Lecture 19: Opioids Flashcards Preview

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Flashcards in Lecture 19: Opioids Deck (89):
1

Which two compounds are naturally found in opium?

Morphine and codeine

2

3 opioid receptors and their endogenous opioid. These receptors are all which type? Analgesics act where?

Mu (endorphin), delta (enkephalin), kappa (dynorphin); GPCRs; mu

3

Where is each receptor localized? Give more detail on the subtypes of mu receptors (function)

Mu: brain, spinal cord, peripheral nerves, intestinal tract; mu1 = analgesia, mu2 = respiratory depression, miosis, euphoria, GI motility, mu3 = vasodilation; Delta: brain, peripheral nerves; Kappa: brain, spinal cord, peripheral nerves

4

Which opioid receptor is associated with dysphoria?

Kappa

5

How do endogenous opioid peptides interact with receptors? When are they released?

Full agonists; during stress/excitement/pain

6

Where are opioid receptors prominently expressed? Main function here?

Terminals of excitatory and inhibitory neurons; hyperpolarize terminal/interfere with Ca2+ entry --> reduce transmitter release

7

Postsynaptic opioid receptors are excitatory or inhibitory?

Inhibitory

8

Describe mu-receptor agonist activity in the periphery

Bind to presynaptic MORs, inhibit release

9

Describe mu-receptor agonist activity in the CNS

Mu agonists inhibit GABA interneurons in the PAG, which disinhibits the medulla --> 5HT and NE release in dorsal horn, inhibiting 2nd order sensory neurons (decrease pain signal)

10

Do opioids ever effect receptors other than MORs? Give 4 examples.

Yes! Morphine = kappa agaonist, buprenorphine = kappa/delta antagonist, methadone = NMDA antagonist, tramadol = block 5HT uptake

11

Describe absorption, distribution, metabolism and excretion of opioids

Absorption: well absorbed via subcutaneous, intramuscular, oral; Distribution: highly perfused; Metabolism: first-pass by liver, polar metabolites excreted by kidneys

12

CNS effects of mu agonists

Analgesia, drowsiness, euphoria respiratory depression, cough suppression, lowered seizure threshold, miosis

13

Cardio effects of mu agonists. Hormone?

Vasodilation; increased histamine

14

GI effects of mu agonists

Decreased motility/secretions

15

Renal effects of mu agonists. Hormone?

Decreased urination; increased ADH

16

Skin effects of mu agonists. Hormone?

Flushing, itching; increased histamine

17

Immune effects of mu agonists

Altered lymphocyte proliferation, Ab production, chemotaxis

18

What are 3 OTHER uses for morphine

Anti-dyspneic (first line therapy for symptom relief), anti-tussive, anti-diarrheal

19

Morphine's mechanism

Full MOR agonist

20

Morphine is good for treating these types of acute pain...Compare nociceptive to neuropathic.

Trauma, peri-operative, acute coronary; nociceptive > neuropathic

21

Morphine: bioavailability, metabolism, excretion

0.25 oral; hepatic, 10% is active (morphine-6-glucuronide, more potent than morphine), 90% is a neurotoxin (morphine-3-glucuronide); 90% urine

22

Morphine: adverse effects w/ tolerance (5).

Sedation (tolerance); nausea (tolerance); constipation; respiratory depression (most common cause of morbidity but not significant at standard doses); other (delirium, seizure, dry mouth, urinary retention, pruritus)

23

Morphine: precautions (4)

Abdominal (worsen GI bc of reduced motility); hepatic (may metabolize poorly --> increased bioavailability); renal (neurotoxic metabolites may accumulate); respiratory disease/head injury (depressed response to pCO2 can worsen respiratory problems and increase ICP)

24

Codeine's mechanism and morphine relation

Weak MOR agonist; pro-drug for morphine

25

Main clinical uses of codeine

Analgesia and cough suppressant

26

T/F: The adverse effects of codeine are better than morphine

False! N/V and pruritus are both worse than morphine

27

Describe codeine's metabolism and importance

Hepatic/CYP2D6, ultra-rapid metabolizers produce high levels of morphine while poor metabolizers may have no effect

28

Describe oxycodone's metabolism and importance

Hepatic/CYP2D6, ultra-rapid metabolizers produce high levels of oxymorphone while poor metabolizers may have no effect

29

These two common drugs are related to oxycodone. What are their relationships?

