Antipyretic, analgesic and antiinflammatory drugs

Department of pharmacology faculty of medicine Lampung university

Contents
Overview History Common pharmacological effects
Aspirin Selective COS-2 inhibitor Other Drugs

Overview
This kind of drug is a group of chemically dissimilar agents that have antipyretic, analgesic and antiinflammatory effects.
The structure of this kind of drug differs from that of steroidal anti-inflammatory drugs. Nonsteroidal anti-inflammatory drugs NSAIDs

History
In ancient Egypt & Greece, dried leaves of myrtle, the bark of willow & poplar tree
In England, active component from willow bark was identified as salicin , which is metabolized to salicylate in 1763.

In Germany, salicylic acid was synthesized in 1860.

In 1875, acetylsalicylic acid was synthesized.

History
In 1899 Aspirin acetylsalicylic acid was named; the "a" --- acetyl grouping and the "spirin" --- botanical genus spiraea, from which salicylates could be extracted. Now, more than 30 million people consume NSAIDs daily and of these 40% of the patients are more than 60 years of age. The consumption of NSAIDs is No. 1 among all drugs.

History
In 1969 the first association between prostaglandin production and the actions of aspirin- like drugs

In 1992 new enzyme was cloned & was called cyclooxygenase 2 (COX- 2) or PGH 2 synthase 2

Common pharmacological effects

These drugs show the same pharmacological
effects

-- antipyretic effect
-- analgesic effect

-- anti-inflammatory effect

1. Antipyretic Effects
"normal" temperature: slightly affected "elevated" temperature: reduced The higher temperature, the more potent Mechanisms of Antipyretic Action

Blocks pyrogen-induced prostaglandin production in thermoregulatory center (CNS)

Prostaglandins pGE2

Pyrogen

thermoregulatory center set point heat production Heat dissipation

NSAIDs
Antipyretic Mechanism

Block prostaglandins production Sites of action: Central Nervous System

Fever

2. Analgesic Effects
Effective to mild to moderate pain
0.5g of aspirin is a weak or mild analgesic that is effective in short, intermittent types of pain as encountered in neuralgia, myalgia , toothache.

Analgesic Effects
Pain may arise from: Musculature, dental work , vascular , postpartum conditions, arthritis , bursitis Sites of action: peripherally -- sites of inflammation subcortical sites

NSAIDs
Prostaglandins
pGE2 pGF2

factors

+
Nerve ending of pain

Bradrkinin histamine

block prostaglandins production

Sites of action: peripheral tissue

Pain

3. Anti-inflammatory Effects
NSAIDs only inhibit the symptoms of inflammation But they neither arrest the progress of the disease nor do they induce remission

Anti-inflammatory Effects
Reduced synthesis: --eicosanoid mediators Interference: --kallikrein system mediators --inhibits granulocyte adherence --stabilizes lysosomes --inhibits leukocyte migration

How can NSAIDs inhibit the prostaglandin production?

The Mechanism of NSAIDs

Mechanism of action
The principal pharmacological effect of NSAIDs is due to their ability to inhibit prostaglandin synthesis by blocking the cyclooxygenase COX activity of both COX-1 and COX-2. NSAIDs----- acetylation of COX

(reversible or irreversible)

NSAIDs
Prostaglandins pGE2 pGF2 Inflammatory factors

+
Symptoms of inflammation Red, swelling, Heating, Pain

Bradrkinin
Histamine 5-HT

block prostaglandins production

Sites of action: peripheral tissue

Phospholipids
Phospholipase

Arachidonic Acid
5-lipoxygenase cyclooxygenase

5-HPTE
peroxidase

PGG 2 LTC4 PGH2

LTB4

TXA 2 PGI2 PGE2 PGF2 PGD2

PGE2 vasodilatation, pain sensitization, gastric cytoprotection [mucous/HCO3 secretion], fever PGF2 bronchoconstriction, uterine contraction PGI2 inhibition of platelet aggregation, gastric cytoprotection
TXA2 platelet aggregation

Salicylates
Acetylsalicyclic acid

Aspirin
Sadium Salicylate

 Rapidly absorbed: stomach and upper small intestine, cross BBB and placenta and absorbed through intact skin (methil salicylate)
Distributionthrough the body

Pharmacokinetics

rapidly hydrolyzed --------- acetic acid + salicylate, catalyzed by tissue/blood esterases

 metabolite in liver

Elimination----- Pharmacokinetics

dose 1g/dayone-order elimination T1/2: 3--5 hrs dose 1g/dayzero-order elimination 4g/day T1/2: Excretion: kidney, influenced by pH of urine

Pharmacodynamics
1. Analgesic Effects (300-600mg)

