Pharm - Opiods

Question 1

Physiologic pain

Answer 1

Serves a defensive role
Acute in nature (e.g. labor, surgery and acute trauma)
Easy to manage

Question 2

Pathological Pain

Answer 2

Serves no known beneficial purpose. Chronic in nature, spontaneous, Characterized by: Low pain threshold to both noxious and innocuous stimuli. Associated with nerve damage (e.g. trauma, amputation, diabetes mellitus, HIV and varicella zoster VZV )
Difficult to treat

Question 3

Ascending Pathway for pain transmission

Answer 3

Primary afferent nociceptors -> Dorsal horn cells -> spinothalamic tracts -> VPM -> Cortex

Question 4

Descending Pathway (Inhibitory Regulation)

Answer 4

Originates from frontal cortex, amygdala and cingulate cortex. Synapse on the Periaqueductal gray (PAG), then Rostral ventromedial medulla (RVM) and finally on the dorsal horn cells

Major neurotransmitters include 5HT, norepinephrine, glycine, GABA and opioids

Question 5

Receptor subtype

u (mu)

Answer 5

1. Supraspinal and spinal analgesia
2. Sedation and inhibition of respiration
3. Slow GI transit
4. Modulation of hormones and neurotransmitter release

Physiology:
Stabilize neuronal membrane secondary to enhancing K+ conductance (hyperpolarizing neuron), inhibition of voltage-gated Ca2+ channels

Question 6

Receptor subtype

d (delta)

Answer 6

1. Supraspinal and spinal analgesia
2. Modulation of hormones and neurotransmitter release

Physiology:
Stabilize neuronal membrane secondary to enhancing K+ conductance (hyperpolarizing neuron), inhibition of voltage-gated Ca2+ channels

Question 7

Receptor subtype

k (kappa)

Answer 7

1. Supraspinal and spinal analgesia
2. Slow GI transit
3. Psychomimetic effects

Physiology
κ-Opioid receptor activation by agonists is coupled to the G protein Gi/G0, which subsequently increases phosphodiesterase activity. Phosphodiesterases break down cAMP, producing an inhibitory effect in neurons

Question 8

Strong Agonists

Answer 8

Morphine, Heroin, Methadone, Fentanyl, Meperidine, Levorphanol

Question 9

Mild to Moderate Agonists

Answer 9

Codeine, Oxycodone, Hydrocodone, Diphenoxylate

Question 10

Weak Agonist

Answer 10

Propoxyphene

Question 11

Mixed Agonists /Antagonists

Answer 11

Pentazocine

Question 12

Partial Agonists

Answer 12

Buprenorphine

Question 13

Antagonists

Answer 13

Naloxone, Naltrexone,

Question 14

Codeine

Answer 14

Naturally Occurring Opioids
Mild to Moderate Agonists

undergoes hepatic de-amination to morphine
genetic polymorphism of CPY2D6 and CPY3A4 of clinical significance
oxycodone, hydrocodone, effective mild analogues of codeine

Question 15

Morphine

Answer 15

Naturally Occurring Opioids
Strong Agonists
Hepatic metabolism to M3G or M6G, (M6G has analgesic effects)
Hydromorphone, widely used more potent morphine derivative

Question 16

Methadone

Answer 16

Synthetic Opioid receptor Agonist
Strong Agonists

Long plasma t½ (lipophilic, plasma protein binding) , used mostly for chronic pain in terminally ill cancer patients

High risk of respiratory depression, QT prolongation → torsades de pointes

Question 17

Meperidine

Answer 17

Synthetic Opioid receptor Agonist
Strong Agonists

Poor oral bioavailability, metabolites may cause seizures
Similar analgesic efficacy as morphine, less potent
Causes mydriasis rather than miosis – unlike other opioids

Question 18

Fentanyl

Answer 18

Synthetic Opioid receptor Agonist
Strong Agonists

Short acting, 100x more potent than morphine, highly lipophilic
Sufentanil, alfentanil and ramifentanil are synthetic analog
Available in transdermal patch for slow delivery

Question 19

Butorphanol

Answer 19

Mixed Agonists / Antagonist

Agonist at κ, partial agonist at u-opioid receptor
Analgesia with milder euphoria
Clinical applications:
treatment of opioid addiction
Maintenance in balance anesthesia, labor pain

Question 20

Buprenorphine

Answer 20

Partial Agonists

Partial agonist at µ, antagonist at κ-opioid receptors
Clinical applications:
Pain, chronic (moderate or severe), long-term management of pain

