1. Opioids bind to receptor 2. G-protein is activated 3. Adenylate cyclase is inhibited 4. cAMP production is decreased 5. Ca++ conductance is decreased 6. K+ conductance is increased

Pharmacology 2 - Opioid agonists/antagonists Flashcards by Bailey Bass

What are the 4 steps of pain transmission?

Transduction
Transmission
Modulation
Perception

How well did you know this?

Not at all

Perfectly

What is hyperalgesia?

Increased response to a painful stimulus

How well did you know this?

Not at all

Perfectly

What is allodynia?

Decreased threshold to a painful stimulus

How well did you know this?

Not at all

Perfectly

How is pain transmitted?

Through a 3 neuron pathway
First order neuron: periphery to dorsal horn via spinothalamic tract
Second order neuron: from dorsal horn to thalamus
Third order neuron: from thalamus to cerebral cortex

How well did you know this?

Not at all

Perfectly

What is the most important site of modulation?

Substantia gelatinosa in the dorsal horn (Lamina II and III)

How well did you know this?

Not at all

Perfectly

When is pain inhibited?

Spinal neurons release GABA and glycine

2. Descending pain pathway release NE, 5-HT, and endorphins

How well did you know this?

Not at all

Perfectly

Where does the descending pain pathway begin? end?

Begins in the periaqueductal gray and rostroventral medulla

Ends in the substantia gelatinosa

How well did you know this?

Not at all

Perfectly

How is pain augmented?

Wind up & central sensitization

How well did you know this?

Not at all

Perfectly

What are the 4 opioid receptors?

Mu
Delta
Kappa
ORL1 (not relevant)

How well did you know this?

Not at all

Perfectly

Opioid MOA (6 steps)

Opioids bind to receptor
G-protein is activated
Adenylate cyclase is inhibited
cAMP production is decreased
Ca++ conductance is decreased
K+ conductance is increased

How well did you know this?

Not at all

Perfectly

What does decreased Ca++ conductance result in with pain modulation?

Decreased NT release in presynaptic neuron

How well did you know this?

Not at all

Perfectly

What does increased K+ conductance result in with pain modulation?

Decreased RMP
More resistant to depolarization
Hyperpolarization of postsynaptic neuron

How well did you know this?

Not at all

Perfectly

Where are opioid receptors located (3 locations)?

Brain: periaqueductal gray, locus ceruleus, and rostral ventral medulla
Spinal cord: primary afferent neurons in dorsal horn and interneurons
Peripheral: sensory neurons and immune cells

How well did you know this?

Not at all

Perfectly

What are the precursors of opioid receptors (3)?

Pre-proopiomelanocortin: endorphins (Mu receptor)
Pre-enkephalin: enkephalins (Delta receptor)
Pre-dynorphins: dynorphins (Kappa receptor)

How well did you know this?

Not at all

Perfectly

Mu1 receptor symptoms

ANALGESIA (supraspinal and spinal)
BRADYCARDIA
Miosis
Hypothermia
Urinary retention
Euphoria
Low abuse potential

How well did you know this?

Not at all

Perfectly

Mu2 receptor symptoms

ANALGESIA (spinal only)
RESPIRATORY DEPRESSION
CONSTIPATION
PHYSICAL DEPENDENCE

How well did you know this?

Not at all

Perfectly

Mu3 receptor symptoms

IMMUNE SUPPRESION

How well did you know this?

Not at all

Perfectly

What drug increases biliary pressure the LEAST?

Meperidine

How well did you know this?

Not at all

Perfectly

How to decrease biliary pressure with opioids?

Glucagon or nalaxone

How well did you know this?

Not at all

Perfectly

What opioids have histamine releasing properties?

Morphine, meperidine, & codeine

How well did you know this?

Not at all

Perfectly

What gender is more sensitive to opioids?

Women

How well did you know this?

Not at all

Perfectly

What is morphine associated with in women?

Greater analgesic potency
Decreased postoperative opioid consumption
Slower onset of action
Longer duration of action

How well did you know this?

Not at all

Perfectly

Opioids: most potent to least potent

Sufentanil > Remifentanil = Fentanyl > Alfentanil > Hydromorphone > Morphine > Meperidine

How well did you know this?

Not at all

Perfectly

Which opioid is the standard to which all other opioids are compared?

Morphine

How well did you know this?

Not at all

Perfectly

What is tolerance of opioids most likely due to?

Receptor desensitization and increased synthesis of cAMP

1. What does tolerance develop to? | 2. What does tolerance NOT develop to?

1. Analgesia, sedation, euphoria, resp. depression, and emetic effects 2. Miosis and constipation

Early signs and symptoms of withdrawal from opioids?

Diaphoresis, anxiety/restlessness, and insomnia

Later signs and symptoms of withdrawal from opioids?

