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Neuro 2 > TEST #3 Fitzpatrick Opioid and Analgesics > Flashcards

TEST #3 Fitzpatrick Opioid and Analgesics Flashcards

1
Q

List the generic names of soluble, bioavailable, opioid narcotic AGONISTS used for analgesia / other indications.

A
  • CODEINE
  • FENTANYL
  • HEROIN
  • HYDROCODONE
  • HYDROMORPHONE
  • MEPERIDINE
  • METHADONE
  • MORPHINE
  • OXYCODONE
  • OXYMORPHONE
  • TRAMADOL
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2
Q

List the generic names of opioid narcotic  receptor ANTAGONISTS used for management of opioid narcotic overdose/ addiction / side effects.

A
  • NALOXONE
  • NALTREXONE
  • METHYL NALTREXONE (GI specific)
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3
Q

List the generic names of opioid PARTIAL AGONISTS OR MIXED AGONISTS/ ANTAGONISTS

A
  • BUPRENORPHINE
  • BUPRENORPHINE-NALOXONE
  • PENTAZOCINE
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4
Q

List the generic names of ‘INSOLUBLE’, POORLY ABSORBED OPIOID RECEPTOR AGONISTS USED FOR DIARRHEA

A
  • LOPERAMIDE

- DIPHENOXYLATE

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5
Q

List the generic names of the most COMMON OPIOID RELATED ANTI-TUSSIVE AGENTS (cough suppression)

A
  • CODEINE
  • DEXTROMETHORPHAN
  • HYDROCODONE
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6
Q

Is Pain Undertreated or Overtreated?

A
  • Pain is “EXPERIENCED” subjectively. Patients can find it difficult to communicate their particular experience. Others can find it difficult to comprehend and respond – support? criticize? enable? isolate?

BELIEFS:
- RELIGIOUS: Suffering = atonement.

  • SOCIAL: Overtreatment of pain leads to drug addiction, drug diversion, social ills.
  • MEDICAL: Pain as vital sign & cure vs care bias.
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7
Q

Types of Opioid Receptors & Their Physiological Ligands

A

RECEPTOR:

1) Mu:
- Peptides- Endorphins

2) Kappa:
- Peptides- Dynorphins

3) Delta:
- Peptides- Enkephalins, Endorphins

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8
Q

Opioid Sites of Action

A
  • Thalamus & hypothalamus
  • Reticular formation
  • Locus caeruleus
  • Raphe nuclei
  • Periaqueductal gray
  • Spino-thalamic,
    a) Mesencephalic
    b) Reticular tracts
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9
Q

Opioid Agonists sites of action

A
  • Periphery Primary Afferent Nociceptor
  • Dorsal Horn Spinal Cord
  • Secondary Afferent Neuron
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10
Q

Pain Impulse: Pre and Post Synaptic

A

1) Afferent Sensory Signal
2) INCREASE Ca2+ Influx
3) INCREASE Glutamate Discharge
4) INCREASES NMDA Receptor- Na+ Influx

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11
Q

Opioid Agonist-Mediated Signaling

A

1) BLUNTS Afferent Signal
2) BLUNTS Ca2+ Influx
3) BLUNTS Glutamate Discharge
4) INCREASES K+ EFFLUX

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12
Q

Drugs That Bind to μ Opioid Receptors

A

FULL AGONISTS:

  • Fentanyl
  • Morphine

PARTIAL AGONIST/ MIXED:
- Buprenorphine

ANTAGONIST:

  • Naloxone
  • Naltrexone
  • Opioids bind to G-protein-linked membrane receptors: MU (μ), KAPPA (κ) & DELTA(δ). Sub- types, splice variants CONFER DIVERSITY.
  • Receptors are widely distributed throughout the human body, including BRAIN, SPINAL CORD, GUT, UTERUS, etc. THE MAJORITY OF CLINICALLY USEFUL OPIOID ANALGESIC DRUGS HAVE SIGNIFICANT AGONIST ACTIVITY AT μ RECEPTORS.

