Opioid

Question 1

Enkephalins

Answer 1

Endogenous opioid
Precursor: proenkephalin
Leucine and methionine enkephalins have wide CNS distribution (especially in interneurons, including those in pain pathways)
Most selective for delta receptor and somewhat for Mu
Work on presynaptic and postsynaptic Mu opioid receptors- hyperpolarization

Question 2

Opioid Pharmacology

Answer 2

Analgesia- most are full agonists and equally effective except codeine and propoxyphene and decrease perception and appreciation of pain
Cough Suppression- codeine and dextromethorphan; directly suppress the brainstem cough centers but may not be mediated by opiate receptors
Anti diarrheal effect and constipation- central and peripheral effects, Mu receptors on GI nerves
Euphoria (rush, high)
Sedation
Respiratory Depression- most serious side effect; decrease in sensitivity of brainstem chemoreceptors to CO2
Nausea- stimulation of chemical trigger zone in area postrema and more when standing
Endocrine effects- decrease LH (Mu effect) and increased ADH secretion- Mu and decrease ADH- kappa
Pupillae constriction- miosis (stimulation of EW nucleus of occulomotor and no tolerance possible)
Peripheral Vasodilation, reduced peripheral resistance, inhibition of baroreceptors reflex- Orthostatic hypotension fainting possible when supine patients assume head up position (release of histamine to cause vasodilation and blunting of vasoconstriction in response to increased Pco2)

Question 3

Functional affects of acute and chronic opioid use

Answer 3

Desensitization (acute tolerance)- minute to hours; mediated by receptor phosphorylization and then internalization (agonist dependent to enkephalins cause rapid but morphine no internalization); uncoupling from G -protein

Tolerance: (days to weeks) right shift in dose-effect curve (need higher dose for same effect) and reversible with removal of the drug
Incomplete cross-tolerance (if on morphine for many years then substitute another drug- get only some tolerance to new drug)
Effects- rapid (nausea and vomiting), more gradual (analgesia, euphoria, respiratory depression, endocrine), Little or none (miosis, constipation)

Dependence: state of adaptation and revealed by drug withdrawal or antagonist treatment, withdrawal produces opposite symptoms of acute exposure (somatomotor and autonomic outflow increased and get hyperalgesia, hyperthermia, pupillary dilation and aversion)

Addiction- not same as dependence, compulsive use and overwhelming involvement with procurement and use, drug seeking/taking occurs in spite of adverse consequences

Question 4

Effects of Opioid Drugs

Answer 4

Analgesia 
Cough suppression 
Anti diarrheal/constipation
Resp depression
Peripheral vasodilation, reduced peripheral resistance, inhibition of baroreceptors reflexes
Nausea
Pupillary constriction
Sedation
Euphoria
Endocrine effects
Increased biliary pressure

Question 5

Fentanyl

Answer 5

Selective at Mu receptor 
No release of histamine from mast cells
Structurally related to meperidine 
100 times as potent as mrophoine 
Short acting- 1 to 1.5 hours 
Available in injectable form and transdermal patches

Question 6

Suboxone

Answer 6

Buprenorphine plus Naloxone

Question 7

Naloxone

Answer 7

Non selective antagonists with most activity at Mu and less for Kappa and less at Delta (works at all 3)
Poor bioavailability
Much greater activity parenterally than orally
Short duration: 1-2 hours
Used: to treat opioid overdoses (rapidly reversed even if on the verge of death) and start with small doses and titrated up; also used in drug diversion (oral/sublingual preparations of opioid agonists or partial agonists to prevent euphoria when injected)
Combined with opioids to decrease parenteral abuse liability
Component of newer treatment for addiction- suboxone

Question 8

Treatment of Opioid abuse

Answer 8

Methadone (slow acting Mu agonist-orally)
Suboxone (buprenorphine/naloxone- sublingual)
Naltrexone (overtime see craving opioid and drugs like alcohol so reduce this craving)

Symptoms: euphoria, craving, drug seeking behavior, withdrawal, low in clinical settings

Question 9

Salvinorin A (Salvia)

Answer 9

High selective at Kappa receptor

Question 10

Oxycodone

Answer 10

More efficacious and useful for moderate to sever pain
Abuse problems
Available as sustained release oral preparation

