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N926 Pharmacology > Opioids > Flashcards

Opioids Flashcards

1
Q

Opiate

A

Naturally occurring

Morphine & Codeine

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2
Q

Semi-Synthesized Opioid

A

Heroin

Modified natural occurring opiate form (Morphine or Codeine)

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3
Q

Synthetic Opioids

A

Contain a phenanthrene nucleus
Synthesized rather than modified
Created from scratch; completely man-made
Derivatives: Methadone (recent resurgence; long half-life), Benzomorphan, & Phenylpiperidine
Fentanyl, Sufentanil, Alfentanil, & Remifentanil
Different w/ regards to potency, rate of plasma equilibrium, and action site

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4
Q

Opium Classes

A

Phenanthrenes - Morphine, Codeine, & Thebaine

Benzylisoquinolines - Papaverine & Noscapine

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5
Q

Opioid Receptor Locations

A

Primarily located central in brain and spinal cord
Receptors throughout body involved w/ pain perception, impulses, & responses
Peripheral receptors - least likely site
Injecting opioid at pain site Ø to minimal response d/t no peripheral receptors

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6
Q

MOA

A

GPCR
Decrease neurotransmission
Mimics actions of endogenous ligands (enkephalins, endorphins, dynorphins, NE)
Post-synaptic attach to GPCRs 2nd messenger causes increased K+ conductance = decreased function

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7
Q

Endogenous Pain Modulation

A

Survival benefit
Substances: Endorphins, enkephalins, dynorphins, norepinephrine
Natural response to modulate pain
Pre-synaptic inhibit release ACh, dopamine, NE, and substance P

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8
Q

Who hypothesized pain perception r/t brain?

A

Rene Descartes

Treatise of Man

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9
Q

Chronic Pain

A

Receptors can be located peripherally at pain site and initiated anywhere along the pain pathway
Opioids not the best drugs to treat

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10
Q

What substances are released at site that send pain signal when cell destruction occurs?

A 
Substance P
Calcitonin gene-related peptide
Serotonin
Histamine
Swelling causes pain on nerves
Neuro-electrical stimulation creates nerve impulse
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11
Q

Pain Pathway

A

Injury/damage to cell → substances release → neuro-electrical stimulation/impulse → 1st order neuron → DRG → synapse at 2nd order neuron in spinal cord → transmission to midbrain → 3rd order neuron → signal to associated part experiencing the pain (4th order neuron) → motor response → Fight or flight response triggered
Spinal reflex arc

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12
Q

Opioid Agonist Role

A

Produce analgesia - block pain pathway transmission
Do NOT cause:
Loss of touch
Loss or proprioception (perception or awareness of the position and movement of the body)
Loss of consciousness (in appropriate doses)

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13
Q

Where are pain fibers located?

A

Rexed lamina 1, 2, & 5

Located in substantia gelatinosa of the dorsal horn

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14
Q

Another Receptor Site

A

NMDA receptors

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15
Q

In regards to MOA, Opioids do not…

A

Block nerve impulses (only LA)

Alter afferent nerve ending responsiveness to noxious stimulation

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16
Q

Brain Receptors

A

Periaqueductal gray - recognized pain and tells body to release endogenous substances
Locus coeruleus - r/t alertness (same receptor site as Dexmedetomidine)
Rostral ventral medulla - motor response

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17
Q

Spinal Cord Receptors

A

Primary afferent and interneurons of the dorsal horn

Where pain signals transmitted

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18
Q

Mu Receptors

A

Principally responsible for supraspinal and spinal analgesia
Mu1 - analgesia (supraspinal and spinal), euphoria, miosis, bradycardia, urinary retention
Mu2 - analgesia (spinal), ventilation depression, physical dependence, consitipation

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19
Q

Delta Receptors

A

Response to endogenous ligands known as enkephalins & may serve to modulate Mu receptor activity
Analgesia (supraspinal and spinal), respiratory depression, physical dependence, urinary retention, and constipation

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20
Q

Kappa Receptors

A

Activation results in inhibition of neurotransmitter release
Analgesia (supraspinal and spinal)
Dysphoria, sedation
Miosis
Diuresis
Lesser extent - hypoventilation and high-intensity pain
Agonist-antagonist often act primarily on K receptors (limited response; not full efficacy)
Low abuse potential

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21
Q

Metabolism

A

Most metabolized in liver
Exception: Remifentanil
Active metabolites must be conjugated to inactivate
Small dose effects terminated through redistribution
Metabolism terminates effects of multiple doses and infusions

