PO Opioids/NSAIDs Flashcards
(68 cards)
1
Q
3 Major Sites of Action of Opioids
A
Brain, Spinal Cord and Periphery:
- Brain (supraspinal): Opioids work pre- and post- synaptically to activate descending inhibitory pathways
- Spinal cord (spinal): Directly on dorsal horn of spinal cord
- Periphery: Peripheral terminals of nociceptive neurons
2
Q
Opioids are used in Anesthesia for:
A
- Attenuate SNS response to noxious stimuli
- Adjunct to inhaled agents during anesthesia
- Sole anesthetic (fentanyl/sufent/morphine- cardiac anesthesia, critically ill pts)
- Peri-op and post-op control of pain
3
Q
Unique Opioid Characteristics set them apart from other Analgesics
A
- Moderate to severe pain
- No max dose or ceiling effect
- Tolerance can develop w/ chronic use
- Tolerance associated w/ physical dependence but not necessarily w/ psychological dependence
- Cross-tolerance
- Produce analgesia w/out loss of
- Touch
- Proprioception
- Consciousness (in smaller doses)
4
Q
Opioid Classification
A
- Naturally occurring
- Morphine and codeine
- Semisynthetic: Analogs of morphine
- Heroin and Dihydromorphone
- Synthetic
- Exogenous, 4 groups
- Further classified into:
- Agonist, Partial agonist, Mixed agonist/antagonis, Antagonist
5
Q
Opioids: Mechanism of Action:
Post-synaptic
A
- Activate stereospecific G-protein coupled receptors
-
Post-synaptic - directly decreases neurotransmission
- Increased K+ conductance (hyperpolarization)
- Ca++ channel inactivation (decreased NT release)
- Modulation of phosphoinositide – signaling cascade and phospholipase C
- Inhibit adenylate cyclase (decreased cAMP)
-
Post-synaptic - directly decreases neurotransmission
6
Q
Opioids: Mechanism of Action:
Pre-synaptic
A
- Activate stereospecific G-protein coupled receptors
-
Pre-synaptic- inhibits release of excitatory NT’s
- ↓ release of Ach, DA, norepi, substance P
-
Pre-synaptic- inhibits release of excitatory NT’s
7
Q
Opioid Receptors
A
- Receptors: mu, kappa, and delta
- Theory: synthetic opioids mimic action of endogenous opioids by binding to opioid receptors
- Activate endogenous pain modulating systems
- Variable affinity and efficacy at different receptors types among different drugs in this class
8
Q
Mu receptor
A
- Subtypes mu-1 and mu-2
- Mu-3 receptors thought to be involved in immune process
- All endogenous and exogenous agonists act on mu receptors
- Mu receptors in brain, periphery and spinal cord
9
Q
Mu-1 receptor
A
- Mu-1 receptor
- Supraspinal, spinal, and peripheral analgesia
- Low abuse potential
- Euphoria
- Miosis
- Bradycardia
- Hypothermia
- Urinary retention
- All endogenous and synthetic opioid agonists act on these receptors
10
Q
Mu-2 Receptor
A
- Mu-2 Receptor
- Spinal analgesia (also some supraspinal)
- Physical dependence
- Hypoventilation
- Constipation
- All endogenous and exogenous agonists act on these receptor
11
Q
Kappa Receptor
A
- Kappa Receptor
- Supraspinal, spinal and peripheral analgesia
- Low abuse potential
- Dysphoria
- Sedation
- Miosis
- Diuresis
- Dynorphins act on these receptors
- Opioid agonist-antagonists often have principle actions at kappa receptor
12
Q
Delta Receptor
A
- Delta Receptor
- Supraspinal, spinal, and peripheral analgesia
- Physical dependence
- Hypoventilation
- Constipation
- Urinary retention
- Enkephalins work on these receptor
13
Q
Genetics of CYP450 System and Influence on Opioids
A
-
CYP2D6 = 5 common mutations can alter metabolism of:
- Codeine, oxycodone, hydrocodone, and methadone
- Unpredictable pharmacokinetics and ½ lives
- Fentanyl’s metabolism least likely to be impacted by genetic variability in surgical population = predictable pharmacokinetics
- Rate of metabolism may influence side effect rate
- Studies indicate ultra-rapid metabolizers at ↑ r/f PONV
14
Q
Systemic Effects of Opioids
A
- Many systemic effects similar among opioids
- Although different opioids are active at different receptors to different degrees
-
Variable SE and efficacy profiles
- Variance in chemical structures
- Morphine = prototype
15
Q
CNS Effects
A
- Analgesia
- Euphoria
- Drowsiness/sleep
- Miosis
- Nausea- chemoreceptor trigger zone
- Does not produce amnesia
16
Q
Pulmonary Effects
A
- ↓RR and ↑TV
- At higher doses = ↓ RR & TV → leading to apnea
- ↓ response to CO2 and hypoxia
17
Q
GI Effects
A
- N/V
- Decreased gastric emptying
- Direct stimulation of chemoreceptor trigger zone on floor of 4th ventricle
- Partial dopamine agonist?
