Pharm: NSAIDs and Non-Narcotic Analgesics Flashcards
Explain the relationship between inflammation and AA, COX-1, and PGE2?
- Inflammation stimulates AA release
- COX-1 converts AA –> PGE2
- PGE2 causes sx’s –> erythema, edema, and pain
What is the role of COX-2 in relation to the inflammatory resposne?
- Inflammation also induces COX-2 expression
- COX-2 also converts AA –> PGE2 which amplifies sx’s of COX-1 activation
- Worse erythema, edema, and pain
How does the location and action of COX-1 vs. COX-2 differ?
- COX-1 expressed in ‘all’ tissues, ‘all’ the time –> prominent role = responding to physiological stimuli
- COX-2 induced in ‘some’ tissues, ‘some’ times: has physiologic role in kidney, complements COX-1 and prominent role in response to any pathologic stimuli that release AA from cells (i.e., inflammation)
What are the 4 major beneficial actions of Aspirin?
- Suppression of inflammation (due to COX-1 and COX-2 inhibition)
- Relief of mild to moderate pain (due to COX-1 and COX-2 inhibition)
- Reduction of fever (due to COX-1 and COX-2 inhibition)
- Prevention of MI and stroke due to inhibition of COX-1 in platelets, suppresses platelet aggregation
Because Aspirin inhibits COX-1 and COX-2, it may lead to what 3 complications?
- Gastric ulceration
- Bleeding
- Renal impairment
What is the nature of the interaction between cyclooxygenase and aspirin, but not other NSAIDs?
Irreversible
What is the effect of aspirin on cyclooxygenase and why is this significant?
- Irreversible inhibition of cyclooxygenase –> effects persist until cells make more COX because platelets cannot synthesize new COX
- Anti-platelets effects last for life of platelet (~8 days)
What are 2 ways to minimize risk of aspirin-induced ulcers?
- Test for/eliminate H. pylori before starting therapy
- Give a proton pump inhibitor
What are the effects of ibuprofen, naproxen, and other non-aspirin NSAIDs on the antiplatelet actions of aspirin?
Antagonize the antiplatelet actions
Pt’s on which drugs are at a higher risk of bleeding when taking aspirin?
Those on warfarin, heparin, and other anti-coagulants
Long-term aspirin use may lead to what serious kidney dysfunction?
Renal papillary necrosis
Aspirin can impair renal function, causing Na+ and H2O retention, edema and HTN, adverse outcomes are more likely in people with what conditions?
- Advanced age
- Pre-existing renal dysf.
- HYPOvolemia
- HTN
- Hepatic cirrhosis
- Heart failure
Aspirin can cause hypersensitivity rxns, especially in those with what underlying conditions; treated how?
- Asthma, rhinitis, and nasal polpys
- Tx w/ epinephrine
Explain the 5 stages of progression in aspirin/salicylate toxicity?
- Salicylates uncouple mitochondrial OxPhos in the CNS
- Respiratory center senses ↓ ATP as hypoxemia, responds w/ hyperventilation
- ↓ CO2 –> respiratory alkalosis - eventually prompts kidney to deplete HCO3
- Organic acids accumulate because ATP is no longer generated via Krebs cycle
- Metabolic acidosis becomes life-threatening
Although the MOA is similar to aspirin, what are some important difference with non-aspirin NSAIDs?
- Are reversible, so effects decline as blood levels decline
- Suppress platelet aggregation, but use acutally ↑ risk of MI and stroke
- Therefore, should use lowest effective dosage for shortest possible time
Which NSAID causes less gastric ulceration and is indicated for patients with chronic pain/inflammation whom suffer from GI problems (i.e., ulcers)?
Celecoxib –> selectively blocks COX-2
What are the AE’s of the 2nd gen. NSAID, Celecoxib?
- Does NOT inhibit platelet aggregation –> risk of bleeding
- ↑ risk of MI and stroke
Where NSAID therapy is required for pt’s at risk of cardiovascular complications, what is the recommended NSAID of choice?
Naproxen
What are 5 contraindiction for NSAID use?
