Analgesics: Opioids And Nsaids Flashcards
3 sites of action of opioids
Brain (supraspinal)
Spinal cord (spinal)
Periphery
Action of opioids in brain
Pre and post synaptically to activate descending inhibitory pathways
Where opioids work in spinal cord
Dorsal horn directly
Where opioids work in periphery
Peripheral terminals of nociceptive neurons
Opioids used in anesthesia for 4
- Attenuate sns response to pain
- Adjust to inhaled agents
- Sole anesthetic (Fent/sufent/morphine-cv Anes/crit ill)
- Peri op and post op pain control
How opioids diff from other analgesics
Mod to severe pain
No max dose/ceiling effect
Tolerance can develop, assoc w phys dep but not nec psych dep
Cross tolerance
Analgesia w/o loss of: touch, proprioception, consciousness (smaller doses)
Opioids classifications
Naturally occurring (morphine and codeine)
Semisynthetic (analogs of morphine- heroin and dihydromorphone)
Synthetic (exogenous, 4 groups)
Opioid mechanism of action overall
Activate sterospecific G protein coupled receptors
Opioid MOA post synaptic
Decreased neurotransmission. Inc K conduc (hyperpolarization), ca channel inactiv (dec NT release), modulation of phosphoinositide- signaling cascade, inhib Adenylate cyclase (dec cAMP)
Opioid pre synaptic MOA
Inhibits release of excitatory NTs (acetylcholine, dopamine, norepi, substance p)
Opioid receptors
3
Theory
Mu, kappa, delta
Synthetic opioids mimic action of endogenous opioids by binding to opioid receptors
Opioid receptors
What they do
W drugs
Activate endogenous pain modulating systems
Variable affinity and efficacy at the diff receptor types among diff drugs in this class
Mu receptor
Subtypes
What acts on them
Where they are
Mu-1, mu-2, mu-3 (3-immune process)
Endogenous & exogenous agonists
Brain, periphery, spinal cord
Mu 1 receptor
Where effects are
What effects are
What acts on them
Supraspinal*, spinal, and peripheral
Euphoria, miosis, bradycardia, urinary retention, hypothermia
Endogenous and synthetic opioid agonists
Mu 2 receptor
Effects
Analgesia type
What acts on them
Hypoventilation, phys dependence, constipation
Spinal (some supraspinal)
Endogenous and exogenous agonists
Kappa receptor
Where
Effects
What acts on them
Supraspinal, spinal, peripheral
Dysphasia, sedation, miosis, dieresis
Dynorphins and opioid agonist-antagonists
Delta receptor
Where
Effects
What works on them
Peripheral*, supraspinal, spinal
Hypoventilation, constipation, urinary retention
Enkephalins
Mu 1 effects
Euhpohoria, miosis, bradycardia, hypothermia, urinary retention
Mu 2 effects
Ventilation depression, constipation
CYP2D6
What mutations alter metabolism of
Effects
Codeine, oxycodone, hydrocodone, methadone
Unpredictable pharmacokinetics and 1/2 lives
Which drug metab least likely to be impacted by genetic variability
Fentanyl
Rate of metabolism may influence what
Side effect rate
Ultra fast metabolizes at inc risk for PONV
Periop opioid CV effects
Minimal impairment alone (additive cv effects w anesthetics), bradycardia (vagal stim, sa and av depression), vasodilation/dec SVR. Impairs SNS responses and pronounced effect w hypovolemia
Morphine and Demerol CV effects
Dose dependent and infusion rate dep histamine release. Bronchospasm, drop in SVR and BP, variable responses in pts
Periop cv effects
Demerol unique effects
Tachycardia, direct myocardial depression
Opioid CNS effects
Analgesia, euphoria, drowsy, miosis, nausea, doesnt produce amnesia*
How do opioids produce nausea
Direct activity at chemoreceptor trigger zone
Opioid CNS effects if hypoventilation prevented
Modest decrease ICP, decrease CBF
Periop renal effects of opioids
Inc tone and peristaltic activity of ureter. Inc detrusor muscle tone. Inc urgency with decreased ability to void
GI effects opioids
Spasm of GI smooth muscle. Constipation (decreased gi motility), prolonged gastric emptying
Decreased catecholamine release and cortisol prevents SNS activity
Gallbladder effects from opioids
Spasm of sphincter of oddi and gallbladder contraction, inc in biliary pressure
How opioids cause NV
Decreased gastric emptying, direct stim of chemoreceptor trigger zone in 4th ventricle. Partial dopamine agonist. Balanced by depression of medullary vomiting center.
