NSAIDs
Non-Steroidal Anti-Inflammatory Drugs.
Prostaglandins
Tissue injury leads to arachidonic acid (AA) release. AA can either become prostaglandins via cyclooxygenase (COX), or leukotrienes via lipoxygenase (LO). These lead to inflammatory response.
COX-1
- Constitutive
- Found in stomach, intestines, kidney, platelets
- Regulates renal and gastric functions
- Inhibited by NSAIDs
COX-2
- Inducible
- Found in brain, kidney, prostate, uterus
- Expression enhanced by endotoxins and cytokines
- Upregulated by macrophages and synoviocytes
- Inhibited by glucocorticoids and NSAIDs
Because COX-1 has important regulatory and housekeeping roles, it is best to only block COX-2. However, most drugs also touch COX-1, although with lesser potency. There is a ceiling on the anti-inflammatory efficacy of NSAIDS, as they are all equivalently efficacious to aspirin.
Clinical pearl: Reye's syndrome
Children under 12 should not be given aspirin for viral infection as it has been show to increase their risk for this deadly condition, which includes brain inflammation.
NSAID chemical structure
They are carboxylic acids, meaning they exhibit a high plasma protein binding potential via albumin.
As inflamed tissue is acidic, the low pH allows the albumin-NSAID complex to dissociate, concentrating the NSAID within the inflamed site. Therefore, NSAIDS are retained longer in the synovial fluid than the serum.
The reason acetaminophen is a weak COX inhibitor is because it is a weak base, making it unwilling to accumulate.
Acute and Chronic Pain
Blocking the sensitization of the primary afferent C nerve fibers traveling to the brain is how
both NSAIDS and steroids reduce pain sensation.
There is an analgesic ceiling of aspirin at 600 mg. Important to note is that COX potency does not predict the analgesic ceiling. The analgesic properties and anti-inflammatory properties are different mechanisms. However, combination therapy with an NSAID and opioid will have a synergistic effect and "raise" the analgesic ceiling for both drugs.
Fever
During infection, the hypothalamus will reset core body temperature to a higher set point through a prostaglandin-mediated mechanism. As NSAIDs inhibit prostaglandin synthesis, they also inhibit prostaglandin-mediated temperature increase.
Through an unknown mechanism, acetaminophen has been shown to be an effective fever reducing agent as well.
Primary Dysmenorrhea
Painful menstruation mediated by prostaglandin induced uterine smooth muscle contraction. As NSAIDs inhibit prostaglandin synthesis, they also reduce the pain scores. Ibuprofen is the way to go with this one.
Post-Myocardia Infarction
This one is aspirin only.
In platelets, COX-1 is expressed at low levels for synthesizing thromboxanes (mediates platelet aggregation). Conversely, in the vascular endothelium, COX-1 and COX-2 are expressed for producing prostacyclins (mediates vasodilation).
Low-dose aspirin is an irreversible inhibitor of COX-1/2 in platelets because platelets lack nuclei. Without nuclei, the platelets can’t synthesize a new COX enzyme. Conversely, in endothelial cells, new COX enzymes can by synthesized and the effect will be transient.
All this to say, with low-dose aspirin, there is an inhibition of platelet aggregation without the vasoconstrictive effect. This is not seen with other NSAIDs. Therefore, low-dose aspirin is approved for prophylactic use in patients with unstable angina and prevention of myocardial infarction recurrence.
Patent Ductus Arteriosus
For more on the embryology, see here: Mesoderm - Cardiovascular > Clinical pearl Patent Ductus Arteriosus
After birth when prostaglandin levels drop, the ductus arteriosus is able to fully constrict and close. When prostaglandin levels don't drop, neonates with a patent ductus arteriosus can be treated with the NSAID indomethacin.
Side Effects
Cardiovascular
Longer bleeding time and vasoconstriction. Therefore, they are contraindicated for surgeries (pre and post) and acetaminophen is typically used. Aspirin especially is discontinued at least a week before surgery to reduce bleeding risk as it is irreversible.
Gastrointestinal
Can contribute to GI bleeding risk in chronic users, as well as ulcer development. NSAID-related GI bleeds are almost as frequent a killer as HIV.
Ulcer development comes from blocking of oxidative phosphorylation and mucosal proliferation. Decreasing prostaglandin/thromboxane synthesis also reduces the proliferation of gastric cells.
