PPM1Analgesics

Objectives:

1.         List and categorize the most commonly used opioid analgesics and antagonists into the following types:  

                        strong opioid agonists  (morphine, methadone, meperidine, oxycodone)

                        moderate opioid agonists  (codeine, propoxyphene)

                        mixed opioid agonists-antagonists  (pentazocine, butorphanol )

                        opioid antagonists  (naloxone, naltrexone)

(Common or representative drugs are listed above.  Learn the indications for each drug listed.)

EChing, Brenner, P248-251   

Strong opioid agonists

Morphine: severe pain associated with trauma, myocardial infarction, and cancer.  In pts with myocardial infarction, it relieves pain and anxiety while also dilating coronary arteries and reducing the myocardial oxygen demand.  P248

Methadone: most often administered orally to ambulatory pts for the tx of opioid addiction or pain.  Use of the oral formulation by opioid-dependent pts can prevent their craving for heroin or other opioids, but it does not cause significant euphoria or other reinforcing effects.  The tx of opioid-dependent pts is called a methadone maintenance program. P249

Meperidine: the parenteral formulation is often used as an obstetric or postsurgical analgesic.  The oral formulation is used to treat moderate to severe pain in the outpatient setting.  Due to its toxic metabolite, it is usually employed for the short-term treatment of acute pain s syndromes. P249

Oxycodone: usually administered orally in combination with a nonopioid analgesic, such as acetaminophen, for the treatment of moderate or severe pain. P249

Moderate opioid agonists

Codeine:usually given in lower doses in combination with a nonopioid analgesic for the treatment of mild to moderate pain.  Also produces a significant antitussive effect and is included in many cough syrups to alleviate or prevent coughing. P250

Propoxyphene: frequently used in combination with acetaminophen for the treatment of mild to moderate somatic and visceral pain. P250

Mixed opioid agonists-antagonists

Pentazocine: parenteral formulation is primarily used as a preanesthetic medication and as a supplement to surgical anesthesia.  The oral formulations are used to treat moderate to severe pain. P251

Butorphanol: administered parenterally (parenterally administered drugs of this class are primarily used for preoperative and postoperative analgesia and for obstetric analgesia during labor and delivery) and also available as a nasal spray (nasally administered drugs of this class are used for the alleviation of moderate to severe pain). P250-251

Opioid antagonists

Naloxone: in cases of opioid overdose, it is administered intravenously to rapidly terminate respiratory depression and other toxic effects of opioid agonists.  It is included in an orally administered formulation of pentazocine in order to discourage parenteral use of this preparation by drug addicts. P251

Naltrexone: used to prevent and treat opioid dependence and addiction.  Can be used on a long-term basis by opioid addicts who have undergone detox and are no longer using opioids.  It has also been useful in the tx of alcohol dependence. P251

Anonymous Brenner pp 245-252

Strong opioid agonists:

*Morphine—remains the standard of comparison for analgesics.  Severe pain associated with trauma, MI, and CA

*Methadone—most often administered po to ambulatory pts for the tx of opioid addiction or pain.

*Meperidine—the IV form is often used as an OB or postsurgical analgesic.  The PO form is used to treat moderate to severe pain in the outpatient setting.

*Oxycodone—is usually administered PO in combination with a nonopioid analgesic such as acetaminophen, for the tx of moderate or severe pain.

Moderate opioid agonists:

*codeine—usually given in lower doses in combination with a nonopioid analgesic for the tx of mild to moderate pain.  It produces a significant antitussive effect and is included in many cough syrups to alleviate or prevent coughing—similar to hydrocodone.

*Propoxyphene—most frequently used in combination with acetaminophen for the tx of mild to moderate somatic and visceral pain.

Mixed opioid agonists-antagonists:

*Pentazocine—The IV form is primarily used as a preanesthetic med and as a supplement to surgical anesthesia.  The PO form is used to TX moderate to severe pain, and one of them contains naloxone (an antagonist, w/a low oral bioavailability) to discourage parenteral abuse of the drug.

*Butorphanol—IV and nasal forms.  Primarily used for preoperative and postoperative analgesia and for obstetric analgesia during labor and delivery.  Used nasally for the alleviation of moderate to severe pain.

Opioid antagonists:

*Naloxone—IV--Tx of opioid OD and the prevention and TX of opioid dependence and addiction.  

*Naltrexone—Tx of opioid od and the prevention and TX of opioid dependence and addiction. It has also been useful in the TX of alcohol dependence.

Anonymous  

• strong opioid agonists  (morphine, methadone, meperidine, oxycodone)

  • morphine- Treatment of severe pain associated with trauma, MI and CA.

  • methadone- administered orally for the treatment of opioid addiction or pain.

  • meperidine- parenteral form- used for obstetric or postsurgical pain.

  • oral form- treatment of moderate to severe pain.

  • oxycodone-  treatment of moderate to severe pain.

• moderate opioid agonists  (codeine, propoxyphene)

  • codeine- treatment of mild to moderate pain.  Also has significant anti-tussive effect.

  • propoxyphene-mild to moderate somatic and visceral pain.

• mixed opioid agonists-antagonists  (pentazocine, butorphanol )

  • pentazocine- parenteral form-preanesthetic medication and as a surgical anesthesia supplement.

  • oral form-  treatment of moderate to severe pain.  One form contains naloxone to discourage parenteral abuse.

  • butorphanol- only given parenterally.  Primarily for pre/post-operative analgesia, obstetric analgesia during labor and delivery.

• opioid antagonists  (naloxone, naltrexone)

  • naloxone- used during opioid overdose to terminate respiratory depression and other toxic effects of opioid agonists.

  • naltrexone- used to prevent and treat opioid dependence and addiction.

April T. Brenner p. 249-251

Strong opioid agonists indications-

            Morphine- Is the standard, In MI helps relieve anxiety, and also diates coronary arteries.  Used to treat severe pain associated with trauma, MI, and CA

            Fentanyl- most potent, Often used in a skin patch for continuous relief of severe pain.  Used as an adjunct to general anesthesia, causes less nausea than morphine.

            Meperidine-synthetic opioid, no antitussive activity, used in obstetric or postsurgical analgesic, for short term treatment of acute pain. Moderate to severe pain.

            Methadone- treatment of opioid addiction, and pain.  Administered once per day.

            Oxycodone- usually administered with a non-opioid med. Such as acetaminophen, moderate to severe pain.

Moderate opioid agonists indications-

            Codeine and hydocodone- usually mixed wit a non-opioid like acetaminophen, ASA, or ibuprofen to treat mild to moderate pain and to alleviate coughing.

