Pain & Opioids Exam 2 Flashcards
What are opioids effects on the CO₂ medullary center?
Opioids inhibit the CO₂ medullary center.
Differentiate opioids from narcotics.
- Opioids: all exogenous substances that bind to endogenous opioid receptors.
- Narcotic: any substance that can produce physical dependence (stupor).
What two types of opioid chemical structures are there?
- Phenanthrenes
- Benzylisoquinolines
What types of drugs are Phenanthrenes? What types of drugs are benzylisoquinolines?
Phenanthrenes: Morphine, codeine, thebaine
Benzylisoquinoline: Papaverine, noscapine
What is papaverine mostly used for?
Treating intra-arterial barbiturate administration (dilates the highly constricted artery).
What portions of the brain are the source of descending inhibitory signals? (3)
- Periaqueductal gray (PAG)
- RVM
- Dorsal horn
What endogenous substances have the same effect as opioids?
- Endorphins
- Enkephalins
- Dynorphines
Presynaptic inhibition of what neurotransmitters occurs with opioid administration?
- ACh
- Dopamine
- NE
- Substance P
How do opioids modulate pain at the cellular level?
- Agonizes opioid receptors in pre/post synapse
- hyperpolarization of cells
- decreased neurotransmission (ACh, NE, dopamine, Substance P)
Where are opioid receptors located in the brain?
- PAG
- Locus Coeruleus
- RVM (rostral ventral medulla)
- Hypothalamus
Where is the primary site of opioid receptors in the spinal cord?
- interneurons
- Substantia gelatinosa (aka Laminae 2)
Where is/are opioid receptors found outside the CNS?
- Sensory neurons
- immune cells
What are the four (most important) types of opioid receptors?
- Μu1 (μ₁)
- Μu2 (μ₂)
- Κappa (κ)
- Delta (δ)
Which opioid receptor(s) is/are responsible for respiratory depression & physical dependence?
- Μu2
- delta δ
Which receptors are responsible for constipation?
Mu 2 > delta
Which receptors can cause urinary retention? Are there any receptors that cause diuresis when bound?
- Retention: Μu1 and delta δ
- Diuresis: Kappa κ
All opioid receptors induce analgesia at both the brain and the spinal cord. T/F?
False
Μu2 receptors only cause analgesia at the spinal cord level.
What opioid receptors have low abuse potential when bound?
- Μu1
- Kappa κ
Which opioid receptor is responsible for euphoria, bradycardia, hypothermia, and miosis when bound?
Mu1
What agonists bind to each of the four opioid receptors?
- Mu1 & Mu2 = endorphins, morphine, synthetics.
- κ = dynorphins.
- δ = enkephalins.
Describe the adverse side effects of opioids on the cardiovascular system.
- ↓BP, venous return, and CO
- ↓HR or histamine release = ↓BP
- +N2O or benzo = CV depression
What possible cardiovascular benefits do opioids provide?
Myocardial ischemia protection (decrease oxygen demand)
What are the respiratory effects of opioids? What would symptoms of overdose be?
Depressed CNS response to CO₂ causing a right shift of PaCO₂ (↑)
Overdose = apnea, miosis, coma
What drug is given to treat apnea from opiod overdose?
- Physostigmine
- inhibits acetylcholinesterase
- increased ACh levels
- reverses ventilatory depresson but not analgesia
What would cause a leftward shift in PaCO₂? What would cause a rightward shift?
Leftward: Metabolic acidosis (to breathe off all that CO₂)
Rightward: sleep, opiates, anesthesia
Why should caution be used when administering opioids to head trauma patients?
Opioids ↓CBF and possibly ICP
What musculoskeletal abnormality occurs with opioid administration? What makes this condition worse? How is it treated?
- Skeletal chest wall and abdominal muscle rigidity.
- Mechanical ventilation
- Muscle relaxants and/or naloxone
What are sphincter of Oddi spasms? Which drugs can cause this?
Biliary smooth muscle spasm
* Fentanyl (99%)
* Morphine (53%)
* Meperidine (61%)
How are opioid-induced sphincter of Oddi spasm’s treated?
- Naloxone 40 mcg
- Glucagon (2mg IV given incrementally) and causes no opioid antagonism.
- atropine 0.2 mg
- nalbuphine 10 mg
- NTG 50 mcg
What drugs should be used for ERCP cases?
Non-opioids (multimodal approach w/ NSAIDs, gabapentin, etc.)
How long does it take (generally) to develop tolerance to opioids? What causes tolerance?
- 2-3 weeks
- morphine = 25 days
- Downregulation (desensitized and decreased number of opioid receptor)
What is the dosage of morphine? When does it peak? How long does it last?
- 1 - 10 mg IV
- Peak: 10 - 20 minutes
- Duration: 4-5 hours
How is morphine metabolized? What is the active metabolite and its significance?
- Glucuronic acid conjugation in the liver
- Morphine-6-glucuronide = active analgesic causing late resp depression
What would occur with morphine overdose in a renal failure patient?
Prolonged ventilatory depression.
What receptors does meperidine agonize?
