Non-opioid analgesics Flashcards
At what dose do ASA and Acetaminophen reach their ceiling affect?
How does that compare to other NSAIDS?
- between 650-1300 mg
- NSAIDS other than aspirin may have a higher ceiling
- Exceeding the ceiling dose will result in increased adverse effects, no added efficacy
- tolerance does not develop to the analgesic effects of these drugs
How does Acetaminophen work?
What is it a good choice to treat?
- We dont really know how it works
- Central anti-prostaglandin effect
- antipyretic
- Lacks peripheral activity
- weak anti-inflammatory (not a true NSAID)
- Good choice to treat:
- PUD
- pediatric patients
- pts who need well funtioning platelets
Acetaminophen
PO dose
IV dose
When was IV dose FDA approved?
- PO dose: 325-650 mg q4-6 hours
- similar potency as ASA; same time-effect curve for single analgesic doses
- IV dose: 1 g over 15 min q 4-6 hours, not to exceed 4,000 mg in 24 hours
- make sure no other sources of acetaminophen
How is acetaminophen metabolized?
Describe the plasma concentration chart comparing IV acetaminophen to PO
- Conjugated and hydroxylated to inactive metabolites; very little excreted unchanged by kidneys
How does an acetaminophen overdose injure the liver?
- Liver can only metabolize a limited amount of the hepato-toxic metabolite N-acetyl-p-benzoquinone with glutathione
- When the glutathione is outnumbered during an OD, hepatic injury occurs
- Max safe dose 4,000mg/day
- lower with ETOH abuse
- lower with isoniazid
What can be used to substitute for glutathione in the case of an acetaminophen OD?
What is the time frame for administration?
Acetylcusteine
within 8 hours of OD
How does acetaminophen cause renal toxicity?
What has higher risk of renal toxicity, NSAIDS or acetaminophen?
- Renal papillary accumulation of metabolites can cause renal cell necrosis
- may be responsible for some cases of ESRD
- NSAIDS have higher risk of renal toxicity
Arachadonic acid is released from phospholipids by the enzyme phospholipase A2.
What can it be immediately metabolized by? (3 enzymes)
What will it form with these different metabolizations?
-
Cyclooxygenase
- prostaglandins
- prostacylcin
- thromboxanes
-
Lipoxygenase
- Leukotrienes
- Lipoxins
-
Epoxygenase
- 4 types of Epoxyeicosatetraenoic acids that regulate inflammation; further research necessary
What is aspirin used for?
- most mild to moderate pain
- HA, muscle pain, arthritis
- antipyretic
- MI/stroke prevention; protection during MI
How does aspirin differ from other NSAIDS?
-
irreversible inhibition of COX
- single dose inhibits platelet function for the lifetime of the platelet (8-10 days)
- large doses can also decrease prothrombin
- zero order kinetics
- does NOT induce ESRD with chronic use
What are some other effects of aspirin?
- Can increase LFTs (usually reversible)
- Single dose can cause asthma problems in aspirin-sensitive pts
- cross-sensitivity with other NSAIDS
- Can cause GI bleeding, PUD
- CNS stimulation
Aspirin dosing:
analgesic/antipyretic
anti-inflammatory
- analgesic/antipyretic: 325-650 mg
- anti-inflammatory: 1,000 mg (3-5 g/day)
- increase dose gradually
- follow serum salicylate levels
- rarely used d/t GI side effects
How is aspirin cleared?
- Hepatic clearance
- E1/2t is 15020 minutes for aspirin and 2-3 hours for the active metabolite salicylic acid
- overdose will cause metabolic acidosis and tinnitus
What makes nonacetylated salicylates more favorable than aspirin?
- They do not interfere with platelet aggregation
- rarely associated with GI bleeding
- well tolerated by asthmatic patients
Why should aspirin not be used in children/teens with viruses?
Risk of Reye’s syndrome (encephalopathy)
What is the MOA of NSAIDS?
absorption?
PB?
VD?
metabolization?
half lives?
- Cyclooxygenase (COX) inhibition
- blocks conversion of arachidonic acid to prostaglandins
- decreases production and release of prostaglandins
- weak acids, well absorbed
- >95% PB
- Small volume distribution
- extensively metabolized and excreted in urine
- half lives vary from <6 to >12 hours
How do NSAIDS affect platelets?
-
Reversible inhibition of platelet aggregation
- inhibition of COX-1 blocks synthesis of thromboxane A2 which inhibits platelet aggregation
What are some of the RARE adverse effects of NSAIDS?
Can they be taken during pregnancy?
- Rare adverse effects:
- hepatic injury
- aseptic meningitis
- Pregnancy
- best avoided but category B if necessary
- Avoid in 3rd trimester, Category D d/t premature closure of DA
What are some GI adverse effects of NSAIDS?
What are the risk factors for these GI SEs?
- Dyspepsia, GI bleeding, PUD
- inhibition of prostaglandins that maintain normal gastric and duodenal mucosa
- increases acid production
- decreases mucous production and gastric blood flow
- local irritation
- lipid soluble at low pH- enters mucosal cells, lose lipid solubility and become trapped in cell (ion trapping)
- risk factors:
- high doses
- prolonged use
- previous GI ulcer or bleeding
- excessive ETOH
- elderly
- corticosteroid use
Which NSAIDS are low risk for GI issues?
moderate risk?
high risk?