- Balanced by depression of medullary vomiting center
18
Q
Pruritis
A
- Cause unknown
- Occurs primarily on face particularly nose
- “fentanyl nose itch”
- Histamine release most probable cause w/ some (MSO4)
19
Q
Morphine
A
- Severe acute pain almost always IM or IV admin
- PO used for chronic pain and CA pain
- Slow release formulations available – delayed onset 3-5 hrs (not used pre-op/intra-op much)
- Considerable first pass effect
- E½t 3-4 hrs converted to active metabolite (morphine -6-glucuronide)
20
Q
Codeine (3-methylmorphine)
A
-
Mild Pain Relief
- Better for cough (lower dose) than pain relief
- PO
- E½t = 3 hrs
-
Prodrug: 10% is metabolized by CYP2D6 to its active form
- Active form = morphine
- Remaining drug demethylated to inactive metabolite
- 10% Caucasians, 30% Asians lack 2D6 = no analgesic effect
- Antitussive effect remains even w/out conversion
21
Q
Hydrocodone
A
- AKA – Vicodan
- PO
- Always combined w/ either ASA, antihistamine, acetaminophen, ibuprofen
- Used for chronic pain
- Analgesic and antitussive
- High abuse potential
22
Q
Oxycodone
A
- AKA Oxycontin, Percocet, Percodan
- oxycontin -sustained release preparation
- PO
- Moderate to severe pain; useful for chronic and post-op pain
- Also in combo w/ ASA or acetaminophen
- No active metabolites - safer in renal dysfunction
- High abuse potential
23
Q
Methadone
A
- PO, IV, SubQ
- Synthetic
- Long E½t- 8-59 hrs or 13-100 hrs (sources vary)!
- No active metabolites - safer w/ renal dysfunction
- Opioid addiction treatment (maintenance) dosed QD
- Chronic pain syndrome treatment: doses BID or TID (q4-8 hr)
- Neuropathic pain
- At r/f severe resp depression 2° to prolonged & unpredictable E½t
24
Q
Tolerance to Opioids
A
- Tolerance common w/ chronic use (after 2-3 wks of use)
- Cross-tolerance exists among all full agonists but not complete
- When switching to another opioid, start w/ ½ or less of customary equianalgesic dose
- Switching opioid-tolerant pts to methadone may improve pain relief
- Tolerance to sedative and emetic effects develop rapidly, but not constipation
- A stimulant laxative +/- a stool softener should be started early (senna/docusate)
25
Tolerance to Opioids:
Patient notices...
* Pt notices:
1. **Reduction in adverse effects**
2. **Shorter duration** of analgesia
3. **Decreased effectiveness** of each dose
4. **Tolerance** to most adverse effects include:
* Respiratory and CNS depression
* Can be surmounted by increasing dose
26
Dependence
* *Physical dependence* causes abstinence symptoms w/ sudden d/c
* *Clinically significant dependence* develops only after several wks of chronic tx
* Addiction involves *psychological dependence* and biologic and social factors
* CA pain and acute pain pts **rarely** experience euphoria; even more rarely develop psychological dependence or addiction
27
Dosage (PO)
* Dose varies widely from pt to pt
* No min or max dose except limitation by dose of acetaminophen or aspirin
* Use dose required to _maintain optimum pain relief_ w/ _tolerable SE's_
* After initial titration w/ short-acting opioid in first 12-24 hrs, dose determination by around-clock dosing recommended
* **Use sustained release formulas in chronic pain**
* Immediate release doses that are 10 to 15% of total daily dose should be used for breakthrough pain
* PCA, given IV, SQ or other routes now widely used when PO route not feasible
28
Non-opioid Analgesics
* **Acetaminophen** (Tylenol)
* **Cyclooxygenase-2 Specific Inhibitors**
* Celecoxib (Celebrex)
* **Acetylated Salicylate**
* Aspirin (ASA)
* **NSAIDS**
* _(1) Ibuprofen (Motrin),_ (2)_Naproxen (Naprosyn)_
* (3) Oxaprozin (Daypro)
* (4) Sulin**dac** (Clinoril), (5) Etodo**lac** (Lodine)
