Higher doseswork directly on the respiratory center in the medulla, resulting in hyper ventilation and respiratory alkalosisthat usually is adequately compensated for by the kidney. At toxic levels, central respiratory paralysis occurs, and respiratory acidosis ensues due to continued production of CO2.


Effect on platelets: TXA2 enhances platelet aggregation, whereas PGI2 decreases it. Low doses (60-81mg daily) of aspirin can irreversibly inhibit thromboxane production in platelets via acetylation of cyclooxygenase. Because platelets lack nuclei, they cannot synthesize new enzyme, and the lack of thromboxane persists for the lifetime of the platelet .

As a result of the decrease in TXA2, platelet aggregation (the first step in thrombus formation) is reduced, producing an anticoagulant effect with a prolonged bleeding time. Finally, aspirin also inhibits cyclooxygenase in endothelial cells, resulting in

reduced PGI2 formation; however, endothelial cells possess nuclei able to re-synthesize new cyclooxygenase. Therefore, PGI2 is available for antiplatelet action.


Actions on the kidney: Cyclooxygenase inhibitors prevent the synthesis of PGE2 and PGI2â€”prostaglandins that are responsible for maintaining renal blood flow, particularly in the presence of circulating vasoconstrictors . Decreased synthesis of prostaglandins can result in retention of sodium and water and may cause edema and hyperkalemia in some patients. Interstitial nephritis can also occur with all NSAIDs except aspirin.


Adverse EffectsAdverse Effects

RespirationRespiration

GastrointestinalGastrointestinal

BloodBlood

Metabolic processesMetabolic processes

Endocrine functionsEndocrine functions

PregnancyPregnancy


Side Effects That Appear to be Unrelated to the Side Effects That Appear to be Unrelated to the Inhibition of CyclooxygenaseInhibition of Cyclooxygenase

1- Allergic1- Allergic:: Hypersensitivity reaction Hypersensitivity reaction bronchospasm, anaphylactic/ anaphylactic bronchospasm, anaphylactic/ anaphylactic reactions, serum sickness.reactions, serum sickness.

2- 2- CardiovascularCardiovascular:: Vasodilatation, pallor, Vasodilatation, pallor, elevation of blood pressure, palpitation, angina, elevation of blood pressure, palpitation, angina, arrhythmias, pericarditis, perivascular arrhythmias, pericarditis, perivascular granulomata.granulomata.

3- 3- Respiratory 5- RenalRespiratory 5- Renal

4- Urogenital4- Urogenital


Toxicity:Salicylate intoxication may be mild or severe. The

mild form is called salicylism and is characterized by nausea, vomiting, marked hyperventilation, headache, mental confusion, dizziness, and tinnitus (ringing o roaring in the ears). When large doses of salicylate are administered, severe salicylate intoxication may result. The symptoms listed above are followed by restlessness, delirium, hallucinations, convulsions, coma, respiratory and metabolic acidosis, and death from respiratory failure.


2 .Propionic acid derivativesIbuprofen was the first in this class of agents to become available

in the United States. It has been joined by naproxen fenoprofen, ketoprofen,, flurbiprofen and oxaprozin. All these drugs possess anti-inflammatory, analgesic, and antipyretic activity; additionally, they can alter platelet function and prolong bleeding time.

They have gained wide acceptance in the chronic treatment of RA and osteoarthritis, because their GI effects are generally less intense than those of aspirin. These drugs are reversible inhibitors of the cyclooxygenases and, thus, like aspirin, inhibit the synthesis of prostaglandins but not of leukotrienes. All are well absorbed on oral administration and are almost totally bound to serum albumin. They undergo hepatic metabolism and are excreted by the kidney. The most common adverse effects are GI, ranging from dyspepsia to bleeding. Side effects involving the central nervous system (CNS), such as headache, tinnitus, and dizziness, have also been reported.


3 .Acetic acid derivativesThis group of drugs includes indomethacin, sulindac and etodolac . All

have anti-inflammatory, analgesic, and antipyretic activity. They act by

reversibly inhibiting, toxicity of indomethacin limits its use to the

treatment of acute gouty arthritis, ankylosing spondylitis, an

osteoarthritis of the hip. Sulindac is an inactive prodrug that is closely

related to indomethacin. Although the drug is less potent than

indomethacin, it is useful in the treatment of RA, ankylosing

spondylitis, osteoarthritis, and acute gout. The adverse reactions caused

by sulindac are similar to, but less severe than, those of the other

NSAIDs, including indomethacin. Etodolac has effects similar to those

of the other NSAIDs. GI problems are less common.


4 .Oxicam derivativesPiroxicam and meloxicam are used to treat RA,

ankylosing spondylitis, and osteoarthritis. They have long half-lives, which permit once-daily administration, and the parent drug as well as its metabolites are renally excreted in the urine. GI disturbances are encountered in approximately 20 percent of patients treated with piroxicam. Meloxicam inhibits both COX-1 and COX-2, with preferential binding for COX-2, and at low to moderate doses shows less GI irritation than piroxicam. However, at high doses, meloxicam is a nonselective NSAID, inhibiting both COX-1.


5. FenamatesMefenamicacid and meclofenamate have no advantages over

other NSAIDs as anti-inflammatory agents. Their side effects, such as diarrhea, can be severe, and they are associated with inflammation of the bowel. Cases of hemolytic anemia have

been reported.


