Goldstein Opioids

Front 1

1) As a class, are opioid agonists well absorbed orally?
2) Do opioids undergo extensive first-pass hepatic metabolism? Bioavailability?

Back 1

1) Yes
2) Many have high 1st pass metabolism=>lower bioavailability w/oral route

Front 2

1) Which tissue do opioids distribute to most?
2) What other tissues are acted on by them?
3) Slow or rapid distribution

Back 2

1) Skeletal muscle (54%)
2) Gut, Kidney, Lungs, Spleen, Brain
3) Rapid

Front 3

How are opioids generally metabolized? (2)

Back 3

1) Hepatic glucoronidation-->excreted by kidney
2) Hepatic oxidation--> metabolites may be active --> produce neurotoxic effects

Front 4

Which 2 opioids have active metabolites which have neurotoxic side effects (i.e. seizures)? Which patients are at increased risk for these SEs?

Back 4

1) Morphine
2) Meperidine
Patients w/renal problems at increased risk b/c they cannot excrete toxic metabolites

Front 5

1) Do opioids act on mu-opioid receptors (MORs) on the pre-synaptic/post-synaptic/both neurons in the pain pathway?
2) What kind of receptor is the MOR?

Back 5

1) Both
2) G-protein coupled receptor (inhibitory)

Front 6

How do opioid agonists ACTIVATE inhibitory (descending) fibers from the thalamus to suppress pain signaling to the cortex?

Back 6

MOR binding by drug --> inhibits the inhibitory GABAergic interneurons that are suppressing the "pain killer signal" from the thalamus --> pain suppressing signals can now reach dorsal columns of spinal cord to nip pain signal at the bud

Front 7

Tolerance develops to which effects of opioids? (4)

Back 7

1) Analgesia
2) Respiratory depression
3) Euphoria
4) Sedative
Tolerance=>need more drug to achieve original effect

Front 8

Tolerance DOES NOT develop to which effects of opioids? (3)

Back 8

1) Miosis
2) Constipation
3) Convulsions

Front 9

Opioid effects on CNS? (8)

Back 9

1) Analgesia
2) Sedation
3) Euphoria
4) Respiratory/cough suppression
5) Nausea/vomitting
6) Truncal rigidity
7) Miosis
8) Altered temperature regulation

Front 10

Neuroendocrine effects?

Back 10

1) Stimulates release of ADH
2) Stimulates prolactin and somatotropin
3) Inhibits LH release

Front 11

Peripheral effects?

Back 11

1) Bradycardia/hypotension in susceptible patients
2) Urinary/biliary colic
3) Urinary retention
4) Pruritis, urticaria

Front 12

When are STRONG opioids indicated?

Back 12

Severe, CONSTANT pain

Front 13

What are therapeutic uses of the opioid class?

Back 13

1) Analgesia
2) Anesthesia (pre-op sedative or intra-op adjunct)
3) Cough Suppression/Diarrhea
4) Acute MI
5) Pulmonary Edema
6) Post-op shivering (meperidine)

Front 14

Why are opioids contraindicated in asthma patients?

Back 14

Opioids can induce histamine release=> can lead to seve bronchoconstriction

Front 15

What specific SE makes opioids a contraindication for a patient with a head injury?

Back 15

Opioids can increase intracranial pressure due to respiratory depression: CO2 not blown off due to respiratory depression (i.e. respiratory acidosis) --> cerebral vasodilation

Front 16

What are 3 classes of drugs that opioids have potentially dangerous interactions?

Back 16

1) Sedative-hypnotics (i.e. benzos)/Alcohol (inc. resp depress)
2) Antipsychotics/TCAs (inc. sedation/cardioresp effects)
3) MAOIs (risk of hyperpyrexic coma/HTN)

Front 17

Which opioid is an absolute contraindication w/MAOI use?

Back 17

Meperidine

Front 18

1) Morphine has a low/high oral bioavailability?
2) How is morphine metabolized?
3) Are the metabolites active? Effects?

Back 18

1) Low (25-33%)
2) Extensive first-pass hepatic; glucuronidation (M3G/M6G)
3) M3G (primary)=>has neurotoxic effect (convulsions)
M6G= is 4-6X more potent at MOR than parent drug

Front 19

Which morphine metabolite is largely responsible for its analgesic effect?

Back 19

Morphine-6-glucuronide (M6G)

Front 20

What are the therapeutic uses of morphine? (3)

Back 20

1) Analgesia
2) Anesthesia
3) Dyspnea (as during an AMI)

Front 21

Codeine is a prodrug of what?

Back 21

Codeine = Methylmorphine
Prodrug of morphine

Front 22

Codeine has lower/higher/same oral bioavailability compared to morphine?