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22
Q

Excretion

A

Primarily kidneys

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23
Q

Cardiovascular Effects

A

Bradycardia w/ sustained BP
Impaired SNS response - orthostatic hypotension, venous pooling, & histamine release
Does not sensitize the heart of catecholamines
Synergism w/ other drugs often causes myocardial effects (Benzodiazepines & nitrous oxide)
Cardiac protectant effect - enhances myocardial resistance to oxidative and ischemic stresses (Sigma & Kappa receptors)

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24
Q

Respiratory Effects

A

Dose-dependent ventilation depression (Mu & delta receptors in the brainstem)
Regulate breathing rate & rhythm
Decreased responsiveness to CO2 - less acetylcholine & right shift in CO2 response curve
Decreased RR accompanied by TV compensation (slow, deep breaths)
Bronchial - decrease ciliary action & increase airway resistance (bronchial smooth muscle & histamine release)

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25
Cough Suppression
Medullary cough centers depression Codeine - bulky substitution on number 3 carbon position Dextromethorphan - dextrorotary - cough suppression w/out analgesia or respiratory depression Narcotic on induction (primarily Fentanyl) may stimulate cough reflex
26
CNS Effects
NOT anesthetics; awareness possible Most effective for visceral and dull pain Sedative & euphoric effects Analgesic effects - inhibit ascending transmission of nociceptive information & activate descending pathways Vasodilation - increased CBF & possibly ICP Use cautiously in head trauma patients - alter wakefulness, miosis, ventilation depression, increased sensitivity when blood-brain barrier compromised Do NOT alter neuromuscular blocking drug effects Miosis d/t action on autonomic nervous system component of Edinger-Westphal nucleus of oculomotor nerve - antagonized by atropine or Naloxone
27
Muscle Rigidity
NO effect on nerve conduction - cannot cause muscle contraction Skeletal muscle hypertonus "truncal rigidity" r/t Mu receptors acting on dopamine & GABA channels Resistance d/t laryngeal musculature contracture
28
Sedation
Morphine induces sedation that precedes analgesia | Unresponsive patient not necessarily pain free
29
Biliary Tract
Biliary smooth muscle & Oddi sphincter spasm Glucagon 2mg IV will reverse smooth muscle spasm, does not antagonize analgesic effects Pancreatic duct contraction - increase in amylase & lipase levels (mimics acute pancreatitis) Morphine NOT appropriate after cholecystectomy - Dilaudid or Fentanyl instead
30
GI Effects
Decreased gastric motility, propulsive activity, & emptying time - increase aspiration risk or delay drug absorption Opioid-induced constipation (can be debilitating in chronic users) Methylnatrexone can antagonize effects
31
N/V
Primary patient complaint Stimulation of chemoreceptor trigger zone in medulla - serotonin type 3 (5 hydroxytriptamine or 5-HT3) & dopamine type 2 receptors Increased GI secretions & delayed gastric emptying N/V not common in recumbent patient - vestibular effect?
32
GU Effects
Opioid-induced augmentation of detrusor muscle tone results in urgency Enhanced urinary sphincter tone makes voiding difficult
33
Cutaneous Changes
``` Causes blood vessels to dilate - warm, flushed skin Histamine release (not an allergy) -conjunctival erythema, pruritis, itching, rash, urticaria Especially intrathecal (epidural/spinal) Morphine - more long-term effects as compared to Fentanyl ```
34
Placental Transfer
Readily crosses placenta - results in neonatal depression Morphine greater than meperidine Chronic use can cause neonatal physical dependence Naloxone may precipitate NAS
35
Drug Interactions
Cholinergic system - positive opioid analgesia modulator | Ventilatory effects can be exaggerated by other drugs: Amphetamines, Phenothiazines, MOAIs, Tricyclics, Benzodiazepines
36
Overdose
Ventilation depression - slow, deep breathing TRIAD: Miosis, hypoventilation, coma Hypotension and seizures develop if arterial hypoxemia persists Treatment - mechanical ventilation, supplemental oxygen, antagonist to reverse
37
Reflex Coughing
"Provocation" of coughing - cause unclear Imbalance b/w sympathetic and vagal nerve innervation (SNS/PSNS) Juxtacapillary irritant receptors stimulation Fentanyl, sufentanil, & alfentanil NOT seen w/ Morphine or Hydromorphone