- Chronic kidney disease: with creatinine clearance of <60 mL/min
- Active duodenal or gastric ulcer
- CV disease, particularly heart failure or uncontrollable HTN
- NSAID allergy
- Ongoing tx with anticoagulants - Warfarin
What is the effect of acetaminophen on pain, fever, and inflammation; where does it exert its MOA?
- Inhibition of prostaglandin synthesis in the CNS, but not the periphery
- Suppresses pain and fever
- NOT inflammation
Acetaminophen overdose results in what; how is it treated?
- Hepatic necrosis; due to accumulation of a toxic metabolite that forms when glutathione is depleted
- OD is treated w/ acetylcysteine, a drug that substitutes for depleted glutathione
What is the effect of acetaminophen on warfarin?
Inhibits the metabolism of Warfarin and therefore can ↑ risk of bleeding
What is the most widely studied TCA used for chronic pain?
Amitriptyline
What are some of the AE’s associated with Amitriptyline used as anti-depressant and analgesic?
- Anticholinergic: dry mouth & constipation
- Cardiovascular: tachycardia & palpitations
- GI: nausea & vomiting
- Neurologic: sedation & mental clouding
What are two dual reuptake inhibitors of serotonin and norepinephrine (SNRIs) that may be used in patients as analgesics with concurrent depression?
Venlafaxine & Duloxetine
What is the MOA of Pregabalin and Gabapentin?
- GABA analog, but exerts its effects by binding to α2δ subunit of voltage-gated Ca2+ channels within CNS
- Modulates Ca2+ influx at the nerve terminals, thereby inhibiting excitatory NT release
*Don’t be tricked, it doesn’t bind GABA*
What are the 4 approved indications for using Pregabalin?
- Neuropathic pain assoc. w/ diabetic neuropathy**
- Postherpetic neuralgia
- Adjunctive therapy for partial seizures
- Fibromyalgia
Gabapentin has broad-spectrum anti-seizure activity, but what are 5 common off label uses it is prescribed for?
- Post-herpetic neuralgia
- Diabetic neuropathy
- Prophylaxis for migraine
- Tx of fibromyalgia
- Restless leg syndrome
What is the MOA of Tramadol as an analgesic?
- Codeine analog, weak mu-opioid agonist, but works primarily by blocking NE and 5-HT reuptake
- Activates monoaminergic spinal inhibition of pain
What is Tramadol used for?
Moderate to moderately severe pain
What are some of the AE’s associated with Tramadol?
Sedation + dizziness + HA + dry mouth + constipation
What is the MOA of Tapentadol used as analgesic?
- Moderate to severe opioid agonist at mu-receptors
- Also blocks re-uptake of NE
What is the MOA of Dexmedetomidine and what is it used for?
- α2-adrenergic agonist used for analgesia and sedation
- Approved for: short-term sedation in critically ill pt’s who were intubated and are undergoing mechanical ventilation
- Sedation prior to/during surgeries
What are some of the AE’s of the analgesic, Dexmedetomidine?
HYPOtension + bradycardia + nausea + dry mouth + transient HTN + agitation + constipation + respiratory depression
What is the MOA and use for Clonidine?
- α2-adrenergic agonist used for 1) HTN and 2) relief of severe pain
- Blocks transmission of pain signals from periphery –> brain
What are some of the AE’s associated with Clonidine?
Highly lipid soluble, escapes blood to cause HYPOtension + confusion + dry mouth
What is the MOA of the analgesic, Ziconotide?
- Selective antagonist at N-type voltage sensitive Ca2+ channels on nociceptive afferent neurons in doral horn of spinal cord
- Prevents transmission of pain signals from periphery –> brain
What is Ziconotide indicated for; how is it administered?
Only for chronic severe pain in those for whom intrathecal administration is warranted and when refractory to other tx’s
What are some AE’s associated with Ziconotide?
- CNS effects w/ cognitive impairment and psychiatric sx’s = common
- Also causes muscle injury (↑ serum creatine kinase levels)
What are the MOA of Capsaicin and Camphor used as topical analgesics?
- Capsaicin: “heat” from red peppers; counterirritant via stimulation of TRPV1 receptors, desensitizes and/or depletes substance P
- Camphor: “heat,” also desensitizes TRPV1 receptors
What is the MOA of Menthol as a topical analgesic?
Stimulates the TRPM8“cold” receptors to cause cool sensation
