Opioid agonists

[Ref: SH(H)4:p90]

 

??? Not mentioned pethidine, diamorphine

Need more details on tramadol

Morphine

The prototype opioid agonist

Actions

• Analgesia
• Euphoria
• Sedation
• Diminished ability to concentrate
• Nausea

Other effects

• Sensation of body warmth
• Sensation of heaviness of the extremities
• Dryness of mouth
• Pruritis (especially around nose)

NB:

• In absence of pain, morphine may produce dysphoria instead.
• Gender may affect action
  * In women, greater analgesic potency and slower offset

Pharmacokinetics

• Peak effect after IV = 15-30min
  * Delayed compared to fentanyl and alfentanil
  * Plasma concentration of morphine does not correlate closely with pharmacologic activity
• pK = 7.9
• 23% nonionized at pH 7.4
• Protein-binding = 35%
• Elimination half-time = 1.7-3.3

Metabolism

Conjugation with glucuronic acid in hepatic and extrahepatic sites (especially the kidneys)
* May be impaired by monoamine oxidse inhibitor

Renal metabolism is significant
* No decrease in systemic clearance in hepatic cirrhosis

In renal failure, elimination of metabolites is impaired
--> Accumulation of metabolite
--> Increased risk of ventilation depression

Metabolites

75-85% appear as morphine-3-glucuronide
* Inactive

5-10% appear as morphine-6-glucuronide
* Active --> can cause analgesia and ventilation depression

Side effects

Cardiovascular system

Unlikely to cause myocardial depression

Possible impairment of compensatory sympathetic response
--> Orthostatic hypotension

Morphine-induced hypotension can also occur from
* Bradycardia
* Histamine release

Respiratory system

Ventilation depression

Dose-dependent ventilation depression

Via agonist effect at mu2 receptors
--> Depressant effect on brainstem ventilatory centres
--> Decreased respons to carbon dioxide
--> CO2 response curve displaced to the right

Ventilation depression
--> Decreased frequency
--> Compensatory increase in tidal volume
--> But overall minute volume still decrease

Factors which increase the ventilatory depressant effect
* Advanced age
* Natural sleep

Factors which decrease the ventilatory depressant effect
* Surgical stimulus

Cough suppression

Cough reflex is depressed via actions on medullary cough centres

Codeine and dextromethorphan are used for this purpose

Nervous system

ICP

Opioids decrease cerebral blood flow and possibly ICP in absence of hypoventilation

But use with caution in head injury because
* Sedation effect
* Production of miosis
* Ventilatory depression (increased PaCO2 increases ICP)

Sedation

Sedation often precedes the onset of analgesia

Nausea and vomiting

Opioids directly stimulates the chemoreceptor trigger zone in the floor of the 4th ventricle

May also have a vestibular component
--> Movement can exacerbate nausea

Musculoskeletal system

Skeletal muscle rigidity is common after large and rapid IV opioids

Common in the thoracic and abdominal muscles

Thus,

If large doses of opioid (e.g. fentanyl or sufentanil) is used as induction agent
--> Possible rigidity of chest
--> Difficulty in IPPV

GIT system

Biliary tract

Opioid can cause spasm of biliary smooth muscle
--> Increased intrabiliary pressure
--> Can trigger biliary colic

• Naloxone can relieve biliary colic pain caused by opioid
• Glucagon (2mg IV) can also relieve biliary spasm caused by opioid
  * But does not reverse analgesic effect
• Nitroglycerin can relieve both biliary colic pain and myocardial ischaemic pain

Other GIT effects

Spasm of GIT smooth muscles
* Constipation
* Biliary colic
* Delayed gastric emptying

Genitourinary system

Morphine can increase the tone and peristaltic activity of the ureter

Skin

Cutaneous blood vessel dilation in the face, neck, and upper chest

Placenta

Opioids can be transfered to the fetus
--> Possible depression of the neonate

Immune system

Prolonged exposure and abrupt withdrawal may induce immunosuppression

Drug interaction

Ventilatory depressant effect is exaggerated by

• Amphetamine
• Phenothiazine
• Monoamine oxidase inhibitor
• Tricyclic antidepressant

Tolerance and dependence

• Tolerance develops to the analgesic, euphoric, sedative, ventilatory depression, and emetic effects
• Tolerance does NOT develop to the effect of miosis and constipation
• Physical dependence on morphine requires 25 days to develop
  * Sooner in some emotionally unstable patients

Morphine withdrawal

Onset = 6-18 hours

Peak intensity = 36-72 hours

Duration = 7-10 days

Overdose of opioids

Triad:

• Miosis
  * But severe hypoxemia may result in mydriasis
• Hypoventilation
  * Main manifestation
• Coma

Other S&S:

• Upper airway obstruction
• Pulmonary oedema
• Hypotension
• Seizure

Treatment of opioid overdose

• Mechanical ventilation with oxygen
• Administration of naloxone (or other antagonist)
  * May trigger acute withdrawal

Morphine-6-glucuronide

650-fold more potent in analgesic effect than morphine

Binds to mu receptor with similar affinity as morphine

Meperidine (= pethidine)

Synthetic opioid agonist at mu and kappa receptor

Analogs include:

• Fentanyl
• Sufentanil
• Alfentanil
• Remifentanil

Structurally similar to atropine
--> Mild atropine-like antispasmodic effect

Pharmacokinetics

• 1/10 potency of morphine
• Well-absorbed from the GIT
  * Unlike morphine
• In equal analgesic dose
  --> Similar sedation, euphoria, N&V, ventilatory depression as morphine
• pK = 8.5
• 7% non-ionized at pH 7.4
• Elimination half-time = 3-5 hours

Metabolism

Meperidine
--> (Demethylation)
--> Normeperidine
--> (Hydrolysis)
--> Meperidinic acid

Normeperidine has 1/2 analgesic potency as meperidine
* But also cause CNS stimulation (myoclonus seizures)

Clinical uses

• Analgesia
  * Postoperative
  * During labour
• Suppression of post-operative shivering
• Not effective as anti-tussive or antidiarrhoea
  * Unlike morphine

Side effects

Similar to morphine, except:

• Due to its atropine-like quality
  * May cause tachycardia instead of bradycardia
  * Causes mydriasis instead of miosis
• Less constipation and urinary retention than morphine
• Large dose leads to depression of myocardial contractility
  * Unique among opioids
• Delirium and seizure
  * Due to accumulation of normeperidine

Fentanyl

Phenyl piperidine-derivative synthetic opioid agonist
* Structurally related to meperidine

 

In comparison with morphine:

• 75-125 times more potent analgesic action
• More rapid onset
• Shorter duration

Pharmacokinetics

With multiple doses or infusion
--> Progressive saturation of inactive tissues
--> Duration of action prolonged
* Context-sensitive half-time increases after infusion is over 2 hours

• pK = 8.4
• 8.5% non-ionized at pH 7.4
• Protein binding 84%
• (???) Partition coefficient = 955
• Elimination half-time = 3.1-6.6 hours
• Context-sensitive half-time 4 hour infusion = 260min
  * Much higher than sufentanil
• Effect-site time = 6.8min

Metabolism

Metabolite = norfentanyl
* Minimal pharmacological action

Clinical use

• Analgesia
  * 1-2 microgram/kg IV
• Blunting of circulatory response to laryngoscopy or surgical stimulation
  * 2-20microgram/kg IV
• Anaesthesia
  * 50-150microgram/kg IV
  * Stable haemodynamically
  * Lack of direct myocardial depression
  * Lack of histamine release
  * Suppression of stress response to surgery

Side-effects

Similar to morphine, except:

• Does not invoke histamine release
• More prominent bradycardia
• Modest increase in ICP (6-9mmHg)
• Marked synergism with benzodiazepine (e.g. midazolam) in hypnosis and depression of ventilation

Sufentanil

Thienyl analog of fentanyl

 

Analgesic potency is 5-10 times of fentanyl
* Due to greater affinity for opioid receptors

Pharmacokinetics

• Lipophilic
• High tissue affinity

Thus,

• Faster penetration through BBB
• Faster onset of CNS effect

Short duration due to rapid redistribution
--> Multiple doses saturate inactive tissues
--> Longer duration of action

• pK = 8.0
• 20% nonionized at pH 7.4
• Protein-binding = 93%
• Partition coefficient = 1727
• Elimination half-time = 2.2-4.6 hours
• Context sensitive half-time 4 hour infusion = 30min
• Effect-site time = 6.2min

Metabolism

(N-dealkylation)
--> Inactive metabolite

Shorter context sensitive half-time than alfentanil (60min) due to larger Vd
* Sufentanil = 123L
* Alfentanil = 27L

Clinical uses

0.1-0.4 microgram/kg IV
--> Longer analgesia and less ventilation depression than fentanyl (1-4microgram/kg IV)

Side effects

• Decreased cerebral metabolic oxygen requirement
  --> Decreased cerebral blood flow
• Bradycardia
  * May be sufficient to reduce cardiac output

Alfentanil

Analog of fentanyl

• Less potent than fentanyl
  * 1/5 to 1/10 potency
• 1/3 duration of action of fentanyl
• More rapid onset of action than fentanyl and sufentanil

