OPIOIDS: Classification, Pharmacokinetics, Neuroleptanalgesia– ANESTHESIA

Balanced Anaesthesia

Use of multiple drugs in a titrated way to provide different components of general anaesthesia.

• One component required during GA is analgesia 
• OPIOID because of it anti-naive septic effect has a huge role in providing infra operative analgesia
• Apart from analgesic effect, opioid is also used as an adjuvant of other drugs.
• Has a strong role in balanced anesthesia

OPIOID

History

• Opium: Mean juice from poppy plants
• Opiates: Natural drugs separated from opium 
• Morphine: First drug to be separated from opium  

• Natural or synthetic drugs acting on opioids receptors and producing morphine like effects 
• 3 types 
• r (rew)
• r1
• r2
• k (Kappa)
• δ (delta)

Action

• Act as an agonist at stereospecific opioid post synaptic sites in CNS and outside CNS in peripheral tissue.
• Opioid receptors are located on primary afferent neurons

Classification

• 4 groups

1. Pure agonist: With intrinsic action

• Morphine
• Pethidine (Meperidine)
• Fentanyl
• Sufentanil
• Alfentanil
• Remifentanil

1. Partial agonist: With CI intrinsic activity 

• Buprenorphine
• Agonist: Antagonist
• Pentazoane (P)
• Nalbuphine (N)
• Butorphanol (B)

• Pure Antagonist
• Naloxone
• Naltrexone
• Nalmefene

Opioid agonists

• Opioid agonist are most likely to be used with inhaled and intravenous anaesthesia as adjuvant during general anaesthesia
• Large doses can be used as sole anesthetic in critically ill patients (CVS stable)

Morphine

• Is the prototype opioid agonist to which all opioids will be compared

Routes

• IV
• IM Onset time 15 – 30, Peak effect 45 – 90 min
• Oral
• Nebulization
• Intrathecal

Slow effect site equilibrium

• Poor lipid solubility
• High degree of ionization
• High protein binding
• Rapid conjugation with glucuronic acid

Metabolism

• Hepatic metabolism by conjugation with glucuronic acid
• 2 intermediate products

1. Morphine 3 – Glucuronide
2. Morphine 6 – glucuronide
3. Morphine 3 – glucuronide

• 75 – 85%
• Inactive

1. Morphine 6 – glucuronide

• 15 – 25%
• Active
• Completely eliminated through kidney

Pharmacodynamics

CVS

• No myocardial depression
• No hypotension
• Depresses compensatory SNS response cause bradycardia
• Little decrease in systemic vascular resistance due to histamine release
• Morphine is CVS stable

Respiratory system

1. Dose dependent direct depression of ventilation through effect on respiratory centre on brain stem
2. Decrease responsiveness of ventilator centre to CO2
3. Interferes with pattern of breathing 

• Rhythm is disturbed with long pauses

1. Depression of ventilation is for prolonged period
2. Depression of ciliary activity in airway

CNS

• ↓ Cerebral metabolic oxygen requirement
• ↓ Cerebral blood flow
• ↓ Intracranial pressure
• ↓ EEG

Skeletal muscle rigidity 

• Thoracic
• Abdominal rigidity 
• Due to ↑ed skeletal muscle tone because of imbalance between Dopamine & GABA

Miosis

• Due to an excitatory action in the ANS component of Edinger Westphal nucleus of oculomotor nerve

Biliary tract

• Spasm of biliary smooth muscle resulting in ↑ intrabiliary pressure

CTZ center

• Caused by direct stimulation of chemoreceptor trigger zone (CTZ) in the form of 4th ventricle

Genitourinary system

• Increases tone and peristaltic activity of ureter
• Urinary urgency is produced because augmentation of tone of Detrusor augmentation of tone of Detrusor muscle

Cutaneous changes

• Dilate cutaneous vessels causing flushing of face, neck and upper thorax.

