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MSK Week 6 > ICL 7.1: Opioid Pharmacology > Flashcards

ICL 7.1: Opioid Pharmacology Flashcards

1
Q

what is an opioid?

A

any molecule, natural or synthetic, that acts on opioid receptors

morphine is the prototype or standard opioid analgesic

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2
Q

what are the 3 clinically important opioid receptors?

A
  1. mu
  2. kappa
  3. delta

the reduction of awareness and reaction to pain is controlled through a combination of mμ, kappa and delta receptors within the brain

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3
Q

what are the 3 endogenous peptides? which opioid receptors do they bind to?

A
  1. endorphins –> mu receptors
  2. enkephalins –> delta receptors
  3. dynorphins –> kappa receptors

these are the endogenous opioids that we make in our own body that then go bind to the mu, delta, or kappa receptors!

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4
Q

what is the location and effects of binding to the mu receptor?

A

location = brain, spinal cord

effects = analgesia, respiratory depression**, euphoria, addiction, ALL pain messages blocked

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5
Q

what is the location and effects of binding to the kappa receptor?

A

location = brain, spinal cord

effects = analgesia, sedation, all non-thermal pain messages blocked

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6
Q

what is the location and effects of binding to the delta receptor?

A

location = brain

effects = analgesia, antidepression, dependence

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7
Q

where are endorphins released from?

A

pituitary and hypothalamus and other brain regions

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8
Q

where are enkephalins released from?

A

CNS and peripheral nerve endings

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9
Q

where are dynoprhins released from?

A

pain nerve endings

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10
Q

what is the MOA of when something binds to mu and kappa receptors?

A

Inhibit neurotransmitter release (e.g. Substance P) –> substance P is what normally helps you sense that there’s a injury

so binding will inhibit nociceptor signals from reaching the spinal cord

this leads to reduced nerve excitability, and alter pain perception

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11
Q

what are the traditional opioids?

A
  1. morphine
  2. oxymorphine
  3. oxycodone
  4. methadone
  5. fentanyl

these are pure agonists referred to as mμ agonists

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12
Q

what are the “other” non-traditional opioids?

A
  1. malbuphine
  2. butorphanol

they are partial agonists stimulate kappa receptors but block mμ receptors

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13
Q

what biochemistry happens when you stimulate a mu, kappa or delta receptor?

A
  1. inhibition of adenylyl cyclase
  2. reduced opening of voltage-gated Ca2+ channels.
  3. stimulation of K+ current
  4. activation of PKC and PLCβ
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14
Q

which endogenous peptides have a similar effect to morphine?

A

enkephalins and endorphins

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15
Q

why are opioids addictive?

A

opioids cross the blood-brain barrier which is what causes addiction!!

the pain-inhibitory neuron is indirectly activated by opioids (exogenous or endogenous), which inhibit an inhibitory (GABAergic) interneuron

GABA usually inhibits your pain-inhibitory neuron and what opioids do is inhibit GABA so that your pain-inhibitory neuron is working well!

this results in enhanced inhibition of nociceptive processing in the dorsal horn of the spinal cord

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16
Q

what is the MOA of morphine?

A

morphine decreases the action potential or it can block the influx of calcium –> this inhibits release of glutamate from primary afferent fibers in the spinal cord

morphine can also decrease the release of neuropeptides such as substance-P, neurokinin A, neurokinin B –> substance P usually tells your brain that there is pain/injury

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17
Q

which drugs act as agonists at the opioid receptors?

A
  1. Morphine
  2. Heroin
  3. Methadone
  4. Oxycodone
  5. Codeine
  6. Meperidine
  7. Fentanyl
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18
Q

which drugs act as antagonists at the opioid receptors?

A
  1. naloxone
  2. naltrexone
  3. nalmefene
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19
Q

which drugs act as partial agonists at the opioid receptors?

A
  1. pentazocine,
  2. nalbuphine
  3. buprenorphine
  4. butorphanol
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20
Q

what are the effects of morphine on the body?

A
  1. analgesia
  2. reduced consciousness
  3. respiratory depression
  4. constriction of pupils
  5. antitussive action
  6. nausea and vomiting
  7. impaired temperature regulation; reduced body temperature
  8. itching
  9. suppressed immune function
  10. increased skeletal muscle tone = truncal rigidity
  11. seizures
  12. cardiovascular effects
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21
Q

how does morphine cause respiratory depression?

A

there is reduced sensitivity to CO2

this causes increased arterial CO2 pressure and increase cerebral blood flow because you’ve desensitized the chemoreceptors to CO2 and they are no longer sensing that there’s an increase in CO2

respiratory depression is the COD in ODs

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22
Q

what cardiovascular effects does morphine have?

A
  1. modest orthostatic hypotension
  2. hypotension (in overdosed patients)
  3. pronounced hypotension
  4. increased intracranial blood flow and CSF pressure
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23
Q

what is the effect of morphine on smooth muscle in the GI tract, kidney, and uterus?