38
Tolerance/Dependence
Cross-tolerance can occur b/w all opioids Tolerance w/out physical dependence possible, but not vice versa Pharmacodynamic tolerance - receptor desensitization & down regulation, cAMP up-regulation (Morphine 2-3 weeks - much quicker w/ more potent drugs) Everything except miosis & bowel motility - all or nothing Long-term opioid use activates NMDA receptors - down regulates spinal glutamate receptors
39
Withdrawal Abstinence Syndrome
Initial symptoms - yawning, diaphoresis, lacrimation Insomnia & restlessness common Cramps, N/V, and diarrhea peak at 72hrs then decline in the next 7-10 days (up to 2 weeks) Tolerance quickly lost during withdrawal
40
Morphine
STANDARD to compare all other opioids Produces analgesia, euphoria, sedation, decreased concentration Nausea, body warmth, pruritis (nose), dry mouth, extremity heaviness Increases pain threshold & modifies noxious stimulation perception Effective against visceral, muscles, joints - against slow, dull pain when given preemptively
41
Morphine PK
Onset 15-30min (slow compared to other opioids) Only small portion reaches CNS - poor lipid solubility, high ionization degree, protein binding, rapid liver conjugation Increased CBF d/t vasodilation Accumulates rapidly in kidneys, liver, & muscle NO first-pass effect in the lungs Primary metabolism - conjugation w/ glucuronic acid Significant renal metabolism
42
Morphine Metabolites
75% morphine-3-glucuronide (inactive) 5-10% morphine-6-glucuronide (active) Normorphine
43
Morphine-6-Glucuronide
Active Morphine metabolite More potent than Morphine Longer duration of action High analgesic potency 65x higher than Morphine
44
Codeine
Know implications for patient coming into surgery Naturally occurring opioid Elimination half-life 3-3.5hrs PRODRUG - inactive compound metabolized in body to produce drug (Morphine) Morphine 10x more potent than Codeine
45
Meperidine
Basis for most drugs used now Synthesized in 1939 - phenylpiperdine ring Several analogues (structurally similar) - Fentanyl, Sufentanil, Alfentanil, Remifentanil Structurally similar to Atropine - mild antispasmodic effects Mu receptor agonist Primary use: Anti-shivering postoperatively Stimulates KAPPA receptors High doses - negative cardiac inotropic effects & histamine release
46
Meperidine PK
1/10 as potent as Morphine Duration of action 2-4hrs Similar sedation, euphoria, nausea, vomiting, ventilation depression Extensive first pass metabolism by liver - limits oral usefulness
47
Meperidine Metabolites
90% demethylization to normeperidine Normeperidine active - needs to be broken down 10% hydrolysis to meperidinic acid
48
Normeperidine
``` Meperidine active metabolite Half as active as Meperidine Elimination half-life 15hrs >30hrs in renal failure Increased sensitivity in elderly Eventually undergoes hydrolysis to meperidinic acid ```
49
Meperidine Elimination
Excretion pH dependent Decreased renal function can result in metabolites accumulation
50
Meperidine SE
Similar to Atropine d/t structural Mydriasis (dilated pupils) & increase HR High doses - decrease myocardial contractility Delirium & seizures reflects normeperidine accumulation (high CNS effects) Serotonin syndrome in patients taking MAO inhibitor or Fluoxetine Less biliary tract spasm Withdraw develops more rapidly & shorter duration Elimination half-life 2-4hrs
51
Opioid Potencies
``` Tramadol/Meperidine 1/10 MORPHINE Buprenorphine 0.3mg IM = 10mg Morphine Methadone 1/4 (long-acting) Hydromorphone 5x Fentanyl 75-125x ```
52
Fentanyl Analogue Potencies
MOST POTENT Sufentanil 5-10x more potent than Fentanyl Fentanyl 75-125x more potent than Morphine Remifentanil (similar to Fentanyl) Alfentanil (less potent than Fentanyl) LEAST POTENT
53
Fentanyl Analogue Vd
Fentanyl 4L/kg Sufentanil 2L/kg Alfentanil 0.6L/kg Remifentanil 0.35L/kg
54
Fentanyl Analogue Ionization
Alfentanil 90% non-ionized Remifentanil 58% Sufentanil 20% Fentanyl 10%
55
Fentanyl Analogue pKa
Fentanyl pKa 8.4 Sufentanil 8.1 Remifentanil 7.1 Alfentanil 6.5
56
Fentanyl
Most widely used opioid analgesic in anesthesia Phenylpiperidine ring 75-125x more potent than Morphine
57
Fentanyl PK
