Nonopioid Analgesics, Nonsteroidal

Anti-inflammatories, and Antigout

Drugs

CHAPTER 20
 Table of contents
01 03 05
MEDIATORS OF CLINICAL ADVERSE EFFECTS,
INFLAMMATION INDICATIONS TOXICITIES, AND
CONTRAINDICATIONS

02 04 06
ACTIONS OF NON-
DRUGS THAT SUPPRESS OPIOID ANTI- DRUGS USEFUL IN
INFLAMMATION INFLAMMATORY TREATING GOUT
ANALGESICS
 01
Mediators of inflammatory
The process of inflammation: normal response to injury.

● Tissue damaged → substances released →

vasodilation and increased permeability of
capillary walls → Pain receptors
stimulated, and proteins, fluid leak out of
the injured cells → Phagocytes migrate to
the area to destroy harmful substances.

● These effect result in redness, edema,

warmth, pain and loss of function.
 Prostaglandins
● Prostaglandins (PG) are mediators of the inflammatory response
and are formed in the cell membranes of most organs. Enzymatic
conversion of membrane phospholipids forms the parent of all
prostaglandins, arachidonic acid, which undergoes further
conversion through the enzyme cyclooxygenase to form G2 and
H2.
● Prostaglandins are capable of stimulating peripheral pain
receptors, constricting (PGE2) or dilating (PGF2α) blood vessels,
and elevating body temperature (fever PGE1), and contracting
(PGF2α) or relaxing (PGE2) smooth muscles of the bladder,
intestines, bronchioles, and uterus. Prostaglandin PGE2 is
involved in the production of erythema (abnormal redness),
edema, and pain that accompany the inflammatory process; PGF2α
is associated with uterine contraction and vasodilation.
 Cyclooxygenase

Cyclooxygenase (COX) is a family of enzymes

required to make prostaglandins from arachidonic
acid.
There are 2 types: COX1 and COX2.
COX-1 is believed to always be available in all
cells, especially in the platelets, kidneys, and
gastrointestinal tract, so that homeostasis in these
cells is maintained.
COX2 appears to be produced in activated
macrophages in response to local tissue injury or
damage.
 02
DRUGS THAT SUPPRESS
INFLAMMATION
 Classes of Anti-inflammatory Analgesics
● When the inflammation process become excessive or prolonged which result in further tissue
damaged. In this cases, inflammation itself becomes a disease process that must be treated
with drugs which inhibit the inflammatory response (anti-inflammatory).
● These drugs inhibit prostaglandin synthesis, restoring normal activity and reducing pain,
edema, and inflammation.
● These drugs are also known as nonsteroidal anti-inflammatory drugs (NSAIDs) because
they are not structurally related to cortisol (an adrenal steroid) and produce their anti-
inflammatory action via a different mechanism.
● Cortisone is a powerful anti-inflammatory hormone that is used to treat specific inflammatory
diseases when other nonsteroidal agents have failed.
● The site of inhibition distinguishes one class of anti-inflammatory drugs from another.
Steroidal anti-inflammatory substances (cortisol, hydrocortisone, prednisone) inhibit the
formation of arachidonic acid while NSAIDs selectively inhibit the cyclooxygenase enzymes
further along the pathway.
 Classes of Anti-inflammatory Analgesics
● Anti-inflammatory analgesics are classified into three types:
+ salicylates and aspirin (the original NSAID)
+ acetaminophen (a non-NSAID)
+ synthetic NSAIDs, Ex: ibuprofen (Advil) and celecoxib (Celebrex).
● The three groups within this class are distinguished by their predominant site of
inhibition within the prostaglandin pathway.
● NSAIDs can be used to reduce local inflammatory responses by interrupting PG synthesis
at two major locations, phospholipase A2 and cyclooxygenase. Older NSAIDs like
aspirin, ketoprofen, and indomethacin are nonselective- that is any COX will do, while
celecoxib (Celebrex) is a selective COX-2 inhibitor that alleviates pain and reduces
inflammation.
Classes of Anti-inflammatory Analgesics

All of the NSAIDs are referred to as nonopioid analgesics.