A
  1. gastrointestinal tract (myenteric plexus): decreased peristalsis, decreased secretions, increased sphincter tone, manifested as cramping, constipation
  2. reduced renal function, increased tone of ureter, bladder and sphincter
  3. increased biliary tone
  4. uterus – can prolong labor
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24
Q

what are the effects of morphine on neuroendocrine actions?

A
  1. decreased release of GnRH and CRH
  2. reduction in circulating levels of LH, FSH, ACTH and beta-endorphin
  3. hypogonadism may occur with chronic use
  4. prolactin and vasopressin release are increased
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25
Q

what are the psychological effects of moprhine?

A
  1. euphoria/dysphoria: partly determined by expectations and environment, the particular drug, route of administration, previous experience, presence of pain
  2. reduced anxiety secondary to analgesia
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26
Q

what is the chemical composition of opioids?

A

they are weak bases, not well absorbed in the acid environment of the stomach

so instead, they are absorbed in the intestines were the pH is more alkaline!

metabolic inactivation of the opioids occurs in the hepatic drug microsomal metabolizing system however, heroin is not metabolized to inactive product; heroin is rapidly changed into morphine

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27
Q

what is the MOA of morphine?

A

it’s a very strong mu and/or kappa receptor agonist

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28
Q

how long do the effects of morphine last?

A

peak within 1 hour (minutes after i.v.); duration 4-6 hours

29
Q

what is the MOA of heroine?

A

it’s a mμ very strong and/or kappa receptor agonist

it’s 3-5 times more potent than morphine!!! but lasts for the same time as morphine though

30
Q

what are the effects of heroine on the body?

A
  1. euphoria, alternately alert and drowsy state
  2. mouth dryness
  3. skin flushing
  4. slowed breathing
  5. muscle wekaness
  6. addition, tolerance, dependence
  7. collapsed veins
  8. infection of heart and lining of the valves
  9. pneumonia
  10. decreased liver function
31
Q

what is the MOA of codeine?

A

it’s selective for mμ receptor agonist, but with a much weaker affinity than morphine

about 10% is converted to morphine which accounts for the analgesic effect

often administered with a non-opioid analgesic like acetaminophen

it’s 1/12 as potent as morphine, but almost equal for antitussive action

32
Q

what is the thing you should be worried about with codeine?

A

some patients have a certain enzyme, CYP2D6, which will metabolize codeine to morphine really quickly

so this is why codeine should NOT be prescribed to children because it can cause unanticipated respiratory depression and deaths in children who are ultra rapid metabolizers of codeine

33
Q

what is the MOA of hydrocodone?

A

it’s a mu receptor agonist

widely used as a combination product with acetaminophen = Vicodin®, Lortab®, and others

34
Q

what do you need to be careful of with hydrocodone?

A

like codeine, it is metabolized to hydromorphone by CYP2D6, which may accumulate in patients with renal failure

also, the wide availability of hydrocodone-containing products has raised concerns related to drug abuse

35
Q

what is the MOA of dextromethorphan?

A

NMDA receptor antagonist

you block glutamate receptor

but it’s not acting at a true opioid receptor

36
Q

what is the function of dextromethorphan?

A
  1. effective antitussive

2. NO analgesic action

37
Q

what is the MOA of meperidine? how long does it work for?

A

mu receptor agonist

it also inhibits the rey-take of serotonin and norepinephrine!

faster onset (<1 hour) than morphine but shorter duration (2-4 hours)

38
Q

what is the effect of meperidine on the body?

A
  1. CNS excitation
  2. convulsions
  3. delirium
39
Q

what is serotonin syndrome?

A

it’s what happens when meperidine acts as a monoamine oxidase inhibitor

can cause:
1. delirium

  1. hyperthermia
  2. headache
  3. hyper or hypotension
  4. rigidity
  5. convulsions
  6. coma
  7. death
  8. severe depression
40
Q

what is the MOA of diphenoxylate?

A

mu receptor agonist

low potency, very poor solubility and poor penetration of BBB

prepared in combination with atropine = Lomotil

low abuse liability

41
Q

what is diphenoxylate used for?

A

to control diarrhea

42
Q

what is loperamide used for?

A

binds to the opiate receptor in the gut wall and decreases the frequency of diarrhea

low abuse liability

43
Q

what is the MOA of fentanyl? how long does it last?

A

VERY strong mu receptor agonist

80-100 times more potent than morphine!!!!!!!!!!

very short duration of action after IV injection due to distribution

very low oral bioavailability; not used orally

44
Q

what is the liability with fentanyl?

A

fentanyl and similar chemicals are widely abused and account for a large fraction of overdoses and deaths in opioid abusers

80-100 times more potent than morphine!!!!!!!!!! this why if you get a patient that’s having a fentanyl OD, put on gloves and a mask because you could inhale it or absorb it through your skin

45
Q

what is fentanyl used for?

