Eisenberg – Aspirin/Acetaminophen – NS Exam 2
Pain
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Definition
o the result of stimulating peripheral pain receptors, free nerve endings, by tissue mediators released
through injury
o pain sensation information is transmitted from the site of injury to the dorsal horn of the spinal cord
where it is either suppressed or enhanced by local neuronal circuitry
o transmission of this information to higher pain centers for processing and reaction - uncomfortable,
anxiety-producing
o individual pain tolerance
o produces numerous reactions
Two different types of nociceptive pain - stubbed toe example
o Neospinothalamic tract
 sharp, well-defined, focused pain
 carried by A-delta fibers
 treated with cyclo-oxygenase inhibitors
 aspirin, naproxen, ibuprofen, acetaminophen
o Paleospinothalamic tract
 dull, persistent ache, burning, less well-defined pain
 carried by C-fibers
 treated with opioids
o Comparison of Drug Treatment:
Neuropathic pain
o Caused by nervous system dysfunction rather than stimulation of intact afferent nerve endings
 a burning, shooting or tingling pain
 tumor or treatment-related nerve damage, acute herpes zoster (shingles), post-herpetic
neuralgia, phantom limb pain, and diabetes
 related to a defect in NMDA receptor function - antagonists are being studied
o Treatment is with non-traditional agents - only modest success
 Gabapentin (adjunct antiseizure medication) - effective in many neuropathic pain modalities
 Dizziness and somnolence can be resolved by adjusting the dose
 Carbamazepine, possibly phenytoin in the future (major antiseizure medications)
 SN (norepi) RIs - venlafaxine, duloxetine
 tricyclic antidepressants - cause anticholinergic effects and orthostatic hypotension, particularly
in the elderly
o New drug approaches:
 Capsaicin receptor TRPV1 agonists
 Drugs acting at special sodium and calcium channels
 Marijuana acts at the CB1-receptor and can synergize w/ the mu-opioid receptor to act at the
capsaicin receptor
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Salicylates - Aspirin
 History and current uses
o Analgesia
o Anti-inflammatory and antirheumatoid effect
o Antipyretic effect – lower fever
o Anticoagulant effect
 Activity is through the action of salycyclic acid which is freed
 Pharmacologic effects
o Analgesia - treatment of pain
 Prostaglandins are products of cyclo-oxygenase(s) conversion of arachidonic acid
 maintains the sensitivity of the peripheral pain receptors
 COX-1 (ubiquitous) appears to exist in most tissues and is involved in homeostasis
 COX-2 is induced when inflammatory cells are activated; exists constitutively in brain and kidney
 Aspirin, acetaminophen, and other NSAIDS act to suppress both enzymes.
 The suppression of COX-1 often results in the disruption of its protective properties (i.e., gastric
mucosa).
 Newer agents are available with more COX-2 selective antagonism.
o Anti-inflammatory - antirheumatoid effect
 Maintains capillary wall integrity - reduces edema
 Inhibits the release of chemotactic factors which mobilize neutrophils to the site of injury/
inflammation
 Stabilizes lysosomes - prevents release of proteases (that cause tissue injury during inflamm)
 Inhibits the formation of oxygen-derived free radicals
 Largely replaced by ibuprofen and naproxen
o Antipyretic effect
 COX inhibition in the central nervous system
 Inhibition of interleukin-1 (released from macrophages)
o Anticoagulant effect
 Decreased adhesiveness of platelets
 irreversibly inhibits platelet COX
 Decrease in prothrombin level
Absorption, metabolism & excretion
 Rapid absorption after oral administration
o part from the stomach - low pH, un-ionized from
o most from the small intestine because of the larger surface area - even though higher pH, less is in
the un-ionized form
 First conversion is to free salicylic acid
 Excretion by glomerular filtration and tubular secretion
o alkalinization of the urine will prevent reabsorption - more drug in the ionized form
o increasing urine volume reduces the absorption of un-ionized drug
o tubular secretion is an active process
Side/toxic effects
 Data for a typical year – ER contacts (ODs)
o aspirin alone: 16,640
o aspirin/codeine: 5,443
o deaths: 50