OVERDOSE

• Morphine overdose principal manifestation
• TRIAD
• Respiratory depression
• Miosis
• Coma

Treatment

• Support Ventilation
• Give Naloxone

MEPERIDINE

• Synthetic opioid agonist on mu and kappa receptor 

Structure

• Phenylpiperidine
• Structurally similar group to local anesthetic

• Tertiary amine
• Ester group
• Lipophilic phenyl group

• It has local anesthetic effect
• Structurally resemble Atropine
• Produces Mydriasis
• Antispasmodic effect

Pharmacokinetics

• 1/10th as potent as morphine
• Duration of action: 2 – 4 hrs

Metabolism

• Liver metabolism: 90% by demethylation to Normeperidine
• Normeperidine: Eliminated by Kidney
• In presence of renal failure, Normeperidine can accumulate and cause CNS stimulation
• Seizure
• Myoclonus

Clinical use

• Principal use

1. Labor analgesia

• Post-operative analgesia

1. As local Anesthetic

• For subarachnoid block

1. Anti-shivering agent

• Through effect on K receptor and also by being α2 – agonist

Side effects

1. Tachycardia
2. Metabolite

• Normeperidine accumulation can cause CNS stimulation

1. Serotonin syndrome

• Symp stimulation: ↑ BP, ↑ HR, Diaphoresis, ↑ core temp.
• NMJ: Myoclonus, ↑ tone
• CNS effect: Behavioural change

Fentanyl and its congener

• All are phenyl piperidine derivatives
• Synthetic opioids
• Drugs
• Fentanyl
• Sufentanil
• Alfentanil
• Remifentanil

Pharmacokinetics

Uses

Fentanyl

1. Low dose as analgesic

• 1 – 2 µg / kg BW

1. Dose

• 2 – 10 µg / kg BW as adjuvant to inhalational & intravenous anesthetic

1. Dose

• 50 – 100 µg / kg BW as sole anesthetic
• Advantages as sole aesthetic
• Advantage: CVS stability
• Disadvantage: Prolonged resp. depression

1. Intrathecal

• 25 µg

• Spinal anesthesia
• Lobour analgesia

1. Transdermal Fentanyl patch

• Patch is applied by base skin for analgesia
• 75 to 100 µg/ hr is released 
• Peak effect will be after 18 hrs after application
• Once a patch is removed, the effect remains because of the slow release of fentanyl from the skin depots.

1. Transmucosal

• Oral lozenges (Lollipops)
• Used in pediatric as premedical
• Dose 5 – 20 µg/kg
• Not very popular because of the high incidence of nausea and vomiting 

Sufentanil

• More potent than fentanyl
• Fast effect site equilibrium

Uses

1. Analgesia: 0.1 to 0.4 µg/ Kg IV
2. Anesthesia: 10 to 30 µg/ Kg IV
3. Sympatholytic use before laryngoscopy and intubation
4. As an adjuvant with local anesthetics for spinal anaesthesia  

Alfentanil

• 1/10th of fentanyl
• Effect site equilibrium 1.8 min

Uses

1. As sympatholytic agent before laryngoscopy and intubation
2. Analgesia
3. Anesthesia
4. As adjuvant to local anesthetic for spinal anesthesia

Remifentanil

• Most potent
• Unique structure: Ester linkage: metabolized by ester hydrolysis
• Ultra short duration
• Fastest effect site equilibrium: 1.1 min

Benefit

• Brevity (small duration) of action

Uses

1. Analgesia
2. Anesthesia
3. Short procedure: rapidly metabolised (fast offset)
4. Sedation
5. TIVA: Propofol + Remifentanil (most popular combination)
6. Labour analgesia: Best opioid 

• Even if it cross placental barrier and goes to fetus
• It will get metabolized in the fetus because of its ester hydrolysis
• It does not require contribution of organ for its metabolism
• Because of its unique metabolism even fetus can metabolize

PARTIAL AGONIST DRUG

Tramadol

• Centrally Acting opioid with moderate effect on receptor and weak effect on k and δ receptor

Structure

• 4 – Phenyl – piperidine analogue of codeine (synthetic opioid)
• Dextro (+) and levo (-) enantiomer in equal amount (Racemic mixture)
• Both enantiomer has synergistic effect
• Both enhance spinal descending inhibitory effect on pain.
• Dextro (+) enantiomer inhibits uptake of serotonin
• Levo (-) enantiomer inhibits uptake of non adrenal
• Dextro (+) enantiomer has r receptor

Route

• IV : 50/ 100 mg, mex 800 mg in 24 hrs
• IM
• Oral

Metabolism: Liver 

Uses

1. Moderate to severe pain

• Good agent for post-operative analgesia

• Less respiratory depression
• Low abuse potential

1. Ant shivering agent 

Advantage effect

1. Nausea and vomiting
2. Dizziness, drowsiness, sweating 
3. Dry mouth

Severe adv. Effect

1. Seizure
2. Serotonin syndrome
3. Resp. depression

Opioid Agonist – Antagonist

• The drugs have Antagonist effect or on effect on r receptor
• The drugs have Agonist effect on K and δ receptor