How opioids cause pruritis
Unknown. Primarily on face/nose (esp fentanyl). Histamine most probably cause, esp morphine.
Skeletal muscle SF opioids
Rigidity where
Which drugs
Rigidity in chest, abdomen, jaw, and extremities. Esp if large/fast dose. Common w fentanyl, sufentanil, and hydromorphone.
Skeletal muscle SF opioids
A/w changes
High a/w p from inc intrathoracic p/dec venous return
Glottic rigidity and closure reported
Periop vent effects opioids
Resp depression
Dose dependent
Small dose: inc vt, dec rr, overall decrease in minute vent (inc co2 dec o2)
Large: dec rr and vt
Periop vent effects opioids
Overall 4
Decrease chest wall compliance, cough suppression, constriction of pharyngeal/laryngeal muscles, decreased response hypercarbia/hypoxia
Periop vent effects opioids
Which 2 in particular have AE
Morphine and meperidine have histamine related bronchoconstriction
Factors that inc magnitude and duration of opioid resp depression
Amt of pain, surgical stim, natural sleep, cont vs intermittent gtt, speed of injec, admin of other anesthetics, age, decreased clearance
Morphine
Indication/routes
Severe acute pain IM or IV
PO for chronic and cancer pain
Morphine
Metabolism, 1/2 life, duration
Slow release- 3-5 hrs
Large 1st pass effect
1/2 life 3-4 hrs, converted to active metabolite
Active metabolite of morphine
Morphine 6 glucuronide
Chemical name codeine
3 methylmorphine
Codeine
Indication, route
Half time
Mild pain relief, PO, 3 hrs
Codeine
Metabolism
Active form
Prodrug: 10% metab by CYP2D6 to its active form (morphine). Leftover drug demethylated to inactive metabolite
Codeine
Analgesic variation
Better for what
10% whites 30% asians lack 2D6, no analgesic effect
Antitussive effect remains without conversion (better for cough than pain relief)
Hydrocodone
Other name
Route
Given with
Vicodan
PO
Asa, ibuprofen, antihistamine, acetaminophen
Hydrocodone
Uses
Risk
Analgesic, antitussive, chronic pain
High abuse potential
Oxycodone
Route
Other names
Sustained release name
Po
Oxycontin, Percocet, percodan
OxyContin
Oxycodone Use Combo w Safe in who, why Risk
Moderate to severe pain, chronic pain, post op pain
Asa and acetaminophen
No active metabolites so safe if renal dysfunction
High abuse potential
Methadone
Routes
Composition
1/2 life
Po, iv, sq
Synthetic
Long. 8-59 hrs or 13-100 hrs
Methadone
Tx for what
Safe for who
Opioid addiction QD
Chronic pain syndrome BID or TID (neuropathic pain, resp dep risk)
No active metabolites- safe if renal dysfunction
How naloxone works
Competitive agonist at opioid receptor. Binds to same site but doesnt activate it
Tolerance to opioids
Common when
What happens
2-3 weeks of use
Reduction in adverse fx, shorter duration of relief, decrease in effectiveness, tolerance of: resp and cns dep
Tolerance to opioids
Cross tolerance in what
When switching to another opioid do what
Full agonists
Start w 1/2 or less of equianalgesic dose
Tolerance to opioid
Do what to improve pain relief
Tolerance to what effect isn’t as rapid, what is
Switch to methadone
Constipation
Sedative and emetic effects
Opioid dependence
How long it takes
Factors
Who doesnt experience it
Several weeks of chronic tx
Psychological dep, biological, and social factors
Cancer and acute pain pts, rarely experience euphoria
Dosage
Limits
Dose determination
No min/max except limit by dose of aspirin or Tylenol
After short acting opioid 1st 12-24h need around the clock dose determination
Dosage (PO)
What for chronic pain
What for breakthrough pain
Sustained release formula
Immeadiate release doses that are 10-15% of total daily dose
Titration of opioids in general anesthesia
Titration to BP, HR (if NM blocker and controlled vent), and RR (mainly)
If pain is well controlled and switching opioids do what
Calculate equivalent dose and reduce by 25% for dose of new drug
Neuraxial effects opioids
Where they go/effect
Diffuse across the dura to mu receptors in substantia gelatinosa. Into vasculature for systemic effect
Opioids given epidural/spinal differences from IV
Diff onset, duration, and side effects are different than same drug given IV
Opioids in epidural space may undergo what
Uptake into fat, systemic absorption, or diffusion into CSF
Cephalad movement of opioid in CSF depends on
Lipid solubility
What has limited migration by uptake in spinal cord
Highly lipid soluble meds, fentanyl
Which meds remain in CSF for transfer to cephalic locations
Less soluble opioids, morphine
How lipid solubility relates to uptake and concentration of opioid in neuraxial anesthesia
More lipid soluble means quicker peak and systemic concentration
Dose of opioid in epidural vs spinal
How these affect local anesthesia dose
Epidural dose 5-10x higher than spinal
Can reduce LA dose and overall anesthetic reqs
Non opioid analgesics
Indication
Ceiling effect of what
1st line mild - moderate pain
ASA and acetaminophen of 650-1300 my
NSAIDs other than aspirin, analgesic ceiling may be higher
Acetaminophen
MOA
Central anti prostaglandin effect. Antipyretic. Pain reduced by block of NMDA receptor activation in CNS. Substance P in spinal cord
Acetaminophen
Lacks what
Good in who
Peripheral activity, weak anti-inflammatory action
PUD, peds, pts who need well functioning platelets
Acetaminophen
Potency
Po dose
Similar potency as ASA, same time-effect curve
325-650 mg q4-6h
Acetaminophen
IV dose/timing
1g over 15 min infusion only** q4-6 hours. Max 4000mg in 24h.
