•Red : important
•Black : in male / female slides
•Pink : in female’s slides only
•Blue : in male’s slides only
•Green : Dr’s notes
•Grey: Extra information, explanation
Editing File
LECTURE 1:
NSAIDS
OBJECTIVES:
✓ To focus on the general mechanism of
action of NSAIDs.
✓ To outline the common
pharmacodynamic effects and ADRs of
NSAIDs.
✓ To classify NSAIDs on basis of their
specifity to COX enzyme.
✓ To detail on the pharmacokinetic
properties and pharmacodynamic effects
of selected NSAIDs.
NSAIDs Epidemiology
1. NSAIDs account for 3.8% of all prescriptions.
2. A significant quantity is sold over the counter (OTC).
3. Use increases with age
4. 90% of all NSAIDs prescriptions are issued to patients
at ages over 65 years.
5. NSAIDs is the most prominent risk for gastric
ulceration, hemorrhage and perforation.
6. The prevalence of NSAIDs-induced ulcers is 10% -
30%.
what are NSAIDs?
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are group of
drugs that share in common the capacity to induce the following
effects:
NSAIDs effects
Antipyretic Analgesic
Anti-inflammatory
(reduce fever) (painkiller)
Pyrogens (substances typically Prostaglandins + bradykinin
produced by bacteria or virus) and histamine at the site of
When there is an inflammation, the injury normally sensitize
Prostaglandins + bradykinin and stimulate formation of
Prostaglandins, which then pain sensors at the
histamine and 5HT “serotonin” nociceptors found at nerve
initiate the symptoms of increases the set point of the
thermoregulatory center in the endings to produce PAIN.
INFLAMMATION: (Redness, NSAIDs analgesics
swelling, heat, pain, and brain. This leads to
↑ heat production and ↓ heat mechanism: block PGs
sometimes loss of function). production.
NSAIDs anti-inflammatory dissipation (loss), resulting in
FEVER. Site of action: peripheral
mechanism: block PGs production tissue
Site of action: peripheral tissues NSAIDs antipyretics mechanism:
clinical uses:
block PGs production
clinical uses:
Site of action: CNS
clinical uses: • Headache, Migraine*
headache that affects one side
• Rheumatoid arthritis / Myositis*
Reducing fever back to of the head
inflammation and degeneration of
normal body temperature. • Dysmenorrhea* painful
muscle tissue.
menstruation and abdominal
• Common cold
cramps
• Dental pain (moderate pain).
Mechanism of action of NSAIDs:
Inhibition of CycloOxygenase (COX) enzyme which leads to the
inhibition of Prostanoids (Thromboxane,Prostacyclin, Prostaglandin) synthesis
which promotes inflammation, pain and fever. As a consequence, ongoing
inflammation, pain and fever are reduced < All actions and side effects are due
to this inhibition. (Corticosteroids inhibits phospholipase A2 and the formation of
arachidonic acid which produces the prostanoids)
Normal function:
COX 1 Constitutive 1- protects the mucosal lining
Homeostatic
“constitutive” of the stomach.
functions: 2-supports blood clotting
function of platelets
GIT, Renal
tract,platelet After taking NSAIDs
function,
macrophages
which inhibit COX-1:
differentiation They can cause ulcers in the
stomach and promote
Activ bleeding “undesirable effects”
a
IL-1, ted by
COX Isoforms
TNF
Inhib
i
gluc ted by IL
ocor -
ticoi 4,
ds
Normal function:
Causes inflammation and
pain
COX 2 “Induced”
“induced” Inflammation
After taking NSAIDs
which inhibit COX-2:
Pain & inflammation will be
reduced “desirable effect”
COX 3
found in the brain of
animals only.
Classification of COX inhibitors :
Type Example
Nonselective Aspirin, Diclofenac, Ibuprofen,
(inhibits COX-1&2) Naproxen
Selective COX-2 Coxibs
( inhibits only COX-2 )
Preferential COX-2 inhibitors Meloxicam
(Prefers inhibiting COX-2 more than
COX-1)
COX-3 inhibitors Paracetamol
ADRs ( Adverse drug reactions ):
Renal ADRs:
NSAIDs cause hemodynamically-
mediated acute renal failure.They
prevent the synthesis of PGE2 &
PGI2 by inhibiting COX-1 & COX- 2
leading to the prevention of
vasodilation, and reducing
GFR(Glomerular filtration rate).
