N O N S T E R O I D A L A N T I - I N F L A M M AT O R Y

DRUGS (NSAIDS)AND OPIOIDS

A S S T . P R O F. L E V E N T H A C I S Ü L E Y M A N
 I N F L A M M AT I O N
• Inflammation is a complex response to cell injury that
primarily occurs in vascularized connective tissue and
often involves the immune response.
• The mediators of inflammation function to eliminate the
cause of cell injury and clear away debris, in preparation
for tissue repair.
• Inflammation also causes pain and, in instances in which
the cause of cell injury is not eliminated, can result in a
chronic condition of pain and tissue damage such as that
seen in rheumatoid arthritis.
• cyclooxygenase is the enzyme that converts arachidonic
acid into the endoperoxide precursors of prostaglandins,
important mediators of inflammation.
• Cyclooxygenase has at least 2 isoforms: COX-1 and
COX-2. COX-1 is primarily expressed in noninflammatory
cells, whereas COX-2 is expressed in activated
lymphocytes and other inflammatory cells.
 ASPIRIN & OTHER NSAIDS
• Aspirin (acetylsalicylic acid) is the prototype of the salicylates and
other NSAIDs.
• Indomethacin has greater anti-inflammatory effectiveness; and
ketorolac has greater analgesic effectiveness.
• Aspirin and nonselective NSAIDs inhibit both cyclooxygenase
isoforms and thereby decrease prostaglandin and thromboxane
synthesis throughout the body.
• The major difference between the mechanisms of action of aspirin
and other NSAIDs is that aspirin (but not its active metabolite,
salicylate) acetylates and thereby irreversibly inhibits
cyclooxygenase, whereas the inhibition produced by other NSAIDs is
reversible. The irreversible action of aspirin results in a longer
duration of its antiplatelet effect and is the basis for its use as an
antiplatelet drug.
• Celecoxib was the first member of a newer NSAID subgroup, the cyclooxygenase-2
(COX-2)-selective inhibitors, which were developed in an attempt to lessen the
gastrointestinal toxicity associated with COX inhibition while preserving efficacy.
• The COX-2-selective inhibitors have less effect on the prostaglandins involved in
homeostatic function, particularly those in the gastrointestinal tract.
 EFFECTS AND USES
• Arachidonic acid derivatives are important mediators of inflammation; cyclooxygenase
inhibitors reduce the manifestations of inflammation (anti inflammatory effect).
• These inhibitors also suppress the prostaglandin synthesis in the CNS and thereby
reduce fever (antipyretic effect).
• Activation of peripheral pain sensors may be diminished as a result of reduced
production of prostaglandins in injured tissue (analgesic effect).
• NSAIDs are used for the treatment of mild to moderate pain, especially the pain of
musculoskeletal inflammation such as that seen in arthritis and gout.
• They are also used to treat many other conditions, including dysmenorrhea, headache,
and patent ductus arteriosus in premature infants.
 TOXICITY
• The most common adverse effect from therapeutic anti-inflammatory doses of aspirin is gastric upset.
• Chronic use can result in gastric ulceration, upper gastrointestinal bleeding, and renal effects, including
acute failure.
• Aspirin increases the bleeding time.
• persons with aspirin hypersensitivity can experience asthma from the increased synthesis of leukotrienes.
• Children with viral infections who are treated with aspirin have an increased risk for developing Reye's
syndrome, a rare but serious syndrome of rapid liver degeneration and encephalopathy.
• The COX-2-selective inhibitors have a reduced risk of gastrointestinal effects, including gastric ulcers
and serious gastrointestinal bleeding.
• The COX-2 inhibitors carry the same risk of renal damage as nonselective COX inhibitors.
• The COX-2 inhibitors carry an increased risk of myocardial infarction and stroke.
 AC E TA M I N O P H E N
• The mechanism of analgesic action of acetaminophen is unclear. The drug is only a
weak COX-1 and COX-2 inhibitor in peripheral tissues, which accounts for its lack of
anti-inflammatory effect. Evidence suggests that acetaminophen may inhibit a third
enzyme, COX-3, in the CNS.
