PHRM845-FINAL EXAM Flashcards
Pharmacology of opiate drugs
What two types of alkaloids does opium contain?
Phenanthrenes and Benzylisoquinolines
What drugs contain phenanthrenes?
Morphine
Codeine
Thebaine
What drugs contain benzylisoquinolines?
Noscapine
Papaverine
Opioids are (synthetic/non-synthetic)
Synthetic
___ are only those opioids that are naturally occurring.
Opiates; plant-derived compounds like morphine
Structure activity relationships (SAR) of phenanthrenes
-3 position substitutions ether or ester produces decreased potency (codeine)
-6 position increases activity (hydromorphone or hydrocodone from codeine)
-14 position OH has increased potency (oxycodone)
-N-allyl give antagonists (or mixed antagonists)–naloxone or naltrexone
What gives partial agonist or antagonist activity on mu opioid receptors?
Substitutions on N
Which drugs are non-phenanthrenes?
Tramadol, Meperidine, Fentanyl, Methadone
The human genome contains several genes encoding (endogenous/exogenous) opioids.
Endogenous; Found in our body to help modulate pain
Large precursor proteins are cleaved into more ____
Opioid subtype selective peptides
Degree of redundancy in peptides
- Pro-opiomelanocortin (POMC) is cleaved to:
~Beta-endorphin targets Mu opioid - Preproenkephalin is cleaved to:
~Leu-enkaphalin targets delta opioid
~Met-enkaphalin targets mu and delta receptors - Preprodynorphin is cleaved to:
~Dynorphin targets kappa opioid - Nociceptin/Orphanin FQ
Types of opioid receptors
-GPCR
-Mu (M-morphine)
-Kappa (K-ketocyclazocine)
-Delta (D-Deferens–>where identified)
-Nociceptin, orphanin FQ receptor
-Sigma receptors (once they were cloned, it was determined they were not an opioid receptor)
GPCR opioid receptor
-Family A: peptide receptors
-Gi/o coupled: inhibit cAMP production
-Open GIRK potassium channels: inwardly rectifying K+ channels to maintain membrane potential (makes K+ flow out–>interior to be more negative–>hyperpolarized and hard to conduct an action potential–>reduces firing of pain signals)
-Close calcium channels
Endogenous opioid for mu receptors
Endorphin
Endogenous opioid for kappa receptors
Dynorphin
Endogenous opioid for delta receptors
Enkephalin
Endogenous opioid for nociceptin receptors
Nociceptin
Mu agonists work (pre/post/both) synaptically
Pre and post-synaptically
Presynaptic signaling for mu agonists
Inhibit calcium channel (Gi) which decreases neurotransmitter release and blocks conduction
Post-synaptic signaling for mu agonists
Activate the GIRK channel (G-beta/gamma); efflux of K+ leading to hyperpolarization
Beta-endorphins for the mu opioid receptor
-Endogenous morphine
-Pro-opiomelanocortin (POMC)
-Component of runners high
Therapeutic use for mu opioid receptor
-Analgesia: Not as effective for chronic pain
~Cancer pain, palliative (relief from end of life pain), patient-controlled analgesia, helpful for acute pain
-Sedation
-Antitussive: suppression of cough center in the medulla oblongata
Opioid induced side effects from mu activation
(mostly on-target effects)
-Respiratory depression
~Brian stem
~pre-Botzinger complex in the ventrolateral medulla
-Constipation
~GI tract
-Pruritus (itch)
~Side effect from opioid-induced histamine release; NOT AN ALLERGIC RESPONSE
-Addiction
-Urinary retention
~Opioid induced ADH release
-Nausea and vomiting
~Chemoreceptor trigger zone–medulla
-Miosis
~Oculomotor nerve (PAG)
~Not mepiridine (has anticholinergic effects)
Can an opioid be used as an anti-diarrheal?
Yes, some are designed to stay out of the CNS and slow motility
Kappa opioid receptors
-Dynorphins natural ligand (preprodynorphin)
-Activation is dysphoric and aversive (negative effect)
-Potential use for treatment of addiction (reduces dopamine release)
-Counterbalance mu opioid receptor effects
Delta opioid receptors
-Enkephalins are natural ligands (Preproenkephalin)
-More dynamic expression (intracellular, “externalized” upon chronic stimuli)
-Protective role in hypoxia/ischemia/stroke (hibernation release of enkephalin like opioid)
-Reduce anxiety
-Reduce depression
-Treat alcoholism
-Relief hyperalgesia, chronic pain
-Side effect: seizures
-No FDA-approved delta opioids
Ventral tegmental area–>nucleus accumbens
-Important for reward (linked to addiction)
-Almost all known substances of abuse are linked to these circuits
Depressants can cause DA release just like stimulants. Describe the process
- Opioid binds mu receptor
- Gi signaling inhibits neurotransmitter release
- Less GABA to activate GABA-A
- Less inhibition of dopamine neuron activity
- Increase DA release
- Increase activation of opioid receptors
**Leads to addiction associated with opioids
Routes of opioid administration
-IV
-Intra-axial: intrathecal and epidural
-Intramuscular
-PO
-Topical/transdermal
**Route of administration has an impact on duration to onset
Which medication bolus has a slower and more sustained concentration?