• Opioid receptors bind endogenous peptides and drugs:
1) μ AGONIST (e.g. MORPHINE)

2) μ PARTIAL AGONIST (buprenorphine)
3) κ/μ MIXED AGONIST (pentazocine)
4) μ ANTAGONIST (naloxone)

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13
Q

Pain Treatment Ladder Is Based On “Opioid-Sparing” Rationale

A

1) MILD (Pain)
- NSAID
- Acetaminophen

2) MODERATE or Persisting or Uncontrolled Mild Pain
- Codeine
- Codeine related +/- Acetaminophen
- Tramadol

3) SEVERE or Persisting or Uncontrolled Moderate Pain
- Morphine
- Fentanyl
- Extended release forms

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14
Q

Analgesic Mechanisms & Clinical Utility

A

1) ACETAMINOPHEN (NSAIDS):
- TISSUE INJURY&raquo_space; Acure or Nerve Injury

  • COX (-1,-2)

2) OPIOIDS PROTOTYPE: MOPRHINE
- TISSUE INJURY = ACUTE STIMULI ≥ NERVE INJURY

  • Mu Receptor Agonists

3) ANTI-CONVULSANTS (Gabapentin)
- NERVE INJURY > Tissue Injury = Acute

  • Ca+ Channel Antagonists

4) ANTI-DEPRESSANTS (Amitryptilene)
- NERVE INJURY ≥ Tissue injury&raquo_space; Acute stimuli

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15
Q

Clinical Pharmacology of Agonists Acting at Opioid Receptors

A

1) MU RECEPTOR:
-  ANALGESIA (supra-spinal)
- Euphoria
-  CNS & Respiratory Depression
-  DRUG DEPENDENCY!!!
-  Miosis (pupil contraction)
-  GI, uterine motility

2) KAPPA RECEPTOR:
-  ANALGESIA (spinal) 
- Sedation
-  Miosis
-  GI, uterine motility

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16
Q

Tolerance to Morphine (Mu Agonists)

A
  • Analgesia
  • Euphoria
  • Sedation
  • Nausea
  • Respiratory depression

TOLERANCE: Over time, for a given dose, the response deteriorates, necessitating an INCREASE IN DOSE, or a ‘rotation’ to different opioid

NO TOLERANCE TO:

  • Miosis
  • Constipation
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17
Q

Morphine Depresses Respiration

A

• Morphine ( agonists) DEPRESSES Sensitivity to CO2

• Dose-related drop of RESPIRATION RATE (3-4 /minute in severe toxicity),
minute volume , tidal exchange

CONTRA-INDICATIONS:

  • Brian Injury
  • Emphysema
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18
Q

Clinical Indications for Morphine

A

• Post-operative Pain
- Procedures & surgery

• Cancer Pain
- Primary & metastatic Malignancy

• Other pain
- SICKLE CELL CRISIS, trauma….. Severe Diarrhea, Dyspnea caused by pulmonary edema from left ventricular failure

19
Q

Opioid Drugs that are Mu Agonists

A

GROUP 1:

    • Full Agonists
    • Parenteral and Oral
  • MORPHINE
  • Methadone
  • Meperidine
  • Hydromorphone
  • Oxymorphone
  • Levaphanol

GROUP 2:

    • Full Agonists
    • Short Acting
  • FENTANYL
  • Sufentanil
  • Remifentanyl

GROUP 3:

  • ** CODEIN-RELATED
  • Hydrocodone
  • Oxycodone
20
Q

Group 1 Full Agonists

A
  • Potency
  • Bioavailability

…. are important when “SWITCHING” from parenteral to oral dosing, or “ROTATING” between opioids. They also dictate some of the clinical uses of these drugs.

  • Methadone and Levorphanol have GOOD ORAL BIOAVAILABILITY
  • Meperidine (Very High), Hydromorphone, Oxymorphone, Levorphanol all have a high Efficacy than Morphine
21
Q

Oral: Parenteral Potency Ratio

A
  • Parenteral (i.v., i.m, s.c, patch, buccal) opioids have HIGH BIOAVAILABILITY
  • Oral morphine:
    *** First-pass metabolism
    POOR BIOAVAILABILITY
22
Q

Methadone

A
  • Mu Agonist (Full Agonist)
  • Exhibits the pharmacology of a Mu Agonist
  • Longer t1/2 (27 hrs vs. 2 hrs for morphine)
  • BETTER Oral absorption / bioavailability (90% vs. 20% for morphine)

PHARMACOKINETIC PROPERTIES are what makes it so useful for:
• WITHDRAWAL / MAINTENANCE
• DETOXIFICATION

** Methadone can affect cardiac electrical conduction, producing QT-INTERVAL PROLONGATION IN ACUTE OVERDOSE OR DURING LONG-TERM METHADONE TREATMENT

** This effect is UNRELATED to its interaction with  receptors…it delays cardiac repolarization by BLOCKING the flow of potassium ions through HERG channels (K+ channels)

23
Q

Meperidine

A

DISTINCTIONS AS A MU AGONIST!!!

