Leukotriene C4 and D4

Mediate airway inflammation, edema, bronchoconstriction, secretion of thick mucus 

Monteleukast and Zafirleukast

Alternatives for long term control of mild to moderate asthma

Not used for acute treatment; they reduce the incidence of attacks 

Zafirleukast will inhibit CYP2C9 and CYP3A4

Monteleukast does not interact with CYP450

Zileuton 

Alternative for long term control of mild to moderate asthma

The drug must be taken 4x/day -- poor adherence

Inhibits CYP1A9 and CYP3A4

AE: Flu like symptoms, GI upset, elevation of liver enzymes 

TXA2 synthesis in platelets is activated when the vessel is injured and platelets bind the endothelium

TXA2 causes aggregation -- COX1 major enzyme responsible

PGI2 released from endothelium inhibits aggregation - COX2 is major enzyme responsible

Thromboxane causes vasoconstriction and prostacyclin causes dilation

Consumption of omega 3 -- weaker forms of thromboxane, TXA3 - leading to decrease in strokes and heart attacks 

PGE2 and PGI2 cause vasodilation, particularly in elderly and those with renal insufficiency

Effect maintains renal blood flow and glomerular filtration 

Also will increase sodium and water excretion 

COX inhibitors disrupt the delicate balance possibly causing hypertnesion or even kidney failure 

PGE2 and PGI2 maintain patency of ductus arteriorus 

Vessel will close after birth but in preemies, might stay open 

Indomethacin or ibuprofen are two COX inhibitors that could be used to close a PDA 

In some cases of congenital heart problems, it may be necessary to maintain patency, while the patient is awaiting surgery -- this is done with alprostadil, a PGE1 analogue 

PGE2 and PGI2 cause arterial vasodilation in the lung to increase pulmonary blood flow 

PGI2 analogue - epoprostenol, is used to treat primary and secondary pulm HTN

Epoprostenol side effects: hypotension, flushing, headache, nausea, diarrhea

Other possible treatments: calcium channel blockers (nifedipine), supplemental O2, bosentan - endothelin antagonist, sildenafil (phosphodiesterase inhibitor) 

MOA: PGI2 analogue

AE: hypotension, flushing, headache, nausea, and diarrhea 

PGE1 causes vasodilation, which can be used to treat erectile dysfunction, by injection

Trimix (alprostadil, plus papaverine, and phentolamine)

PGI2 inhibits acid secretion and (PGE2 and PGF2a) stimulates mucus synthesis 

Also regulate contraction of longitudinal and circular muscles 

Misoprostol - PGE1 synthetic analogue - prevention of NSAID induced peptic ulcers

Misoprostol side effects: abdominal discomfort and diarrhea; contraindicated in pregnancy

Dinoprostone (vaginal gel or insert) is a synthetic preparation of PGE2 that induces labor by causing cervix to soften by increasing proteoglycan content and changing the biophysical properties of collagen -- promotes labor

Stimulating contraction of uterus

Also may be used as an abortifacent; may cause N/V/D 

PGF2a analog

Abortion in second trimester

Intramuscular injection 

Can cause vomiting and diarrhea 

Misoprostol - PGE2 analog used in combo with mifeprestone to produce early abortion

Mifeprestone terminates pregnancy by blocking progesterone receptors

Misoprostol works by expelling the fetus

AE: cramping pain and diarrhea

Adaptive: protecting the organism from injury or promoting healing when injury has occurred

Nociceptive pain

Inflammatory pain 

Maladaptive - expression of abnormal sensory processing - persistent/recurrent

Neuropathic pain or functional pain 

Constantly active

GI protection (PGI2) inhibits acid secretion and stimulates (PGE2 and PG2Fa) mucus synthesis

Platelets: TXA2 stimulates aggregation

Regulation of blood flow

Kidney function: prostaglandins cause vasodilation, balancing the effect of vasoconstrictors 

Inducible enzyme

Involved in inflammation, pain, and fever 

COX 1 selective: ketorolac

Relatively cox 1 selective: flurbiprofen

PGE2 thought to make terminal membrane excitability more exciteable

NSAIDs lead to decreased sensation of pain

Used for low intensity pain 

May be used in combination with opioids

Inhibits cyclooxygenase - thus decreasing prostaglandin production 

Prostaglandins cause vasodilation and increased permeability of post capillary venules, leading to edema

Rheumatoid arthritis 

Pyrogens - PGE2 in hypothalamus (cox-2) - raise temperature set point - fever

NSAIDs block action of pyrogens 

Does not affect temperature in normal healthy individuals 

Decreased risk of myocardial infarction and strokes (80 mg/day)

Aspirin is an anticoagulant - inhibits platelet aggregation 

Low intensity pain, reduces fever, anti inflammatory (325 - 650 mg)

Rheumatoid arthritis (1 g to 4 g/day)

Long erm uses at low doses lower incidence of clon cancer and possibly other cancers 

TXA2 in platelets enhances platelet aggregation -- PGI2 found in endothelial cells inhibits platelet aggregation 

Platelets can't resynthesize COX whereas endothelial cells can

Also used immediately after heart attack to prevent another infarction

Dose = 80 mg/day

Patient profile will determine appropriateness 

Readily absorbed from stomach (weak acid) or small intestine (more surface, salicylate more soluble) and widely distributed in all tissues (eg CSF, peritoneal cavity, synovial fluid) 

Bound to plasma proteins, therefore, aspirin can displace other drugs from these proteins and increase their toxicity - aspirin acetylates albumin

Deacylated in liver and plasma to yield salicylic acid (also an NSAID). Low dose (325 - 650 mg): 3 hours. High dose (1 g): 15 hours. 

