Peripherally Acting Analgesics 751 Canvas.pptx

Peripherally Acting Analgesics 751 Terry C. Wicks, DNP, CRNA  Peripheral analgesics have their Peripheral site of action within damaged Analgesics tissues. They act at the sensory level to block transmission of pain impulses to higher cortical...

Peripherally Acting Analgesics 751 Terry C. Wicks, DNP, CRNA  Peripheral analgesics have their Peripheral site of action within damaged Analgesics tissues. They act at the sensory level to block transmission of pain impulses to higher cortical structures.   Activators of  Peripheral Activity at primary sensory inhibitory nerve the local neurons endings  Prostanoids  Opioid level  Bradykinin  Alpha adrenergic  Adenosine  Cholinergic triphosphate  Adenosine  Histamine  Cannabinoid  Serotonin Nociceptors have their cell bodies in the DRG and synapse with second order neurons in the dorsal horn   NSAIDs block the biosynthesis of prostaglandins from Nonsteroidal arachidonic acid by binding to the COX enzyme active site Anti-  COX1 inflammatory  COX2  Central inhibition of COX2 may modulate nociception Drugs centrally COX 1 & COX2 COX 1 & COX1 COX2 COX2  Locally mediates: Catalyzes production  Pain of prostaglandins:  Inflammation  Maintain normal renal  Fever function  COX2 may also mediate  Mucosal protection of the GI tract nociception centrally  Production of  Coxibs are COX2 thromboxane A2 selective following platelet activation  Have no effect on platelet aggregation  NSAIDS are rapidly absorbed from the GI tract  90% bound to albumin – acid type compounds  Hypoalbuminemia increases the fraction of unbound drug and risk of adverse events  NSAIDs are metabolized in the liver and eliminated in urine and bile  Impaired renal function prolongs NSAID half life  Moderate to severe liver disease impairs NSAID NSAID metabolism increasing the potential for toxicity Kinetics  Platelet function Platelet COX1 catalyzes thromboxane A2 production. COX1 is inhibited by aspirin and NSAIDS NSAID COX2 specific inhibitors have no effect on Side GICOX Side Effects 1 NSAIDS are associated with ulcers, Effects perforation and bleeding High doses of NSAIDs, older age, H pylori infection, use of low dose aspirin, anticoagulants, corticosteroids, or history of ulcer increase risk COX2 specific inhibitors carry less risk   NSAIDs are associated with increased NSAID risk of adverse cardiovascular events Cardiovascu  Likely the result of imbalance between lar Side COX2 mediated thromboxane Effects production and antiaggregatory prostaglandin I2 production in endothelial cells.  This tendency, to various degrees holds true for virtually all NSAIDs including COX2 selective agents.  Risks may be substantially lower with naproxen   NSAIDs may Other  Decrease excretion of sodium  Increase risk of interstitial nephritis Risks:  Alter filtration rate and tubular transport Renal  All NSAIDS can induce reversible impairment of GFR Side  Risk factors include Effects  Diabetes  Hypertension  Atherosclerosis  Hypovolemia  Salt depletion  hypoalbuminemia   Liver: Other Side  Aspirin/NSAID use decreased risk of Effects hepatocellular carcinoma and death d/t chronic liver disease  Non-aspirin NSAID use was only associated with reduced risk of death d/t chronic liver disease.  Pulmonary:  NSAIDs inhibit prostaglandin synthesis, increasing risk of anaphylaxis  Particularly patients with allergic rhinitis, nasal polyposis and/or history of asthma  Hypersensitivity & Drug-Drug Last, but Allergic reaction  Bronchoconstriction Interactions  Additive inhibition not  Rhinitis of platelet least…  Urticaria aggregation  Decreased lithium Idiosyncratic adverse clearance events  Decreased digoxin  Skin rash clearance  Photosensitivity  Displacement of  Aseptic meningitis phenytoin and  Tinnitus, hearing loss valproic acid from their binding sites.  Neutropenia   Antipyretic and analgesic Acetaminoph  Little anti-inflammatory effects en  Central analgesic effect mediated through activation of descending serotonergic pathways  At the spinal cord level acetaminophen antagonizes neurotransmission by NMDA, substance P, and nitric oxide pathways  IV formulation (Ofirmev) is currently available  Acetaminophen is the leading cause of acute liver failure in the U.S.   Aspirin blocks the action of COX enzymes Acetylsalicyl and prevents the production of ic Acid prostaglandins  Aspirin inactivation is irreversible and (Aspirin) inhibits platelet aggregation.  Symptoms of overdose include:  Nausea, vomiting, abdominal pain  Tinnitus, hearing impairment, CNS depression  Higher doses:  Metabolic acidosis  Renal failure  Agitation, confusion, coma  Treat with symptomatic support and correction of acid base balance   Anti-inflammatory action results in Cortico- the decreased production of a steroids variety of inflammatory mediators amplifying and maintaining pain.  Hydrocortisone is the primary corticosteroid  Different steroids very in their duration of action and relative corticosteroid and mineralocorticoid activity.  See Table 9-3   Clinical toxicity/side effect are Steroids: generally related to repeated or Side prolong administration (See Table 9-4) Effects  Adrenal suppression  Osteonecrosis  Impaired wound healing  Steroids enhance analgesia, prolong regional anesthesia block duration, reduce post op N/V  Often used to treat arthritis and chronic pain conditions.   IV lidocaine, oral mexiletine, and tocainide may Systemic block voltage gated sodium channels within Local the spinal cord or dorsal root ganglia Anesthetics  Oral lidocaine has poor oral bioavailability  Elimination half time 1.5-2 hours  Elimination is prolonged with decreased liver blood flow (CHF)  Oral mexiletine has excellent bioavailability  Elimination half time 10-12 hours  Elimination half time is prolonged with liver impairment (25 hours)  Side effects and toxicity are characteristic of local anesthesia toxicity. Topical 5%  Used to treat post- Lidocaine herpetic neuralgia  Rapid onset  Long duration  Low risk of toxicity or drug-drug interaction   Capsaicin is a transient receptor Capsaici potential vanilloid channels agonist. n  TRPV1 channels are located on C fiber endings in the periphery  TRPV1 receptor activation causes the release of substance P (initial burning). Continued channel activation by capsaicin exhausts substance P and decreases C fiber activation.  Capsaicin patch is used to treat postherpetic neuralgia neuropathic pain.   Ketamine: NMDA receptor Ketamin antagonist and modulates central sensitization induced by: e  Incision  Tissue damage  And opioid induced hyperalgesia  Doses of 0.15-1 mg/kg are effective  Use is limited by psychotropic side effects  Can be used locally due to sodium channel blocking ability   Both clonidine and dexmedetomidine Clonidine are central α2 agonists & decrease Dexmedetomidi sympathetic outflow from the CNS. ne  Diminishes post operative shivering, opioid induce muscle rigidity  Its effects are:  Sedative  Pro-anesthetic  Pro-analgesic  Lowered BP  Acceptable adjunct of general or regional anesthesia  Use in pediatrics for emergence delirium   Opioid receptors are widespread Opioids  CNS  Peripheral neurons  Neuroendocrine organs (pituitary, adrenals)  Immune  Ectodermal cells  Opioids have been shown to have peripheral antinociceptive effects in inflammation  Opioids injected locally (soft tissues or joints) produce potent analgesic effects  Opioids may facilitate Ischemic Pre- Conditioning