These analgesics relieve mild to moderate pain associated with
inflammation without affecting consciousness or mental
function. Nonopioid analgesics differ from opioid analgesics
Non-opioid in four ways. First, these analgesics are not chemically or
Analgesics structurally related to morphine (nor are they related to each
other by a common structure). Second, they are not effective
against severe, sharp (visceral) pain. Third, they produce
analgesia (pain relief) through both a central (central nervous
system [CNS]) and a peripheral (site of injury) mechanism of
action. Fourth, they do not produce tolerance or physical
dependency with chronic use.
 03
CLINICAL
INDICATION
NSAIDs are approved for use in adults for the relief of mild to moderate pain where opioids are not
indicated or warranted. This includes pain arising from local inflammatory responses, including
headache, dental extraction, soft tissue injury, sunburn, musculoskeletal, and joint overexertion and
strain.

NSAIDs also are indicated for the chronic treatment of dysmenorrhea (difficult or painful
menstruation) and for controlling the signs and symptoms of osteo- and rheumatoid arthritis.

Aspirin is not recommended for children, even for the management of fever. These anti-
inflammatory drugs are used in the treatment of a variety of chronic and intermittent inflammatory
conditions such as tendinitis, bursitis, rheumatoid arthritis, and osteoarthritis.

For the treatment of spondylitis (inflammation of the vertebrae), and gout, aspirin also can be the
drug of choice.
 04
Action of non-opioid anti-
inflammatory analgesics
Salicylates (Aspirin) and NSAIDS:
● The nonopioids anti-inflammatory anaglesics will be
presented in two parts: Salicylates and traditional
NSAIDs followed by acetaminophen.
● The salicylates, represented by aspirin and salicylic
acid.
● Salicylates were discovered centuries ago and are used
to relieve headaches and toothaches. They include
sodium salicylate (salicylic acid), aspirin
(acetylsalicylicacid), and methylsalicylate. Salicylic
acid is the active ingredient in OTC products and
NSAIDs are available OTC and by prescription.
 Antipyresis and Analgesia:

● The centers of the brain that regulate pain and ● Produced by affecting both the
temperature are located in the hypothalamus. hypothalamus and the site of injury.
● Bradykinin, prostaglandins, and histamine
● The mechanism of the central action involves
are examples of active chemicals that are
blockade of prostaglandin stimulation of the CNS. released.
● For the relief of fever in adults, aspirin is still a ● Aspirin is the most potent inhibitor of
drug of choice. COX in the salicylate group.
 Anti-inflammation action:
● All NSAIDs and salicylates are excellent anti-inflammatory drugs due to their inhibition of COX-1 and COX-2 of
pathways in PG synthesis.
● NSAIDs may be used for short periods (up to 7 days) for the relief of acute inflammation.
● In osteoarthritis, Sulindac (Clinoril), tolmetin (Tolectin), meclofenamic acid (Ponstel), meclofenamate (Meclomen),
piroxicam (Feldene), and celecoxib (Celebrex) are anti-inflammatory drugs used in the treatment.
● Several NSAIDs, including indomethacin (Indocin), naproxen (Naprosyn), sulindac (Clinoril), and aspirin are also
used in the management of gout.
 Anticoagulant and Cardiovascular Benefit
Anticoagulant
● Aspirin and salicylamide irreversibly inhibit the
aggregation of platelets necessary for blood
clot formation.
● Low dose aspirin has been used as a blood
thinner to prevent clots after cardiac bypass
surgery and surgery for clogged coronary
arteries.
Cardiovascular Benefit
● Aspirin has been used for decades to prevent
atherosclerotic cardiovascular disease
(ASCVD) by inhibiting platelet function,
reducing risk of blood clots in the blood
vessels, but at the risk of bleeding in the GI
tract.
 Gastrointestinal Effects:

● Many people are sensitive to this action and

experience nausea after taking aspirin.
● In some individuals, vomiting occurs as a result
of GI irritation and CNS stimulation.
● All anti-inflammatory drugs may produce
nausea, GI distress, and ulceration.
 Drug Preparations and Disposition:
Aspirin and NSAIDs:

● Aspirin has become widely accepted as safe for use in adults.

