Anti-inflammatory drugs

Classification

I group: Nonsteroidal anti-inflammatory drugs (Nonsteroidal ntiinflammatory )

(NSAIDs)
A-non- selective NSAIDs
1) Salicylates: acetylsalicylic acid
2) Pirazolone and pirazolidine derivates: fenylbutazone
3) Indolacetic acids: indomethacin
4) Arhylacetic acids: diclofenac
5) Propionic acids: ibuprofen,
naproxen
6) Fenamates: mefenamic acid,
flufenamic acid
7) Oxicam derivatives: piroxicam,
meloxicam,
lornoxicam
8)Paraaminophenols derivates: paracetamol
B-selective NSAIDs
Nimesulid
meloxicam
celecoxib
II group: Steroid anti-inflammatory drugs:
Glucocorticoids: hydrocortisone,
prednesolone,
dexamethasone,
prednisone
III group: Slow-acting , anti-inflammatory drugs:
a) 4-aminoquinoline derivatives: chloroquine
hydroxichloroquine
b) Gold-salts: auranofin, gold sodium thiomalate, aurothioprol.
c) D-Penicillamine
d) Sulfanilamide drugs: sulfasalazine
e) Cytostatics: methotrexate
azathioprine
cyclosporine
mercaptopurine

Nonsteroidal Antiinflammatory

Mechanism of action: Cyclooxygenase , the enzyme that converts arachidonic

acid into the endoperoxide precursors of prostaglandin, (COX) has two isozymes:COX1, a constitutive form present in stomach and kidney; and COX-2, which is induced in
inflammatory cells in response to appropriate stimuli. Presently available NSAIDs
(Nonselective) inhibit both isozymes. The search for COX-2-selective agents (Celecoxib,
Rofecoxib) is intensifying because, in theory, these thought to be tolerated better.
Inhibition of COX1 explains antiinflammatory, analgesic, antipyretic effects, but
inhibition of COX2 determine some unwanted effects like:
Gastrointestine disturbance (ulcer, hemorrhages) ,renal effects ( acute failure,
interstitial nephritis) , and frequent can be allergic reactions.
Thease drugs are competitive antagonist with arachidonic acid for the enzyme.
Pharmacological effects:
1. antiinflammatory effect.
because these drugs inhibit COX activity, they decrease (diminishes) the formation
of prostaglandins and thus modulate those aspects of inflammation in with
prostaglandins act as mediators (inhibit II phase of inflammation).
2. analgesic effect:
Prostaglandin E2 is thought to sensitize the nerve endings to the action of
bradykinin, histamine, and other chemical mediators released locally by the
inflammatory proceses. Thus, by decreasing PGE2 synthesis these drugs repress
the sensation of pain.
3. antipyretic effect:
Fever occurs when the set-point of the anterior hypothalamic thermoregulatory
centre is elevated. This can be caused by PGE2 synthesis. The salicylates lower
body temperature in patients with fever by impeding PGE2 synthesis and release.
Aspirin produces peripheral vasodilatation and sweating, but it has no effect on
normal temperature.
4. antiaggregant effect:
aspirin can irreversibly inhibit thromboxane production in platelets without
markedly affecting TXA2 production in the endothelial cells of the blood vessels
(reversibly).
5. antiallergic action:
they inhibit immigration of T lymphocytes, eozinophils, neutrophils, in foci of
inflammation.
Pharmacokinetics.
NSAIDs are well absorbed enterally .They have high absorption and bioavailability. Halflife is short(2-4 hours), with some exceptions, (piroxicam-31-57 hours, flufenamic acid- 9
hours, naproxen-15-19 hours, indomethacin 5-10 hours, phenylbutazone-5-10 hours.
All drugs bind with plasmatic proteins, are metabolized in the liver and are eliminated by
urine. They are highly bound to plasma proteins. They are eliminated at different speeds:
diclofenac (t1/2 = 12 h) and piroxicam (t1/2 ~ 50 h); thus, dosing intervals and risk of
accumulation will vary. The elimination of salicylate, the rapidly formed metabolite of ASA,
is notable for its dose dependence. Salicylate is effectively reabsorbed in the kidney, except
at high urinary pH. A prerequisite for rapid renal elimination is a hepatic conjugation
reaction, mainly with glycine (! salicyluric acid) and glucuronic acid. At high dosage, the
conjugation may be come rate limiting. Elimination now ncreasingly depends on unchanged
salicylate, which is excreted only slowly.
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Indications:
neuritis, allergic syndrome, headache, toothache, muscle rheumatic fever, pain,
dysmenorrhea, rheumatic arthritis, gout, osteoarthrosis, thrombosis prevention,
collagen diseases .
Contraindications for Nonsteroidal Antiinflammatory:
Absolutely
Relatives
1. gastric ulcer or duodenitis
1. gastric ulcer in anamnesis
2. allergy
2. digestive hemorrhages in anamnesis
3. hemorrhages
3 renal disease in anamnesis
4. severe renal failure
4. hepatic failure
5. pregnancy (I-II trimesters)
5. asthma
6. in children
6. mental dysfunction, epilepsy
7 parkinsonism

