Lecture 6: Opioid Agonists and Antagonists

Question 1

Three main subtypes of Opioid Receptors?

Answer 1

Mu (u), Kappa (K), and Delta

Question 2

Higher affinity

1. Mu Receptor?
2. Kappa?
3. Delta?

Answer 2

1. Endorphins > Enkephalins > Dynorphins
2. Dynorphins&raquo_space; endorphins and enkephalins
3. Enkephalins > endorphins and dynorphins

Question 3

1. At the Presynaptic Terminal, Mu and Kappa and delta receptors do what 2 things?
2. At Postsynaptic Neuron, Mu receptors cause what to occur?

Answer 3

1. Decrease gCa2+, and decrease transmitter release (ACH, NE, Glutamate, 5HT, Substance P)
2. Increase gK+ and thus an IPSP (producing hyperpolarization and inhibition of postsynaptic neurons)

Question 4

1. Activation of Mu Receptors produces 3 effects of opiates, as well as what else?

Answer 4

1. Analgesic, Euphoric, and Sedative effects, as well as most of their UNTOWARD SIDE EFFECTS

Question 5

1. Activation of KAPPA Receptors may contribute to what?
   a. Esp in whom?
   b. Frequently causes what?
   c. Drugs that bind to KAPPA Receptors may have what?

Answer 5

1. ANALGESIA
   a. in Women
   b. DYSPHORIA
   c. a Lower Addiction Potential

Question 6

Delta and Sigma, may contribute to what effects of Opiates?

a. Which is NOT an OPIOD RECEPTOR?

Answer 6

Dysphoric

a. SIGMA

Question 7

1. Afferent Pain neurons cross midline of spinal cord and ascend in what 2 tracts?

Answer 7

Spinoreticular or Spinothalamic Tracts which Synapse in different regions of the THALAMUS

Question 8

Overall Effects of Opioid Agonists

1. Inhibition of what Pain Transmitting Systems?
2. Stimulation of what systems?
3. important binding sites of Opiates are found in what pathways?
4. Inhibition of what pathway that would normally decrease activity of the Descending pain inhibition pathway.
5. Systemic Administration of Opioids may also cause a release of what?

Answer 8

1. Ascending Pain Transmitting Systems
2. of Descending Systems that inhibit pain transmission
3. in Descending pathways that modulate pain transmission (rostral ventral medulla, locus coeruleus, midbrain periaqueductal gray)
4. of Inhibitory neurons (GABA)
5. of Endogenous opioids which could contribute to and enhance the overall effect of the drug

Question 9

Pharmacological Actions of Opioids

1. Antitussive Effect
   a. Doses needed to SUPPRESS cough are how than those need for ANALGESIA?

b. Which drug is most often used for this?
c. What other drug could also be used?
d. WHAT drug DOES NOT SUPPRESS COUGH?

Answer 9

1. a. Generally Lower
   b. CODEINE
   c. DEXTROMETHORPHAN
   d. MEPERIDINE does NOT SUPPRESS COUGH

Question 10

Pharmacological Actions of Opioids

1. What patients SHOULD NOT be GIVEN MORPHINE?
2. Pupillary Constriction (MIOSIS) is seen with ALL OPIOIDS EXCEPT?
3. What Opiate may Cause TACHYCARDIA due to ANTICHOLINERGIC ACTIVITY?

Answer 10

1. Those with HEAD TRAUMA or INCREASED INTRACRANIAL PRESSURE!
2. MEPERIDINE (Constriction is usually a sign of OPIOID OVERDOSE)
3. MEPERIDINE

Question 11

Pharmacological Actions of Opioids

1. GI: Most common effect?
   a. What 2 other things may occur?

Answer 11

1. CONSTIPATION is common.

a. DECREASED GASTRIC MOTILITY and BILIARY COLIC may occur due to constriction of biliary muscle

Question 12

Tolerance and Physical Dependence

1. Tolerance may develop due to persistent stimulation of what receptor?
2. What receptor Antagonist may prevent tolerance from occurring?
3. HYPERALGESIA may also occur. What does this mean?
4. TOLERANCE may develop to SOME OF THE EFFECTS of OPIOIDS (like what) but not to others?

