Pharm 2 - E2: Opioids

all opioids are based off of? what is it?

opium = brownish residue from the dried juice

opiate is =

the drug derived from opium

how do opioid agonists work

blocks the ascending pathway via 1st and 2nd order neuron and engages the descending pathway via agonizing GABA (increasing cl)

what are the 2 main chemical classification groups of opioids?

what is their structure?

1. benzylisoquinoline alkaloid: benzene ring not fused together

2. phenanthrenes: 3 fused benzene rings = phenanthrene ring

benzene ring pic

phenanthrene ring pic

what class does papaverine belong to?

what are its properties?

what does its chemical structure look like?

• benzylisoquinoline alkaloid

• non-analgesic and antispasmodic properties

• 3 benzene rings but they are NOT fused together

what class does morphine belong to?

what is its significance? (2)

where does it come from?

• phenanthrene

• principle active compound from opium used for pain

• used as a comparison for all other agents when judging strength

• naturally occuring and comes from opium!

substitution of an ether for an alcohol of the phenanthrene nucleus of morphine =

codeine

what was the 1st synthetic opioid?

meperidine “demerol”

what is the prototype for phenylpeperidine?

meperidine

fentanyl cogeners means:

“cousins” of fentanyl

what class of opioids is created when morphine is split btwn the 12th and 13th carbon to get a benzene connected to a 5 ring structure?

phenylpiperidine

what is the relation btwn synthetic opioids and the basic morphine molecule?

they only have 2 of the original 5 rings

Opioid Drug Classes Chart

	NATURAL	SEMI-SYN.	SYNTHETIC
AGONIST	morphine thebaine codeine	hydromorphone heroine oxymorphone oxycodone	methadone fentanyl remifentanil alfentanil meperidine sufentanil tramadol
PARTIAL-AGONIST		buprenorphine	butorphanol (stadol)
AG-ANTAG			nalbuphine (nubane)
ANTAGONIST		naloxone naltrexone	nalmefene

which semi-synthetics are "morphine derivatives"? (3)

(i.e. synthesized by making small changes to morphine molecule)

1. heroine

2. oxymorphone

3. hydromorphone

what is the highlight effect of codeine?

cough suppression

what does a "synthetic" opioid mean?

it contains the phenanthrene nucleus of morphine and is manufactured by synthesis instead of a chemical modification of morphine

general principles of opioids: (5)

1. highly lipid soluble & protein bound

2. mostly central acting

3. weak base

4. largely ionized at physiologic pH

5. pKa usually > 7.45

what are the 3 opioid receptor classes?

what kind of receptors are they in general?

GPCRs

1. mu (mop)

2. kappa (kop)

3. delta (dop)

what are the endogenous opioid agonists? (6)

1. enkephalins

2. endorphins

3. dynorphins

4. nociceptin

5. endomorphin 1

6. endomorphin 2

________________ are individual peptides that have their own specific precursors and share a common _________ with a small variation

• opioid agonists (endogenous & exogenous)

• amino acid terminal sequence

1. what is the shared amino acid terminal sequence all opioid agonists?

2. what is this sequence labeled as?

3. why is it necessary?

4. what part makes it an agonists on a receptor level?

• try-gly-gly-phe-met or leu

  • met or leu will be at the C-terminus

• labeled as “opioid motif” or “opioid message”

• necessary for the endo agonists action w/ the receptor

• terminus

what other drug/structure is enkephalin similar to?

morphine

G protein coupled receptor includes a ____membrane loop that is both _______ and ________

• 7

• intra and extracellular

3 opioid receptor subtypes share ___-___% sequence homology (same structure) but diversity is greatest in the _______ of the protein

• 55-58

• extracellular loops/external portions

what is thought to be the importance of the external loops of an opioid receptor?

discriminating btwn ligands

what are the steps/effects of when an opioid agonist binds with a receptor?

1. opioid agonist binds w/ receptor (endo or exo; doesnt matter)

2. 3 distinct subunits of the g-protein become activated

3. produces inhibitory effects

4. results in membrane hyperpolarization and reduction of neuron excitability

what are the inhibitory effects that are produced from the g-protein activation?

1. ↓ cAMP (alpha) = adenyl cyclase is inhibited → ATP cant be converted into cAMP → ↓ cAMP ⇨ relaxes smooth muscle

2. ↓ Ca influx (alpha, beta & gamma) = ↓ neuronal excitation

3. ↑ K efflux (beta & gamma) = hyper-polarization

overall, what does ↓ cAMP cause?

