Opiates/Opioids

Opioid

ANY drug that acts on Opioid Receptors of the Brain/CNS

Short Peptides derived from long precursors

Synthetic Drugs

Opioid Drugs

Opioid Drugs

1. Hydrocodone

2. Oxycodone

3. Fentanyl

4. Heroin

Opiates

opium and its derivatives

NATURALLY derived from the Poppy Plant

Opiate Drugs

1. Morphine

2. Opium

3. Codeine

Term used to describe BOTH Opiates and Opioids

Opioid

Peptide Neurotransmitters

short chains of amino acids linked together by covalent peptide bonds;

Opioids that are LONGER LASTING

Produce Opioid Short Peptides Endogenously (in the body naturally that bind to Opioid Receptors)

NATURALLY produced in the CNS

Opioid Receptors

mu, kappa, delta

Opioid Receptors are

Metabotropic Receptors (GPCRs)

Opioid Receptors function

Relieve Stress and Pain

--> Why they are targeted by:

1. Analgesics

2. General Anesthetics (some)

3. Drugs of Abuse

Neuromodulator

a naturally secreted substance that acts like a neurotransmitter except that it is not restricted to the synaptic cleft but diffuses through the extracellular fluid

--> Influences activity of other synaptic transmitters

Endogenous Opioid Peptides do this!!

Consensus Opioid Sequence

- Classical opioid peptides have consensus opioid sequence:

Tyr-Gly-Gly-Phe-Leu/Met

- highly conserved for active site recognition

Three Families/Types of Endogenous Opioid Peptides

1. Enkephalins

2. Endorphins

3. Dynorphins

Note: Generated from longer, Pre-cursor Proteins

Endogenous Opioids that have a UNIQUE Sequence/Structure (test question)

Endomorphins

Tyr-Pro-Trp/Phe-Phe/NH2

Endogenous Opioids Neuromodulator Activity

1. INHIBIT Glutamate Release

2. INHIBIT activation of Spinal Nociceptive Neurons (pain receptors... duhhhh b/c keep us from feeling pain)

Opioid Receptors expressed in the

1. Brain

2. Spinal Cord

3. Peripheral Nerves

Note: Expressed in CNS at sites of PAIN MODULATION

When are Endogenous Opioids released?

During painful states, during stress, and after exposure to rewarding things

Result = Alleviate Pain

Endorphins bind

Delta and Mu Receptor

Enkephalins bind

Delta Receptors > Mu Receptors

NO Kappa binding

Dynorphins bind

Kappa Receptors

Sensitizes Nociceptive Signals in the Dorsal Horn (Test question)

Dynorphins

Endomorphins bind

Mu Receptors ONLY

--> Target for Analgesics

Mu, Delta, and Kappa Receptors are expressed on

1. Primary Afferent/Sensory Receptors --> In the Periphery

2. Nociceptive/Pain Neurons

Presynpatic (Primary Afferent) Expression of Opioid Receptors

ALL Three (Mu, Delta, Kappa)

Post-Synaptic (Nociceptive Neurons) Expression of Opioid Receptors

ONLY Mu Receptors

--> Why Analgesics target these receptors!!

1. Spinal Nociceptive Neurons

2. Peripheral Terminals of Sensory Neurons

Sites of action of opioids on pain transmission: Pre- and Post- Synaptic Mechanisms

1. Spinal Cord

2. Supraspinal Effects (going to the brain)

Sites of action of opioids on pain transmission: Post-Synaptic Mechanisms

Peripheral Terminals

Pathway of Pain Stimulus

1. Pain Stimulus Experienced (Periphery)

2. Primary Afferent Neuron relays information --> Pain Transmission Neuron

3. Pain Transmission Neuron --> Spinal Cord --> Brain

4. Brain perceives Pain and reacts -> Descending Pathway (Modulation)

5. Pain Inhibitory Neuron Activated (once Brain receives Pain signal) --> b/c Pain signal already received by the Brain = Inhibits Transmission of Pain (brain says, "oh yeah, I got it, I am going to do something about it now!)

6. GABA Neurons can inhibit the Pain Inhibitory Neurons --> ALLOWS the brain to receive Pain stimulus!

Regulate/Inhibit Pain Inhibitory Neurons

GABA Neurons --> Hyperpolarization (Chloride Influx)

--> Inhibits Pain Inhibitory Neurons from firing and stopping the pain stimulus from reaching the brain

Endogenous Opioid Agonists

Endorphins

Natural Opioid Agonist

Morphine

Synthetic Opioid Agonist

Fentanyl

MOA of Opioid Drugs (Slide 12-17)

1. Mu, Kappa, Delta Receptors --> Pre-Synaptically when bound

--> GPCR --> Gi protein --> BetaGamma Subunit INHIBITS Voltage-Gated Ca2+ Channel from depolarizing

Result: Glutamate (excitatory neurotransmistter) release INHIBITED --> NO PAIN STIMULUS

Decrease Ca2+ influx, Decrease Glutamate Release

2. Mu Opioid Receptor --> Post-Synaptically when bound

--> GPCR --> Gi protein --> BetaGamma Subunit ACTIVATES GIRK CHANNEL --> K+ EFFLUX --> Hyperpolarization