COX-2 is found as a constitutive
isoenzyme in the kidney.
Diclofenac
Aspirin
Ibuprofen
Non
Ketoprofen selective cox Indomethacin
inhibitors
Naproxen Piroxicam
Aspirin (Acetylsalicylate): Non selective COX1/COX2 inhibitor
Mechanism of action
Aspirin binds with the active site of COX enzyme and makes it inactive
-acetylation- . (This process is irreversible) - Aspirin is the only one with that nature.
Pharmacokinetics
1. Higher dose of aspirin has a long plasma half- life.
Aspirin follows Zero-Order kinetics, which means a high dose of Aspirin will not be excreted which leads to
accumulation in the body causing toxicity
Low dose: t1/2 = 3h. Higher dose: t1/2 = 15h.
2. Metabolized by hydrolysis and then conjugation.
- Taking a salicylate “like aspirin” with antacid slows food absorption.
(Antacids reduce acidity of stomach leading to dysfunctioning enzymes hence there
will be slower food absorption)
Clinical uses
1. Acute rheumatic fever.
2. Reducing the risk of myocardial infarction (cardioprotective). Inhibition of
thrombosis formation. They prevent platelet COX-1, inhibiting TBA2 formation which is
essential for platelet aggregation.
3. Prevention of pre-eclampsia. ﺗﺳﻣم اﻟﺣﻣل
4. Chronic use of small doses reduce the incidence of colon cancer.
Contraindications ﻣواﻧﻊ اﻻﺳﺗﻌﻣﺎل
1. Peptic ulcer. 2. Patients taking Anticoagulants.
3. Hemophilic patients. 4. Children with viral infections.
(Reye’s Syndrome) 5. Pregnancy. 6. Gout (at small doses).
red box is important
At clinical dose
• Hypersensitivity
• Acute gouty arthritis.Because of uric acid retention.
• Reye's syndrome. Affects children with viral infection
who take aspirin.
• Impaired haemostasis. Bleeding
• GIT side effects, dyspepsia, nausea and vomiting
• Mucosal damage ---> hemorrhage
. Bronchospasm in aspirin- sensitive asthmatics
At overdose
1. Hyperthermia. The nutrients producing energy will be oxidized, but no ATP will be made so the
energy of bond formation will act as heat throughout the body. .
2. Gastric ulceration and bleeding.
3. Salicylism (Ringing of ear, vertigo). Treated by stopping the administration of Aspirin.
Diclofenac (voltaren) Non selective cox1 / cox2 inhibitor
Mechanism of action
nonselective COX-2 Inhibition It has activity for both COX-1 and COX-2 but
increased affinity for COX-2
Clinical uses
1. Analgesic.
2. Antipyretic.
3. Anti-inflammatory. Strong effect.
4. Acute gouty arthritis. remember, this is one of the adverse effects of low doses of aspirin.
5. Locally to prevent postoperative ophthalmic inflammation (solution). (eye drops)
for treating inflammation after operations on the eye. ophthalmic= related to the eye.
Preparation
selective cox-2 inhibitors (Coxibs): This
group of drugs of NSAIDs inhibit COX-2 selectively with
no effect on COX-1. Those drugs include:
Valdecoxib is
converted into
Rofecoxib
Celecoxib Paracoxib Rofecoxib
Etoricoxib Lumiracoxib *Valdecoxib
*It’s withdrawn because
of risk of myocardial
infarction and stroke
General action
1. Potent anti-inflammatory.
2. Antipyretic & analgesic.
3. Lower incidence of gastric upset.
4. No effect on platelet aggregation(COX-1) No cardioprotective effect.
General ADRs
1. Renal toxicity
2. Cardiovascular, do not offer the cardioprotective effects of nonselective
group (not anti-platelet) COX-2 is found only in endothelial cells where
Prostacyclin is found and Thromboxane is NOT found.
