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Pharm Block 3 > 2 - Opioids > Flashcards

2 - Opioids Flashcards

1
Q

What is an opiate? What is an opioid? What are endogenous opioids?

A

Opiate: a compound that is structurally related to products found in opium (morphine, codeine)

Opioid: any agent, regardless of structure, that has the functional and pharmacological properties of an opiate. (endogenous opioids are naturally occurring ligands for opioid receptors)

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2
Q

What is a narcotic?

A

A drug that produces a stuporous sleep-like state, may or may not be analgesic.

Includes opioids and some other abused drugs.

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3
Q

What is pain?

A

A subjective symptom or unpleasant sensory or emotional experience that is typically associated with actual or potential tissue damage from mechanical or thermal causes or disease.

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4
Q

What is analgesia? What are analgesics?

A

Analgesia: a state in which no pain is felt despite the presence of normally painful stimuli.

Analgesics: drugs that alleviate pain without impairing other sensory modalities

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5
Q

What are endorphins? What is their precursor? Where are they found?

A

Endogenous opioid peptides; precursor POMC.

B-endorphin in hypothalamus and nucleus tractus solitarius. Also in anterior pituitary co-released with ACTH during stress.

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6
Q

What are Enkephalins? What is their precursor? Where do they have their actions?

A

Endogenous opioid peptides; precursor proenkephalins.

Leucine and methionine enkephalins have wide CNS distribution, esp in interneurons and the pain pathways.

Peripheral sites include adrenal medulla, nerve plexuses, and exocrine glands of the stomach and intestine.

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7
Q

What are Dynorphins? What is their precursor and where is their action?

A

Endogenous opioid peptides; precursor prodynorphin.

Dynorphine A co-localized with vasopressin in magnocellular cells of hypothal and post. pituitary.

Shorter dynorphins have wide CNS distribution; some in pain pathways of spinal cord.

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8
Q

What are the amino acid similarities among endogenous opioids?

A

The first five amino acids are highly conserved among endogenous opioids, particularly the first four amino acids.

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9
Q

What is the selectivity of the endogenous opioids?

A

Beta-endorphins, Met-enkephalins, and Leu-enkephalins agonize the Mu and Delta receptors.

Dynorphin A agonizes Mu and Kappa receptors.

Dynorphin B agonizes Mu, Delta, and Kappa receptors.

These are not as specific as the opioid drugs we give.

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10
Q

What do plasma opioid peptide levels reflect? What is the flip side to this?

A

The release from secretory systems such as the pituitary and adrenals. They do NOT reflect neuraxial release.

Conversely, levels of peptides in the brain/sp cd and CSF arise from neuraxial systems and not from peripheral systems.

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11
Q

What are the three types of opioid receptors? What are a few properties of each?

A
  1. Mu: supraspinal and spinal analgesia. Slowed GI transit. Modulation of hormone release.
  2. Delta: supraspinal and spinal analgesia. Modulation of hormone and nt release.
  3. Kappa: supraspinal and spinal analgesia. Psychotomimetic effects. Slowed GI transit.
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12
Q

What is the distribution of opioid receptors?

A

Wide distribution in brain and periphery.

Neuronal cell soma and axom terminals, macrophage cell types, astrocytes, and enteric NS.

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13
Q

Which drugs are opioid receptor agonists?

A

Morphine, fentanyl, methadone, and codeine.

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14
Q

Which drugs are opioid receptor mixed agonists-antagonists?

A

Buprenorphine, nalbuphine, and pentazocine.

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15
Q

What drugs are opioid receptor antagonists?

A

Naloxone and Naltrexone.

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16
Q

What is the ascending pain pathway? What are the different type of pain fibers?

A

Noxious stimuli activate nociceptors.

A-delta fibers (myelinated) mediate sharp, localized pain to the dorsal horn: somatic pain, lamina 1 (Glu)

C fibers (unmyelinated) mediate dull and diffuse pain, aching, burning: visceral or neuropathic pain. Lamina II (Glu and Substance P)

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17
Q

What occurs next in the pain pathway after nociceptors are activated?

A

2nd order neurons in the spinothalamic tract go to the thalamus, limbic system, somatosensory and associated cortex (emotional cortex).

