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Therapeutics P2 Winter Semester > PHRM845-FINAL EXAM > Flashcards

PHRM845-FINAL EXAM Flashcards

Pharmacology of opiate drugs

1
Q

What two types of alkaloids does opium contain?

A

Phenanthrenes and Benzylisoquinolines

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2
Q

What drugs contain phenanthrenes?

A

Morphine
Codeine
Thebaine

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3
Q

What drugs contain benzylisoquinolines?

A

Noscapine
Papaverine

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4
Q

Opioids are (synthetic/non-synthetic)

A

Synthetic

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5
Q

___ are only those opioids that are naturally occurring.

A

Opiates; plant-derived compounds like morphine

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6
Q

Structure activity relationships (SAR) of phenanthrenes

A

-3 position substitutions ether or ester produces decreased potency (codeine)
-6 position increases activity (hydromorphone or hydrocodone from codeine)
-14 position OH has increased potency (oxycodone)
-N-allyl give antagonists (or mixed antagonists)–naloxone or naltrexone

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7
Q

What gives partial agonist or antagonist activity on mu opioid receptors?

A

Substitutions on N

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8
Q

Which drugs are non-phenanthrenes?

A

Tramadol, Meperidine, Fentanyl, Methadone

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9
Q

The human genome contains several genes encoding (endogenous/exogenous) opioids.

A

Endogenous; Found in our body to help modulate pain

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10
Q

Large precursor proteins are cleaved into more ____

A

Opioid subtype selective peptides

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11
Q

Degree of redundancy in peptides

A
  1. Pro-opiomelanocortin (POMC) is cleaved to:
    ~Beta-endorphin targets Mu opioid
  2. Preproenkephalin is cleaved to:
    ~Leu-enkaphalin targets delta opioid
    ~Met-enkaphalin targets mu and delta receptors
  3. Preprodynorphin is cleaved to:
    ~Dynorphin targets kappa opioid
  4. Nociceptin/Orphanin FQ
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12
Q

Types of opioid receptors

A

-GPCR
-Mu (M-morphine)
-Kappa (K-ketocyclazocine)
-Delta (D-Deferens–>where identified)
-Nociceptin, orphanin FQ receptor
-Sigma receptors (once they were cloned, it was determined they were not an opioid receptor)

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13
Q

GPCR opioid receptor

A

-Family A: peptide receptors
-Gi/o coupled: inhibit cAMP production
-Open GIRK potassium channels: inwardly rectifying K+ channels to maintain membrane potential (makes K+ flow out–>interior to be more negative–>hyperpolarized and hard to conduct an action potential–>reduces firing of pain signals)
-Close calcium channels

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14
Q

Endogenous opioid for mu receptors

A

Endorphin

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15
Q

Endogenous opioid for kappa receptors

A

Dynorphin

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16
Q

Endogenous opioid for delta receptors

A

Enkephalin

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17
Q

Endogenous opioid for nociceptin receptors

A

Nociceptin

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18
Q

Mu agonists work (pre/post/both) synaptically

A

Pre and post-synaptically

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19
Q

Presynaptic signaling for mu agonists

A

Inhibit calcium channel (Gi) which decreases neurotransmitter release and blocks conduction

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20
Q

Post-synaptic signaling for mu agonists

A

Activate the GIRK channel (G-beta/gamma); efflux of K+ leading to hyperpolarization

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21
Q

Beta-endorphins for the mu opioid receptor

A

-Endogenous morphine
-Pro-opiomelanocortin (POMC)
-Component of runners high

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22
Q

Therapeutic use for mu opioid receptor

A

-Analgesia: Not as effective for chronic pain
~Cancer pain, palliative (relief from end of life pain), patient-controlled analgesia, helpful for acute pain
-Sedation
-Antitussive: suppression of cough center in the medulla oblongata

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23
Q

Opioid induced side effects from mu activation
(mostly on-target effects)

A

-Respiratory depression
~Brian stem
~pre-Botzinger complex in the ventrolateral medulla
-Constipation
~GI tract
-Pruritus (itch)
~Side effect from opioid-induced histamine release; NOT AN ALLERGIC RESPONSE
-Addiction
-Urinary retention
~Opioid induced ADH release
-Nausea and vomiting
~Chemoreceptor trigger zone–medulla
-Miosis
~Oculomotor nerve (PAG)
~Not mepiridine (has anticholinergic effects)

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24
Q

Can an opioid be used as an anti-diarrheal?

