Pain Exam 1: Harrold Opioid Analgesics and Antagonists

mu, kappa, delta

3 major subtypes of opioid receptors

1. ___ (OP3)

2. ___ (OP2)

3. ____ (OP1)

mu, kappa

Current drugs target __ and ___ receptors

Gi, G0

Both μ (mu) and κ (kappa) receptors are coupled with ___ and __ proteins

inhibitory, ion channel

remember

Gi= think ____

G0= think ___ ___

ceiling effect

There is no ___ ___ of analgesia for opiates (means increasing the dose → always increases analgesia)

close, open

Opioids

-____ N-type voltage-operated Ca2+ channels

-____ calcium-dependent K+ channels

no

Do opioids alter the pain threshold of afferent nerve endings?

no

Do opioids affect the conductance of impulses across peripheral nerves?

tolerance

Adverse effects of μ agonists

1. sedation/dizziness

2. constipation (patients will NOT develop ___ to this)

respiratory

Adverse effects of μ agonists

3. ___ depression (this is what causes death in overdose)

4. nausea/vomiting

miosis, tolerance

Adverse effects of μ agonists

5. ___ or "pinpoint pupils" (patients will NOT develop ___ to this)

euphoria, tolerance

Adverse effects of μ agonists

6. ____ (bc increased dopamine release), addictive behavior, and dependence liability (patients will NOT develop ___ to this)

dysphoria, withdrawal

Adverse effects of κ agonists

1. sedation/dizziness, nausea/vomiting

2. ___ (bad mood)

3. precipitation of __ symptoms in μ agonist dependent patients

euphoria, dysphoria

μ receptor → increases dopamine release → causes ___

κ receptor → decreases dopamine release → causes ___

pure agonists

Opioid receptor-mediated actions

1. __ ___ (ie full agonist): produce an analgesic acitivity

pure antagonists

Opioid receptor-mediated actions

2. ___ ___: blocks the actions of opioids at all receptor subtypes

antagonist/agonist

Opioid receptor-mediated actions

3. ____/____

agonists, antagonists

Most opioids with antagonist/agonist activity are ___ at the κ receptor and ___ at the μ receptor

antagonism, dose

Exception to usual antagonist/agonist activity is buprenorphine, which produces:

-weak ___ at κ receptor

-____-dependent agonist or antagonist activity at the μ receptor

tolerance

________: a decrease in the apparent effectiveness of a drug with continuous or repeated agonist administration. This effect will disappear over time whenever the agonist is discontinued

dependence

________: refers to a state of adaptation manifested by receptor/drug withdrawal syndrome produced by cessation of drug exposure (either by abstinence or administration of antagonist)

addiction

________: refers to a behavior pattern characterized by compulsive use of the drug

pure agonist

Morphine

-an alkaloid obtained from the opium poppy plant

-___ ___ at all opioid receptors

basic

Morphine

-a ___ drug

-

Morphine

-contains 5 asymmetric centers, the activity resides only in the (___) enantiomer

4

There are ____ sites of variation on morphine that are modified to create other opioid drugs

masking

The only modification from morphine in codeine is the ___ of the C3-OH

decreased, decreased

Because codeine replaced the C3-OH with C3-OCH3, it has ____ analgesic activity and ___ potency compared to morphine

less

Codeine

-causes ___ respiratory depression than morphine (none at normal doses)

better

Codeine

-has a ___ oral/parenteral ratio than morphine

-(morphine only 16% orally active, codeine is 60% orally active)

-phosphate and sulfate salts of codeine are used for solutions, elixers, etc

decrease

Key SAR for Morphine Analogs:

1. if you mask the C3-OH with a C3-OCH3 → ___ activity by 1/10th

increase

Key SAR for Morphine Analogs:

2. if you reduce the Δ⁷ (ie double bond between C7 and C8) and oxidize the C6-OH to a ketone → ___ activity by 5-fold

increase

Key SAR for Morphine Analogs:

3. if you introduce a 14-OH group → ___ activity by 2-fold

antagonists, mixed

Key SAR for Morphine Analogs:

4. if you alter N-CH3 → produce ___ and ___ agonists/antagonists

hydromorphone, oxymorphone

Hydrocodone undergoes minor pathway → ____

Oxycodone undergoes minor pathway → ____

OCH3, OH

hydrocodone and oxycodone→ has C3-____

hydromorphone and oxymorphone→ has C3-____

potent

Since hydromorphone and oxymorphone have a C3-OH (not masked with a methyl group), they will always be more __ than their parent compounds

midway

Hydrocodone

-pharmacological effects ___ between morphine and codeine

increases, decreases

Hydrocodone

-pharmacological effects midway between morphine and codeine because of these 2 variations from morphine:

