of Pharmacology Selected Opiods
Spring 2011
Harvey Alan Berman, PhD, MPH
Department of Pharmacology and Toxicology [e-mail] 829-2658
Opioid classification Agonist
Strong Mild-to-moderate
Opioids with mixed actions
Agonist-antagonist (Ag-Antag) Partial agonist
Antagonist
Strong Agonists
Morphine Heroin Hydromorphone (DILAUDID) Oxymorphone (NUMORPHAN) Methadone (DOLOPHINE) Meperidine (DEMEROL) Fentanyl (SUBLIMAZE) Levorphanol (LEVO-DROMORAN)
Metabolism of Heroin
N CH3
Heroin is biologically inactive In the body it is converted to MAM and then into morphine MAM and morphine are responsible for the effects elicited upon injection of heroin
O H3CC O
O
HEROIN
O O CCH3
N
CH3
O H3CC O
O
OH
MONOACETYLMORPHINE
N
CH3
HO
O
OH
MORPHINE
Methadone (Dolophine)
-Agonist Similar to morphine Prolonged use give rise to tolerance Uses:
Relief of pain Treatment of opioid abstinence Treatment of opioid dependence Oral efficacy !
CH3 CH3 CH2 O C C N HC CH2 CH3 CH3 CH3 CH3 N CH3 CH3 O
Opioid Withdrawal Syndrome
W/i hours of missing first dose of morphine
sense of intense fear (this can be alleviated by a placebo)
8-16 hrs: lacrimation, rhinorrhea (as in a severe head cold), yawning, sweating, mydriasis, anorexia, nervousness, irritability, tremors, increased anxiety and fear, restless sleep
W/i 36 hrs:
skeletal muscle fasciculation and twitch severe/painful cramps develop in legs and stomach intense/uncontrolled vomiting, salivation, diarrhea, and urination weakness, depression, chilliness/sweating, gooseflesh ("cold turkey"), muscle spasms, kicking movements ("kicking the habit"). patient is unable to sleep; respiratory rate, blood pressure, temperature, blood sugar, basal metabolic rate Withdrawal syndrome reaches its peak within 48-72 hours, and subsides over the next 10 days.
Withdrawal reaction is evidence for physical dependence.
Intensity of withdrawal reaction depends
Half-life of drug being used
For morphine, with a short half-life, symptoms of abstinence are intense but brief. For methadone, with a long-half-life, symptoms are less intense but more prolonged.
Degree of physical dependence
Withdrawal syndrome of methadone and codeine qualitatively the same but less intense than for morphine.
It is to be emphasized that, although withdrawal from opioids is unpleasant, the opioid withdrawal syndrome is rarely dangerous to the patient. In contrast, withdrawal from CNS depressants (barbiturates; alcohol) can be lethal.
Methadone Why is it used in treatment of opioid dependence?
Methadone withdrawal is
Slower in onset Longer in duration Much less intense
Why dont opioid addicts like it?
Differences in Response to Heroin and Methadone
O
Meperidine (Demerol)
N
C
O
CH2 CH3
-Agonist. Actions are similar to morphine. In equianalgesic doses produces as much sedation, respiratory depression, and euphoria as does morphine. Constipation, urinary retention less common than with morphine.
The rise in bile duct pressure is thought to be less than that caused by morphine.
CH3
Meperidine Toxicity
Meperidine
N-demethylation
Normeperidine
Large, repeated does can lead to an excitatory syndrome
Hallucinations; tremors; muscle twitches; dilated pupils; hyper-reflexia; convulsions Due to the accumulation of normeperidine
t1/2 15-20 hours (meperidine=3 hours)
Not drug of choice for treatment of severe, prolonged pain
Phenylpiperidine opiates
Diphenoxylate
+ Atropine=LOMOTIL
Loperamide
IMODIUM
Fentanyl
A -agonist. 80-times more potent than morphine as an analgesic. USES:
For anesthesia and post-op analgesia. Duragesic (transdermal patch) releases fentanyl over a period of 72 hours (for treatment of chronic pain; cancer pain) Patient controlled anesthesia (Actiq) Buccal tablets, buccal film (Fentora)
H N C O N CH2CH2 CH2CH3
included in this summary.
