OPIOID ANALGESIC Flashcards
MOA of Opioid analgesics?
• Opioid agonists produce analgesia by activating
receptors located primarily in brain and spinal
cord involved in transmission and modulation of pain.
Opioid Receptor Types?
• Three major classes of opioid receptors: mu, delta and kappa.
• The three are G protein linked receptors.
• The three couple to Gi.
• The majority of opioid analgesics act primarily
at the µ receptor.
Relation of physiological effects to receptor type?
Supraspinal analgesia
Spinal analgesia
Respiratory depression
Reduced GI motility
Psychotomimesis
Sedation
Supraspinal analgesia µ,mu,delta
Spinal analgesia µ,kappa,delta
Respiratory depression µ
Reduced GI motility µ
Psychotomimesis kappa
Sedation µ,kappa
CELLULAR ACTIONS OF OPIOIDS?
• The opioids have two actions on neurons:
• They close voltage-gated Ca2+ channels on
presynaptic nerve terminals.
• They open K+ channels on postsynaptic
neurons.
• Both actions reduce neurotransmitter release.
Analgesia effects due to
- Inhibit ascending pain transmission.
* Activate descending pain-inhibitory circuits.
Spinal analgesia is due to opioids inhibiting?
Opioids inhibit ascending pain transmission
Describe supraspinal analgesia?
• The descending pain-inhibitory neurons are
inhibited by GABA.
• Opioids inhibit GABAergic neurons.
• In this way opioids activate the pain-inhibitory
descending neurons.
• This results in enhanced inhibition of pain
transmission.
Pure agonists, mixed agonist-antagonist, and antagonist?
Pure agonists
• High affinity for mu receptors.
• Lower affinity for gamma and kappa receptors.
Mixed agonist-antagonists
• Agonist and antagonist activity on different receptors.
Antagonists
• Antagonists at all receptors
CNS Effects of opioids?
- Analgesia
- Euphoria
- Sedation and drowsiness
- Respiratory depression
- Cough suppression
- Miosis
- Truncal rigidity
- Nausea and vomiting
Peripheral effects of opioids?
• Hypotension • Constipation • Contraction of biliary smooth muscle. May result in biliary colic. • Pruritus
Metabolism of opioids?
• Opioids are converted mainly to glucuronides,
which are then excreted by the kidneys.
Metabolism of morphine and Heroine?
Morphine is conjugated to:
• Morphine-3-glucuronide (M3G)
• Morphine-6-glucuronide (M6G)
• Heroin (diacetylmorphine) is hydrolyzed to monoacetylmorphine and to morphine.
What metabolizes Codeine, oxycodone, and hydrocodone
• Codeine, oxycodone, and hydrocodone are
metabolized by CYP2D6.
• Codeine is converted to morphine.
Metabolism of Meperidine?
• Meperidine is converted to normeperidine.
• Accumulation of normeperidine, may occur in
patients with decreased renal function.
• In high concentrations, normeperidine may
cause seizures.
Metabolism of Fentanyl and Methadone?
• Fentanyl is metabolized by CYP3A4 to inactive
metabolites.
• Methadone is metabolized by multiple P450 enzymes.
Use for opioid analgesics?
• Analgesia: Treatment of moderate to severe pain. • Acute Pulmonary Edema • Cough • Diarrhea • Applications in Anesthesia
AE of opioid analgesics?
- Adverse effects of the opioid analgesics include
- Nausea
- Vomiting
- Sedation
- Itching
- Constipation
- Urinary retention
- Hypotension
- Respiratory depression
• The most common adverse effects reported with
the use of opioid analgesics are
- Nausea
- Vomiting
- Sedation
- Itching
- Constipation
Define dependence and addiction?
• With frequent administration there is tolerance.
• Physiological dependence develops too.
• Dependence is defined as the occurrence of a
withdrawal syndrome.
• Physical dependence is common when opioids
are used for therapeutic purposes.
• However, addiction is not.
Contraindications and cautions of opiods?
USE OF PURE AGONISTS WITH WEAK PARTIAL
AGONISTS
• When a weak agonist is given to a patient
receiving a strong agonist, there is a risk of
diminishing analgesia or even inducing a state of
withdrawal.
PATIENTS WITH HEAD INJURIES
• CO2 retention caused by respiratory depression
results in cerebral vasodilation.
• In patients with elevated intracranial pressure, this
may lead to lethal alterations in brain function.
Contraindications and cautions of opioids continued?
PREGNANCY
• The fetus may become dependent.
PATIENTS WITH IMPAIRED PULMONARY
FUNCTION
• The depressant properties of the opioid
analgesics may lead to acute respiratory failure.
PATIENTS WITH IMPAIRED HEPATIC FUNCTION
• Morphine and its congeners are metabolized
primarily in the liver.
PATIENTS WITH IMPAIRED RENAL FUNCTION
• Half-life of opioids is prolonged
Drug interactions of sedative hypnotics and MAO inhibitors?
Sedative-hypnotics
• Increase CNS depression, particularly respiratory depression.
MAO Inhibitors
• Some opioids inhibit serotonin reuptake: e.g.,
methadone, meperidine, tramadol, fentanyl.
• The concurrent use of these opioids and an
MAOI may trigger a “serotonin syndrome.”
• Features: Delirium, hyperthermia, headache,
hyper- or hypotension, rigidity, convulsions,
coma, and death.
