B-16. Semisynthetic and synthetic opiates

Question 1

Semi-synthetic opiates, strength of agonism

Answer 1

Semi-synthetic: all are phenanthrenes

Strong μ agonists:
Heroin - diacetylmorphine
Oxycodone

Weak-Intermediate μ agonists:
Dihydrocodeine

Mixed agonist / antagonists:
Nalbuphine
Buprenorphine

Antagonists:
Naloxone
Naltrexone

Question 2

Synthetic opiates, strength antagonism

Answer 2

Synthetic:

Strong μ agonists: all are phenylpiperidines (exc. methadone)
Meperidine
Fentanyl; Al- / Su- / Remifentanil … (Fentanyl family consists of “Al, Sue and Remy”)
Methadone

Weak-Intermediate μ agonists:
Dextromethorphan
Diphenoxylate
Loperamide
Tramadol
Tapentadol

Mixed agonist / antagonists:
Butorphanol
Pentazocine

Question 3

Heroin 
Type of molecule?
Metabolisation?
Characteristics?
Effects?
DOA?

Answer 3

a phenanthrene; diacetylmorphine;

metabolized to morphine via tissue esterases

Highly lipophilic → enters brain suddenly in high concentration

Strong euphoric effect;

long-lasting (2 hour DOA);

no medical use - a drug of abuse

Question 4

Oxycodone 
Type of molecule?
Absorption?
Indications?
First pass effect?

Answer 4

phenanthrene derivative; similar to morphine,
better oral absorption

Indications: cancer-related pain and cough; other moderate-severe pain
Often combined with atg naloxone

(oral → high first-pass effect; only works in GI to prevent constipation)

Question 5

Dihydrocodeine -
Characteristics compared to morphine and codeine?
Indications?

Answer 5

Stronger than codeine, weaker than morphine

Indications: used as analgesic, antitussive (esp. in pleuritis)

Question 6

Buprenorphine
MOA?
Kinetics (doa)
metabolism

Answer 6

MOA :
acts as a partial μ agonist and κ antagonist … (all “bu” drugs are partial μ agonists)

kinetics :
long DOA

Metabolism : sublingual admin to avoid first-pass transderm

Question 7

Buprenorphine

Indications:

Answer 7

Breakthrough pain - sublingual
Chronic pain - transdermal
Opiate addiction - as “bridge” therapy; slow receptor dissociation → milder withdrawal symptoms

Question 8

Nalbuphine
MOA
Side Effects
Indications

Answer 8

MOA: acts as a κ agonist and partial μ agonist … (all “bu” drugs are partial μ agonists)
κ receptor not involved in respiratory depression → respiratory dep. effects max out before lethality
Less euphoria → less dependence

Side Effects:
Dysphoria - κ agonist effect
Sedation
Sweating

Indications:
Pain - moderate to severe
Surgery - in combo with other anesthetics + for pre- and post-op pain
Obstetric - analgesia during labor/delivery

Question 9

Naltrexone
DOA
Indication

Answer 9

• semisynthetic μ atg; given orally;
  DOA : 10 hr
  Indication : used for treating opiate addiction

Question 10

Naloxone
DOA;
indication

Answer 10

semisynthetic μ atg
DOA 1-2 hour ;
parenteral;

indication : used for opiate overdose (short DOA → repeat doses)

Question 11

synthetic opioids groups.

Answer 11

diphenylheptan
Phenylpiperidines
Morphinans
Benzomorphans
Others

Question 12

synthetic opioids

diphenylheptans

Answer 12

Methadone

Question 13

synthetic opioids

Phenylpiperidines

Answer 13

Fentanyl
Meperidine (Pethidine)
Diphenoxylate

Question 14

synthetic opioids

Morphinans:

Answer 14

Dextromethorphan

Butorphanol

Question 15

synthetic opioids

Benzomorphans

Answer 15

Pentazocine

Question 16

synthetic opioids

others

Answer 16

Tramadol

Tapentadol

Question 17

methadone

Answer 17

a diphenylheptane
Good oral availability; accumulates in tissues → slow elimination → easier to discontinue due to weaker withdrawal sx
Used for tx of opiate addiction

