Lect. 8 Pain, Narcotic and Non-narcotic Analgesics (Analgesic Antipyretics)
1. DRUGS USED IN DISORDERS OF THE
CENTRAL NERVOUS SYSTEM AND
TREATMENT OF PAIN
Lecture 8:
Pain, Narcotic (Opioid) and Non-Narcotic Analgesics
Marc Imhotep Cray, M.D.
(NSAIDs & Other Analgesic Antipyretics)
2. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Learning Objectives:
2
OPIOID ANALGESICS:
1. Familiarity with the brain’s opioid system; in particular the major opioid receptors,
their principal endogenous ligands and the signal transduction pathways that they utilize.
2. The role of opioid transmission in the pain experience and how opioid agonists induce
analgesia.
3. The concepts of opioid-induced tolerance, physical dependence, addiction and pseudo-
addiction, and how to recognize each.
4. The indications, mechanism of action, clinical effects, adverse effects and
contraindications of the major classes of opioid analgesics used in the management of
pain.
3. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Learning Objectives cont.
3
NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)
1. The role of cyclooxygenase enzymes and prostaglandins in the etiology of
inflammation, pain and fever.
2. The role of prostaglandins in the homeostatic regulation of: a) gastric function, b)
kidney function, c) regulation of vasoconstriction and platelet activation
3. The indications, mechanism of action, adverse effects, contraindications and potential
drug interactions of:
a) Aspirin and the salicylates, b) Traditional NSAIDs e.g. ibuprofen and naproxen
c) Celecoxib, d) acetaminophen
4. The rationale behind the unique indication for low dose aspirin as a prophylactic
treatment in the prevention of platelet aggregation and the development of
cardiovascular heart disease.
5. The pharmacokinetics of aspirin and the mechanisms that lead to the development of
salicylate toxicity
6. The mechanisms underlying acetaminophen poisoning and its treatment
4. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Learning Objectives cont.
4
TREATMENT OF HEADACHES
1. Recognition of the primary headache disorders, including migraine, cluster
headache, and tension headache
2. The major differences between primary and secondary headache disorders
3. The current concepts in migraine pathophysiology
4. Identification of the treatment strategies for the various headache disorders
5. The indications for the various abortive migraine-specific medications and
headache preventive medications.
6. The mechanisms of action and adverse effects of the various abortive migraine-
specific medications and headache preventive medications.
5. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8Classification Schema:
Narcotic (Opioid) and Non-Narcotic Analgesics:
5
A. Analgesics
Morphine
Hydromorphine
Methadone
Meperidine
Fentanyl
Codeine
Oxydocone
Hydrocodone
Propoxyphene
Dextromethorphan
B. Mixed Receptor Agonist-
Antagonists
Pentazocine
Nalbuphine
Buprenorphine
Butorphanol
C. Opioid Antagonists
Naloxone
Naltrexone
6. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Analgesics Classification Schema cont.
6
A. Aspirin and Salicylic Acids
Aspirin (Bayer)
Diflusinal (Dolobid)
Salsalate (Disalcid)
B. Non-Selective and traditional NSAIDs
Ibuprofen (Advil/Motrin/Nuprin)
Naproxen (Aleve/Anaprox/Naprosyn)
Oxaprozin (Daypro)
Ketoprofen (Actron)
Indomethacin (Indocin)
Diclofenac (Cataflam)
Sulindac (Clinoril)
Ketorolac (Toradol)
NSAIDS cont.
Tolmetin (Tolectin)
Meloxicam (Mobic)
Piroxicam (Feldene)
Meclofenamate (Meclomen)
Mefenamic acid (Ponstel)
Etodalac (Lodine)
C. Coxibs: COX-2 specific inhibitors
Celecoxib (Celebrex)
D. Non-NSAID Related Analgesic
Acetaminophen (Tylenol/ Paracetemol)
8. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Pain Pathways:
8
Tissue injury can lead to cellular changes involving release of
chemicals (e.g., histamine) that start or quicken neuronal impulses
that are interpreted as pain
Many neuronal pathways transmit pain sensation
For example, pain from peripheral injury reaches CNS via primary afferent
neurons, whose cell bodies form the dorsal root ganglia (DRG)
Disorders such as phantom limb pain may involve abnormal DRG structure or
function
Primary afferents end mainly in the dorsal horn of the spinal cord
Secondary neurons cross spinal cord and ascend in pathways to the
thalamus, the cerebral cortex, and other sites
9. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Pain Pathways(2)
9
A descending system of opioid (endorphins, enkephalins), 5-HT
(e.g., from raphe nuclei), and noradrenergic (e.g., from locus
ceruleus) pathways can lessen afferent signals
Drugs that act at pathways mediating pain sensation or
perception are:
local (e.g., lidocaine) and
general (e.g., halothane) agents,
opioids (e.g., morphine), and
nonopioids (e.g., aspirin and acetaminophen)
11. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
MedPharm Case 19
11
From: MedPharm Clinical Case Studies
An 18-year-old man is brought into the emergency department after
being found on the street unresponsive. He is lethargic and does not
answer questions. He has been given 1 ampule of Dextrose
intravenously without result. On examination, his heart rate is 60 beats
per minute, and respiratory rate is 8 per minute and shallow. His pupils
are pinpoint and not reactive. There are multiple intravenous track
marks on his arms bilaterally. The emergency physician concludes that
the patient has had a drug overdose.