• Manufacturers of opioids contraindicate the
concurrent use of MAOIs.////
List opioid agonists?
MORPHINE, HYDROMORPHONE, OXYMORPHONE HEROIN MEPERIDINE FENTANYL METHADONE LEVORPHANOL CODEINE, OXYCODONE, HYDROCODONE
Describe MORPHINE, HYDROMORPHONE &
OXYMORPHONE affinities?
- Useful in treating severe pain.
- High affinity for mu receptors.
- Lower affinity for delta and kappa receptors.
- Morphine is the DOC for severe pain.
Describe heroin metabolism to morphine and consequences of its metabolism?
• Rapidly hydrolyzed to 6-MAM, which is
hydrolyzed to morphine.
• Both heroin and 6-MAM are more liposoluble
than morphine and enter the brain more readily.
• Morphine and 6-MAM are responsible for the
pharmacological actions of heroin.
Meperidine receptor affinity, recommendation, pk, and ae?
• µ receptor agonist.
• Not recommended for chronic pain due to
metabolite toxicity. Only used for short-term
treatment of acute pain.
• Meperidine has a half-life of 3 hours.
• The metabolite normeperidine has a half-life of 20 hours.
• When doses of meperidine are repeated at short intervals normeperidine accumulates.
• This leads to tremors, muscle twitches, and
seizures.
Fentanyl affinity, pk, and use?
- mu agonist.
- Rapid onset.
- Short duration of action (15-30 minutes).
- 100 times more potent than morphine.
- Used for severe pain.
Methadone spectrum, pk, and moa?
- Less euphoria than morphine.
- Longer duration of action than morphine.
- Effective in severe pain.
- MOA:
- μ receptor agonist
- NMDA receptor antagonist
- 5-HT and NE reuptake inhibitor
Methadone uses?
• Methadone substitution is the preferred method of managing opioid withdrawal for addicted patients.
• This is because methadone has a long half-life and less profound sedation and euphoria
• Due to the long half-life of methadone, the
abstinence syndrome is prolonged but less
severe.
• Methadone is a useful drug for detoxification and
maintenance of the chronic relapsing heroin addict.
Methadone AE?
• QT prolongation, torsades de pointes and death
have been reported.
Action of Levorphanol?
- μ, δ, and κ agonist.
- Serotonin and norepinephrine reuptake inhibitor
- NMDA receptor antagonist
- Used in severe pain.
Difference between oxycodone and hydrocodone?
• Oxycodone is used for moderate to severe pain.
Formulated alone or in combination with a
nonopioid.
• Hydrocodone is used for moderate to severe
pain. Only available in combination with
acetaminophen or a NSAID.
Codeine use, affinity, and conversion metabolism?
• Codeine is used for mild to moderate pain.
• Codeine has low affinity for opioid receptors.
• The analgesic effect of codeine is due to its
conversion to morphine by CYP2D6.
list the mixed agonist-antagonists?
PENTAZOCINE
BUTORPHANOL
NALBUPHINE
BUPRENORPHINE
• The mixed opioid agonist–antagonists are potent
analgesics in opioid-naive patients.
• They precipitate withdrawal in patients who are physically dependent on opioids.
kappa agonist and a µ antagonists.
- Pentazocine
- Butorphanol
- Nalbuphine
Buprenorphine affinities?
• Buprenorphine: weak µ agonist and kappa antagonist
PENTAZOCINE, BUTORPHANOL, NALBUPHINE &
BUPRENORPHINE recommendations and ae?
• Not recommended as routine analgesics,
because they have ceiling effect.
• Pentazocine, butorphanol and nalbuphine
may cause psychotomimetic effects.
• Buprenorphine is approved for management of opioid addiction.
Tramadol actions, uses, and ae?
• Weak mu agonist and norepinephrine and serotonin reuptake inhibitor. • Used to treat moderate pain. • Useful in neuropathic pain. • Increased risk of seizures in patients with a seizure disorder.
Naloxone and Naltrexone actions and uses?
• Antagonists at mu, delta, and kappa receptors.
• Naloxone is used in the treatment of acute
opioid overdose.
• Naltrexone is used for opioid and alcohol
addiction.
High efficacy Opioids?
Morphine Hydromorphone Oxymorphone Methadone Meperidine Fentanyl Levorphanol Nalbuphine Buprenorphine Butorphanol
Moderate-high efficacy, moderate, and low efficacy opioids?
Oxycodone: Moderate-High
Hydrocodone
Pentazocine:
Moderate
Codeine: Low
ANTITUSSIVES: DEXTROMETORPHAN & CODEINE cough suppressant mechanism?
• Opioid analgesics are very effective for the
suppression of cough.
• This effect is often achieved at doses below
those necessary to produce analgesia.
• The receptors involved in the antitussive
effect appear to differ from those associated
with other actions of opioids.
ANTIMOTILITY AGENTS:
DIPHENOXYLATE AND LOPERAMIDE uses, actions?
• Widely used in the treatment of diarrhea.
• Their actions are mediated by µ receptors on
enteric nerves, epithelial cells, and muscle.
• At usual doses, diphenoxylate and
loperamide lack analgesic effects.
• They decrease motility of smooth muscle of the
intestinal wall.
• Pentazocine
• Butorphanol
• Nalbuphine
action?
Kappa agonist and a µ antagonists.