            Propoxyphene-weak form of methadone, mild to moderate somatic and visceral pain.  Tolerated well may lead to accumulation of toxic metabolite if used for prolonged period.

Mixed opioid agonists-antagonists- safer in an overdose, less constipation.  However can cause more anxiety, nightmares, hallucinations. Used for preoperative and postoperative analgesia, used in labor and delivery.  Used for moderate to severe pain.

            Pentazocine-  parenteral or oral use primarily used as a preanesthetic contains naloxone.  Available in combination form with ASA, acetaminophen.  Can cause cardiopulmonary reactions.

            Butorphanol- parenterall or is available as a nasal spray

Opioid Antagonists- rapidly reverse the affects of the opioid.  

            Naloxone- used in overdose, short ½ life, may need repeat doses. Low oral bioavailability,

                        Naltrexone- treat opioid dependence and addiction.  High oral bioavailability.

Anonymous

• strong opioid agonists  (morphine, methadone, meperidine, oxycodone)

• morphine- Treatment of severe pain associated with trauma, MI and CA.

• methadone- administered orally for the treatment of opioid addiction or pain.

• meperidine- parenteral form- used for obstetric or postsurgical pain.

• oral form- treatment of moderate to severe pain.

• oxycodone-  treatment of moderate to severe pain.

• moderate opioid agonists  (codeine, propoxyphene)

• codeine- treatment of mild to moderate pain.  Also has significant anti-tussive effect.

• propoxyphene-mild to moderate somatic and visceral pain.

• mixed opioid agonists-antagonists  (pentazocine, butorphanol )

• pentazocine- parenteral form-preanesthetic medication and as a surgical anesthesia supplement.

• oral form-  treatment of moderate to severe pain.  One form contains naloxone to discourage parenteral abuse.

• butorphanol- only given parenterally.  Primarily for pre/post-operative analgesia, obstetric analgesia during labor and delivery.

• opioid antagonists  (naloxone, naltrexone)

• naloxone- used during opioid overdose to terminate respiratory depression and other toxic effects of opioid agonists.

• naltrexone- used to prevent and treat opioid dependence and addiction.

Anonymous Brenner p. 245

            In humans, the strong opioid agonists are tolerated when they are given in a dosage sufficient to relieve severe pain.  However moderate opioid agonists will cause intolerable side effects if they are given in a dosage sufficient to alleviate pain that is severe. For this reason, the moderate agonists are administered in submaximal doses for the treatment of moderate to mild pain, and are usually given in combination with nonopioid analgesics to enhance their clinical effectiveness. The mixed opioid agonist-antagonists are analgesic drugs that have varying combinations of against, partial agonist, and antagonist activity and varying degrees of affinity for the different opioid receptor subtypes. The pure antagonists have no analgesic effects. They are used to counteract the adverse effects of opiods taken in overdose.

A.     Strong Opioid Agonists:

Morphine: It is primarily used to treat severe pain associated with trauma, myocardial infarction, and cancer. Brenner p. 248

Methadone: Although it is available in parenteral formulations, it is most often administered orally to ambulatory patients for the treatment of opioid addiction or pain. Brenner 249

Meperidine (Demerol): The parenteral formulation of meperidine is often used as an obstetric or postsurgical analgesic. The oral formulation is used to treat moderate to severe pain in the out patient setting. Brenner p. 249

Oxycodone: is usually administered orally in combination with a nonopioid analgesic, such as acetaminophen, for the treatment of moderate to severe pain, Brenner p. 249

B.     Moderate Opioid Agonists:

Codeine: Is usually given in lower doses in combination with a nonopioid analgesic for the treatment of mild to moderate pain. Codeine also produces a significant antitussive effect and is included in many cough syrups to alleviate or prevent coughing. Brenner p. 250

Proproxphene (Darvon): It is most frequently used in combination with acetaminophen for the treatment of mild to moderate somatic and visceral pain. Brenner p. 250

C.     Mixed Opioid Agonists-Antagonists:

Pentazocine (Talwin): The parenterally administered agonist-antagonist drugs are primarily used for preoperative and postoperative analgesia and for obstetric analgesia during labor and delivery. The orally and nasally administered drugs are used for the alleviation of moderate to severe pain. Brenner p. 250-251

            Butorphanol (Stadol): Ditto to above

D.     Opioid Antagonists:

Naloxone (Narcan): Naloxone and Naltrxone are competitive opioid receptor antagonist that can rapidly reverse the effects of morphine and other opioid agonists. The antagonists have two primary clinical uses: the treatment of opioid overdose and the prevention and treatment of opioid dependence and addiction. Brenner p. 251

            Naltrexone: Ditto to above

2.         List or recognize common organ system effects of morphine and other opioid analgesics.  Identify which of these effects are clinically useful, and which are toxic and/or undesired effects.

EChing, Brenner, P246-248

Morphine is a potent agonist, and m receptors are responsible for most of its pharmacologic effects.

1) Central Nervous System Effects.  Morphine acts in the central nervous system to produce analgesia, sedation, euphoria or dysphonria, miosis, nausea, vomiting, respiratory depression, and inhibition of the cough reflex.

The major adverse effect of morphine and other opioids is respiratory depression, which is usually the cause of death in severe overdoses.  Opioids reduce the hypercapnic drive (the stimulation of respiratory centers by increased carbon dioxide levels) while producing relatively little effect on the hypoxic drive.  Opioids reduce the respiratory tidal volume and rate, causing the rate to fall to 3 or 4 breaths per minute after an opioid overdose.

2) Cardiovascular Effects.  Morphine causes vasodilation, which is partly due to histamine release from mast cells in peripheral tissues.  Morphine may cuase orthostatic hypotension owing to decreased peripheral resistance and a reduction in baroreceptor reflex activity.  In pts with coronary artery disease, the decreased peripheral resistance leads to a reduction of cardiac work and myocardial oxygen demand.

3) Gastrointestinal, Biliary, and Genitourinary Effects.  Morphine and other opioids act to increase smooth muscle tone.  In the gastrointestinal tract, increased muscle tone leads to inhibition of peristalsis and causes constipation.  For this reason, the opioids are the oldest and most widely used medication for the treatment of diarrhea.  By stimulating the chemoreceptor trigger zone in the medulla, the opioids also cause nausea and vomiting.

When morphine and other opioids increase the tone of the biliary sphincter, this increases the biliary pressure and may cause an exacerbation of pain in pts with biliary dysfunction.  Opioids also increase the tone of the bladder sphincter and may cause urinary retention in some pts.  Herapeutic doses of morphine may prolong labor.

