Opioids or Opiates

peptide neurotransmitters are

longer lasting, more diffuse effects

often co-released with conventional small molecule transmitters

opioids are

diverse short peptides from long precursors

t/f opioid receptors are ligand gated ionotropic receptors

FALSE

Opioid receptors are metabotropic receptors (Gi coupled protein coupled receptors)

examples of opioid receptors

All are Gi coupled

Mu (u), Delta (S), and Kappa (K)

Function of the opioid receptor

to alleviate stress and pain

Targeted by analgesics, some general anesthetics and drugs of abuse

Three families of opioid peptides

Enkephalins

Dynorphins

Endorphins

• generated from precursor proteins

endogenous opioids role

inhibit neurotransmitter release (glutamate)

inhibit activation of spinal nociceptive neurons

Opioid receptors are __ coupled and are expressed where?

Opioid receptors are Gi coupled GPCRs expressed in brain, spinal cord, and peripheral nerves

Endorphins relationship to

mu, delta, and kappa

Endorphins

Delta - Mu, NO KAPPA

Enkephalins relationship to

mu, delta, and kappa

Delta > mu, NO KAPPA

Dynorphins relationship to

mu, delta, and kappa

ACTIVATE K

• sensitize nociceptive signals in the dorsal horn

Endomorphins relationship to

mu, delta, and kappa

u selective

pain target for pain meds

where is the main target for pain meds?

mu receptor

mu, delta, and kappa

expression on presynaptic expression

All three receptor types are expressed presynaptically

Primary afferent

mu, delta, and kappa

post-synaptic expression

mu on spinal nociceptive neurons, peripheral terminals of sensory neurons

spinal cord acts via

pre and post synaptic mechanisms

supraspinal effects in the brain act via

pre and post synaptically

peripheral terminals

post-synaptic mechanisms

examples of opioid agonists at the mu receptor

Endogenous: Endorphins

Natural: Morphine

Synthetic: Fentanyl

opioid peptides bind opioid receptors and activate: ________________

Thereby inhibiting _________

Opioid peptides bind opioid receptors and activate G-proteins, thereby inhibiting Calcium (Ca++) influx

Opioid receptors mediate postsynaptic inhibition of pain by enhancing

Cl influx and K efflux

What receptor is the primary therapeutic target of opioid analgesics?

mu receptors

• analgesia, euphoria, respiratory depression, dependence

Selective Kappa agonists are effective analgesics can cause

dysphoric reactions (anxiety, panic, delirium)

k receptors are important in

sedative and GI effects s

delta receptors are likely to contribute to

tolerance

Full/STRONG mu OR Agonists

Phenanthrenes: Morphine, hydromorphone, oxymorphone, heroin

Phenylethylamines: methadone

Phenylpiperidines: meperidine, fentanyl, sufentanil, alfentanil, remifentanil

Morphinans: levorphanol, dextromethorphan

Partial/Mild mu OR agonists

Phenanthrenes: codeine, oxycodone, hydrocodone

Phenylethylamines: propoxyphene

Phenylpiperidines: diphenoxylate, difenoxin, loperamide

mixed (mu or kappa OR) Agonists/Antagonists

Phenanthrenes: Nalbuphine, Buprenorphine

Morphinans: Butorphanol

Benzomorphans: Pentazocine, dezocine

u OR antagonists

Naloxone, naltrexone

metabolism of phenanthrenes

converted to non-active polar glucuronides in the liver and excreted by kidneys

exception is morphine (full agonist) e

exception of phenanthrene metabolism

morphine (full agonist)

• morpgine-3-glucuronide

• neurotoxic - seizures

Explain this

Role of GABA: inhibits descending inhibitory neurons

Opioids bind to the mu opioid receptor. This negatively regulates gaba interneurons. If GABAergic neurons previously NEGATIVELY regulated the pain inhibitory neuron, then taking GABA away allows for the Pain inhibitory neuron (Descending neuron) to REDUCE more pain. This increases the flow of descending pathways by inhibiting the ascending pathway.