A

Yes, some are designed to stay out of the CNS and slow motility

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25
Q

Kappa opioid receptors

A

-Dynorphins natural ligand (preprodynorphin)
-Activation is dysphoric and aversive (negative effect)
-Potential use for treatment of addiction (reduces dopamine release)
-Counterbalance mu opioid receptor effects

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26
Q

Delta opioid receptors

A

-Enkephalins are natural ligands (Preproenkephalin)
-More dynamic expression (intracellular, “externalized” upon chronic stimuli)
-Protective role in hypoxia/ischemia/stroke (hibernation release of enkephalin like opioid)
-Reduce anxiety
-Reduce depression
-Treat alcoholism
-Relief hyperalgesia, chronic pain
-Side effect: seizures
-No FDA-approved delta opioids

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27
Q

Ventral tegmental area–>nucleus accumbens

A

-Important for reward (linked to addiction)
-Almost all known substances of abuse are linked to these circuits

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28
Q

Depressants can cause DA release just like stimulants. Describe the process

A
  1. Opioid binds mu receptor
  2. Gi signaling inhibits neurotransmitter release
  3. Less GABA to activate GABA-A
  4. Less inhibition of dopamine neuron activity
  5. Increase DA release
  6. Increase activation of opioid receptors
    **Leads to addiction associated with opioids
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29
Q

Routes of opioid administration

A

-IV
-Intra-axial: intrathecal and epidural
-Intramuscular
-PO
-Topical/transdermal

**Route of administration has an impact on duration to onset

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30
Q

Which medication bolus has a slower and more sustained concentration?

A

Morphine

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31
Q

Metabolism of morphine and phenanthrenes

A

-Readily absorbed in the GI tract
-First pass metabolism (morphine bioavailability is 25%)
-Hepatic (CYP2D6 and CYP3A4)
~Elimination half-life is increased with compromised liver function
-Morphine-6-glucuronide (M6G) is an active metabolite (still potent)

32
Q

Excretion of morphine and phenanthrenes

A

-Glomerular filtration
-90% excreted in 24 hours

33
Q

Which opioid metabolites are still active?

A

-Heroin, codeine, tramadol=prodrugs (MUST be metabolized to get active compound)
-Fentanyl and methadone do not produce active metabolites
-Onset and duration is influenced by lipophilicity

34
Q

Codeine is a prodrug that is metabolized to ___

A

Morphine and hydrocodone

35
Q

Tramadol is a opioid that is metabolized to ___

A

O-desmethyltramadol

36
Q

Heroin is a prodrug that is metabolized to ___

A

Morphine

37
Q

CYP3A4 (FOUR) makes opioids starting with ___

A

Nor; don’t have a methyl group and are less active

38
Q

Which CYP converts codeine to morphine?

A

CYP2D6

39
Q

Which CYP converts hydrocodone to norhydrocodone?

A

CYP3A4

40
Q

What are the four groups of metabolizers?

A

PM: poor metabolizer
IM: intermediate metabolizer
EM: extensive metabolizer
UM: ultra-rapid metabolizer

41
Q

UM of CYP2D6 is of high prevalence worldwide. Frequency of 40% in ___.
-What happens when they are given codeine?
-(higher/lower) incidence of adverse effects

A

-North America
-Up to 50% higher plasma concentrations of morphine than EM
-Higher

42
Q

PM of CYP2D6 phenotype is more common in ___.
-Therapeutic effect from codeine?
-(Higher/lower/same) adverse effects

A

-Caucasians
-No therapeutic effect from codeine because codeine is a pro-drug metabolized to morphine by CYP2D6 and cannot be activated if CYP2D6 is a poor metabolizer.
-Same