* (6) Ketoro**lac** (Toradol), (7) Diclofe**nac** (Voltaren)
* (8) Indomethacin (Indocin)
* (9) Nabumetone (Relafen), (10) Tolmetin (Tolectin)
* (11) Pir**oxicam** (Feldene), (12) Mel**oxicam** (Mobic)
29
Non-opioid Analgesics:
Factors to be considered
* First line agents for **mild to moderate** pain
* _Ceiling effect_ of ASA and acetaminophen b/t 650-1300 mg
* NSAIDs other than ASA may have higher analgesic ceiling
* **Exceeding ceiling dose** of any of these drugs = increased adverse effects w/ **no added efficacy**
* Tolerance does not develop to analgesic effects of these drugs
30
Acetaminophen
effect/activity
* Central **anti-prostaglandin** effect
* Antipyretic
* Pain reduced via blockade of:
* NMDA receptor activation in CNS
* Substance P in spinal cord
* Lacks peripheral activity – **weak anti-inflammatory** action (not true NSAID)
* Good choice in: PUD, Peds pts, Pts who need well functioning platelets
31
Acetaminophen:
metabolism/excretion
Conjugated and hydroxylated to inactive metabolites; very little excreted unchanged by kidneys
32
Acetaminophen
Dosing
* PO similar potency as ASA (in single analgesic doses, has same time-effect curve)
* **PO Dose = 325-650 mg Q4-6 hrs**
* **IV dose** = **1 g over 15 min** **Q4-6 hrs**
* no \> **4000 mg in 24 hrs** (check to make sure no other sources of acetaminophen)
33
Acetaminophen
Dosing/Toxicity
* **_Overdose_** can cause serious or fatal **hepatic** injury
* Liver can only metabolize limited amount of hepatotoxic **metabolite N-acetyl-p-benzoquinone** w/ glutathione
* When glutathione outnumbered by OD of acetaminophen, hepatic injury occurs
* Max safe dose 4 g/day
* Safe dose lower in ETOH abuse (use caution)
* Also ↑ r/f toxicity in pts taking **isoniazid**
* **Acetylcysteine** can substitute for glutathione and prevent hepatic injury if given w/in 8 hrs of OD
* **_Renal toxicity_**
* Renal papillary accumulation of metabolites can cause renal cell necrosis
* May be responsible for development of some cases of ESRD
* However, NSAIDS higher risk of renal toxicity than acetaminophen
34
Review Physiology of Arachidonic Acid Metabolism
* Arachadonic acid is released from phospholipids by enzyme phospholipase A2
* Arachadonic acid is immediately metabolized by either:
* _Cyclooxygenase_ leads to formation of:
* Prostaglandins
* Prostacylcin
* Thromboxanes
* _Lipoxygenase_ leads to formation of:
* Leukotrienes
* Lipoxins
* _Epoxygenase_ leads to formation of:
* Epoxyeicosatetraenoic acid (4 types) – regulates inflammation further research necessary to determine precise role
35
Salicylates: Aspirin
Effects
* Unlike other NSAIDs, **irreversible inhibition** of COX
* Single dose inhibits plt function for lifetime of plt (8-10 days)
* Large doses can also decrease prothrombin
* **ESRD**
* Not induced by chronic ASA (in contrast to other NSAIDS)
* Prolonged bleeding (up to 15 min) in these pts w/ ASA
* Can **increase LFTs** (usually reversible)
* Single dose can ppt **asthma** in aspirin-sensitive patients
* **Cross-sensitivity** w/ other NSAIDS
* Like other NSAIDs, can cause **GI bleeding, PUD**
* **CNS stimulation**
36
Aspirin Uses
* Aspirin effective in most mild-mod. pain: Headache, muscle pain, arthritis
* Antipyretic
* MI/stroke prevention; protection during MI (anti-plt)
37
Aspirin Clearance
* Hepatic clearance:
* **E½t = 15-20 min for aspirin** and **2-3 hrs** for active **metabolite salicylic acid**
38
Salicylates: Aspirin
Analgesic vs Anti-inflammatory dosing
* _Analgesic/antipyretic_: 325-650 mg
* _Anti-inflammatory_: 1000 mg (3-5 g/day)
* Increase dose gradually
* Follow serum salicylate levels
* Rarely used d/t GI side effects
39
Salicylate overdose
metabolic acidosis,
tinnitus
40
When should aspirin not be used?
