HNS16 Narcotic Analgesics

Question 1

Local anaesthetic vs Opioid analgesic

Answer 1

LA:

• block Na channel —> may cause motor / sympathetic block as well
• ***block pain signals transduction
• work locally only

Opioid analgesic:

• just relieve pain without affecting other sensation e.g. thermoception / proprioception
• ***modify pain signals
• work systemically

Question 2

Natural pain modulators (Endogenous opioid)

Answer 2

1. Enkephalins

2. Endorphins

Question 3

First guy to extract active ingredient from opium

Answer 3

Friedrich Wilhelm Serturner

Question 4

2 main SE of opioid

Answer 4

1. Respiratory depression

2. Dependence

Question 5

Classification of opioids (based on chemical structure)

Answer 5

1. Morphine related compounds
2. Phenylpiperidines
   - Pethidine
3. Methadone and propoxyphene
   - Dextropropoxyphene
4. Mixed agonist antagonist (Partial agonist)
   - Pentazocine, Buprenorphine, Butorphanol, Tramadol

Question 6

Classification of opioids (based on strength)

Answer 6

1. Strong
   - Morphine
   - Pethidine
   - Fentanyl
   - derivatives (e.g. Heroin, Codeine: prodrug)
2. Mild
   - Partial agonists
   - Dextropropoxyphene
   —> Propoxyphene group
   —> others: Doloxene, Dologesic (dextropropoxyphene + paracetamol)
   —> NOT available in world now due to arrhythmia
   —> mild opioid (much less respiratory depression)

Question 7

Unique opioid: Methadone

Answer 7

• Physeptone
• Slow onset (lower addictive potential)
• Longest acting
• Opioid abuse (opioid detoxification)
• ***“Complex” analgesic —> action not only on opioid receptor

Question 8

Giving agonist together with partial agonist

Answer 8

Overall weaker analgesic effect

—> since partial agonist (elicit <100% response) can displace agonist from opioid receptor

Question 9

Mixed agonist / antagonist

Answer 9

1. Pentazocine
2. Buprenorphine
3. Butorphanol
4. ***Tramadol (complex pharmacological properties / MOA)

Question 10

Opioid receptor classification

Answer 10

• **1. μ receptor
• responsible for ***pain control clinically
• responsible for ***respiratory depression
• primarily found in CNS (brain / spinal cord) —> opioid analgesic must be able to pass BBB (high lipid solubility / high non-ionised fraction at blood pH)

2. κ receptor
3. δ receptor

Question 11

Routes for opioid analgesic administration

Answer 11

1. Oral
   - convenient
2. IV
   - faster onset
   - better absorption
3. SC injection
   - fairly good absorption since opioids are lipid-soluble
4. Transmucosal (in US)
   - lollipop
5. Epidural
   - catheter into epidural space
   - lower dose needed
6. Patient-control analgesia
7. Transdermal
   - Fentanyl patch
8. Inhalation
   - military use
   - hard to control dose

Question 12

Plasma and effect site (CNS) concentration

Answer 12

When given IV:

Plasma conc ↓ —> CNS conc ↑ (drug diffuse into CNS) —> to a point where 2 curves meet —> equilibrium concentration —> beyond equilibrium point both conc starts ↓

Drugs that diffuse quickly to CNS (e.g. Alfentanil):

• reach equilibrium point in shorter time with ***higher equilibrium concentration
• faster onset —> more addictive
• less time lag between plasma conc and drug effect —> easier to titrate

Drugs that diffuse slowly to CNS (e.g. Fentanyl, Sufentanyl):

• reach equilibrium point in a longer time with ***lower equilibrium concentration
• slower onset —> less addictive
• more time lag between plasma conc and drug effect —> harder to titrate

Question 13

When consider duration of action in IV infusion

Answer 13

1. Elimination half-life
   - only one fixed number for each drug
2. Context sensitive half time
   - also consider how long infusion has been carried on before discontinuing / minutes since beginning of infusion (隻藥infuse左幾耐)
   —> infuse得越耐 —> context sensitive half-time越長
   - some drugs more context sensitive (當用耐左, context sensitive half-time升好多) —> ***Significance: Accumulation of drug in body
   - less context sensitive (infuse耐左, context sensitive half-time都唔會變)