Pentazocine 

• Benzomorphan derivative

Pharmacokinetic

• Extensive first pass metabolism
• Elimination half-life is 2 – 3 years

Clinical use

• IV or oral for mild to moderate pain
• Sequential analgesic anesthesia

Side effect

• Sedation
• Diaphoresis
• Dizziness
• Dysphoria
• Fear of death
• High risk of physical dependence 

Nalbuphine

• Antagonist on r receptor
• Agonist on δ and K receptor

Pharmacokinetic

• Fast onset 5 – 10 min
• Duration long 3 – 6 hrs.
• Long plasma elimination time
• Hepatic metabolism

Uses

• Analgesia for acute post-operative pain and chronic pain

Butorphanol

• Agonist on K receptor
• Antagonist on r receptor
• 5 – 10 times more potent than morphine.
• Only parenteral preparation is available

Onset 

• Fast
• Peak effect in 1 hr
• Plasma t1/2: 2 – 3 hrs

Clinical use

1. Analgesia
2. Intraoperative period
3. Acute postoperative pain
4. Epidural analgesia

Side effect

• Drowsiness
• Sweating
• Nausea

PARTIAL AGONIST 

Buprenorphine

• The bain derivate
• r receptor partial agonist 
• 33 times more potent than morphine

Pharmacokinetics

• Highly Lipophilic

• Strong association 
• Slow dissociation with receptor
• Slow onset
• Peak effect at 3 hrs
• Duration:  9 – 10 hrs

Metabolism: Liver

Uses

1. Analgesia in intraoperative period
2. Post-operative period

OPIOID Antagonist

• Pure opioid antagonist 

• Short duration of action: 30 – 40 min
• Onset: 1 – 2 min.

1. Treat opioid induced respiratory depression 

• Post operatively dose: 1 – 4 µg/Kg/ hr

1. Reverse ventilatory depression in Neonate

1.  Nausea & Vomiting
2. ↑ BP, ↑ HR

1. Alcoholism
2. Post anesthetic apnea in infants
3. Benzodiazepine, Barbiturates & alcohol reversal
4. Intractable pruritus 

Naltrexone

• Antagonist on r, k and δ receptor
• Longer t1/2: 8 – 12 hrs
• Decreased 1st pars metabolism
• Cardiovascular stimulation

Nalmefene

• Pure antagonist
• More effect on r receptor
• Long acting
• Oral preparation available
• Parental preparation also
• Hepatic metabolism

NEUROLEPTANALGESIA – ANESTHESIA

• Coined by De castro and mundeler
• This technique combines a strong tranquilizer (Droperidol) + Potent – Opioid (Fentanyl)
• Produces detached pain free state of immolization

Characteristics

1. Analgesia
2. No evident motor activity
3. Suppression of autonomic reflex
4. Cardiovascular stability
5. Amnesia

Neuraval opioid

• Placement of opioids in epidural or subarachnoid space to manage acute or chronic pain
• Opioid receptor (r) present on dorsal horn in the substantia gelatinosa of the spinal cord 

• Compared to L.A it is not associated with sympathetic block, skeletal muscle weakness or loss of proprioception

Opioids

• Epidural dose is 5 to 10 times of subarachnoid space

Epidural

Side effects / Epidural opioid 

• 4 classical side effects

1. Pruritis

• Most common
• Localized to the face, neck or upper thorax
• More common in obs. Patient 

Mechanism 

• Cephalad migration of the opioid, in CSF and subsequent interaction with opioid receptor in trigeminal nucleus

Treatment 

• Naloxone

2. Urinary retention

• More common with epidural opioid than IV opioid

Mechanism

• • Interaction of drug with sacral opioid receptor

• Inhibit sacral parasympathetic outflow.

Treatment

• Naloxone

3. Depression of ventilation

• Respiratory depression
• 2 types 

1. Early: IV uptake (systemic effect)
2. Late: Cephalad migration of drug through spinal cord.

Management

• Ventilation
• Naloxone

4. Nausea & Vomiting

• This is due to cephalad migration of drug to CT2 centre

5. Sedation
6. CNS excitation

Post operative Analgesia