Commonly used ANALGESICS & NSAIDs:
| Â | Analgesics/NSAIDS | Mechanism | Uses | Side Effects |
|  | AcetaminophenClass: nonopioid analgesic | Weakly inhibits COX compared to salicylates (selective COX3 inhibition?)° dose-dependent (0 order) elimination ° Excretion: CYP450 metabolism ???? sulfate and glucuronide conjugation by GSH | ° analgesic (=aspirin)° antipyretic (=aspirin)° (NO anti-inflam.)° use in children w/ viral illness | ° no prolonged bleeding° no GI effects° no uric acid inhibition° no Na retention° no hypersensitivity° analgesic nephropathy (papilla and interstitium)° ↑ warfarin anticoagulation° Toxicity: hepatic centrilobular necrosis caused by formation of reactive quinone metabolite ???? binding to hepatic protein ???? toxicity. (Risk ↑ in alcoholics, CYP3A inducers, glutathione depletion) Antidote: acetylcysteine to replenish glutathione and bind toxic intermediate (administered asap) |
|  | AspirinClass: salicylate | Irreversible inhibition of COX via acetylation of active site; ° May inhibit NF-kB (↓ exp’n of inflammatory mediators, ↓ COX 1&2 exp’n)° Excretion: rapid deacetylation to salicylic acid ???? pH dep. renal excretion and hepatic conjugation ° Dose-dependent (0 order) excretion | ° analgesic° antipyretic° ↑ ED50 for anti-inflam. b/c of ↑ COX??° Thromboembolic disorders (TIA, MI) | ° prolonged bleeding due to irreversible TXA2 block in platelets (doubles bleeding time for 4-7 days); contraindicated before surgery and w/ bleeding disorders° inhibits uric acid excretion/ antagonism of uricosuric drugs° Renal effects: Na retention and edema ° NEVER give to children with varicella or influenza ???? Reye’s (encephalopathy)° Toxicity: ↑ depth and rate of respiration (resp. alkalosis);depression of resp. center in medulla (resp. acidosis); inhibition of enzymes in CBH, protein, and fat metabolism (metabolic acidosis); tinnitus, coma, CNS effects |
|  | Aspirin, IbuprofenClass: NSAIDs | Inhibition of COX (more selective for COX2) ° Also includes salicylates, ibuprofen and congeners, diclofenac, ketorolac (iv for pain), indomethacin, NOT acetaminophen° Alternatives: DMARDs, immunosuppressants, biological response modifiers |
° Anti-inflam.° Joints: RA, psoriatic, IBD-related arthritis; osteoarthritis° IBD: ulcerative colitis, Crohn’s disease(treat w/ prodrugs)° Acute rheumatic fever | ° Dose-dependent GI effects (esp. in elderly and alcoholics) due to ↓PG in GI mucosa: blood loss/ hemorrhage, gastric and duodenal ulcers, dyspepsia (Treat w/acet., COX2, DMARD; PGE analog (misoprostol) or acid inhibitor (omeprazole))° ↓ risk of colon cancer due to anti-inflam.° Renal effects: Na retention and edema ° analgesic nephropathy (papilla and interstitium)° aspirin insensitivity: bronchospasm, rhinorrhea, urticaria due to leukotrienes; esp. in asthmatics |
|  | Ibuprofen,naproxenClass: propionic acids |  | ° analgesic° antipyretic° anti-inflam. | ° safer than aspirin or acetaminophen in acute overdose |