E.g. Fentanyl very context sensitive:
當infuse耐左 —> 要勁長時間先eliminate到

Alfentanyl less context sensitive:
當infuse耐左 —> half life都唔會點變

Question 14

Morphine metabolism

Answer 14

Metabolised in liver by ***glucuronidation
—> mostly morphine-6-glucuronide (more water soluble for renally excreted)
—> active metabolite
—> can still enter CNS and exerts its effect

Question 15

Pethidine metabolism

Answer 15

Pethidine
—> majority: **Esterase
—> minor metabolite: **Norpethdine (neurotoxic —> seizure / convulsion)

At risk patient:

• Normal liver function + Poor renal function
• repeatedly received Pethidine

Question 16

***Side effects of opioids (acute use)

Answer 16

(more common, more severe —> less common, less severe)

1. Sedation
2. N+V
3. Respiratory depression (dose dependent)
4. Euphoria
5. Miosis (瞳孔縮小) (can be beneficial —> diagnosis to see if patients have been on opioids e.g. drug addicts)

Question 17

Therapeutic window of opioid

Answer 17

LD05 - ED95 (LD05: 5% die at the dose, ED95: 95% effective at the dose)

Opioid: ED95 = LD05 and ED50 close to LD50 (very narrow window)

—> but for each patient there is always an effective dose that will not kill him

Question 18

Opioid dosing

Answer 18

Start at low dose

—> until get satisfactory pain control

Question 19

Patient Controlled Analgesia (PCA)

Answer 19

Use patients’ own sensation of pain as feedback

—> self-administered dose of opioid

Question 20

Side effects of opioids (prolonged use)

Answer 20

1. All acute side effects
2. Constipation (esp. oral use)
3. Tolerance / dependence

Question 21

Euphoria / Addictiveness

Answer 21

Pethidine > Morphine > Methadone

Question 22

Tolerance

Answer 22

Physiological state characterised by decrease in effects of drug with chronic administration
—> **physiological change in body
—> patients require **larger dose over time

Question 23

Dependence

Answer 23

1. Physical dependence
   - **physiological adaptation of body to presence of opioid
   - development of **withdrawal symptoms when opioids are:
   —> discontinued
   —> dose reduced abruptly
   —> when an antagonist (e.g. Naloxone) administered
   —> when an agonist-antagonist (e.g. Pentazocine) administered
2. Psychological dependence (Addiction)
   - **compulsive use of drugs for non-medical reasons
   - characterised by **craving for mood altering effects but not pain relief
   - should not happen with proper supervision
   - dysfunctional behaviour:
   —> denial of drug use
   —> lying
   —> forgery of prescription
   —> theft of drugs
   —> selling / buying drugs on the street
   —> used prescribed drugs to get high

Question 24

Regulations of opioids

Answer 24

• Classified as Dangerous drugs
• Medical practitioners are required to maintain proper records of ALL dangerous drugs, whether supplied, dispensed, administered

Question 25

Tramadol

Answer 25

Complex MOA:

1. ***Mixed agonist-antagonist at opioid receptor
2. also ***inhibits uptake of serotonin and catecholamine in CNS —> DDI with antidepressants esp. SSRI

Indication:
- mild to moderate pain

SE:

• does not cause much sedation
• almost does not cause respiratory depression
• no euphoria —> very little addiction

Question 26

Naloxone (Narcan)

Answer 26

• for opioid overdose
• opioid antagonist (pure antagonist)
• relatively short half-life (75 mins) —> shorter than most opioids —> wear off before opioid effects —> need to observe patients before discharging

Question 27

Choosing an opioid

Answer 27

1. Efficacy
2. SE
3. Onset and duration
4. Route of administration and availability
5. Safety
6. Addictive potential