NSAID Side Effects
Welcome to this video on non-steroidal anti-inflammatory drugs and their effects. Nonsteroidal anti-inflammatory drugs are most often referred to as NSAIDs [enseds]. NSAIDs have anti-inflammatory effects that are similar to those of steroids but without some of the serious adverse effects.
Indications for NSAIDS include:
- Mild to moderate pain
- Fever
- Various ophthalmic uses
- Primary dysmenorrhea
- Tendinitis and bursitis
- Ankylosing spondylitis
- Rheumatoid arthritis
- Juvenile rheumatoid arthritis
- Osteoarthritis
- and Gout, specifically acute gouty arthritis
Mechanism of Action
NSAIDs act by inhibiting the enzyme cyclooxygenase (COX). Cyclooxygenase enzymes include two isoenzymes:
- Cyclooxygenase 1 (COX-1) and
- Cyclooxygenase 2 (COX-2)
NSAIDs inhibit both COX-1 and COX-2 OR COX-2 alone.
Cyclooxygenase acts by converting arachidonic acid (which is released from phospholipids in cell membranes) to prostaglandins and related compounds, which are necessary to carry out many bodily processes.
COX-1 is found in tissues throughout the body where it has primarily beneficial functions, such as:
- Protecting gastric mucosa
- Supporting renal function
- Promoting platelet aggregation AND
- Promoting macrophage differentiation
Thus, inhibiting COX-1 does not relieve pain or inflammation.
COX-2, however, has primarily inflammatory functions.
COX-2 is active primarily at the site of injuries, where it mediates the inflammatory response, and in the brain, where it responds to injuries by:
- Promoting vasodilation (in inflammation)
- Sensitizing receptors to painful stimuli
- Mediating the fever response AND
- Mediating the perception of pain
Thus, inhibiting COX-2 relieves pain and inflammation.
However, in addition to the harmful processes, COX-2 also has some beneficial processes:
- Promoting renal function and perfusion, and
- Promoting vasodilation (preventing vasoconstriction)
Most first-generation NSAIDs are non-selective cyclooxygenase inhibitors, meaning that they inhibit both COX-1 and COX-2.
Some later generations are selective for COX-2 only.
The most commonly used NSAIDs are non-specific, especially the older drugs, such as:
- Ibuprofen
- Naproxen AND
- Indomethacin
Specific COX-2 inhibitors include:
- Celecoxib (Celebrex®)
- Meloxicam AND
- Diclofenac (a topical preparation)
Most NSAIDs are available by prescription, but some, such as ibuprofen and naproxen, are available in lesser doses over-the-counter.
So, what happens when COX-1 and COX-2 are inhibited?
Let’s look first at the effects of an NSAID on COX-1.
- Instead of protecting the gastric mucosa, ulceration and bleeding occurs
- Instead of supporting renal function, renal impairment occurs
- Instead of promoting platelet aggregation, anti-platelet action occurs AND
- Instead of promoting macrophage differentiation, macrophages develop a more inflammatory state
While most of the changes resulting from COX-1 inhibition are harmful, the anti-platelet action may be beneficial because it can reduce the risk of myocardial infarction and stroke.
This is the reason that aspirin (a first-generation NSAID) is usually avoided for control of pain and inflammation but used in low doses for its antiplatelet action.
Adverse Effects and Safety Guidelines
Now, let’s take a look at the effects of an NSAID on COX-2:
- Instead of promoting vasodilation, it causes vasoconstriction, which reduces swelling but also increases the risk of myocardial infarction and stroke
- Instead of sensitizing receptors to painful stimuli and mediating the perception of pain, it reduces pain
- Instead of promoting renal function and perfusion, it impairs renal function
Most of the adverse effects associated with NSAIDs result from COX-1 inhibition, especially their effects on the GI system. While most therapeutic effects result from COX-2 inhibition, selective COX-2 inhibitors also pose risks.
Some of the early COX-2 inhibitors, such as rofecoxib (Vioxx®) were taken off of the market because they doubled the risk of heart attack and stroke.
Adverse effects of NSAIDs may include:
- Gas, stomach pain, nausea, vomiting, gastric ulcers, GI bleeding, hemorrhage, or diarrhea
- Tinnitus and possible hearing loss
- Headache and dizziness
- Allergic reactions, sometimes as serious as anaphylaxis
- Acute renal failure
- Hepatic toxicity
- Heart failure, myocardial infarction, or stroke AND
- Altered hemostasis (that is associated with platelets)
A range of NSAIDs is now available in both nonspecific and COX-2-specific formulations. So, while one may be ineffective, another may be effective.
While aspirin is an NSAID, it differs from other NSAIDS in that its effects on COX-1 and COX-2 are irreversible. In other words, COX-1 and COX-2 remain inhibited until new COX-1 and COX-2 are synthesized.
The effects of other NSAIDs on COX-1 and COX-2 are reversible and decrease along with the blood titre.
Contraindications to the use of NSAIDs include:
- Pregnancy at 20 weeks or later (risk of low amniotic fluid)
- Breastfeeding
- Anticoagulant therapy
- Inflammatory bowel disease
- Uncontrolled hypertension
- Sensitivity to specific ingredients within the drug, and
- The preoperative period: generally NSAIDs should be avoided for one week prior to surgery to reduce the risk of bleeding
Additional contraindications include:
- A history of coronary artery bypass, transient ischemic attack, stroke, and heart disease
- A history of cirrhotic liver disease, heart disease, and renal disease
NSAIDs are the most commonly prescribed medications for pain and inflammation, accounting for up to 10% of all prescriptions. However, every year thousands of people die from adverse effects, most often GI bleeding,
Because some NSAIDs are inexpensive and available over-the-counter, people often view them as safer than they actually are.
It’s critical to stress the importance of following directions and limiting use to no more than 3 days for fever or 10 days for pain unless monitored by a physician.
Thanks for watching and happy studying!