Oxycontin: ER formula; Percocet: combo with acetaminophen

30

What is Vicodin?

Hydrocodone + acetaminophen

31

Hydrocodone is derived from what? Clinical uses (2)

Codeine; analgesia and anti-tussive (more potent than codeine)

32

What is special about hydromorphone? (3)

1. Safer in patients with liver disease; 2. Safer in patients with kidney disease (no active metabolites); 3. More potent than morphine (7-8x)

33

How does heroin work?

Morphine prodrug that is hydrolyzed in blood, liver, RBCs and easily crosses BBB due to lipophilicity

34

What is special about fentanyl? (2)

Does not cause histamine release and has no active metabolites

35

What is the clinical use, mechanism, and side effects of loperamide?

Diarrhea; slows intestinal contractions to allow moisture reabsorption; GI pain, dry mouth, anorexia, hyperglycemia, rare: necrotizing enterocolitis

36

What is the mechanism of action of Tramadol? Adverse effects?

Weak MOR agonist, 5HT releasing agent, NE reuptake inhibitor, NMDA antagonist, nicotinic antagonist, muscarinic antagonist; N/V, sweating, seizures but NOT sedative (respiratory depression, sedation, drowsiness, constipation)

37

What agonist has low efficacy?

Codeine

38

What agonists have moderate-to-high efficacy? (3)

Oxycodone, tramadol, buprenorphine

39

What agonists have high efficacy? (5)

Morpine, heroin, hydromorphone, fentanyl, methadone

40

Three theories of opioid tolerance

1. Up-regulation of cAMP signaling pathway; 2. Reduced receptor recycling; 3. Receptor uncoupling from G proteins

41

What do you develop tolerance to first (days)? Weeks? Maybe never?

Sedation, respiratory depression, vasodilation; dyspnea relief, N/V, pruritus; analgesia, constipation, miosis

42

How do opioids cause miosis and why is this significant?

Disinhibit parasympathetic input to eye; no tolerance so reliable sign of opioid intoxication

43

What are the "pain steps"

Step One: NSAIDS; Step Two: Weak opioids (moderate pain); Step Three: strong opioids (severe pain)

44

What drugs produce toxic metabolites that can accumulate if pts have renal disease? What are better substitutes?

Morphine, oxycodone, codeine; fentanyl, methadone, hydromorphone

45

What are the two steps of rotating opioids?

1. Calcuate equianalgesic dose; 2. Adjust dose for incomplete cross-tolerance

46

Why might incomplete cross-tolerance occur? What do you do when rotating opioids to take this into account?

Subtle differences in molecular structure/receptor interactions; reduce equianalgesic dose by 50%

47

How are Schedule 1 drugs unique? (2)

No currently accepted medical use and a high potential for abuse

48

Dependence

Development of withdrawal syndrome following dose reduction or administration of antagonist

49

Tolerance

Change in dose-response relationship induced by exposure to drug and need for higher dose

50

Craving

Desire for more of a substance/activity to experience the euphoric effect or avoid withdrawal aspects

51

Opioid Use Disorder

Problematic pattern of opioid use leading to clinically significant impairment or distress

52

Addiction

Compulsive use despite harm, craving, impaired control of drug use

53

Pseudo-addiction

Behaviors that are reminiscent of addiction, but are driven by pain and disappear with more adequate analgesia

54

What percent of adolescents use psychotherapeutics

About 7%, with opioids being the most common

55

How prevalent is OUD? Deaths?

5% of adults used opioids non-medically w/ 1.8 million OUD due to prescriptions and 500,000 due to heroin; 17,000 deaths annually due to OUD

56

Where are people getting these prescriptions?

Often just their one doctor or friend/relative's one doctor; prescription rates are increasing

57

How long do we have data on long-term safety/efficacy for use of opioids?