Acetaminophen
Metabolism
Conjugated and hydroxylated to inactive metabolites. Very little excreted unchanged by kidneys.
Time to reach concentration 30 min faster iv than oral
Acetaminophen
Why OD happens
Liver can only metab ltd amt of hepato toxic metabolic n acetyl p benzoquinone w glutathione. When glutathione outnumbered by OD of tyelenol- liver injury
Tyelenol
Max safe dose, considerations
How to prevent injury
4g/day. Even lower in ETOH use/abuse
Inc toxicity risk if taking isoniazid. Acetylcysteine can substitute for glutathione and prevent liver injury if given within 8h of OD
Tyelenol
About renal toxicity
Renal papillary accum of metabolites can cause renal cell necrosis. Can develop ESRD. NSAIDs higher risk than tyelenol for renal toxicity
Arachidonic acid released by what
Metabolized to what
Phospholipids by the enzyme phospholipase A2
Metab by cyclooxygenase, lipoxygenase, or epoxygenase
Breakdown products of arachidonic acid
Cyclooxygenase: prostaglandins, prostacyclin, thromboxanes
Lipoxygenase: leukotrienes, lipoxins
Epoxygenase: epoxy. Acid
Prostacyclin does what
Thromboxane does what
P- vasodilation and inhib plt activation
T- vasoconstriction and plt aggregation
Epoxy. Acid role
Regulates inflammation
Cox 1 does what
Breaks arachidonic acid into prostaglandins (gastric protection, hemostasis, renal function)
Cox 2 does what
Inducible, breaks into prostaglandins that mediate pain, inflammation, and fever
Aspirin
Uses
HA, muscle pain, arthritis, antipyretic
Mild to moderate pain
MI/stroke prevention
In MI for anti plt action
Aspirin
How its unlike other nsaids
Irreversible inhibition of COX. Single dose lasts lifetime of plt 8-10 days. Large doses can decrease PT
Aspirin
Adverse fx
ESRD: not induced by chronic asa, prolonged bleeding (15 min) Inc LFTs (reversible) Ppt athsma Cross sensitive w other nsaids GI bleed, cns stim
Aspirin
Dosing
Analgesic/antipyretic 325-650 mg
Anti-inflammatory 1000mg (3-5g/day)
Inc dose gradually, follow serum levels, rarely used d/t gi fx
Aspirin clearance
OD leads to what
E 1/2t 15-20 min aspirin and 2-3h for active metabolite salicylic acid
Metabolic acidosis and tinnitus
Aspirin
When it shouldn’t be used
Viral syndromes in kids and teens, risk Reye’s syndrome encephalopathy
How non acetylated salicylates compare to aspirin
More favorable toxicity profile. Dont mess w plt aggregation, rarely assoc w gi bleed, tolerated by athsmatics
NSAIDs
Use for
Arthritis, musculoskeletal pain, ha, dysmenorrhea
Ceiling effect in postop pain
More effective than aspirin or tyelenol
NSAIDs
Mechanism
Cox inhibition. Blocks conversion of arachidonic acid to prostaglandins (upstream). Decreases release and production of PGs. Anti-inflammatory, antipyretic, analgesic
NSAIDs
About drug and metabolism
Weak acid, well absorbed Highly protein bound Small Vd Extensively metabolized and excreted in urine 1/2 life 6-12h, varies
NSAIDs
Reaction/who
Interaction w platelets
Athsma and anaphylactic reaction in aspirin sensitive pts
Reversible inhibition of plt agg. Cox 1 blocks synthesis of thromboxane A2
NSAIDs
Adverse effects
Pregnancy
Hepatic injury, aseptic meningitis
Category b, avoid in pregnancy. Esp 3rd trimester, category d d/t premature closure of DA
NSAIDs peri-op
SE in surgery
Inhib of cox can lead to renal injury, gastric ulceration, excessive bleeding, and impaired bone healing
NSAID effects on GI
Fx/how
Dyspepsia, GI bleed, PUD
