Opioids Agonists (Exam II)

Question 1

What are opioids effects on the CO₂ medullary center?

Answer 1

• Opioids inhibit the CO₂ medullary center.

Question 2

Differentiate opioids from narcotics.

Answer 2

• Opioids = all exogenous substances that bind to endogenous opioid receptors.
• Narcotic = any substance that can produce dependence (stupor)

Question 3

What two types of opioid chemical structures are there?

Answer 3

• Phenanthrenes
• Benzylisoquinolines

Question 4

What types of drugs are Phenanthrenes?
What types of drugs are benzylisoquinolines?

Answer 4

• Phenanthrenes: Morphine, Codeine, Thebaine
• Benzylisoquinoline: Papaverine, Noscapine

Question 5

What is papaverine mostly used for?

Answer 5

Treating intra-arterial barbiturate administration (dilates the highly constricted artery).

Question 6

What portions of the brain are the source of descending inhibitory signals?

Answer 6

• Thalamus
• PAG
• Locus Coeruleus

Question 7

What endogenous substances have the same effect as opioids?

Answer 7

Endorphins, Enkephalins, and Dynorphines.

Question 8

Presynaptic inhibition of what neurotransmitters occurs with opioid administration?

Answer 8

• ACh
• Dopamine
• NE
• Substance P

Question 9

How do opioids modulate pain at the cellular level?

Answer 9

• ↑ pK⁺ (hyperpolarization)
• Ca⁺⁺ channel inactivation

Both lead to decreases in neurotransmission and main modulation (anti-nociceptive)

Question 10

Where are opioid receptors located in the brain?

Answer 10

• PAG
• Locus Ceruleus
• RVM (rostral ventral medulla)
• Hypothalamus

Question 11

Where is the primary site of opioid receptors in the spinal cord?

Answer 11

Interneurons and primary afferent neurons of the substantia gelatinosa (aka Laminae 2)

Question 12

Where is/are opioid receptors found outside the CNS?

Answer 12

• Sensory neurons & immune cells

Intraarticular morphine after knee surgery.

Question 13

What are the four (most important) types of opioid receptors?

Answer 13

• Μu₁ (μ₁)
• Μu₂ (μ₂)
• Κappa (κ)
• Delta (δ)

Question 14

Which opioid receptor(s) is/are responsible for respiratory depression & physical dependence?

Answer 14

• Μu₂ and δ

Question 15

Which receptors are responsible for constipation?

Answer 15

• Μu₂ primarily
• δ (less)

Μu₂ (μ₂) receptors in the stomach cause peristalsis

Question 16

Which receptors can cause urinary retention?
Are there any receptors that cause diuresis when bound?

Answer 16

• Retention: Μu₁ and δ
• Diuresis: κ

Question 17

All opioid receptors induce analgesia at both the brain the spinal cord. T/F?

Answer 17

• False. Μu₂ receptors only cause analgesia at the spinal cord level.

Question 18

What opioid receptors have low abuse potential when bound?

Answer 18

Μu₁ and κ

Question 19

Which opioid receptor is responsible for euphoria, bradycardia, hypothermia, and miosis when bound?

Answer 19

Μu₁

Question 20

What agonists bind to the four opioid receptors?
What about antagonists?

Answer 20

• Mu1 & Mu2 = endorphins, morphine, synthetic opioids.
• κ = dynorphins.
• δ = enkephalins.
• All receptors bound by same antagonists: Naloxone, Naltrexone, and Nalmefene

Question 21

Describe the adverse side effects of opioids on the cardiovascular system.

Answer 21

• ↓CO, venous return, and BP D/T ↓SNS tone
• ↓HR + histamine release = ↓BP\
• Adding N20 or benzo = CV depression (CO & BP)

Orthostatic hypotension likely, as well as syncope

Question 22

What possible cardiovascular benefits do opioids provide?

Answer 22

• Myocardial ischemia protection (won’t cause myocardial depression) unless given with nitrous or benzo

Question 23

What are the respiratory effects of opioids?
What would symptoms of overdose be?

Answer 23

• Depressed CNS response to CO₂ causing a right shift of PaCO₂ (↑PaCO2 at rest)
• Cough suppression seen in Codeine and Dextromethorphan (no analgesia)
• Overdose = apnea, miosis, ↓RR, coma.

Caution: Provocation of reflex coughing d/t pre-induction dose

Question 24

What drug would treat opioid ventilatory depression but not reverse analgesia?
How?

Answer 24

• Physostigmine would by increasing CNS ACh levels.

This will effectively antagonize ventilatory depression but not reverse analgesia like narcan.

Question 25

What is normal PaO₂? What shift in PaO₂ would be seen with metabolic acidosis? What shift in PaO₂ would be seen with general anesthesia, opiate use, and even sleeping?

