Download Nonsteroidal Anti-inflammatory Drugs

Nonsteroidal Antiinflammatory Drugs
• 1. Non selective drugs
• Salicylates e.g. Aspirin is the
prototype drug
• Mechanisms of action
• 1- Antiinflammatory
• A) Inhibit prostaglandines synthesis
through irreversible inhibition of
cyclo-oxygenase enzymes ( Cox-1 &
Cox-2).
• B) Interferes with the chemical
mediators of the kallikrein system.
Mechanisms of action
(cont.)
• B) Inhibits the migration of
polymorphonuclear leukocytes
to the site of inflammation.
• C) Anti-oxidant activity.
• D) Stabilizing lysosomes
2- Analgesics
• 1- For mild & moderate dull
aching pain as antiinflammatory
• 2- Inhibits pain stimuli at
subcortical site
3- Antipyretic
• 1- COX inhibition in the C.N.S.
• 2- Inhibition of IL-1
4- Antiplatelet
• Irreversible inhibition of platelet
COX
• Aspirin effect lasts 8-10 days (
life of platelets )
Pharmacological actions
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A) Analgesic
B) Antipyretic
C) Antithrombotic
D)Anti-inflammatory
E) Uricosuric ( large dos)
Clinical uses
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A) Analgesic
B) Antipyretic
C) Anti-inflammatory
D) Antithrombotic( cardioprotective)
E) Chronic gouty arthritis
F)Cancer pain in combination with
opioid drugs
Adverse effects
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At therapeutic doses
A) Gastric upset ( intolerance)
& gastric or duodenal ulceration
B) Gouty arthritis
C) Asthma, rashes
D) Hepatotoxicity & renal
toxicity are less frequent.
• E) Reye syndrome
High doses or Prolonged
use of aspirin
• A) Salicylism( tinnitus,vertigo,
decreased hearing).
• B) Hyperapnea
• C)Respiratory alkalosis
• D) Metabolic acidoses
• E) Hyperthermia
• F) Gastric & doudenal ulcer &
bleeding
• H) Glucose intolerance
Contraindications
• A) Pregnancy
• B) Haemophilic patients
• C) Hypersensitivity reaction to
aspirin
• D) Viral infections mainly in
children
• E) Peptic ulcers
Drug-Drug interactions
• Potentiates the gastric irritant
effect of alcohol
• Potentiates the hypoglycaemic
effects of oral hypoglycaemic
drugs
PARACETAMOL
• Is effective only as analgesic &
antipyretic.
• Has no antiinflammatory effect.
• Has no platelet effect.
• Can be used in patients with
haemophilia or peptic ulcer or
allergic to aspirin.
PARACETAMOL (cont.)
• Can be used during pregnancy.
• In children with viral infections.
ADVERSE EFFECTS
• Mainly on liver due to its active
metabolite ( N-acetyl-pbenzoquinone).
• At therapeutic doses increases
hepatic enzymes.
• At high doses causes hepatic
necrosis & renal necrosis.
• Treatment of paracetamol toxicity
with N-acetylcystine (SH donor ) as
life saving
2-Propionic acid
derivatives
• 1. Ibuprofen
• Pharmacokinetics
• Rapidly absorbed after oral
ingestion.
• Half-life 1-2 hours
• Highly bound to plasma proteins
• Excreted through kidney as
metabolites.
Ibuprofen
• The same mechanism &
pharmacological actions of
aspirin Except that it is
reversible inhibitor for COX
enzymes
• More potent as antiinflammatory
than aspirin
Clinical uses
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A) Analgesic
B) Antipyretic
C) Anti-inflammatory
D)Acute gouty arthritis
E) Patent ductus arteriosus
Preparations of
Ibuprofen
• Oral preparations.
• Topical cream for osteoarthritis.
• A liquid gel for rapid relief of
postsurgical dental pain.
• Intravenous route as In patent
ductus arteriosus
Adverse effects
• 1. Gastric upset ( less frequent
than aspirin ).
• 2. Fluid retention
• 3.Hypersensetivity reactions
• 4. Ocular disturbances
• 5. Rare hematologic
effects(agranulocytosis &
aplastic anaemia ).
