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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.
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
-- 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
Prostaglandins pGE2
Pyrogen
NSAIDs
Antipyretic Mechanism
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
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Nerve ending of pain
Bradrkinin histamine
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
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
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Symptoms of inflammation Red, swelling, Heating, Pain
Bradrkinin
Histamine 5-HT
Phospholipids
Phospholipase
Arachidonic Acid
5-lipoxygenase cyclooxygenase
5-HPTE
peroxidase
LTB4
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
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)
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
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
SIDE EFFECTS
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
Anti pyretic
Side action
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cox2 i.m
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