Aspirin, Acetaminophen and Eicosanoids Overview

• The lecture provides and overview of Aspirin and Acetaminophen
• Eicosanoids, as well as their effects on pain, headaches, and migraines are reviewed

Drug Targets on the Prostanoid Biosynthesis Pathway

• Phospholipase A-2 is a drug target
• Glucocorticoids target Phospholipase A-2
• Glucocorticoids prevent the production of PGs, LTs, HETEs, and Tx
• Glucocorticoids are effective, but only for acute use, and have side effects
• Cyclooxygenases is another drug target
• COX-1 acts in peripheral tissues
• COX-2 is produced locally in response to inflammation
• NSAIDs target both COX-1 and COX-2
• COX-2 selective inhibitors affect inflammation without affecting prostaglandins elsewhere
• Aspirin is an irreversible COX-1 inhibitor

COX1 and COX2 Inhibition Among NSAIDs

• Aspirin inhibits COX-1 greater than COX-2 at a ratio of 166x
• Indomethacin inhibits COX-1 greater than COX-2 at a ratio of 60x
• Ibuprofen inhibits COX-1 greater than COX-2 at a ratio of 15x
• Celecoxib inhibits COX-2 greater than COX-1 at a ratio of 1,000x
• Rofecoxib inhibits COX-2 greater than COX-1 at a ratio of 1,000x

Prostaglandins and Pain

• Prostaglandins mediate peripheral (PGE2, PGI2) and central pain (PGE2)
• Aspirin prevents this induction of pain for both peripheral and central pain
• Acetaminophen only acts on central pain
• Aspirin prevents prostaglandin-mediated inflammation
• Prostaglandin (PGE1) inhibits stomach acid production
• Aspirin prevents this effect, which can cause gastric hyperacidity and ulceration with chronic use
• Aspirin directly irritates the stomach lining
• Misoprostol (PGE analog) is administered along aspirin to inhibit stomach acid production
• Prostaglandins mediate fever
• PGE2 increases thermoregulatory set point at the brain
• Aspirin and acetaminophen lower prostaglandin production in the brain, useful for patients with fever
• Thromboxane A2 mediates platelet aggregation
• Aspirin prevents TxA2 production
• Aspirin is a blood thinner and can cause bleeding

Aspirin

• Aspirin is an analgesic for mild to moderate pain
• Aspirin provides symptomatic relief for headache, myalgia, arthralgia, dysmenorrhea, and achiness from cold and flu
• Aspirin can be combined with narcotics to treat severe pain
• Aspirin is an antipyretic and reduces fever
• Aspirin is an anti-inflammatory agent used for arthritis
• Aspirin is an anti-platelet blood thinner, decreasing heart attack rates, strokes, and colon cancer -Baby aspirin (around 80mg per day) significantly reduces thrombotic events with no major side effects
• Aspirin increases gastric acid production, leading to gastric ulcers and bleeding
• Aspirin should avoided in patients with bleeding disorders
• Increased bleeding can occur when combined with anticoagulants and should be stopped a week before surgery
• Aspirin can cause renal toxicity, potentially shutting down kidneys in patients with renal insufficiency
• Cross-allergic reactions can be triggered by aspirin; about 5% of patients with aspirin allergies will have asthmatic attacks
• Aspirin intolerance results in allergy symptoms, including rhinitis, urticaria, bronchoconstriction, hypotension, and vasomotor collapse
• Aspirin can delay childbirth and may cause premature closure of the ductus arteriosus on the fetus
• Aspirin can increase uricemia and should be avoided in patients with gout
• Aspirin can cause Reye's Syndrome, which is characterized by vomiting, lethargy, disorientation, and liver damage
• Reye's Syndrome happens most often in children, particularly with viral infections like flu and chicken pox
• Larger doses of aspirin can cause hyperglycemia and glycosuria
• Toxic doses of aspirin increase oxygen uptake and carbon dioxide production, while also decreasing lipogenesis and increasing lipolysis
• High doses of aspirin can increase corticosteroid production and displace plasma thyroid hormones

