Bannon: Opiod Drugs Flashcards
Hydromorphone (Dilaudid)
Older semi-synthetic morphine derivative used as painkiller
More potent than morphine; equivalent efficacy
Oft-requested in ER
Was used primarily as immediate release, but now other formulations (extended-release in ‘11)
Opiate Receptors:
Mu
Kappa
Delta
Mu:
Encoded by:
Mu: for morphine (endogenous ligands are beta-endorphin and more recently recognized endomorphins)
- Encoded by MOP gene
- Many opioid agonists and antagonists show preference here
Kappa:
Encoded by:
What is relatively strong here?
In some cases, have actions opposite to:
Kappa: for ketoclazocine (endogenous ligand is dynorphin)
- Encoded by KOP gene
- Partial agonists relatively strong here
- May have more importance in spinal anesthesia
- In some cases, have actions opposite to mu receptors
Delta:
Encoded by:
Morphine and other opioid drugs:
Delta: for vas deferens (endogenous ligand is enkephalin)
- Encoded by DOP gene
- Morphine and other opioid drugs weaker here
Opioid-Like Receptor NOP:
Insensitive to:
Elicits : (2)
Opioid-Like Receptor NOP: nociceptin/orphanin FQ peptide receptor
o Insensitive to classical opioid antagonists
o Elicits hyperalgesia (increased sensitivity to pain) and anti-opiod effects suprasinally
o Elicits antinociceptive spinal effects
Single Gene Results in Several Receptor Subtypes Seen Pharmacologically
Example:
Single Gene Results in Several Receptor Subtypes Seen Pharmacologically:
Example: MOP gene elicits μ1, μ2, and μ3
Single Gene Results in Several Receptor Subtypes Seen Pharmacologically
Possible Explanations: (3)
Alternative splicing of common gene products (really not important)
Receptor dimerization to give different subtypes (may be important)*
Interaction of common gene product with signaling proteins (may be important)*
- For example, drug dependent activation of signaling pathways (which pathway gets activated depends on which drug bind)
Morphine (Gold Standard)
Absorption:
Metabolism:
Absorption: well absorbed by multiple routes of administration (oral, IM, IV, subQ, rectal, epidural or intrathecal)
Metabolism: extensive first-pass metabolism limits oral use (~35% bioavailability)
Morphine (Gold Standard)
Excretion:
Polar metabolites excreted in the urine
- After chronic use, polar metabolite morphine-6-glucuronide is responsible for analgesic effects
- Therefore, toxicity may result in renal insufficiency due to decreased clearance of this active metabolite (confusion, agitation)
- Morphine-3-glucuronide is another minor metabolite that may be proconvulsant (CNS excitatory properties; again, take care with renal insufficiency)
Glucoronide conjugates also secreted in bile
Morphine (Gold Standard)
Formulations: (4)
Long-Acting SR Beads
Morphine SR + Naltrexone (Embeda)
Post-Surgical Formulations (DepoDur)
Infumorph/Astromorph/Duramorph
Morphine
Long-Acting SR Beads:
Long-Acting SR Beads: to be swallowed; if chewed or combined with alcohol, can cause release of too much morphine
Morphine
Morphine SR + Naltrexone (Embeda):
Morphine SR + Naltrexone (Embeda): for continual use with decreased risk of abuse (if crushed, opioid antagonist naltrexone will be freed)
Morphine
Post-Surgical Formulations (DepoDur):
Post-Surgical Formulations (DepoDur): single liposomal injection (last 48 hours)
Morphine
Infumorph/Astromorph/Duramorph:
Infumorph/Astromorph/Duramorph: continual epidural or intrathecal infusion formulations
Uses/Effects of Morphine:
Analgesia
Basics:
Basics:
- Pain relief without general sensory loss or loss of consciousness
- Pain reported as present but no longer bothers the patient
- Better against continuous dull pain than sharp, intermittent pain
- Multiple supraspinal (ie. brain) and spinal sites of action
Uses/Effects of Morphine:
Analgesia
Issues: (2)
SIGNIFICANT tolerance to this effect (as well as most others)
Paradoxical hyperalgesia may occur (MOA unclear- possibly increased glutamate transmission in the dorsal horn)
Uses/Effects of Morphine:
Analgesia
Use:
Use: surgical anesthesia (in combination with other drugs- multimodal anesthesia)
Uses/Effects of Morphine
Mood and Cognitive Effects
Basics:
In normal (Pain-Free) Individuals:
Basics: cause euphoria and tranquility
Normal (Pain-Free) Individuals: often unpleasant
o Dysphoria (intense feelings of depression or discontent)
o Difficulty thinking
o Drowsiness
o Nausea
Uses/Effects of Morphine
Mood and Cognitive Effects
Site of Action:
Side Effects:
Use in Combat Injured Subjects:
Site of Action: unclear (locus ceruleus, mesolimbic DA, nucleus accumbens all possible)
Side Effects: confusion and sedation (especially in the elderly)
Use in Combat Injured Subjects: prompt administration of morphine reduced risk for PTSD
Uses/Effects of Morphine
Miosis
Cause:
Sign of Toxicity/Abuse:
Cause: excitation of the PS innervation to the pupil
Sign of Toxicity/Abuse: little/no tolerance to this effect with chronic use
Uses/Effects of Morphine
Cough Inhibition
Mechanism:
Mechanism: depression of cough reflex mediated by medullary cough center (can administer a dose that easily provides cough suppression without respiratory depression)
Uses/Effects of Morphine
Respiratory Depression
Mechanism:
Importance:
Mechanism: dose-related depression mediated via brainstem centers
- Decreased response to CO2
- Synergistic depression seen with many other CNS drugs
Importance: especially of concern in patients with COPD and pain
Uses/Effects of Morphine
Increased Intracranial Pressure
Mechanism:
Importance:
Mechanism: due to increased pCO2 (causes cerebrovascular dilation)
Importance: needs to be taken into consideration with head trauma
Uses/Effects of Morphine
Nausea/Emesis
Mechanism:
Mechanism: mediated by area postrema chemoreceptor trigger zone
- Relatively uncommon in supine patients but common in ambulatory patients (hints at possible vestibular component to mechanism)
- Tolerance to this effect develops rapidly
Uses/Effects of Morphine
Cardiovascular
Effects:
Mechanism:
Effects: peripheral vasodilation (reduced peripheral resistance) and inhibition of baroreceptor reflex
- Not evident in supine patient, however, orthostatic hypotension and fainting can be seen upon standing
Mechanism: may be due in part to histamine release
Uses/Effects of Morphine
Cardiovascular
Use:
Use: IV morphine used for immediate relief of dyspnea from acute pulmonary edema associated with left ventricular failure
- Decreases anxiety, venous tone and peripheral resistance
Uses/Effects of Morphine
GI
Effects:
Effects: decreased propulsive contractions (leads to increased water absorption and constipation)
- Little tolerance to this effect and therefore can be a problem with chronic use
Uses/Effects of Morphine
Ureter:
Uterus:
Itching:
Ureter: increase sphincter tone to decrease urinary output (especially in the elderly)
Uterus: leads to prolongation of labor (also need to worry about fetal effects)
Itching: due to effects on CNS and peripheral nerves
- Mechanism: probably substance P and/or histamine related
Morphine
Toxicity
Causes:
Causes: clinical overuse, renal insufficiency, accidental OD or suicide attempt
Morphine
Toxicity
Key Signs:
Key Signs: coma, respiratory depression and pinpoint pupils
Heroin
Potent and fast-acting (“heroic”)
Converted to morphine by deacetylation in vivo
Oxycodone
Use:
Cancer patients:
with aspirin:
acetaminophen:
ibuprofen:
Use: painkiller (has a morphine backbone) for the short-term relief of moderate pain
- Cancer patients (ER release form)
- In combination with aspirin (Percodan)
- In combination with acetaminophen (Percocet)
- In combination with ibuprofen (Combunox)
Oxycodone
Absorption:
Efficacy:
Absorption: more orally active than morphine
Efficacy: roughly equivalent maximal efficacy to oral morphine
Oxycodone:
Acurox:
Popular Drug of Abuse: possibly lethal
Acurox: recently FDA approved drug used as a deterrent for abuse
- Combination of niacin (unpleasant effects) and inactive ingredients that convert to a gel upon attempted extraction
- Unfortunately, has driven up abuse of other opiates
Meperidine
Use:
Use: painkiller whose use is now limited to acute pain management (ie. post-surgical)
- Rapid onset and short duration of action
- Irritating to tissue if given IM
Meperidine
Unique Toxicity:
Unique Toxicity:
- Seizures, twitching, delirium and psychiatric changes
- Due to accumulation of a long-lived metabolite
Codeine
MOA:
MOA: weak full agonist with modest analgesic activity after deacetylation to morphine
- However, 10% of the population lack the enzyme for conversion
Codeine
Pharmacokinetics; (3)
Absorption: good oral absorption
Highly protected from first pass glucuronidation
High oral:parenteral potency ratio
Codeine
Use:
- Most often given in combination formulations (ie. Tylenol 3)
- Also a sustained release formulation
- Antitussive effects (possibly through distinct receptors; efficacy questioned for this use)
Fentanyl
Pharmacokinetics
Potency:
Duration of Action:
Potency: 80-100x more potent than morphine (effective but potentially dangerous)
Duration of Action: short (with no active metabolites)
Fentanyl
Use: (2)
- IV use for surgical anesthesia (often with droperidol)
- Acute post-op pain (patient controlled analgesia by transdermal iontophoresis)
Fentanyl
Other unique delivery routes for pain in opioid-tolerant patients:
Transdermal patch (change every 48-72 hours)
o Be careful of exposure of patch to heat
o Be careful with concurrent use of CYP3A4 inhibitors (ie. clarithromycin, ketoconazole)