FENTORA should be placed above a rear molar tooth between the upper cheek and gum. You may feel a g 1 Summary sensation between your cheek and gum as the tablet dissolves. FENTORA should not be chewed bubbling View swallowed.
Sections Modified Summary of Changes to Contraindications and Warnings BOXED WARNING Fentora is indicated only for the management of breakthrough pain in patients with cancer who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. BOXED WARNING MEDICATION GUIDE What are the possible or reasonably likely side effects of Fentora?
Links on this page:
About half of the fentanyl in FENTORA is absorbed through the lining of your mouth and into your bloodstre 1. /Safety/MedWatch/SafetyInformation/Safety-RelatedDrugLabelingChanges/ucm103512.htm other portion gets swallowed and absorbed more slowly through your stomach and intestines, like the medic
As soon as the fentanyl enters the bloodstream, it is carried throughout your body. It travels to your central n system the brain and spinal cord where it works to relieve your pain. Some patients may start to feel r as 15 minutes.
If a flare or episode of breakthrough pain is not relieved within 30 minutes, your doctor may instruct you to t additional dose. See the special instructions for taking an additional dose in the Medication Guide or by clic ut
How to Take FENTORA Video
Learn about proper administration of FENTORA with this helpful video ate
Play Video
Mild-to-Moderate Agonists
Codeine Oxycodone (OXYCONTIN) Hydrocodone (VICODIN) Propoxyphene (DARVON)
N CH3 N CH3 OH
PROPOXYPHENE
N
CH3
H3CO
O
OH H3CO
O
O
H3CO
O
O
CODEINE
OXYCODONE
HYDROCODONE
Codeine
High oral/parental ratio
Partially protected from conjugation by the methyl group at C3
Has very low affinity for opioid receptors Analgesic efficacy is due to its conversion to morphine
Polymorphisms in cytochrome P450 isoform CYP2D6
Dispensed alone or in combination with aspirin or acetaminophen
Norcodeine
Codeine-6-Glucuronide Codeine
10-15%
CYP3A4
50-70%
CYP2D6
0-15%
Morphine
CYP3A4
CYP2C8
UGT UGT Normorphine
UGT
Morphine-3-Glucuronide
Morphine-6-Glucuronide
Codeine and gene polymorphisms
Neonate without pain relief 57-year-old Ethiopian man who derives no pain relief from codeine 37-year-old Caucasian woman who post-dental procedure derives no pain relief from codeine
Question: Is it safe to prescribe codeine for nursing mothers?
Codeine and gene polymorphisms
Poor metabolizers Ultra-rapid metabolizers Caucasians (7%) Saudi Arabia, 20% Ethiopia, 29%
A newborn died from morphine poisoning when his mother used codeine while breastfeeding.
Madadi, et al., Clin. Pharmacol. Ther., 85(1) 31-35 (2009) Weinshilboum, NEJM, 348 (6), 529-537 (2003)
Role of gene duplication in drug response: CYP2D6
Weinshilboum, NEJM, 348 (6), 529-537 (2003)
Wilkinson, NEJM, 352 (21) 2211-2221 (2005)
Codeine Hydrocodone Oxycodone
CYP2D6 activation
Morphine
inhibits CYP2D6 activation
Paroxetine Fluoxetine PMs: appear to be protected from dependence on these oral opioids.
Independent mechanisms of analgesia
Hydrocodone
Dispensed only in combination with other drugs
Acetaminophen (NORCET, VICODIN, LORTAB) Ibuprofen (VICOPROFEN)
Oxycodone (OXYCONTIN)
Dispensed alone or in combination with
Aspirin (PERCODAN) Acetaminophen (PERCOCET) Ibuprofen (COMBUNOX)
Propoxyphene
90-120 mg Propoxyphene 60 mg Codeine 600 mg Aspirin
Dispensed alone (DARVON) or in combination with aspirin and caffeine (DARVON Compound-65) or acetaminophen (DARVOCET-N)
Ototoxicity
Rapid, progressive, and profound (> 83%) sensorineural hearing loss in patients taking Vicodin
Successful rehabilitation with cochlear implants
Hearing loss reported with propoxyphene Other ototoxic agents?