Question 18

Meperidine (Pethidine)
moa
indication
side effects

Answer 18

trade name Demerol

similar to morphine but with less urinary retention, uterine relaxation, and sedation
no constipation or antitussive effect; no meiosis → OD harder to detect

Indications:
Obstetrics - previously the #1 opioid analgesic for L&D; less now due to toxic metabolite + sfx
Diverticulitis - preferred analgesic due to effect of ↓ GI luminal pressure

Side Effects:
Antimuscarinic effects - dry mouth, visual disturbances, tachycardia, no meiosis
With MAOI → serotonin syndrome
metabolite norpethidine can cause seizures

Question 19

Fentanyl
kinetics:
Indications:

Answer 19

100x analgesic effect of morphine; strongest clinical opioid

Severe respiratory depression effect!

Kinetics: DOA only 30-60 mins → IV, transdermal patch, sublingual pill

indications:

Neuroleptanalgesia - given IV in combo with antipsychotic (droperidol)
Surgical analgesia - IV
Chronic Cancer Pain - transdermal patch
“Breakthrough” pain - any acute increase in pain in cancer pts; as sublingual pill

Question 20

Fentanyl

Analogs

Answer 20

Analogs:Sufentanil + Alfentanil - shorter DOAs; Remifentanil - shortest DOA (1-10 mins)
Remember Sue, Al and Remy as the members of the Fentanyl family; longest name = shortest DOA

Question 21

Diphenoxylate

Loperamide

Answer 21

Diphenoxylate
antidiarrheal; low BBB entry; combo w/ atropine (trade name Reasec) for watery diarrhea

Loperamide
antidiarrheal; not absorbed from GI tract

Question 22

Dextromethorphan
MOA
side efffects

Answer 22

MOA: SERT/NET inhibitor; sigma-1 agonist, μ agonist
also NMDA-R non-competitive atg; nAChR negative allosteric modulator; 5-HT/H1/α-2/M ligand
Indications: cough suppression
Side Effects: many, but not listed in slides… see Wiki

Question 23

Butorphanol

Indications:

Answer 23

Butorphanol
- a μ and κ partial agonist … (all “bu” drugs are partial μ agonists)
Indications:
migraine as an intranasal spray; moderate pain - parenteral admin

Question 24

Benzomorphans:

indications :

Answer 24

Pentazocine - a κ agonist and μ antagonist

Indications: pain - but has a “ceiling effect” → above certain doses no additional effect is achieved

Question 25

Tramadol

MOA:
SFX:

Answer 25

MOA: weak μ agonist; weak NE reuptake inhibitor; enhances 5HT release
less respiratory depression; low abuse potential
Indications:
Mild-Moderate Pain - when NSAIDs not sufficient
SFX:
nausea/vomiting, dizziness, sweating
Seizures - with high doses
Serotonin syndrome - w/ MAOI, TCA, SSRI co-admin

Question 26

Tapentadol

MOA:
Indications:

Answer 26

moa :
acts as a μ agonist and NET inhibitor → similar effect to tramadol
indications:
Diabetic Neuropathy - NET inhibition is helpful in neuropathic pain conditions
Other musculoskeletal pain

Question 27

Opiate Addiction Treatment

Methadone

Answer 27

good for oral admin; withdrawal is slower/less severe

Question 28

Opiate Addiction Treatment

Naltrexone

Answer 28

pt first goes through withdrawal, then takes naltrexone as an antagonist
2 theories:
give original drug of abuse with naltrexone → disconnect drug of abuse from desired effect
give naltrexone alone → if pt relapses, drug of abuse does not have effect

Question 29

Opiate Addiction Treatment

Buprenorphine

Answer 29

bridge therapy; replace original drug with partial agonist to decrease craving, withdrawal without strong euphoria
slow elimination → eventual withdrawal is easier; less euphoria / resp depression than methadone

Question 30

Opiate Addiction Treatment

UROD

Answer 30

ultra-rapid opioid detoxification → anesthetize patient + administer antagonist

Question 31

Other drugs:
Clonidine
β Blockers
BZDs

Answer 31

Clonidine - sedative, antihypertensive
releases β endorphin → diminished withdrawal symptoms
β Blockers - less tremor, anxiety, htn
BZDs - to ↓ anxiety