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18
Q

Describe the descending pain pathway? What is released and what is its function?

A

Originates in the periaqueductal gray (midbrain) and rostro-ventral medulla to the dorsal horn.

Release NE, 5HT, enkephalin that act on

Inhibit activity of the ascending pain pathway directly via Mu receptors or act on interneurons that release enkephalins that inhibit pain.

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19
Q

What are the three mechanisms of Mu opioid receptor (MOR) induced analgesia?

A

Supraspinal: disinhibition of periaqueductal gray (PAG) output neurons, resulting in increased medulla modulation of 5-HT and NE outputs.

Spinal cord: pre and post synaptic effects on ascending pathway

Peripheral: specific to inflammatory pain, normalizes hyperalgesia.

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20
Q

What role do opioids play in cough suppression? Which drugs do this?

A

Direct actions on medullary cough center. May not be mediated by opioid receptors.

Codeine and hydrocodone.

Independent of respiratory depression.

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21
Q

What effect do opioids have on the respiratory system? What is the mechanism by which this occurs?

A

Most serious side effect is respiratory depression.

Decreased sensitivity of the brainstem chemoreceptors to CO2.

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22
Q

What CV effects can opioids have? When is this worsened?

A

Peripheral vasodilation, reduced peripheral resistance, inhibition of baroreceptor reflexes.

These effects may be minimal when pt is supine, but when pt assumes heads-up position, orthostatic hypotension and fainting can occur.

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23
Q

What mechanisms cause the CV effects of opioids (peripheral vasodilation, reduced peripheral resistance, and inhibition of baroreceptor reflexes)?

A

Release of of histamine from mast cells (fentanyl and sufentanil have much less effect on histamine).

Blunting of reflex and vasoconstriction by increased Pco2.

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24
Q

How do opioids cause miosis (pupil constriction)?

A

Disinhibition of Edinger-Westphal output neurons.

-inhibition of local GABAergic interneurons disinhibit output neurons.

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25
Q

What effect do opioids have on wakefulness?

A

They cause sedation, drowsiness, and cognitive impairment.

Can increase respiratory depression.

Likely due to general CNS inhibition.

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26
Q

What is the euphoria caused by opioids associated with?

A

Primarily mediated by the mesolimbic circuit:

  • Mu receptors on GABA interneurons in ventral tegmental area (VTA) disinhibit dopamine (DA) neurons.
  • Mu receptors on GABA medium spiny neurons in nucleus accumbens (NAc)
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27
Q

What are the endocrine effects of opioids on men and women??

A

Male: reduced cortisol, testosterone, gonadotropins
Females: same as male, also reduced LH and FSH.

Thought to involve both hypothalamic effects (reduced GnRH and CRF) and pituitary effects (direct inhibition of pituicytes).

Minimal effects on thyrotropin

28
Q

What effects do opioids have on the anterior pituitary?

A

Plasma prolactin elevated.
Dopamine released from tuberoinfundibular neurons inhibits prolactin release from pituitary lactotrope cells.
-opioids inhibit dopamine release by presynaptic mu receptors.

29
Q

What effect do opioids have on the biliary system?

A

They increase biliary pressure.

They suppress inhibitory innervation of sphincter of oddi (morphine does 10 fold in 15 min).

The effect may exacerbate pain in patients with biliary colic.

30
Q

What effect do opioids have on the GI system? What drug does this?

A

Central and peripheral antidiarrheal effect and constipation, mu receptors on GI nerves.

Loperamide (immodium).

31
Q

Most full agonists are equally effective at analgesia except _______ and _______?

A

Codeine and propoxyphene.

32
Q

How do opioids cause nausea?

A

Stimulation of chemical trigger zone in the area postrema.

More when standing.

33
Q

What words describe the pharmacokinetics of opioids?

A

Absorption
Distribution
Metabolism
Excretion

34
Q

Describe the absorption of opioids? What is their onset of action related to?

A

Oral and F: varies by compounds. Poor for morphine and naloxone due to first pass. Good for methadone.

Rectal: adequate absorp.

Transdermal: high for lipophilic opioids like fentanyl

Onset of action related to lipophilicity.

