Opioid Analgesics Flashcards by Chris Rodarte

Comorbidities for chronic pain

Anxiety
Depression
Insomnia (red. immunity, inc. inflamm)
Activation of Glia (astrocytes and microglia)
Hyperalgesia, allodynia

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Two types of opioid alkaloids

Phenanthrenes

Benzyliso-quinolines

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Phenantherenes agents

Morphine (10%)

Codeine (.5%)

Thebaine (.2%)

(Also Hydrocodone, buprenorphine)

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Benzylisoquinolines agents

Noscapine (6%)

Papaverine (1%)

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Mu opioid receptor drugs - Phenanthrenes

Morphine

Hydrocodone

Buprenorphine (partial)

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Mu opioid receptor drugs - Non-phenanthrenes

Tramadol

Meperidine

Fentanyl

Methadone

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Morphine metabolism rxn

Enzyme?

Glucuronidation (3’ and 6’)

CYP-2D6

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Effect of alcohol on morphine metabolism

May increase serum levels of 2D6, reducing the available time of effect.

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Morphine excretion (where and rate?)

Glomerular excretion

90% excreted in 24h

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Primary metabolite of morphine is __ conjugated

3’

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Opioid receptors are ____

Three types?

GPCR’s

They are Gi/o coupled (inhibit cAMP)

Mu - Morphine

Kappa - Ketocyclazocine

Delta - Deferens

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Two ‘other’ receptors (one opioid, one not)

Nociceptin, orphanin FQ receptor

Sigma receptor - NOT an opioid receptor

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The types of pain for which opiates are not indicated

Acute, sharp pain

Neuropathic pain

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Mu opioid AE’s

Respiratory depression

GI immotility

Itch

Tolerance

Urinary retention (ADH)

Nausea/Vomiting

Muscle rigidity

Miosis (PAG - Oculomotor nerve)

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Opioid that doesnt cause Biliary SMC contraction

meperidine

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Kappa natural ligand

Dynorphins

(preprodynorphin)

(Salvia contains an agonist. Not an alkaloid)

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Kappa receptor function

Counterbalance Mu effects

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Delta opioid natural ligand

Enkephalins (prepro)

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Delta has more ___ expression

dynamic

(intracellular, externalized upo chronic stimuli)

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Delta has a role in…

ischemia, hypoxia, stroke

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Major Mu receptor endogenous ligand

Endorphins (from POMC)

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Opioid receptor transduction hinges upon __

Adenylyl Cyclase inactivation

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Two synaptic mehanisms for opioid receptors

Presynaptic = Inhibit Ca++ channel

Postsynaptic = Activate GIRK channel (Gby)

(Efflux of K+ = hyperpolarization)

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What is GIRK?

G protein inward rectifying K+ channel

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Covered by medicare and preferred over oxycontin

Morphine

Oxycontin plus paracetamol

Percocet

Clinically used opioid agonists

1. Sufentanil 2. Remifentanyl 3. Fentanyl 4. Hydromorphone 5. Morphine 6. Hydrocodone 7. Oxycodone

Weaker clinically used opioid agonists

Methadone Meperidine Codeine Tramadol Loperamide Propoxyphene (wd)

\_\_\_, ___ have SNRI properties Use?

Tramadol, Tapentadol (non-phenanthrenes) --\> management of mild non-neuropathic pain

What are the metabolite effects of demerol that you need to watch for?

Active metabolite (Nor-meperidine) can accumulate, cause **CNS irritability** + **myoclonic seizures**

Meperidine is dangerous in whom?

Patients with decreased renal function (renally excreted)

Methadone is a ____ antagonist Half life?

NMDA antagonist 15-60 hrs

This analgesic's half life is shorter than the serum half life

Levorphanol

Levorphanol is a ___ antagonist

NMDA

NMDA antagonists? Which for chronic, and which for neuropathic

Methadone (chronic) Levorphanol (neuropathic)

Buprenorphine receptor subtype activity

Partial mu agonist Weak K agonist Delta antagonist

Buprenorphine is used for...

treatment for opioid withdrawal in addiction therapy

Buprenorphine combined with ...

naoxone (Suboxone)

Mu antagonists

Naloxone (narcan) Naltrexone (oral)

These are used for **surgery** because of their fast onset and short duration

Fentanyl, Sufentanil, remifentanil

These are used for **post-op** or **epidural** because of potency and _longer half life than fentanyl_

hydromorphone, morphine

These are used for management because of oral BA have a longer half life than fentanyl

Oxycodone, HC, Oxycontin (Zohydo = extended-release HC)

Used for terminal cancer pain because of lower cost, history of knowledge, and irrelevant risk for dependence/abuse

Morphine

Used in opioid intolerance

Meperidine

Issue with meperidine/demerol metabolism

metabolites NOT blocked by NTX MAOi's are contraindicated

Shortest onset opioid

Fentanyl

Opioid with longest dosing interval

Hydromorphone

When dosing opoiod analgesics it is important to ______ as compared to\_\_\_\_\_\_

calcuate dose compared to morphine

Which comes first: Somnolescence/miosis -or- Itching/urinary retention

Somnolescence/miosis

Senna MOA

Irritates colon and causes fluid secretion and CONTRACTION

Polythylene glycol MOA

Osmotic increase in GI water content

Docusate MOA

softens stool and increases peristalsis

Peripherally restructed mu antagonists

Methylnaltrexone (4' amine, no BBB pass) Alvimopan Naloxegol

Opioid induced itch requires \_\_\_\_\_\_

**MOR1D splice variant** of the mu receptor

What is the GRPR in the MOR1D-GRPR? What happens downstream?

**G**astrin-**R**eleasing **P**eptide **R**eceptor _Downstream_ = IP3 is formed and Ca++ is released from the ER

Symptoms with NO TOLERANCE (or limited tolerance)

Constipation Itch Miosis

A few mechanisms for tolerance

Receptor adaptation decreased receptor number Decreased coupling to effector

A few mechanisms for hyperalgesia

Altered excitability of target neurons NMDA, Cholecystokinin, dynorphin, substance P

Alterations in ___ and ____ receptors also contribute to pain response

NMDA and Substance P

Signs of Opioid induced hyperalgesia

Pain not relieved by opioid Diffuse pain Cold pressor test (arm in ice bath--withdrawal time)

Solution to OIH?

Switch opioid class - phenanthrenes vs non (6 glucuronide metabolites of phenanthrenes act as NMDA agonists) Methadone is NMDA antagonist

Opioid detox - switch to \_\_\_\_

clonidine/diazepam

Precautions taken when given to paients with these diseases

Respiratory compromise (CB, Asthma, Emphysema) Seizure disorders Hepatic disease

DDIs for opioids

Depressants (EtOH, Benzo, Barbiturarates) Antipsychotics TCA Antihistamines Meperidine

Meperidine DDI

MAO's, SSRI's SEROTONIN SYNDROME, hyperpyrexic coma

Tx for acute opioid toxicity

Resp and Cardio support Naloxone (Narcan) ... SMALL IV dose initially

Drugs to treat opioid abuse

Methdone Buprenorphine Suboxone (bup+naloxone)

3 approaches to long term treatment of opioid addiction

1. **Agonist Maintenance** (Methadone Maint. Therapy) 2. **Partial Agonist Therapy** (Buprenorphine) 3. **Antagonist Maintenance** (Naltrexone)

Opioids to treat Alcohol use disorders

Naltrexone (once per month) Nalmefene