TEST #3 Fitzpatrick Opioid and Analgesics Flashcards
List the generic names of soluble, bioavailable, opioid narcotic AGONISTS used for analgesia / other indications.
- CODEINE
- FENTANYL
- HEROIN
- HYDROCODONE
- HYDROMORPHONE
- MEPERIDINE
- METHADONE
- MORPHINE
- OXYCODONE
- OXYMORPHONE
- TRAMADOL
List the generic names of opioid narcotic receptor ANTAGONISTS used for management of opioid narcotic overdose/ addiction / side effects.
- NALOXONE
- NALTREXONE
- METHYL NALTREXONE (GI specific)
List the generic names of opioid PARTIAL AGONISTS OR MIXED AGONISTS/ ANTAGONISTS
- BUPRENORPHINE
- BUPRENORPHINE-NALOXONE
- PENTAZOCINE
List the generic names of ‘INSOLUBLE’, POORLY ABSORBED OPIOID RECEPTOR AGONISTS USED FOR DIARRHEA
- LOPERAMIDE
- DIPHENOXYLATE
List the generic names of the most COMMON OPIOID RELATED ANTI-TUSSIVE AGENTS (cough suppression)
- CODEINE
- DEXTROMETHORPHAN
- HYDROCODONE
Is Pain Undertreated or Overtreated?
- 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.
Types of Opioid Receptors & Their Physiological Ligands
RECEPTOR:
1) Mu:
- Peptides- Endorphins
2) Kappa:
- Peptides- Dynorphins
3) Delta:
- Peptides- Enkephalins, Endorphins
Opioid Sites of Action
- Thalamus & hypothalamus
- Reticular formation
- Locus caeruleus
- Raphe nuclei
- Periaqueductal gray
- Spino-thalamic,
a) Mesencephalic
b) Reticular tracts
Opioid Agonists sites of action
- Periphery Primary Afferent Nociceptor
- Dorsal Horn Spinal Cord
- Secondary Afferent Neuron
Pain Impulse: Pre and Post Synaptic
1) Afferent Sensory Signal
2) INCREASE Ca2+ Influx
3) INCREASE Glutamate Discharge
4) INCREASES NMDA Receptor- Na+ Influx
Opioid Agonist-Mediated Signaling
1) BLUNTS Afferent Signal
2) BLUNTS Ca2+ Influx
3) BLUNTS Glutamate Discharge
4) INCREASES K+ EFFLUX
Drugs That Bind to μ Opioid Receptors
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)
Pain Treatment Ladder Is Based On “Opioid-Sparing” Rationale
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
Analgesic Mechanisms & Clinical Utility
1) ACETAMINOPHEN (NSAIDS):
- TISSUE INJURY»_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»_space; Acute stimuli
Clinical Pharmacology of Agonists Acting at Opioid Receptors
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
Tolerance to Morphine (Mu Agonists)
- 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
Morphine Depresses Respiration
• 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
Clinical Indications for Morphine
• 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
Opioid Drugs that are Mu Agonists
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
Group 1 Full Agonists
- 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
Oral: Parenteral Potency Ratio
- Parenteral (i.v., i.m, s.c, patch, buccal) opioids have HIGH BIOAVAILABILITY
- Oral morphine:
*** First-pass metabolism
POOR BIOAVAILABILITY
Methadone
- 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)
Meperidine
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.
Group 1 vs Group 2 Agonists
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
Remifentanil
- 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.
Fentanyl: Anesthesia and Breakthrough Pain
- 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!!!!!!]
Group 3 = Codeine: Moderate Pain & Cough
- 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)
A Safer Antitussive Agent
- DEXTROMETHOPHAN relieves cough INDEPENDENTLY OF OPIOID RECEPTORS.
- Not analgesic; not addictive
How Safe is Codeine?
- MU Receptor interaction dictates strength of Response: Partial Versus FULL AGONISTS
- Acetaminophen COMPLICATES OVERDOSE MANAGEMENT
Codeine Metabolism
CYP2D6!!!!!!!!!!
- Converts Codeine into ACTIVE MORPHINE!!!!!
Codeine and CYP2D6 Pharmacogenomics
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
Death of Children from Post-Op Codeine:
- 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.
Drug and Active Metabolite
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!!!!
Opioids and the Gut
- 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)
Tramadol
• 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!!!!
Pentazocine- Mixed
** KAPPA Agonist plus MU PARTIAL Agonist / GAMMA Antagonist
- Supra-Spinal analgesia
- Can precipitate ‘WITHDRAWAL’ (in abusers)
- Side effects TACHYCARDIA, hallucinations….
Buprenorphine – Partial /MIXED
*** MU PARTIAL Agonist plus KAPPA & GAMMA ANTAGONIST
- Analgesia
- Can precipitate ‘WITHDRAWAL’ (in abusers)
- OFFICE-BASED DETOX/ MAINTENANCE IN COMBINATION WITH NALOXONE
Heroine: Illegal Substance
** Penetrates blood-brain barrier RAPIDLY —-> EXAGGERATED EUPHORIA ——–> ADDICTION LIABILITY
Addiction Program Compliance
% Retention – 1 Year
- Methadone Maintenance:
50 – 80% - Buprenorphine-Naloxone:
40 – 50% - Naltrexone Maintenance:
10 – 20% - “Drug Free”
5 – 20%
Opioid Analgesic Overdose
• Respiratory rate
MU Receptor ANTAGONISTS
- 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
Mu Receptor Antagonists
- 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
Constipation and Opioids
- 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.
What strategies might work for opioid-induced side effects such as constipation?
** 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.