Side effects:
Group-specific adverse effects can be attributed to inhibition of cyclooxygenase. The
most frequent problem, gastric mucosal injury (gastric ulceration, irritation of gastric
mucosa, gastritis, errosis) with risk of peptic ulceration, results from reduced synthesis of
protective prostaglandins (PG), apart from a direct irritant effect. Gastropathy may be
prevented by co-administration of the PG derivative, misoprostol. In the intestinal tract,
inhibition of PG synthesis would similarly be expected to lead to damage of the blood
mucosa barrier and enteropathy. Other unwanted effects are edema and a rise in blood
pressure. Moreover, drug-specific side effects deserve attention. These concern the CNS
(e.g., indomethacin: drowsiness, headache, disorientation), the skin (piroxicam:
photosensitization), or the blood (phenylbutazone: agranulocytosis).
Actions on the kidney (in big doses) :
PGE2 and PGI2 are responsible for renal blood flow. PG also regulate renal blood flow as
functional antagonists of angiotensin II and norepinephrine. If release of the latter two is
increased (e.g., in hypovolemia), inhibition of PG production may result in reduced renal
blood flow and renal impairment. Decreased synthesis oh prostoglandines can result in
retention of sodium and water and may cause edema, hyperkalemia in some patients.Also can
be: interstitial nephritis, nephrotic syndrome with proteinuria, big edemas, hypertension.

hepatotoxic action (immuno-allergic hepatitis)

Cutaneous: 10-15% after 1-3 weeks
- skin eruptions
- urticaria
- photosensibilization
- toxico-dermia, pemphigus
CNS deregulations 6%-headache, vertigo, dizziness, somnolence or insomnia,
hallucinations.
Indomethacin is deposited in cornea and can produces visual deregulations
hemathopoetic
deregulations: anemia, thrombocytopenia, leucopenia, agranulocytoses.(metamisol)
decrease masculine fertility
theratogenic effect (malformations)
respiration- respiratory depression, In predisposed patients, asthma attacks may occur,
probably because of a lack of bronchodilating PG and increased production of leukotrienes.
Because this response is not immune mediated, such pseudoallergic reactions are a potential
hazard with all NSAIDs.
Hypersensitivity: 15% of patients have hypersensitiv reactions. (urticaria, bronchoconstriction,
angioneurotic edema. Fatal anaphylactic shock is rare).
Aspirin given during viral infections can produces fulminating hepatitis with cerebral edema.
(Antirheumatic) Agents At relatively high dosage (>4 g/d), ASA may exert
antiinflammatory effects in rheumatic diseases (e.g., rheumatoid arthritis). In this dose range,
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central nervous signs of overdosage may occur, such as tinnitus, vertigo, drowsiness, etc. The
search for better tolerated drugs led to the family of nonsteroidal antiinflammatory drugs
(NSAIDs). Today, more than 30 substances are available, all of them sharing the organic acid
nature of ASA. Structurally, they can be grouped into carbonic acids (e.g., diclofenac, ibuprofen,
naproxene, indomethacin or enolic acids (e.g., azapropazone, piroxicam, as well as the longknown but poorly tolerated phenylbutazone). Like ASA, these substances have analgesic,
antipyretic, and antiinflammatory activity. In contrast to ASA, they inhibit cyclooxygenase in a
reversible manner. Moreover, they are not suitable as inhibitors of platelet aggregation. Since
their desired effects are similar, the choice between NSAIDs is dictated by their pharmacokinetic
behavior and their adverse effects. Salicylates additionally inhibit the transcription factor NFKB,
hence the expression of proinflammatory proteins. This effect is shared with glucocorticoids and
ibuprofen, but not with some other NSAIDs.
Slow-acting , anti-inflammatory drugs:
Gold-salts- They can not repair existing damage. They can only prevent further injure. It
is believed that gold salts are taken up by macrophages and suppress phagocytosis and lysosomal
enzyme activity. This mechanism retards the progression of bone and articular destruction. Also
they inhibit antibody production by B-lymphocites.
Indications; Rheumatoid arthritis, rheumatoid polyarhtritis and psoriatic arthritis
Contraindication:
1. severe hepatic diseases
4.
hemathologic disturbances
2. nephritis
5.
exema and dermatitis
3. cardiac failure
Side effects:
1. nephrotic syndrome: proteinuria, hematuria,
2. thrombocytopenia, leucopenia, anemia
3. stomatitis, enterocolitis, hepatitis, pulmonary infiltrations
4. erythematous eruptions