43
Q

Fentanyl

A

-Very potent synthetic opioid
-Contaminating heroin products and can lead to death
-100 times more potent than morphine
-50 times more potent than heroin
-Used for palliative care (breakthrough pain)
-Can cause respiratory depression if dosed too high

44
Q

Opioid agonists

A

-Sufentanil
-Remifentanil
-Alfentanil
-Fentanyl
-Hydromorphone
-Oxymorphone
-Morphine
-Hydrocodone
-Oxycodone

45
Q

Sufentanil, Remifentanil, Alfentanil

A

-Used for anesthesia and sedation
-Breakdown by plasma esterase due to ester linkage

46
Q

Fentanyl

A

-Comes as an IV, patch, and lollipop

47
Q

Hydromorphone and oxymorphone

A

-No opioid-active metabolites
-Comes as an IV, or oral liquid-PCA

48
Q

Morphine

A

-Relatively inexpensive
-Comes as an IV or PO - PCA
-Covered by medicare
-ER form (MScontin)
~Long-acting, lower ‘rush’, M6G contribution to pain relief. Risk for abuse if IV injected at once.

49
Q

Hydrocodone

A

-Usually in combo with something that contains acetaminophen

50
Q

Non-phenanthrene opioids are a special subclass of opioids. What are examples?

A

-Tramadol
-Tapentadol
-Meperidine

51
Q

Tramadol

A

-Mild opiate analgesic
-Has SNRI properties (5HT/NE reuptake inhibitor; stimulates 5HT release)
-Management of mild neuropathic pain
-Painkiller used when you don’t want to prescribe a stronger opioid
-Schedule IV

52
Q

Meperidine

A

-Used to tx rigors (shivering)
-Has toxic metabolite normeperidine (metabolized by CYP3A4)
~Metabolite is devoid of analgesic activity
~Metabolite is neurotoxic that can cause nervousness, tremors, muscle twitches, and seizures
~Many pts have euphoric feeling

-Renally excreted
~Dangerous in pts with decreased renal function (accumulation)
~Not recommended without good justification

53
Q

Methadone

A

Non-phenanthrene
-NMDA receptor antagonist: want to block some of the pain signal from being sent to the brain)–>may be secondary tx to help with pain
-Primarily used for opioid dependence
-Long duration of action/long half-life
-Fat soluble
-Prolonged QTc (unwanted effect)
-For chronic pain

54
Q

Clinically used opioids (non-analgesic)

A

Codeine
Dextromethorphan
Diphenoxylate with atropine
Loperamide
Eluxadoline

55
Q

Codeine

A

-Schedule II
-Cough/antitussive
-Schedule V in certain formulations

56
Q

Dextromethorphan

A

-Cough/antitussive
-Enantiomer of levomethorphan
-Limited opioid activity (not scheduled)
-At high doses, acts as an SSRI and NMDA antagonist

57
Q

Diphenoxylate with atropine

A

-Anti-diarrheal
-Schedule V

58
Q

Loperamide

A

-Anti-diarrheal
-Strong P-gp substrate (Low BBB penetration)
-Schedule V/decontrolled: OTC

59
Q

Eluxadoline

A

-Anti-diarrheal
-For irritable bowel syndrome with diarrhea
-Mu/kappa agonist, delta antagonist
-Enteric nervous system localization
-Schedule IV

60
Q

Pentazocine

A

-Used for moderate pain
-Kappa agonist, partial agonist/antagonist at mu
-Parenterally administered
-Side effects: less dysphoria, hallucinations, increased BP and HR

61
Q

Butorphanol

A

-For moderate pain
-Schedule IV
-Kappa agonist, partial agonist/antagonist at mu
-Parenterally administered
-Side effects: less dysphoria, hallucinations, increased BP and HR

62
Q

Nalbuphine

A

-For moderate pain
-Schedule IV
-Full agonist at kappa; antagonist at mu
-Antagonism produces withdrawal from those with addiction to mu meds
-Administered parenterally (IV, IM)

63
Q

Buprenorphine

A

-For moderate pain
-Schedule III
-Partial mu agonist, weak kappa agonist, and delta antagonist
-Primarily used in opioid replacement therapy