2 months

58

What are some problems w/ opioids (4)

1. Cause euphoria; 2. Limited safety/efficacy data for LT use; 3. Intensify response w/ snorting; 4. Tolerance

59

Neurobiological reason of addiction. Opioids? (2)

Drugs of abuse increase DA neurotransmission through mesolimbic pathway; opiods specifically disinhibit GABA neurons --> more transission AND mimic endorphins with influence NA

60

Substance Use Disorder

Recurrent use that causes clinically and functionally significant impairment; 2 symptoms over 12-month period; disease severity based on number of symptoms

61

Signs of OUD or diverting prescribed opioids (9)

Call for early refills/lose, demands specific opioid, neg urine drug screen (should be positive), doctor shopping, refuses communication with other providers, uses for indication other than pain, change in behavior, signs of opiate intoxication, pain out of proportion to exam

62

Likelihood that a patient with develop OUD w/ chronic opioid prescription

Depends on substance abuse history, about 0-7%

63

Factors associated w/ developing OUD

Personal/family history, male, poor social support, trauma history, comorbid psych disorder, history of conviction related to drugs/DWI

64

What can healthcare providers do to prevent OUD?

Prescribe responsibly: screen, give opioids when other treatments not effective, prescribe only necessary quantity, patient-provider agreements, talk with w/patients about safe use, storage, disposal; use drug monitoring programs; learn about pain

65

T/F: Urine drug screening is helpful all the time

False! Mixed efficacy (not all opiates identified, false positives), but probably helpful in identifying misuse in pain clinic

66

Pyschosocial treatments (3)

Counseling, residential programs, peer support groups

67

T/F: Recovery is greater when psychosocial + medication combined

True!

68

Three clinical settings for care

Inpatient (detox), residential, outpatient care (methadone clinics)

69

Methadone mechanism

Mu opioid receptor agonist and NMDA glutamate antagonist

70

Methadone clinical use

Analgesia (chronic especially if other opioids don't work), opioid abuse detox

71

Methadone pharmacokinetics

Very greatly from person to person! Wide range in bioavailability (36 - 100%) and half-life (though long-acting), excreted renally and fecally

72

Methadone side effects (3 categories)

Same as mu opioid + NMDA SEs = depression, hallucinations + other = prolonged QTc/arrythmias

73

Why does methadone work?

Prevent withdrawal, slow release and less euphoria

74

Methadone maintenance of OUD

Must be enrolled in methadone maintenance program w/ strict rules (18+, dependent on opioids for >1 year); low doses w/ titration until withdrawal/craving disappears

75

Buprenorphine mechanism

Partial mu receptor agonist, antagonist at delta/kappa receptors, blocks VG-Na+ channels

76

Buprenorphine clinical use

Pain and opioid withdrawal/dependence

77

Special features of Buprenorphine

High affinity but low intrinsic activity for mu receptors (displace other opiates), slow rate of dissociation, ceiling effect for opiate effects and respiratory depression

78

How do you give Buprenorphine

Low oral bioavailability: sub-lingual

79

Does Buprenorphine require a clinic?

Nope! But clinician must take special course

80

Buprenorphine SEs

Similar to other opioids, safer in terms of overdose (less respiratory depression)

81

Naloxone mechanism

Opioid antagonist

82

Naloxone clinical use

Opioid overdose

83

Naloxone comes in what special form...

Auto-injector

84

Naloxone pharmacokinetics

Works quickly w/ short half-life

85

What is the combination of naloxone and Buprenorphine. Why?

Suboxone; pts who try to crush medication will get the effects of the Naloxone causing withdrawal

86

What is Naltrexone? Indication? Wait for what?

Long-lasting version of Naloxone; opioid/alcohol use disorders to maintain abstinence (blocks access of narcotics to opiate receptors sites); patient must have been through detox

87

Naltrexone common and rare but serious SEs

Headache, nausea, anxiety; DVTs, depression

88

Symptoms of opioid withdrawal

Anorexia, rhinorrhea, goosebumps, yawning, tearing, N/V, abdominal pain, muscle craps, sweating

89

T/F: Mortality is low in opioid withdrawal

True! As compared to alcohol

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