↓ conductance of Ca channels & opened K+ channels ⇨ ↓ neuronal excitation and inhibition of neurotransmitter/neuropeptide release

what is the result of abrupt opioid withdrawal?

rebound dis-inhibition of cAMP ⇨

1. abd. pain

2. chills

3. diarrhea

4. muscle cramps

5. mydriasis

6. restlessness

7. sweating

8. tremors

9. ↑ irritability & HR

where are the different opioid receptors located in the CNS?

1. brain 🧠

   • periaquaductal gray

   • area postrema

   • limbic system

   • cerebral cortex

   • thalamus

2. spine

   • substantia geletanosa of dorsal horn

where are the different opioid receptors located in the PNS?

intestines

what are the 4 additional locations of opioid receptors?(4)

1. vaculature

2. 🫀

3. 🫁

4. immune system 🦠

what is the anatomy related action of the brain and opioid receptors?

the brainstem modulates nociceptive transmission via inhibitory pathways of the spinal cord

what is the anatomy related action of the spine and opioid receptors?

• inhibits the release of substance P

• blocks transfer of pain upwards

what is the anatomy related action of GI/GU and opioid receptors?

• constipation/post op ileus

• ↑ urinary sphincter tone

how does supra-spinal analgesia occur?

• through activation of opioid receptors in brain that cause inhibition of nerves involved in pain pathways ⇨ message cant be propagated anymore

how does spinal analgesia occur?

via activation of presynaptic opioid receptors in spine, ↓ing release of the neurotransmitters of the nociception

supraspinal analgesia + spinal analgesia = _________

synergistic pain relief

what kind of analgesia will mu and kappa both cause? supra-spinal, spinal, both, none?

supra-spinal & spinal

what are the CV effects of mu receptors?

↓ HR

what are the respiratory effects of mu and kappa receptors?

• mu = respiratory depression

• kappa = possible depression if high dose

  • dose dependent resp depression!!!

what are the CNS effects of mu receptors? (6)

1. euphoria

2. sedation

3. prolactin release

4. mild hypothermia

5. catalepsy

6. indifference to environmental stimulus

what are the CNS effects of kappa receptors? (3)

1. sedation

2. dysphoria

3. psychomimetic reactions (delirium, hallucinations)

what are the pupil effects of mu and kappa receptors?

miosis

which opioid receptor will inhibit peristalsis and cause N/V?

mu

what are the GU effects of mu and kappa receptors?

• mu = urinary retention

• kappa = diuresis d/t inhibition of vasopressin release

which opioid receptors can cause pruritus?

mu and delta

what is the difference in physical dependence btwn mu and kappa receptors?

• mu = high abuse potential

• kappa = low abuse potential

what opioid receptor is involved with antishivering?

kappa

what are the effects of the delta receptors?

1. resp depression

2. urinary retention

3. pruritus

4. physical dependence

which endogenous opioid ligands agonize mu receptors?

1. B-endorphin

2. endomorphin

which endogenous opioid ligand agonizes kappa receptors?

dynorphin

which endogenous opioid ligand agonizes delta receptors?

1. Leu- Enkephalin

2. Met-Enkephalin

what are the routes of opioid admin? (7)

1. epidural

2. IM/IV

3. intrathecal

4. nasal

5. oral

6. suppository

7. transdermal

how would you describe opioid absorption orally?

modest

do opioids have a 1st pass effect?

yes, a big one

are opioids mainly lipophilic or hydrophilic?

how does this affect absorption?

↑ lipophillic = ↑ absorption through nasal and oral mucosa and skin

how are opioids distributed throughout the body? via the _________ compartment model

via the 2 compartment model (vessel rich group)

1. how are opioids metabolized?

2. do they have active metabolites?

3. what is the exception? explain

• CYP450

• some

• remifentanil → metabd in blood by esterase

how are opioids excreted?

1° = kidney

2° = biliary system & GI tract

what are the differences in use of opioids r/t anesthesia practice?

1. higher analgesic requirement
2. co-admin of potent anesthetics and sedative agents
3. require the ability to support respirations until emergence

what effect does small dose opioids have on the DOA?

terminates it via redistribution into peripheral compartments

what effect does larger doses/multiple doses/continuous infusions of opioids have on the DOA?

becomes more dependent on metabolism

what is the key factor in the effect of an opioid being therapeutic or adverse?

clinical setting ⇨ sedation from mu receptor may be part of therapeutic intent (OR) versus being an adverse effect (ER)

what other factors are opioids dependent on? (5)

1. body weight

2. renal and hepatic failure

3. CABG

4. acid-base changes

5. hemorrhagic shock

what are the pharmacokinetic considerations of opioids? (7)

1. narrow therapeutic index

2. balance btwn optimizing pain control and sedation

3. resp depression

4. variability btwn patients (dose & DOA)

5. patients perception of pain (hx of chronic pain, opioid use? etc.)