Inhib of PGs that maintain normal gastric and duodenal mucosa- inc acid production and decreases mucus production/gastric bf
NSAIDs
Local gastric irritation caused by what
Lipid soluble at low ph, enter gastric mucosal cells, lose lipid solubility, become trapped in cell
GI adverse effects of NSAIDs
Risk factors
High dose, prolonged use, prev ulcers, ETOH intak, elderly, corticosteroid use**
Low GI risk nsaids
Low dose: ibuprofen and naproxen
Also: etodolac, sulindac, celecoxib
Moderate risk nsaids gi
Ibuprofen and naproxen and med to high doses
Diclofenac, oxaprozin, meloxicam, nabumetone
High risk nsaids to gi
Tolmetin, peroxicam, aspirin, indomethacin, ketorolac
NSAIDs renal adverse effects
Dec synthesis of renal vasodilator PGs (pge2)
Decreased renal bf, na and fluid retention, can cause renal fail/htn.
Interstitial nephritis rare.
NSAIDs renal AE
RFs
People who require prostaglandins for renal perfusion: elderly, CHF, htn, dm, renal insufficiency, ascites, volume depletion, diuretic therapy
Renal risk of specific nsaids
Can occur with all
Inc risk: longer 1/2 life, potent cox inhibitors (toradol and indocin), higher dose
Renal risk nsaids
Which ones are renal roaring
Lower risk but not devoid of risk
Sulindac, nabumetone, celecoxib
NSAIDs drug interactions
Increases effects of what/how
Displaces highly protein bound agents: warfarin, phenytoin, sulfonylureas, sulfonamids, digoxin
NSAIDs
Reduces effects of
Diuretics, b blockers, ACEIs via suppression of renal PGs
NSAIDs
Inc __ levels
What increases levels of most nsaids
Lithium
Probenecid, avoid w ketorolac
Ketorolac
Comparison
IM or IV compared to mild opioids. Similar timing of pain relief to morphine but no vent/cv depression
Ketorolac
Adverse effects
Similar to typical nsaids
GI, bleeding time, renal toxicity, bronchospasm
Ketorolac
Max use
Onset
E 1/2t
5 days max
10 min IV
5 hours, prolonged 30-50% in elderly
Ketorolac
About drug
DOA
Metabolism
99% protein bound
6-8hrs
Conjugated in liver
Ketorolac
IV dose
30 mg IV x 1 or q6 hrs
Max dose daily 120 mg
Cut dose in 1/2 for elderly
Selective nsaids
Which/action
Celebrex. Inhibit cox 2. Not more effective at pain/inflam but less gastric effects, same renal AE
Celebrex
Dosage
Consider what
Dont give to who
<200mg/day
Comparable to 500mg of naproxen bid
Risk for CV and GI events
Take w food and dont give to pts w sulfonamide allergy
Selective and non selective nsaids
Black box warnings
Inc risk cv thrombotic events, mi, stroke
Inc gi bleed/ulcer/perf of stomach or intestines
Adjuvant analgesics
Antidepressants and anticonvulsants for neuropathic pain
Neurontin for what
Diabetic neuropathy and postherpetic neuralgia
Lyrica
How it works
For what
Gabanergic
Diabetic neuropathy
Postherpetic neuralgia
Fibromyalgia
Tegretol
How it works
For what
Na channel blocker and gabanergic
Trigeminal neuralgia
Dilantin, depakote, klonopin, and topamax for what
Neuropathic pain
Lamictal
How it acts
For what
Gabanergic
Central post stroke pain and HIV associated pain
Hydroxyzine
Indication and action
Low dose iv/Im adds analgesic effect to opioids in cancer and post op pain, reduces ponv
Antihistamine and antiinflammatory
Corticosteroids
Indication
Analgesia in pts w inflammatory diseases or tumor infiltration of nerves
Topical analgesics
Which drugs
Lidoderm-post herpetic neuralgia
Topical Emla
Capsaicin- neuropathic/OA pain
Transdermal clonidine patch- pain/hyperalgesia in sympathetically maintained pain
