Barker Pharmacology of Opiate Drugs Flashcards
Two types of alkaloids contained in opium
-Phenanthrenes
-Benzylisoquinolines
What are examples of phenanthrene opioids?
-Morphine
-Codeine
-Thebaine
What is the structure of phenanthrenes?
Three ring structure
Difference between opiates and opioids
-Opioids describe all kinds of opiates
-Opiates only describe naturally occurring opiates
How does the three position ether or ester substitution change the effect of the phenanthrene?
Produces decreased potency
How does the 6 position change the effect of the phenanthrene?
Increases activity
How does the 14 position OH change the effect of the phenanthrene?
Increases potency
How does the N-allyl change the effect of the phenanthrene?
Gives antagonist effect
What are the proteins that are cleaved into opioid peptides?
-Pro-opiomelanocortin (POMC)
-Preproenkephalin
-Predynorphin
-Nociceptin/orphanin FQ
What peptides does pro-opiomelanocortin create when cleaved?
beta-endorphin
What peptides does preproekephalin create when cleaved?
-Leu-enkephalin
-Met-enkaphalin
What peptides does preprodynorphin create when cleaved?
Dynorphin
How do opioids inhibit pain signals?
Inhibition of cAMP production through the Gi/o coupled receptors
What is the endogenous opioid for Mu receptors?
Endorphin
What is the endogenous opioid for kappa receptors?
Dynorphin
What is the endogenous opioid for delta receptors?
Enkephalin
What is the endogenous opioid for nociceptin, orphanin FQ receptors?
Nociceptin
What are sigma receptors?
Not opioid receptors
What are the presynaptic effects of opioids?
Inhibit calcium channel (Gi) decrease in neurotransmitter release
What are the postsynaptic effects of opioids?
-Activate GIRK channel (Gbetagamma)
-Efflux of K+ leads to hyperpolarization
Therapeutic use of beta-endorphins
-Analgesia for acute pain such as cancer pain, palliative care, and PCA
-Sedation
-Cough suppression in the medulla oblongata
Opioid-induced side effects
-Respiratory depression
-Constipation
-Pruritus (itch) (not allergic response)
-Addiction
-Urinary retention
-Nausea/vomiting
-Miosis
Can you use an opioid as an anti-diarrheal?
Yes, only opioids that can stay out of the CNS
What is the effect of the activation of kappa opioid receptors?
Dysphoric aversive effects
Potential uses of kappa opioid receptors
Treatment of addiction by reducing dopamine release by counterbalancing the effects of the mu opioid receptors
Effects of delta opioids
-Role in hypoxia/ischemia/stroke
-Reduce anxiety
-Treat alcoholism
-Relief hyperalgesia, chronic pain
-Side effect: seizures
How do opioids cause a release of dopamine?
-Opioid binds mu receptors
-Gi signaling inhibits neurotransmitter release
-Less GABA to activate GABAa
-Less inhibition of dopamine neuron activity
-Increase dopamine release
-Increased activation of dopamine receptors
Administration routes of opioids
-Intravenous
-Intra-axial: intrathecal, epidural
-Intra muscular
-Oral
-Topical/transdermal
How rapidly is morphine metabolized?
-Readily absorbed
-Undergoes first pass metabolism
-Bioavailability of 25%
How is morphine metabolized
In the liver morphine undergoes glucuronidation at the 3 and 6 position to form morphine-6-glucuronide which is a potent active metabolite
Which enzymes metabolize morphine?
-CYP2D6
-CYP3A4
How is morphine excreted?
-Glomerular filtration
-90% excreted in 24h
Which opioids are prodrugs?
-Heroin
-Codeine
-Tramadol
Which opioids do not produce active metabolites?
-Fentanyl
-Methadone
How is the onset and duration influenced for opioids?
Onset/duration is influenced by lipophilicity
What is codeine metabolized into?
-Hydrocodone
-Morphine
What is heroin metabolized into?
Morphine
How does the lipophilicity affect the onset/duration of morphine?
-Low lipophilicity
-Slower passage across BBB
-Prolonged duration of action
How does the lipophilicity affect the onset/duration of fentanyl?
-High lipophilicity
-Rapid onset
-Short duration
Which enzyme makes opioids starting with nor?
CYP3A4
Which group of people is more likely to have the CYP2D6 ultra-rapid metabolizer phenotype?
People of North African descent
What effects do people with the ultra-rapid metabolizing phenotype of CYP2D6 see when given codeine?
-Up to 50% higher plasma concentrations of morphine than extensive metabolizer
-Higher incidence of adverse effects
Which group of people is more likely to have the CYP2D6 poor metabolizer phenotype?
-No therapeutic effect from codeine
-Same incidence of adverse effects
How potent is fentanyl compared to other opioids?
-~100x potent over morphine
-~50x potent over heroin
What is fentanyl used for?
-Palliative care
-Breakthrough pain
What are the opioid agonists?
-Sufentanil, remifentanil, alfentanil
-Fentanyl
-Hydromorphone (Dilaudid), oxymorphone (Opana)
-Morphine
-Hydrocodone
-Oxycodone
What are sufentanil, remifentanil, and alfentanil used for?
Anesthesia/sedation
Why are sufentanil, remifentanil, and alfentanil not as powerful as fentanyl?
They are broken down by plasma esterases due to the ester linkage in their structure
What makes hydromorphone and oxymorphone different from the other opioids?
No opioid-active metabolites
Why is morphine preferred over oxycontin?
It is covered by medicare
What is MScontin?
Extended release morphine
What are the non-phenanthrene opioids?