64
Q

Senna

A

-Used for prevention and acute management of ileus and constipation
-Irritates the colon–causes fluid secretion and colonic contraction

64
Q

Polyethylene glycol

A

-Used for prevention and acute management of ileus and constipation
-Stool softener–Osmotic increase in GI water content

65
Q

Dioctyl sodium sulfosuccinate/docusate

A

-Used for prevention and acute management of ileus and constipation
-Stool softener, peristalsis if pt uses > 400 mg/day

66
Q

Opioid tolerance

A

-Decreased effect over time even when higher doses of opioids are given
-Be aware of opioid-induced hyperalgesia–>secondary pain pathway begins to form–>probably from change in glutamate receptor pathway
-Analgesic effects (Pain relief)
-Nausea
-Urinary retention
-Respiratory depression (biggest risk of death in withdrawn pts/users)
-Euphoria

67
Q

Limited/no tolerance to opioids

A

Constipation
Itch
Miosis (small pinpoint pupil)–ask if it is due to tolerance or opioid-induced hyperalgesia

68
Q

Methadone

A

-Full agonist
-Helps with opioid dependence
-Full mu opioid receptor agonist (cross tolerance)
-Provides relief from withdrawal (greater potency than morphine)
-‘Slow acting’: 2-4 hrs which is why you have decreased risk of the “high” effect and prevents withdrawal symptoms to prevent opioid use
-Slow PK: accumulates with repeated doses (elimination half-life is 8-50 hours)
-Racemic mixture: (+) NMDA antagonist; structurally different from morphine

69
Q

Buprenorphine

A

-Mu opioid receptor partial agonist
-Helps with opioid dependence
-Ceiling effect
-Blocks full agonist effect (heroin, oxycodone)
~Antagonist
~Use 4 hours after last heroin use
-Provides some activation
~Agonist
~Less withdrawal
-Subutex because it does have some agonist activity
~Abuse potential
-Suboxone (4:1 bup:Nx)
~Partially blocks agonist effects when taken IV

70
Q

Naltrexone

A

-Full antagonist
-Helps with opioid dependence
-IM injection
-ER
-Once monthly (PO administration=Revia)
-Decent oral bioavailability
-Medium half-life (4h)
-Will cause withdrawal
-Works better if pt has been drug free for 1 month or more

71
Q

Are naloxone and naltrexone interchangeable?

A

NO

72
Q

Naloxone vs. Naltrexone

A

Naloxone
-IV or intranasal
-Limited oral bioavailability
-Rapid onset
-Short half-life (30-90 min)

Naltrexone
-Decent bioavailability
-PO administration
-Medium half-life (4 hours)–remember: longer word than naloxone
-Prevents high in reinforcement which decreases the risk of withdrawal

73
Q

Naloxone (Narcan)

A

-IV or intranasal
-Limited oral bioavailability
-Rapid onset
-Short half-life
-Give multiple shots to avoid return of respiratory depression
-Presence of fentanyl and other synthetic opioids means even more doses (repeat q2-5min if not conscious)
-Causes strong withdrawal

74
Q

Neonatal abstinence syndrome

A

-Drug dependent
-Symptoms: some hospitals may have newborn abstinence scores (tremors, yawning, poor feeding, sweating)
-Onset of sx: may begin 24-48h after birth or as late as 5-10 days
-From mother using opiates while pregnant: causes serious withdrawal in the baby. Some sx can last as long as 4-6 months. Seizures may also occur in babies born to methadone users.
-Opioids can also present in breast milk

75
Q

Non-pharm tx of neonatal abstinence syndrome

A

-Swaddling
-Hypercaloric formula
-Frequent feedings
-Observation (sleep, temp, weight loss/gain, and change in sx)
-Rehydration (IV fluids if dehydration is severe)

76
Q

Pharmacological tx of neonatal abstinence syndrome

A

-Morphine sulfate: oral morphine diluted to 0.4 mg/ml
-SL buprenorphine
-Methadone
-Morphine and buprenorphine linked with shorter hospital stay than methadone
-Clonidine (alpha-2 agonist) may also be useful to decrease withdrawal sx

Therapeutics P2 Winter Semester (29 decks)

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