Pharm: NSAIDs and Non-Narcotic Analgesics Flashcards by Erik Hammond

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

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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

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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)

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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

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Because Aspirin inhibits COX-1 and COX-2, it may lead to what 3 complications?

Gastric ulceration
Bleeding
Renal impairment

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What is the nature of the interaction between cyclooxygenase and aspirin, but not other NSAIDs?

Irreversible

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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)

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What are 2 ways to minimize risk of aspirin-induced ulcers?

Test for/eliminate H. pylori before starting therapy
Give a proton pump inhibitor

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What are the effects of ibuprofen, naproxen, and other non-aspirin NSAIDs on the antiplatelet actions of aspirin?

Antagonize the antiplatelet actions

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Pt’s on which drugs are at a higher risk of bleeding when taking aspirin?

Those on warfarin, heparin, and other anti-coagulants

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Long-term aspirin use may lead to what serious kidney dysfunction?

Renal papillary necrosis

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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

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Aspirin can cause hypersensitivity rxns, especially in those with what underlying conditions; treated how?

Asthma, rhinitis, and nasal polpys
Tx w/ epinephrine

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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

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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

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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

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What are the AE’s of the 2nd gen. NSAID, Celecoxib?

Does NOT inhibit platelet aggregation –> risk of bleeding
↑ risk of MI and stroke

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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 are some of AE's of ketamine and what effect makes it stand out from other anesthetics?

- **Psychological rxns**: such as **agitation**, **confusion**, and **hallucinations** - Has a **tendency** to ↑ **BP**, unlike other anesthetics that lower it

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?

**HYPO**tension + **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**

How is the α₂-adrenergic agonist Dexmedetomidine administered vs. Clonidine?

- **Dexmedetomidine**: administered **IV** for pain - **Clonidine**: administered by **continous infusion** through an **epidural catheter**

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