Opioid Analgesics

Question 1

Receptor subtypes

Answer 1

Mu receptors: Mu1 and Mu2
Kappa receptors: Kappa1, Kappa 2, Kappa3
Delta receptors: Delta1 and Delta 2

Question 2

Endogenous opioids

Answer 2

Pro-opiomelanocortin peptides: Beta-endorphin
Pro-enkephalin peptides: met-enkephalin peptides, leu-enkephalin
Prodynorphin peptides: Dyn-A, Dyn-B, and alpha-neo-endorphin
Endomorphins: Endomorphin-1 and Endomorphin-2
Nociceptin (orphinan F/Q)

Question 3

Opioid receptors, endogenous ligands and function

Answer 3

Mu receptors: Mu1: Beta endorphin, endomorphin, leu-enkephalin
Mu2: Beta-endorphin, endomorphin
Kappa receptors: Kappa1: dynorphins, Beta-endorphin
Kappa2/3:dynorphins, nociceptin
Delta receptors: Delta1: enkephalins, Beta-endorphin dynorphins
Delta2:enkephalins, Beta-endorphin

Question 4

Cloned Opioid receptors

Answer 4

MOR, DOR, KOR
7 transmembrane domains
G-protein linked (Gi or Gs) to adenyl cyclase or potassium channels (GIRKs)

Question 5

In vivo assays

Answer 5

1. Analgesic properties
2. Reinforcing properties
3. Stimulus properties

Question 6

Analgesic assays

Answer 6

Thermal simuli
Tactile stimuli
Inflammation
Neuropathy

Question 7

Reinforcing properties

Answer 7

Self-administration

Conditional Place Preference

Question 8

Stimulus properties

Answer 8

Discrimination tasks

Addiction research center inventory

Question 9

Desirable properties of morphine as an analgesic

Answer 9

Effective over a wide range of doses
Effect on mood
Sedation

Question 10

Undesirable properties of morphine

Answer 10

Sedation, mental clouding, Dysphoria, constipation, dizziness/circulatory depression, N/V, respiratory depression, cough reflex depression, miosis, pruritis and rash, biliary tract spasms, ureter and vesical spasms, urinary retention, behavioral dependence, physical dependence, tolerance, sexual dysfunction

Question 11

Tolerance

Answer 11

Associative or behavioral tolerance, nonassociative or pharmacologic tolerance, cross-tolerance, intrinsic efficacy, may affect development of tolerance and cross-tolerance

Question 12

Multiple sites of action

Answer 12

Dorsal horn of the spinal cord
Activate descending inhibitory system
peripheral receptors

Question 13

Morphine uses

Answer 13

Acute and chronic moderate to severe pain
-surgical
-postsurgical
-cancer
Often less effective for neuropathic pain

Question 14

Morphine contraindications

Answer 14

asthma, COPD, apnea, or other breathing disorders
liver or kidney disease
underactive thyroid
curvature of the spine with respiratory compromise
a history of head injury or brain tumor
epilepsy or other seizure disorder
low blood pressure
gallbladder disease
Addison's disease or other adrenal disorders
enlarged prostate, urination problems
mental illness
a history of drug or alcohol addiction

Question 15

Metabolism of morphine

Answer 15

Morphine-3beta-glucuronide (inactive)
Morphine-6beta-glucuronide (active)
Accumulate in patients with renal damage

Question 16

Heroin

Answer 16

Crosses BBB more rapidly than morphine

converted to morphine

Question 17

Hydromorphine

Answer 17

About 8-10X potency of morphine
slightly shorter duration than morphine
available as suppository

Question 18

Oxymorphine

Answer 18

same as hydromorphine

Question 19

Codeine (methylmorphine)

Answer 19

About 1/10th the potency of morphine
lower efficacy than morphine
about 10% converted to morphine by CYP 2D6
67 allelic variants. 7-10% of patients are poor metabolizers
small population of northern Pacific islanders are “super metabolizers”

Question 20

CYP2D6

Answer 20

Allelic variation in this makes a patient a poor metabolizer and the drug doesn’t work well

Question 21

Oxycodone

Answer 21

About 10 times potency of codeine
Also metabolized by CYP2D6, but has efficacy on its own
Controlled release formulation (Oxycontin)
Targin (oxycodone+naloxone)

Question 22

Hydrocodone (Dicodid and others) and dihydrocodeine

Answer 22

Same as oxycodone
Extended release formulation now also available (Zohydro)
Abuse deterrents