4) Other Effects.  Opioids have an effect on neuroendocrine and immunologic funtion.  In the hypothalamus, they stimulate the release of antidiuretic hormone and prolactin and inhibit the release of luteinizing hormone.  Opioids also suppress the activity of certain types of lymphocytes, including natural killer cells, and this action may contribute to the high rate of infectious diseases in heroin addicts.

Anonymous *Undesired/adverse effects are in red, beneficial effects are in blue.

Central Nervous System Effects- produces analgesia, sedation, euphoria or dysphoria, miosis, nausea, vomiting, respiratory depression (major adverse effect) and inhibition of cough reflex.

Cardiovascular Effects- vasodilation, orthostatic hypotension, decreased peripheral resistance leading to decrease in cardiac work load and myocardial oxygen demand.

Gastrointestinal, Biliary and Genitourinary Effects- increased muscle tone leads to inhibition of peristalsis and causes constipation. Therefore, can be used to treat diarrhea. By stimulating the chemoreceptor trigger zone in the medulla, opioids also cause nausea and vomiting. Opiods increase the tone of the biliary sphincter, which increases biliary pressure and may exacerbate pain in patients with biliary dysfunction. Also increase tone of the bladder sphincter and may cause urinary retention. Morphine can prolong labor, so butorphanol, meperidine or nalbuphine are used for obstetric analgesia.

Other System Effects- Stimulate release of ADH and prolactin and inhibit release of LH. Suppress activity of some lymphocytes, such as natural killer cells. Brenner, p. 248

Anonymous  Brenner, p. 246-248        

April T Brenner p.246-248

            CNS- analgesia, sedation, euphoria, dysphoria, miosis, nausea, vomiting, respiratory depression, and inhidition of cough reflex.  

            Undesired- respiratory depression which is the cause of death in severe overdoses.   Reduce resp. tital volume,

            Cardiovascular- vasodilation, decreased peripheral resistance, this reduces cardiac work load in patients with CAD.

                        Undesired- decreased peripheral resistance = orthostatic hypotension.

            Gastrointestinal- ^tone

                        Undesired- ^ tone= decreased peristalsis= constipation.  Stimulation of the medulla causes nausea and vomiting.  ^ biliary pain with a pt. with biliary dysfunx, urinary retention.  May prolong labor, so other drugs are used.

            Other- depressed immunity, allergic reactions

Anonymous Brenner, p. 246-248

Anonymous

            1) CNS effects: Morphine acts in the CNS to produce analgesia, sedation, euphoria or dysphoria, miosis, nausea, vomiting, respiratory depression, and inhibition of the cough reflex. (Brenner p. 246)

            2) Cardiovascular effects: The most prominent cardiovascular effect of morphine and many other opioids is vasodilation, which is partly due to histamine release from the mast cells in peripheral tissues. Morphine may cause orthostatic hypotension owing to decreased peripheral resistance and a reduction in barorecptor reflex activity. In patients with coronary artery disease, the decreased peripheral resistance leads to a reduction of cardiac work and myocardial oxygen demand. Brenner p. 247-248

            3) Gastrointestinal, Billary, and Gentourinary effects: Morphine and most other opioids act to increase smooth muscle tone in the gastrointestinal, billary, and genitourinary systems. This leads to inhibition of peristalsis and causes constipation, increase in bladder tone causing urinary retention, and increase in the tone of billary sphincter causing billary pain. Opioids can also cause nausea and vomiting. Brenner p. 248

            4) Other effects: Opioids have an effect on neuroendocrine and immunologic function. In the hypothalamus, they stimulate the release of antidiuretic hormone and prolactin and inhibit the release of luteinizing hormone. Opioids also suppress the activity of certain types of lymphocytes, including natural killer cells, and this action may contribute to the high rate of infection diseases in heroin addicts. Brenner p. 248

3.         Describe the problems of tolerance and dependence with opioid use.

EChing, Brenner, P248

Repeated administration of an opioid agonist will lead to pharmacodynamic tolerance not only of the administered drug but also of other opioid agonists.  Tolerance is primarily due to down-regulation of opioid receptors.  The degree of tolerance depends on the potency and dosage of the drug being administered.

Drug tolerance is usually accompanied by a similar degree of physical dependence, which is defined as a physiologic state in which a person’s continued use of a drug is required for his or her well0being.  Tolerance and physical dependence appear to represent the establishment of a new equilibrium between the neuron and its environment, wherein the neuron becomes less responsive to the opioid while requiring continued opioid inhibition to maintain cellular homeostasis.

Tolerance develops to most of the effects of opioids but not to miosis and constipation.

Anonymous   Brenner pg. 248

Repeated administration of an opioid agonist will lead to pharmacodynamic tolerance not only of the administered drug but also of other opioid agonists.  Tolerance is primarily due to down-regulation of opioid receptors.  The degree of tolerance depends on the potency and dosage of the drug being administered.  Drug tolerance is usually accompanied by a similar degree of physical dependence.  

Physical dependence is defined as a physiologic state in which a person’s continued use of a drug is required for his/her well-being.  Tolerance and physical dependence appear to represent the establishment of a new equilibrium between the neuron and its environment, wherein the neuron becomes less responsive to the opioid while requiring continued opioid inhibition to maintain cellular homeostasis.

Anonymous  Brenner 248

            Tolerance is primarily due to down-regulation of opioid receptors.  The degree of tolerance depends on the potency and dosage of the drug.  

            Drug tolerance is usually accompanied by a similar degree of physical dependence.  Tolerance and physical dependence appear to represent the establishment of a new equilibrium between the neuron and its environment, wherein the neuron becomes less responsive to the opioid while requiring continued opioid inhibition to maintain cellular homeostasis.  If  the opioid drug is withdrawn, hyperexcitability occurs.  This produces a withdrawal reaction, the manifestations of which depend on the particular type of drug.

April T Brenner p. 248

            Tolerance depends on potencu and dose.  The neuron becomes less responsive to the opioid and requiring continued opioid inhibition to to maintain cellular homeostasis.  If abrupt withdrawl occurs  the equilibrium is disrupted and rebound hyperexcitability occurs owing the the loss of inhibitory influence of the drug. One drug can substitute for another to prevent symptoms of withdrawl .  Tolerance develops to most affects but not to miosis and constipation.  Respiratory depression has slight tolerance.

Anonymous Brenner 248

            Tolerance is primarily due to down-regulation of opioid receptors.  The degree of tolerance depends on the potency and dosage of the drug.  