Rapid onset 1-3min Shorter duration Lipid soluble Redistribution terminates single dose effect 1st pass uptake in lungs Metabolism: N-dealkylation & hydroxylation Minimal metabolites Longer elimination half-time than Morphine Vd 4L/kg more than 80% leaves the plasma < 5min Elderly prolong elimination d/t ↓ clearance Highly protein-bound Cirrhosis does not prolong elimination half-time Context sensitive half-life increases w/ infusion > 2hrs
58
Fentanyl Dose
``` Block sympathetic stim 1-3mcg/kg (prior to anesthesia induction) Analgesia 1-3mcg/kg Surgical as sole anesthetic 50-150mcg/kg Peds PO 15-20mcg/kg (pre-op sedation) Transdermal available ```
59
Fentanyl SE
Similar profile to Morphine "Secondary peaks" d/t 1st pass lung uptake True allergy extremely rare - does not evoke histamine release; hypotension unlikely Bradycardia more prominent Associated w/ modest ICP increases Seizure activity; myoclonus (inhibitory neurons inhibition)
60
Sufentanil
Thienyl Fentanyl analogue | 5-10x more potent than Fentanyl
61
Sufentanil PK
Extensive protein binding Rapid redistribution terminates effects Significant 1st pass pulmonary uptake Metabolism: N-dealkylation & O-demethylation Active metabolite - Desmethyl Sufentanil Clearance sensitive to hepatic blood flow Normal renal function important to clearance
62
Sufentanil Dose
Analgesia 0.1-0.4mcg/kg Longer duration & less respiratory depression Chest wall rigidity after induction doses
63
Alfentanil
pKa 6.5 Less potent than Fentanyl Shorter duration
64
Alfentanil PK
``` Rapid onset & offset 90% non-ionized Bound by alpha 1 glycoproteins Vd 0.6L/kg Metabolism: Piperidine N-dealkylation to Noralfentanil & Amide N-dealkylation to N-Phenylpropionamide ```
65
Alfentanil Dose
Blunt stim 15mcg/kg Noxious stim 30mcg/kg Induction (unconsciousness) 150-300mcg/kg Combination w/ inhalation anesthetic 15-150mcg/kg/hr
66
Alfentanil SE
More significant ↓ BP Diminished N/V incidence Acute dystonia (avoid in untreated Parkinson's patients)
67
Remifentanil
Selective Mu agonist Similar potency to Fentanyl ESTER linkage Synergistic w/ Propofol Brief action, titratable, does not accumulate, & rapid recovery Cases requiring transient profound analgesic effect - retrobulbar block, direct laryngoscopy, tracheal intubation, NSGY head pins
68
Remifentanil PK
``` Small Vd Rapid clearance Context sensitive half-life = 4min Metabolism: Non-specific plasma esterases No active metabolites Unchanged w/ renal or hepatic failure ```
69
Remifentanil Dose
Induction 0.25-1mcg/kg bolus prior to induction agent Analgesia 0.05-0.2mcg/kg/min Sedation 0.05-0.1mcg/kg/min in combination w/ 2mg Midazolam
70
Remifentanil SE
N/V Ventilation depression ↓ systemic BP Administer longer acting opioid to treat post-op analgesia Hyperalgesia 2nd to acute opioid tolerance (Ketamine or Magnesium to block) "Seizure-like" activity
71
Hydromorphine (Dilaudid)
5x more potent than Morphine Slightly shorter duration Less hydrophilic - faster onset, more sedation, less euphoria Alternative to treat moderate to severe pain Side effects: Agitation & myoclonus
72
Methadone
``` Synthetic opioid Oral opioid in chronic pain settings Withdrawal & drug suppression Half-life 12hrs Variation* ```
73
Methadone Dose
1/4 dose Morphine | 20mg IV produces post-op analgesia >24hrs
74
Methadone SE
``` Ventilation depression Miosis Constipation Biliary tract spasm Sedative & euphoric effects less ```
75
Methadone Chronic Pain Treatment
Low abuse potential NMDA antagonist activity potentially beneficial to treat neuropathic pain Disadvantage - prolonged & unpredictable half-life Drug accumulation & ventilation depression
76
Tramadol
Synthetic Codeine analog Weak/moderate Mu agonist Less potent than Morphine Less addictive chronic pain treatment option Enhances descending inhibitory pathway function
77
Tramadol Metabolism
CYP450 | Metabolite O-desmethyltramadol (modest analgesic effects)
78
Tramadol Disadvantages
Interacts w/ Coumadin Drug-related seizures (may lower threshold) High N/V incidence Ondansetron (Zofran) may interfere w/ analgesic component 5-hydroxytryptamine reuptake
79
Heroin
``` Synthetic opioid More rapid onset Rapidly penetrates the CNS where hydrolyzed to active metabolites - Monoacetylmorphine & Morphine Less nausea ↑ physical dependence liability ```
80
Opioid Agonist-Antagonist
