Nonsteroidal antiinflammatory

drugs

Analgesics-antipyretics
 Prostaglandins, thromboxanes,
leukotrienes, lipoxins)
is the name given to a
group of 20-carbon
unsaturated fatty acids,
derived principally from
arachidonic acid in cell
walls.
  Inflammatory stimulus
 matory stimul
Ex (+)
Phospholipids Phospholipase A2

In

Arachidonic acid
Cyclooxy genase (COX)

5-lipoxygenase 15-lipoxygenase- Endoperoxides

Leucotrienes Lipoxins
PGs TxA2
 Analgesics –Drug Against---- Pain

 Antipyretics - Drugs against fever

 Nonsteroidal antiphlogistics (NSAIDs) -

 Against inflammation, fever and pain
Non selective Cox Inhibitors
1. Salicylic acid derivatives-Aspirin
2. Aniline derivatives-Phenacetin
3. Pyrazolones derivative-Phenylbutazone.
4. Propionic acid derivatives-Ibuprofen
5. Acetic acid derivatives-Ketorolac
6. Fenamates-Mephenamic acid
7. Enolic acid or Oxicams derivative-
Piroxicam,
8. COX-2 preferential inhibitors-Nimesulide
9. Selective Cox 2 inhibitors-Celecoxib
10. Paraaminophenol derivative Paracetamol
A. Nonselective COX Inhibitors
 1. Salicylic acid derivatives
 Aspirin, sodium Salicylate, diflunisal
 2. Para-aminophenol derivatives
 Paracetamol
 3. Pyrazolone derivatives
 Phenylbutazone,azapropazone
 4. Indole acetic acid derivatives
 Indomethacin, sulindac
 5. Arylacetic acid derivatives-
Diclofenac, ketorolac, tolmetin
 6. Propionic acid derivatives
 Ibuprofen, fenoprofen,carprofen,
naproxen,ketoprofen,
flurbiprofen,oxaprozin
 7. Anthranilic acids (Fenamates)
 Flufenamic acidmefenamic acid,
enfenamic acid,meclofenamic acid

 8. Oxicams
 Piroxicam, tenoxicam, meloxicam
 9. Alkanones
 Nabumetone
 B. Selective COX-2 Inhibitors
 Nimesulide, celecoxib, rofecoxib,
valdecoxib, etodolac
 Cyclooxygenase (COX)
 is found bound to the endoplasmatic
reticulum.
 It exists in 3 isoforms:
 COX-1
 (constitutive) acts in physiological
conditions.
 COX-2
 (inducible) is induced in inflammatory
cells by pathological stimulus.
 COX-3
 (in brain).
 Duringinflammation,
arachidonic acid liberated
from membrane phospholipids
is converted to prostaglandins
(PGs), catalysedby the enzyme
cyclo-oxygenase (COX).
 NSAIDs inhibit the PG synthesis by
inhibiting the enzyme cyclo-oxygenase

 These prostaglandins produce

hyperalgesia – they sensitize the nerve
endings to pain caused by other mediators
of inflammation like bradykinin and
histamine.
• COX-1 – constitutive – prostanoids involved in
physiological processes (gastroprotective effects,
platelet activities)
• COX-2 – inducible– activity enhanced by
proinflammatory factors(IL-1, IL-2, TNF-,
oncogenes,..)
– prostanoids  inflammation, fever, pain
• COX-3 – central mechanism of analgesic and
antipyretic effect (localization: heart + CNS)
 Membrane phospholipides
Glucocorticoids
Phospholipase A2

Arachidonic acid
Inh. 5-LOX
NSAID
lipoxygenase
cycloxygenase
Leucotrienes
PROSTAGLANDINS
PROSTACYCLINS
TROMBOXANES

phagocytosis
endothelial permeability
inflammation inflammation
 General mechanism is COX-2 inhibition and their
effect in peripheral tissues:
 PAIN---PGE2and PGI2 increase nociceptors sensitivity to
bradykinin, histamine, serotonin and other pain
mediators

