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OPIOIDS (Definitions ('OPIATE' = naturally occurring compounds…

- - - - Chemical:
        
        synthetic
        
        diacetylated morphine derivative
        
        PRODRUG!
      - Uses: Analgesia (severe pain, epidural, spinal), dyspnoea of pulmonary oedema
      - Presentation:
        
        tablets
        
        white power for injection
      - Actions:
        
        No affinity itself
        
        metabolites have MOP and KOP agonist effect
        
        greatest euphoric effect (drug of abuse)
      - Dose: 2x potency of morphine
      - Side effects: less N&V
      - Pharmacokinetics
        
        Distribution
        
        40% PPB
        
        Higher lipid solubility means less likely delayed respiratory depression vs morphine when given epidural or intrathecal
        
        Metabolism
        
        Ester hydrolysis: liver, plasma, CNS
        
        forms 6-monoacetylmorphine
        
        6-monoacetylmorphine then glucuronidated to morphine
        
        Absorption
        
        pKa 7.6
        
        high lipid solubility → well absorbed gut, effective s/c route
        
        low oral BA (extensive 1st pass metabolism)
        
        Excretion
        
        half-life: 5 mins (rapid metabolism to active forms)
        
        as per morphine metabolites
    - - Synthetic opioid - structurally similar to codiene (2x as potent)
      - Oral BA 20%
      - Hepatic metabolism → analogous pathway to codeine
        urinary excretion
      - Greater efficacy at MOP receptor than codeine (Less dependent on CYP2D6 to form morphine)
    - - Semi synthetic
      - Full MOP Agonist
      - Similar potency and half-life to morphine → thus similar dosing
      - Higher oral BA than morphine (60% vs 30%)
      - Hepatic metabolism and renal excretion
  - - - ALFENTANIL
        
        Chemical: Synthetic phenylpiperidine derivative
        
        Uses: Short term analgesia and sedation
        
        Presentation: Clear colourless solution 500mcg/ml or 5mg/ml
        
        Action: μOP receptor agonist (highly selective)
        
        Dose: 5-25 mcg/kg
        
        Onset and offset: Rapid (faster than fentanyl)
        
        Less lipid soluble
        
        Elimination half-life shorter despite smaller clearance
        
        smaller initial Vd (less distributed to fat & muscle)
        
        Less potent than fentanyl - more molecules for same effect
        
        pKa 6.5 (90% unionised at pH 7.4)
        
        Route: IV
        
        Effects as per morphine but 20x potency
        
        Pharmacokinetics
        
        Absorption: Given IV
        
        Distribution:
        
        Vd smaller than fentanyl (0.6 vs 4.0 L/kg)
        
        higher PPB 90%
        
        Metabolism:
        
        hepatic: N-demethylation
        
        metabolite= noralfentanil
        
        midazolam metabolised by same CYP3A4 → prolong effect
        
        Excretion: urine
      - FENTANYL
        
        Uses:
        
        perioperative analgesia
        
        obtunds hypertensive response to laryngoscopy
        
        opioid based analgesia
        
        sedation via infusion
        
        Presentation:
        
        colourless solution for injection: 50 mcg/ml
        
        transdermal patches 25-100 mcg/hr for 72hrs
        
        lozenges
        
        Action: MOP receptor agonist (Some KOP)
        
        Dose:
        
        pain with surgery 1-2 mcg/kg
        
        opioid based induction 50-100 mcg/kg
        
        spinal 10-25 mcg
        
        epidural 25-100 mcg
        
        Onset:
        
        rapid (high lipid solubility - 600x morphine)
        
        duration short when IV (redistribution)
        
        Route: IV/transdermal/buccal/spinal/epidural
        
        Effects:
        
        as for morphine but 50x potency
        
        less histamine release
        
        decrease surgical stress response
        
        risk bradycardia
        
        chest wall rigidity in high doses
        
        Pharmacokinetics:
        
        Distribution
        
        PPB 80%
        
        Vd 4L/kg
        
        very lipid soluble → short duration due to redistribution
        
        Metabolism
        
        Hepatic metabolism:
        
        N-demethylation to norfentanil (inactive) then dehydroxlation
        
        inactive metabolites
        
        Absorption
        
        absorbed from small intestine (very lipid soluble)
        
        oral BA 33%
        
        pKa 8.4% (9% unionised at pH 7.4)
        
        Excretion
        
        Inactive metabolites excreted in urine
        
        Chemical: synthetic phenylpiperidine derivative
      - PETHIDIINE:
        