4-aminoquinoline derivatives: chloroquine, hydroxichloroquine

The mechanism of action of this drugs is unknown, It is propose some theories:
1. they stabilize lysosomal membranes and trap free radicals
2. they inhibit blastransformation of T lymphocytes.
3. inhibit collagen synthesis
Indications:
1. rheumatoid polyarhtritis in children and adults.
2. malaria
3. scleroderma
4. lupus erythematous
5. other collagenosis.
6. hepatic amebiasis
Contraindications:
1. pregnancy
2. psoriasis
3. retinopathy
Side effects:
1. dyspepsia
4.
thrombocytopenia
2. skin eruptions
5.
visual deregulations.
3. leucopenia
D-penicillamide:
Mechanism of action: -it interacts with rheumatoid factor and inhibits its synthesis
2. it inhibits collagen maturation
3. cytostatic action (it binds with bivalent metals: Cu, Zn, Mg, I and inhibits protein synthesis)

Indications:
1. rheumatoid polyarhtritis (severe
3. intoxications with heavy metals
forms)
4. hemolytic disease in newborns
2. Wilson disease ( liver degeneration)
Contraindications:
1. nephropathy
3. severe dermatosis
2. hemathopaphy
4. allergy to penicillin
Side effects:
taste deregulations ( decrease vit. B6), dyspepsia. Skin eruptions, hyperthermia, hematuria,
proteinuria, renal toxicity,
Cytostatics: in the small diseases and in administration for a long time they have
immunosuppressive action. They inhibit lymphocytes function, cell proliferation, and also inhibit
B-lymphocytes proliferation. In the big doses and short time they are given in cancer.
Side effects:
dyspepsia, pancytopenia, immunodeficiency.

Rheumatoid Arthritis
Rheumatoid arthritis or chronic polyarthritis is a progressive inflammatory joint
disease that intermittently attacks more and more joints, predominantly those of the fingers and
toes. The probable cause of rheumatoid arthritis is a pathological reaction of the immune system.
This malfunction can be promoted or triggered by various conditions, including genetic
disposition, agerelated wear and tear, hypothermia, and infection. An initial noxious stimulus
elicits an inflammation of synovial membranes that, in turn, leads to release of antigens
through which the inflammatory process is maintained. Inflammation of the synovial membrane
is associated with liberation of inflammatory mediator substances that, among other actions,
chemotactically stimulate migration (diapedesis) of phagocytic blood cells (granulocytes,
macrophages) into the synovial tissue. The phagocytes produce destructive enzymes that
promote tissue damage. Due to the production of prostaglandins and leukotrienes and other
factors, the inflammation spreads to the entire joint. As a result, joint cartilage is damaged and
the joint is ultimately immobilized or fused.
Pharmacotherapy. Acute relief of inflammatory symptoms can be achieved by
prostaglandin synthase inhibitors; nonsteroidal anti-inflammatory drugs, or NSAIDs, such as
diclofenac, indomethacin, piroxicam), and glucocorticoids. The inevitably chronic use of
NSAIDs is likely to cause adverse effects. Neither NSAIDs nor glucocorticoids can halt the
progressive destruction of joints. The use of disease-modifying agents may reduce the
requirement for NSAIDs. The use of such agents does not mean that intervention in the basic
pathogenetic mechanisms (albeit hoped for) is achievable. Rather, disease-modifying therapy
permits acutely acting agents to be used as add-ons or as required. The common feature of
disease diseasemodifiers is their delayed effect, which develops only after treatment for several
weeks. Among possible mechanisms of action, inhibition of macrophage activity and inhibition
of release or activity of lysosomal enzymes are being discussed.
Included in this category are: sulfasalazine (an inhibitor of lipoxygenase and
cyclooxygenase), chloroquine (lysosomal binding), gold compounds (lysosomal binding; i.m.:
aurothioglucose, aurothiomalate; p.o.: auranofin, less effective), as well as D-penicillamine
(chelation of metal ions needed for enzyme activity). Frequent adverse reactions are: damage to
skin and mucous membranes, renal toxicity, and blood dyscrasias. In addition, use is made of
cytostatics and immune suppressants such as methotrexate (low dose, once weekly) and
leflumomid as well as of cytokin antibodies (infliximab) and soluble cytokin receptors
(etanercept). Methotrexate exerts an anti-inflammatory effect, apart from its anti-autoimmune
action and, next to sulfasalazine, is considered to have the most favorable risk:benefit ratio. In
most severe cases cytostatics such as azathioprin and cyclophosphamide will have to be used.
Surgical removal of the inflamed synovial membrane (synovectomy) frequently
provides long-term relief. If feasible, this approach is preferred because all pharmacotherapeutic
measures entail significant adverse effects.