1) reduction of the Δ⁷ (ie double bond between C7 and C8) and oxidization the C6-OH to a ketone → ___ activity 5-fold

2) masking of the C3-OH → ___ activity 10-fold

greater

Hydromorphone

-pharmacological effects are 5-fold ____ than morphine because only 1 variation from morphine, which is reduction of the Δ⁷/ oxidization the C6-OH to a ketone

increases

-oxycodone/oxymorphone have an additional SAR change compared to hydrocodone/hydromorphone, which is addition of a C-14 OH (remember this increases receptor binding, and therefore ____ activity 2-fold)

equipotent

Oxycodone

-pharmacological effects are ____ with morphine because of these 3 variations from morphine:

1) reduction of the Δ⁷ and oxidization the C6-OH to a ketone → increases activity

2) masking of the C3-OH → decreases activity

3) introduction of 14-OH → increases activity

greater

Oxymorphone

-pharmacological effects are 10-fold ___ than oxycodone because of these 2 variations from morphine:

1) reduction of the Δ⁷ and oxidization the C6-OH to a ketone → increases activity

2) introduction of 14-OH → increases activity

normorphine, decreased

Removal of -CH3 from morphine gives ____, which has ___ activity

agonist/antagonist, antagonist

If you lengthen the N-substituent on morphine, you will change the activity from an agonist to a mixed ___/___ or pure ___

nalbuphine

An example of a "normal" mixed agonist/antagonist is ____

antagonist, agonist

Nalbuphine

-competitive μ ____

-κ _____ (resulting in analgesia)

withdrawal

In a patient who is dependent on pure agonists, switching to a mixed agonist/antagonist can produce ___ symptoms

equipotent, ceiling

Nalbuphine Advantages

-___ with morphine at the kappa receptor

-has a ___ effect for respiratory depression (meaning at a certain point, increasing dose will not increase respiratory depression)

addiction

Nalbuphine Advantages

-lower ___ potential

dysphoria

Nalbuphine Disadvantages

-____ due to kappa agonism

normorphine, codeine

Metabolism of Morphine

1. morphine → ___ (which is less active)

2. O-dealkylation of ____ → morphine

3. Morphine 3-O sulfate or glucuronate → morphine

4. Morphine 6-O glucuronate → morphine

reverses

Giving small doses of pure antagonist Naloxone IM or IV promptly ___ the effects of μ agonists (increases resp rate, reverses sedative effects, lowers BP if elevated)

1-4

Naloxone

-duration of effects is __-__ hours

dependence

We can use Naloxone to check for ___ (because will precipitate withdrawal syndrome)

not

Naloxone does ___ produce dependence

increase, exaggeration

Long-term Administration of Naloxone will:

-___ density of opioid receptors in brain and cause a temporary ___ of response to subsequent doses of agonists

metabolized

Naloxone

-is orally absorbed but completely ____ via glucuronide conjugation before reaching systemic circulation

spray, solution

Naloxone

-are orally absorbed but completely metabolized before reaching systemic circulation, so given in nasal ___ and ___ for injection

orally, longer

Naltrexone Advantages (over naloxone)

-___ active

-___ duration of action

agonist, antagonist

Buprenorphine is a UNIQUE mixed agonist/antagonist:

-partial ___ at μ receptor

-weak ____ at κ receptor

depression, dependence

Remember that stimulation of μ receptor produces:

-analgesia

-respiratory ___

-euphoria

-physical ___

antagonist

Buprenorphine is a partial μ agonist, at high doses, its analgesic effect plateaus and it behaves more like an ___

less

Due to the partial agonist activity, buprenorphine exhibits a ceiling to its pharmacological effects, thus, the danger of overdose, abuse liability, and toxicity may be ___ than with full opioid agonists

kappa

Patients with opioid or cocaine dependence have increased __ receptor sensitivity

euthymia

Patients with opioid or cocaine dependence have increased kappa receptor sensitivity, thus these patients are more likely to experience ____ (mental peace and tranquility) with buprenorphine vs patients receiving naltrexone

longer, lower

Buprenorphine

-dissociates very slowly from the μ receptor, providing a ___ duration of action than morphine, and a much ___ level of manifested physical dependence

abuse

Why do we add naloxone to buprenorphine (Suboxone)?

