Eicosanoids and Pain Relief

Lecture Overview

• Eicosanoids, aspirin, acetaminophen, headache pain, and migraines are the topics covered

Drug Targets on Prostanoid Biosynthesis Pathway

• Phospholipase A-2 is a target, which glucocorticoids can act on
• Glucocorticoids prevent the production of PGs, LTs, HETEs, and Tx
• Glucocorticoids are effective, but only for acute use, and have side effects
• Cyclooxygenases are also drug targets
• 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 by NSAIDs

• Aspirin inhibits COX-1 more than COX-2 by a factor of 166x
• Indomethacin inhibits COX-1 more than COX-2 by a factor of 60x
• Ibuprofen inhibits COX-1 more than COX-2 by a factor of 15x
• Celecoxib inhibits COX-2 more than COX-1 by a factor of 1,000x
• Rofecoxib inhibits COX-2 more than COX-1 by a factor of 1,000x

Prostaglandins and Pain

• Prostaglandins mediate peripheral (PGE2, PGI2) and central pain (PGE2)
• Aspirin prevents the induction of both peripheral and central pain
• Acetaminophen acts only on central pain
• Prostaglandins mediate inflammation (PGE2 and PGD2)
• Aspirin prevents prostaglandin mediated inflammation, which is important for arthritis and RA
• Prostaglandin (PGE1) inhibits stomach acid production
• Aspirin prevents this effect, resulting in gastric hyperacidity and ulceration with chronic use
• Aspirin directly irritates stomach lining
• Misoprostol, a prostoglandin analog, is administered along with aspirin to inhibit stomach acid production
• Prostaglandins mediate fever
• PGE2 increases the thermoregulatory set point in 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
• This thins the blood and can cause bleeding

Aspirin Properties

• Aspirin is an analgesic for mild to moderate pain, providing symptomatic relief
• It treats headache, myalgia, arthralgia, dysmenorrhea, and achiness from cold and flu
• It can be combined with narcotics to treat severe pain
• It reduces fever and acts as an anti-inflammatory agent for arthritis
• It also prevents platelet aggregation, decreasing heart attack rates, strokes, and colon cancer
• Meta-analysis of 100,000 patients showed that baby aspirin (around 80mg per day) significantly reduces thrombotic events with no major side effects. There may be a link with cancer/metastasis

Aspirin: Side Effects

• Increases gastric acid production and is the second leading cause of gastric ulcers and bleeding
• Increased bleeding can occur and is to be avoided in patients with bleeding disorders
• This effect increased when combined with anticoagulants
• Patients should stop taking aspirin one week before surgery
• Can cause renal toxicity and can shut down kidneys in patients with renal insufficiency
• Allergic reactions include rhinitis, urticaria, bronchoconstriction, hypotension, vasomotor collapse
• Cross-allergic reactions may occur and should be avoided if the allergic reaction is severe
• 5% of patients with aspirin allergies will have asthma attacks
• Should be avoided with viral infections, such as the flu and chicken pox, due to the risk of Reye's Syndrome
• Can delay childbirth and could cause premature closure of the ductus arteriosus on the fetus
• Aspirin can increase uricemia causing gout
• Reye’s Syndrome includes vomiting, lethargy, disorientation, and liver damage, especially in children
• Larger doses cause hyperglycemia and glycosuria
• Toxic doses cause increased oxygen uptake and carbon dioxide production, decreased lipogenesis, and increased lipolysis
• Effect on the endocrine system can cause increased corticosteroid production and displacement of plasma thyroid hormones

Aspirin: Pharmacokinetics

• Highly bound to plasma proteins
• Peak plasma concentration occurs in 1-2 hours
• Elimination half-life is 3-16 hours
• Rapidly absorbed and metabolized
• Hydrolyzed to acetic acid and salicylate by esterase
• Serum half life is 15-20 minutes
• Glucuronic and glycine conjugation produces salicyluric acid
• 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
• Higher urine pH enhances its excretion

Aspirin: Adverse Effects

• Salicylism occurs with ingestion of more than 50mg/dL
• These include ringing in ears, visual problems, nausea, vomiting, sweating, thirst, headache, confusion, dizziness, and hyperventilation
• Toxicity from heavy overdose includes severe metabolic acidosis, compensated for by respiratory alkalosis, respiratory depression, dehydration, fever, hallucinations, progressing to convulsions, coma, cardiac collapse, and respiratory failure
• For aspirin overdose, gastric lavage is used to limit absorption
• Restore acid-base balance, treat symptoms and consider hemodialysis
• Make urine basic to eliminate and maintain vital signs.