Inflamation-PG induces vasodilation and endothelial

permeability during inflammation

 Fever --PGE2 sets the body temperature onto higher

value in hypothalamus
 Effects
 Analgesic
 Antiphlogistic
 Antipyretic
 Antirheumatic
 Antitrombotic
 Myocardial infarction and stroke prevention
 Inhibition of platelets functions (antiaggregants)
 ASA (acetylsalicylicacid),
cholinsalicylate
Lysinsalicylate,
Diflunisal
( analg. and antiphlog. effect,
butm is not antipyretic),
 Salicylism (.) – hearing impairment, tinnitus, deafness,
vertigo
 Allergy - bronchospasm, itching, rash, anaphylaxis,
bronchoconstriction (LT)
 GIT - nausea, dyspepsia, bleeding, ulcer disease
 Nephropathy – reversible decrease of glomerular filtration
 Hepatopathy
Pregnancy- differs in trimesters
 Children- Rey‘s syndrome
 Elders- more sensitive
 Hemophilia and other diseases influencing
blood coagulation
 administration prior to surgery
 gastroduodenal ulcers
 gastritis
 children to 12 years
 Rey‘s syndrome (hyperpyrexia, acidosis, seizures,
vomiting, psichiatric disorders, hepatopathy)
 pregnancy (only temporary)
 asthma, allergy, nasal polyps
• Antipyretic 500 mg

• Analgesic 500 mg (4 - 6 hrs)

• Anti-phlogistic-rheumatic, - uratic 3–4

g/day

• Anti aggregative, Antiplatlet activity 30 –100 mg

 Paracetamol (acetaminophen)
Analgesic, antipyretic

• IS NOT ANTIINFLAMMATORY active!

• does not influence blood coagulation or uric
acid levels
• central mechanism due to COX-3 inhibition
• indirect effect on 5-HT3 spinal receptors
• elevates PGG2 to PGH2conversion in peripheral
tissues
Pharmacokinetics:
 Good absorbtion, maximum in 30-60 min, low
protein binding, hepatic metabolism
 production of hepatotoxic mtb.- binding to
gluthathione

 overdose(10-15g)
 antidote: N-acetylcysteine
 Allergy
 Hepatotoxicity after ↑ doses
 Comorbidities
 Alcoholaddiction
 Nephropathy
 Hepatopathy
 Phenylketonuria– aspartam as sweetener in paracetamol
preparations
 better tolerance!!!
 drug of choice to  fever and pain in
children younger than 12 years

 Pain in adults
 300 to 500 mg every 3-4 hrs
 650 mg every 4 to 6 hrs
 1000 mg every 6 hrs

 Total daily dose up to 4g

Phenacetin
 Analgesic, antipyretic
 Strong nephrotoxicity,
Phenylbutazon
 Good antipyratic effect, weak analgesic
 Accumulated in joints and effective
concentration persists for 3 weeks after last
dose

Propyphenazone
 less toxic
 in combinations (with paracetamole and caffein)
Ibuprofen
 Good analgesic and antipyratic effect
 Used often for acute pain therapy
 Low AE incidence, well tolerated NSAID,
indicated for children
EX--ketoprofen
flurbiprofen
naproxen
tiaprofenic acid – good penetration to
synovial fluid
Diclophenac
 Anti inflammatory, analgesic,
 weak antipyretic ef.
 bioavailability 30-70 %
 short biological halftime
 daily dose 50-150 mg
mild: cephalgia, insomnia, irritation, GIT
disorders, photosensitivity
Indications: muscle and postoperative pain,
cephalgia, gynaecology
 Acetic acid derivatives

Indomethacin
 very strong nonselective COX inhibitor
 toxic  short-time treatment of acute states
 urikosuric effects
 used in gout attacks
 GIT,cephalgia, depression, confusedness,
hallucinations, hematoxicity, cartilages destruction
 Sulindac
• prodrug– metabolite is 500x more potent
• adverse skin reactions
• Preferential Cox -2 Inhibitors