3. Dyspepsia & heartburn. it is not as potent as the one caused by COX-1
inhibitors
4. Allergy
Clinical uses
1. Short-term use in postoperative patients to reduce inflammation and increased
body temperature.
2. Acute gouty arthritis
3. Acute musculoskeletal pain (cause it’s potent anti-inflammatory).
4. Ankylosing spondylitis (inflammation in the joints of spine, leading to pain and
stiffness) (muscle pain)
contraindications ﻣواﻧﻊ اﻻﺳﺗﻌﻣﺎل
Shouldn’t be given to a patient with CV diseases
cox-2 inhibitors (selective, preferential):
Celecoxib Meloxicam,
Drug Nimesulide,
Nambumetone
P.K 1. Half-life 11 hours Half-life 20 hours prolong
2. Food decreases its effect
absorption (Not
given with food)
3. Highly bound to
plasma proteins
MOA Selective COX-2 inhibitor Preferentially inhibits COX-2
It is the best among over COX-1, particularly at
those inhibitors low dose it becomes
non-selective in the case of an
overdose
Indication - Used for Osteoarthritis and
rheumatoid arthritis
ADRs - Associated with lower GIT
symptoms and complains
compared to non-selective
COX inhibitors
Contradiction Contraindicated in -
patients with
Sulphonamides allergy.
More damaging Less damaging
Non selective, preferential COX-2 inhibitor, Selective COX-2 inhibitors
Paracetamol (acetaminophen): Cox-3 inhibitors
(does NOT belong to NSAIDs)
General features
1. COX-3 selective inhibitor.
2. Given orally, well absorbed.
3. t½ =2-4 h
4. Metabolized by conjugation at therapeutic doses.
5. Weak anti-inflammatory effect. It is not given in conditions associated with
inflammation.
Clinical uses
Commonly used analgesic antipyretic instead of aspirin in cases of:
1. Peptic or gastric ulcers
2. Pregnancy
3. Viral infections in children
4. Bleeding tendency
5. Allergy to aspirin
REMEMBER:
aspirin can’t be used in these cases.
1. An ADR of aspirin is peptic ulcer, therefore,
consuming it by patients who already suffer from
gastric ulcer will make it worse.
2. Can’t be used by pregnant women because of its
defects on the fetal cardiovascular system.
3. aspirin + kids with viral infections = Reye's
syndrome.
4. aspirin also causes impaired hemostasis and
leads to bleeding tendency.
5. it also causes hypersensitivity reactions.
Adverse Drug Reactions
ADRs
Therapeutic dose Large doses Chronic abuse
ADRs are mainly on liver, due
Elevate liver enzymes, to its active metabolite (N- Nephrotoxicity
No significant ADR. acetyl-p-benzoquinone
imine), which causes liver
damage
-Treatment of toxicity of paracetamol is by N- acetylcysteine to neutralize the toxic
metabolite. (This molecule binds to Paracetamol active metabolites before they reach
Sulfhydril ‘SH’ in tissues to cause cytotoxicity, N-acetylcysteine neutralizes the active
metabolite ‘N-acetyl-p-benzoquinone imine’ to stop that process.)
-Binding of paracetamol to COX is inhibited by peroxides produced in inflammatory sites,
there’s no evidence that COX3 exists in humans. Found in animals only.
QUIZ
QUIZ
1.A drug class that provide analgesic (pain killer) and
antipyretic effect (lower temperature) and have anti-
inflammatory effects. In addition, it’s called (non- steroid)
to distinguish from steroid drugs
2.Inhibition of Cyclo Oxygenase (COX) enzyme
3.Nonselective COX1/COX2 inhibitors
4.Small dose of aspirin.
5.Aspirin
6. GIT upsets ( nausea, vomiting) - GIT bleeding &
ulceration
7.Meloxicam
8. Preferentially inhibits COX-2 over COX-1
9.large doses of Paracetamol
10.N-acetylcysteine
GOOD LUCK
Team Leaders
Nouf Alshammari Zyad Aldosari
Team Members:
Reema Almutawa
Shahad Althaqeb
Najla Alkilani
Njoud Almutairi
Shahad Alsahil
Noura Almazrou
Sources:
Team 435
Team 437