● Available in a variety of oral formulations ranging from tablets, capsules, and gum to solutions and liquids.
● Because of the incidence of Reye’s syndrome occurred, FDA, Pediatric Academies, and the surgeon general
proposed that aspirin not be given to children under 12 years of age as a preventative measure
● Only ibuprofen (Advil), naproxen (Aleve, Midol Extended Relief), and ketoprofen (Nexcede) are currently
available OTC.
Drug Disposition:
● Salicylates and NSAIDs are
fast-absorbing acids.
● Drugs exert their analgesic
action within 30 minutes, with a
4- to 6-hour duration of action.
● They can be administered with
meals, especially in patients
who are susceptible to gastric
irritation.
 Clinical Indications:

● Ibuprofen, naproxen, and aspirin OTC are used for fever reduction and in mild to moderate pain.
● Aspirin or aspirin-containing products should not be taken during pregnancy or by children for fever during viral
illnesses.
● Low-dose aspirin (50–100 mg daily) reduces the risk of developing myocardial infarction, transient ischemic attacks
and stroke.
 Acetaminophen:
● Acetaminophen is often considered an aspirin substitute.
However, this assumption is not entirely correct.
● Acetaminophen (Panadol, Tylenol) produces adequate analgesia
for the relief of a minor headache and antipyresis but has no anti-
inflammatory activity.
● Acetaminophen is effective for headache, but not for muscle
aches and inflammation, especially arthritis.
● Acetaminophen does not produce GI irritation or ulceration.
● No benefit has been associated with the use of this drug in stroke
or infarction.
Clinical Indications:

● Acetaminophen is approved to reduce fever, headache, minor

musculoskeletal pain, and discomfort associated with the common cold and
flu in adults and children.
● It is particularly indicated for use in patients allergic to aspirin, those
receiving anticoagulant therapy for coagulation disorders, or patients who
have upper GI disease and for whom aspirin therapy is not an option
● It is not interchangeable with these products for chronic therapy of
inflammatory conditions such as osteoarthritis.
Dose and Formulation Availability
● Acetaminophen is available in OTC products in doses ranging from
pediatric doses to 650 mg per tablet, capsule, or caplet. The recommended
adult doses are 325 mg every 4 hours or 500 mg every 8 hours.
● As of 2011, acetaminophen intended for infants or older children will be
supplied as a standard concentration of 160 mg/5 ml.
● Because of its acceptability for use in children, acetaminophen is available
in a variety of formulations ranging from suppository to solution, elixir,
suspension, and syrup. At all doses and formulations, acetaminophen is
available without prescription, OTC.
 Special Considerations: Dose Changes
and Hepatotoxicity
● Acetaminophen is used in more combination products than any other drug in
doses from 160 to 500 mg per dose. It has been estimated that one-third of the
people in the United States take acetaminophen in some form at least once a
month.
● The excessive use of acetaminophen causes metabolites of the drug to bind to
tissue groups in the kidney and liver, causing hepatotoxicity.
● Safety information and dose recommendations are directed to the attention of
the consumer/patient, not just medical personnel. The FDA is promoting a
“Don’t Double Up on Acetaminophen” campaign through the Consumer
Update on its website
 05
ADVERSE EFFECTS,
TOXICITIES, AND
CONTRAINDICATIONS
 01 02 03