Answer 12

1. of the MU Receptors or possibly uncoupling of receptors to G-proteins
2. NMDA receptor Antagonist
3. Sensation of pain is actually INCREASED in patients who take opioids chronically.
4. Analgesia, sedation, euphoria, nausea; but not to Miosis or Constipation

Question 13

Adverse Effects

1. Side effects are generally EXTENSIONS of their pharmacologic Actions. They INCLUDE what 8 things?

Answer 13

1. Abuse and Addiction frequently occur; Constipation (treat for it when opioid use is initiated); Itching; Nausea and Vomiting; Physical Dependence; Respiratory Depression and Urinary Retention (w/ benign prostatic hyperplasia)

Question 14

1. Addiction may be more likely if how much opioids are given?

Answer 14

1. If they’re underprescribed or prescribed too infrequently.

Question 15

1. the ABSTINENCE SYNDROME can be Precipitated by Tx w/what?

Answer 15

1. w/an OPIOID ANTAGONIST in PHYSICALLY DEPENDENT PATIENTS

Question 16

Overdose

1. CNS?
2. Lungs?
3. Pupils?

Answer 16

1. CNS DEPRESSION (Stupor or coma)
2. DEPRESSED depth and rate of RESPIRATION
3. PIN POINT PUPILS (If patient is severely hypoxic (very close to death), pupils may be DILATED)

Question 17

Tx of Overdose

1. What support is given?
2. What type of drug is given?
   a. What drug should be REPEATED if coma and respiratory inhibition return?

Answer 17

1. SUPPORT RESPIRATION
2. Opioid Antagonist like NALOXONE
   a. NALOXONE administration

Question 18

Drug Interactions

1. Sedative Hypnotics will do what 2 things?
2. Antipsychotic Drugs: will do what 3 things?

Answer 18

1. Increased CNS depression and Increased Respiratory Depression
2. Increased SEDATION, variable effect on Respiratory depression and INCREASED Cardiovascular effects

Question 19

Drug Interactions

1. MAO Inhibitors: Should they be used?
   a. What 2 drugs are considered the worst for interaction w/MAOIs?

Answer 19

1. NO! Avoid with ALL OPIOID ANALGESICS due to HIGH incidence of HYPERPYREXIC COMA!
   a. Meperidine and Dextromethorphan

Question 20

INHIBITORS of CYP2D6

1. ALL CODEINE DERIVATIVES have to be Demethylated to the corresponding morphin derivative in order to bind to Mu Receptors.

How does this affect peeps w/genetic issues or who take SSRIs ?

Answer 20

1. Those who don’t have enough CYP2D6 due to genetic factors or take SSRIs that inhibit them, will not have enough Analgesia w/codeine derivatives.

Question 21

Contraindications

1. Major issues?

Answer 21

1. Using Pure Agonist w/Partial Agonist; pts with head injuries (increase CO2…increased intracranial pressure); use during pregnancy; etc….

Question 22

Strong Agonists

1. Morphine
   a. What Opiate receptors does it bind to and STIMULATE?

b. How can it be given?
c. Best way to give it and why?
d. Half life?
e. How long does Analgesia last?
f. Metabolized by what?
g. CONJUGATED with what? What does this form?

Answer 22

1. a. All of them
   b. Pretty much any way.
   c. Injected vs oral due to High First Pass Metabolism
   d. 1.5-2 hrs
   e. 3-7 hrs
   f. CYP2D6
   g. Glucuronic Acid to make 3-Glucuronide, 6-glucuronide and 3,6-glucuronide

Question 23

Strong Agonists

1. Hydromorphone
   a. It’s a Morphine derivative. How strong is it?

b. Used for what pain type?
c. Useful in patients with what dysfunction? Why?
d. Less likely to produce what?
e. How can it be taken?
f. Duration time?

Answer 23

1. a. More POTENT than Morphine and just as effective
   b. Moderate-to-Severe Pain
   c. RENAL DYSFUNCTION. Cuz Metabolites don’t accumulate
   d. Itching
   e. pretty much any way
   f. slightly shorter than Morphine

Question 24

Strong Agonists

1. METHADONE
   a. Duration of Action?
   b. What receptors does it hit?
   c. May MINIMIZE development of what?
   d. Useful in what type of pain?
   e. Also used for Maintenance Therapy in whom?
   f. Withdrawal strength?