Antineoplastic agents, such as cisplatin Loop diuretics: Furosemide, ethacrynic acid Analgesics: Aspirin Macrolide antibiotics: erythromycin Aminoglycoside antibiotics: gentamycin
Opioids with mixed actions Agonist-Antagonist Opioids
Substances that appear to be agonists at some receptors but antagonists at others.
Pentazocine (Talwin; Talwin-NX) Nalbuphine (Nubain) Butorphanol (Stadol)
Partial agonists:
Buprenorphine (Buprenex; Suboxone)
Drug Drug Action at and Receptors
Receptor Subtype
Pure Opioid Agonists Morphine, codeine, meperidine, and other morphine-like agents Agonist-Antagonist Opioids
Pentazocine, butorphanol Antagonist Buprenorphine
Agonist
Agonist
Agonist Antagonist Antagonist
Partial agonist
Pure Opioid Antagonists Naloxone, naltrexone Antagonist
Pentazocine
The intrinsic antagonistic activity is sufficient to afford advantages over morphine as analgesic 20 mg respiration = 10 mg morphine
Doses do not cause proportionate depression of respiration
But, high doses BP; HR
Cardiac work in patients with coronary artery disease
May precipitate withdrawal when given to opioid dependent individual
Pentazocine
Talwin-NX (50mg Talwin + 0.5mg naloxone)
Oral pill laced with naloxone, to prevent abuse potential through injection.
The added naloxone is degraded in liver. If oral pill is powdered for injection naloxone produces aversive effects in individuals dependent on opiods.
Levorphanol [LEVO-DROMORAN]
OH
3
Levallorphan
OH
3
17
17
N
CH3 H
6
N
CH-CH
CH2
H
6
Strong agonist
Ag-antag
Levorphanol Only commercially available agonist of the morphinan series Pharmacological effects parallel those of morphine Clinical reports suggest that levorphanol may produce less vomiting and nausea Metabolized less rapidly than morphine Elimination half-life = 12-16 hrs Repeated administration can lead to accumulation of the drug in the plasma
Ag-Antag Opioids Butorphanol (Stadol)
HO
N
CH2
More potent that morphine (on a per weight basis)
2-3 mg 10 mg morphine Onset, peak activity, duration morphine Lowest abuse potential
Actions similar to pentazocine.
Pulmonary arterial BP work of heart Thus, less useful in patients with CHF or MI
AG-ANTAG SUMMARY
Pentazocine* Nalbuphine Butorphanol*
Why developed? Same intensity of side effects as morphine Psychotomimetic effects Precipitate withdrawal effects in addicts Analgesia has ceiling effect
* Pulmonary arterial tension HR
Cardiac work
Ag-Antag Opioids Buprenorphine (Buprenex)
HO
N
CH2 HO CH3 CH3 CH3 OCH3
Highly lipophilic opioid derivative of thebaine Partial -agonist; 25-50-fold more potent than morphine.
0.4 mg 10 mg morphine (im)
Produces analgesia and other CNS effects to those of morphine. Duration of analgesia is longer than that of morphine. On a per weight basis, more potent and longer lasting than morphine.
Opioid Antagonists
Opioid antagonists produce few effects unless opioid agonists have been administered previously. Naloxone Naltrexone
Devoid of agonist activities Probably interact with all opioid receptors (albeit with different afnities)
Naloxone: Clinical use
1. In treatment of opioid toxicity, especially respiratory depression.
In patients with respiratory depression small doses IM or IV promptly reverse effects of -opioid agonists
Respiratory rates, within 1-2 minutes Sedation is reversed BP, if reduced, returns to normal
In dependent subjects PPTs withdrawal syndrome.
Naloxone
2. In diagnosis of physical dependence on opioids.
In opioid-dependent subjects: IM small doses of naloxone preciptate moderate-to-severe withdrawal syndrome. Symptoms appear within minutes and subside in about 2 hours. Severity and duration ? Are related to dose and degree of dependence
Naloxone Oral efficacy Elimination t1/2
100-1000 times less potent orally than parenterally 1 hour
Naltrexone
Efficacious by the oral route Duration of action 24 hours
Naltrexone (Trexan) Used in long-term management of opioid addiction
The long duration of action serves as a safety valve after detoxification for patients with high motivation to remain opioid-free
The End .