L16 - Narcotic Analgesics

Question 1

Local anesthetic can be used for analgesia of diffus pain. T or F?

Answer 1

False

Not used for analgesia especially diffuse, generalized pain except in dental surgery

Question 2

Brief overview of the nociceptive pathway?

Answer 2

Nociceptor in skin/ deep tissue

> > Primary afferent neuron

> > Dorsal root ganglion

> > synapse with 2nd order neuron at dorsal horn (laminae I, II, V)

> > Brainstem, Thalamus

Question 3

Function of endogenous opioid? List 2 instrinsic opioid peptides?

Answer 3

Descending modulation of nociceptive information

1) β-endorphin (precursor = pro-opioimelanocortin (POMC))
2) Enkephalin

Release from from pituitary act on opioid receptors in:

• Periaquaductal grey
• Locus ceruleus

Question 4

Classes of opioids according to chemical structure? MMMP

Answer 4

• Morphine derivatives
• Methadone and propoxyphene
• Mixed agonist antagonist (partial agonist)
• Phenylpiperidines

Question 5

Classes of opioids according to clinical use?

Answer 5

1) Strong
– Morphine derivatives,
– Phenypiperidine (pethidine, fentanyl & derivatives)

2) Mild
– Partial agonists,
– dextropropoxyphene

Question 6

List some morphine derivatives?

Answer 6

• Morphine
• Morphine-6β-glucuronide
• Codeine (methylated morphine)
• Heroin (di-acetyl Morphine)

Question 7

List some fentanyl derivatives?

Answer 7

• Fentanyl
• Remifentanil (ultra-potent, ultra short-acting)
• Alfentanil
• Sufentanil

Question 8

Subclasses of Phenylpiperidine?

Answer 8

1) Pethidine

2) Fentanyl + derivatives

Question 9

Pharmacokinetics of Morphine? Metabolism, solubility, excretion…etc

Answer 9

Metabolism:

• Lipid soluble, can cross BBB
• Tend to accumulate in body, so Context- sensitive
• Metabolized in liver by glucuronidation into mostly Morphine-6β-glucuronide (water soluble)
• Excreted by Kidney

Question 10

Difference in duration of action and potency between Morphine and Morphine-6β-glucuronide?

Answer 10

Morphine-6β-glucuronide = More opioid receptor acitivity, Longer lasting effect as active metabolite , more water soluble than morphine

Question 11

Metabolism, onset and potency of codeine?

Answer 11

Codeine = prodrug

> > demethylated in liver
slower onset, less euphoric

Question 12

Pethidine metabolism pathway?

Answer 12

Major:
Esterase + Conjugation of Pethidine for renal excretion

Minor:
Converted to norpethidine intermediate, which is NEUROTOXIC

Question 13

What precautions are taken when admin. Pethidine?

Answer 13

Minor Intermediate Norpethidine is neurotoxic&raquo_space; neural seizure, convulsion

Patients at risk: normal liver function but bad kidney function

Question 14

Is the gap between ED95 and LD05 of Narcotic analgesics large or small?

Answer 14

ED95 and LD05 overlaps

Absolutely minimal therapeutic window&raquo_space; easy to OD

Question 15

What does the gap between ED95 and LD05 signify?

Answer 15

Therapeutic window of a drug

Large gap = large window

Question 16

Rank the Fentanyl derivatives in terms of elimination half life.

Answer 16

Increasing time:

Remifentanil&raquo_space; Alfentanil&raquo_space; Sulfentanil&raquo_space; Fentanyl

Question 17

Rank the Fentanyl derivatives in terms of relative potency.

Answer 17

Decreasing potency:

Sufentanil
Fentanyl
Remifentanil
Alfentanil

Question 18

Compare Alfentanil and Sufentanil in terms of Onset, Ease of titration and euphoria strength?

Answer 18

1) Alfentanil: crosses BBB quickly (faster onset, less time lag):
stronger euphoria, easier to titrate
(Remifentanil also rapid)

2) Sufentanil: crosses BBB slowly (time lag):
lower peak brain concentration = weaker euphoria, harder to titrate (may be overdosed)

Question 19

Explain the mechanism of Context-sensitivity.

Answer 19

Context sensitive = t1/2 of opioid depends on the duration of admin/ infusion

i.e. Continuous infusion by IV leads to higher t1/2 than expected, drug stays in CNS for longer and exert more effect

Question 20

What is the solubility and non-ionized fraction of most clinically used opioids?

Answer 20

To cross BBB effectively:

High lipid solubility
Non-ionized fraction at body pH

Question 21

Relate onset time of opioid to addictive potential. Give an opioid with rapid onset.

Answer 21

Faster onset time = faster diffusion into CNS = Higher addictive potential due to stronger effect/ euphoria

Remifentanil = rapid onset

Question 22

Relate the change in plasma concentration of opioids to the EEG response.

Answer 22

EEG reflects drowsiness

Rise in plasma concentration of opioid matches closely with sharp increase in EEG = little time between infusion and patient drowsiness

Question 23

Give one opioid that is easy to titrate and explain why?

Answer 23

Alfentanil

Plasma concentration closely reflects dosage administered and EEG response

Almost immediate effect of drowsiness with no time lag

Question 24

Give examples of most context-sensitive and context-insensitive opioids.