Answer 24

1. a. VERY LONG. 15-60 hrs half life
   b. Potent MU AGONIST. Also Blocks NMDA Receptors and INHIBITS Reuptake of Monoamines
   c. of Tolerance
   d. Hard-to-treat pain (neuropathic pain, cancer)
   e. Opioid Addicts and to decrease withdrawal symptoms
   f. Milder, but more prolonged than from other opioids

Question 25

Strong Agonists 1. Meperidine a. 2 Ways to administer it? b. Recommended only for what? c. Not Good for Long-term use: WHY? d. Normeperidine may also accumulate and cause what? e. Has what activity? May cause what 2 things? f. Does not suppress what? g. Causes what?

Answer 25

1. a. Oral and Parenteral b. Very brief use in pts that are Healthy or have issues w/other Opiate Agonists c. Duration of action is TOO short, Metabolite (Normeperidine) accumulates that cause seizures, and Large doses cause TREMOR, muscle twitches, convulsions d. Seizures in pts w/renal failure e. Antimuscarinic activity. can cause Tachycardia and Dilates PUPILS f. Cough g. Euphoria, Significant Addiction Potential

Question 26

Strong Agonists: Meperidine MEPERIDINE BLOCKS REUPTAKE of WHAT hormone? a. Should not be used in Patients taking What 2 things?

Answer 26

SEROTONIN a. ANTIDEPRESSANTS or MAOIs (like phenelzine or linezolid)

Question 27

Strong Agonists 1. FENTANYL a. How much stronger is it than Morphine? b. How long does it last? c. What is it used for? d. Metabolized by what? e. What other 3 drugs are Synthetic Opiate Agonists used in Anesthesia? (ARS)

Answer 27

1. a. 100 times more. b. Very short duration and half life c. General Anesthesia and to supplement regional and spinal analgesia, and premedication or to induce conscious sedation prior to diagnostic or therapeutic procedures d. CYP3A4 e. Alfentanil, Remifentanil, and Sufentanil

Question 28

Moderate-to-Strong Agonist 1. HYDROCODONE a. Derivative of what? b. Used for what kind of pain? c. How is it taken? d. it is CONVERTED to what? By what Enzyme? What is this METABOLITE RESPONSIBLE FOR? e. Half life?

Answer 28

1. a. Codeine b. Moderate to moderate-to-severe pain c. Oral. Absorbed well into the GI tract d. to HYDROMORPHONE; By CYTOCHROME P450 ENZYME; for SOME OF THE ANALGESIC EFFECT e. 3.8 hours

Question 29

Moderate-to-Strong Agonist 1. OXYCODONE a. WIDELY USED to CONTROL what kind of PAIN? b. Can be taken Orally or how ELSE? c. FREQUENTLY COMBINED with what 2 drugs? d. It has a DIRECT RECEPTOR EFFECT, some of the ANALGESIA REQUIRES what? So Effectiveness is reduced in peeps taking what? e. COMBINATION of HYDROCODONE and OXYCODONE with ACETAMINOPHEN now DISCOURAGED due to what?

Answer 29

1. a. MODERATE to SEVERE PAIN b. in a CONTROLLED-RELEASE TABLET c. ASPIRIN or ACETAMINOPHEN d. REQUIRES METABOLISM BY CYP2D6; in peeps taking SSRIs or w/low CYP2D6 activity e. due to ACETAMINOPHEN TOXICITY at HIGH DOSES!

Question 30

Moderate-to-Strong Agonist 1. OXYMORPHONE a. Active metabolite of what? b. Used for what pain?

Answer 30

1. a. of OXYCODONE. Doesn't need to be activated by CYP2D6 | b. Moderate to Severe Pain

Question 31

Moderate Agonists 1. CODEINE a. Widely used as what agent? b. Used for what kind of pain? c. how does codeine become an analgesic agent?

Answer 31

1. a. ANTITUSSIVE Agent b. Mild to moderate pain c. metabolized to morphine by CYP2D6.