  • EYE: Pupil DILATION (mydriasis). Abuse difficult to “detect” via pinpoint pupils. Accordingly, those who abuse this drug can escape detection.
  • NORMEPERIDINE, a toxic metabolite, accumulates & causes seizures.
24
Q

Group 1 vs Group 2 Agonists

A

Group 1: FULL AGONISTS

Group 2: SHORT-ACTING FULL AGONISTS

  • Onset and Duration of Action
  • Potency
  • Bioavailability

Ex: Fentanyl
- About 100x more POTENT than Morphine, Methadone

Ex: Sufentanil:
- Kappan, Gamma, and Mu Agonist

Ex: Remifentanil:
- VERY Short-Acting

25
Q

Remifentanil

A
  • Remifentanil is gaining popularity for providing ANALGESIA for CHILDBIRTH if regional analgesia is either contraindicated or not desired.
  • Remifentanil is metabolized by plasma and tissue esterases. Although it transfers across the placenta, its RAPID METABOLISM in the fetus LOWERS the risk for neonatal depression.
  • Its RAPID ONSET of action, within 1 minute following intravenous injection, is another advantage.
26
Q

Fentanyl: Anesthesia and Breakthrough Pain

A
  • Strong MU agonist (meperidine analog)
  • Used in anesthesia
  • RAPID ONSET AND DISTRIBUTION (lipophilic)
  • SHORT DURATION OF ACTION (procedures)

•TRANSMUCOSAL (lollipop)
– breakthrough pain ( with morphine)

•TRANDERMAL PATCH DELIVERY
– Slows onset and prolongs delivery

CAUTION: Respiratory Depression

[Abuse Potential via HEATING PATCHES!!!!!!]

27
Q

Group 3 = Codeine: Moderate Pain & Cough

A
  • As a PARTIAL AGONIST at  receptors codeine has LESS POTENTIAL for drug dependence & respiratory depression.
  • Reliable Oral Absorption / Bioavailability (50% versus 20% for morphine)

• ANALGESIA – MODERATE PAIN
- Some formulations contain ACETAMINOPHEN

•ANTI-TUSSIVE: Cough relief (MU- INDEPENDENT)

28
Q

A Safer Antitussive Agent

A
  • DEXTROMETHOPHAN relieves cough INDEPENDENTLY OF OPIOID RECEPTORS.
  • Not analgesic; not addictive
29
Q

How Safe is Codeine?

A
  • MU Receptor interaction dictates strength of Response: Partial Versus FULL AGONISTS
  • Acetaminophen COMPLICATES OVERDOSE MANAGEMENT
30
Q

Codeine Metabolism

A

CYP2D6!!!!!!!!!!

  • Converts Codeine into ACTIVE MORPHINE!!!!!
31
Q

Codeine and CYP2D6 Pharmacogenomics

A

1) ULTRAFAST METABOLIZER
- CYP2D6 Gene Duplication and “Ultrafast” Allele
* *** Pumps out MORE Morphine!!!!

2) INTERMEDIATE METABOLIZER:
- CYP2D6 Heterozygous

3) POOR METABOLIZER
- CYP2D6 Gene Deletion and “Slow” Allele

32
Q

Death of Children from Post-Op Codeine:

A
  • Codeine is converted to morphine by the liver. These children had evidence of being ULTRA-RAPID Metabolizers of CODEINE, which is an inherited (genetic) ability that causes the liver to convert codeine into life-threatening or fatal amounts of morphine in the body.
33
Q

Drug and Active Metabolite

A

1) MORPHINE:
- M6G and M3G, Hydromorphone

2) Heroin:
- MORPHINE

3) CODEINE:
- MORPHINE

4) Oxycodone:
- Oxymorphone

5) MEPERIDINE:
- Normeperidine (TOXIC!!!)