Back 22

Higher (well absorbed); 53%

Front 23

10% of codeine dose undergoes which metabolic process to become active?

Back 23

Codeine-->Morphine (via CYP2D6)
Morphine -->M3G + M6G (active analgesic) [UGT]

Front 24

Codeine undergoes which reaction to yield inactive metabolites that will be excreted?

Back 24

Codeine--> Codeine-6-G (via UGT2B7/B4)

Front 25

Genetic polymorphisms in which CYP may lead to:
1) Absent codeine levels/effect
2) Too powerful codeine effect

Back 25

1) Absent or defect CYP2D6 (do not convert to morphine)
2) CYP2D6*2X2=>ultra-fast conversion to morphine

Front 26

Is codeine a strong/moderate MOR agonist?

Back 26

It is a partial MOR agonist (60% as effective as morphine)

Front 27

1) Oxycodone and hydrocodone are semisynthetic derivatives of which drug
2) Oxycodone is used for?
3) Hydrocodone?

Back 27

1) Morphine
2) Acute moderate-severe pain or chronic pain (long-acting formula); combined with aspirin/tylenol
3) Available only in combo w/non-opioid analgesics

Front 28

Meperidine PKs:
1) Routes of administration; oral bioavailability?
2) How is meperidine metabolized? CYPs involved?

Back 28

1) Oral, IM, IV; oral BA about 50%
2) N-demethylation via CYPs 2B6, 3A4, 2C19

Front 29

1) What is the active metabolite of meperidine?
2) What are its analgesic effects?
3) CNS effects?
4) Elimination half-life? Excretion?

Back 29

1) Normeperidine
2) Half the analgesic effect as meperidine
3) 2-3X the CNS (neurotoxic) effect as meperidine
4) 15-20 hours (meperidine=>3 hours); renal excretion

Front 30

1) Which patients are at risk of neurotoxic SEs due to the active metabolite of meperidine
2) Oral or IV administration of meperidine produces more of the toxic metabolite normeperidine?

Back 30

1) Patients w/renal failure or liver disease and elderly patients (natural decline of renal fxn)
2) Oral form

Front 31

1) Meperidine is a strong/moderate/weak MOR agonist?
2) Agonist at what other pain receptor?
3) Has what additional effect that results in less smooth muscle spasm and absence of miosis?

Back 31

1) Strong MOR agonist
2) Kappa agonist
3) Meperidine has anti-muscarinic effects

Front 32

Uses of meperidine?

Back 32

1) Moderate to severe pain
2) Obstetric labor
3) Reduce shivering
4) Anesthesia adjunct or pre-treatment

Front 33

When meperidine is given for pain, how long can a patient be on it?

Back 33

Want to avoid giving patient meperidine for longer than 48 hours due to normeperidine-associated SEs which appear w/prolonged use.

Front 34

Why is meperidine given during obstetric labor?

Back 34

1) Does not delay birth process
2) May increase the frequency, duration, and amplitude or uterine contractions
3) Does not inhibit oxytocin release
4) Causes less respiratory depression in newborn than morphine does

Front 35

Meperidine can be used to treat shivering rxns cause by which 2 drugs? (Antifungal and cancer drug); MOA in this scenario?

Back 35

1) Amphotericin B
2) Trastuzumab
Meperidine lowers the shivering trigger temperature and stops shivering via alpha-2 agonist effects

Front 36

What are 3 AEs of meperidine?

Back 36

1) Neurotoxicity
2) Tachycardia (w/IV use)=>caution in pts w/SVTs
3) Hypotension (histamine-induced like in morphine)

Front 37

Can neurotoxicity caused by meperidine be reversed by naloxone?

Back 37

NO; it can potentially worsen the neurotoxicity

Front 38

Using meperidine and a drug from what class can cause serotonin syndrome?

Back 38

Meperidine + MAOI is contraindicated b/c of serotonin syndrome risk

Front 39

Why is meperidine + phenobarbital or phenytoin a dangerous interaction?

Back 39

Phenobarbital/phenytoin are CYP inducers=>increase systemic clearance of meperidine=>decrease bioavailability of meperidine
**This interaction is a/w increased plasma concentration of normeperidine**

Front 40

Which other drugs are not safe to give with meperidine?

Back 40

1) Chlorpromazine; TCAs (enhance respiratory depressant, sedative, and hypotensive effects)
2) Amphetamines (enhance analgesic effect)

Front 41

Name three congeners of fentanyl; MOAs?

Back 41

1) Sufentanil
2) Alfentanil
3) Remifentanil
All are MOR agonists (potent)

Front 42

1) List fentanyl, sufentanil, and alfentanil in order of most potent to least potent:
2) Fentanyl is how many times more potent than morphine?

