Pharmacology II Exam 2: Opiods

Brief hx of opioids:
All opioids are based off of?
Opium is the ?
Opiate is the ?
Opioid is the ?

*Opium
*brownish residue from the dried juice of poppy plant
*drug derived from opium - naturally occurring alkaloids: morphine, codeine, thebaine
*modern term for all substances (natural & synthetic) that bind to opioid receptors

how do opioid agonists work

blocks the ascending pathway via 1st and 2nd order neuron and engages the descending pathway via agonizing GABA (increasing cl)

what are the two main chemical classification groups of opioids and what is their structure?

1. benzylisoquinoline alkaloid - benzene ring not fused together
2. phenanthrenes-phenanthrene ring (3 fused benzene rings)

papaverine is the principle example of ____________________ that is a non-analgesic but an antispasmodic

benzylisoquinoline alkaloid

Morphine is a naturally occuring ___________ and is the principle active compound from opium used for pain

phenanthrene

_______ is the comparative for all agents and altered to make additional components

Morphine

if you substitute an ether for an alcohol of the phenanthrene nucleus of morphine you get _______________

codeine

_________________ was the first synthetic opioid

meperidine aka demerol

___________ is the prototype phenylpeperidine

meperidine

if you take morphine and split it between the 12th and 13th carbon to get a benzene connected to a 5 ring structure you get ____________ class of opioids

phenylpiperidine

T/F: synthetic opoids only have 2 of the original 5 rings of the basic morphine molecule

true

which drugs are your natural opioid agonists

1. morphine

2. thebaine

3. codeine

which drugs are your semi-synthetic opioid agonists

1. hydromorphone

2. heroine

3. oxymorphone

4. oxycodone

what are your synthetic opioid agonists

1. methadone

2. fentanyl

3. remifentanil

4. alfentanil

5. meperidine

6. sufentanil

7. tramadol

what are your semi-synthetic partial agonist opoids

buprenorphine

what meds are your synthetic partial agonists opioids

butorphanol (stadol)

which meds are your synthetic agonist-antagonist opioids

nalbuphine (nubane)

which meds are your semi-synthetic opioid anatagonists

naloxone & naltrexone

which meds are your synthetic opoid antagonists

nalmefene

which semi-synthetics are "morphine derivatives" (i.e. synthesized by making small changes to morphine molecule)

heroine, oxymorphone, and hydromorphone

if something is a "synthetic" opioid that means it contains the _______________ of morphine

phenanthrene nucleus

(generally) opioids are largely _________________ at physiologic pH

ionized (pKa > 7.45)

opioids primarily work _________

centrally

(generally) opioids are highly lipid ______________, weak _____________, and ______________ protein bound

soluble; bases; highly

what are the 3 opioid receptor classes

1. mu
2. kappa
3. delta

what are your endogenous opioid agonists

1. enkephalins
2. endorphins
3. dynorphins
4. nociceptin
5. endomorphin 1
6. endomorphin 2

opioid receptors are what type of receptors

G-coupled protein receptors

________________ are individual peptides that have their own specific precursors and share a common amino acid terminal sequence with a small variation

opioid agonists (endogenous & exogenous)

what is the amino acid terminal sequence all opioid agonists share

try-gly-gly-phe-met or leu

met or leu will be at the C-terminus

what is the terminal amino acid sequence of all opioid agonists called

the opioid motif or the opioid message

the specific amino acid sequence of the opioid agonist is necessary for what?

the endogenous agonists action with the receptor

Enkephalin is similar to the structure of _______

add more info on slide 12?

Morphine

G protein coupled receptor includes ____membrane loops that are both intracellular and extracellular.

7

3 opioid receptor subtypes share ___-___% sequence homology (same structure), Yet
diversity is greatest in the _______ loops/external portions of the protein and are thought to be
important in the discriminating between ligands

55-58
extracellular

describe the steps/effects at the cellular level of when a opioid agonist binds with a receptor

1. binding of opioid agonist with receptor - either endogenous or exogenous
2. activation of the G-protein
(3 distinct subunits)
3. produces inhibitory effects: (alpha) inhibits adenyl cyclase --> cAMP --> relaxes smooth muscle. Causes decreased conductance of Ca++ channels & opened K+ channels and Results in decreased neuronal excitation and inhibition of neurotransmitter/neuropeptide release; (alpha, beta & gamma) --> decreased Ca influx --> decreased neuronal excitation; (beta and gamma) --> increased K efflux --> hyperpolarization
4. results in membrane hyperpolarization and reduction of neuron excitability

abrupt withdrawal of opioid agonist can cause rebound disinhibition of __________________

cAMP

abrupt withdrawal of opioid receptor agonist --> disinhibition of cAMP --> what s/sx