Aspirin should not be used during **viral syndromes in children and teenagers** because of risk of **Reye’s syndrome-encephalopathy**
41
Nonacetylated salicylates
* **Nonacetylated salicylates** have _more favorable_ toxicity profile
* Do not interfere w/ **plt aggregation**
* Rarely associated w/ **GI bleeding**
* Well tolerated by **asthmatic** pts
42
NSAIDs
Mechanism
* Mechanism
* Cyclooxygenase **(COX) inhibition** --\> Blocks conversion of arachidonic acid to prostaglandins (PGs) --\> Decreases production & release of PGs
* **Reversible inhibition** of plt aggregation
* Inhibition of COX-1 blocks synthesis of thromboxane A2 which inhibits plt aggreg
* Analgesic, anti-inflammatory, antipyretic activity
43
NSAIDs
* Analgesic efficacy
* Helpful for arthritis-related pain, musculoskeletal pain, headaches and dysmenorrhea → **ceiling effect w/ post-op pain**!
* More effective than full doses of ASA or acetaminophen
* Equal or greater than usual doses of an opioid combined w/ acetaminophen
* Different NSAIDs: Similar efficacy at equipotent doses. Pt-to-pt differences...Toxicity differences
* Anti-inflammatory
* **Asthma and anaphylactoid** reaction in _aspirin-sensitive_ pts
44
T or F: NSAIDS can cause physical dependence
FALSE.
Unlike opioids, no physical dependence
45
NSAIDS
Adverse Effects
**Rare** adverse effects:
Hepatic injury
Aseptic meningitis
46
NSAIDS and Pregnancy
* Pregnancy
* Best avoided but **Category B** if necessary
* **Avoid in 3rd trimester,** Category **D,** due to premature closure of DA
47
NSAIDS
Pk
* Weak acids - well-absorbed
* **Highly protein-bound** \>95%
* **Small Vd** (non-specific NSAIDS)
* Extensively metabolized and excreted in urine
* Half-life varies from \<6 hrs to \>12 hrs
48
NSAIDs: GI Adverse Effects
* **Dyspepsia, GI bleeding, PUD**
* Inhibition of PGs that maintain normal gastric and duodenal mucosa
* Increases acid production
* Decreases mucus production, gastric blood flow
* Local irritation
* Lipid soluble at low pH - enter gastric mucosal cells - lose lipid solubility - become trapped in cell
49
NSAIDS GI Adverse Effects:
Risk Factors
1. High doses
2. Prolonged use
3. Previous GI ulcer or bleeding
4. Excessive ETOH
5. Elderly
6. **_Corticosteroid use_**
50
GI Risk of Specific NSAIDs
* _Low Risk_
* Ibuprofen and naproxen at low doses
* Etodolac, sulindac
* Celecoxib
* _Moderate Risk_
* Ibuprofen and naproxen at mod-high doses
* Diclofenac, oxaprozin, meloxicam, nabumetone
* _High Risk_
* Ketorolac
* Piroxicam, indomethacin, tolmetin, aspirin
51
NSAIDs:
Renal Adverse Effects
* Decreased synthesis of renal vasodilator PGs (PGE2)
* Leads to decreased renal blood flow
* Fluid and Na+ retention
* May cause renal failure or HTN
* Interstitial nephritis (rare)
* Rarely clinically significant in healthy people
52
NSAIDS Renal Adverse Effects:
Risk Factors
* Risk factors (i.e. people who require prostaglandins for renal perfusion)
1. Old age
2. CHF
3. HTN
4. DM
5. renal insufficiency
6. ascites
7. volume depletion
8. diuretic therapy
53
Renal Risk of Specific NSAIDs
* Can occur w/ all NSAIDs
* **Increased risk**
* Higher dose
* Longer E1/2t
* Highly **potent COX inhibitors**
* Ketorolac, indomethacin
* “Renal sparing” (l**ower risk**, not devoid)
* Sulindac, celecoxib
* Nabumetone
54
NSAIDs: Drug Interactions
* Displaces other **highly protein-bound** agents
* **_Increases levels_** of **warfarin, phenytoin, sulfonylureas, sulfonamides, digoxin**
* Increases **lithium** levels
* **Probencid** increases levels of most NSAIDs
* Avoid w/ ketorolac
* **Increased r/f GI bleed** when combined w/ **anticoags**
* _Reduces effect_ of:
* diuretics, b-blockers, ACEIs via suppression of renal PGs
55
Ketorolac
* Only IV NSAID available in US
* **IM or IV comparable to mild opioids**
* Similar time to pain relief w/ ketorolac or morphine