            Drug tolerance is usually accompanied by a similar degree of physical dependence.  Tolerance and physical dependence appear to represent the establishment of a new equilibrium between the neuron and its environment, wherein the neuron becomes less responsive to the opioid while requiring continued opioid inhibition to maintain cellular homeostasis.  If  the opioid drug is withdrawn, hyperexcitability occurs.  This produces a withdrawal reaction, the manifestations of which depend on the particular type of drug.

Anonymous Brenner p. 248

Repeated administration of an opioid agonist will lead to pharmacodynamic tolerance not only to the administered drug but also of other opioid agonists. Tolerance is primarily due to down regulation of opioid receptors. The degree of tolerance depends on potency and dosage of the drug being administered. Significant tolerance develops after repeated admistration of morphine, whereas relatively little tolerance occurs with the long-term administration of a weaker opioid agonist, such as propoxyphene. Drug tolerance is usually accompanied by a similar degree of physical dependence. Physical dependence is defined as a physiologic state in which a person’s continued use of a drug is required for his or her well-being.

4.         Describe the use of capsaicin, antiepileptic drugs, and antidepressant drugs in the treatment of chronic pain.

EChing, Brenner, P252

Capsaicin activates peripheral nociceptors on primary sensory neurons, thereby leadig to increased release of substance P and eventually to the depletion of substance P in the central nervous system.  It produces a burning sensation for the first few dyas of application, but this is gradually replaced by an analgesic effect.

Antiepileptic drugs, such as carbamazepine, gabapentin, phenytoin, and valproate, are effective in treating pain syndromes with an intermittent lancinating quality, such as trigeminal neuralgia and postherpetic neuralgia.   Also useful in syndromes characterized by continuous, burning neuropathic pain.  They probably act by inhibiting the conduction of pain impulses in the CNS; exact mechanisu is unknown.

Antidepressants drugs: the tricyclic antidepressants (TCAs) are the most widely used antidepressants for the tx of chronic pain.  TCAs such as amitriptyline and desipramine are effective in the management of postherpetic neuralgia, diabetic neuropathy, migraine headache, and neuropathic pain syndromes.  May also be beneficial in pts with chronic fatigue syndrome.

Anonymous

Capsaicin activates peripheral nociceptors on primary sensory neurons, thereby leading to increased release of substance P and eventually to the depletion of substance P in the CNS.  Capsaicin produces a burning sensation for the first few days of application, but this is gradually replaced by an analgesic effect.  Antiepileptic drugs, such as carbamazepine, gabapentin, phenytoin, and valproate are particularly effective in treating pain syndromes with an intermittent lancinating quality, such as trigeminal neuralgia and postherpetic neuralgia.  They are also useful in syndromes characterized by continuous, burning neuropathic pain.  Probably act by inhibiting the conduction of pain impulses in the CNS.  Tricyclic antidepressants (TCAs) are the most widely used antidepressants for the treatment of chronic pain and they may be more effective than SSRIs in this respect.  Amitriptyline and desipramine are particularly effective in the management of postherpetic neuralgia, diabetic neuropathy, migraine HA, and neuropathic pain syndromes.  

Anonymous  Brenner 252

If pain is associated with peripheral nerve or nerve root sensitization, treatment with transcutaneous nerve stimulation or a local anesthetic may help.  Capsaicin activates peripheral noriceptors on primary sensory neurons, thereby leading to increased release of substance P in the CNS.

The most widely used co-analgesics are the antiepiletic drugs and the antidepressant drugs.   These drugs provide pain relief in chronic pain syndromes and may potentiate the effects if opioid and non-opioid analgesics.  Antiepileptic drugs are effective in treating pain syndromes with an intermittent lancinating quality, such as trigeminal neuralgia and postherpetic neuralgia.  

TCA’s are use in the treatment of chronic pain and are more effective then SSRI’s.  Amtriptyline and desipramine are particularly effective in the management of postherpatic pain, diabetic neuropathy, and migraine headaches.

April T. Brenner p.  252

            Capsaicin is a is a cream that activates nociceptors leading to the release of  and eventual depletion of substance P.  It burns at first then has an analgesic effect.

            In chronic pain there is an increase in the pain receptors of the spine.  As these neurons become “wound up” they become more receptive and over a larger area.  

            Antiepileptic drugs such as carbamazepine, gabapentin, phenytoin, valproate are effective in treating chronic pain.  Act by inhibiting, pain nerve impulses in the CNS.  The exact mechanism is unknown.

            TCA- are the most widely used antidepressants used for pain, effective in neuralgia, neuropathy, migraines, and neuropathic pain syndromes.  May also be effective in treating chronic fatigue syndrome.

Anonymous Brenner 252

If pain is associated with peripheral nerve or nerve root sensitization, treatment with transcutaneous nerve stimulation or a local anesthetic may help.  Capsaicin activates peripheral noriceptors on primary sensory neurons, thereby leading to increased release of substance P in the CNS.

The most widely used co-analgesics are the antiepiletic drugs and the antidepressant drugs.   These drugs provide pain relief in chronic pain syndromes and may potentiate the effects if opioid and non-opioid analgesics.  Antiepileptic drugs are effective in treating pain syndromes with an intermittent lancinating quality, such as trigeminal neuralgia and postherpetic neuralgia.  

TCA’s are use in the treatment of chronic pain and are more effective then SSRI’s.  Amtriptyline and desipramine are particularly effective in the management of postherpatic pain, diabetic neuropathy, and migraine headaches.

Anonymous Current 2003 p. 73

Although many types of pain will respond to opioids, neuropathic pain – which patients typically describe as burning, shooting, “pins and needles,” or electricity and which is commonly associated with numbness – may respond better to antidepressants (TCA’s in particular) and anticonvulsants like gabapentin, clonazepam, and carbamazepine. It is therefore critical to ask the patient to describe the pain and listen for the words that suggest neuropathic pain.

5.         Describe the role of cyclooxygenase (COX) and prostaglandins in the development of pain, inflammation, and fever.  

EChing, Brenner, P319

NSAIDs’ pharmacologic effects result primarily from the inhibition of cyclooxygenase (COX), an enzyme that catalyzes the first step in the synthesis of prostaglandins from arachidonic acid and other 20-carbon fatty acids.  Arachidonic acid is released from cell membranes by the action of phospholipase A2, an enzyme that is activated by physical trauma and various chemical stimuli.

Prostaglandins play an important role in the development of pain, inflammation, and fever.  Prostaglandins are released from cells in response to chemical stimuli or physical trauma.  They sensitize sensory nerves to nociceptive stimuli and thereby amplify the formation of pain impulses.  They also promote tissue inflammation by stimulating inflammatory cell chemotaxis, causing vasodilation, and increasing capillary permeability and edema.