|  | CelecoxibClass: COX2 inhibitor | ° 5-50x more selective |  | ° ↑ therapeutic index due to ↓ GI effects° May ↑ risk of atherosclerosis° Renal toxicity: Na retention and edema (COX2 inhibition in macula densa ???? ↑ renin)° analgesic nephropathy (papilla and interstitium) |
|  | MethotrexateClass: DMARDs | Disease Modifying Antirheumatoid Drugs° gold compounds, penicillamine, antimalarials, sulfasalazine, IL-1 receptor antagonist, immunosuppressants, glucocorticoids, leflunomide, methotrexate |  |  |
|  | InfliximabClass: TNF-α inhibitor(biological response modifier) |  |  |  |
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- COX1
- Constituitive
- GI integrity
- Platelet aggregation
- COX1 Inhibition
- Channel block
- Reversible
- COX2
- Inducible by cytokines, GFs, and tumor promoters
- Ovarian function
- Renal function
- COX2 Inhibition
- Channel side pocket confers selectivity
- Time-dependent inhibition
Analgesia: inhibition of PGE synthesis in periphery (dorsal horn of SC); limited CNS effects
- treats headache, dysmenorrhea, and pain (joints, skeletal m., and teeth)
- Combination Preparations: caffeine, opioids, decongestants, and sedative antihistamines
Antipyresis: ↓ fever (but not normal temperature)
- acts on hypothalamic nuclei (inhibits PGE produced by endogenous pyrogens IL-1, TNF-α, and IFN-α)
- ↑ peripheral Q
- ↑ sweating
HISTAMINE ANTAGONISTS
| Â | Â | Â | Â |
|---|---|---|---|
| Â | Receptor | Mechanism & Side effects | Uses |
| Diphenhydramine, ChlorpheniramineClass: 1st H1 antagonist | ↑ IP3/DAG(agonist – 2-methylhistamine) ° dilation of arterioles and venules (EC ???? NO), but constriction of large vessels° ↑ capillary permeability (wheal) ° constriction of bronchial smooth m.° * sensory nerve endings (itch & flare)° CNS arousal |
° relatively non-selective:° local anesthetic° muscarinic blockade (resembles atropine poisoning w/CNS stim.)° weak α-adrenergic blockade° sedation ° allergic dermatitis | ° allergies (rhinitis, conjunctivitis, urticaria)° anti-emetic, motion sickness, sedative-hypnotic |
| Loratidine, Fexofenadine (Allegra)Class: 2nd H1 antagonist | ° more polar – less entry into CNS° arrhythmia due to K channel block (ventricle = torsades de pointes)° interaxn w/ drugs affecting CYP3A (erythromycin) | ° allergies (rhinitis, conjuctivitis, urticaria)° mastocytosis | |
| RaniditineClass: H2 antagonist | ↑ cAMP° agonist – 4-methylhistamine, impromidine° ↑ gastric acid secretion° vasodilation (longer-acting than H1)° β1-like effects on heart | ° contains imidazole-like group (~ histamine)° low incidence, mild° small amt crosses BBB° metabolite inhibits CYP450° cimetidine is an anti-androgen | ° ↓ gastric acid secretion:GI ulcersZollinger-Ellison syndrome (gastrin tumor)Acid reflux |
| Cromolyn sodiumClass: Cromones | Inhibit histamine release @ level of degranulation° administer by inhalation | ° irritation from inhalation | ° prophylaxis against allergic rhinitis and asthma° allergic conjunctivitis (inhibits mast cell degranulation and H1 receptors) |
- Histamine is made from histidine via histidine decarboxylase and stored in mast cells and basophils.