A

used to treat breakthrough pain in patients already tolerant and using regular opioid analgesics

also used IV for analgesia and to reduce consciousness

fentanyl also available as a transdermal patch = Duragesic®

46
Q

what is the MOA of oxycodone?

A

it has agonist activity on mμ, kappa and delta receptors

47
Q

what should you be worried about with oxycodone?

A

it can be metabolized to oxymorphone by CYP2D6, which may accumulate in patients with renal failure

48
Q

what are the time-released tablet forms of oxycodone?

A
  1. percocet = oxycodone + acetaminophen
  2. percodan = oxycodone + aspirin

time-release formulation is widely abused by defeating time-release for rapid drug action, including IV injection

49
Q

what is the MOA of oxymorphone?

A

a mμ receptor agonist

but more potent than oxycodone

time-release formulation became widely abused after “OxyContin” was reformulated “Opana ER” to help abusers from defeating the time-release property

50
Q

what is the MOA of tramadol?

A

mμ agonist

it also inhibits reuptake of serotonin and norepinephrine

WEAK opioid; low analgesic efficacy

51
Q

what is an adverse effect of tramadol?

A

seizures

serious adverse effect

also actions only weakly inhibited by an opioid antagonist

52
Q

what is the MOA of methadone?

A

it’s supplied as a racemic mixture:

L-methadone is mμ agonist (very strong)

D-methadone is NMDA receptor antagonist

it also possibly inhibits the rey-take of serotonin and norepinephrine

53
Q

what is methadone used for?

A
  1. may have greater efficacy in neuropathic pain
  2. acute: for treating dependence
  3. Chronic: maintenance programs as part of treatment for addiction
54
Q

what is the composition of vicodin?

A

hydrocodone + acetaminophen

55
Q

what are some opioids with non-opioid analgesics?

A

Oxycodone + acetaminophen = Percocet

Codeine + acetaminophen

Hydrocodone + acetaminophen = vicodin

56
Q

what is naloxone? what’s its MOA?

A

aka narcan

it’s an antagonist at the mu, kappa and delta receptors (highest for mu)

short duration of action so need to do repeated delivery in 3 minute intervals

used for overdoses! but you still need to call 911 after you use it

57
Q

what is naltrexone? what’s its MOA?

A

aka Revia

it’s an antagonist at mμ, kappa and delta receptors

it’s orally effective, longer acting; long-acting injection for treating addiction (Vivitrol®)

approved as an adjunct for treating alcohol dependence.

58
Q

what is nalmefene?

A

aka revex

it’s a mμ receptor antagonist and weak partial agonist at kappa receptor

also used for treating alcohol addiction**

longer-acting, available for i.v. use

59
Q

which drugs are opioid antagonists?

A
  1. naloxone
  2. naltrexone
  3. nalmefene
60
Q

which drugs are quaternary antagonists? what are they used for?

A

they’re used to block GI effects

61
Q

which drugs are mixed agonist-antagonists of opioids?

A

all these drugs can be used for addiction management to wean people off of opioids and you’re not cutting them off cold turkey

  1. pentazocine = kappa agonist, mμ partial agonist
  2. nalbuphine = kappa agonist, mμ antagonist
  3. butorphanol = kappa agonist, mμ partial agonist
  4. buprenorphine = long actingpartial mμ agonist, kappa antagonist

also approved for use in “maintenance” treatment of heroin dependent subjects

62
Q

what is naltrexone?

A

a long acting opioid antagonist at mu, kappa and delta receptors

used to treat opioid overdoses

also approved as an adjunct for treating alcohol dependence!

63
Q

what are the withdrawal symptoms you’ll see during the first 72 hours after stopping moprhine?

A

8-14 HOURS: restlessness

16-18 HOURS: lacrimation, rhinorrhea, perspiration, yawning.

24 HOURS: all the above intensify.

also chills, gooseflesh, muscle cramps, mydriasis, mild hypertension, hyperpnea, hyperthermia, twitches of extremities, involuntary kicking movements.

36 HOURS: all the above still present, nausea, vomiting, diarrhea, gagging

72 HOURS: signs and symptoms begin to wane

64
Q

how do you treat acute opioid abuse? aka when someone is going through withdrawal

A

you’re treating drug dependence

so stabilize the patient on an agonist and then taper the dose over time

the drug that you chose to use is based on pharmacokinetics

65
Q

how do you treat chronic opioid abuse?

A

you’re treating addiction

raise the dose of the opioid agonist to produce a larger degree of tolerance to prevent any positive effect of drug taking but also produce greater dependence

methadone is most often used

66
Q

opioid peptides inhibit the release of substance P, an excitatory neurotransmitter from primary afferent nerve endings in the spinal cord. the ionic mechanism involves what?

A

decreased influx of calcium ions

67
Q

you are on your way to take an exa and get an attack of diarrhea. what over the counter opioid with antidiarrheal action would you be asking for?

A

loperamide

68
Q

fentanyl patches used to provide analgesia have caused what negative effect?

A

respiratory depression

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