Aspirin Pharmacokinetics

• Aspirin is highly bound to plasma proteins
• The peak plasma concentration of aspirin occurs in 1-2 hours, with an elimination half-life of 3-16 hours
• Aspirin is rapidly absorbed and metabolized via esterase hydrolysis to acetic acid and salicylate
• Serum half-life of aspirin is 15-20 minutes
• Glucuronic and glycine conjugation occur, forming salicyluric acid
• Aspirin is oxidized to gentisic acid and excreted via the kidney
• Salicylate is metabolized with a half-life of 4 hours
• Elimination is greatly slowed down with high concentrations, but a higher urine pH enhances its excretion
• Adverse effects of aspirin include salicylism after ingesting more than 50mg/dL
• Salicylism symptoms include ringing in the ears, visual problems, nausea, vomiting, sweating, thirst, headache, confusion, dizziness, and hyperventilation
• Toxicity from heavy overdose may cause severe metabolic acidosis
• Other effects include respiratory alkalosis compensatory mechanisms, respiratory depression, dehydration, fever, hallucinations, and progression to convulsions, coma, cardiac collapse and respiratory failure
• Aspirin overdose can be treated with gastric lavage, restoring acid-base balance, treating symptoms (fever, headache), possible hemodialysis, making urine basic, maintaining vital signs
• Aspirin has many drug interactions, including increased bleeding with warfarin and heparin
• Aspirin displaces methotrexate, sulfinpyrazone, tolbutamide, and some NSAIDs from plasma protein binding
• Aspirin blocks renal tubular secretion, inhibiting the uricosuric effect of sulfinpyrazone and probenecid
• Aspirin increases the toxicity of carbonic anhydrase inhibitors and blocks the natriuretic effect of spironolactone
• Buffered aspirin does not contain sufficient buffer to be useful; taking aspirin with water decreases irritation
• Enteric-coated and timed-release aspirin reduces stomach irritation by delaying absorption and prolonging action
• Some formulations of aspirin are easier to swallow (gelcaps/liquid)
• Caffeine can be added to aspirin to increase its efficacy

Acetaminophen

• Acetaminophen is also known as Tylenol
• Phenacetin is a prodrug metabolized into acetaminophen, it is considered too toxic for use now.
• Acetaminophen is a weak anti-inflammatory agent
• Acetaminophen only prevents prostaglandin effects on the central nervous system, due to inhibition of COX-3
• Acetaminophen does not cause GI erosion or hyperacidity, increase bleeding time, or affect the cardiovascular or respiratory system
• Moderate doses may cause rash and anemia, although this is rare
• Acetaminophen is relatively safe but can cause occasional allergies, rashes, or fever
• At higher doses (>4 grams per day), metabolites are toxic to the liver, leading to hepatic necrosis and renal toxicity
• Acetaminophen overdose is treated by emesis lavage and oral administration of N-acetylcysteine (NAC)
• Cimetidine can inhibit cytochrome P-450 without interfering with NAC; potentially useful in acetaminophen overdoses
• Infants are more prone to overdose due to less ability to glucuronidate
• Alcoholics are more prone to overdose due to glutathione depletion
• P450 inducing drugs can increase toxic metabolite formation
• High doses can cause nephrotoxicity

Headaches

• 1 in 6 Americans have chronic headaches, and about half of those suffer from migraines
• Of migraine sufferers, 80% are women, with an average of 50-60 migraine attacks per year
• 98% of headaches are primary headaches, as they are not secondary to another disease
• Three main forms of primary headaches include tension-type headache (~70%), neurovascular headache (migraine, 15%), and cluster headaches (.1%)