Result: Signal is NOT PROPAGATED --> NO PAIN STIMULUS

Increase K+ Efflux --> Inhibitory Post Synaptic Potential (IPSP)

ACTIVATION OF POST-SYNAPTIC MU RECEPTOR INHIBITS NEURONAL ACTIVATION AND PAIN TRANSMISSION

Primary Therapeutic Target of Opioid Analgesics

Mu Receptors

Effects:

1. Analgesia

2. Euphoria

3. Respiratory Depression

4. Dependence

New Kappa Selective Agonists can cause

DYSHPORIC REACTIONS

--> Anxiety, Pain, Delirium

Activation of Mu Receptors stimulates

Release of Endogenous Opioids (Endorphins, etc.) that activates ALL THREE opioid receptors (mu, delta, kappa)

Kappa Receptors important in these effects (test question)

Sedative and GI effects

Which Opioid Receptor likely contributes to TOLERANCE (test question) --> big problem with opioid drugs and big cause of overdose

Delta Receptors

What kind of Pt should you NEVER give Opioids to? (test question)

1. COPD Pts, Asthma and pts with respiratory disease

--> b/c Mu receptor activation can cause further RESPIRATORY DEPRESSION

2. Elevated Intracranial Pressure

--> b/c opioid activation can increase Intracranial Pressure --> risk of hemorrhaging

Full/Strong Mu Agonists

1. MORPHINE (caps = focus)

2. Hydromorphone

3. Oxymorphone

4. Heroin

5. Methadone

6. Meperidine

7. Fentanyl

8. Sufentanil

9. Alfentanil

10. Remifentanil

11. Levorphanol

12. Dextromethorphan

Partial/Mild Mu Agonists

1. CODEINE

2. Oxycodone

3. Hydrocodone

4. Propoxyphene

5. Diphenoxylate

6. Difenoxin

7. Loperamide

Mixed (Mu and Kappa) Agonist/Antagonists

1. NALBUPHINE

2. Buprenorphine

3. Butorphanol

4. Pentazocine

5. Dezocine

Mu Receptor Antagonists

1. NALOXONE

2. Naltrexone

Phenanthrenes

1. Morphine

2. Hydromorphone

3. Oxymorphone

4. Heroin

Phenylpiperidines

1. Meperidine

2. Fentanyl

3. Sufentanil

4. Alfentanil

5. Remifentanil

Phenanthrenes are converted to

NON-active Polar Glucuronides in the Liver

--> Excreted by the kidneys

EXCEPTION: Morphine

Morphine (full agonist) metabolized to ___ and its effect is ___

Morphine-3-glucuronide (M3G) and M6G

Neurotoxic --> SEIZURES

Phenylpiperidines are metabolized by

3A4

Meperidine (full agonist) is demethylated to form ____ that is ____

Normeperidine

Neurotoxic --> SEIZURES

Can trigger Seizures (test question)

1. Morphine

2. Merperidine

Absorption and Metabolism of Opioids

Good absorption

Significant First-Pass metabolism by liver

Do opioids cross the placental barrier?

YES --> Contraindicated in Pregnant Women b/c can be teratogenic

Drug Delivery Methods of Opioids

1. Parenteral formulations

2. Sustained Release

3. Rectal suppositories

4. Transdermal patch

5. Intranasal

6. Buccal transmucosal

Organ System Effects of Opioids: CNS

1. Analgesia --> reduced sensory and emotional pain

2. Euphoria

3. Sedation

4. RESPIRATORY DEPRESSION

5. Miosis (pupil constriction)

6. Truncal rigidity --> increased muscle tone (supraspinal effect (in the brain causes)

7. N & V --> activates Brainstem Chemoreceptor Trigger Zone

Which Opioid causes Cough Suppression?

Codeine and Dextromethorphan

Note: Unknown mechanism

Exception to Miosis Effect (test question)

Meperidine

--> Muscarinic Receptor Blocker (Anticholinergic) --> Mydriasis

Does develop Tolerance to Miosis Effect over time?

NO! --> constantly causes while taking

Organ System Effects of Opioids: Peripheral Effects

1. Bradycardia

2. Hypotension

3. Constipation (Opioid receptors in Enteric System)

4. Reduces Uterine Tone --> Can PROLONG BABY DELIVERY

5. Increased Bladder Tone --> URINARY RETENTION

6. Reduces Renal Function

7. Regulates release of LH, ADH, Prolactin

8. Pruritus (Itchiness) depending on ROUTE of administration

9. Inhibits Natural Killer Cells and Lymphocytes

_____ mostly trigger Pruritus

Mu Opioid Receptor Agonists

Does Tolerance develop with Constipation caused by Opioids?