Question 21

Nalbuphine

Answer 21

Mixed Agonists / Antagonist

Agonist at k, antagonist at u
Effective analgesic, (moderate to severe pain), preoperative, postoperative, obstetrical analgesia
high psychological dysphoria may occur

Question 22

Naloxone

Answer 22

Opioid Receptor Antagonists

Competitive antagonist at u, and κ-opioid receptors, t½ is shorter than that of morphine
Administered parenterally
antidote for opioid intoxication / overdose – known or suspected
Reversal of opioid activity (respiratory distress)

Question 23

Naltrexone

Answer 23

Opioid Receptor Antagonists

Administered orally, can be used in outpatient settings
Pure competitive opioid antagonist
For treatment of opioid dependence, relapse, following detoxification, prophylaxis
Alcohol withdrawal

Question 24

Untoward Effects of Opioids

Dependence

Answer 24

Psychological
Distinct from physical dependence or analgesia and is mediated by a different neuronal system (ventral striatum)
Involves interactions between the opioids and dopaminergic system (nucleus accumbens)

Physical
Marked with diaphoresis, insomnia, restlessness, abdominal cramps, nausea, vomiting and diarrhea

Question 25

Untoward Effects of Opioids | Tolerance

Answer 25

mediated (at least in part) via NMDA signaling Mainly cosmetic in nature Rotation therapy may be helpful Minimal or no tolerance Miosis and Constipation Moderate tolerance Bradycardia ``` High Tolerance (most likely to down regulate) Analgesia, Euphoria, dysphoria, Mental clouding, sedation, Respiratory depression, Anti diuresis, Nausea and Vomiting, Cough suppression ```

Question 26

Untoward Effects of Opioids | Respiratory depression

Answer 26

Respiratory depression Decrease sensitivity of chemo-sensitive neurons to PCO2 Occurs at therapeutic doses (unlike case with CNS depressants) Most common cause of death in acute opioid poisoning

Question 27

Untoward Effects of Opioids | GI Disturbances

Answer 27

GI Disturbances Epigastric distress & biliary colic (may be confused with angina) increase tone of pyloric sphincter and enhance and decrease peristaltic movements Constipation is common opioid side effect

Question 28

Untoward Effects of Opioids | Miosis

Answer 28

``` Miosis Independent of tolerance A diagnostic tool u and k-mediated Involves the nucleus of Edinger Westphal ``` Exception is Meperidine which causes Mydriasis

Question 29

Untoward Effects of Opioids | Nausea and vomiting

Answer 29

Nausea and vomiting Often transient, can limit compliance Involves the area postrema

Question 30

Untoward Effects of Opioids | Hypotension and bradycardia

Answer 30

Impairment of sympathetic compensatory responses → orthostatic hypotension (e.g. with morphine) common with rapid iv administration of large doses of opioids (courtesy of non-specific mast cell degranulation) Synthetic opioids (meperidine, diphenoxylate, fentanyl) and short-acting opioids do not evoke histamine release

Question 31

NSAIDs and acetaminophen

Answer 31

Decrease prostaglandin synthesis, decrease pain sensation

Question 32

Adrenergic agonists

Answer 32

Clonidine, effective in both acute and chronic pain state

Question 33

NMDA receptor antagonists

Answer 33

Ketamine and dexamethorphan (for chronic pain syndrome and post operative pain) Ketamine, effective for acute severe pain, strong psycho mimetic effects

Question 34

Antidepressants

Answer 34

Amitriptyline, nortriptyline and imipramine Treatment of chronic pain not responsive to opioids Venlafaxine and duloxetine, used for neuropathic pain

Question 35

Gabapentin

Answer 35

Synthetic GABA analog, inhibits voltage-gated Ca2+ channels Widely used for chronic pain and post-operative pain state Erratic oral bioavailability – a problem

Question 36

Pregabalin

Answer 36

GABA analog, more potent, faster on set of action, predictable bioavailability than gabapentin Inhibits voltage gated Ca2+ channels in the CNS Effective in neuropathic pain, fibromyalgia, spinal cord injury

Question 37

Lamotrigine

Answer 37

Na+ channel blocker, for neuropathic pain, trigeminal neuralgia Skin reaction is common with its use

Question 38

Carbamazepine

Answer 38

Na+ channel blocker, primarily for treatment of trigeminal neuralgia may cause hypotension