6. severity and duration of pain

7. lifestyle (smoking? etoh? illicit drug use?)

what are the therapeutic effects of mu agonists?

1. pain relief (spinal and supraspinal)

2. sedation

3. anti-tussive

mu agonists are good for txing ___________ pain sensations, but less effective for ___________ pain sensations

2° (c-fibers); 1° (a-delta)

mu agonists have a _________ effect on drowsiness/sleep

dose dependent

T/F: opioids can be used as a sole anesthetic

FALSE: they do not reliably produce unresponsiveness and are not an anesthetic

explain the antitussive effect of mu agonists?

suppresses the cough center of the medulla (↓ the stimulation) but does NOT take away the cough

what is the risk a/w bolus doses of opioids?

a paradoxical rxn causing ↑ coughing

what are the adverse effects of opioid agonists? (12)

1. ↓ HR and cellular immunity

2. ↑ biliary pressures

3. constipation/ileus

4. delayed gastric empty

5. euphoria (abuse)

6. miosis

7. muscle rigidity

8. N/V

9. pruritus

10. urinary retention

11. vaso-d

12. ventilatory depression ****mu****

what are the CNS effects of opioids? (5)

1. sedation and eupohoria → mu

   • *both dependent on agent and receptor*

2. dysphoria → kappa receptors or opioids taken in absence of pain

3. analgesia

4. minimal effect of neuromonitoring

5. potential for ↑ ICP → respiratory induced hypercarbia

describe the analgesic MOA of opioid within the CNS

1. inhibit ascending transmission of nociceptive stimuli from dorsal horn of SC

2. activate pain control pathways from midbrain via rostral ventromedial medulla to spinal cord dorsal horn

what kind of pain are opioids most effective for?

continuous visceral dull pain

list the undesired CNS effects of opioids (4)

1. dependence

2. tolerance/cross tolerance

3. awareness

4. hyperalgesia

dependence of opioids can be ________ &________

*they need the drug to fxn properally*

physical and psychological

tolerance to opioids begins with _______ followed by ________

• ↓ in DOA

• ↓ in effect

what are the 5 theories r/t tolerance?

1. not d/t altered receptor #

2. receptor internalization

3. activation of NMDA-Rs

4. 2nd messenger changes

5. G-protein uncoupling (changes in binding sites)

do high dose opioids ↓ the risk of awareness?

NO

hyperalgesia r/t opioids include what? what drug can cause it?

1. ↑ sensitivity to pain

2. damage to nociceptors or periph nerves (ex: degloving)
   
   **Remifentanil can cause this**

what is the most significant adverse effect of opioids?

depression of ventilation

what are risk factors for respiratory depression with use of opioids? (6)

1. high doses

2. advanced age

3. CNS depression

4. renal insufficiency

5. morphine

6. sleep

1. what breathing mechanism is altered by resp depression w/ opioids?

2. what does it ultimately result in?

the natural response to ↑↓ CO2 → RIGHT SHIFT in CO2 CURVE = ↓ resp drive to breath

when is resp depression d/t opioids potentially life threatening?

post-op in morbidly obese or OSA pts

can opioid tolerance be r/t miosis?

NO

what is thought to cause miosis w/ opioid use?

1. opiate depression of GABA →

2. stimulation of edinger-westphal nucleus →

3. PNS signals via ciliary ganglion

4. stimulation of oculomotor n. to constrict

can miosis be reversed? how so?

YES w/ narcan

where does miosis occur?

pupillary reflex arc

is miosis a qualitative or quantitative sign?

quaLitative

what are the best opioids for cough suppression?

1. codeine

2. heroine

how do opioids cause cough suppression?

they depress the cough center in the medulla but PRESERVE/PROTECT glottic reflexes

*just making it less reactive*

how does the antitussive effects of opioids affect tolerance w/ induction/intubation?

↑ tolerance to intubation and ETTs

what are the 5 receptors that cause PONV?

1. 5-HT3

2. dopamine

3. H1 & 2

4. M1

5. NK 1

would patients typically rather have pain or N/V?

N/V!!!!

what kind of pts is PONV r/t opioids higher in?

ambulatory! we dont know why maybe because of quick movement or vestibular component

opioids cause N/V by acting where?

CTZ in the area postrema in the floor of 4th ventricle