Fever often results from an alteration of hypothalamic thermoregulatory mechanisms.  Bacterial toxins and other pyrogens stimulate the production of cytokines by leukocytes, and these cytokines increase prostaglandin synthesis in the preoptic area of the hypothalamus.  The prostaglandins then act to reset the body’s thermostat to a new point above 37° C.  This in turn activates temperature-raising mechanisms, such as a reduction in heat loss via cutaneous vasodilation, and causes the temp to rise.  

(All NSAIDS relieve fever by inhibiting prostaglandin synthesis in the hypothalamus.)

Anonymous

COX is an enzyme that catalyzes the first step in the synthesis of prostaglandins from arachidonic acid and other 20-carbon fatty acids.  Prostaglandins are released from cells in response to chemical stimuli or physical trauma.  They sensitize sensory nerves to nociceptive* stimuli and thereby amplify the formation of pain impulses.  They also promote tissue inflammation by stimulating inflammatory cell chemotaxis, causing vasodilation, and increasing capillary permeability and edema.  

Fever (elevation of body temp. above 37^OC, 98.6^OF) often results from alteration of hypothalamic thermoregulatory mechanisms.  Pyrogens stimulate the production of cytokines which increase prostaglandin synthesis in the preoptic area of the hypothalamus.  The prostaglandins then act to reset the body’s thermostat to a new point above 37^OC.                    

            *nociceptive: capable of appreciation or transmission of pain. (Stedman’s)

COX-1 vs. COX-2: COX-1 is found in relatively constant levels in various tissues, and participates in the synthesis of prostaglandins that have a cytoprotective effect on the GI tract.  It also leads to platelet aggregation and hemostasis.  COX-2 is an inducible enzyme with normally low levels in most tissues.  Levels are rapidly up-regulated during the inflammatory process.  Both COX-1 and –2 appear to participate in renal homeostasis.  

Brenner, pp. 319

Anonymous  Brenner pg 319

• Cyclooxygenase—an enzyme that catalyzes the first step in the synthesis of prostaglandins.

• Prostaglandins--         are released from cells in response to chemical stimuli or physical trauma.  They sensitize sensory nerves to nociceptive stimuli and thereby amplify the formation of pain impulses.  They also promote tissue inflammation by stimulating inflammatory cell chemotaxis, causing vasodilation, and increasing capillary permeability and edema.

• Toxins released by infection stimulate the production of cytokines by leukocytes, and these cytokines increase prostaglandin synthesis in the preoptic area of the hypothalamus.

April T Brennerr p. 319

            Prostaglandins are released from mast cells in response to chemical stimuli or physical trauma.they sensitize sensory nerves to nociceptive stimuli and thereby and plify the formation of pain impulses.  Promote tissue inflammation by stimulating inflammatory chemotaxis, cuaing vasodilation, and increasinf capillary permeability and edema.

            Fever, a body temp. above 37 C, often resultsfrom and alteration of hypothalamic thermoreg.   Bacterial toxins and other pyrogens stimulate the producrion cytokines and leukocytes and these ^ production of prostaglandins in the preoptic area of the hypothalamus. This activates temp. raising mechanisms such as reduced heat loss through vaso dilation and causes the temp. to rise.

            COX 1 found in constant levels helps in the synthesis of prostaglandins that have a cytoprotective effect on the GI tract, also leads to platelet aggregation,  and hemostasis.

            COX 2 – found in low levels, but are up-regulated during the inflammatory process.

Both participate in renal homeostasis.  Most NSAIDS are nonselective inhibitors of COX 1 and 2.

Anonymous Brenner pg 319

• Cyclooxygenase—an enzyme that catalyzes the first step in the synthesis of prostaglandins.

• Prostaglandins--         are released from cells in response to chemical stimuli or physical trauma.  They sensitize sensory nerves to nociceptive stimuli and thereby amplify the formation of pain impulses.  They also promote tissue inflammation by stimulating inflammatory cell chemotaxis, causing vasodilation, and increasing capillary permeability and edema.

• Toxins released by infection stimulate the production of cytokines by leukocytes, and these cytokines increase prostaglandin synthesis in the preoptic area of the hypothalamus.

Anonymous Brenner p. 319

Prostaglandins play an important role in the development of pain, inflammation, and fever. Prostaglandins are released from cells in response to chemical stimuli or physical trauma. They sensitize sensory nerves to nociceptive stimuli and thereby amplify the formation of pain impulses. They also promote tissue inflammation by stimulating inflammatory cell chemotaxis, causing vasodilation , and increasing capillary permeability and edema. Fever, defined as the elevation of the body temperature to a level above 37 degree C (98.6 F), often results from an alteration of hypothalamic thermoregulatory mechanisms. Bacterail toxins and other pyrogens stimulate the production of cytokines by leukocytes, and there cytokines increases prostaglandins synthesis in the preoptic area of the hypothalamus. The prostaglandins then act to reset the body’s thermostat to a new point above 37 degree C.

6.         Distinguish between COX-1 and COX-2, and state the advantages of selective COX-2 inhibitors (representative drug:  celecoxib) over non-selective inhibitors.

Anonymous Brenner pg. 319-320

Cox stands for Cyclooxygenase. Cox 1 participates in the synthesis of prostaglandins that have a cytoprotective effect on the GI tract. It also catalyzes the formation of thromboxane A₂ in platelets leading to platelet aggregation and hemostasis. Cox 2 is an inducible enzyme. Its levels are rapidly up regulated during the inflammatory process by pro-inflammatory substances, such as cytokines, endotoxins and tumor promoters. Both Cox’s seem to participate in renal homeostasis.

The advantage of Cox 2 inhibitors are in their effective anti-inflammatory actions, but having a lower tendency to cause GI bleeding and peptic ulcer disease than do the non-selective Cox inhibitors.

Deb/Brenner,pg.319-320

COX-1 (cyclooxygenase 1) “housekeeping” enzyme found in relatively constant levels in various tissues/participates in synthesis of prostaglandins that have a cytoprotective effect on GI tract/catalyzes formation thrombozane alpha 2 in platelets (leading to plt. Aggregation and hemostasis)

COX-2 is inducible enzyme/levels are normally quite low in most tissues and is rapidly up-regulated during inflammatory processes by proinflammatory substances (i.e. cytokines, endotoxins, and tumor promoters) COX 1 & 2 participate in renal homeostasis

Advant. of COX-2 vs. non-select. Cox inhibit.=cox 2 effective anti-inflammatory with lower tendency to cause GI bleeding and peptic ulcer than non-select. Cox inhibitors

Anonymous  Brenner 319-20

•        COX-1 participates in the synthesis of prostaglandins that have cytoprotective effect on the gastrointestinal tract.  It also catalizes the formation of thromboxane A2 in platelets, leading to platelet aggregation and hemostatis.