Explain normal action potential

An action potential will cause a membrane voltage change

This will be sensed by voltage gated calcium channels

The release of calcium will cause release of glutamate (Excitatory)

Glutamate will bind to the ligand gated cation channel, which will cause a positive influx of cations and depolarize the membrane; enabling more action potentials

Explain opioid receptors

These opioid receptors are located pre (afferent neuron) and post synaptically (within the spinal cord).

An opioid receptor agonist will bind to these receptors.

On the presynaptic, mu, delta, and kappa opioid receptors will cause a G inhibatory effect on the voltage gated calcium channel

On the postsynaptic, the opioid receptor agonist will activate Gi and enhance GIRK channels to release Potassium (Depolarization)

Presynaptic activation of opioid receptors

On the presynaptic, mu, delta, and kappa opioid receptors will cause a G inhibitory effect on the voltage gated calcium channel,

Post synaptic activity of opioid receptors

On the postsynaptic, the opioid receptor agonist (via mu) will activate Gi and enhance GIRK channels to release Potassium (Depolarization)

what is the primary therapeutic target of opioid analgesics

u receptors, responsible for Analgesia, euphoria, respiratory depression, dependence

what are side effects of selective kappa receptor agonists

effective analgesics but can cause dysphoric reactions (anxiety, panic, delirium)

activation of mu opioid receptors stimulate what

release of endogenous opioids that activate all three opioid types

kappa receptors are important in

sedative and gi effectsd

delta receptors likely contribute to

tolerance (mu also)

4 major classes of opioids

Full/strong mu opioid receptor agonists

Partial/mild mu opioid receptor agonists

Mixed (u or kappa opioid receptor) agonist/antagonist

u opioid receptor antagonists:

Examples of full agonists of u receptors

Morphine, Hydromorphone, Oxymorphone, Heroin

Methadone

Meperidine, fentanyl, sufentanil, alfentanil, remifentanil

Levorphanol, dextromethorphan

example of partial mu opioid receptor agonists

codeine, oxycodone, hydrocodone

propoxyphene

diphenoxylate, difenoxin, loperamide

mixed (u and kappa) opioid agonist/antagonist

nalbuphine, buprenorphine

butorphanol

pentazocine, dezocine

mu opioid receptor antagonists

naloxone, naltrexone

morphine metabolism

morphine-3-glucuronide and M6G

Neurotoxic = seizures

meperidine metabolism

demethylated to form normeperidine (can cause seizures)

what 2 drugs are full agonists that can trigger seizures

meperidine and morphine

absorption of opioids

significant first pass metabolism in the liver

*can cross the placental barrier

Opioid effects on the CNS

Analgesia - reduced sensory and emotional pain

Euphoria - pleasant, floating, reduced anxiety

• Rarely: dysphoria, possible via kappa receptor

Sedation

Cough suppression via unknown mechanism (codeine; not via OR)

Respiratory depression. Contraindicated in Asthma, COPD, intracranial pressure

Miosis, truncal rigidity, N/V

Opioid major contraindication

Asthma, COPD, intracranial pressure

Peripheral effects of opioids

Cardiovascular effects

• bradycardia (not meperidine)

• slight hypotension

GI tract

• constipation

• tolerance does not develop in the colon

Uterus

• reduce uterine tone to prolong baby delivery

Renal and other effects of opioids

Renal: increased bladder tone, urinary retention, reduces renal function

Pruritus (itchiness)

• triggered by mu opioid receptor agonists

Immune responses

• inhibits NK cells, lymphocytes

clinical use of opioids for analgesia

Opioids are usually indicated in severe acute pain

• most effective against severe constant pain

considerations for opioid analgesic use

maximal efficacy

pain experience is self-reported

duration of action/duration of therapy

Route of administration

Side effects/adverse reactions

individual history with opiates and opioids

considerations used in chronic pain

tolerance and depedence

limited efficacy

considerations for regional analgesic use of opioids via epidural delivery

reduced supraspine adverse effects

Usually morphine or combined fentanyl with local anesthetics

Respiratory depression may still occur

Rare “epidural HA”