 CNS effects
o stimulation followed by depression: confusion, dizziness, tinnitus, then delirium, psychosis, stupor
and coma
o nausea and vomiting - CTZ stimulation - dopaminergic
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GI problems
o gastric upset, aggravation of peptic ulcer, gastritis
 probably due to COX-1 inhibition
 Celecoxib (Celebrex) and rofecoxib (Vioxx), COX-2 inhibitors, show less upset
 increase fluid intake
 formulations with better solubility
 enteric coating may cause erratic absorption
o gastric bleeding - usually not clinically significant
Respiration and acid-base balance
o Phase I – low level OD
 Respiration rate  by direct action on medulla
 Uncoupling of oxidative phosphorylation increases CO2 formation which indirectly stimulates
respiration; the increased metabolism increases body temperature
 blow off CO2  H2CO3 decreases  respiratory alkalosis
o Phase II – high level OD
 Respiration rate decreases by direct action on the medulla
 conserve CO2  H2CO3 increases  respiratory acidosis
 neurogenic drive, pCO2, pO2
Effects on other systems
o Increased metabolic rate
 increase in body temperature
 metabolic acidosis- pyruvic & lactic acid, sulfates & phosphates build up
o Renal
 renal failure in patients with renal insufficiency
 overdose may cause acute tubular necrosis
o Cardiovascular
 peripheral vasodilation (direct action)
 toxic doses depress central vasomotor centers
Treatment approaches
o Activated charcoal to reduce GI absorption
o Alkalinize by giving bicarbonate
 regain proper acid-base balance
 aids excretion of weak acids
 ionizes salicylic acid reducing CNS entry
o Lower body temperature by mechanical means
o Fluids for replacement and to aid excretion
o Supportive measures
Interactions/precautions
 Displaces thyroid hormones and corticosteroids from plasma proteins
 Often given in combination with opioids
 Precautions in some patients
o peptic ulcer, gastritis – COX-1 inhibition
o blood coagulation disorders
o allergies
 Reye’s syndrome in children
o encephalopathy and hepatic injury
o causal relationship is now in question
o aspirin is still avoided in children
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Review of therapy:
 Proven uses
o analgesia
o antipyretic action
o inflammation
o anticoagulation
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Proven or suggested uses
o prevention of heart attacks and strokes
o maintaining coronary bypass graft patency
o reducing deaths from acute heart attacks
o treating hypertension (toxemia) of pregnancy
o preventing clots on artificial heart valves
o reducing recurrences of migraine
o strengthening immunity
o prevention of colon cancer
Acetaminophen (Tylenol):
Pharmacologic effects
 Analgesia, antipyresis
 No anti-inflammatory and antirheumatic properties
o inhibits cyclogenases in the brain but not at sites of inflammation in peripheral tissues
 Higher doses can produce sedation and euphoria
Added benefits
 Little gastric erosion
 no anticoagulant effect
 no change in acid-base balance
 Does not interfere with the uricosuric effects of agents to treat gout
 No problem with Reye's Syndrome
Side/toxic effects
 Acetaminophen toxicity - 50,000 ER visits annually
 The most common drug taken in overdose
 Liver - occurs 24-48 hours after overdose
o hepatic lesions occur with overdose
o formation of a toxic intermediate N-acetyl-p-benzoquinone imine(NAPQI) causing cell death inactivated by glutathione
o cysteine or cysteamine is the specific treatment to increase glutathione
o alcoholics are at special risk
 existing hepatic problems
 require more acetaminophen because it is metabolized faster - cytochrome p450 is induced
 dietary deficiencies reduce existing glutathione
 Kidney
o “phenacetin nephritis” with chronic use/abuse
o preliminary studies suggest that this does not occur with acetaminophen
o there are reports of renal damage without hepatic damage - 8% of new dialysis patients were taking
at least one dose of acetaminophen per day
 Blood
o cyanosis, particularly with phenacetin, though rare with acetaminophen
o sulfhemoglobinemia
o hemolytic anemia
Review of therapeutic uses
 Analgesia
 Antipyretic effect
 No anti-inflammatory action
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