NO --> persistent constipation in the colon

Opioid that does NOT cause Bradycardia (test question)

Meperidine --> Tachycardia b/c Muscarinic Antagonist

Clinical Use of Opioids

1. Analgesia

a) Severe Acute Pain

b) Chronic Pain

Concern: Tolerance and Dependence

c) Terminal Illness

d) Labor and Delivery

e) Pre-operative as sedative

f) During surgery to complement anesthetics

g) Surgically implanted pump for chronic pain

2. Acute Pulmonary Edema

3. Diarrhea

4. Cough Suppression

Dependence NOT a major issue

Terminal Illness

Regional (specific location) Analgesia is delivered via

Epidural Delivery to the Spinal Column!

1. Morphine

or

2. Fentanyl with Local anesthetics

Note: Respiratory Depression can still occur!

Epidural Headache

If the needle goes through arachnoid mater, then cerebrospinal fluid can leak out and the loss of this fluid can cause enormous brain pain.

Opioid used in Labor and Delivery

Meperidine

Note: Fetus closely monitored for Respiratory Depression b/c opioids cross the placental barrier

Acute Pulmonary Edema is alleviated by

Morphine (not clear how)

The dyspnea is alleviated

Opioids that treat Diarrhea are

1. Diphenoxylate

2. Difenoxin

3. Loperamide

Partial/Mild Mu Agonists with FEW CNS side effects --> low risk for abuse

Low Solubility --> Low CNS penetration --> NOT used as analgesics

ALL ____ have high potential for Physical Dependence and Addiction

Full Agonists

1. Morphine

2. Hydromorphone

3. Oxymorphone

4. Heroin

Used to treat SEVERE PAIN only

Potencies of Phenylpiperidines

Sufentanil > Fentanyl > Alfentanil

Avoid using Meperidine in pts with

1. Tachycardia

2. Decreased RENAL function

b/c Muscarinic Blocker (Anticholinergic) --> further increases heart rate and reduced renal function --> MI and Kidney Failure can result

Used to treat Opioid Use Disorder (OUD)

Methadone

b/c LONGER DOA --> used for DETOX --> Lessens Withdrawal Severity

Methadone effect on Heroin

Blocks rewarding effects of Heroin

--> Used for Maintenance/Relapse Prevention

Methadone MOA

Blocks NMDA Receptors and Monoaminergic Uptake

Morphine Alternative in Opiate Rotation

Methadone

--> can be used as a Therapeutic Analgesic! NOT just for withdrawal

Should partial/mixed agonists be given to patients receiving full agonists?

NO

--> b/c Partial Agonist will COMPETE with full agonist and hinder it from reaching the MAXIMUM EFFECT --> pt will be in more pain as a result

Insufficient for Extreme Pain

Propoxyphene

Mixed Agonists partially bind

ALL 3 receptors (mu, kappa, delta)

Variable efficacy as analgesics --> due to not being full active

ALL Mixed agonist have potential for

Negative Psychotogenic Effects

--> Delusion and HALLUCINATIONS

Mixed Agonists

1. Nalbuphine

2. Butorphanol

3. Pentazocine

Nalbuphine activity

Kappa Agonist

Mu Antagonist

Butorphanol activity

Kappa Agonist

Partial Agonist at Mu Receptor

Pentazocine activity

Kappa Agonist

Weak Mu Antagonist

Buprenorphine activity

Mixed Agonist

Partial Mu Agonist

Antagonist at Delta and Kappa Receptors

Long Acting Partial Mu Agonist

Buprenorphine

Detox and Maintenance for Addictions

Buprenorphine

Which has Lower Risk, Methadone or Buprenorphine?

Buprenorphine b/c Partial Mu Agonist

LOWER Respiratory risk than Methadone (full mu agonist)

Used for Detox and maintenance for addictions and functions as an Analgesic

Tramadol MOA

Serotonergic Analgesic (SERT Blocker)

--> Increases Serotonin levels in synapse

Weak Mu Receptor Agonist

Tramadol adverse effects

Seizures, Nausea, Serotonin Syndrome

Tapentadol MOA

NET Block (Inhibits NE Reuptake)

Weak Mu Receptor Agonist

Cough Suppressant that is a Partial Mu Agonist

Codeine

--> sub-analgesic doses

Cough Suppressant that is a Full Mu Agonist

Dextromethorphan

NON-HABIT FORMING and LESS constipating than Codeine

Partial Agonists noteworthy Adverse Effects

May PRECIPITATE Withdrawal Symptoms in patients receiving Full Agonists

--> b/c not receiving full analgesic dose

Pre-Existing Intracranial Pressure or Head Injury

Opioids should NOT be used

Respiratory Depression --> CO2 Retention --> Vasodilation --> More IOP

Mild Fetal Withdrawal Syndrome

Diazepam controls

Severe Fetal Withdrawal Syndrome

Methadone controls

Contraindications for Opioid Use

1. Elevated IOP

2. Pre-Existing Pulmonary Impairments

3. Impaired Renal or Hepatic Function

--> Dosage should be REDUCED if given

4. Hypothyroidism or Low Adrenal Activity

--> Opioids effects are exaggerated

Opioid Antagonists have a High Affinity for

Mu Receptors

Opioid Antagonists are ____ in the absence of an ___

Inert

Opioid Agonist (ex: Fentanyl)

Opioid Antagonists use

acute opioid overdose