Abdominal pain and N/V

Fentanyl and meperidine withdrawal symptoms time line

Onset: 2 - 6 hours Peak: 6 - 12 hours Duration: 4 - 5 days

Morphine and heroin withdrawal symptoms time line

Onset: 6 - 18 hours Peak: 36 - 72 hours Duration: 7 - 10 days

Methadone withdrawal symptoms time line

Onset: 24 - 48 hours Peak: 3 - 21 days Duration: 6 - 7 weeks

1. Which opioids have active metabolites? | 2. Which do not?

1. Meperidine and Morphine | 2. Sufentanil, remifentanil, alfentinil, fentanyl, and dilaudid

1. What metabolites does morphine posses? | 2. Active or inactive?

1. Morphine 3- gluconaride and Morphine 6- gluconaride | 2. 3 = inactive; 6 = active

What opioid should renal failure patients not receive?

Morphine - unable to eliminate it even with dialysis, thus respiratory depression and toxicity can occur

Who else (other than renal failure) may develop M6G toxicity and accumulation?

Chronic morphine use with normal renal function

1. What does M3G cause? | 2. What does M6G cause?

1. Hyperalgesia, agitation, myoclonus, delirium | 2. Resp. depression, drowsiness, N/V, coma

What does meperidine result in?

Decreased seizure threshold and increased CNS excitability

S/S of meperidine CNS excitability?

Muscle twitches, seizures, tremors

Who should meperidine be avoided in?

Elderly and patients on dialysis

What is remifentanil metabolized by?

Tissue and plasma esterases

How is remifentanil dosed?

IBW

What is meperidine metabolized to?

Normeperidine

What drugs should be avoided with meperidine?

MAOI's due to the risk of serotonin syndrome (Meperidine acts like an SSRI)

S/S of serotonin syndrome?

``` Hyperthermia Mental status changes Hyperreflexia Seizures Death ```

Examples of MAOI's?

Phenylxine Isocarboxazid Tranylcypromine

What drug is meperidine structurally related to?

Atropine - anticholinergic effects (tachycardia, mydriasis, drymouth)

What receptor is stimulated with meperidine to decrease shivering?

Kappa

How fast is alfentanils effect site concentration time?

~ 1.4 minutes This is due to the low pKa of it (6.5) More unionized particles (~ 90%) and faster onset

What drug inhibits metabolism of alfentanil?

Erythromycin - increased respiratory depression risk/time

How is alfentanil metabolized?

CYP3A4 (cytochrome p450 enzymes) | Renal failure does not effect clearance

Big complication with pain control after remifentanil?

Hyperalgesia - tend to increase opioid use in post op period

How to decrease opioid induced hyperalgesia after remifentanil infusions?

Ketamine and magensium

Why cant remifentanil be used intrathecally or via epidural?

It has glycine (inhibitory NT) as a buffer when reconstituted which can cause skeletal muscle weakness

What circumstances is methadone best used for?

Opioid withdrawal treatment Chronic pain management Cancer pain

Which opioid is prepared as a racemic mixture?

Methadone

By what three mechanisms does methadone reduce pain?

NMDA antagonism Monoamine reuptake inhibition in synaptic cleft Mu receptor agonism

What potential complication can arise with methadone use?

``` QT prolongation (very rare) Can lead to torsades de pointes ```

Whats the most common cause of increased skeletal muscle rigidity?

Rapid IV administration of opioids

What is the best treatment for skeletal muscle rigidity?

Paralyzing and intubating

What is the MOA of opioid induced skeletal muscle rigidity?

Mu receptor stimulation of the SNS (dopamine and GABA motor pathways)

RESPIRATORY complications with opioid induced SKM rigidity?

``` Hypoxia Hypercarbia Increased O2 consumption Decreased SVO2 Decreased FRC Decreased thoracic compliance Decrease minute ventilation ```

CV complications with opioid induced SKM rigidity?

Increased CVP, PAP, PVR

OTHER complications with opioid induced SKM rigidity?

Increased ICP | Increased intragastric pressure with mask ventilation

Common characteristics of partial agonists?

Have a ceiling effect Less efficacious as full agonists Can cause acute opioid withdrawal in opioid addicts Used in patients who cant tolerate full agonists Produce analgesia without respiratory depression Less likely to be abused Can cause dysphoric reactions

Dose of narcan?

1 - 4 mcg/kg or 20 - 40 mg IV

DOA of narcan?

30 - 45 minutes

Narcan use?

RD with opioid overdose RD in neonate whose mother received opioids Treatment of opioid overdose

What receptors does narcan work on?

Mu, kappa, and delta (Mu the most!)

What complications arise with narcan?

- SNS stimulation (tachycardia, pulm. edeam, HTN, arrythmias, excitation, anxiety, etc.) - N/V (less with slow titration over 2 - 3 minutes)

What is methylnaltrexone? | Whats the problem with its use?

- An opioid reversal agent - Its a quartinary amino group (cant cross BBB and reverse RD) - Better used for peripheral symptoms (bowel dysfunction)

Problem with narcan?

Very high first pass metabolism (may need continuous infusion or multiple doses if narcotic has a longer DOA than the narcan)

Nalmefene dosing

0.1 - 0.5 mcg/kg

Benefit of naltrexone?

Does not undergo first pass metabolism and has a very long half life of around 24 hours