35
Q

Describe the distribution of opioids?

A

All binds plasma proteins w varying affinity and rapidly leave blood and localize in highest concentration in highly perfused tissues (brain, lungs, liver, kidneys, spleen).

Adipose tissue-important consideration with freq. high dose admin.

36
Q

What is the metabolism of opioids?

A

Morphine-like compounds - many are converted to polar metabolites. Mostly glucuronides. Metabolites may be active (codeine)

Non-morphine-like compounds: hepatic oxidative metabolism. (warning for meperidine in pts with decreased renal function or those getting high dose).

37
Q

How are opioids excreted?

A

Polar metabolites, including glucuronide conjugates of opioids analgesics are excreted in urine.

Small amts of unchanged drug in urine.

38
Q

What drug is a Mu agonist with low oral to parenteral potency ratio (1/3) that’s available in injectable, oral, oral sustained release, and suppository forms? What is it’s duration of analgesia? What drug is 2-3x more potent?

A

Morphine.

4-5 hr analgesia.

Hydromorphone is 2-3x more potent

39
Q

What drug is a diacetyl morphine that’s more lipophilic than morphine? What is it converted to?

A

Heroin. (structurally similar to morphine)

Converted to 6-acetyl morphine and morphine.

High abuse potential.

40
Q

What opioids agonist is structurally similar to morphine and can be used for mild pain and is often used in combination with aspirin or acetaminophen?

A

Codeine

Morphine-like efficacy is not achievable at any dose.

Some metabolized to morphine.

41
Q

Which opioids agonists are structurally related to morphine and can be used for moderate to severe pain but are associated with a major abuse problem?

A

Oxycodone and hydrocodone.

Available as sustained release oral prep.

Often used in combo with aspirin or acetaminophen.

42
Q

What opioid agonist is structurally distinct from morphine, have a long duration of action, and can be used in the treatment of opioid abuse and chronic pain?

A

Methadone

Equivalent efficacy to morphine, good oral availability.

43
Q

Describe receptor signaling through the Delta and Mu receptors?

A

GPCR coupled to Gio:

Works through BY subunit to:

  • increase K+ conductance and cause membrane hyper-polarization and suppress depolarization
  • decrease Ca2+ channel activity and therefore decreases the release of nts

Aio-GTP subunit to decrease adenylul cyclase and thus decrease cAMP and PKA.

44
Q

Describe the signaling through kappa receptors?

A

Works through Go.

Aio-GTP to decrease adenylyl cyclase, cAMP, and PKA.

BY to decrease Ca2+ channel activity and decrease nt release.

45
Q

What opioid agonist is structurally distinct from morphone, have a shorter duration of analgesia than morphine, and forms a toxic metabolite that can accumulate? What is the toxic metabolite? What does the drug interact with?

A

Meperidine - a phenylpiperidine

Toxic metabolite: normeperidine

Interactions with MAO inhibiters.

46
Q

What opioid agonist that’s structurally different from morphine is a mu agonist that’s 100x as potent as morphine and is short acting (1-1.5 hrs)? What forms is it given in?

A

Fentanyl.

Available in injectable forms, transdermal patches, and buccal soluble film for breakthrough pain.

47
Q

What opioid receptor agonists was removed from the market in the US due to cardiac arrhythmias?

A

Propoxyphene

48
Q

What drug has affinity at the MOR, KOR, and DOR and inhibits the reuptake of 5HT and NE? What else does this drug do and what is the onset?

A

Levorphanol

5HT/NE reuptake inhibitor and an NMDA receptor antagonist.

Rapid onset, modest duration of action.

49
Q

What drug is a weak Mu agonist that blocks NE and 5HT uptake? What is the use of this drug?

A

Tramadol.

Used for mild to moderate pain.

50
Q

What mixed agonist is a partial Mu agonist with 25-50x greater potency than morphine and is used to treat moderate to severe pain? How can it be given?

A

Buprenorphine

Transdermal patch.

Oral version can be combined with naloxone to treat opioid dependence: Suboxone.

51
Q

What mixed agonist drug is similar in efficacy and potency to morphine, has little euphoria, and can precipitate withdrawl in opioid dependent patients? How is this given?