Question 11

Meperidine

Answer 11

A phenylpiperidine
Shorter duration of analgesia than morphine
Forms toxic metabolite, normeperidine that can accumulate with frequent use
Interact with MAO inhibitor

Question 12

Endorphins

Answer 12

Endogenous opioid
Precursor is POmC
Beta endorphin in hypothalamus and nucleus tract us solitaries
Also in anterior pituitary: co-released with ACTH during stress
Highly selective at both Mu and Delta receptors

Question 13

Dextromethorphan

Answer 13

D-isomer of levorphanol
Not a Mu agonist
Cough suppressant
NMDA receptor antagonist

Question 14

Nalbuphine

Answer 14

Antagonist of Mu and agonist at Kappa
Similar in efficacy and potency to morphine
Little europhoria and low abuse potential
Can precipitate withdrawal in opiate dependent patients
Available only by injection

Question 15

Hydromorphone

Answer 15

Agonist at opioid receptor

2-3 times as potent as morphine

Question 16

Opioid Pharmacokinetics

Answer 16

Oral absorption and bioavailability varies y compound (poor for morphine and naloxone where oral potency is 1/3 of parenteral)
Onset of action related to lipophilicity
Duration of action relegated to both lipophilicity and elimination rate
Ultimately metabolized by liver to more polar and less active metabolites

Question 17

Tramadol

Answer 17

Weak Mu agonist
Block NE and serotonin uptake
Mild and moderate pain
Available for oral use including sustained release preparation

Question 18

Dynorphins

Answer 18

Precursor: prodynorphin
Dynorphin A co-localized with vasopressin in magno cellular cells of hypothalamus and posterior pituitary
Shorter dystrophies have wide CNS distribution; some are associated with pain pathways, especially in the spinal cord
Most selective for Kappa receptors and some at Mu receptor

Tyr-Gly-Gly-Phe-Met (consensus sequence)

Question 19

Hydrocodone

Answer 19

Moderate to severe pain
Often in combination with NSAIDs or acetaminophen
Available as sustained release oral preparation- Major abuse problem

Question 20

Codeine

Answer 20

Low selectivity at Mu and Delta
Cough suppression
Converted to active drug by metabolism to morphogenetic
For mild to moderate pain and morphine like efficacy not achievable
Used with aspirin or acetaminophen

Question 21

Morphine

Answer 21

Selective at Mu
Poor oral bioavailability
Low oral to parenteral potency- 1/3 bioavailability
Available as injectable, oral and oral sustained and suppository form
Duration of analgesia is 4-5 hours

Question 22

Buprenorphine

Answer 22

Mixed action (stimulation of receptors but not to same degree as full agonist)
Partial agonist at Mu opioid receptor (25 to 50 times greater potency than morphine)
Antagonist at kappa receptor
Help people with opioid dependence problems (not used clinically)
Used to treat moderate to severe pain and a transdermal patch is available
Orally combined with naloxone (antagonist at all three opioid receptors) and is used to treat opioid dependence - Suboxone=Naloxone and Oral buprenorphine

Question 23

Proxyphene

Answer 23

Agonist of opioid receptor

Withdrawn from US market because of cardiac arrhythmias

Question 24

Methadone

Answer 24

Full agonist at Mu opioid receptor
Wean people off of the other drugs like heroine and morphine
Good bioavailability and absoprtion
Chemically a phenylheptylamine
Longer duration of action
Equipment with morphine
Used in treatment of opioid abuse and chronic pain

Question 25

Heroine

Answer 25

Fast onset of action because very lipophilic
Intravenous
Converted to active drug like morphine and diacetlymorphine
High abuse potential

Question 26

Opioid Receptor Signaling

Answer 26

Mu, delta, kappa: all are GI coupled
Effects: open K channels and cause hyperpolarization (posysnaptic), reduce NT release through decrease in cAMP and Ca entry blocked (presynaptic effect)
Mu: supra spinal and spinal analgesia, sedation, inhibition of respiration, slowed GI transit, modulation of hormone release
Delta: supra spinal and spinal analgesia, modulation of hormone and NT release
Kappa: supra spinal and spinal analgesia, psychotomimetic effects, slowed GI transit

Question 27

Naltrexone

Answer 27

Antagonist with most selectivity at Mu and Kappa and less at delta
Orally active with long half life (24+ hours)
Used in treatment of alcoholism and opiate addiction (not used for overdose)