Back 42

1) Sufentanil>fentanyl>alfentanyl
2) 100X more potent

Front 43

Fentanyl and congener PKs:
1) Onset/termination
2) Metabolism
3) Which patients are at risk for tox due to increased duration of action and increased elimination half-life?

Back 43

1) Rapid onset and rapid termination
2) Hepatic and extrahepatic
3) Elderly patients, pts undergoing cardiopulmonary bypass, and pts with liver disease

Front 44

Which fentanyl congener does not have increased tox risk in patients w/liver disease? How is this drug metabolized?

Back 44

Remifentanil; hydrolyzed by blood and tissue esterases

Front 45

1) How is fentanyl metabolized?
2) What is the duration of analgesia w/fentanyl use? Why?

Back 45

1) Via CYP3A4 in intestinal and skin (transdermal patch)--> inactive metabolites --> renal excretion
2) 30-60 minutes; drug redistributes from highly perfused areas to other areas (skeletal muscle and fat)

Front 46

Why is fentanyl advantageous as an adjuvant in surgical anesthesia? (2)

Back 46

1) Rapid onset, short duration of action, high potency
2) Does not cause histamine release and direct depressant effect on cardiac myocardium (unlike other opioids)

Front 47

Fentanyl transdermal patches are indicated for chronic pain management. One patient population, however, has a contraindication to this?

Back 47

Patients who have never been treated w/opioids should not be given fentanyl transdermal patch

Front 48

Along w/common SEs of opioid class, what SE is a/w fentanyl and congeners?

Back 48

Truncal rigidity (mostly w/rapid IV use of highly lipid soluble drugs)

Front 49

1) Dextromethorphan is the D-isomer of which opioid analgesic?
2) MOA of dextromethorphan?
3) Dextromethorphan metabolism

Back 49

1) Levorphanol
2) Non-competitive NMDA inhibitor; SERT inhibitor
3) CYP2D6

Front 50

1) Compared to morphine, what is methadone's oral bioavailability?
2) Peak concentration of methadone achieved when? High/low plasma protein binding?

Back 50

1) Much greater (over 85% BA for methadone)
2) About 4 hours; high (90%) PP-bound

Front 51

Methadone CYPs?

Back 51

3A4, 2B6, 2C19 (covert methadone to inactive metabolites)

Front 52

What accounts for methadone's cumulative effects w/long-term use?

Back 52

Methadone binds to tissue and plasma-proteins and this includes the brain

Front 53

1) Methadone is short/moderate/long acting MOR agonist?
2) Methadone is a racemic mixture: L-methadone actions vs D-methadone?
3) What are non-MOR effects of methadone that account for its efficacy in treating difficult pain cases?

Back 53

1) Long-acting MOR agonist
2) L-methadone=>8-50X more potent MOR agonist than D isomer=> L-methadone responsible for the analgesic effect
3) NMDA-R antagonist and SERT/NET/DAT inhibitor

Front 54

Clinical uses of methadone?

Back 54

1) Chronic pain (neuropathic/cancer)
2) Pts in whom morphine has failed to reduce pain
3) Treatment of heroin users

Front 55

Is methadone abuse potential less than/equal to/greater than w/morphine use?

Back 55

Same abuse potential as morphine

Front 56

1) What is the prototype of the MOR agonist/NE reuptake inhibitors?
2) What is this drug a synthetic analog of?

Back 56

1) Tramadol
2) Codeine

Front 57

Tramadol PKs:
1) Metabolism?
2) What is the significance of its primary metabolite?

Back 57

1) Extensive hepatic=>CYPs 2D6 and 3A4
2) It is the O-demethylated metabolite of tramadol=> metabolite is 2-4X as potent as tramadol (may account for analgesic effect)

Front 58

Tramadol is a weak/moderate/potent MOR agonist?

Back 58

Weak (affinity for MOR is 1/6000 that of morpine)

Front 59

1) What accounts for tramadol's analgesic effect?
2) Used for mild/moderate/severe pain?
3) Tramadol SEs

Back 59

1) Weak MOR agonist and inhibition of 5-HT and NE reuptake
2) Mild-moderate pain
3) GI (nausea/vomiting/constipation), dizziness, dry mouth

Front 60

1) Tramadol can cause what severe adverse effect even at recommended doses?
2) Tramadol is contraindicated in patients with which organ dysfxn?

Back 60

1) Seizures
2) Pts w/pulmonary disease contraindicated for tramadol

Front 61

What is a closely related drug to tramadol?

