FENTANYL & CONGENERS

27/11/2023
FENTANYL
• Potent synthetic opioid
• Is a Phenylpiperidine
• First produced in 1960
• 50 to 100 times more potent than morphine
Pharmacokinetics
• Lipophilic & readily crosses the BBB

• Rapid onset of action, with peak analgesic effect within 5 minutes of

IV injection

• Clinical effect starts to wear off after 30-40 min due to redistribution
to inactive sites such as fat and skeletal muscle

• Plasma concentrations are maintained by slow uptake from inactive

sites
Pharmacokinetics-2
• Metabolized by N-demethylation in the liver to the principal
metabolite, norfentanyl

• <10% is excreted unchanged

• Excretion is via the kidneys

Routes of administration
• IV
• Transdermal patch
• Useful in cancer-related pain
• Buccal tablet
• Useful in children
MoA
• Is a µ-selective receptor agonist- responsible for its analgesic effect
via:
➢Closure of voltage-gated Ca++ channels on presynaptic nerve terminals &
thereby reducing transmitter release OR
➢Opening K+ channels on postsynaptic neurons, causing hyperpolarisation
and thus inhibition of the neurons.

• Also able to activate delta and kappa receptors

• Addiction to fentanyl may occur due to its effect on increasing
dopamine levels in the reward area of the brain
.
Adverse Effects
• Euphoria, confusion, drowsiness
• Respiratory depression (which, if extensive and untreated, may lead
to arrest)
• Nausea, visual disturbances, hallucinations, delirium
• Constipation
• Muscle rigidity
• Addiction
• Loss of consciousness, hypotension, coma, and even death.
Drug interactions
• Alcohol, cocaine & heroin can synergistically exacerbate fentanyl's
adverse effects.

• CYP3A4 inhibitors eg. macrolide antibiotics, azole antifungals and

protease inhibitors may increase plasma concentrations of fentanyl,
extending the opioid drug action and exacerbating the opioid-induced
respiratory depression.
Contraindications
• The use of fentanyl is contraindicated in patients in the following
situations:
1. After operative interventions in the biliary tract, as these may slow
hepatic elimination of the drug.
2. With respiratory depression or obstructive airway diseases eg.
asthma, COPD, obstructive sleep apnea
3. With liver failure
Fentanyl overdose
• Typically presents with respiratory depression
➢Requires oxygen supplementation & respiratory support
➢Opioid antagonist eg naloxone can help to manage the respiratory depression
➢Typically, repeated doses of naloxone are required since fentanyl has
increased receptor affinity compared to some other opioids
SUFENTANIL
• Also a phenylpiperidine
• First synthesized in 1974
• Greater affinity for opioid receptors compared to Fentanyl
• 5-7 times more potent
Pharmacokinetics
• Lipophilic (twice that of fentanyl)
• Rapid onset of action
• Undergoes redistribution to inactive tissue sites
• Vd is less due to high plasma protein binding (92%)
Pharmacokinetics-2
• Metabolized by N-dealkylation or O-demethylation
• Metabolite desmethyl sufentanil has about 10% the activity of
sufentanil
• <1% excreted unchanged in urine
Adverse effects
• Respiratory depression
• Skeletal muscle rigidity
• Hypotension
• Bradycardia
• Nausea & vomitting
• Pruritus
Other Phenylpiperidines

• Alfentanil
➢Less potent than fentanyl
➢Acts more rapidly & has a much shorter duration of action

• Remifentanil
➢Metabolized very rapidly by blood & tissue esterases
➢Short half life (12- 30 minutes)

• Carfentanil
➢Used in vet medicine for sedating elephants
LEVORPHANOL
.
Levorphanol
• Is a Morphinan
• First developed in the 1940s as an alternative to morphine
• More potent than morphine
Pharmacokinetics
• Administered orally/IV/SC/IM
• When given orally peak analgesic effect occurs 1 hr after
administration
• When given IV- analgesic effect within 20 minutes
• Duration of analgesic effect= 6-15 hours
Pharmacokinetics- 2
• Undergoes glucuronidation to levorphanol-3-glucuronide, an active
metabolite
• Excreted by the kidneys
• Has a long half life (30hrs)
Mechanism of action
• Agonist at µ, delta and kappa receptors
• Also a non-competitive antagonist at NMDA receptors
.
Adverse Effects
• Nausea, vomitting
• Lower incidence compared to morphine
• Sedation
• Constipation
• Pruritus due to histamine release
• Increases bile duct pressure and should be avoided in biliary surgery
• Causes contraction of biliary smooth muscle
PETHIDINE
.
PETHIDINE
• Synthetic opioid
• Also known as meperidine
• Can be given orally but is less effective than when given parenterally
• Produces prompt but short duration of analgesia
• Less constipating & less potent than morphine
• Not suitable for severe continuing pain
Pethidine cont..
• Less respiratory depression than other opioid analgesics ~ use for
analgesia in labour
• Causes dilatation of pupil because of an atropine-like activity
• Well absorbed from the GIT compared with morphine but most often
given IM
• Duration of action (2-4hrs) shorter than that of morphine (4-6hrs)
• Addictive
Pethidine cont….
• Half life = 3-4 hrs
• Prolonged elimination half life of 22 hours in neonates
• One of its metabolites, normeperidine, has serotonergic properties
and may increase risk of serotonin syndrome & seizures
• Serotonin syndrome: Potentially life-threatening condition associated with
increased serotonergic activity in the CNS. Presents with agitation, twitching,
dilated pupils, hypertension, muscle rigidity
Clinical Uses
• Moderate to severe pain
• Obstetric analgesia
• Peri-operative analgesia
• Can be used as an adjunct to preoperative medications due to its anti-
shivering effect
• Anti-shivering effect may be due to stimulation of kappa receptors
Adverse Effects
• Respiratory depression
• Vomitting
• Delayed gastric emptying
THE END
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