Contraindications
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1. Peptic ulcer
2. Allergic patients to aspirin
3. Kidney impairment
4.Liver diseases
5.Pregnancy
6.Haemophilic patients
The concomitant administration of
ibuprofen antagonizes the irrevesible
platelet inhibition of aspirin( limit
cardioprotective effect of aspirin ).
Oxicam derivatives
• Piroxicam
• Tenoxicam
Piroxicam
• Mechanism of actions
• A) Non-selective inhibitors to
Cox1 & Cox2
• B) Traps free radicals
• C) Inhibits polymorphonuclear
leukocytes migration
• D) Inhibits lymphocyte function.
Pharmacokinetics
• Well absorbed orally
• Half- Life 45 hours
• Given once daily
Adverse effects
• Less frequent gastric upset
(20%) .
• Dizziness
• Tinnitus
• Headache
• Allergy
Acetic acid derivatives
• 1. Diclofenac
• Mechanism of action
• A) As aspirin ,but non-selective
inhibitor to cox1 & Cox2.
• More potent as antiinflammatory than analgesic
and antipyretics
Pharmacokinetics
• Accumulates in synovial Fluid
Clinical uses
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A) Any inflammatory conditions
B) Musculoskeletal pain
C) Dysmenorrhoea
D)Acute gouty arthritis
E) Fever
F) Locally to prevent or treat post
opthalmic inflammation
• G) A topical gel for solar keratoses
Adverse effects
• Gastric upset
• Renal impairment
• Elevation of serum
aminotransferase
• Salt & water retention
Preparations of
Diclofenac
• Diclofenac with misoprostol
decreases upper gastrointestinal
ulceration ,but result in diarrhea.
• Diclofenac with omeprazole to
prevent recurrent bleeding.
• .1% opthalmic preparation for
postoperative opthalmic
inflammation.
• A topical gel 3% for solar keratoses.
• Rectal suppository as analgesic or
for postoperative nausea.
Preparations of
Diclofenac
• Oral mouth wash.
• Intramuscular preparations.
Selective Cox2
inhibitors
• Advantages :
• 1. Highly selective inhibitors to
cox2 enzyme.
• 2. Potent anti-inflammatory.
• 3. Have analgesic& antipyretic
• 4. Highly bound to plasma
proteins.
Selective Cox2
inhibitors
• 5. Lower incidence of gastric upset
• 6. No effect on platelet aggregation
(cox1 )
• 7. Renal toxicities ( they are not
recommended for patients with
severe renal insufficiency)
• 8. High incidence of cardiovascular
thrombotic events with some of them
as rofecoxib.
Selective Cox2
inhibitors
• 9- They are recommended in
postoperative patients undergoing
bone repair.
• 10- Also, indicated in primary familial
adenomatous polyposis,
dysmenorrhea,
• Acute gouty arthritis, acute
musculoskeletal pain , ankylosing
spondylitis.
Celecoxib
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Absorption is decreased by food.
Half-life 11hours
Highly bound to plasma proteins
No effect on platelet aggregation
Metabolized in liver by CYP2C9 to in
active metabolite.
• Its clearance is decreased in liver
impairment.
• Given twice daily.
Clinical uses
• Rheumatoid arthritis
• Osteoarthritis
Side effects
• Dyspepsia & heart burn.
• edema & renal adverse effects.
• Allergy (skin rash ).
Drug interactions
• With warfarrin potentiate
its,through interfering with its
metabolism. actions
Meloxicam
• Relatively selective Cox2
inhibitors.
• Safer than piroxicam.
Pharmacokinetics
• Given orally ,rectally, I.M.,I.V.
• Metabolized in liver to inactive
metabolites.
• Excreted in urine 50% and in
feces 50%.
• Half-life 20 hours.
• Given once daily.
Clinical uses
• Analgesic
• Rheumatoid arthritis
• Osteoarthritis.
Adverse effects
• Gastric upset
• Skin rash
• Headache
Drug interactions
• Cholestyramine increases the
clearance of the drug .
Nabumetone
• Well absorbed orally.
• Metabolized in liver to active
metabolities.
• Half-life 26 hours.
• Taken once daily.
Clinical uses
• Rheumatoid arthritis
• Osteoarthritis
Adverse effects
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Gastric upset
Allergy (skin rash ).
