L1. Opioid Analgesics I

What. are the 3 types of opioid receptors?

mu, kappa, delta

Opioid receptors are --- coupled receptors

GPCR

Endogenous opioid peptide are --- produced by the body and act similarly to ---

naturally produced

act similarly to opioids

Endogenous opioid peptides: 3 genes encode 3 precursor peptides

proenkephalin

prodynorphin

proopiomelanocortin

Proenkephalin binds with high affinity to --- and --- receptors

mu and delta

Proenkephalin functions as a ---

neurotransmitter

True / False: Proenkephalin are widely distributed in brain, spinal cord, adrenal medulla, and gastrointestinal tract

true

Where are prodynorphins distributed?

Brain and spinal cord

Dynoprhin ---- has a high affinity for kappa opioid receptors

A 1-17

Prodynorphins function as ---

neurotransmitters

Beta-endorphins function as --- or ---

neuromodulators or neurohormones

What is released in response to stress?

beta-endorphins

Beta endorphins have high affinity for -- and -- receptors

mu and delta

Proopiomelanocortin can be processed into

1. ACTH

2. a-MSH

3. beta-endorphin

Proopiomelanocortin has limited distribution of cell bodies to the --- and ---

intermediate lobe of pituitary gland

arcuate nucleus of hypothalamus

Proopiomelanocortin has axonal projections to

amygdala

periaquaductal gray (pain modulation)

brainstem and spinal cord

Opiod receptors are mainly in the

brain

brainstem

spinal cord

peripheral neurons

intestines

Mechanism of action of opioids

inhibit adenylyl cyclase = no cAMP

close voltage gated Ca channels = inhibits neurotransmitter release

open K channels = increase hyper-polarization

What happens when opioids inhibit adenylyl cyclase and reduce cAMP?

decrease cell excitability

Pharmacological effects of opioids

analgesia

Analgesia effects can be --

central, spinal, or peripheral

Periaquaductal gray (PAG) is in the ---- and activates descending pain inhibition pathways

midbrain

Central (supra spinal) analgesia is pain modulation in the ---

brain

Spinal analgesia is pain modulation in the --- neurons of the spinal cord

dorsal horn

Peripheral analgesia is activation of opioid receptors located on --- and --- fibers

alpha delta and C fibers

Pain transmission pathway from peripheral receptors

dorsal root ganglion

tract of lissaur

dorsal horn of spinal cord (decussate in anterior white commissure)

travel up neospinothalamic or paleospinothalamic pathway to VPL of thalamus

Pain transmission pathway from periaquaductal gray

PAG receives input from cortex/amygdala/hypothalamus

sends transmission to rostral ventral medulla

RVM sends 5-HT and norepinephrine to interneurons in dorsal horn of spinal cord

Interneurons inhibit pain

Central effects of opioids

Respiratory depression

Cough suppression

Miosis

Euphoria

Nausea/vomiting

How do opioids cause respiratory depression?

decrease brainstem centers response to CO2

decrease pontine/medullary centers

What do pontine and medullary centers regulate?

Respiratory rate, frequency, tidal volume

How do opioids cause cough suppression?

depress cough reflex in brainstem

How do opioids cause miosis?

central effect on oculomotor nerve = depress sphincter pupillae muscle

cause pupil dilation / no pupil constriction

How do opioids cause nausea / vomiting?

stimulates chemoreceptor trigger zone inthe medulla

Peripheral effects of opioids

Constipation

Cardiovascular effects

Pruritis

How do opioids cause constipation?

increase smooth muscle tone

decrease propulsive motility though GI

True / False: urinary retention sometimes occurs with opioid due to increased smooth muscle tone

true

How do opioids cause pruritis?

Histamine release and central action on central pruritocetive neural circuits

How do opioids cause cardiovascular effects?

cause histamine release = peripheral vasodilation / orthostatic hypotension

True / False: opioids have minimal direct effects on heart rate and blood pressure

true - effects are secondary due to histamine release

Cerebral vasodilation is ---- to --- depression.

Can also increase ---

secondary to respiratory depression

can also increase CSF

Tolerance is a ---- of a drug as a consequence of prior exposure to that drug

decreased efficacy

Tolerance results in a --- shift of the dose response curve

rightward

True / False: Tolerance can develop to some effects of opioids but not to others

true

Tolerance can be overcome by --- the dose

increasing

Tolerance occurs when repeated use of opioids leads to a --- response to the same dose. Over time, --- are needed to achieve the same analgesic (pain-relieving) effect

reduced response

higher doses

What causes tolerance?

reduced efficacy

short duration of action

True / False: tolerance remains when the opioid is discontinued

false - tolerance is lost

What happens when opiates are given together?

cross tolerance

---- refers to the development of a new, atypical physiological state produced by repeated administration of a drug, which then makes its continued use necessary to prevent the appearance of a withdrawal syndrome