Morphine
Metabolism of morphine and phenanthrenes
-Readily absorbed in the GI tract
-First pass metabolism (morphine bioavailability is 25%)
-Hepatic (CYP2D6 and CYP3A4)
~Elimination half-life is increased with compromised liver function
-Morphine-6-glucuronide (M6G) is an active metabolite (still potent)
Excretion of morphine and phenanthrenes
-Glomerular filtration
-90% excreted in 24 hours
Which opioid metabolites are still active?
-Heroin, codeine, tramadol=prodrugs (MUST be metabolized to get active compound)
-Fentanyl and methadone do not produce active metabolites
-Onset and duration is influenced by lipophilicity
Codeine is a prodrug that is metabolized to ___
Morphine and hydrocodone
Tramadol is a opioid that is metabolized to ___
O-desmethyltramadol
Heroin is a prodrug that is metabolized to ___
Morphine
CYP3A4 (FOUR) makes opioids starting with ___
Nor; don’t have a methyl group and are less active
Which CYP converts codeine to morphine?
CYP2D6
Which CYP converts hydrocodone to norhydrocodone?
CYP3A4
What are the four groups of metabolizers?
PM: poor metabolizer
IM: intermediate metabolizer
EM: extensive metabolizer
UM: ultra-rapid metabolizer
UM of CYP2D6 is of high prevalence worldwide. Frequency of 40% in ___.
-What happens when they are given codeine?
-(higher/lower) incidence of adverse effects
-North America
-Up to 50% higher plasma concentrations of morphine than EM
-Higher
PM of CYP2D6 phenotype is more common in ___.
-Therapeutic effect from codeine?
-(Higher/lower/same) adverse effects
-Caucasians
-No therapeutic effect from codeine because codeine is a pro-drug metabolized to morphine by CYP2D6 and cannot be activated if CYP2D6 is a poor metabolizer.
-Same
Fentanyl
-Very potent synthetic opioid
-Contaminating heroin products and can lead to death
-100 times more potent than morphine
-50 times more potent than heroin
-Used for palliative care (breakthrough pain)
-Can cause respiratory depression if dosed too high
Opioid agonists
-Sufentanil
-Remifentanil
-Alfentanil
-Fentanyl
-Hydromorphone
-Oxymorphone
-Morphine
-Hydrocodone
-Oxycodone
Sufentanil, Remifentanil, Alfentanil
-Used for anesthesia and sedation
-Breakdown by plasma esterase due to ester linkage
Fentanyl
-Comes as an IV, patch, and lollipop
Hydromorphone and oxymorphone
-No opioid-active metabolites
-Comes as an IV, or oral liquid-PCA
Morphine
-Relatively inexpensive
-Comes as an IV or PO - PCA
-Covered by medicare
-ER form (MScontin)
~Long-acting, lower ‘rush’, M6G contribution to pain relief. Risk for abuse if IV injected at once.
Hydrocodone
-Usually in combo with something that contains acetaminophen
Non-phenanthrene opioids are a special subclass of opioids. What are examples?
-Tramadol
-Tapentadol
-Meperidine
Tramadol
-Mild opiate analgesic
-Has SNRI properties (5HT/NE reuptake inhibitor; stimulates 5HT release)
-Management of mild neuropathic pain
-Painkiller used when you don’t want to prescribe a stronger opioid
-Schedule IV
Meperidine
-Used to tx rigors (shivering)
-Has toxic metabolite normeperidine (metabolized by CYP3A4)
~Metabolite is devoid of analgesic activity
~Metabolite is neurotoxic that can cause nervousness, tremors, muscle twitches, and seizures
~Many pts have euphoric feeling
-Renally excreted
~Dangerous in pts with decreased renal function (accumulation)
~Not recommended without good justification
Methadone
Non-phenanthrene
-NMDA receptor antagonist: want to block some of the pain signal from being sent to the brain)–>may be secondary tx to help with pain
-Primarily used for opioid dependence
-Long duration of action/long half-life
-Fat soluble
-Prolonged QTc (unwanted effect)
-For chronic pain
Clinically used opioids (non-analgesic)
Codeine
Dextromethorphan
Diphenoxylate with atropine
Loperamide
Eluxadoline
Codeine
-Schedule II
-Cough/antitussive
-Schedule V in certain formulations
Dextromethorphan
-Cough/antitussive
-Enantiomer of levomethorphan
-Limited opioid activity (not scheduled)
-At high doses, acts as an SSRI and NMDA antagonist
Diphenoxylate with atropine
-Anti-diarrheal
-Schedule V
Loperamide
-Anti-diarrheal
-Strong P-gp substrate (Low BBB penetration)
-Schedule V/decontrolled: OTC
Eluxadoline
-Anti-diarrheal
-For irritable bowel syndrome with diarrhea