A

Nalbuphine.

Given only by injection.

52
Q

What opioid antagonist has high affinity for mu receptors , less for kappa and delta, and much greater activity parenterally than orally? What is the duration of action of this drug? What is it used for?

A

Naloxone (Narcan)

Short duration: 1-2 hrs.

Used to treat opioid overdoses, can be combined with opioids to decrease parenteral abuse liability (low oral F)

53
Q

What opioids antagonist is orally active with a long half-life or 24+ hours and is used to treat alcoholism and opioid addiction?

A

Naltrexone.

Used for more long term treatment compared to naloxone.

54
Q

What are the two functions of naloxone?

A

Overdose treatment: admin parenterally to reverse effects of opioid OD.

Drug diversion: added to oral/sublingual preparations of opioid agonists or partial agonists to prevent euphoria when injected IV. Poor F so when taken orally there’s no significant effect.

55
Q

What rapid, gradual, and no tolerance is associated with opioid use?

A

Rapid: nausea and vomiting.

More gradual: analgesia, euphoria, respiratory depression, endocrine.

Little or none developed (these occur no matter how long you take the drug): miosis and constipation

56
Q

What is the difference between desensitization, tolerance, dependence, and addiction/substance use disorder?

A

Desensitization: minutes to hours

Tolerance: days to weeks

Dependence: occurs during the course of tolerance

Addiction/substance use disorder: behavioral pattern (dependence does not equal addiction).

57
Q

Desensitization (acute tolerance) is probably mediated by receptor phosphorylation and then…?

A
  1. Internalization: mu and delta show rapid agonist-induced internalization. Beta-arrestin dependent endocytosis.
    - Etorphine and enkephalins do this rapidly, morphine does not.

And/or

  1. Uncoupling from G-protein
58
Q

What does tolerance look like on the dose-effect curve? How can tolerance be overcome or reversed?

A

A right shift: you need more drug to have the same response/efficacy. Ie potency is reduced and efficacy is not changed.

Surmountable with higher doses. Reversible with removal of drug.

Incomplete cross tolerance between drugs.

59
Q

What is dependence?

A

A state of adaptation revealed by drug withdrawl or antagonist treatment.

Withdrawl produces opposite symptoms of acute exposure: Somatomotor and autonomic outflow is increased, aversion.

60
Q

What symptoms occur 6-12 hours after withdrawl?

A

Drug-seeking behavior; restlessness, lacrimation, rhinorrhea, sweating, yawning.

61
Q

What symptoms occur 12-24 hours after withdrawl?

A

Restless sleep for several hours; irritability, tremor, dilated pupils, anorexia, gooseflesh.

62
Q

What symptoms occur 24-72 hours after withdrawl

A

Increased intensity of symptoms seen in earlier hours, depression, nausea, vomitting, cramping, alternating chills and flushes, aches and pains, increase HR and BP, dehydration.

63
Q

What symptoms occur more than 72 hours after withdrawl

A

Previously stated symptoms of autonomic hyperactivity alternate with brief periods of restless sleep with gradual decrease in intensity until recovery occurs within 7 to 10 days, but still exhibits strong craving for drug.

Mild signs and symptoms last for up to 6 mo.

64
Q

Describe opioid abuse?

A

Taking for euphoria, craving, drug-seeking behaviour, withdrawl.

Low likelihood in a clinical setting when appropriately used.

65
Q

Why is an opioid use disorder not the same as dependence?

A

Tolerance and dependence are natural consequences of chronic exposure.

66
Q

What are criteria for an opioid use disorder in the DSM-5?

A

Taken in large amounts or over a longer period than intended.

Persistent desire or unsuccessful efforts to cut down or control opioid use.

Great deal of time spent in activities necessary to obtain opioids, use it, or recover from its effects.

67
Q

What are pharmacological (FDA approved) treatments for opioid use disorder? What other options are available?

A

Methadone: slow acting mu agonist

Suboxone (buprenorphine/naloxone-sublingual)

Naltrexone: antagonist

Behavioral psychosocial intervention such as cognitive behavioral therapies.

Pharm Block 3 (15 decks)

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