Adverse effect Toxicities Contraindication

 Adverse effects and Boxed Warnings:
- Common adverse effects associated with anti-inflammatory drugs are vertigo, vomiting , mental
confusion, and head-aches.
- All NSAIDs may produce nausea, GI distress, and ulceration. The most serious effects with chronic use
are ulcers and bleeding, kidney or liver failure.
- Acetaminophen- its most serious side effect is liver damage
 Gastrointestinal Effects of NSAIDs:
- Gastrointestinal effects can range from superficial mucosal irritation to the most significant effect- ulceration
- Ulceration can lead to GI bleeding and perforation of the stomach/ intestines
- Occur at any time during use and without warning symptoms, especially elder patients
- To minimize GI side effect, medication should be taked with meals, milk,…
- Alcohol should be avoided because of increasing the side effect of drug
BOXED WARNING: The term NSAID and recommendations must be highlighted on the front label of every
product. Some cases need carefully when taking a medicine:
-Aged 60 years or older
-Taking other drug: NSAID, blood thinning, steroid,…
-Frequently have alcoholic drinks
Cardiovascular effects of NSAIDs:
Boxed Warning:
-In nonaspirin NSAID may cause an increased risk of serious cardiovascular thrombotic events,
myocardial infarction, and stroke
-The risk can occur as early as the first weeks of using an NSAID.
- Patients with cardiovascular disease/ risk factors for cardiovascular disease may be greater risk
Hypersensitivity and Allergic Effects of
NSAID:
-Hypersensitivity to aspirin may produce skin rashes, laryngeal edema, and asthma
- Hypersensitivity reactions may include mild mild rashes, fever, hepatic damage, and respiratory distress
in asthmatic individuals
-All NSAIDs may produce serious side effects such as exfoliative dermatitis and Steven’s Johnson
syndrome
Hematologic Effects of NSAIDs:
-Megaloblastic anemia, signaled by large, immature red blood cells, has occurred with these drugs
because the intestinal absorption of folic acid has been impaired.
-Adverse effects are more likely to occur in patients receiving large doses in the chronic treatment of
arthritis, especially rheumatoid arthritis.
 TOXICITY
Acetaminophen: has reported that 66% of OTC overdose events
-Occur as a result of accidental ingestion of large amounts of drug
-Within 36 hours of ingestion of a toxic dose, hepatic damage may result
-Hepatic serum enzymes may rise ( SGOT, SGPT, billirubin, thrombin), elevation of SGOT may exceed 20,000
Salicylates and NSAID: has reported that 15% of OTC overdose events
-The dangerous and often fatal reactions of acute poisoning involve respiratory depression and acidosis
-The acute lethal dose of aspirin is estimated to be 10 to 30g for aldults and 4g for children
TOXICITY
Chronic Toxicity: GI and CNS Effects
-Large-dose therapy is more frequently associated with nonlethal toxic reactions
-Salicylism is a series of symptoms that include nausea, ringging in the ears (tinnitus),
headache, delirium and hyperventilation.
-Many foods are known to contain salicylates naturally, such as curry powder, paprika, licorice,
tea,…
Contraindications
-Children and teenagers should never given salicylates for chickenpox or flu symptoms before
a doctor is consulted because of the possibility for Reye’s syndrome to occur
-The syndrome has ocurred most in children 1 to4 and 10-14 years old and seems to diminish
after 18 years old
 06
DRUGS USEFUL IN
TREATING GOUT
Gout:
- A special inflammatory disease. It is associated with the deposition of uric acid in joint fluid
and soft tissue.
-Uric acid is formed every day from the metabolism of nucleic acids by the liver. If the liver
produces 80 percent of daily uric acid which increases the uric acid level of blood
(hyperuricemia).
-Humans cannot use uric acid, so it is normally secreted into the urine by the renal tubules. A
condition of hyperuricemia occurs above 7 mg/dl blood
-Hyperuricemia can be either primary or secondary
Mechanism of Gout:
Phagocytes (nucleophils, white blood cells) enter the area and attack the uric acid crystals, and this
activity leads to a decrease in pH (acid) of the joint fluid, causing more uric acid to accumulate in
the joint. This vicious cycle of inflammation produces the edema, redness, and severe pain
characteristic of acute gout. In chronic gout, uric acid slowly deposits in soft tissue, causing bulging,
deformed joints known as tophi.
Treatment
Colchicine: not a general anti-inflammatory drug for the relief of other forms of muscle and joint pain. It
is anti-inflammatory in the specific condition of acute gout. A new colchicine product, Colcrys, was
approved to treat acute gout flares as well as for prophylaxis.
Indications: extremely useful during the first 48 hours of an acute attack.
Prophylactic therapy involves the long-term use of drugs to prevent the occurrence of gouty attacks and
tophi.
There are 2 major drug classes have been used in long-term prophylaxis: hypouricemic agents and
uricosuric agents. There is now a new class and new drug, pegloticase (Krystexxa) for the treatment of
refractory gout.
Drugs
Allopurinol:
Drug class: xanthine oxidase inhibitors. It works by reducing the production of uric acid in the body.
Therefore, no uric acid is formed, and hypoxanthine is excreted into the urine. Eventually, the uric acid
in the blood decreasesdevelopment of tophi and urate stones in the kidneys.
Drugs
Febuxostat:
Drug class: xanthine oxidase inhibitor.
It is used for the chronic management of hyperuricemia in patients with gout.
More potent than allopurinol.
Indications: once-daily oral medication is effective at 40 and 80mg/ day
Febuxostat is not recommended for use in patients with secondary hyperuricemia.
While not contraindicated in patients with myocardial infarction and stroke, it is recommended that patients be
monitored while on febuxostat.
 Review
question

1. C
2. B
3. A
4. D 9. C
5 .B 10.D
6. B 11. E
7. D 12. B
8. B 13. C
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