Answer 25

- Normal PaO₂ is 80 mmHg - Left shift - Right shift ## Footnote Anything that would cause an increase in PaCO ₂ at rest will cause a rightward shift

Question 26

What would cause a leftward shift in PaO₂? What would cause a rightward shift?

Answer 26

- Leftward: Metabolic acidosis (to breathe off all that CO₂) - Rightward: sleep → opiates → anesthesia

Question 27

Why should caution be used when administering opioids to head trauma patients?

Answer 27

- Opioids ↓CBF and possibly ICP ## Footnote Myoclonus can occur with large doses

Question 28

What musculoskeletal abnormality occurs with opioid administration? What makes this condition worse? How is it treated?

Answer 28

- Skeletal chest wall and abdominal muscle rigidity (wooden chest syndrome). - Mechanical ventilation - Muscle relaxants and/or naloxone ## Footnote Rigid chest is typically caused with rapid administration of opiates such as fentanyl.

Question 29

What are sphincter of Oddi spasms? Which drugs can cause this?

Answer 29

- Biliary smooth muscle spasm - **Fentanyl** (99%), Morphine (53%), and Meperidine (61%). *I think maybe all opioids can cause this but these are the primary culprits*

Question 30

What drugs should be used for ERCP cases?

Answer 30

- Non-opioids (multimodal approach w/ NSAIDs, gabapentin, etc.)

Question 31

How are opioid-induced sphincter of Oddi spasm's treated?

Answer 31

Usually one of these: - **Glucagon** (2mg IV given incrementally) and causes no opioid antagonism. - Naloxone 40mcg IV - Atropine 0.2mg IV - Nalbuphine 10mg IV - NTG 50mcg IV

Question 32

What are some common GU side effects to opiates? How about cutaneous or placental?

Answer 32

- GU: urinary urgency - Cutaneous: histamine release leads to flushed face, neck, & upper chest. - Placenta: neonate depression and dependence (chronic use)

Question 33

How long does it take (generally) to develop tolerance to opioids? What causes tolerance?

Answer 33

- 2-3 weeks (morphine is 25 days) - Downregulation of opioid receptors ## Footnote Cross tolerance can develop between all opioids

Question 34

What is the dosage of morphine? When does it peak? How long does it last?

Answer 34

- 1 - 10 mg IV - Peak: 15 - 30 minutes (IV) 45-90 minutes (IM) - Duration: 4-5 hours

Question 35

How is morphine metabolized? What is the active metabolite and its significance?

Answer 35

- Glucuronidation in the kidneys. - **Morphine-6-glucuronide** = comprises only 5-25% of morphine metabolites but is an **active anaglesic causing late resp depression**.

Question 36

What would occur with morphine overdose in a renal failure patient?

Answer 36

- Prolonged ventilatory depression.

Question 37

What receptors does meperidine agonize?

Answer 37

- μ and κ receptors - α2 receptors as well

Question 38

What are the analogues of meperidine? What other drugs does meperidine have a similar organic structure to?

Answer 38

- Fentanyl & it's derivatives - Lidocaine & Atropine

Question 39

How potent is Meperidine? How long does it last?

Answer 39

- 10% (1/10th) as potent as morphine - Duration: 2-4 hours

Question 40

What is the primary indication for meperidine? What dose is used?

Answer 40

- Post-operative shivering - 12.5mg IV

Question 41

When should meperidine not be used?

Answer 41

- Bronchoscopies (promotes coughing)

Question 42

How potent is fentanyl? (compared to morphine)

Answer 42

- 75 - 125 x morphine.

Question 43

What is the blood-brain equilibration of fentanyl? What does this mean?

Answer 43

- 6.4 minutes - Potent with rapid onset and ↑ lipid solubility.

Question 44

What percent of fentanyl is subject to lung first-pass effect? What does this mean?

Answer 44

- 75% - Drug is taken up into lung tissue and possibly subjected to breakdown via pulmonary esterases.

Question 45

Where is fentanyl metabolized? What is its principal metabolite?

Answer 45

- Liver via CYP3A - Norfentanil

Question 46

How does fentanyl dosing change for the elderly or liver patients? How about morphine?

Answer 46

**No change in elderly or cirrhotic patients.** - Caution with morphine use in renal and elderly patients b/c metabolites stick around longer in renal disease. Serum plasma concentrations increase with age.

Question 47

Describe what the graph below is showing.

Answer 47

Fentanyl has the greatest context-sensitive half-time of any of the fentanyl derivatives. ## Footnote Context-sensitive half-time describes the time it takes for the plasma concentration of a drug to decrease by 50% **after an infusion is stopped**.

Question 48

What is the analgesia dosage of fentanyl? Induction dose?

Answer 48

- Analgesia: 1 - 2 μg/kg IV - Induction: 1.5 - 3 μg/kg IV (5min prior)

Question 49

What Fentanyl dose is used as an adjunct with inhaled anesthetics?