Aspirin: Drug Interactions

• Increases bleeding with warfarin and heparin
• Displaces methotrexate, sulfinpyrazone, tolbutamide, and some NSAIDs from plasma protein binding
• Blocks renal tubular secretion of sulfinpyrazone and probenecid, inhibiting their uricosuric effect
• Increases the toxicity of carbonic anhydrase inhibitors
• Blocks the natriuretic effect of spironolactone

Aspirin Preparations

• Buffered aspirin does not contain sufficient buffer to be useful
• Taking aspirin with water decreases irritation
• Enteric coated and timed released aspirin reduce stomach irritation but delays absorption
• Some formulations are gelcaps or liquids and are easier to swallow
• Caffeine added can increase efficacy

Acetaminophen

• Tylenol
• Phenacetin is a prodrug metabolized into acetaminophen, but it is too toxic
• Antipyretic and analgesic, but a weak anti-inflammatory agent
• Only prevents prostaglandin effects on the CNS due to the inhibition of COX-3
• Does not cause GI erosion or hyperacidity, nor does it increase bleeding time
• No effect on the cardiovascular or respiratory system
• In moderate doses, side effects may include rash and anemia

Acetaminophen Toxicity

• Relatively safe, with occasional allergies, rashes, or fever can occur
• At higher doses (>4 grams per day), metabolites are toxic to the liver and can lead to hepatic necrosis and renal toxicity
• Overdose can be treated by emesis lavage and oral administration of N-acetylcysteine (NAC)
• Cimetidine can inhibit cytochrome P-450 but does not interfere with NAC, making it potentially useful in acetaminophen overdoses
• Infants and alcoholics are more prone to overdose
• Infants have less ability to glucuronidate, while alcoholics experience glutathione depletion
• P450 inducing drugs can increase toxic metabolite formation
• High doses can cause nephrotoxicity

Headaches

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

Tension Headaches

• Tension, stress, or muscle contraction headaches
• 70% in males and 80% in females
• Mild to moderate intensity pain that doesn’t last more than 30 minutes
• Episodic (<15 days/month) or chronic (>15 days/month for 6 months)
• Bilateral, and nausea may occur along with chronic headache
• Feeling of pressure and tightness in neck muscles
• Treated with simple analgesics
• Acetaminophen or over the counter NSAIDs like aspirin, naproxen, or ibuprofen may be used
• If severe or persistent, consider anti-migraine medicines or more aggressive NSAIDs therapy

Cluster Headaches

• Extremely severe unilateral headache
• Pain in the areas around and above eyes
• Associated with redness of the eye, lacrimation, nasal congestion, forehead and facial sweating, contraction of the pupil, and puffy eyelid
• Attack lasts for 15 minutes to 3 hours in series, predominantly in men
• Treated with oxygen inhalation, Sumatriptan (imitrex) injections or nasal spray, Dihydroergotamine (migranal) injection or nasal spray, and Lidocaine (xylocaine) nasal drops
• Oral aspirin, naproxen, ibuprofen, and other NSAIDs are not effective

Migraine Headaches

• Unilateral throbbing headache
• Lasts from 4-72 hours (3-4 attacks per month)
• Signs and symptoms include nausea, vomiting, photophobia, phonophobia, and sweating
• Often stimulus triggers the attack, such as smoke, fear, pressure, and certain foods
• Physical activity aggravates pain and are therefore seen along generations
• 25% are classical migraines with an aura that precedes the attack with visual disturbances and hallucinations of light or sounds and loss of vision
• 75% are common migraines with no aura
• Cerebral vessels undergo vasoconstriction, then vasodilation
• Swelling then activates pain receptors along the trigeminal nerve
• Serotonin promotes vasoconstriction and interferes with pain transmission
• 5HT1b and 1D agonists can treat migraines
• Considered as a seizure-like attack since other seizures have auras
• Anti-seizure medications are being studied for migraine prophylaxis

Treatment of Migraines

• Based on severity, mild migraines can be treated with basic analgesics like NSAIDs, aspirin, or ibuprofen, with dimenhydrinate or metoclopramide often taken for nausea
• Treat moderate migraines with a combination of caffeine, acetaminophen, and aspirin (excedrin migraine) or ergotamine and triptans
• Treat severe migraines with triptans first, then analgesics
• Non-selective serotonin agonist are Ergotamine
• Dihydroergotamine is a more potent option that can cause Nausea, peripheral vasoconstriction, rise in blood pressure
• Triptans are 5HT-1D and 1B agonists
• Sumatriptan is 14% bioavailable and can be taken by SC (quick) or nasal spray (slow) with a short half life
• Longer acting options include Rizatriptan, naratriptan, zolmitritan with are more bioavailable
• Zolmitriptan is the most potent
• Naratriptan is longer acting (6 hours) and has less side effects

Triptans: Side Effects

• High BP/cerebrovascular hemorrhage
• Coronary vasospasm
• Pain in jaw, neck
• Light headiness, fatigue, pressure sensation
• Contraindicated with uncontrolled hypertension, prone to coronary artery disease, and pregnant women
• Do not combine with ergots, MAOI, or SSRIs

Preventing Migraines

• Beta blockers such as propranolol are used
• These are contraindicated in diabetics, asthmatics, heart block or failure, and pregnant women
• Calcium channel blockers such as verapamil is used
• They are contraindicated in hypotension, CHF, pregnancy, and arrhythmias
• Antidepressants such as amitriptyline are used
• Anticonvulsants such as valproic acid are used
• Anti-serotonergics medications such as methysergide are used
• These can cause extreme nausea, cramps, insomnia, weight gain, hypertension, and pulmonary fibrosis

Novel Migraine Therapeutics

• Antiepileptics such as Valproic acid are effective as prophylactic for 255% of patients
• Topirimate is also an effective as prophylactic
• Botulinum toxin injection and surgery can be done at trigger points