* **Advantage: No ventilatory or CV depression**
* Adverse effects similar to typical NSAID:
* Increased **bleeding** time, peri-op blood loss, **GI bleeding, ulceration**, perforation and/or **renal toxicity** (esp in elderly or hypovolemic), potential life-threatening **bronchospasm**
* **Do not exceed 5 days of use**
56
Ketorolac
Pharmacokinetics
* IV onset: ~ 10 min
* DOA: 6-8 hrs
* E½t: 5 hrs (prolonged in elderly 30-50%)
* Highly protein bound (99%)
* Conjugated in liver
57
Ketorolac
Dose
* Dose IV:
* 30 mg IV X 1 or q 6 hrs
* Daily max dose 120 mg
* Elderly: (if you use at all) cut dose in ½
58
Selective NSAIDs
* Celecoxib (Celebrex) only agent available today
* *Rofecoxib (Vioxx), Valdecoxib (Bextra) withdrawn from market d/t ↑ MI risk*
* **Selectively inhibit COX-2** (nonselective NSAIDs inhibit COX-1 and COX-2)
* No more effective at reducing pain and inflammation
* _COX-1:_ gastric protection and production of TxA2 (vasoconstrictor, **plt aggregator**)
* _COX-2_: production of prostacyclin (vasodilator, **plt inhibitor**)
* Same risk of renal adverse effects
59
Celecoxib
* Use lowest effective dose
* _\<_ 200 mg/day
* 200 mg/day = naproxen 500 mg BID
* Consider pt’s r/f: **CV and GI** events
* Weigh risk vs. benefit
* PO
* Taken w/ food
* Avoid in pts w/ **sulfonamide allergy**
60
Black Box Warnings
Selective and non-selective NSAIDs
* CV Risk
* ↑ r/f serious CV thrombotic events, MI, stroke, which can be fatal
* GI Risk
* ↑ r/f bleeding, ulceration, perforation of stomach or intestines → can be fatal
61
Adjuvant Analgesics
* Antidepressants and anticonvulsants - drugs of choice for neuropathic pain syndromes
* TCAs (amitriptyline, nortriptyline, etc.)
* Diabetic neuropathy, postherpetic neuralgia, polyneuropathy, and nerve injury or infiltration with cancer
* May also improve underlying depression and insomnia
* Venlafaxine (Effexor)-SSNRI
* Neuropathic pain, headache, fibromyalgia, postmastectomy pain
* Duloxetine (Cymbalta)-SSNRI
62
Other Agents
* Hydroxyzine
* Low-dose IV/IM add analgesic effect to opioids in CA and post op pain while ↓ incidence of N/V
* Corticosteroids
* Can produce analgesia in some pts w/ **inflammatory** dz or **tumor infiltration of nerves**
* Topical analgesics
* 5% Lidocaine (lidoderm) approved for post herpetic neuralgia
* Topical EMLA useful for cutaneous anesthesia
* Capsaicin cream (Zostrix) for neuropathic and osteoarthritic pain
* Transdermal clonidine patch may improve pain and hyperalgesia in sympathetically maintained pain
* THC/CBD
* Ketamine
* Magnesium
63
Adjuvant Analgesics: Anticonvulsants (List them)
1. **Gabapentin (Neurontin)** –mechanism not well understood
2. **Pregabalin (Lyrica)** –gabanergic, analogue of GABA
3. **Carbamazepine (Tegretol)**-Na channel blocker, and GABAnergic
4. **Phenytoin (Dilantin)**, Sodium Valproate (Depakote), Clonazepam (Klonopin), and Topiramate (Topamax)
5. **Lamitrogen (Lamictal)**-Gabanergic
64
Gabapentin (Neurontin)
Gabapentin (Neurontin)
* Mechanism not well understood
* Diabetic neuropathy, postherpetic neuralgia
65
Pregabalin (Lyrica)
* Gabanergic, analogue of GABA
* Diabetic neuropathy, postherpetic neuralgia, fibromyalgia
* Analgesic effects may be related to Ca++ influx inhibition as well as inhibition of release of excitatory NT's in spinal and supraspinal pathways via binding to α 2 δ-1 subunit of presynaptic voltage-gated Ca++ channels in CNS.
66
Carbamazepine (Tegretol)
* **Na channel blocker** and GABAnergic
* FDA approved for **trigeminal neuralgia**
67
Phenytoin (Dilantin), Sodium Valproate (Depakote), Clonazepam (Klonopin), and Topiramate (Topamax)
May relieve **neuropathic** pain
68
Lamitrogen (Lamictal)
* Gabanergic
* Effective for central post-stroke pain and HIV-associated painful sensory neuropathies
