Non-Steroidal Antiinflammatory

Drugsby

Dr. Sherif Ahmed Shaltout

AnalgesicsDrugs which relieve pain .They are classified into:

Narcotic Non narcotic-Relieve all types of pain -Relieve pain of moderate

except itching and colic to low intensity-It is accompanied with - NO

Changes in mood -Addiction liability -No

ANTIPYRETIC ANALGESICS Group of drugs which lower high body

temperature, relieve pain (without narcosis) and some have anti inflammatory action

Mechanism; inhibition of prostaglandin synthesis by inhibition of their synthetizing enzyme namely cyclooxgenase enzyme.

Cyclooxgenase enzyme (COX)

1- COX-1: constitutive (its inhibition……..> S/E)

2- COX-2: Inducible (its inhibition……> Therapeutic)

Classification: I-Non selective COX inhibitors:

1-Salicylates: Acetyl salicylic acid, Na salicylates, Salicylamide.

2- Pyrazolone derivatives: Dipyrome, phenylbutazone.

3- Indol derivates: Indomethacin, sulindac.

4- Fenamates: Mefenamic acid, flufenamic acid.

5-Pro ionic acid derivatives: Ibuprofen, ketoprofen naproxene.

6- Aryl acetic acid derivatives: Diclofenac. 7- Oxicams: Piroxicarn, Meloxicam.

8-Aniline derivatives: Phenacetin, paracetamol .

II-Selective COX2 inhibitors: Rofecoxib, celecoxib, etodolac, nimesulide

 

(1)- SalicylatesSalicylic acid derivatives. Classification: 1- Locally acting (Irritant): salicylic acid and methyl salicylate. 2- For systemic use: Acetylsalicylic acid (Aspirin) and Na salicylates. Pharmacokinetics: 1- Absorption : orally from upper GIT, WHY?? 2- Distribution : All over the body.50-80% bound to pl.albumin. 3- Metabolism : Main: is conjugated in liver with glucuronic acid and glycine .1 % is oxidized into gentesic acid which is also active. 4- Excretion is renal and is increased by ???.

Pharmacodynamics: Local actions:

1- Salicylic acid: Keratolytic (20% in colloid). Anti fungal and antiseptic

2- Methyl salicylate (oil of winter green) irritant, used as counter irritant for painful muscles or joints.

Systemic actions

1- CNS:

1- Analgesic : Relieve somatic pain rather than deep visceral pain . Salicylates analgesia induced centrally by elevating pain threshold in subcortical area (thalamus) and peripherally  PGs released during inflammation & sensitize nerve endings to kinins.

2- Antipyretic in fevers, no effect on normal body temp. pyrogen-induced PGE2 in fever*  resetting of hypothalamic thermostat to normal   temperature-regulating mechanisms  VD & sweating

Toxic dose ---> hyperpyrexia due to uncoupled oxidative phosphorylation

3- Anti-inflammatorv action: (Large dose> 5 g/day) :

Inhibition of : PGs. Bradykinines Protease and Hydrolase enzymes Hyaluronidase and Fibrinolysin Hyaluronic acid the "ground substance

(Inhibit antigen antibody reaction through increased ACTH ---> increase cortisone release)

2- CVS : decreases blood pressure -Small therapeutic dose due to vasodilatation by inhibition of rho dependent

tyrosine kinase. - large dose due to inhibition of VMC and direct action on the walls.

3- BloodInhibit platelet aggregation with small dose due to inhibition of thromboxane A2 Hypoprothrombinemia : (Large dose 5 g/day) competes with vit K. leading to decrease synthesis of prothrombin and factor VII IX and X In patients with G-6-PD deficiency ---> haemolysis (idiosyncracy) (Reduction of ESR and leucocytosis)

4- Respiration and acid base balance: Large dose ---> respiratory alkalosis due to stimulation of respiratory center (directly and through Co2 production from uncoupling of oxidative phosphorylation)….> hyperventilation ---> loss of Co2

- then compensated respiratory alkalosis due to excretion of bicarbonate, sodium and potassium by the kidney - Toxic dose causes metaboilc acidosis in children. precipitate acute bronchial asthma in susciptable patients by inhibition of cycloxygenase enzyme, therefore arachidonic acid will be acted upon by lipoxygenase (LOX) enzyme ---> excess leukotrienes.

5- GIT: a- Nausea and vomiting centrally due to stimulation of CTZ peripherally due to local irritation.

b- Gastric irritation and hyperacidity locally release of acetylsalicylic acid and systemically by decrease synthesis of PG E1 and PGI

c-ulceration ---> bleeding

6- Kidney (blood uric acid) a- Small dose (<5 g/day): decrease uric acid excretion by distal convoluted tubules ---> hyperuricaemia ---> worsen gout.

b- Large dose (> 5 g/day): decrease uric acid reabsorption from proximal convoluted

7- Endocrine actions:

a- Stimulate adrenaline release from adrenal medulla.

b- Stimulate hypothalamus ---> anterior pituitary ---> increase ACTH secretion ---> adrenal cortex ---> increase adrenal cortical hormone levels.

c- Displaces T3 and T4 from plasma proteins ---> decrease TSH ---> decrease radioactive iodine uptake by thyroid.