Urinary excretion is pH dependent. Sodium bicarbonate increases urine pH and thus promotes excretion of salicylic acid (weak acid is charged at alkaline pH)

GI upset (bleeding, ulceration, and perforation)

Strong association between aspirin taken for viral illness and development of Reyes syndrome

Salicylism: too much aspirin

Acid base imbalance

Anticoagulant 

Renal failure in patients with chronic renal disease, congestive heart failure, or using diuretics

Gout (therapeutic levels decrease elimination; toxic levels increase uric acid elimination) 

AERD: increased to almost 20% in asthmatics; even higher in patients with asthma and polyps

AERD thought to be due to shift of arachidonic acid metabolism to leukotriene pathway

Another type of sensitivity is aspirin induced urticaria/angioedema due to histamine release 

True anaphylaxis is rare 

Uncouple oxphos/CO2 production -- respiration stimulated by increased CO2  --> respiratory alkalosis -- kidney excretes by making more bicarb

Hypokalemia, dehydration/fever

Large doses depress respiratory center -- leads to CO2 retention -- plasma bicarb already low --> respiratory acidosis

Superimposed on a metabolic acidosis due to build up of pyruvic, lactic, and acetoacetic acids and aspirin itself

Hypokalemia, fever/dehydration 

Therapeutic levels of salicylate <300 ug/ml

Mild moderate (500 - 700) oral or IV rehydration with attention to K levles

Marked signs/sx of salicylism >750: oral activated charcoal, simple alkalinization NaHCO3 over 2 hours (pH > 7.5), and hemodialysis if >1000, persistent/progressive acidosis, deteriorating consciousness 

Decreased blood volume: cirrhosis, nephrosis, heart failure, diuretics

Decreased blood flow: renal disease or cardiovascular disease

NSAIDs can cause too much vasoconstrictor response without enough vasodilation response --> acute renal failure 

Topical effect on stomach lining (minor) -- harmful H+ trapped in gastric mucosal cells

Systemic effect - inhibition of prostaglandin synthesis --> decreased gastric mucous secretion, increase acid secretion, antiplatelet effect

Mechanism: Reduces acid secretion

Side effects: diarrhea, constipation, abdominal pain, headaches, long term use may lead to stomach infections 

Motrin or Advil

Approximately equal to aspirin for relief of arthritic pain; lower frequency of GI irritation 

2400 mg/day is anti-inflammatory but lower doses have analgesic properties 

Concomittant use with aspirin may limit anti-inflammatory and anti-platelet effect

Cross allergy with aspirin

Naproxen also

Used for rheumatoid arthritis and osteoarthritis 

For moderate to severe arthritic pain

Drug is very potent COX inhibitor with significant GI toxicity

Reserved for gouty arthritis, ankylosing spondylitis, and osteoarthritis of hip

Patent ductus arteriosus, also ibueprofen

Sulindac is a prodrug related to indomethacin - side effects less severe 

only NSAID available for IM administration. also intranasal and oral

used for moderate to severe pain (post op pain) since it has analgesic potency equivalent to morphine

Not used as an anti-inflammatory

Short term use only 1-5 days

GI upset renal effects risk of bleeding -- do not use before surgery 

Gi distress less than with aspirin but still occurs

REnal problems with continued use, similar to aspirin

Cross reactive with aspirin in terms of allergy 

Analgesia: ketorolac > ibueprofen/naproxen > aspirin

Unlike aspirin, no effect on acid base or uric acid elimination

Unlike aspirin, the effect on platelet function is not long lasting 

1. relief of signs and symptoms of osteoarthritis and rheumatoid arthritis in adult patients

2. management of acute pain in adults

3. treatment of primary dysmenorrhea

4. management of FAP; to reduce the number of adenomatous colorectal polyps

Non anti-inflammatory

Is analgesic and anti-pyretic

Mechanism unknown: may inhibit COX III

Metabolized by cytochrome P450 Mixed function oxidase

Resulting benzoquinone imine normally reacts with glutathione to form non-toxic metabolite

Large doses deplete glutathione and the metabolite reacts with sulfhydryl groups in hepatic proteins causing necrosis

Rx: providing free SH groups --> N-acetyl cysteine 

Acetaminophen - 250 mg x 2

Aspirin - 250 mg x 2

Caffeine - 65 mg x 2

Currently up to 1000 mg/dose

Decrease to 650 mg/dose

Maximum 2700 mg/day

Use of excessive quantities of abortive or analgesic medications (>15 days/month)

Daily or near daily headaches that vary in severity, type, and location

Preditable, frequent, early morning 2 AM - 5 AM

Low pain threshold upon physical or cognitive exertion

Headahces accompanied by weakness, nausea, and other GI symptoms, restlessness, anxiety, irritability, mood, and cognitive defects 

Development of tolerance to analgesics