Pharmacokinetics

• pK = 6.5
  * Low compared to other opioids
• 89% non-ionized at pH 7.4
  * High compared to other opioids
  * Faster effect in CNS
• Effect-site equilibrium = 1.4 minutes
• Vd = 27L
  * Much lower than other opioids
  * Due to higher protein-binding (???)
• Elimination half-time = 1.4-1.5 hour
• Context-sensitive half-time 4 hours = 60min
  * Longer than alfentanil due to smaller Vd

Metabolism

Efficient hepatic metabolism
--> 96% clearance within 60min

Most likely CYP3A4 involved

Noralfentanil is the major metabolite recovered in urine

Clinical uses

Blunting of CVS response to direct laryngoscopy
* 15 microgram/kg IV 90 seconds before

Induction of anaesthesia
* 150-300 microgram/kg IV
* Production of unconsciousness in 45 seconds

Remifentanil

Selective mu receptor agonist

• Analgesic potency is
  * Similar to fentanyl
  * 15-20 times as potent as alfentanil
• Effect-site time similar to alfentanil
  * Remifentanil = 1.1min
  * Alfentanil = 1.4min

Ester linkage

Structurally unique because of the ester linkage

Therefore,

Susceptible to hydrolysis by
* Nonspecific plasma esterase, and
* Tissue esterase

Thus

• Short duration of action
• Fast titratable effect
  * Due to fast onset and offset
• Noncumulative effect
• Rapid recovery

Pharmacokinetics

Due to:

• Rapid metabolism
• Small Vd (30L)

Thus remifentanil has minimal cumulative effect

 

• pK = 7.3
• 58% non-ionized at pH 7.4
• Protein-binding = 66-93
  * Less than alfentanil and sufentanil 
• Clearance = 4000 mL/min
  * Much higher than other opioids
• Vd = 30L
  * Small, similar to alfentanil (27L)
• Elimination half-time = 0.17-0.33 hour
  * Very short
  * Alfentanil is 1.4-1.5 hour
  * Clinically remifentanil behaves like a drug with an elimination half-time of <6min
• Context-sensitive half-time 4 hours = 4mins
  * Independent of duration of infusion
• Effect-site equilibration time = 1.1min

Metabolism

Metabolism is by nonspecific plasma esterase and tissue esterase

Not by pseudocholinesterase
--> Not affected by cholinesterase difficiency or anticholinergics

Very little variability between individuals
--> Very predictable effect

Clinical use

• Induction of anaesthesia
  * 1 microgram/kg IV
• Pre-medication prior to induction
  * 0.5-1 microgram/kg IV
• (???) Maintenance of anaesthesia

Side effect

• No histamine release
• No change in ICP and intraocular pressure
• No neonatal effect (despite passage through placenta)
• Remifentanil and propofol are synergistic in depression of ventilation

Acute opioid tolerance

Post-operatively, analgesic requirement is larger
--> Possible acute opioid tolerance

Not all data support acute opioid tolerance following remifentanil-based anaesthesia

Codeine

Substitution of a methyl group for the hydroxyl group on carbon 3 of morphine

Effective antitussive
* PO 15mg

Maximal analgesia occurs at 60mg
* Similar to 650mg of aspirin

Hydromorphone

Alternative to morphine for moderate to severe pain

Oxymorphone

10 times more potent than morphine

Cause more nausea and vomiting

Great risk of physical dependence

Oxycodone

Provides stable plasma concentration

Used for treatment of moderate to severe pain

Abuse potential is high

Hydrocodone

For treatment of chronic pain

Abuse potential is high

Methadone

Synthetic opioid agonist

Highly effective by PO route

Low abuse potential

Some action on NMDA receptor

Clinical uses

• Suppression of withdrawal symptoms in physical dependency of heroin and morphine
• Chronic pain treatment

Tramadol

Centrally acting analgesic

Mechanism of action

Moderate affinity for mu receptor

Weak affinity for kappa and delta receptors

Action

5 to 10 times less potent than morphine as an analgesic

Absence of depression of ventilation

Clinical uses

Low potential for development of tolerance, dependence, and abuse

Treatment of moderate to severe pain
* 3 mg/kg PO,IV, IM

Heroin

Synthetic opioid

Acetylation of morphine
--> Diacetylmorphine

Mechanism of action

Rapid penetration into CNS
--> (Hydrolysis)
--> Monoacetylmorphine and morphine (both active)

Compared with morphine

• Faster onset
• Lack of nauseating effect
• Greater potential for physical dependency