Back 61

Tapentadol

Front 62

What are the 4 mixed opioid agonist-antagonists (agonist at kappa but partial agonist/weak antagonist at MOR)?

Back 62

1) Pentazocine
2) Nalbuphine
3) Butorphanol
4) Buprenorphine

Front 63

Pentazocine is a KOR agonist (and partial agonist/antagonist of MOR). What happens when agonist binds to KOR?

Back 63

Spinal (primarily) and supraspinal analgesia

Front 64

1) Pentazocine routes of admin?
2) Metabolism? Excretion?
3) Therapeutic use?

Back 64

1) Oral, IV, sub-Q
2) Extensive 1st-pass hepatic metabolism; oxidation and glucuronidation; renal excretion
3) Moderate pain

Front 65

Oral form of pentazocine is formulated with what drug? Why?

Back 65

Oral pentazocine is formulated w/naloxone to prevent patients to dissolve tablet and use it in IV form to get high. Naloxone is rapidly inactivated by liver in oral form=>no opioid withdrawal symptoms

Front 66

Patients w/pre-existing disease of what organ are at risk for pentazocine toxicity?

Back 66

Patients w/angina pectoris=>pentazocine increases HR and MAP=>increased workload for heart

Front 67

1) Nalbuphine PKs: Admin; Metabolism; Excretion
2) Therapeutic use?
3) Side effects compared to pentazocine?

Back 67

1) Parenteral ONLY; hepatic metabolism; renal excretion
2) Moderate-severe pain; treat pruritis a/w fentanyl
3) Less dysphoria; does not increase work of heart in pts w/stable angina or post-MI; increased respiratory depression; sedation, headaches, and sweating are common SEs

Front 68

1) How is butorphanol unique in terms of route of admin?
2) Is butorphanol useful for acute/chronic pain?

Back 68

1) Can be given nasally; always given parenterally
2) Acute (i.e. ureteric colic)

Front 69

Nasal form of butorphanol is particularly useful for which condition causing pain?

Back 69

Migraine headaches

Front 70

Buprenorphine has what effects on:
1) MOR
2) KOR
3) DOR

Back 70

1) Partial agonist (high affinity)
2) Antagonist
3) Antagonist

Front 71

1) Buprenorphine ROA?
2) Metabolism?
3) Elimination half-life of parent/metabolites? Excretion?

Back 71

1) IV, IM, sublingual, patch
2) Hepatic=>CYP3A4-->active metabolite (norbuprenorphine)
3) 35 hours; renal and fecal excretion

Front 72

Buprenorphine has similar CNS effects as morphine except one factor?

Back 72

Buprenorphine has a longer duration of action on the CNS than morphine

Front 73

Why is naloxone (MOR blocker) not as effective of treating buprenorphine tox? How is this overcome?

Back 73

Buprenorphine has a very high affinity for the MOR=>harder for naloxone to compete and block MOR; overcome by giving naloxone before buprenorphine admin

Front 74

What are 3 uses of buprenorphine?

Back 74

1) Acute pain (moderate to severe)
2) Chronic pain (moderate to severe)
3) Opioid withdrawal treatment (w/naloxone)

Front 75

For each indication of buprenorphine, which form of drug?
1) Acute pain?
2) Chronic pain?
3) Opioid withdrawal treatment?

Back 75

1) IV/IM
2) Transdermal
3) Sublingual

Front 76

Name 3 MOR antagonists? Routes of admin?

Back 76

1) Naloxone (IV)
2) Naltrexone (Oral/IM)
3 Nalmefine (no longer used in US)

Front 77

At high doses the MORs can also block which receptors?

Back 77

KOR and DOR

Front 78

1) What is the treatment of choice for opioid overdose?
2) What is the duration of action of this drug? Why is this significant?

Back 78

1) Naloxone
2) 30-120 mins; may have to continue giving naloxone to avoid relapse into a coma

Front 79

Respiratory depression caused by which drugs may require higher doses of naloxone?

Back 79

The mixed agonist/antagonists (pentazocine, buprenorphine)

Front 80

Naltrexone DOA when given orally? IM?

Back 80

Oral: 2-3 days
IM: 4 weeks

Front 81

What is a Boxed Warning of naltrexone?

Back 81

Hepatotoxicity

Front 82

What are the 2 peripherally-acting MOR antagonists?

Back 82

1) Methylnaltrexone
2) Alvimopan

Front 83

What is the main indication for methylnaltrexone?

Back 83

Reverse opioid-induced constipation that is refractory to laxatives

Front 84

Main indication for alvimopan? Route of admin? Metabolism?

Back 84

Treatment of post-op ileus; oral (low BA); hydrolyzed in gut flora