•        COX-2 is an inducible enzyme.  Its levels are quite low in the tissues but are rapidly up-regulated during the inflammatory process by pro inflammatory substances.  Representative drug Celecoxib (Celebrex), or rofecoxib (Vioxx).

Anonymous Brenner 319-20

•        COX-1 participates in the synthesis of prostaglandins that have cytoprotective effect on the gastrointestinal tract.  It also catalizes the formation of thromboxane A2 in platelets, leading to platelet aggregation and hemostatis.

•        COX-2 is an inducible enzyme.  Its levels are quite low in the tissues but are rapidly up-regulated during the inflammatory process by pro inflammatory substances.  Representative drug Celecoxib (Celebrex), or rofecoxib (Vioxx).

Anonymous Brenner p. 319-320

COX-1 is a constitutive or “housekeeping” enzyme that is found in  relatively constant levels in various tissues. COX-1 participates in the synthesis of prostaglandins that have a cytoprotective effect on the gastrointestinal tract. It also catalyzes the formation of thromboxane A₂ in platelets, leading to platelet aggregation and hemostasis. In contrast the COX-2 is an inducible enzyme. The discovery of COX isozymes recently led to the development of the selective COX-2 inhibitors, such a celecoxib. These selective inhibitors are effective anti-inflammatory drugs, and they have a lower tendency to cause gastrointestinal bleeding and peptic ulcer disease that do the nonselective COX inhibitors.

 7.        Describe the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on prostaglandin biosynthesis.

Anonymous Brenner, pg. 319

NSAIDs comprise a large family of weakly acidic drugs whose pharmacologic effects result primarily from the inhibition of cyclooxygenase (COX), an enzyme that catalyzes the first step in the synthesis of prostaglandins from arachidonic acid and other 20-carbon fatty acids.  Arachidonic acid is released from cell membranes by the action of phospholipase A2, an enzyme that is activated by physical trauma and various chemical stimuli.

            Prostaglandins play an important role in the development of pain, inflammation, and fever.  Prostaglandins are released from cells in response to chemical stimuli or physical trauma.  They sensitize sensory nerves to nociceptive stimuli and thereby amplify the formation of pain impulses.  They also promote tissue inflammation by stimulating inflammatory cell chemotaxis, causing vasodilation, and increasing capillary permeability and edema.

            Fever, defined as the elevation of body temperature above 37^oC (98.6^oF), often results from an alteration of hypothalamic thermoregulatory mechanisms.  All NSAIDs relieve fever by inhibiting prostaglandin synthesis in the hypothalamus, but these drugs are not capable of reducing body temperature below normal.

Deb/Br.,pg.319

NSAIDS relieve fever by inhibiting prostaglandin synthesis in hypothalamus

Anonymous  Brenner pg 319

            NSAIDs inhibit cyclooxygenase, an enzyme that catalyzes the first step in the synthesis of prostaglandins from fatty acids.    All NSAIDs relieve fever by inhibiting prostaglandin synthesis in the hypothalamus.

 Anonymous Brenner pg 319

            NSAIDs inhibit cyclooxygenase, an enzyme that catalyzes the first step in the synthesis of prostaglandins from fatty acids.    All NSAIDs relieve fever by inhibiting prostaglandin synthesis in the hypothalamus.

Anonymous Brenner p. 319

Like aspirin, the NSAIDs are antipyretic, analgesic, and anti-inflammatory. NSAIDs inhibit prostaglandin synthesis, inhibiting platelet aggregation and consequently increasing the risk of gastrointestinal bleeding by 1.5 times normal. (Current p. 67) The nonsteroidal anti-inflammatory drugs, or NSAIDs, comprise a large family of weakly acidic drugs whose pharmacologic effects result primarily from the inhibition of cyclooxygenase (COX), and enzyme that catalyzes the first step in the syntheses of prostaglandins from arachidnoic acid and other 20-carbon fatty acids.

8.         List the three major actions of NSAIDs.  (answer:  analgesic, anti-inflammatory, and antipyretic)  Recognize other clinical uses for NSAIDs in the treatment or prevention of Alzheimer’s disease and colon cancer.

Anonymous Brenner Ch.30 pp. 317-24

Recent studies have shown that NSAIDs can slow the progress of Alzheimers by inhibiting the inflammation that accompanies the neurodegeneration of the disease.

The selective COX-2 inhibitor celecoxib, more so than non-selectives, has appeared to be protective against colon cancer by inhibiting COX + prostaglandin formation in lab studies.

Deb/Br.,pg.320

Analgesic- relieves pain caused by tissue inflammation or bone or joint trauma and combine with opiods to get greater analgesic effect

Antiinflam.-inhibit G protein signal transduction and phospholipase C activation in leukocytes and thereby decreases adhesiveness of cells in inflamed tissues

Antipyretic-by inhibiting prostaglandin synthesis (see #7)

NSAIDS delay or slow progression of Alzheimers (neurodegeneration is accompanied by inflamm. mechanisms that involve COX and activation of complement cascade)/NSAIDS decrease risk of colon cancer by inhibiting COX and prostaglandin formation

Anonymous  Brenner 320        

• Three actions:  analgesic, anti-inflammatory, and antipyretic

• Non-selective inhibitors are well known as NSAIDS.  Studies show that NSAIDS can delay or slow the progression of Alzheimer’s Disease.  The neurodegeneration that occurs in this disease is accompanied by inflammatory mechanisms that involve COX and the activation of the compliment cascade.

• Studies also indicate that NSAIDS reduce the risk of colon cancer by inhibiting COX and prostaglandin formation.

Anonymous Brenner 320

            Three actions:  analgesic, anti-inflammatory, and antipyretic

• Non-selective inhibitors are well known as NSAIDS.  Studies show that NSAIDS can delay or slow the progression of Alzheimer’s Disease.  The neurodegeneration that occurs in this disease is accompanied by inflammatory mechanisms that involve COX and the activation of the compliment cascade.

• Studies also indicate that NSAIDS reduce the risk of colon cancer by inhibiting COX and prostaglandin formation.

Anonymous Brenner p. 320

Analgesic, anti-inflammatory, and antipyretic.