- Degranulation is triggered by bradykinin, C3a and C5a, interaction w/ IgE, and some basic drugs (morphine)
- Fast turnover in enterochromaffin-like cells of gastric mucosa, histaminergic neurons of CNS, and epidermis
H3 is a presynaptic inhibitor that ↓Ca influx. Ag: methylhistamine. Ant: thioperamideGOUT & HYPERURICEMIA
| Â | Â | Â | Â |
|---|---|---|---|
| Â | Mechanism | Uses | Side Effects |
| Colchicine, NSAIDs (indomethacin)Class: Anti-inflammatory | Suppression of inflammation° inhibits microtubules° suppresses leukocyte motility and phagocytosis | ° prophylaxis | ° Chronic: bone marrow suppression, myopathy° Toxicity: GI damage° DO NOT use salicylates (↓ renal clearance of uric acid and antagonize uricosurics) |
| ProbenecidClass: Uricosuric | ° ↑ renal clearance of uric acid by blocking tubular reabsorption @ oatp |  | ° prevent secretion of organic acids° alkaline urine protects against renal urate ppt° DO NOT use w/ nephrolithiasis° loses effectiveness w/renal failure |
| AllopurinolClass: Xanthine Oxidase Inhibitor | ° inhibits xanthine oxidase (catalyzes hydroxylation of xanthine and hypoxanthine); precursors are more soluble and are cleared more rapidly by the kidneys ° long-lasting metabolite° converted to a ribonucleotide ???? feedback inhibition of de novo purine synthesis° can be combined w/ other classes | ° hyperuricemia due to overproduction ° patients w/ impaired renal fxn° preexisting renal urate stones | ° hypersensitivity (rash) |
Uric acid is the end product of purine metabolism
- overproduction: primary familial gout, myeloproliferative disorders, cytotoxic drugs
- impaired excretion: renal disease, drugs that ↓ tubular secretion (diuretics)
Low solubility or uric acid ???? ppt in joints and kidneys ???? pain and inflammation
Frequently Asked Questions
What are the common side effects of aspirin?
Aspirin can cause prolonged bleeding due to its effect on platelets, which makes it unsuitable for use before surgery or in people with bleeding disorders. It may also cause gastrointestinal issues such as ulcers and dyspepsia, especially in the elderly or those consuming alcohol. Additionally, aspirin can lead to renal problems, sodium retention, and is contraindicated in children with viral illnesses due to the risk of Reye's syndrome.
How does acetaminophen differ from NSAIDs in pain management?
Acetaminophen is an analgesic and antipyretic but lacks the anti-inflammatory properties of NSAIDs. It is less likely to cause gastrointestinal issues or prolonged bleeding, making it a safer option for children and those with bleeding risks. However, it can cause liver damage at high doses or in individuals with alcohol use or liver conditions.
Why is acetaminophen considered safer for children with viral illnesses?
Acetaminophen is recommended for children with viral illnesses because it does not carry the risk of Reye's syndrome, a potentially fatal condition associated with aspirin use in children. Acetaminophen effectively reduces fever and provides pain relief without affecting blood clotting or causing gastrointestinal issues.
What role does COX inhibition play in the effectiveness of NSAIDs?
NSAIDs work by inhibiting the cyclooxygenase (COX) enzymes, particularly COX-2, which are responsible for producing prostaglandins that promote inflammation, pain, and fever. By reducing prostaglandin production, NSAIDs alleviate symptoms of pain and inflammation but can also affect the stomach lining and platelet function due to COX-1 inhibition.
What are the potential risks of long-term NSAID use?
Long-term NSAID use can increase the risk of gastrointestinal bleeding, ulcers, and renal impairment due to reduced prostaglandin production. It may also lead to cardiovascular issues such as increased blood pressure and, in some cases, atherosclerosis. Patients with existing conditions or those taking high doses are at higher risk.
How does celecoxib differ from other NSAIDs?
Celecoxib is a selective COX-2 inhibitor, which means it primarily targets the COX-2 enzyme responsible for inflammation, minimizing gastrointestinal side effects compared to non-selective NSAIDs. However, it may increase the risk of cardiovascular events like heart attacks and strokes, necessitating careful use in patients with heart disease.
What is the role of glucocorticoids in managing arthritis?
Glucocorticoids, such as prednisone, are often used as disease-modifying antirheumatic drugs (DMARDs) in managing arthritis. They work by suppressing inflammation and immune responses, providing relief from pain and swelling. However, long-term use can lead to side effects such as osteoporosis, weight gain, and increased infection risk.
How do histamine antagonists help with allergies?
Histamine antagonists, or antihistamines, block the action of histamine, a chemical released during allergic reactions that causes symptoms like itching, sneezing, and runny nose. First-generation antihistamines like diphenhydramine can cause sedation, while second-generation options like loratadine are less likely to cross into the brain, reducing drowsiness.