2. Antipyretic Effects (300-600mg)

3. Anti-inflammatory Effects (3-6g)

do not influence the progress of disease

4. Effects on Platelets (40-100mg) Reduced platelet aggregation reduces thromboxane A2 (TXA2) formation

Low doses 40-100mg/day Platelets Endothelial cell No nuclei Has nuclei No new COX1 New COX1 produce produce TXA2 production Lifetime: 8-11 days

Pharmacodynamics
5. Other effects Immune inhibition Effect on metabolism of connective tissue Effects on metabolism of glucose, fat, protein ---- catabolism ACTH release

Clinical Uses
1. Commonly used for management of mild to moderate pain (300-600mg) 2. Combination agents (cold) 3. Used for reducing fever (300-600mg) 4. Useful in treatment of: (high doses 3-6g) T1/2 > 12 hours 0 rheumatic fever 0 rheumatoid arthritis 0 other inflammatory joint diseases

Clinical Uses
5. Antiplatelet: (low doses) 40-100mg reduce incidence of transient ischemic attacks (prophylaxis) reduce incidence of unstable angina (prophylaxis) may reduce incidents of coronary artery thrombosis

Clinical Uses
6. Hypertension in pregnancy : (low doses) 60-100mg TXA2 7. Local indication GI inflammation : 5-amido-salicylic acid 8. Ekternal aplication
salicylic acid is used topicaly to treat acne, corn, caluses, and warts

SIDE EFFECTS
1. CNS: excitation----inhibition salicylic acid reaction: Headaches; confusion; hallucinations; tremors; vertigo; behavior disturbance

2. GI effects: direct stimulation

PGE2 & PGI2

Esophagitis; gastric ulcerations; GI hemorrhage .

 To diminish dispepsia:
Should be tken with food and large volume of fluid Add misoprostol and PPI

In pregnancy ; category C in 1st an 2nd trimeter, category c in 3rd trimester Drug interaction
Warfarin, phenytoin, or valproic acid higher free concentration of other agent Probenecid and sufinpirazone decrease excretio of uric acid Ketolorac increase risk og GI bleeding and platlet aggregation inhibitor

3. Liver & renal toxicity Reye's syndrome

SIDE EFFECTS

Dose dependence toxicity

a potentially fatal disease that causes numerous detrimental effects to many organs, especially the brain and liver.; causes hepatitis with jaundice and encephalopathy
Must be avoided in children and teengers ( less than 20 years old) with viral infection

SIDE EFFECTS
4. Other reaction Hematologic: platelet TXA2 decreased platelet aggregation; prolonged bleeding time. Respiratori : in toxi dose respuratori depresion Hypersensitivity: rashes, urtikaria, bronchoconstrictio, and angioedema Acid-base Imbalance

 Toxicity
Mild (salicylism) ; nausea, vomiting, marked hiperventilation, headache, mental confusion, dizzines, and tinnitus Severe;, rest lessnes, delirium, hallucinations, convulsion , respiratory and metabolic acidosis, and death from respiratory failure Children prone to salicylate intoxication Therapy
Measurement salicylate concentration and pH Increasing urinary pH eliminate salicylate Correction of acid base and electrolite balances dialysis

Acetaminophen
MOA:
Inhibits prostaglandin syntesis in CNS Has less effet on cyclooxygenase on peripheral tissue Weak anti-inflammatory properties Not considered to be an NSAID

Therapeutic used
Analgenitic and antipyretic effect in patient with gastic complaint

 Therapeutic use
Analgesic/ antipiretic of choice for children with viral infection, Patient with gout

Pharmacokinetik
Rapidly absorbed from GI Metabolite in hepar
A portion of acetaminofen is hidroxylted to form N-acetyl-p-benzoquinoneimine, or NAPQI that react with sufhydryl group and cause liver damage

Excreted in urine

 Adverse effect
With normal therapeutic dose , acetaminophen is virtually free of significant adverse effects Skin rash and minor allergic reaction Minor alteration in leukocyte count Renal tubular necrosis is rare Hepatic necrosis with large dose
Patient with heptic disease, viral hepatitis, or hitory of alcholism are at higher risk of acetaminophen induce hepatotoxicity

Indomethacin
More potent than aspirin As an anti-inflammatory agent More adverse reaction

Ibuprofen
More analgesia Fewer adverse reaction
BrufenBenzeneacetic acid Fenbid EmodinMotrin

Phenylbutazone
Powerful anti-inflammatory effects Weak analgesic & antipyretic activities Promote excretion of uric acid Used for acute gout, rheumatic & rheumatoid arthritis More adverse reaction Can induce activities of drug metabolize-E Can displace other drugs from plasma proteins

 Less adverse reactions Do not impact platelet aggregation

Meloxicam Celecoxib Nimesulide Rofecoxib Valdecoxib

Selective COX-2 inhibitors

Anti pyretic

analges Antiic inflammatory

Side action

Acetaminophen Indomethacin sulindac tolmetin diclofenac Ibuprofen meloxicam Phenylbutazone ketorolac

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cox2 i.m

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