6. Heteroaryl acetic acidDiclofenac are approved for long-term use in the treatment of

RA,osteoarthritis, and ankylosing spondylitis. Diclofenac is more potent

than indomethacin or naproxen. An ophthalmic preparation is also

available.. Tolmetin is an effective anti-inflammatory, antipyretic, and

analgesic agent with a half-life of 5 hours. . Ketorolac is a poten

analgesic but has moderate anti-inflammatory effects. It is available for

oral administration, for intramuscular use in the treatment of

postoperative pain, and for topical use for allergic conjunctivitis.

Ketorolac undergoes hepatic metabolism, and the drug and its

metabolites are eliminated via the urine. Ketorolac is indicated for

short-term relief of moderate to severe pain This agent is to be

avoided in pediatric patients; patients with mild pain, and those with

chronic conditions, the dose should not exceed 40 mg/day. Ketorolac

can cause fatal peptic ulcers a well as GI bleeding and/or perforation

of the stomach or intestines.


7. Nabumetone

Nabumetone is indicated for the treatment of RA and osteoarthritis and is associated with a low incidence of adverse effects. Nabumetone is hepatically metabolized by the liver to the active metabolite.


8. Celecoxib Celecoxib is significantly more selective for inhibition of COX-2 than of

COX-1 . Unlike the inhibition of COX-1 by aspirin(which is rapid and irreversible), the inhibition of COX-2 is time dependent and reversible. Celecoxib is approved for treatment of RA, osteoarthritis, and pain. Unlike aspirin, celecoxib does not inhibit platelet aggregation and does not increase bleeding time. Celecoxib has similar efficacy to NSAIDs in the treatment of pain and the risk for cardiovascular events. Celecoxib, when used without concomitant aspirin therapy, has been shown to be associated with less GI bleeding and dyspepsia; however, this benefit is lost when aspirin is added to celecoxib therapy. In patients at high risk for ulcers (that is, history of peptic ulcer disease), use of PPIs with celecoxib and aspirin may be necessary to avoid gastric ulcers.

Pharmacokinetics: Celecoxib is readily absorbed. Its half-life is about 11 hours; thus, the drug is usually taken once a day but can be administered as divided doses twice daily. The daily recommended dose should be reduced by 50 percent in those with moderate hepatic impairment, and celecoxib should be avoided in patients with severe hepatic and renal disease.

Adverse effects: Headache, dyspepsia, diarrhea, and abdominal pain are the most common adverse effects.

Celecoxib is contraindicated in patients who are allergic to sulfonamides.


9. Acetaminophen

Acetaminophen inhibits prostaglandin synthesis in the CNS. This explains its antipyretic and

analgesic properties. Acetaminophen has less effect on cyclooxygenase in peripheral tissues, which accounts for its weak anti-inflammatory activity. Acetaminophen does not affect platelet function or increase blood clotting time


Therapeutic uses Acetaminophen is a suitable substitute for the analgesic and antipyretic effects of aspirin for those patients with gastric complaints, those in whom prolongation of bleeding time would be a disadvantage, or those who do not require the anti-inflammatory action of aspirin. Acetaminophen is the analgesic/antipyretic of choice for children with viral infections or chickenpox (recall that aspirin increases the risk of Reye's syndrome). Acetaminophen does not antagonize the uricosuric agents probenecid or sulfinpyrazone and, therefore, may be used in patients with gout who are taking these drugs.

PharmacokineticsUnder normal circumstances, acetaminophen is conjugated in the liver to

form inactive glucuronidated or sulfated metabolites. A portion of acetaminophen is hydroxylated to form N-acetylbenzoiminoquinone highly reactive and potentially dangerous metabolite that reacts with sulfhydryl groups. At normal doses of acetaminophen, the N-acetylbenzoiminoquinone reacts with the sulfhydryl group of glutathione, forming a nontoxic substance (Figure 41.12). Acetaminophen and its metabolites are excreted in the urine


Adverse effectsWith normal therapeutic doses, acetaminophen is virtually free of any

significant adverse effects. Skin rash and minor allergic reactions occur infrequently. There may be minor alterations in the leukocyte count, but these are generally transient. Renal tubular necrosis and hypoglycemic coma are rare complications of prolonged, large dose therapy. With large doses of acetaminophen, the available glutathione in the liver becomes depleted, and

N-acetylbenzoiminoquinone reacts with the sulfhydryl groups of hepatic proteins, forming covalent bonds). Hepatic necrosis, a very serious and potentially life-threatening condition, can result. Renal tubular necrosis may also occur. [Note: Administration of N-acetylcysteine, which contains sulfhydryl groups to which the toxic metabolite can bind, can be lifesaving if administered within 10 hours of the overdose.] This agent should be avoided in patients with severe hepatic impairment. Periodic monitoring of liver enzymes tests is recommended for those on high-dose acetaminophen.


Disease-Modifying Antirheumatic Agents

1. Methotrexate2 . Leflunomide3. Hydroxychloroquine4. Sulfasalazine5. D-Penicillamine6. Gold salts7. Biologic Therapies in Rheumatoid Arthritis-- A. Etanercept B. Infliximab C. AnakinraE. Rituximab


Drugs Employed in the Treatment of Gout

dr. mahmoud h. taleb 1 بسم الله الرحمن الرحيم lecture 11 analgesics and non-...

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