Aceclofenac.Diclofenic Nimusulide

• Has significant analgesic and anti-inflammatory

effect with good tolerance (low occurrence of GIT
adverse effects) - higher adherence to treatment of
chronic diseases
 N-fenylanthranil acid derivatives
 high efficacy
 high AE incidence – only for the treatment
of acute painfull states
E.g.Tolfenamic acid,mefenamic acid,
meclofenamic acid, flufenamic acid.
etofenamic acid
Piroxicam
 well tolerated even after chronic
administration
 20 mg daily

Meloxicam
 COX-2 more selective
 lower AE incidence
lornoxicam
 balanced blockade of COX 1 and 2

 good therapeutic efficacy

 profitable safety profile (lower occurrence of GIT

adverse effects – compared to other NSAIDs)
Nabumetone
 Prodrug, hepatic activation

Nimesulide
 scavenger
 inhibits enzymes (elastases,
collagenases) destroys cartilage
 Selective Cox 2 inhibitors
Adverse Effect :
 Celecoxib Thrombembolic
cardio and
 Parecoxib cerebrovascular
 Etoricoxib complications

 Rofecoxib
Increase of thrombembolisms
(myocardial infarction, strokes)
after chronic use
 Type A – Augmented – dose dependent
 GIT toxicity
 Nephrotoxicity
 Bronchospasm – after salicylates and other NSAIDs, (NOT
after paracetamol)
 inhibition of platelet functions
 Type B – Bizzare – non-predictable
 Allergy
 Rey‘s syndrome
 rash …
 because of COX-1 inhibition:
 GIT -  cytoprotective PGE2, PGI2
 erosions, ulcerations
 thrombocytes -  TXA : inhibition of thrombocytes
2
aggregation
 increased bleeding
 PGE , PGI regulation of renal functions
2 2
 renal failure
  LT production induces in predisposed people
bronchoconstriction
 asthma attack
 uterus -  PGE/F: inhibition of constriction
 prolongation and complications during delivery
 Dose reduction

 Combination with protective drugs

 Antiulcerotics– proton pump inhibitors (lansoprazole,

omeprazole)

 prostaglandine analogues (substitution)

 H2 antihistamines – (cimetidine, ranitidine, famotidine)

 antacids

 think about selective COX-2 inhibitors

1. NSAID
2. DMARDs + Biolog. therapy
3. Other antirheumatics
 steroid antiphlogistics (glucocorticoids)
 cytostatics and antimetabolites
 imunosuppressants
 proteolytické enzymy

Chronic therapy!
 chloroquine
antimalarics
 hydroxychloroquine

 antiphlogisticand immunomodulant
 leukocyte chemotaxis inhibition
 in milder forms of disease
 AE: skin symptoms, retinal impairment
sulfasalazine
 E. coli cleaves sulfasalazine in colon into
aminosalicylate (antiphlogstic) and sulfonamide
(antibiotic)
 gradual dose increase – effect onset in 1 – 2 months

Golden salts
 natrium aurothiomalate (i.m.), auranofin
(p.o.)
 inhibits
phagocytosis
 30-40 % AE: skin and mucosal changes,
hematopoesis impair, liver and kidney toxicity
Biologic therapy
 targeted effect on the immune cells involved in
rheumatoid artritis pathophysiology
 anti-TNF drugs:
 fast onset of effect, inhibition of progression, relaps after
withdrawal
 risk of infectious disease, CI live vaccines immunization
AE: GIT problems, weakness, BP changes, increased
risk of infections, allergy
infliximab
 recombinant monoclonal antibody
 create complexes with TNF-
 suitable for combination with methotrexate

etanercept
 recombinant protein from TNF receptor z subunit
and IgG1fragment
 binds to TNF-
1. Antiphlogistic steroids
 glucocorticoids
2. Cytostatics and antimetabolites
 methotrexate
 azathioprine
 cyclophosphamide
3. Immunosuppressants
 cyclosporin A
4. Proteolytic enzymes
 bromelain
 papain
 trypsin