        Presentation: tablets 50mg, solution 10/50 mg/ml
        
        Action:
        
        MOP and KOP receptor agonism
        
        anticholinergic effect
        
        inhibits 5HT reuptake (avoid with SSRI, MAOI)
        
        Uses: analgesia (especially in labour), post-op shivering
        
        Dose:
        
        PO: 50-150mg every 4 hours
        
        IM/IV: 0.5-1.0mg/kg every 4 hours
        
        Epidural: 25mg
        
        Chemical: synthetic Phenylpiperidines derivative
        
        Route: IV/IM/PO/PR/epidural
        
        Pharmacodynamics:
        
        similar to morphine
        
        anticholinergic → less meiosis, dry mouth, tachycardia
        
        serious interaction with MAOI → central serotonergic hyperactivity → CV instability, hypepyrexia, seizure, coma
        
        Pharmacokinetics:
        
        Absorption:
        
        more lipid soluble → faster onset than morphine, oral BA 50%
        
        Distribution:
        
        PPB 50%
        
        VD 4L/kg
        
        Metabolism:
        
        Hepatic → active metabolite (norpethidine)
        
        norpethidine is epileptogenic
        
        Excretion:
        
        Urinary
        
        norpethidine accumulates in renal failure → seizure risk, hallucinations
        
        Cautions:
        
        interactions: MAOI
        
        significant amounts reach foetus (lipid solubility high)
        
        reduced foetal clearance so risk norpethidine accumulation
    - - REMIFENTANIL
        
        Presentation: white crystalline powder 1/2/5mg (reconstitution with 0.9% saline)
        
        Chemical: synthetic phenylpiperidine derivative
        
        Action: pure μOP receptor agonist
        
        Dose: Given as infusion: 0.05-2 mcg/kg/min
        
        Onset: rapid Onset and offset
        
        Route: IV Infusion
        
        Side effects: bradycardia, chest wall rigidity
        
        Pharmacokinetics:
        
        Distribution
        
        very small Vd (0.3 L/kg)
        
        70% PPB
        
        pKa 7.1
        
        Metabolism
        
        non-specific plasma and tissue esterases (ester hydrolysis)
        
        duration of action determined by metabolism rather than distribution (cf - alfentanil and fentanyl)
        
        abundance of esterases → context INSENSITIVE half-time
        
        elimination half life of 3-10minutes.
        
        Unaffected by hepatic or renal dysfunction
        
        no effect of plasma cholinesterase deficiency or anticholinesterase drugs
        
        Absorption
        
        only Given IV (Very low lipid solubility)
        
        Excretion
        
        carboxylic acid metabolites excreted in urine
        
        Uses:
        
        intraoperative analgesia
        
        hypotensive anaesthesia
        
        Sedation (ICU, AFOI)
        
        TIVA
    - - Chemical: Propionate anilides
      - Uses: opioid replacement programmes
      - Presentation: syrup
      - Action: μOP agonist, some antagonism of NMDAR
      - Pharmacokinetics:
        
        Well absorbed, low first-pass → high oral BA (75%)
        
        long plasma half-life (90% PPB) → OD administration
        
        hepatic metabolism (inactive metabolites)
        
        urinary excretion (40% unchanged)
    - - Presentation: tablet 50/100mg (also MR form), solution 100mg in 2ml
      - Action:
        
        weak agonist all opioid receptors (greatest affinity μOP)
        
        inhibits reuptake NA and 5HT
        
        stimulate presynaptic relase 5HT (modulate pain via descending pathways)
      - Uses: analgesic
      - Dose: 50-100mg 6hourly
      - Chemical: cyclohexanol derivative. racaemic mixture.
      - Pharmacodynamics:
        
        as for morphine but 1/10 potency
        
        less respiratory depression
        
        less constipation
        
        lowers seizures threshold → relative contraindication in epileptics
      - Interactions:
        
        Drugs inhibiting reuptake of NA or 5HT ( → SSRI, SNRI, TCA, MAOI)
      - Pharmacokinetics:
        
        absorption: well absorbed gut, oral BA >70%
        
        distribution: VD 4L/kg,
        
        metabolism: hepatic → has active metabolite (o-desmethyltramadol)
        
        excretion: urine
  - - - Chemical:
        
        Basic amine
        
        naturally occurring phenanthrene derivative
        
        pKa 8.0
      - Uses: Anaglesia, CCF.
      - Presentation:
        
        tablets, suspensions, suppositories, slow-release capsules
        
        parenteral clear colourless solution 10-30 mg/ml
      - Action: MOP Receptor agonist (some KOP & DOP)
      - Pharmacodynamics
        