1. increased irritability
2. restlessness
3. tremors
4. chills
5. muscle cramps
6. sweating
7. mydriasis
8. abdominal pain
9. diarrhea
10. increased HR

where are the opioid receptor locations in the brain

1. periaquaductal gray
2. limbic system
3. area postrema
4. cerebral cortex
5. thalamus

where are the opioid receptor locations in the spine

substantia geletanosa of the dorsal horn

where are the opioid receptors located in the GI system

intestines

Opioid receptors are also located in the? (4)

1. Vasculature
2.Heart
3. Lung
4. Immune system

_______________ analgesia occurs through activation of the opioid receptors in the brain that cause inhibition of the nerves involved in pain pathways- the message is not propagated anymore.

supraspinal

In supraspinal analgesia, the brainstem modulates ______transmission via inhibitory pathways of the ______.

nociceptive
spinal cord

_______________ analgesia occurs via activation of the presynaptic opioid receptors in the spine decreasing release of the neurotransmitters of the nociception

spinal

supraspinal analgesia + spinal analgesia =

synergistic pain relief

brainstem modulates nociceptive transmission via ________________ pathways of the spinal cord

inhibitory

opioid receptors in the _______________ inhibits the release of substance P and blocks the transfer of pain upwards

spine

opioid receptors in the GI --> __________________; and in the GU --> ________________

constipation/post-op ileus; increased urinary sphincter tone --> urinary retention

mu will cause ____________________ analgesia and kappa will cause _______________ analagesia

supraspinal & spinal; supraspinal & spinal

mu receptors cause what CV effects? kappa causes what CV effects

mu = bradycardia
kappa = no CV effects

respiratory effects of mu? kappa?

mu = respiratory depression
kappa = possible depression if high dose

CNS effects of mu

1. euphoria
2. sedation
3. prolactin release
4. mild hypothermia
5. catalepsy
6. indifference to environmental stimulus

CNS effects of kappa

1. sedation
2. dysphoria
3. psychomimetic reactions (delirium, hallucinations)

effect of mu and kappa on the pupil

miosis

which opioid receptor if activated will inhibit peristalsis, and cause N/V?

mu

which opioid receptor when agonized causes urinary retention? which receptor causes diuresis d/t inhibition of the vasopressin release

mu; kappa

which opioid receptor if activated causes pruritus

mu

_________ opioid receptors have high risk of physical dependence, and _______ receptors have a low abuse potential

mu; kappa

What opioid receptor is involved with antishivering?

Kappa

The delta receptor has what effects?

Resp depression
Urinary retention
Pruritus
physical dependence

which endogenous opioid ligands agonize the mu receptor

1. B-endorphin
2. endomorphin

which naturally occurring opioid ligand agonizes the kappa receptor

dynorphin

Which naturally occurring opioid agonizes the Delta receptor

Leu- Enkephalin
Met-Enkephalin

what are the different routes of opioid administration?

1. oral

2. nasal

3. transdermal

4. IM/IV

5. intrathecal

6. epidural

7. suppository

opioids absorption is _____________ orally, due to extensive _________________. Often why PO dose is much higher.

modest; first pass

the more _________________ an opioid is the __________ the absorption through nasal mucosa, oral mucosa and skin.

lipophillic; increased

opioids are distributed throughout the body via the _________ compartment model

2 (Vessel rich group)

metabolism of opioids

liver via cyp450 - some have active metabolites

The exception is ________ that is metabolized in the blood by esterase

remifentanil

generally primary excretion of opioids = ______________ and secondary = _______________

kidney; biliary system & GI tract

differences in use of opioids r/t anesthesia practice

1. higher analgesic requirement
2. co-administration of potent anesthetics and sedative agents
3. require the ability to support respirations until emergence

small dose opioids will have a termination of DOA by ________________

redistribution into peripheral compartments

larger doses/multiple doses/continuous infusions of opioids DOA is more dependent on __________________

metabolism

________________ is a key factor in if the effect of an opioid is therapeutic or adverse

Clinical setting

**Sedation from the mu receptor may be part of the therapeutic intent (OR) versus being an adverse effect (ER).

Opiods also dependent on?