8- Metabolic actions:

a-Carbohydrate: - Small dose: hypoglycemia (increase uptake of glucose by tissues) - Large dose: hyperglycemia due to increase glycogenolysis (increase adrenaline and cortisone release) .

b- Protein: -Large therapeutic dose: increase protein breakdown (catabolic effect of cortisone). -Large dose: accumulation of glutamine ---> convulsions.

Preparations : 1- Acetylsalicylic acid (aspirin) 325 gm tables.

2-Na Salicylate: as enteric coated tables 0.6-1.2 gm

3-Effervescent aspirin

4-Lysine acetyl salicylic acid only parentrally 500 IM or IV.

5- Ditlunisalis a salicylic acid derivative more potent analgesic and antiinflammatory activity, longer duration of action, less gastric bleeding, inhibit platelet aggregation and has a uricosuric effect. 250-500 mg twice daily, orally.

6-Diflunisal: is salicylate derivative, not metabolized to salicylate. more potent anti-inflammatory effect, less side effects .It is partially COX-2 selective. used in dental pain and cancer pain either orally or topically 500-1000 mg twice daily.

Therapeutic uses:

1. Small dose (75-150 mg/d):prophylaxis for transient ischemic attacks, unstable angina, acute myocardial infarction

2. Intermediate dose (325mg 1-2tab/4hr) Mild to moderate pain 2ry to inflammation , e.g.

arthritis, dental pain (ineffective in severe visceral pain).

Headache, dysmenorrhea. Postpartum pain, postoperative & cancer pain (added

to opioids to  their dose).

3. Large dose (4-8 g/d) Rheumatic fever.Rheumatoid arthritis & other inflammatory joint diseases.

4.Local uses: -Salicylic acid: - Keratolytic (removes corns and warts) - Antifungal and antiseptic - Remove scales (hair lotion) - Methyl salicylates (oil of winter green) counter irrtant for arthritis and myositis

Adverse effects:A. Effects Common to all NSAIDs (particularly in the elderly)1. GIT : Dyspepsia, nausea, vomiting, gastritis, ulceration with ↑ risk of bleeding. 2. Nephrotoxicity (less with aspirin)Analgesic nephropathy: irreversible chronic nephritis due to chronic use of high doses of combinations of NSAIDs.In renal insufficiency or in hypovolemic patients whose GFR depends on vasodilator PGs (e.g. heart failure or extensive diuretic therapy),  vasodilator PGs by NSAIDs renal blood flow resulting in:a. Salt & water retention (edema),  BP.b. Hyperkalemia.c. Acute renal insufficiency 3. Hypersensitivity reactions Skin rash, rhinitis, asthma especially in asthmatics & patients with nasal polyps .4.  Bleeding tendency (stop aspirin ???)Antiplatelet effect.Displacement of warfarin from plasma proteins potentiating its effect.5. Hepatotoxicity

B. Effects Specific to Aspirin 1. Hypoprothrombinemia: bleeding risk. 2. Hyperuricemia (low-dose aspirin in gout):. 3. Reye’s syndrome: encephalopathy and liver damage in children with

fever due to viral infection (CI as antipyretic in children < 12 years). 4. Chronic toxicity (salicylism): prolonged administration of large doses

dizziness, tinnitus, nausea & vomiting.

5. Acute toxicity: Nausea, vomiting and bleeding Hyperventilation, increase sweating,dehydration and hyperthermia

- Respiratory alkalosis (adults) or metabolic acidosis (children) - Hyperglycemia -Delerium, convulsion, coma and death Treatment of acute toxicity : 1-Gastric lavage with NaHC03 --> neutralizes hyperacidity. 2- Alkalinization of urine to help excretion of salicylates 3- Correct hyperthermia by cold fomentations 4- Correction of dehydration by fluids, depending on the type of

acid base disturbance present. 5-Vit K.or blood transfusion for haemorrhagic phenomena. 6- Haemodialysis in severe cases.

Contraindications and precautions:

1- Allergy and idiosyncracy

2- Peptic ulcer

3-Bleeding tendency

4-Bronchial asthma

5-Pregnancy

6- Small dose of salicylate in gout

7- They should not be given to the "under twelve" with influenza or chicken pox for fear of Reye's syndrome

8- They are better given after meals

9-Large doses are better avoided in presence of liver or renal disease

Drug interactions: Can displace other drugs from plasma

proteins as dicoumarol and oral hypoglycemic Compete with other uricosurics as

probenecid and phenybutazone . Barbiturates poteniates analgesic effect of

salicylates.