Effervescent buccal tablet, buccal film or lonzenge on a stick (for breakthrough pain)
Propoxyphene (Darvon)
MOA:
Efficacy:
Safety:
MOA: partial agonist painkiller
Efficacy: very low
Safety: low therapeutic index (not very safe)
Propoxyphene (Darvon)
Formulations:
Toxicity:
Formulations:
- Combinations with aspirin/caffeine (Darvon compound)
- Combinations with acetaminophen (Darvocet)
Toxicity: accumulation of a toxic metabolite can lead to a variety of effects
- Cardiotoxicity, convulsions, OD (being pulled from the market!)*
Nalbuphine/Butophanol/Pentazocine
MOA:
Side Effects:
MOA: kappa agonists and weak mu mixed agonists or antagonists
Side Effects:
- More adverse behavioral symptoms (psychomimetic effects/Salvinorin-A like effects)
Nalbuphine/Butophanol/Pentazocine
Effects: (4)
Effects:
- Less analgesia
- Less respiratory depression
- Less tolerance
- Less naloxone reversibility*
Tramadol
Structure:
MOA:
Use:
Structure: synthetic codeine derivative
MOA: active metabolite is a weak mu agonist
- Also blocks 5HT and NE uptake
- Some GABA mechanisms also suspected
Use: should be limited to chronic neuropathic pain (due to need for slow titration); however, being seen more and more for use in acute pain
Tramadol
Formulations:
- Extended release
- In combination with acetaminophen (Ultracet)
Tramadol
Side Effects: (3)
- Reports of increased frequency of seizures
- Esp. in patients with seizure history or on antidepressant medications
- DDIs may lead to serotonin syndrome (buildup of serotonin)
Tapentadol
Structure:
MOA:
Risks:
Structure: tramadol-like compound
MOA: weak mu agonist (also a NE reuptake inhibitor; NOT 5HT)
Risks: risk of abuse and serotonine syndrome unclear at this point
Methadone
MOA:
Pharmacokinetics:
Half-life:
MOA: full agonist
Pharmacokinetics:
- Long Half-Life: slow metabolism in most people and high fat solubility
- Need careful initial titration
- Hepatic metabolism: no active metabolites, and therefore safe in patients with renal problems
Methadone
Use:
Chronic pain (esp. in patients with renal issues)
Addict detoxification or maintenance
Buprenorphine
MOA:
Pharmacokinetics:
Duration:
MOA: partial agonist at mu receptor (but more potent than full agonist methadone)
Pharmacokinetics:
- Long Duration of Action: very slow dissociation from receptor (resistance to naloxone receptor)
Buprenorphine
Use:
Formulations: (3)
Use:
- Opiate dependence (can be prescribed in office setting)
Formulations:
- Sublingual formulation
- Combination with naloxone (Suboxone) to prevent abuse
- Sustained release formulation (once a month dosing) currently being tested
Naloxone and Naltrexone
MOA:
MOA: opiate receptor antagonists (mu > kappa and delta)
Naloxone:
ER form for opiate OD
Blocks antidiarrheal, antitussive and analgesic effects of opioids
Naltrexone:
Oral form used for prevention of relapse to heavy drinking
- Poor compliance
- Hepatotoxicity if taken at 3-4x the recommended dose
Recently approved injectable ER formulation (once a month) to maintain alcohol abstinence
Naltrexone SR + Buprenorphine SR (Contrave):
Naltrexone SR + Buprenorphine SR (Contrave): recently approved for obesity treatment
- Modestly effective
- Concerns about cognitive and CV side effects
Methylnaltrexone
MOA:
Administration:
Use:
MOA: opiate antagonist that does NOT cross BBB (therefore, will not affect analgesia)
Administration: injectable
Use: approved recently for opioid-induced constipation in terminal patients under palliative care
Diphenoxylate/Loperamide
MOA:
Action:
MOA: mu receptor agonists
Action: meperidine congeners that have very poor absorption from the gut (exclusive use in diarrhea)
Diphenoxylate/Loperamide
Formulations: (2)
Diphenoxylate + Atropine (Lomotil)
Loperamide (Immodium)
Dextromethorphan
Structure:
MOA:
Structure: D isomer of methylated levorphanol (does not have typical opioid effects)
MOA: NMDA receptor antagonist and sigma receptor agonist
Dextromethorphan
Use: (2)
Antitussive (MOA unclear, efficacy questioned but seems to work)
Abuse potential now evidence
Dextromethorphan
Contraindications:
Contraindications: young children; also discouraging use of combination products (ie. with antihistamines etc.)
Nalfurafine
MOA:
Use:
MOA: new kappa opioid receptor agonist (no action at mu receptors)
Use: relief of itching
- However, taking a kappa agonist should be VERY unpleasant (recall psychomimetic effects)
Current Investigative Uses of Opioid Drugs: (3)
- Antidepressants
- Anti-addiction
- Cardioprotection
.
General Principles of Therapeutic Use of Opioids: (2)
Only symptomatic relief: do not treat underlying disease
Tolerance: repeated administration can lead to tolerance and physical dependence; however, important to note that most people that are using prescribed opioids do NOT become addicts