Recent studies have shown NSAIDs can delay or slow the progress of Alzheimer’s disease. The neurodegeneration that occurs in this disease is accompanied by inflammatory mechanisms that involve COX and the activation of the complement cascade.

9.         List or recognize common adverse effects and potential drug interactions of NSAIDs.

Anonymous Brenner 320

Although NSAIDs are effective in relieving the pain of chronic disorders, their long-term use is associated with a number of adverse effects, including gastrointestinal bleeding, peptic ulcers, and renal and hypatic dysfunction. Acetaminophen can be used in combination but combinations should generally be avoided because they increase the risk of GI and other side effects and because they may have adverse interactions.  Aspirin and other salicylates displace some NSAIDs, such as ketrolac, from plasma proteins and thereby increase their serum levels significantly.  Most NSAIDs inhibit the renal excretion of lithium and may increases lithium serum levels and toxicity.  They may reduce the clearance of methotrexate and aminoglycoside drugs.  They may also interfere to varying degrees with the antihypertensive effect of diuretics, B-adrenergic receptor antagonists, ace inhibitors and other antihypertensive drugs.  When given with potassium-sparing diuretics, NSAIDs may cause potassium retention and lead to hyperkalemia.  High doses of salicylates exert hypoglycemic effects that may alter the effects of antidiabetic drugs.  Indomethacin reduces the natriuretic effect of diuretics and my cause nephrotoxicity when given with triamterene.  They are not recommended during the 2^nd half of pregnancy (except acetaminophen) because of GI bleeding, platelet inhibition, renal dysfunction and premature closure of the ductus arteriosus.

Deb/Br.,pg.320

GI bleeding, peptic ulcers, renal and hepatic dysfunction/ASA and other salicylates displace some NSAIDSàincrease in their serum levels significantly/NSAIDS inhibit renal excretion of lithiumàincrease in lithium levels and toxicity/interferes with anti HTN drugs with potassium sparing diurecticsàpotassium retention and hyperkalemia

Anonymous  Brenner pg 320

• Adverse effects—gastrointestinal bleeding, peptic ulcers, and renal and hepatic dysfunction.  If combined with Tylenol, may increase serum levels significantly.

• Potential drug interactions—inhibit the renal excretion of lithium, methotrexate, and aminoglycosides and may increase their levels.  

• --Interfere to varying degrees with the antihypertensive  effect of diuretics, B-andrenergic receptor antagonists, angiotension inhibitors and other antihypertensive drugs.  

• --when given with potassium-sparing diuretics, may cause K+ retention and lead to hyperkalemia.

• --high doses of salicytes exert a hypoglycemic effect.

•         --if given with too much Tylenol, may cause gastrointestinal bleeding, platelet inhibition, renal dysfunction, and premature closure of the ductus arteriosus

Anonymous Brenner pg 320

• Adverse effects—gastrointestinal bleeding, peptic ulcers, and renal and hepatic dysfunction.  If combined with Tylenol, may increase serum levels significantly.

• Potential drug interactions—inhibit the renal excretion of lithium, methotrexate, and aminoglycosides and may increase their levels.

  • --Interfere to varying degrees with the antihypertensive  effect of diuretics, B-andrenergic receptor antagonists, angiotension inhibitors and other antihypertensive drugs.  

  • --when given with potassium-sparing diuretics, may cause K+ retention and lead to hyperkalemia.

  • --high doses of salicytes exert a hypoglycemic effect.

•         --if given with too much Tylenol, may cause gastrointestinal bleeding, platelet inhibition, renal dysfunction, and premature closure of the ductus arteriosus

Anonymous Brenner p. 320

Although NSAIDs are effective in relieving the pain of chronic disorders, their long-term use is associated with a number of adverse effects, including gastrointestinal bleeding, peptic ulcers, and renal and hepatic dysfunction. Most NSAIDs inhibit the renal excretion of lithium and may increase lithium serum levels and toxicity. NSAIDs may reduce the clearance of methotrexate and aminoglycoside drugs. NSAIDs may also interfere to varying degrees with the antihypertensive effects of diuretics, B-adrenergic receptors antagonists, angiotension inhibitors, and other antihypertensive drugs. When given with potassium-sparing diuretics, NSAIDs may cause potassium retention and lead to hyperkalemia.

10.       List the two major effects of acetaminophen, and note its weak anti-inflammatory effect.

Anonymous Brenner, p. 321

Two major effects- analgesic and antipyretic.

Only has a weak anti-inflammatory effect because it is inactivated by peroxides produced in the cells of inflamed tissue, so should not be considered a first-line drug for arthritic disorders.

Deb/Br.,pg.320

Analgiesic and antipyretic/lacks significant antiplatelet and anti-inflamm. activity

Anonymous    Brenner 320

Treatment of mild pain and fever.

It has only weak anti-inflammatory activity because it is inactivated by peroxides produced in the cells of inflamed tissue.  Although not a first-line drug, it is used as an analgesic in those with mild arthritis.

Anonymous Brenner 320

Treatment of mild pain and fever.

It has only weak anti-inflammatory activity because it is inactivated by peroxides produced in the cells of inflamed tissue.  Although not a first-line drug, it is used as an analgesic in those with mild arthritis.

Anonymous Brenner p. 320-321

The drug is a p-aminophel derivative that exerts analgesic and antipyretic effects at doses that are well tolerated and produce remarkably few adverse effects during short-term administration.  For ever 100 years, acetaminophen had been available for the treatment of mild pain and fever. Acetaminophen has only weak anti-inflammatory activity because it is inactivated by peroxides produced in the cells of inflamed tissues.

11.       List indications for use of acetaminophen, and situations where it is preferable to aspirin.

Anonymous Brenner 320-1

Indications: mild pain and fever, mild arthritis (not first line).

Acetaminophen is preferable to aspirin with patients who have a fever due to viral illnesses (Aspirin can cause Reye’s syndrome).

Anonymous  Brenner 321

            Unlike aspirin use, acetaminophen use has not been associated with Reye’s syndrome, so acetaminophen can be safely given to patients with fever due to viral illness.

Anonymous, Brenner, pg 321

Indications: Mild pain and fever, mild arthritis. There are few adverse side effects with the use of acetaminophen. It is preferable for children with viral illness to avoid Reye’s Syndrome 

Anonymous Brenner 321

            Unlike aspirin use, acetaminophen use has not been associated with Reye’s syndrome, so acetaminophen can be safely given to patients with fever due to viral illness.