Answer 49

2 - 20 μg/kg IV Used in cases of : - Direct laryngoscopy during intubation - Sudden changes in surgical stimulation level

Question 50

1mg of PO fentanyl = ____ mg of IV morphine

Answer 50

5 ## Footnote IV fentanyl is 75-125x as potent as morphine.

Question 51

What is the intrathecal dosage of fentanyl?

Answer 51

25 mcg

Question 52

What is the adult oral dose of fentanyl (transmucosal)? Pediatric (rapid dissolving film/lozenges)?

Answer 52

- Adult: 5 - 20 mcg/kg - Peds (2-8yr olds): 15 - 20 mcg/kg 45min prior

Question 53

What is the transdermal dose of fentanyl?

Answer 53

- 75 - 100 μg (18 hours steady state)

Question 54

What cardiovascular side effects should be known about fentanyl? What CNS side effects should be known?

Answer 54

- ↓BP & ↓CO (depressed carotid sinus baroreceptor reflex) - Can cause seizures (doses>30 μg/kg IV) & modestly increase ICP (6-9mmHg).

Question 55

How much more potent is sufentanil than fentanyl?

Answer 55

- 5-12 times more potent.

Question 56

How much of sufentanil is subject to first pass effects?

Answer 56

- 60% lung first-pass

Question 57

How much of sufentanil is protein bound? What protein is it bound to?

Answer 57

**92.5% α-1 acid glycoprotein bound.**

Question 58

What is the analgesia dose of sufentanil?

Answer 58

- Analgesia: 0.1 - 0.4 μg/kg IV

Question 59

What is the induction dose of sufentanil?

Answer 59

18.9 mcg/kg IV **What an odd number** but it is referenced directly in the text.

Question 60

What is the potency of alfentanil? What is its onset?

Answer 60

- 20% (1/5th) as potent as fentanyl - Onset: 1.4 min (faster than all derivatives except remifentanil)

Question 61

What is the alfentanil induction dose? What about laryngoscopy dose and when should it be given? What about maintenance?

Answer 61

- Induction Alone: 150 - 300 mcg /kg IV - Laryngoscopy (give 90sec prior): 15 - 30 mcg/kg IV - Maintenance: 25 - 150 mcg/kg/hr with inhaled anesthetics

Question 62

Considering Alfentanil's pharmacokinetics, would you give it to a cirrhotic patient? Does alfentanil have any metabolites?

Answer 62

- Yes but remember that Cirrhosis patients result in a longer elimination half-time - Metabolite: noralfentanil (hepatic P450 3A4) ## Footnote - Higher protein binding: same with sufentanil - 90% nonionized at normal pH --> lower lipid solubility

Question 63

What drug can cause acute dystonia when given to a Parkinson's patient?

Answer 63

Alfentanil

Question 64

What receptor affinity does remifentanil have? How potent is it?

Answer 64

μ opioid agonist that is equipotent to fentanyl

Question 65

What is remifentanil's structure and why is it important?

Answer 65

**Ester Structure** = hydrolyzed by plasma & tissue esterases. - Rapid onset & recovery (15min) - Very titratable - **No accumulation**

Question 66

What drug was said to be a great choice for carotid procedures in lecture?

Answer 66

Remifentanil

Question 67

Answer the following characteristics of remifentanil below: Clearance: Peak effect:

Answer 67

- Clearance: 3-L/min (8x faster than alfentanil) - Peak: 1.1 min (fastest fentanyl derivative)

Question 68

What is the induction dose of remifentanil?

Answer 68

- 0.5-1 mcg/kg IV over 30-60sec

Question 69

What is the maintenance dosing of remifentanil?

Answer 69

0.25-1μg/kg IV OR - 0.005 - 2 μg/kg/min IV

Question 70

What is the recommended spinal dose for Remifentanil?

Answer 70

Trick question, Remifentanil is **NOT** recommended for spinal or epidural use :)

Question 71

What are the primary S/E of Remifentanil?

Answer 71

Question 72

How potent is hydromorphone? What dose should be given? What benefits does hydromorphone have over morphine?

Answer 72

- 5x more potent than morphine - 0.5mg → 1-4 mg total - **No histamine release & no active metabolites.**

Question 73

Why is codeine not given IV?

Answer 73

- Induced hypotension via histamine release.

Question 74

What is the dose of codeine for cough suppression? Analgesia?

Answer 74

- Cough: 15mg - Analgesia: 60mg (= about 5mg morphine)

Question 75

Which opioid is most cleared?

Answer 75

- Remifentanil (3-4L/min)

Question 76

Which opioid(s) is/are the most protein bound? Which is the least?

Answer 76

- Sufentanil, alfentanil, & remifentanil - Least = morphine

Question 77

Which opioid is the highest percent non-ionized?

Answer 77

- Alfentanil

Question 78

Morphine tends to relieve _____ type pain more than _____ type pain.

Answer 78

Dull: sharp