Question 32

Mixed Agonist-Antagonists 1. Bupenorphine a. Partial agonist at what 2 receptors? b. What drug craving does it reduce? c. Usually given how? d. Tablets are Formulated TOGETHER with what drug?

Answer 32

1. a. Mu and Kappa receptors b. In Heroin Addicts and used in tx of heroin addiction c. by Injection d. with NALOXONE, which isn't absorbed sublingually...prevents dissolving the tablets in water and injecting the solution in IV

Question 33

Mixed Agonist-Antagonists 1. Pentazocine a. Agonist with what receptors? b. Partial AGONIST at what receptors? c. Use in what pain? d. How is it administered? e. It CAN PRECIPITATE what issues?

Answer 33

1. a. at KAPPA RECEPTORS b. at MU RECEPTORS c. Moderate pain d. Oral or parenterally e. WITHDRAWAL SYNDROME IN OPIOID ADDICTS (partial agonist will act as an ANTAGONIST!) Combination with STRONG AGONISTS is CONTRAINDICATED!

Question 34

1. TRAMADOL a. Approved for use in what pain? b. How does it work on the receptor? c. INHIBITS REUPTAKE of what 2 things? d. Combination with what DRUGS may RESULT IN SEIZURES? e. SHOULD NOT BE COMBINED with WHAT dRUGS? Why?

Answer 34

1. a. Mild to moderate pain b. WEAK MU AGONIST c. NOREPINEPHRINE and SEROTONIN like TCAs d. with ANTIDEPRESSANTS MAY RESULT IN SEIZURES e. with TCAs, SSRIs, or MAOIs; may cause SEROTONIN SYNDROME

Question 35

1. TAPENTADOL a. Agonist on what receptor? b. Inhibits what? c. Stimulates what other receptors? d. Used for what kind of pain tx? e. Also used for what other pain Tx? Why? f. Produces what 3 things?

Answer 35

1. a. MU RECEPTOR AGONIST b. NE Re-uptake c. A2 Receptors d. Moderate to severe pain e. Chronic and Neuropathic pain; Cuz of effect on NE re-uptake f. Nausea, Vomiting, Sedation **SCHEDULE 2 DRUG

Question 36

ANTITUSSIVES (CODEINE and...) 1. DEXTROMETHORPHAN a. Good cough suppressant with no what? b. What does it Block? May potentiate Analgesic Effect of what? c. COMBINATION WITH MAOIs may CAUSE what? d. Has become a SIGNIFICANT DRUG OF ABUSE AMONG WHOM? e. Available OTC in what? f. INGESTION of PURE DEXTROMETHORPHAN can cause what?

Answer 36

1. a. Analgesic effects b. NMDA Receptors; of MORPHINE c. MAY CAUSE SEROTONIN SYNDROME d. TEENAGERS e. COUGH SYRUPS f. DEATH, and other SERIOUS ADVERSE EVENTS like Brain damage, seizures, loss of consciousness, and irregular heart beat.

Question 37

Opioid Anatagonists 1. NALOXONE a. Type of Antagonist? b. DOC for what? c. How does it have to be given? d. Duration of Action?

Answer 37

1. a. Pure Opioid Antagonist b. for OPIOID OVERDOSE c. PARENTERALLY (can reverse respiratory depressant effects of opioids) d. Short (about 2 hrs)

Question 38

Opioid Anatagonists 1. NALTREXONE a. How is it taken? b. How long does it last? c. Used to Prevent what? d. When can it be used? e. Risk of HEPATOTOXICITY?

Answer 38

1. a. Oral. b. Long acting Antagonist (24 hrs) c. Recovering addicts from getting an effect "high" if they abuse an Agonist d. After Opioid addict has been Detoxified. Pt Compliance is an issue e. It's a Serious Drawback

Question 39

Opioid Anatagonists 1. NALMEFENE a. Approved for Tx of what? b. Appears very similar to what drug? What is different though? c. Been used to Treat what? Why?

Answer 39

1. a. Opioid overdose b. Naloxone; Has a longer duration (2-6 hrs) c. Alcoholism; Has less liver effect than Naltrexone