Headache
Tinnitus
Pseudoporphyria
Photosensitivity
Slow acting anti-inflammatory
drugs(Disease modifying drugs ).
• 1.Used as a second line in
treating arthritis.
• 2.When the disease is
progressing & causing
deformties.
• 3. Can not repair existing
damage,but prevent further
injury.
Slow acting anti-inflammatory
drugs(Disease modifying drugs ).
• 4. Have no analgesic effects
• 5. Need weeks or months to act.
Hydroxychloroquine
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Mechanism of action
1. Suppress T lymphocytes
2. Decrease leukocytes action
3. Stabilize lysosomal activity
4. Inhibits DNA& RNA synthesis
5. Traps free radicals
Clinical uses
• Arthritis used in a large doses &
long duration
Adverse effects
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Nausea & vomiting
Cinchonism ( tinnitus.vertigo )
Irreversible retinal damage
Ototoxicity
Corneal deposits
Allergic skin reaction
Hepatitis
Methotrexate
• Mechanism of action
• 1. Dihydrofolate reductase
inhibitor
• 2. Immunosuppressive agent
Adverse effects
• 1. Nausea
• 2. Mucosal ulcers
• 3. Bone marrow depression
which can be reversed by
leucovorin.
• 4. Hepatotoxicity is dose
related.
Anti- TNF-alpha drugs
• Infliximab
• 1. Is a chimeric(25%mouse
&75%human).
• 2. Binds with high affinity to human
TNF-alpha.
• 3. Given as I.V. infusion
• 4. Half-life 8-12 days.
• 5. Given at 0,2,6 weeks followed by
intervals of rest 4-6 weeks.
Infliximab
• Improvement reaches up to 60%
• Can be used in combination with
methotrexate reduce the
prevalence of human
antichimeric antibodies.
Clinical uses
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Rheumatoid arthritis
Ulcerative colitis
Psoriasis
Psoriatic arthritis
Giant cell arteritis
Sarcoidosis
Adverse effects
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Upper respiratory tract infections.
Cough.
Nausea.
Headache.
Rash.
Activate latent tuberculosis
Infusion site reaction
Leflunomide
• 1. Immunosuppressive drug used
in the treatment of R.A.
• 2. Undergoes rapid conversion in
intestinal mucosa & plasma to
active metabolities.
Pharmacokinetics
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Orally effective
Half-life 15 days
Highly bound to plasma proteins
Cholestyramine increases its
clearance
Mechanism of action
• 1. Inhibits dihydroorotate
dehydrogenase which lead to
inhibition of ribonucleotide
synthesis & arrest the
stimulated cells in G1 phase.
• 2. Inhibits T cell proliferation &
production of autoantibodies by
β cells.
Mechanism ( cont.)
• Increase interleukin 10 receptor
• mRNA.
• Decrease interleukin 8 receptor
type A m RNA.
• Decrease TNF-α- dependent
NFkB
Clinical uses
• Rheumatoid arthritis
• Can be given with methtrxate
Adverse effects
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Diarrhea
Elevated liver enzymes
Mild alopecia
Weight gain
Increased blood pressure
Leukopenia & thrombocytopenia
Contraindicated in pregnancy
SulfASALAZINE
• MECHANISM OF ACTION
• Through its active metabolite
sulfapyridine &the parent drug
itself.
• Suppression of T cell .
• Inhibition of B cell proliferation
Pharmacokinetics
• Only 10-20% of orally
administered sulfa is absorbed.
• Fraction undergoes
enterohepatic circulation into
the bowel.
• Reduced by intestinal bacteria
to liberate 5-aminosalicylic acid
Pharmacokinetics
• And sulfapyridine which is well
absorbed while 5-aminosalicylic
remains unabsorbed.
• Excreted partly unchanged as
sulfasalazine in urine
• Sulfapyridine metabolized in liver by
acetylation &hydroxylation
• Half-life 6-17 hours.
Clinical uses
• Rheumatoid arthritis reduce the
rate of appearance of new joint
damage.
• Juvenile chronic arthritis
• Ankylosing spondylitis.
Adverse effects
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Nausea, vomiting
Headache
Skin rash
Hemolytic anemia
Methemoglobinemia
Reversible infertility in men
Neutropenia & thrombocytopenia
(rare)