- Low risk
- ibuprofen and naproxen at low doses
- those selective to COX2 inhibition (Etodolac, sulindac, Celecoxib)
- Moderate risk
- ibuprofen and naproxen at moderate to high doses
- Diclofenac, oxaprozin, meloxicam, nabumetone
- High risk
- Ketorolac, Tolmetin, piroxicam, aspirin, indomethacin
What are some Renal adverse effects of NSAIDS?
Who is at risk?
- decreased synthesis of renal vasodilator PGs (PGE2)
- leads to decreased RBF
- fluid and Na retention
- may cause renal failure or HTN
- interstitial nephritis (rare)
- rarely an issue in healthy ppl
- Ppl at risk are those who rely on PGs for renal perfusion:
- elderly
- CHF, HTN
- DM
- renal insufficiency
- ascites
- volume depletion
- diuretic therapy
What are some drug interactions seen with NSAIDS?
- Displaces other highly protein-bound agents
- increases levels of warfarin, phenytoin, sulfonylureas, sulfonamides, digoxin
- reduces the effects of diuretics, Beta blockers, ACE inhibitors via suppression of renal PGs
- increased risk of GI bleed when given in conjunction with anti-coagulants
- Probencid increases levels of most NSAIDS
- avoid with ketorolac
Ketorolac
route of administration
how does it compare to morphine?
adverse effects?
- Only IV NSAID in US
- IM or IV comparable analgesic effect to mild opioids
- similar time to pain relieve btw ketorolac and morphine
- no ventilatory or cardiac depression
- adverse effects similar to typical NSAID
Ketorolac:
limitations of use
onset
E1.2t
DOA
PB
matab
dose
- do not exceed 5 days of use
- Onset 10 min
- E1/2t = 5 hours, prolonged in elderly
- DOA = 6-8 hours
- 99% PB
- conjugated in liver
- dose
- 30 mg IV x1 or q 6 hours
- daily max dose 120 mg
- elderly: if you use at all, cut dose in half
What is the only selective NSAID available today?
What is the difference between inhibiting COX1 and COX2?
- Celecoxib (Celebrex)- COX2 inhibitor
- no more effective in reducing pain and inflammation than non selective NSAIDS
- Cox1- gastric protection and production of thromboxane adn A2 (vasoconstrictor and platelet aggregator)
- COX2- production of prostacyclin (vasodilator, platelet inhibitor)
Celecoxib (celebrex)
dose
taken with ____
avoid in pts with _____
- Use lowest effective dose <200 mg/day
- 200 mg/day = 500 mg BID naproxen
- weigh the risks vs benefits, taking into consideration pts risk for GI or CV events
- Taken with food
- Avoid in pts with a sulfonamide allergy
What are the black box warnings for NSAIDS?
- CV risk
- increased risk of serious thrombotic evetns, MI, stroke
- GI
- increased risk of bleeding, ulceration, perforation of stomach and intestines
- **same for selective and non selective NSAIDS
What are the drugs of choice for neuropathic pain syndromes?
- Antidepressnats and anticonvulsants
- TCAs
- diabetic neuropathy, postherpetic neuralgia, polyneuropathy, nerve injury or infiltration with cnacer
- may improve underlying depression or insomnia
- Venlafaxine (Effexor)-SSRI
- Neuropathic pain, HA, fibromyalgia, postmastectomy pain
- Duloxetine (Cymbalta)-SSRNI
What are Gabapentin and Pregabalin used for?
How do they work to help with pain?
- Diabetic neuropathy, postherpetic neuralgia, fibromyalgia
- mechanism not well understood
- may be related to Ca influx inhibition and inhibition of excitatory neurotransmitters in spinal and supraspinal pathways by binding to alpha 2 and delta 1 subunits of presynaptic voltage-gated channels in the CNS
What are all the adjunct analgesics?
- TCAs
- SSRIs
- gabapentin
- pregabalin
- carbamazepine
- phenytoin
- sodium valproate
- clonazepam
- topiramate
- lamitrogen
- hydroxyzine
- corticosteroids
- topicals
What kind of pain is hydroxyzine used for?
Corticosteroids?
- low dose hydroxyzine can add analgesic effect to opioids in cancer and postoperateive pain while reducing incidence of N/V
- Corticosteroids can produce analgesia in some patients with inflammatory diseases or tumor infiltration of nerves
What are the different topical agents and what do they help with?
- 5% lidocaine- post herptic neuralgia
- EMLA- cutaneous anesthesia
- Capsaicin cream (Zostrix)- for neuropathic and osteoarthritic pain
- doesn’t really work
- Clonidine patch- may improve pain and hyperalgesia in sympathetically maintained pain
Which Caneboid receptor has more to do with aneshesia?
Where is it found?
- CB1-
- found in interneurons and CNS
- CB2- found in periphery, more to do with inflammation