•Body weight
•Renal failure
•Hepatic failure
•Cardio-pulmonary bypass
•Acid-base changes
•Hemorrhagic shock

considerations with the pharmacokinetics of opioids (7)

1. Narrow therapeutic index
2. balance btwn optimizing pain control and sedation
3. respiratory depression
4. variability between patients- dose and DOA
5. patients perception of pain - hx of chronic pain, opioid use? etc.
6. severity and duration of pain
7. lifestyle - smoking? etoh? illicit drug use?

what are the therapeutic effects of mu agonists (3)

1. pain relief (spinal and supraspinal)
2. sedation
3. anti-tussive

mu agonists are good for txing ___________ pain sensations, but less effective for ___________ pain sensations

"second pain" (c-fibers); "first pain" (A-delta)

Opioids provide a _____Dependent effect on drowsiness/sleep

dose

T/F: opioids can be used as a sole anesthetic

false; they do not reliably produce unresponsiveness and are not an anesthetic

T/F: The antitussive effect of Mu agonists suppress the cough center of the medulla (decreases the stimulation) but does not take away the cough

True

there is a risk for _____________________ reaction of increase in _______________ with bolus dosing opioids

paradoxical; coughing

what are the adverse effects of opioid agonists (13)

1. euphoria --> abuse
2. N/V
3. miosis --> pupillary constriction
4. vasodilation
5. bradycardia
6. ventilatory depression
7. increased biliary pressure
8. muscle rigidity
9. pruritus
10. delayed gastric emptying
11. ileus/constipation
12. urinary retention
13. depressed cellular immunity



**make sure all details form slide 20 on individual system cards

opioid CNS effects

1. sedation and eupohoria (mu) *both dependent on agent and receptor*
2. dysphoria (kappa) receptors or opioids taken in the absence of pain
3. analgesia
4. minimal effect of neuromonitoring
5. potential for increased ICP --> respiratory induced hypercarbia

analgesic MOA of opioid within the CNS

1. inhibit ascending transmission of nociceptive stimuli from the dorsal horn of SC
2. activate pain control pathways from the midbrain via the rostral ventromedial medulla to the spinal cord dorsal horn

opioids are most effective for continuous ____________ dull pain. At high doses, opioids will relieve _____pain.

visceral
any

undesired CNS effects of opioids (4)

1. dependence
2. tolerance/cross tolerance
3. awareness
4. hyperalgesia

Dependence of the drug can be _____&______. They need the drug to function properally

Physical and Psychological

_______________ to opioids begins with a decrease in DOA followed by decrease in effect. Chronic tolerance may involve?

tolerance
desinsitization? Down regulation?

There are lots of theories r/t tolerance that includes?

•Not due to altered receptor number
•Receptor internalization
•Activation of NMDA receptors
•2nd messenger changes
•G-protein uncoupling (changes in the binding sites)

Awareness: Mu agonists are ______anesthetics and do not reliably produce unresponsiveness or amnesia

NOT

Hyperalgesia can include?

*Increased Sensitivity to pain
*Damage to nociceptors or peripheral nerves
(Ex. degloving)

**Remifentanil can cause this

what is the most significant adverse effect of opioids

depression of ventilation

who is at increased risk of respiratory depression with use of opioids

1. High dose opioids
2. advanced Age
3. CNS depressants
4. renal insufficiency
5. Morphine sulfate
6. sleep: natural sleep depresses the response to co2 and potentiates resp depression caused by opioids

T/F: respiratory depression 2/2 opioid use is not an issue intraoperatively when the airway is secured and ventilation is controlled

true. Life threatening in post op period. Morbidly obese or OSA PTS are at increased risk of M and M

opioids will depress the response to ____________ and ____________ which results in a _____________ shift of the co2 responsive curve depressing the hypoxic drive to breathe

increased CO2; decreased O2; right

T/F: tolerance to opioids will decrease the miosis pupillary response

false; tolerance does not effect miosis with use

what is though to cause miosis with opioid use

1. opiate depression of GABA -->
2. stimulation of edinger-westphal nucleus -->
3. PNS signals via ciliary ganglion
4. stimulation of the oculomotor nerve to constrict

T/F: miosis with opioid use is reversible with narcan

true

Is miosis a qualitative or quantitative sign?

Qualitative