-Tramadol
-Meperidine
-Methadone
Tramadol clinical pearls
-Mild opiate analgesic
-Has SNRI properties
-Schedule 4
What is tramadol used for?
-Management of mild neuropathic pain
-Painkiller used when you do not want to prescribe a stronger opioid
What is meperidine used for?
Used to treat rigors
Meperidine clinical pearls
-Has neurotoxic metabolite normeperidine devoid of analgesic
-Renally excreted - dangerous in patients with decreased renal function (accumulation)
Side effects of meperidine
-Nervousness
-Tremors
-Muscle twitches
-Seizures
When is meperidine recommended?
Not recommended without good justification
What is methadone primarily used for?
-Opioid dependence
-Chronic pain
Methadone clinical pearl
-Long duration of action/long half life (15-60hrs)/ fat solubility
-Prolonged QTc - unwanted effect
-NMDA antagonist
Which opioids are used for cough suppression?
-Codeine
-Dextromethorphan
Dextromethorphan clinical pearls
-Enantiomer of levomethorphan
-Limited opioid activity (not scheduled)
-At high doses acts as SSRI, NMDA antagonist
Which drugs are used for anti-diarrheal?
-Diphenoxylate with atropine
-Loperamide
-Eluxadoline
Loperamide clinical pearls
-Strong P-glycoprotein substrate - low BBB penetration
-Schedule 5/decontrolled=OTC
Eluxadoline clinical pearls
-Irritable bowel syndrome with diarrhea
-Mu/kappa agonist, delta antagonist
-Enteric nervous system localization
-Schedule 4
What are the opioids that act at Mu and kappa receptors?
-Pentazocine and butorphanol
-Nalbuphine
-Buprenorphine
Pentazocine and butorphanol activity at receptors
K agonist and partial agonist/antagonism at Mu
Pentazocine and butorphanol side effects
-Less dysphoria
-Hallucinations
-Increase in BP and HR
How are pentazocine and butorphanol administered?
Parenterally
Nalbuphine activity at receptors
Full agonist at k, antagonist at Mu
Nalbuphine clinical pearls
-Antagonism of Mu receptors produces withdrawal in patients with addiction to opioids
-Parenterally administered
Buprenorphine effects on receptors
-Partial mu agonist
-Weak kappa agonist
-delta antagonist
When is buprenorphine primarily used?
Primary use in opioid replacement therapy
Which drugs are used for preventative and acute management of ileus and constipation?
-Senna
-Polyethylene glycol
-Dioctyl sodium sulfosuccinate/docusate
What is senna mechanism of action
Irritates colon - causes fluid secretion/colonic contraction
Polyethylene glycol mechanism of action
Stool softener - osmotic increase in GI water content
Dioctyl sodium sulfosuccinate/docusate mechanism of action
Stool softener, peristalsis when taking more than 400mg/day
What effects can people develop tolerance too when taking opioids chronically?
-Analgesic effects
-Nausea
-Urinary retention
-Respiratory depression
-Euphoria
What is opioid induced hyperalgesia?
Prolonged exposure to opiates causes formation of secondary pain pathways
What symptoms do people not see any tolerance to?
-Constipation
-Itch
-Miosis
What is the mechanism of action of methadone?
Full Mu opioid receptor agonist
What is the indication of methdone?
Provide relief from tolerance due to a higher potency than morphine, oxycodone, and Dilaudid
Methadone clinical pearls
-Slow acting
-Accumulates with repeated dose
-Elimination half-life (8-50hrs)
-Racemic mixuture ((+)=NMDA antagonist)
-Does not have three rings like morphine
Buprenorphine mechanism of action
-Mu opioid receptor partial agonist
-Ceiling effect
-Blocks full agonist effect
-Antagonist by blocking effects of other narcotics
-Use 4hrs after last heroin use
-Provides some activation because of agonist effect to provide less withdrawal symptoms
Side effect of subutex
Abuse potential
Suboxone mechanism of action
Partially blocks agonist effects when taken IV
Naltrexone clinical pearls
-Intramuscular injection
-Extended release
-Once monthly for IM
-PO is once daily dose
-Decent oral bioavailability
-Medium half-life
-Will cause withdrawal
-Works better if patient has been drug free for 1 month or more
Naloxone clinical pearls
-IV or intranasal administered
-Limited oral bioavailability
-Rapid onset
-Short half-life
-Give multiple shots to avoid return of respiratory depression
-Presence of fentanyl and other synthetic opioids means even more doses
-Repeat dose every 2-5 minutes if not conscious
-Causes strong withdrawal
Symptoms of neonatal abstinence syndrome
-Tremors
-Yawning
-Poor feeding
-Sweating
-Serious withdrawal in the baby
-Seizures may also occur in babies born to methadone users
-Some symptoms can last as long as 4 to 6 months
-Opioids can also be present in the breast milk
-Some hospitals may have Newborn Abstinence Scores to help the diagnosis
Onset of neonatal abstinence syndrome
Symptoms may begin 24 to 48hrs after birth or as late as 5 to 10 days
What medications cause neonatal abstinence syndrome?
Heroin and other opiates, including methadone
Non-pharmacological treatment for neonatal abstinence syndrome
-Swaddling
-Hypercaloric formula
-Frequent feedings
-Observation - sleep, temperature, weight gain/loss, and change in symptoms
-Rehydration - IV fluids dehydration is severe
Pharmacological treatment of neonatal abstinence syndrome
-Morphine sulfate - oral morphine diluted to 0.4 mg/ml
-Sublingual buprenorphine
-Methadone - 0.05 to 0.1 mg/kg/dose every 6 hours
-Morphine and buprenorphine linked with shorter hospital stay than methadone
-Clonidine may also be useful