• Acetaminophen is an analgesic and antipyretic agent; it lacks anti-inflammatory or
antiplatelet effects.
• Toxicity: when taken in overdose or by patients with severe liver impairment, the drug
is a dangerous hepatotoxin. The mechanism of toxicity involves oxidation to cytotoxic
intermediates by phase I cytochrome P450 enzymes. This occurs if substrates for phase
II conjugation reactions (acetate and glucuronide) are lacking.
 O P I AT E S A N D O P I O I D S
• Both groups of drugs are "narcotics." (The word "narcotic" means sleep-inducing or numbness-inducing).
• Both opiates and opioids are used medically. They may be prescribed for pain relief, anesthesia, cough
suppression, diarrhea suppression.
• Opiates are chemical compounds that are extracted or refined from natural plant matter (poppy sap and
fibers). Examples of opiates:
• Opium
• Morphine
• Codeine
• Heroin
• Opioids are chemical compounds that generally are not derived from natural plant matter. Most opioids are
"made in the lab" or "synthesized".
• Dextromethorphan
• Loperamide
• Hydrocodone
• Oxycodone
• Meperidine
• Methadone
• Fentanyl
• Opioid peptides are endogenous substances that exhibit the pharmacological properties of morphine. These
peptides include endorphins, enkephalins, and dynorphins.
OPIOID ANALGESICS
• The opioid analgesics may be classified in several ways.
• Spectrum of Clinical Uses:
• Analgesics
• Antitussives
• Antidiarrheal drugs
• Strength of Analgesia (Partial agonists are opioids
that exert less analgesia than morphine, full agonist):
• Strong
• Moderate
• weak agonists
• Ratio of Agonist to Antagonist Effects:
• agonists (full or partial receptor activators)
• antagonists (receptor blockers)
• mixed agonist-antagonists(capable of activating one
opioid receptor subtype and blocking another subtype).
 MECHANISMS OF ACTION
• There are three major opioid receptor subtypes. μ, δ, and κ receptors.
• All 3 receptor subtypes appear to be involved in the analgesic mechanisms at both
spinal and supraspinal levels.
• At the presynaptic level, opioid receptor activation can close voltage-gated calcium
ion channels to inhibit multiple neurotransmitter release, including acetylcholine,
norepinephrine, serotonin, glutamate, and substance P.
• At the postsynaptic level, activation of these receptors can open potassium ion
channels to cause membrane hyperpolarization (inhibitory postsynaptic potentials)
and a reduction in neuronal excitability.
 P H A R M AC O K I N E T I C S
• Most drugs in this class are well absorbed when taken orally, but morphine,
hydromorphone, and oxymorphone undergo extensive first-pass metabolism.
• In most cases, opioids can be given parenterally, and sustained-release forms of
some drugs are now available, including morphine and oxycodone.
• Fentanyl is available as a transdermal patch.
• Opioid drugs cross the placental barrier and exert effects on the fetus that can
result in respiratory depression.
 ACUTE EFFECTS
1. Analgesia: The opioids are the most powerful drugs available for the relief of pain.
• Strong agonists (ie, those with the highest analgesic efficacy, full agonists) include
morphine, methadone, meperidine, fentanyl, and heroin.
• Drugs with mixed agonist-antagonist actions (eg, buprenorphine) may antagonize
the analgesic actions of full agonists and should not be used concomitantly.
• Codeine, hydrocodone, and oxycodone are partial agonists with mild to moderate
analgesic efficacy.
• Propoxyphene, a very weak agonist drug, is also available combined with
acetaminophen.
2. Sedation and Euphoria: at doses lower than those required for maximum analgesia.
3. Respiratory Depression: Opioid actions in the medulla lead to inhibition of the respiratory center.
4. Antitussive Actions: Suppression of the cough reflex is the basis for the clinical use of opioids as
antitussives.
5. Nausea and Vomiting.
6. Gastrointestinal Effects: Constipation occurs through decreased intestinal peristalsis. This powerful
action is the basis for the clinical use of these drugs as antidiarrheal agents.