Answer 24

Most sensitive = Fentanyl

Least sensitive = Remifentanil
(regardless of duration of infusion, t1/2 is the same after withdrawal)
Very useful in operating room

Question 25

Example of partial agonist narcotic analgesic?

Answer 25

Tramadol

Question 26

Indication of Tramadol?

Answer 26

For patients with mild-moderate pain, short-moderate term use

Question 27

D/D interaction of Tramadol and MoA?

Answer 27

MoA = Increases serotonin, catecholamine levels by blocking reuptake >> serotonin syndrome D/D = Serotonin- reuptake inhibitor antidepressants (e.g. tricyclics, SSRI)

Question 28

Give an example of Propoxyphene and associated commercial names. Is it still used?

Answer 28

Dextropropoxyphene Commercial names: Doloxene Dologesic (dextropropoxyphene + paracetamol) Associated with arrhythmia = withdrawn by FDA = no longer available

Question 29

Indication of Methadone?

Answer 29

Longest acting >> for chronic, stable pain Slow onset >> Do not notice euphoria Indicated for opioid abuse - helps quitting addiction

Question 30

Explain the D/D interaction between certain types of opioids?

Answer 30

Strong opioids and mixed agonists/ mild opioids Mild opioids or mixed agonist opioids can displace strong opioids from receptors >> Paradoxically reduce effect

Question 31

Explain the D/D interaction between certain types of opioids?

Answer 31

Strong opioids and mixed agonists/ mild opioids Mild opioids or mixed agonist opioids can displace strong opioids from receptors >> Paradoxically reduce effect

Question 32

Which type of opioid receptors are most activated by narcotic opioids?

Answer 32

μ receptors μ1 and μ2

Question 33

Compare the analgesia produced by Opioids acting on μ1 and μ2 receptors.

Answer 33

μ1 = Supraspinal + peripheral analgesia (+ Prolactin release, Ach release in hippocampus and Feeding) μ2 = Spinal analgesia + Respiratory depression (+ Gastrointestinal transit + Dopamine release by nigrostratial neurons + Feeding)

Question 34

List all route of admin of opioids?

Answer 34

```  Intravenous  Oral  Indwelling subcutaneous cannula  Transmucosal  Intraspinal injection  Ventilatory system ```

Question 35

Indication for Indwelling subcutaneous cannula admin of opioids?

Answer 35

 Lipid-soluble = well absorbed  When oral is not feasible (e.g. nausea, vomiting) i.e. terminally ill or dysphagia

Question 36

Indication for transmucosal admin of opioids?

Answer 36

 For kids  Absorbed through oral mucosa  Can cause overdose, addiction  dangerous

Question 37

Advantages of intraspinal injection of opioids?

Answer 37

Bypass BBB Very high bioavailability Very low dose needed compared to IV/ oral = reduce side effects

Question 38

List acute side effects of opioids?

Answer 38

* Sedation * Nausea/ vomit * Respiratory depression (lethal) * Euphoria * Miosis

Question 39

Specific side effects of Propoxyphene and Pethidine?

Answer 39

Propoxyphene = arrhythmia Pethidine = neurotoxicity = convulsion/ seizure esp. in kidney failure/ fast liver metabolizer

Question 40

Why is miosis a useful indicator of opioid intake?

Answer 40

Persists effect even after lifelong opioid abuse: useful for:  Unconscious patients  check for injection marks  Telling whether the patient takes the drug

Question 41

List side effects from long term opioid use?

Answer 41

Acute side effects Constipation Dependence: physical Addiction Tolerance

Question 42

Define dependence on opioids.

Answer 42

Dependence is not addiction Physical dependence: = physiological adaptation of body to the presence of an opioid = development of withdrawal symptoms after chronic use when:  Opioids are discontinued;  Dose is reduced abruptly;  An antagonist (e.g. naloxone) / agonist-antagonist (e.g. pentazocine) is administered

Question 43

Define addiction on drugs?

Answer 43

compulsive use of drugs for nonmedical reasons Characterized by a craving for mood-altering drug effects, not pain relief

Question 44

What dysfunctional behaviors may arise from drug addiction?

Answer 44

```  Denial of drug use  Lying  Forgery of prescriptions  Theft of drugs from other patients / family members  Selling, buying drugs on the street  Using prescribed drugs to get "high" ```

Question 45

Define tolerance to drugs?

Answer 45

physiological state characterized by decreased effects of a drug (e.g. analgesia, nausea or sedation) with chronic administration >> higher dose to get same effect i.e. due to reduced downstream events of opioid receptors (expected)

Question 46

Technique used to control opioid administration?

Answer 46

Patient controlled analgesia (PCA)

Question 47

Mechanism of PCA in opioid admin?

Answer 47

Find desirable plasma conc. range for opioids - Increase loading dose until side effects appear to set upper limit - Repeated self- admin. within safe zone for Post- op pain relief: sufficient analgesia vs. respiratory depression

Question 48

Pethidine, morphine and methadone. Rank euphoria?

Answer 48

pethidine>morphine> methadone

Question 49

T1/2, MoA and indication of Naloxone (Narcan)?

Answer 49

pure competitive antagonist (binds on opioid receptor but zero effect Treats opioid overdose Half-life ~75 min-1 (shorter T1/2 than most agonist) Need constant monitoring and admin to ensure safe levels