-Mu/kappa agonist, delta antagonist
-Enteric nervous system localization
-Schedule IV
Pentazocine
-Used for moderate pain
-Kappa agonist, partial agonist/antagonist at mu
-Parenterally administered
-Side effects: less dysphoria, hallucinations, increased BP and HR
Butorphanol
-For moderate pain
-Schedule IV
-Kappa agonist, partial agonist/antagonist at mu
-Parenterally administered
-Side effects: less dysphoria, hallucinations, increased BP and HR
Nalbuphine
-For moderate pain
-Schedule IV
-Full agonist at kappa; antagonist at mu
-Antagonism produces withdrawal from those with addiction to mu meds
-Administered parenterally (IV, IM)
Buprenorphine
-For moderate pain
-Schedule III
-Partial mu agonist, weak kappa agonist, and delta antagonist
-Primarily used in opioid replacement therapy
Senna
-Used for prevention and acute management of ileus and constipation
-Irritates the colon–causes fluid secretion and colonic contraction
Polyethylene glycol
-Used for prevention and acute management of ileus and constipation
-Stool softener–Osmotic increase in GI water content
Dioctyl sodium sulfosuccinate/docusate
-Used for prevention and acute management of ileus and constipation
-Stool softener, peristalsis if pt uses > 400 mg/day
Opioid tolerance
-Decreased effect over time even when higher doses of opioids are given
-Be aware of opioid-induced hyperalgesia–>secondary pain pathway begins to form–>probably from change in glutamate receptor pathway
-Analgesic effects (Pain relief)
-Nausea
-Urinary retention
-Respiratory depression (biggest risk of death in withdrawn pts/users)
-Euphoria
Limited/no tolerance to opioids
Constipation
Itch
Miosis (small pinpoint pupil)–ask if it is due to tolerance or opioid-induced hyperalgesia
Methadone
-Full agonist
-Helps with opioid dependence
-Full mu opioid receptor agonist (cross tolerance)
-Provides relief from withdrawal (greater potency than morphine)
-‘Slow acting’: 2-4 hrs which is why you have decreased risk of the “high” effect and prevents withdrawal symptoms to prevent opioid use
-Slow PK: accumulates with repeated doses (elimination half-life is 8-50 hours)
-Racemic mixture: (+) NMDA antagonist; structurally different from morphine
Buprenorphine
-Mu opioid receptor partial agonist
-Helps with opioid dependence
-Ceiling effect
-Blocks full agonist effect (heroin, oxycodone)
~Antagonist
~Use 4 hours after last heroin use
-Provides some activation
~Agonist
~Less withdrawal
-Subutex because it does have some agonist activity
~Abuse potential
-Suboxone (4:1 bup:Nx)
~Partially blocks agonist effects when taken IV
Naltrexone
-Full antagonist
-Helps with opioid dependence
-IM injection
-ER
-Once monthly (PO administration=Revia)
-Decent oral bioavailability
-Medium half-life (4h)
-Will cause withdrawal
-Works better if pt has been drug free for 1 month or more
Are naloxone and naltrexone interchangeable?
NO
Naloxone vs. Naltrexone
Naloxone
-IV or intranasal
-Limited oral bioavailability
-Rapid onset
-Short half-life (30-90 min)
Naltrexone
-Decent bioavailability
-PO administration
-Medium half-life (4 hours)–remember: longer word than naloxone
-Prevents high in reinforcement which decreases the risk of withdrawal
Naloxone (Narcan)
-IV or intranasal
-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 q2-5min if not conscious)
-Causes strong withdrawal
Neonatal abstinence syndrome
-Drug dependent
-Symptoms: some hospitals may have newborn abstinence scores (tremors, yawning, poor feeding, sweating)
-Onset of sx: may begin 24-48h after birth or as late as 5-10 days
-From mother using opiates while pregnant: causes serious withdrawal in the baby. Some sx can last as long as 4-6 months. Seizures may also occur in babies born to methadone users.
-Opioids can also present in breast milk
Non-pharm tx of neonatal abstinence syndrome
-Swaddling
-Hypercaloric formula
-Frequent feedings
-Observation (sleep, temp, weight loss/gain, and change in sx)
-Rehydration (IV fluids if dehydration is severe)
Pharmacological tx of neonatal abstinence syndrome
-Morphine sulfate: oral morphine diluted to 0.4 mg/ml
-SL buprenorphine
-Methadone
-Morphine and buprenorphine linked with shorter hospital stay than methadone
-Clonidine (alpha-2 agonist) may also be useful to decrease withdrawal sx