Question 23

Mixtures containing Codeine, hydrocodone, dihydrocodeine, or oxycodone

Answer 23

Acetaminophen or NSAIDS

Logic: additive or synergistic analgesia without concomitant increase in adverse effects

Question 24

Synthetic compounds

Answer 24

Meperidine
Fentanyl, Sufentanyl, Alfentanyl, Remifentanyl
Methadone
L-alpha-acetyl-mathadol:LAAM
Propoxyphene

Question 25

Meperidine

Answer 25

``` About 1/8th potency of morphine Shorter duration No miosis biotransformed to a toxic metabolite that builds up and can cause seizures synergistic with gila monster venom ```

Question 26

Fentanyl

Answer 26

``` 80--100X potency of morphine fast onset, short duration used iv for anesthesia available as patch available as oral slow release device ```

Question 27

Fentanyl derivative

Answer 27

Alfentanil, Sufentanil, Remifentanil, carfentanil, lofentanil

Question 28

Methadone

Answer 28

Potency is similar to morphine for iv administration, but 4 times more potent orally long plasma half life used in treatment of narcotic dependence Duration of action increases with repeated use

Question 29

Individual differences in response to mu opioid receptor agonists

Answer 29

Pharmacokinetic differences: metabolism CYP2D6, excretion of active metabolites Pharmacodynamic differences: Multiple MOR splice variants

Question 30

Opioid antagonists

Answer 30

Naloxone Naltrexone Nalmefene Methyl naltrexone

Question 31

Signs of overdose

Answer 31

``` Stuporous or in coma Respiratory rate extremely low pinpoint pupils low body temperature flacid skeletal muscles, jaw relaxed ```

Question 32

Naloxone

Answer 32

Short half-life | Nor effective orally

Question 33

Naltrexone

Answer 33

``` Long half life effective orally or injected available in oral form only used for treatment of dependence can produce hepatotoxicity with long term use ```

Question 34

Nalmefene

Answer 34

Intermediate duration (8-12 hr) orally active no hepatotoxicity with long term use used for treatment of alcohol dependence

Question 35

Methylnaltrexone

Answer 35

Quaternary form of drug does not cross BBB | Used to treat opioid-induced constipation

Question 36

Naloxegol

Answer 36

``` PEGylated naloxol (polymer opioid antagonist); does not cross BBB Used to treat opioid-induced constipation ```

Question 37

Mixed agonist-antagonist

Answer 37

Nalorphine and cyclazocine Pentazocine: Talwin Butorphanol Nalbuphine

Question 38

Nalophine and Cyclazocine

Answer 38

Kappa3 receptor agaonist Mu receptor antagonists Produce psychotomimetic effects produce dysphoria

Question 39

Pentazocine

Answer 39

Kappa and delta agonist 'Ts and blues' Talwin NX

Question 40

Butorphanol

Answer 40

``` Kappa recptor agonist Mu receptor antagonist Available as nasal spray 5 X more efficacious in women than men Could be due to melanocortin-1 receptor gene, regulated by LH ```

Question 41

Nalbuphine

Answer 41

``` Kappa receptor agonist Mu reeptor antagonist Little dysphoria compared to nalorphine less abuse potential than morphine frequently used in ambulances ```

Question 42

Partial agonist: Buprenorphine

Answer 42

``` Partial agonist at mu receptors Partial agonist at Kappa3 receptors Lower efficacy analgesic than morphine Buprenophine+naloxone Depo buprenorphine ```

Question 43

Tramadol

Answer 43

Opioid receptor agonist (mu and delta) NE and 5-HT reuptake blocker (antidepressant) alpha-2 adrenoceptor agonist These actions are synergistic for analgesia

Question 44

Tapentadol

Answer 44

Opioid receptor agonist (mu and delta) NE reuptake blocker (antidepressant) These actions are synergistic for analgesia

Question 45

Dependence and WIthdrawal

Answer 45

Dependence varies from mild cravinf to compulsion to take the drug Degree depends on dose and frequency Withdrawal signs opposite in direction to drug effects Will last about 72 hours for morphine and heroin Not life threatening

Question 46

Other factors that infuence the effectiveness of opioid treatment

Answer 46

Progression of tissue-damging disease Sensitization of CNS neurons Collateral transmission

Question 47

Salvinorin A

Answer 47

Active ingredient in Salvia Divinorum Very selective kappa opioid agonist Hallucinogen

Question 48

Krokodil

Answer 48

Desomorphine Synthesized from codeine Heroin-like high, but rapid kinetics chronic use produces tissue damage, phlebitis and gangrene