Bind to Mu receptors but produce limited responses or no effect Analgesia w/ limited ventilation depression "Ceiling effect" Patients who cannot tolerate pure agonist
81
Butorphanol
Limited intraoperative use Resembles Pentazocine 20x agonist effects & 10-30x antagonist effects Low Mu receptor affinity - produces antagonism Moderate Kappa receptor affinity - analgesia & anti-shivering
82
Butorphanol PK
``` Rapidly absorbed after IM injection Metabolized in liver Excretion primarily via bile Hydroxybutorphanol - inactive metabolite Elimination half-life 2.5-3hrs ```
83
Butorphanol SE
Sedation, nausea, diaphoresis Dysphoria Ventilation depression ↑ catecholamine response (HR, BP, CO, PAP - pulmonary artery pressure) Mild biliary & GI tract symptoms Concomitant opioid agonist limits effects Withdrawal following acute discontinuation in chronic therapy
84
Nalbuphine
``` Chemically r/t Oxymorphone & Naloxone Morphine analgesic properties 1/4 antagonist Nalorphine Metabolized in liver Elimination half-life 3-6hrs Antagonist effects at Mu receptors Admin prior to opioid may diminish effects peri-op After opioid admin reserves 2-3hrs ventilation depression BUT maintain analgesia ```
85
Nalbuphine SE
Sedation most common Less dysphoria than Butorphanol Ventilation depression has ceiling effect (30mg) Catecholamine stimulation effects - beneficial in cardiac patients needing sedation & analgesia
86
Buprenorphine
Derived from Thebaine Potent 0.3mg IM = 10mg Morphine Post-op pain r/t cancer, renal colic, MI
87
Buprenorphine SE
Drowsiness, N/V, ventilation depression Resistance to Naloxone antagonism Dysphoria unlikely Low abuse risk
88
Opioid Antagonists
Substitute alkyl group for methyl group | Pure Mu antagonists - Naloxone, Naltrexone, & Nalmefene
89
Naloxone
Treat opioid induced hypoventilation, ventilation depression in neonate, deliberate drug overdose, suspected physical dependence Short half-life 30-45min Metabolism: liver conjugation w/ glucuronic acid Naloxone 3-glucuronide (metabolite)
90
Naloxone Dose
IV 1-4mcg/kg PCA 5mcg/kg/hr fix ventilation depression w/out affecting analgesia PO 1/5 as potent d/t 1st pass hepatic metabolism
91
Naloxone SE
Analgesia reversal Titrate to maintain analgesia and reverse hypoventilation N/S Increased SNS activity - sudden pain onset, tachycardia, hypertension, pulmonary edema, cardiac dysrhythmia Fetal withdrawal
92
Naltrexone
Oral antagonist w/ sustained effects >24hrs | Used to treat alcoholism
93
Nalmefene
Pure opioid antagonist | Naltrexone 6-methylene analogue
94
Nalmefene PK
Prophylactic treatment decreases N/V and pruritis in PCA patient Primary advantage - longer duration Metabolized in liver by hepatic conjugation Pulmonary edema SE
95
Nalmefene Dose
15-25mcg until effect achieved MAX 1mcg/kg Equipotent to Naloxone
96
Methylnaltrexone
Quaternary opioid receptor agonist Highly ionized - difficult to penetrate CNS Attenuates Morphine induced delayed gastric emptying Decreases nausea incidence
97
Opioid Allergy
TRUE opioid allergies = rare - Histamine release, orthostatic hypotension, N/V Fentanyl does not cross-react w/ Morphine derivatives
98
Immune Modulation
Opioid receptors present on immune cells Immunosuppression (NK cell depression) following prolonged exposure or abrupt withdrawal Pain itself can impair immune function
99
PCA
Alternative to intermittent bolus Allows patient to address own analgesia Advantages: ↓ healthcare provider workload, ↑ patient satisfaction, ↓ opioid consumption, & inherent safety Marginally improved analgesia, but ↑ pain satisfaction Remifentanil PCA 1st labor stage provides analgesia w/ minimal neonatal effects
100
Neuraxial Opioids
Intrathecal opioids target Mu receptors in substantia gelatinosa in the spinal cord NO sympathectomy, sensory block, or weakness Epidural placement - Mu receptors & systemic absorption & minimal to no IV administration Epi enhances intrathecal Morphine effects PK: Uptake into fat systemic absorption & diffusion across dura & less lipid soluble more likely to stay in CNS SE: Pruritis, N/V, urinary retention, & ventilation depression (classic signs), sedation, myoclonus (rare), herpes virus reactivation, miosis, nystagmus, vertigo, delayed gastric emptying, priapism, spinal cord damage *dose dependent*

N926 Pharmacology (17 decks)

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