6) HYDROMORPHONE:
- NONE!!!!!

7) OXYMORPHONE:
- NONE!!!!

8) FENTANYL:
- NONE!!!!

34
Q

Opioids and the Gut

A
  • LOPERAMIDE
  • DIPHENOXYLATE

ANTI- DIARRHEALS!!!!!
- Interact with  opioid receptors in gut

• POOR SOLUBILITY (limited risk of parenteral abuse)
Poor penetration of blood-brain barrier (limited risk of dependence / toxicity)

35
Q

Tramadol

A

• MODERATE MU AGONIST

  • N-desmethyl ACTIVE METABOLITE
  • Reliable Oral Absorption / Bioavailability (70% versus 20% for morphine)

• ANALGESIA- MODERATE PAIN

• INHIBITS CATECHOLAMINE REUPTAKE
- caution in patients on tricyclic, or SRI anti-depressants.

• Associated with SEIZURES!!!!

36
Q

Pentazocine- Mixed

A

** KAPPA Agonist plus MU PARTIAL Agonist / GAMMA Antagonist

  • Supra-Spinal analgesia
  • Can precipitate ‘WITHDRAWAL’ (in abusers)
  • Side effects TACHYCARDIA, hallucinations….
37
Q

Buprenorphine – Partial /MIXED

A

*** MU PARTIAL Agonist plus KAPPA & GAMMA ANTAGONIST

  • Analgesia
  • Can precipitate ‘WITHDRAWAL’ (in abusers)
  • OFFICE-BASED DETOX/ MAINTENANCE IN COMBINATION WITH NALOXONE
38
Q

Heroine: Illegal Substance

A

** Penetrates blood-brain barrier RAPIDLY —->  EXAGGERATED EUPHORIA ——–> ADDICTION LIABILITY

39
Q

Addiction Program Compliance

% Retention – 1 Year

A
  • Methadone Maintenance:
    50 – 80%
  • Buprenorphine-Naloxone:
    40 – 50%
  • Naltrexone Maintenance:
    10 – 20%
  • “Drug Free”
    5 – 20%
40
Q

Opioid Analgesic Overdose

A

• Respiratory rate

41
Q

MU Receptor ANTAGONISTS

A
  • NALOXONE (I.V.)
  • NALTREXONE (P.O.)
  • OCCUPY, but DO NOT ACTIVATE Mu receptors
  • Competitively inhibit (displace) Heroin, Morphine, Fentanyl etc. (other Mu agonists) from Mu receptors
  • ANTIDOTE FOR OPIOID OVERDOSE
42
Q

Mu Receptor Antagonists

A
  • NALOXONE CAN Reverses Coma & Respiratory Depression about  1 min after i.v. bolus
  • (Depends on what opioid & what dose !!!)
  • (initial .04 mg) If NO response increments to 15 mg Short duration of action 1-2 hrs can lead to apparent “RELAPSE” of overdose symptoms.

*** NALTREXONE has a long duration of action
(48 hrs for single dose ORALLY) in overdose

  • Antidotes for OVERDOSE can Precipitate Withdrawal
43
Q

Constipation and Opioids

A
  • Constipation is major issue re-post surgery – especially GI & biliary surgery – and chronic use.
  • It may be necessary to COMPROMISE and SACRIFICE some analgesic efficacy to circumvent post-operative or peri-operative problems with GI and biliary smooth muscle
  • Opioids increase smooth-muscle tone and INHIBIT the Coordinated Peristalsis required for PROPULSION, which contributes to NAUSEA & VOMITING as well as CONSTIPATION.
44
Q

What strategies might work for opioid-induced side effects such as constipation?

A

** METHYLNALTREXONE is a QUATERNARY derivative of naltrexone with RESTRICTED ABILITY TO CROSS THE BLOOD-BRAIN BARRIER.

  • It functions as a peripheral ACTING OPIOID ANTAGONIST, including actions on the gastrointestinal tract to inhibit opioid- induced decreased gastrointestinal motility and delay in gastrointestinal transit time, thereby decreasing opioid-induced constipation. DOES NOT AFFECT Opioid analgesic effects or induce opioid withdrawal symptoms.

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