Test 4: Opioids Basic Overview & Pharmacokinetics

Question 1

What are the 2 main groups of Opioids?

Answer 1

-Benzylisoquinoline Alkaloids
-Phenanthrenes

Question 2

What are the Benzylisoquinoline Alkaloids?

Answer 2

-Muscle relaxants. No analgesic properties
-Structure is based on benzene ring - 6 carbons
-Ex: Papaverine. Non-Analgesic, antispasmodic

Question 3

What is the chemical structure of the Phenanthrenes?

Answer 3

-3 fused benzene rings (called a Phenanthrene Ring)
-C6H6: 6 carbons in a ring each with 1 hydrogen

Question 4

What is the example drug of the Phenanthrenes?

Answer 4

Morphine: Naturally occurring
-Principle active compound from Opium
-Comparison for all other agents
-Strong agonist useful in treating severe pain.
-Hydromorphone and oxymorphone are also in this class

Question 5

How does Codeine differ in chemical structure from Morphine?

Answer 5

Substitution of an ether for one of the alcohols of the phenanthrene nucleus

Question 6

What is the Phenylpiperidine Class?

Answer 6

Synthetic drugs created by breaking the chemical bonds of morphine and restructuring them.
-Only have 2 of the original 5 rings of the basic morphine molecule.
-Fentanyl, Alfentanil, Remifentanil, Sufentanil, and Meperidine.
-Meperidine was the 1st synthetic opioid.

Question 7

What are the example drugs of the Semi-Synthetic opioid agonist class?

Answer 7

-Hydromorphone (Dilaudid)
-Heroine
-Oxymorphone
-Oxycodone

Question 8

What is Nalbuphine (Nubain)?

Answer 8

A synthetic agonist-antagonist.
-Agonizes Kappa receptors (helpful in pain response without causing respiratory depression. Has a ceiling effect)
-Antagonizes Mu receptors
-Useful in OB (maintains respirations)
-DO not use if hx of recovering narcotic addiction

Question 9

In general, what are the basic pharmacokinetic principles of opioids?

Answer 9

-Highly lipid soluble
-Weak bases
-Highly protein bound
-Largely ionized at physiologic pH (pKa is > 7.4)

Question 10

What are the endogenous opioid agonists?

Answer 10

-Enkephalins, endorphins, and dynorphins.
-All share a common amino acid terminal sequence with a small variation\
-Terminus part is what varies, and that is what makes it an opioid receptor agonist.
-Newer discoveries: Nociceptin, Endomorphin 1 & 2

Question 11

What is the “opioid motif” or “opioid message”?

Answer 11

Try-Gly-Gly-Phe – Met or Leu
-necessary for interaction at the receptor site

Question 12

Describe the cellular MOA of opioids.

Answer 12

1) Opioid agonist binds to the GPCR.
2) The GPCR becomes active (has 3 subunits: Alpha, beta, and gamma)
3) Inhibitory effects are produced
-Alpha: Inhibits adenylyl cyclase = dec cAMP
-Beta & Gamma: Inhibits VG Ca channel = dec Ca influx
-Also K+ efflux is increased = hyperpolarization
4) All of these inhibitory effects result in membrane hyperpolarization and reduction of neuronal excitability.

Question 13

What is different between the 3 opioid receptor subtypes?

Answer 13

They are all GPCRs: have 7 transmembrane loops (both intra and extracellular)
-The 3 opioid receptor subtypes share 55%-58% sequence homology (same structure)
-Diversity is greatest in the extracellular loops/external portions of the protein
-External loops are thought to be important in the discriminating between ligands

Question 14

Describe the inhibitory effects that result from opioid stimulation of the Alpha subunit on the GPCR?

Answer 14

-Inhibition of Adenylyl Cyclase = Decreased cAMP
-Causes decreased conductance of Ca++ channels & opened K+ channels
-Results in decreased neuronal excitation and inhibition of neurotransmitter/neuropeptide release
-Harder for postsynaptic side to respond to an AP. Interrupting pain signaling.

Question 15

Abrupt withdrawal of opioids can cause a rebound disinhibition of cAMP, causing what side effects?

Answer 15

Increased irritability
Restlessness
Tremors
Chills
Muscle cramps
Sweating
Mydriasis
Abdominal Pain
Diarrhea
Increased HR

Question 16

Where are opioid receptors located in the Brain?

Answer 16

-Periaqueductal Gray
-Area Postrema
-Limbic System
-Cerebral Cortex
-Thalamus

Question 17

Where are opioid receptors located in the Spine?

Answer 17

Substantia Gelatinosa of the Dorsal Horn.
-Spinal analgesia occurs by activation of presynaptic opioid receptors, which leads to decreased calcium influx and decreased release of neurotransmitters involved in nociception.

Question 18

Where are opioid receptors located in the Peripheral Nervous System (PNS)?

Answer 18

-GI tract (constipation)
-Vasculature
-Lungs
-Heart
-Immune system

Question 19

How does Supraspinal Analgesia occur?