GI effects can be reduced by encapsulating the drug in an enteric coating or selecting a different NSAID based on its GI toxicity. Adjuvant therapies can also be used (histamine-H2 receptor agonists, Proton Pump Inhibitors, gel coatings, or prostaglandin analogs).
GI sparing therapies
Prodrugs keep the NSAID inactive until it is metabolized in the liver. Sulindac and Nabumetone are examples.
Additionally, COX-2 selective drugs are great in theory, but options are considered unsafe. Celecoxib can be used for arthritis and menstrual pain. Rofecoxib, by contrast, can lead to platelet aggregation and decreased vasodilation, forming clots/hypertension.
Renal
Lots of COX expression in the kidneys.
Prostaglandins vasodilate the arteries, bringing in more blood and increasing the glomerular filtration rate (GFR). In addition, prostaglandins will cause vasodilation in interstitial cells and increase secretion of water and salt (diuresis).
The most important consideration is that GFR is decreased by NSAIDs. This can result in edema and hyperkalemia.
Pregnancy
NSAID use is avoided as there is a higher risk of maternal/fetal bleeding. In addition, there can be decreased uterine contractions (prolonged labor) as well as premature closure of the ductus arteriosus.
Shunt Theory
Taking an NSAID that blocks COX will result in more AA being converted to leukotrienes which can lead to exacerbating hypersensitivity.
Acetaminophen is used as an alternative.
NSAID-Drug Interactions
As NSAIDs and Albumin are lovers, any drug that is also highly bound to Albumin can lead to unintended interactions. Taking an NSAID after the other drug will result in a transient elevation of the drug (as it pops off the Albumin).
Examples
- Oral hypoglycemics: Taking an NSAID will transiently elevate the oral hypoglycemics which will drop your blood glucose
- Phenytoin: Antiepileptic drug that has a high concentration in the plasma and has a narrow therapeutic window
- Methotrexate: Has a high concentration in the plasma and has a narrow therapeutic window
- Anticoagulants: Taking an NSAID will transiently elevate the anticoagulant and increase the risk of bleeding
- Lithium: Given for bipolar disorder. Concentration is high in the plasma. NSAIDs decrease GFR, impairing clearance and leading to lithium toxicity.
Pharmacodynamics
NSAIDs promote hypertension, offsetting antihypertensive medication (like beta-blockers or diuretics). This also promote anticoagulant action, increasing bleeding risk.
The solution to this is to avoid combination or adjust dosage.
Salicylates
Diflunisal
Stabilized form of Aspirin. Longer duration of action, greater efficacy, and longer half-life.
Aspirin
Depending on the dose of aspirin you get various half-lives because you will get a combination of liver metabolism and renal clearance. Low dose of aspirin follows first-order kinetics (liver), while high dose of aspirin follows zero-order kinetics (renal).
Signs of poisoning
- CNS Effects: Tinnitus, dizziness, nausea/vomiting, increased respiration (Respiratory alkalosis)
- Uncoupling Oxidative Phosphorylation: Decrease ATP production, increased CO2 production, increased heat production (paradoxical fever)
- Increased Carbohydrate/Fat Metabolism: Increased blood ketone bodies, metabolic acidosis
- Electrolyte Imbalance: Convulsions, CV collapse, coma
Treatment
Treatment involves alkalinizing the urine (using IV bicarbonate) since Salicylate is a weak acid. This facilitates the transport of Salicylate into the urine.
Acetaminophen
It gets metabolized by p450 enzymes into highly electrophilic compounds, which can make acetaminophen hepato-toxic.
Acetaminophen has an analgesic ceiling similar to Aspirin. Therefore, it is considered a safer alternative to Aspirin
Signs of poisoning
- Elevated serum transaminases
- Liver necrosis
Propionic Acids
Very effective as analgesics and anti-inflammatory.
Ibuprofen
Higher analgesic ceiling compared to aspirin-codeine combination, aspirin alone, and codeine alone
Ketoprofen
Higher analgesic ceiling than Aspirin and Naproxen, but has a shorter half-life
Naproxen
Higher analgesic ceiling than Aspirin and a longer half life
Acetic Acids
Used as anti-inflammatory drugs except for Ketorolac which has very strong analgesic effects.
Indomethacin
Very potent COX-1 blocker
Sulindac
Prodrug with a potential GI sparing effect.
Ketorolac
Very good analgesic effects, equivalent to morphine, but with a longer half-life. However, when given orally it is no better than Ibuprofen.
COX-2 Inhibitors
Similar analgesic effects as existing NSAIDs, but have GI sparing effects.