7. Smooth Muscle: Opioids (with the exception of meperidine) cause contraction of biliary tract smooth
muscle, which can result in biliary colic or spasm, increased ureteral and bladder sphincter tone, and
a reduction in uterine tone, which may contribute to prolongation of labor.
8. Miosis: Pupillary constriction is a characteristic effect of all opioids except meperidine.
9. Opioid analgesics, especially morphine, can cause flushing and pruritus through histamine release.
 CHRONIC EFFECTS
• Tolerance:
• Marked tolerance can develop to the acute pharmacologic effects, with the exception of
miosis and constipation.
• Although there is cross-tolerance between different opioid agonists, it is not complete. This
provides the basis for “opioid rotation,” whereby analgesia is maintained (eg, in cancer
patients) by changing from one drug to another.
• Dependence:
• Physical dependence is an anticipated physiologic response to chronic therapy with drugs
in this group, particularly the strong agonists.
• Physical dependence is revealed on abrupt discontinuance as a "withdrawal syndrome",
which includes rhinorrhea, lacrimation, nausea/vomiting, muscle aches, diarrhea, anxiety,
hostility, autonomic hyperactivity (tachypnea, sweating, hypertension, hyperthermia), and
dilated pupils.
 CLINICAL USES
1. Analgesia:
• oral formulations are most commonly used.
• In the acute setting, strong agonists are usually given parenterally.
• Prolonged analgesia, with some reduction in adverse effects, can be achieved with
epidural administration of certain strong agonist drugs (eg, fentanyl and
morphine).
• Fentanyl has also been used by the transdermal route providing analgesia for up
to 72 h.
• For less severe pain and in the chronic setting, moderate agonists are given by the
oral route, sometimes in combinations with acetaminophen or NSAIDs.
2. Cough Suppression: Useful oral antitussive drugs include codeine and dextromethorphan.
3. Treatment of Diarrhea: diphenoxylate and loperamide (µ-opioid receptor agonists that primarily act
on the receptors located in the gastrointestinal tract with a limited ability to cross the blood–brain
barrier).
4. Management of Acute Pulmonary Edema: Morphine (parenteral) may be useful in acute pulmonary
edema due to its vasodilatory properties resulting in reduction in the preload and therefore reducing
the pulmonary capillary pressure..
5. Anesthesia: Opioids are used as adjunctive agents in balanced anesthesia protocols. High-dose
intravenous opioids (e.g., morphine, fentanyl) are often the major component of anesthesia for cardiac
surgery.
6. Opioid Dependence: Methadone, one of the longer acting opioids, is used in the management of
opioid withdrawal states and in maintenance programs for addicts (Methadone will cause feelings of
relaxation and reduce pain, but it will not give the same high or euphoric feeling as heroin. It works in
treating heroin addiction by reducing the withdrawal symptoms and cravings).
 TOXICITY
• Most of the adverse effects of the opioid analgesics (eg, nausea, constipation, respiratory
depression) are predictable extensions of their pharmacologic effects.
• Overdose:
• Characteristic symptoms include pupillary constriction, coma, and respiratory depression.
• Diagnosis of overdosage is confirmed if intravenous injection of naloxone, an antagonist
drug, results in prompt signs of recovery.
• Treatment of overdose involves the use of antagonists such as naloxone and other
therapeutic measures, especially ventilatory support.
• Drug Interactions: The most important drug interactions involving opioid analgesics are
additive CNS depression with ethanol, sedative-hypnotics, anesthetics, antipsychotic drugs,
tricyclic antidepressants, and antihistamines.
 OTHER DRUGS
• Tramadol
• Tramadol is a weak μ-receptor agonist.
• Its analgesic activity is mainly based on blockade of the reuptake of serotonin.
• it is a weak norepinephrine reuptake blocker.
• Tramadol has been used as an adjunct to opioid analgesics in chronic pain
syndromes.
• Tapentadol has strong norepinephrine reuptake-inhibiting activity (blocked by α
antagonists) and only modest μ-opioid receptor affinity.