Fetus should be monitored for respiratory depression

use of opioids in acute pulmonary edema

causes dyspnea (difficult or labored breathing)

can be alleviated by morphine

acute pulmonary edema is a complication of heart failure

opioids used for cough supression

codeine and dextromethorphan

unknown mechanism, distinct from analgesia

all full agonists have high potential for

physical dependence and addiction

rapid acting full agonists of the fentanyl type

Alfentanil and Remifentanil: rapid action, short T1/2

Meperidine considerations

antimuscarinic activity; can increase heart rate

avoid in tachycardia

avoid in decreased renal function

demethylated for normeperidine → potential for seizures

use of methadone

longer acting, used to treat Opioid Use Disorder (OUD)

• primarily used for detox, lessens withdrawal severity

• Maintenance/relapse prevention: blocks rewarding effects of heroin

• Increasingly used as a therapeutic analgesic

  • potent agonist of mu opioid receptors, blocks NMDA receptors

  • effective in neuropathic pain, morphine-resistant pain

Partial agonists used for diarrhea

diphenoxylate, difenoxin, loperamide are used for diarrhea. Low solubility, low CNS distribution

considerations of partial agonists

Do NOT give partial agonists to patients receiving full agonists

partial agonist dose response curve

will never reach full efficacy

partial agonists examples

codeine, oxycodone, dihydrocodeine, hydrocodone

• combined with aspirin or acetaminophen

• used for less severe pain

• less addictive

Diphenoxylate, difenoxin, and loperamide are used for diarrhea

mixed agonists

all mixed agonists have the potential for negative psychotogenic effects (delusion and hallucination)

mixed agonist examples

nalbuphine: kappa agonist, mu antagonist

butorphanol: kappa agonist, partial agonist at mu receptor

pentazocine: Kappa agonist, weak mu antagonist

buprenorphine characteristics

high potency, long-acting partial mu agonist

antagonist at delta and kappa receptors

used for detox and maintenance for addictions (lower respiratory risk than methadone, full mu agonist)

Functions as an analgesic on its own

Naloxone resistant

tramadol

serotonergic analgesic (SERT Blocker)

Weak mu opioid receptor agonist

Chronic neuropathic pain

No respiratory effects

Seizures, nausea

tapentadol

adrenergic analgesic NET blocker

weak mu opioid receptor agonist

partial agonists may ____ ____ _____ in patients receiving full agonists

Partial agonists may precipitate withdrawal symptoms in patients receiving full agonists

similar to lowering the dose

pre-existing intracranial pressure of head injury considerations for opioids

Opioids should NOT be used in patients with pre-existing intracranial pressure of head injury

contraindications for opioid use

pre-existing pulmonary impairments - respiratory depression compounded

impaired renal or hepatic function: dosage should be reduced due to longer half life

hypothyroidism or low adrenal activity: opioid effects are exaggerated

opioid antagonists characteristics

high affinity for u receptors

inert in the absence of agonist

Used for management of acute opioid overdose

• completely reverse morphine effects

• Can also induce withdrawal due to mu receptor blocking “abstinence syndrome”

opioid antagonist examples

naloxone: short acting

• major clinical use: reverse acute CNS and respiratory effects

naltrexone: long acting

• maintenance drug for addicts

• taked qid to block all heroin effects

• decreases craving for alcohol in alcoholics (reduces alcohol dependence)

what receptor is important for the development and maintenance of tolerance and dependence

mu opioid receptor is important in the development and maintenance of tolerance and dependence

chronic opioid administration may lead to

hyperalgesia

increased sensitivity to feeling pain and an extreme response to pain

limited tolerance develops with

mixed-type opiates and opioid rotation

major symptoms of dependence

Rhinorrhea, lacrimation, hyperventilation, hyperthermia, anxiety

antagonist-precipitated withdrawal

immediate symptoms following administration of naloxone (mu receptor blocker)

abrupt discontinuance of mixed agonist also produces

some withdrawal symptoms but less severe