-because it acts as an ___-deterrent.

no

How is naloxone an abuse deterrent?

-Naloxone has very poor sublingual bioavailability. Therefore, in a SL formulation → naloxone produces ___ clinical effect.

counters

How is naloxone an abuse deterrent?

-When dissolved/injected → naloxone ___ the effects of buprenorphine (abuse deterrent!)

pure agonist

Levorphanol is a ___ ___

mixed, kappa

Butorphanol and Pentazocine are ___ agonist/antagonists. Activity comes from agonism at __ receptors. They also antagonize mu receptors

potent

Levorphanol and Butorphanol are more __ than morphine

abuse

Pentazocine

-is available as an oral tablet in combination with naloxone to prevent ___

dextromethorphan

d isomer of Levorphanol = ____

coughing

Dextromethorphan

-no analgesia or addictive properties (because it is d-isomer, not l-isomer)

-does not act on opioid receptors, acts centrally to elevate the threshold for ___

4-phenylpiperidines

Meperidine, Fentanyl, and Sufentanil are __-___

mu, less

Meperidine

-predominantly a ___ agonist, exerts actions on CNS and GI tract

-___ potent than morphine

antidiarrheal

Meperidine

-the ___ agents (diphenoxylate and loperamide) are analogs of meperidine

slow

Diphenoxylate and loperamide

-act on peripheral μ-receptors in the GI tract and ____ GI transit. They may also inhibit fluid and electrolyte secretion.

atropine

Diphenoxylate is used with ____ to prevent abuse

euphoria, dependence

Why is Diphenoxylate used with atropine to prevent abuse?

-At higher doses, diphenoxylate (if given as a single drug) can cause ___ and ___. Atropine is added to prevent this

CNS

Why does Loperamide NOT need to be used with atropine to prevent abuse?

-Loperamide does not provide analgesia, euphoria, or dependence actions. This is because loperamide does not enter the ___ to any appreciable extent

more, rapid, short

Fentanyl

-a μ agonist that is 80-100x __ potent than morphine

-__ onset and __ duration of action

more

Sulfentanil

-10x ___ potent than fentanyl

racemic

Methadone

-marketed as its ___ mixture (but analgesic activity is primarily due to L-methadone)

-μ agonist

oral, extended, repeated

Methadone Advantages

-effective ___ analgesic

-___ duration of action

-demonstrates persistent effects with ___ administration

agonists, less

Tramadol and Tapentadol have 2 mechanisms of action:

mechanism 1: These two drugs are ___ at μ receptor; however, their affinity for the μ-receptor is __ than morphine

norepinephrine, serotonin, transmission

Tramadol and Tapentadol have 2 mechanisms of action:

mechanism 2: Inhibition of the reuptake of ___ and ___ in the CNS. This action inhibits pain ___ in the spinal cord

less

Tramadol

Advantage over morphine = ___ potential for abuse, dependence, or respiratory depression than other opioids

CYP3A4, CYP2D6

Tramadol requires ___ and ___ to be converted to its more active metabolite

decrease

Tramadol requires CYP3A4 and CYP2D6 to be converted to its more active metabolite. Inhibitors of either CYP3A4 or CYP2D6 would significantly ____ the analgesic action of tramadol but would not affect the actions of tapentadol.

no

If a patient overdosed on Tramadol or Tapentadol, could a pure opioid antagonist such as naloxone counter all of the actions of these agents?

reuptake

Why can't naloxone counter the effects of Tramadol/Tapentadol?

-Naloxone would only block the effects of these drugs at the μ-receptor. IT CANNOT block the actions that these two drugs have on the ___ of norepinephrine and serotonin in the CNS.

GPCRs

Opioid receptors are ____, traditional opioid agonists can bind to other targets and activate additional downstream pathways including those involving β-arrestin.

analgesia, side effects

Traditional Opiods activate 2 main pathways

G-protein pathway → ____

β-arrestin pathway → ___ ___

biased

Oliceridine is NOT a traditional opioid. It is a "____ agonist" at the μ-opioid receptor

selectivity

The term "biased" refers to the ligand-dependent ____ for certain signal transduction pathways relative to a reference ligand at the same receptor.

preferential, minimal

Oliceridine

-____ G-protein activation

-____ β-arrestin recruitment

fewer

Oliceridine

-preferential G-protein activation → analgesia

-minimal β-arrestin recruitment → so ___ side effects like constipation/respiratory depression :)