Physical dependence

Withdrawal reactions are usually the --- of the physiological effects produced by acute administration of the drug

opposite

Physical dependence --- after opioid is discontinued

decreases

Addiction is associated with significant --- dependence and is accompanied by compulsive drug --- and drug taking behaviors

psychological

drug seeking

---- alone does not fulfill the criteria for drug addiction

physical dependence

What is needed for an individual to be considered addicted to opioids?

psychological dependence

physical dependence

What is the diagnosis for opioid addiction?

opioid use disorder

What does profound opioid toxicity cause?

respiratory depression / cough suppression

Signs of an opioid overdose include ---, --- and decreased ---

stupor, miosis, and decreased respirations

What opioid receptor antagonist is administered to restore ventilation?

naloxone

Morphine is a --- receptor agonist

mu

Morphine is a --- and --- receptor agonist at high doses

kappa and delta

Morphine is a natural --- from opium derived from the poppy plant

phenanthrene alkaloid

Morphine is ---- absorbed after oral administration

well

What is the first pass effect of morphine?

large first metabolism in liver

How does first pass metabolism for oral medications occur?

drug travels from stomach to small intestine

absorbed in small intestine

takes portal vein to liver

metabolized by liver

reduced amount of active drug reaches circulation

What opioid has a large first pass metabolism?

morphine

What beta blocker has large first pass metabolism?

propranolol = b1/b2 nonselective antagonist

True / False: Like all opioid analgesics, morphine provides symptomatic pain relief only

true

How is morphine metabolized in the liver?

by glucoronidation

What does morphine become after glucoronidation by the liver?

morphine 6 glucoronide

Morphine 6 glucoronide has high affinity for --- opioid receptors

mu

What happens to morphine metabolites with chronic oral dosing of morphine?

morphine 6 glucoronide can exceed morphine

How is morphine eliminated?

glomerular filtration

What must happen to mophine 6 glucoronide before it is eliminated via glomerular filtration?

must be conjugated

True / False: morphine can accumulate in the tissues

false - once elimination is complete by glomerular filtration there is no morphine left

Morphine half life

2-4 hours

Morphine duration of action

3-5 hours

Morphine recommended dosing interval

q 4hours

Morphine IV to PO ratio

1:3

True / False: morphine causes increased biliary tract pressure

true

Opioid induced hyperalgesia

increased sensation of pain

Opioids induced hyperalgesia is associated with chronic administration of opioid analgesics especially --- and ---

morphine and fentanyl

Potential mechanisms of opioid induced hyperalgesia involve involve --- and activation of --- and --- receptor

spinaldynorphin

bradykinin and NMDA

Why is morphine not given during compromised respiratory status?

depresses pontine and medullary respiratory receptors

depresses brainstem center response to CO2

Why is morphine not given to patients with liver and kidney disease?

metabolized by liver

eliminated by glomerular filtration

Why is morphine not given to patients with head trauma?

indirectly increases CSF

impairs clinical picture

Why are opioids contraindicated in pregnancy?

cause physical dependence / respiratory depression

Why are opioids contraindicated in paralytic ileus and GI obstruction?

increase smooth muscle tone

decrease propulsive motility though GI

What happens to opioids if there is liver dysfunction?

increases plasma levels of opioid

not metabolized

What happens to opioids if there is a kidney dysfunction?

increases plasma levels of opioid metabolites

morphine --> morphine 6 glucoronide

morphine 6 glucoronide is not eliminated by the kidneys

Administration of a drug with mu opioid receptor agonist properties can produce which of the following effects?

A. Diarrhea

B. Mydriasis

C. Hypertension

D. Nausea

E. Anxiety

D. Nausea

Death due to acute opioid overdose is due to which of the following?

A. Convulsions leading to status epilepticus

B. Myocardial infarction

C. Respiratory depression

D. Atrial fibrillation leading to stroke

E. Acute pulmonary edema

C. Respiratory depression

Mu receptor activation causes:

respiratory depression

cough depression

miosis

euphoria

nausea / vomiting

what is the difference between chemical structure of morphine and codeine?

morphine = hydroxy group at 3 position = OH

codeine = methoxy group at 3 position = OCH3

Codeine is a natural --- from opium

phenanthrene alkaloid

What provides greater oral bioavailability of codeine compared to morphine?

methoxy (OCH3) instead of hydroxy group (OH)

Codeine is metabolized by ---

liver

Codeine can be metabolized to ---

morphine

Codeine is eliminated via ---

glomerular filtration (kidneys)

Indications / clinical use for codeine

oral analgesic for mild to moderate pain for ambulatory patients

antitussive

What is effective for relief of mild to moderate pain in ambulatory persons: morphine or codeine?

codeine