- μ and κ receptors
- α2 receptors as well
What are the analogues of meperidine? What other drugs does meperidine have a similar organic structure to?
- Fentanyl & it’s derivatives
- Lidocaine & Atropine
How potent is Meperidine? How long does it last?
10% as potent as morphine
Duration: 2-4 hours
What is the primary indication for meperidine? What dose is used?
Post-operative shivering
12.5mg IV
When should meperidine not be used?
Bronchoscopies (promotes coughing)
How potent is fentanyl?
75 - 125 x morphine.
What is the blood-brain equilibration of fentanyl?
6.4 minutes
Potent with rapid onset and ↑ lipid solubility.
What percent of fentanyl is subject to lung first-pass effect?
- 75%
- Reservoir for drug
- results in decreased amount of active drug
Where is fentanyl metabolized?
Liver via CYP3A
Principal metabolite: Norfentanil.
How does fentanyl dosing change for the elderly or liver cirrhosis?
No change in elderly or cirrhotic patients.
Describe what the graph below is showing.
Fentanyl has the greatest context-sensitive half-time of any of the fentanyl derivatives.
What is the analgesia dosage of fentanyl? Induction dose?
Analgesia: 1-2 mcg/kg IV
Induction: 1.5-3 mcg/kg IV
1mg of PO fentanyl is equivalent to?
5mg IV morphine
What is the intrathecal dosage of fentanyl?
25 mcg
What is the adult transmucosal dose of fentanyl?
Adult: 5 - 20 mcg/kg
Pediatric: 15 - 20 mcg/kg
What is the transdermal dose of fentanyl?
75 - 100 μg (18 hours steady delivery)
What is the fentanyl dose as adjunct with volatile anesthetics?
2-20 mcg/kg IV
What the side effects of fentanyl?
- ↓BP & ↓CO
- Can cause seizures
- modestly increase ICP
How much more potent is sufentanil than fentanyl?
5-12 times more potent.
How much of sufentanil is subject to lung first pass effects?
60%
How much of sufentanil is protein bound? What protein is it bound to?
92.5%
α-1 acid glycoprotein bound
What is the analgesia dose of sufentanil?
Analgesia: 0.1 - 0.4 μg/kg IV
What is the induction dose of sufentanil?
18.9 mcg/kg IV
What is the sufentanil intraop dose? Infusion dose?
intraop: 0.3 - 1μg/kg IV
infusion: 0.5 - 1μg/kg/hr IV.
What are side effects of sufentanil?
- bradycardia
- decreased CO
- chest and abdominal wall rigidity
What is the potency and onset of alfentanil?
1/5th less potent than fentanyl
Onset: 1.4 min > fentanyl/sufentanil
What is the alfentanil induction dose?
- Induction: 150 - 300 μg/kg IV
- Laryngoscopy: 15 - 30 μg/kg IV
- Maintenance: 25 - 150 μg/kg/hr IV with inhaled anesthetics.
Alfentanil is contraindicated for? Why?
- Parkinson’s disease
- acute dystonia
What receptor affinity does remifentanil have?
What is its potency?
- selective μ opioid agonist
- 15-20x as potent as alfentanil (= fentanyl)
What is remifentanil’s structure and why is it important?
Ester Structure = hydrolyzed by plasma & tissue esterases
What are the pharmacokinetics of remifentanil?
- Rapid onset & offset (15 mins), very titratable, no accumulation.
- Clearance: 3-4L/min (8x faster than alfentanil)
- Peak: 30-60 seconds (fastest fentanyl derivative).
What is the induction dose of remifentanil?
1 μg/kg IV over 1 min
What is the maintenance dosing of remifentanil?
0.25-1 mcg/kg IV
or
0.005 - 2 μg/kg/min IV
What is the E1/2 time of remifentanil?
6.3 minutes (99.8%)
How potent is hydromorphone?
What is the dose?
5x more potent than morphine
0.5mg IV → 1-4 mg total
What benefits does hydromorphone have over morphine?
No histamine release & no active metabolites.
Why is codeine not given IV?
Histamine induced hypotension
What is the E 1/2 time of codeine?
3-3.5 hours
What is the dose of codeine for cough suppression?
Analgesia dose?
Cough: 15mg
Analgesia: 60mg (= about 5mg morphine).
Which opioid is most cleared?
Remifentanil (3-4L/min)
Which opioid(s) is/are the most protein bound?
Sufentanil, alfentanil, & remifentanil
Least = morphine.
Which opioid is the highest percent non-ionized?
Alfentanil
Morphine tends to relieve _____ type pain more than _____ type pain.
Dull: sharp
Opioid + N2O or benzos can lead to?
CV depression (CO & BP)
What negative effect does post-op shivering have?
increased metabolic demand 500%
What is the metabolism profile for alfentanil? (metabolized by and metabolite)
metabolized by hepatic p450
metabolite: noralfentanil
How potent is tramadol?
5-10x less than morphine
Tramadol receptor? Dose?
- µ with weak κ & δ
- 3 mg/kg PO
- interaction with coumadin
What is methadone used for?
- Opioid withdrawal
- chronic pain