Anonymous Brenner p. 322

Acetaminophen is used for mild pain and fever.  Because acetaminophen lacks the ability to inhibit thromboxane synthesis and platelet aggregation, it is not used for the prophylaxis of myocardial infarction, stroke, or other thromboembolic disorders. (Brenner p. 320-321) ASA in adults, the salicylates can be used in the management of pain, fever, and inflammation, as well in the prophylaxis of myocardial infarction, stroke, and other thromboembolic disorders.

12.       Recognize the potential for severe or fatal hepatic damage with acetaminophen overdose.

Anonymous Brenner p. 321

Several pathways in the liver extensively metabolize acetaminophen. A small of acetaminophen is converted by cytochrome P450 to a potentially hepatotoxic quinone intermediate. When a therapeutic dose of acetaminophen is taken, the quinone intermediate is rapidly inactivated by conjugation w/ glutathione. However. Toxic doses of acetaminophen deplete hepatic glutathione, cause accumulation of the quinone intermediate, and lead to hepatic necrosis!

Anonymous  Brenner 322

            Because hepatotoxicity gradually progresses over several days following an acetaminophen overdose, prompt treatment with acetylcysteine can prevent or significantly reduce hepatotoxicity.  The ingestion of 20-30 tablets is sufficient enough to cause life-threatening hepatotoxicity. 

Anonymous, Brenner pg 322

Acetaminophen overdose can result in severe or fatal hepatic damage due to the toxic accumulation of the quinone intermediate that will cause hepatic necrosis.

Anonymous  Brenner 322

            Because hepatotoxicity gradually progresses over several days following an acetaminophen overdose, prompt treatment with acetylcysteine can prevent or significantly reduce hepatotoxicity.  The ingestion of 20-30 tablets is sufficient enough to cause life-threatening hepatotoxicity.

Anonymous Brenner p. 322

However, toxic doses of acetaminophen deplete hepatic glutathione, cause accumulation of the quinine intermediate, and lead to hepatic necrosis. Although therapeutic doses of acetaminophen are remarkably nontoxic, the ingestion of 20-30 tablets is sufficient to cause life-threatening hepatotoxicity.

13.       For each of the following NSAIDs, list or recognize major effects and indications, adverse effects, and potential advantages over other NSAIDs:

                        aspirin

                        ibuprofen

                        naproxen

                        indomethacin

                        ketorolac

                        celecoxib

Anonymous Brenner 322-326

 Anonymous  

Anonymous

Anonymous

            A.  Aspirin: Indications:  In adults, the salicylates can be used in the management of pain, fever, and inflammation, as well as in the prophylaxis of myocardial infarction, stroke, and other thromboembolic disorders. Effects: The analgesic, antipyretic, and anti-inflammatory effects of ASA and other salicylates results from nonspecific inhibition of COX in peripheral tissues  and the central nervous system. Adverse effects: The use of ASA in children with chickenpox and other viral infections has been associated with Reye’s syndrome. Therapeutic doses of ASA can cause gastic irritation and contribute to gastrointestinal bleeding and peptic ulcers. Moderately high therapeutic doses can cause tinnitus, which is described as an abnormal auditory sensation or noise. Excessive doses of ASA produce the toxic effects shown in Fig. 30-4 (p. 323) Hyperventilation is due to direct and indirect stimulation of the respitory center in the medulla, and it often leads to increased exhalation of carbon dioxide and respiratory alkalosis. Higher plasma salicylate concentration may cause fever, dehydration, and severe metabolic acidosis. If not treated promptly, these events may culminate in shock, coma, organ system failure, and death. Advantages: ASA is well absorbed in the gut.  Brenner p. 322-323.

            B. Ibuprofen: Indications: Ibuprofen, ketoprofen, and naproxen are propionic acid derivatives that are among the most widely used NSAIDs for pain and inflammation due to trauma, infection, autoimmune disorders, neoplasms, joint degeneration, and other causes. Effects: By reversibly and nonselectively inhibiting COX isozymes, these drugs are able to exert their analgesic, antipyretic, and anti-inflammatory effects. Adverse Effects: Ibuprofen and related grugsa produce dose-dependent gastric irritation, nausea, dyspepsia, and bleeding. Long-term administration of high doses has been associated with peptic ulcer disease, Advantages: but low doses causes very few serious side effects. Brenner p. 323

            C. Naproxen: This drug is grouped with Ibuprofen so ditto info from above.

            D. Indomethacin (Indocin): Indications: Indomethacin is an indoleacetic acid derivative that is often regarded as one of the most potent inhibitors of COX isozymes. Because of its greater tendency to cause adverse effects, this drug is usually reserved for the management of moderate to sever acute inflammatory conditions. It is also used to treat infants with a patent ductus arteriosus. Effects: In these infants, indomethacin inhibits the synthesis of prostaglandins and thereby causes closure of the ductus. Adverse Effects:  The incidence of gastrointestinal and CNS side effects is higher with the use of indomethacin that with the uses of many other NSAIDs. Indomethacin therapy is also associated with a risk of a serious hematologic toxicity. Brenner p. 323-324

            E: Ketorolac (Toradol): Indications:  In studies of postoperative pain, ketorolac produced a level of analgesia comparable with morphine but caused less nausea, vomiting, and drowsiness. Ketorolac has therefore been widely used for the short-term management of moderate to severe pain, such as postoperative pain associated with dental surgery. Although the drug has been used to treat migraine headaches, it does not appear to be superior to ibuprofen for treatment of musculoskeletal pain. The ophthalmic solution of ketorolac is used to treat allergic conjunctivitis and postoperative ocular inflammation. Effects: It has potent analgesic activity and is one of the few NSAIDs that is available for parenteral use as well as oral and topical ophthalmic use. Adverse Effects:  Ketorolac may cause fewer adverse gastrointestinal and CNS effects than do opioid analgesics, but it poses a significant risk of hematologic toxicity and other adverse effects. Advantages:  Able to produces analgesia comparable with morphine but caused less nausea, vomiting, and drowsiness. Brenner p. 324

            F: Celecoxib (Celebrex): Indications: In clinical studies of ostoearthritis and rheumatoid arthritis, celecoxib was shown to be as efficacious as naproxen without causing significant side effects. Effects: Celecoxib is a diaryl-substituted pyrazole compound that acts as a potent analgesic, antipyretic, and anti-inflammatory agent. Adverse Effects: Celecoxib appears to cause a low incidence of adverse reactions, the most common of which are diarrhea, dyspepsia, and abdominal pain. Advantages: The selective cyclooxygenase-2 (COX-2) inhibitors are a new group of drugs that appear to provide potent anti-inflammatory activity without causing significant gastrointestinal toxicity. Brenner p. 324.