Answer 19

Brainstem modulates nociceptive transmission via inhibitory pathways of the spinal cord.
-Occurs through activation of the opioid receptors in the brain that cause inhibition of the nerves involved in pain pathways
-Descending signals to block pain sensors or modulate response in some way.

Supraspinal analgesia occurs through activation of opioid receptors in the medulla, midbrain, and other areas, which causes inhibition of neurons involved in pain pathways.

Question 20

How does Spinal Analgesia occur?

Answer 20

-Occurs via activation of presynaptic opioid receptors in the spine decreasing release of the neurotransmitters of nociception
-Involved in sending pain signals up to the thalamus to be interpreted. Can block the transfer of pain signals upwards
-Pain signals travel to the thalamus via the dorsal horn and the spinothalamic tract.
-Inhibits the release of Substance P.

Question 21

T/F: Supraspinal + spinal = synergistic pain relief

Answer 21

True

Question 22

What are the effects caused by Mu Receptor stimulation?

Answer 22

-Supraspinal & Spinal analgesia
-Bradycardia
-Respiratory Depression
-Euphoria, Sedation, Prolactin release, mild hypothermia, catalepsy, indifference to environmental stimulus
-Miosis
-Inhibition of GI peristalsis; N/V
-Urinary retention
-Pruritus
-Physical dependence

Question 23

What are the effects caused by Kappa Receptor stimulation?

Answer 23

-Supraspinal & Spinal analgesia
-Possible respiratory depression (would need a significant dose to achieve)
-Sedation, dysphoria, psychomimetic reactions (hallucinations, delirium)
-Miosis
-Diuresis (inhibition of vasopressin release)
-Low abuse potential
-Anti-shivering

Question 24

What is Dysphoria?

Answer 24

A distorted sense of impending doom.

Question 25

What are the endogenous ligands of the Mu Receptor?

Answer 25

-B-Endorphin
-Endomorphin

Question 26

What is the endogenous ligand of the Kappa Receptor?

Answer 26

Dynorphin

Question 27

What are the routes of administration for opioids? (Blue Box)

Answer 27

-IM/IV
-Intrathecal
-Epidural
-Oral
-Suppository
-Nasal
-Transdermal

Question 28

Describe the Absorption of Opioids?

Answer 28

-Modest oral absorption
-Extensive 1st pass metabolism via the Liver (reduces therapeutic efficacy of oral dosing). Oral dose > Parenteral dose
-Increased Lipophillic = inc absorption via nasal/buccal mucosa and the skin.
-Well absorbed via mucus membranes, slower in skin.
-

Question 29

What are the differences between Surgical Requirements for analgesic drugs and Non-operative uses of these drugs?

Answer 29

-Higher analgesic requirement (high stimulation)
-Co-administration of potent anesthetics and sedative agents (Might need decreased MAC).
-Require the ability to support respirations until emergence (in larger doses). Have safety equipment available.

Question 30

Describe the Distribution of Opioids.

Answer 30

Opioids are distributed via the 2-Compartment Model.
-Vessel-rich group receives it first (Brain, lungs, liver, kidneys, spleen)

Can accumulate in fatty tissues with frequent high-dose administration or continuous infusion of highly lipophilic opioids that are slowly metabolized, eg, fentanyl.

Question 31

How does termination (offset) differ between small or large doses of opioids?

Answer 31

When small doses of the opioids are used, the effects are usually terminated by redistribution rather than metabolism. Larger or multiple doses or continuous infusions are much more dependent on metabolism for offset.

Question 32

How are opioids metabolized?

Answer 32

In the Liver by both Phase 1 and Phase 2 processes.
-Converted to more polar/less active compounds
-Metabolized by CYP

Question 33

Which opioids have Active Metabolites?

Answer 33

-Morphine: M6G (more potent than Morphine)
-Meperidine: Normeperidine (neurotoxic)

Can increase the DOA, especially in setting of Renal Failure

Question 34

How is Remifentanil metabolized?

Answer 34

Remifentanil was designed with an ester group in its structure and is metabolized by hydrolysis in the plasma and tissues by nonspecific esterases.

Question 35

How are opioids excreted?

Answer 35

-Primarily by the kidneys
-Secondarily by the biliary system and GI Tract

Question 36

How does clinical setting change the effects of opioids? (Blue Box)

Answer 36

Clinical setting is a key factor.
-Sedation from the mu receptor may be part of the therapeutic intent (OR) versus being an adverse effect (ER).

Question 37

Describe the therapeutic index of opioids.

Answer 37

Narrow therapeutic index
-Fine line to balance optimizing pain control and sedative effects (without causing respiratory depression)
-Recognize that there is great variability from patient to patient in response (DOA) and dose requirements.

Question 38

What factors can affect a patient’s perception of pain?

Answer 38

-History of chronic pain/chronic opioid use
-Severity and duration of pain
-Lifestyle habits like smoking, alcohol intake, illicit drug use

Question 39

What are other patient characteristics that can affect the pharmacokinetics/dynamics of opioids?

Answer 39

-Age: elderly need lower dose
-Body weight
-Renal failure
-Hepatic failure
-Cardio-pulmonary bypass
-Acid-base changes
-Hemorrhagic shock