2- Dipyrone (Novalgin): not antiinflammatory, not uricosuric. not used ……..> agranulocytosis

3-Phenylbutazone: is potent. prolonged effect .not used …..> high incidence of side effects including peptic ulcer, renal and hepatic damage, aggranulocytosis

4- Indole derivativesA-Indomethacin: marked antiinflammatory , not used as routine analgesic antipyretic due to its high toxicity. Not used in children except for PDAuses:

1-rh.arthritis, pleurisy, peicarditis, Acute gout

2-closure of patent ductus arteriosus in neonates

3- Dysmenorrhea

Common side effects:

1-CNS: psychosis, confusion, headache and vertigo

2- Eye: blurred vision, corneal opacity

3- Agranulocytosis

B-Sulindac:

- Prodrug, converted in the liver to an active sulphide. similar to indomethacin, but less potent. have renal sparing effect.

5 –Fenamates - Mefenamic acid (ponstan)

weak and short acting. used in dysmenorrhea. side effects: diarrhea, hemolytic anemia

6 -Propionic acid derivatives

Short acting: Ibuprofen, ketoprofen, naproxene ,

Long acting: nabumetone and oxaprozin. -better tolerated due to low incidence of adverse effects. -photosensitivity and skin rash (naproxene and nabumetone).

7- Aryl acetic acid derivatives-Diclofenac and etidorac potent + allergic skin rash. - Ketorlac Analgesic

8- OxicamsPiroxicam (Feldene): potent and long acting antiinflammatory.

Increase risk of GIT bleeding

8- Aniline derivativesacetaminophen (paracetamol)

Phenacetin: more toxic Pharmacokinetic: -A: GIT, rapid and complete. -M: Phenacetin (active) by HME ….> paracetamol (more active) ….> extensively metabolized in the liver and excreted in urine mainly as inactive glucuronate and sulphate conjugates (94%) . -4% is oxidized to a toxic metabolite (N-hydroxy derivative)…..> detoxified by conjugation with hepatic glutathione and excreted in urine). -2% is excreted unchanged.

Pharmacological actions:

analgesic and antipyretic effects not antiinflammatory – inhibits COX-3 ….> inhibit PGs only centrally.

Dose: 500mg orally 4 times/day. Therapeutic uses: Analgesic antipyretic (especially

in salicylate allergy, haemostatic disturbances, bronchial asthma, gastritis and peptic ulcer.)

Side effects :

1- Hepatotoxicity in large dose

2- S/E mostly with Phenacetin.

Haemolytic anaemia, Allergic reaction, Nephritis Methaemoglobinaemia

Acute paracetamol poisoning:

-fatal hepatic necrosis

-due to accumulation of the toxic metabolites secondary to depletion of hepatic glutathione.

-The minimal toxic dose is 10 gm. Treatment:

1-gastric lavage followed by activated charcoal.

2-N-acetyl cystein is a specific antidote. It increases glutathione formation in the liver. Given orally or IV infusion in an initial dose l40mg/kg of followed by 70 mg/kg/4hr for 72 h.

- Methionine increases the conjugation reactions. It can be given orally in a dose of 2gm/2h for 5 doses.

Glutathione itself is not used as it penetrates cells poorly.

II-Specific COX-2 inhibitors (celecoxib)

(meloxicam: COX-2 > COX-1)selectively inhibit COX2 enzymes effect similar to that of non steroidal anti-inflammatory drugs.

due to lack of effect on COX1

Advantages: low incidence of GIT, respiratory or renal side effects little or no bleeding

Disadvant: ineffective in treatment of dysmenorrheal or precipitate labor or prophylaxis against thrombosis or patent ductus arteriosus They paradoxically increase incidence of thrombosis due to inhibition of COX2 mediated prostacyclin. For this reason, most of them are withdrawn from the market e.g rofecoxib and valdecoxib

Slowly acting disease modifying anti-inflammatory drugs

-potent anti-inflammatory effect that starts after several weeks of administration.-no direct analgesic effect. -used in combination with NSAIDS in treatment of chronic immune mediated arthritis e.g rheumatoid arthritis.

1- Gold salts (IM)-uptaken by macrophages….> inhibits phagocytosis and lysosome enzyme activity

-imapirs lymphocyte proliferation. Side effects:

1- Pruritus, dermatitis.

2-Thrombocytopenia, aplastic anaemia

3- Renal damage 4-Peripheral neuritis 5-Teratogenicity

2- D-penicillamine It is a chelating agent which is used in

1-rheumatoid arthitis

2-Heavy metal poisoning due to formation of insoluble non toxic complex with heavy metals except lead

3-Wilson’s disease because it chelates excess tissue cupper .Side effects:Bone marrow depressionNephrotic syndrome.Teratogenicity..Mystheniia gravis

3-other drugs: Methotrexate, Azathioprine, levamisole, chloroquine