What is the most likely diagnosis?
What is the most appropriate medication for this condition?
In addition to its therapeutic actions, what other effects might this
medication produce?
12. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Opioids: Endogenous Opioid Pathway
12
Morphine and related compounds (opioids) mimic effects of
endogenous opioid neurotransmitters —endorphins and enkephalins
Endogenous opioid receptors are located throughout pathways that
relay pain signal from its source to higher CNS centers for processing,
evaluation, and response (such as via the spinoreticular tract (see
previous slide)
Descending pathways, including endogenous opioids, NE, and 5-HT,
modulate transmission of incoming pain signals
These pathways can be activated subconsciously or consciously, which may
account for a large analgesic placebo effect
Opioids alter perception of pain
Such modulation of affective component of pain can improve a patient’s quality
of life even in presence of a continuing sensation of pain
14. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Opioids: Receptor-Transduction
Mechanisms
14
Opioids activate 7-transmembrane GPCRs located presynaptically
and postsynaptically along pain transmission pathways
High densities of opioid receptors- known as μ, δ, and κ-are found
in dorsal horn of spinal cord and higher CNS centers
Most currently used opioid analgesics act mainly at μ-opioid
receptors
Opioids have an onset of action that depends on route of
administration and have well-known adverse effects
constipation
respiratory depression
abuse potential
15. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Opioids Receptor-Transduction
Mechanisms (2)
15
Cellular effects of opioids involve enhancement of neuronal K+
efflux (hyperpolarizes neurons and makes them less likely to
respond to a pain stimulus) and inhibition of Ca2+ influx (decreases
NT release from neurons located along pain transmission pathway)
Brainstem opioid receptors mediate respiratory depression
produced by opioid analgesics
Constipation results from activation of opioid receptors in CNS and
GI tract
Nausea and Vomiting associated with opioids results from activation
CTZ of medulla
17. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Narcotic (Opioid) Analgesics
17
A. PROTOTYPE, MORPHINE, is extracted from opium poppy in which
10% of alkaloid content is morphine and 1% is codeine
B. Morphine and codeine can be modified to form semisynthetic
derivatives, including:
1. Heroin (diacetylmorphine), which is more lipid-soluble and has a more rapid
onset of action
2. Oxycodone (Roxicodone)
C. Many synthetic narcotics have also been produced, such as
1. Meperidine (Demerol)
2. Levorphanol (Levo-Dromoran)
3. Methadone (Dolophine)
4. Fentanyl (Duragesic)
5. Propoxyphene (Darvon, Dolene)
6. Dextromethorphan
18. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Opioid Analgesics (2)
18
D. PROPERTIES of Morphine are representative of most of drugs in this
class
1. Morphine is least lipophilic opioid, but it can still cross BBB
a. Absorption from gut is good, but serum morphine
concentration is variable due to first-pass metabolism by liver
b. Distributes in the total body water
c. It is metabolized by glucuronide conjugation morphine-6-
gluconoride is more active than parent drug
d. Parenteral administration is commonly used to induce a
rapid, predictable analgesic effect
19. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Opioid Analgesics (3)
19
2. Binding sites for morphine are endorphin, dynorphin, and enkephalin
Receptors μ-, κ,- and δ-receptor subtypes have been identified; opioids act
primarily on the μ-receptors
a. Opioid receptors are present in pain-integrating areas of CNS and PNS
b. Receptors are also present in the GI tract and brain stem, which leads to some
undesirable effects of opioids (constipation, depression of respiration)
Morphine effects on pain pathway neurons: (illustrated next slide)
(1) decreasing presynaptic cAMP formation
(2) decreasing presynaptic calcium influx
(3) decreasing presynaptic glutamate and substance P release from vesicles
(4) increasing postsynaptic hyperpolarization due to an increase in potassium efflux
20. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Opioid Analgesics (4)
20
3. Opioids multiple effects on pain pathway neurons shown:
Weiss ST. High-yield pharmacology, 3rd ed. 2009
Analgesia occurs due to a decrease of pain perception and a decrease in psychological response to pain
An inhibitory action on substance P release in spinal cord may account for some of analgesic effects is
accompanied by a mental clouding or drowsiness
Although first dose can be dysphoric, subsequent doses produce euphoria
21. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Opioid Analgesics (5)
21
Morphine induces many additional pharmacological effects:
a. Respiratory depression is induced by a reduction in sensitivity of medullary
respiratory centers to CO2 This occurs with all narcotic analgesics and is primary
cause of death from an acute overdose
b. Physical dependence and tolerance occur with long-term use, which means that a
withdrawal syndrome will develop when the drug is discontinued Cross-tolerance
occurs with all other narcotic analgesics
c. Emesis is often observed with initial doses due to chemoreceptor(CTZ) stimulation
in area postrema in medulla
d. Miosis is induced by increased parasympathetic tone to pupil via stimulation
of Edinger-Westphal nucleus This is less pronounced with meperidine
due to an anticholinergic effect
22. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Opioid Analgesics (6)
22
Morphine pharmacological effects cont.
e. Constipation results from decreased GI motility, even though there is increased
tone of GI smooth muscle
f. Histamine release can be induced morphine can be dangerous to use in patients
with asthma
g. Tone of biliary tract and ureters can be increased causing urinary retention and
inhibiting voiding reflex
h. Antitussive (cough suppressant) actions are prominent
i. Hyperthermia can occur
j. An increase in intracranial pressure can occur due to dilation of cerebral blood
vessels
23. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Opioid Analgesics (7)
23
E. NARCOTIC ANTAGONISTS have a structure that is very similar to
morphine A bulky substitution on the nitrogen results in antagonistic
actions
1. The pure antagonists have no analgesic activity
a. Naloxone (Narcan) will
i. reverse respiratory depression from an overdose of a
narcotic
ii. not affect respiratory depression from a sedative-
hypnotic
iii. induce a withdrawal syndrome in a narcotic addict
24. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Opioid Analgesics (8) Narcotic antagonists (2)
24
Modification of narcotic structure (at N) results in narcotic antagonists
Diagram shows structure of morphine
Weiss ST. High-yield pharmacology, 3rd ed. 2009
25. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Opioid Analgesics (9) Narcotic antagonists (3)
25
b. Naltrexone (Revia) is more effective orally and has a longer
duration of action than naloxone
2. Weak agonist/antagonist analgesics, such as pentazocine (Talwin),
have analgesic activity in addition to antagonistic activity
a. They will not reverse respiratory depression caused by a
narcotic
b. They will induce a withdrawal syndrome in a narcotic addict
c. Most new narcotic analgesics are in this group rationale
behind their use is that these analgesics should cause less
respiratory depression and be less likely to be abused
26. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Opioid Analgesics (10)
26
F. THERAPEUTIC USES of the narcotic analgesics include:
1. Analgesia
a. Morphine is more potent than codeine, which is more potent than aspirin
b. Narcotics are used primarily for short term analgesia (e.g., myocardial
infarction, surgery), except in terminally ill patients analgesic antipyretics
are preferred to treat chronic pain
2. Diarrhea Diphenoxylate with atropine (Lomotil) or loperamide (Imodium) are
preferred as they have few CNS effects
3. Neuroleptic anesthesia (e.g., fentanyl)
4. Antitussive activity
a. Codeine induces more cough suppression than morphine
b. Dextromethorphan (Benylin DM) has little narcotic activity, but it does have
cough suppressant activity Guaifenesin an expectorant, is also a common
ingredient in combination products with codeine or dextromethorphan
5. Reduction of narcotic withdrawal symptoms requires a drug, such as
methadone, with a long duration of action
6. Maintenance of a narcotic addict using methadone
27. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Opioid Analgesics (11)
27
G. CLINICAL USES of narcotic antagonists include:
1. Analgesia with agonist/antagonist analgesics (pentazocine)
2. Tx of respiratory depression from an acute narcotic overdose using
naloxone
3. Diagnosis of physical dependence to a narcotic Naloxone will
precipitate withdrawal in narcotic addicts
4. Management of a narcotic addict. Naltrexone will reduce t euphoric
effects of the narcotics
Buprenorphine (T0.5 12h) (Subutex), a partial agonist, is now available for
outpatient treatment of opioid addicts
5. Management of an alcoholic Naltrexone reduces craving for
ethanol
28. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Opioid Analgesics (12)
28
H. TRAMADOL (Ultram) is an atypical, narcotic-like analgesic that
binds to μ-receptors and also inhibits reuptake of serotonin and
norepinephrine
1. It is indicated for moderate to severe pain
2. Seizures are a serious potential side effect of tramadol; other
side effects include ulcers and GI bleeding
3. Although there is some potential for abuse, tramadol is
currently not categorized as a controlled substance in U.S.
29. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Headaches:
29
Primary headaches are generally mediated via vasodilation
Most common types of headaches are migraine, tension-type, and
cluster headaches
Migraine can usually be distinguished from cluster headaches and
tension-type headaches by its characteristics (next slide)
Migraines, for example, present as a pulsatile, throbbing pain,
whereas cluster headaches present as excruciating, sharp, steady pain
This is in contrast to tension-type headaches, which present as dull
pain, with a persistent, tightening feeling in head
30. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Characteristics of migraine, cluster, and
tension-type headaches
30
Modified from: Lippincott Illustrated Reviews-Pharmacology 6th Ed.. 2015
32. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Sumatriptans and Reuptake inhibitors:
32
Certain types of pain are sometimes successfully treated with
drugs that are not analgesic for other types of pain
Two examples are sumatriptan and related compounds
(triptans) and inhibitors of neuronal reuptake of NE or 5-HT
Triptans (e.g., almo-, ele-, frova-, nara-, riza-, and sumatriptan)
are often first-line therapy for treatment of acute severe
migraine attacks
33. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Sumatriptans and Reuptake inhibitors(2)
33
Reuptake inhibitors (e.g., tricyclics and more selective NE or 5-HT
reuptake inhibitors) are used for some patients with migraine and
for some patients experiencing neuropathic pain with hyperalgesia
(increased sensitivity to painful stimuli) or allodynia (painful
sensitivity to nonpainful stimuli)
Neither triptans nor reuptake inhibitors are very effective against
inflammatory or acute pain
Adverse cardiovascular effects can occur with triptans, and
numerous ANS effects can occur with reuptake inhibitors
36. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8Summary of drugs useful in treatment
and prophylaxis of migraine headaches:
36
Modified from: Lippincott Illustrated Reviews-Pharmacology 6th Ed.. 2015
37. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Nonopioids: NSAIDs, Cyclooxygenase- 2
inhibitors, and Acetaminophen
37
Nonsteroidal antiinflammatory drugs have good analgesic efficacy (but
often less than that of opioids), relatively rapid onset, and adverse
effects (e.g., possibly fatal gastrointestinal bleeding and disturbed salt
and water balance)
All NSAID effects— analgesic, antiinflammatory, antipyretic, and
antiplatelet —are thought to be due to decreased prostanoid
biosynthesis via COX inhibition
Traditional NSAIDs inhibit both COX-1 and -2 isoforms, but newer
COX-2 inhibitors are more selective
38. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Nonopioids: NSAIDs, Cyclooxygenase- 2
inhibitors, and Acetaminophen (2)
38
Analgesic efficacy of selective COX-2 inhibitors (coxibs) is
approximately equal to that of traditional NSAIDs, but adverse
effects of COX-2 inhibition have yet to be fully characterized and
are somewhat controversial
risk of thrombosis, Sulfa allergy
Ability to selectively inhibit COX-2 has been related to difference in
amino acids at position 523 of COX-1 and COX-2: isoleucine in COX-1,
valine in COX-2
Mechanism of action of acetaminophen is uncertain but thought to
be via CNS effects
Elevates pain threshold, possibly by inhibiting NO (nitric oxide) pathway
39. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
NSAIDs and Cyclooxygenase- 2 inhibitors
39
Note: Celecoxib (CELEBREX)
MECHANISM Reversibly inhibits specifically the cyclooxygenase (COX) isoform 2, which is found in
inflammatory cells and vascular endothelium and mediates inflammation and pain; spares
COX-1, which helps maintain gastric mucosa. Thus, does not have the corrosive effects of other
NSAIDs on GI lining. Spares platelet function as TXA2 production is dependent on COX-1.
40. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
40
NSAIDs and Cyclooxygenase- 2 inhibitors
41. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Analgesic Antipyretics: Specific Agents
41
A. All analgesic antipyretics act by inhibiting cyclooxygenase (COX), thereby
reducing prostaglandin synthesis
B. ASPIRIN (acetylsalicylic acid) is a salicylate that acetylates and irreversibly
inhibits
COX-1 and COX-2 New COX must be synthesized to recover from effects
1. Major therapeutic effects include:
a. Mild analgesia, due to reduced prostaglandin synthesis at sensory
nerve endings
b. Antipyresis, due to reduced prostaglandin synthesis in hypothalamic
temperature control center
c. Anti-inflammatory actions at high doses, due to reduced
prostaglandins at sites of inflammation
d. At very low doses, prophylaxis of MI in older people at high risk
2. These effects occur without tolerance and without euphoria
42. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Analgesic Antipyretics (2)
42
ASPIRIN cont.
3. Side effects from aspirin include:
a. Gastric ulcerations (NSAID-induced ulcers) and gastric
hemorrhaging, which can be increased by ingesting ethanol
and decreased by taking with food or misoprostol
Of course, aspirin is contraindicated in persons with known peptic
ulcer disease (PUD)
b. Reducing platelet aggregation by inhibiting formation of
thromboxane A2 (inhibits TXA2 synthesis)
This adverse effect is taken advantage of when managing patients
i. After a myocardial infarction
ii. With transient ischemic attacks
iii. With angina, especially unstable angina
iv. With atrial fibrillation
43. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Analgesic Antipyretics (3)
43
Side effects from aspirin cont.
c. Hypersensitivity reactions that
i. Are not immunologically mediated
ii. May be due to increased leukotrienes
d. Reduced renal uric acid secretion at low doses and reduced uric
acid reabsorption (uricosuria) at high doses
e. Reye’s syndrome, which involves a fatal, fulminating hepatitis and
cerebral edema, in children with chicken pox (varicella) or
influenza viral infections
Thus, aspirin is best avoided in children
44. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Analgesic Antipyretics (4)
44
4. Aspirin induces acute toxic effects in following order as dose is
increased from therapeutic to toxic range:
a. Tinnitus is an early indicator of toxicity
b. Uncoupling of oxidative phosphorylation CO2 production,
which respiration and can lead to hyperthermia at toxic doses
c. Direct medullary stimulation also enhances respiration,
leading to respiratory alkalosis and HCO3 excretion (loss)
d. At even higher doses, metabolic acidosis occurs due to
i. Direct respiratory depression
ii. Acidic products of aspirin metabolism, which leads to fluid and
electrolyte loss
iii. Previous loss of HCO3
45. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Analgesic Antipyretics (5)
45
5. Management of aspirin overdoses involves
a. Emesis, lavage, or dialysis
b. Fluids with HCO3
c. Monitoring blood aspirin concentration beginning 6 hours after
ingestion
C. IBUPROFEN (Motrin, Advil) and naproxen (Aleve) reversibly inhibit COX and have
1. Effects that are very similar to aspirin, including
a. Mild analgesic activity is especially effective for dysmenorrhea
b. Antipyretic activity
c. Anti-inflammatory activity
2. Side effects that are similar to, but milder than, the side effects for
aspirin, including:
a. Gastrointestinal bleeding
b. Increased bleeding times
c. Overdose toxicity like that of aspirin
N.B.-All NSAIDs can cause non-dose-related
episodes of acute renal failure and nephrotic
syndrome. They should be used with caution in
those with renal insufficiency or in patients
taking other potentially nephrotoxic agents.
46. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Analgesic Antipyretics (6)
46
D. KETOROLAC (Toradol) is an unusual NSAID in that it can be given
intramuscularly as well as orally
1. It is only used for the treatment of acute pain
2. It has a clinical efficacy similar to morphine
47. Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 8
Analgesic Antipyretics (7)
47
A. ACETAMINOPHEN (Tylenol) elevates pain threshold, possibly by inhibiting NO
(nitric oxide) pathway
1. Primary effects of acetaminophen are quite different from aspirin, and
include:
a. Mild analgesic activity
b. Antipyretic activity
c. No anti-inflammatory activity
d. None of side effects of aspirin
2. Major adverse effect from high doses is delayed hepatic necrosis
a. A toxic phase 1 metabolite builds up in liver because of depletion of
glutathione
N-acetyl-p-benzoquinone imine (NAPQI)
b. Toxicity is especially prominent in combination with ethanol
c. Hepatotoxicity can be avoided by early administration of N-
acetylcysteine, which replenishes stores of glutathione
Remember: N-acetylcysteine is the antidote for acetaminophen toxicity