Tension Headaches

• Tension, stress or muscle contraction headaches are ~70% in males and ~80% in females
• Mild to moderate intensity pain that doesn't last more than 30 minutes suggests tension headaches
• Tension headaches can be episodic (<15 days/month) or chronic (>15 days/month for 6 months)
• They are often bilateral, and Nausea may occur along chronic headache
• Feelings of pressure and tightness in neck muscles are other symtoms
• Simple analgesics used for treatment of tension headaches
• If severe or persistent, consider anti-migraine medicines or more aggressive NSAIDs therapy

Cluster Headaches

• Cluster headaches are extremely severe and unilateral by nature
• Pain is in the areas around and above eyes
• Associated symptoms include redness of the eye, lacrimation, nasal congestion, forehead and facial sweating, contraction of the pupil, puffy eyelid
• Attack lasts for 15 minutes to 3 hours in series
• Predominantly in men
• Oxygen inhalation as well as Sumatriptan injections or nasal spray are effective treatments
• Dihydroergotamine injection or nasal spray, lidocaine nasal drops are also treatments
• Oral aspirin, naproxen, ibuprofen and other NSAIDs are not effective

Migraines

• Migraine headaches are classified as a unilateral throbbing headache lasting from 4-72 hours (3-4 attacks per month)
• Symptoms that accompany migraines include nausea, vomiting, photophobia, phonophobia, and sweating
• Migraines are often triggered by certain stimuli, such as smoke, fear, pressure, and certain foods
• Physical activity can aggravate migraine pain and they are often seen along generations
• Classical migraines, which account for 25% of all migraines, have an aura which precedes the attack, with visual disturbances, hallucinations of light or sounds, loss of vision
• Common Migraines account for the remaining 75% of all migraines and have no aura

Causes and Treatments of Migraines

• Cerebral vessels undergo vasoconstriction followed by vasodilation
• Swelling activates pain receptors along the trigeminal nerve
• Serotonin promotes vasoconstriction and interferes with pain transmission
• Agonists can be used to treat migraines
• 5HT1b and 1D agonists are most effective
• Migraine may be treated as a seizure
• Anti-seizure medications are currently being studied for migraine prophylaxis
• Treatment options include lifestyle changes, medications, and alternative therapies, such as acupuncture or massage
• Mild migraines can be treated with basic analgesics (NSAIDs like aspirin, ibuprofen)
• Nausea can be treated with dimenhydrinate or metoclopramide
• Moderate migraines can be treated with a combination of caffeine with acetaminophen and aspirin (excedrin migraine); ergotamine, triptans
• Severe migraines can be treated with Triptans first, then analgesics if needed
• Serotonin agonists can be used to relieve migraine symptoms
• Ergotamine are non-selective serotonin agonists
• Dihydroergotamine is more potent, but has more side effects, including nausea, peripheral vasoconstriction, and a rise in blood pressure
• Triptans are 5HT-1D and 1B agonists
• They are effective for moderate to severe migraine headaches
• Sumatriptan has 14% bioavailability, SC (quick) or nasal spray (slow), short half life
• Rizatriptan, naratriptan, and zolmitritan have improved bioavailability
• Zolmitriptan is the most potent, while naratriptan is long acting with fewer side effects
• Side effects of Triptans include high blood pressure/cerebrovascular hemorrhage, coronary vasospasm, pain in jaw and neck, light headiness, fatigue, pressure sensation
• Contraindications for Triptans include uncontrolled hypertension, prone to coronary artery disease, and pregnancy
• They should not be combined with ergots, MAOI or SSRIs
• Beta blockers (propranolol) may be used to prevent migraines but are contraindicated in diabetics, asthmatics, heart block or failure, and pregnant women
• Calcium channel blockers (verapamil) can be used but are contraindicated in hypotension, CHF, pregnancy, and arrhythmias
• Other drugs used to prevent Migraines include antidepressants, anticonvulsants (valproic acid) and anti-serotonergics
• Methysergide has extreme side effects including nausea, cramps, insomnia, weight gain, hypertension, pulmonary fibrosis
• Botulinum toxin injection at trigger points
• Surgery at trigger points can be considered if other treatments are ineffective