        CV:
        
        NO direct myocardial depression
        
        Bradycardia and hypotension (2° to histamine)
        
        RS:
        
        Respiratory depression (blunts response to CO2)
        
        Anti-tussive
        
        bronchospasm (2° to histamine)
        
        GI:
        
        ↓motility, sphincter constriction
        
        Nausea and vomiting (stimulates CTZ via 5HT3 and D2 receptors)
        
        CNS:
        
        analgesia
        
        sedation
        
        meiosis (stimulates Edinger-Westphal nucleus)
        
        seizures and rigidity at high doses
        
        ENDO: ↓ACTH, ↑ADH
        
        GU: ↑detrusor and urinary sphincter tone (retention), ↑uterine tone
      - Dose: PO 5-20mg every 4°, IV/IM 0.1-0.2mg/kg every 4°
      - Onset: peak effect 10min IV, 30min IM.
      - Route: IV/IM/SC/PO/PR/intrathecal/epidural
      - Side effects: see above
      - Toxicity: severe respiratory depression, seizures
      - Pharmacokinetics
        
        Absorption
        
        weak base pKa 8.0 (ionised in stomach → instead absorbed in small bowel)
        
        oral BA 30% (extensive 1st pass metabolism)
        
        Distribution:
        
        30% PPB
        
        low lipid solubility (so brain concentration falls slowly)
        
        peak effect 10/30mins IV/IM, duration 3-4 hours
        
        Metabolism
        
        Hepatic: glucoronidation and N-demethylation
        
        Metabolites: M-3-G, M-6-G (16x activity of morphine!)
        
        Excretion
        
        in urine
        
        accumulate in renal failure
    - - Chemical:
        
        naturally occurring phenanthrene derivative
        
        methylated morphine derivative (3-methylmorphine)
      - Uses: analgesia (moderate pain), antitussive, anti-diarrhoeal
      - Presentation:
        
        tablets 8/15/30/60 mg.
        
        syrup 5 mg/ml
        
        solution for injection 60 mg/ml
        
        preparations with paracetamol
      - Action:
        
        low affinity for opioid receptors
        
        Approx 10% metabolised (O-demethylation) to morphine
        
        ? Prodrug
      - Dose: 30-60mg (10x less potent than morphine)
      - Route: IM/PO
      - Side effects:
        
        avoid children <12 years
        
        avoid in breast feeding (unpredictable metabolism)
        
        IV route avoided as risk histamine release → profound hypotension
      - Pharmacokinetics
        
        Distribution
        
        low PPB (<10%)
        
        Metabolism:
        
        Hepatic metabolism 3 ways:
        
        2) 10-20% N-demethylation to norcodeine
        
        3) 0-15% O-demethylation to morphine (CYP2D6)
        
        1) 60% glucuronidated to codeine-6-glucoronide
        
        Significant genetic polymorphism of CYP2D6
        
        Fast metabolisers → increased morphine
        
        Slow metabolisers (9% U.K, 30% chinese) → less morphine → ineffective analgesia
        
        Absorption
        
        well absorbed orally
        
        oral BA 60%
        
        Excretion:
        
        Up to 15% excreted unchanged in urine.
- - - - effects: analgesia, resp depression, physical dependence
      - Identified in vas deferens of mice
      - Site: Brain
    - - Effect:
        
        Spinal analgesia
        
        sedation
        
        Meiosis
      - Identified by: ketocyclazocine
      - Site: Brain, spinal cord
    - - Effects:
        
        μ1 → Analgesia, physical dependence
        
        μ2 → Meiosis, euphoria, Respiratory depression (↓ sensitivity CO2) , ↓ gut peristalsis
      - Sites: Throughout CNS
        
        Cerebral cortex
        
        Basal ganglia
        
        Spinal cord (presynaptically on 1° Afferent in Dorsal Horn) - rexed laminae 1 and 2
        
        Periaqueductal grey (origin of descending inhibitory pathway)
      - Morphine used to identify it
    - - Sites: Brain, spinal cord
      - Effects:
        
        Hyperalgesia at low dose, analgesia at high dose
        
        anxiety, depression
        
        involved in tolerance
      - Stimulated by: nocicpetin/orphanin FQ
- - - - periaqueductal grey has GABAergic interneurons
        
        these would inhibit descending inhibitory pathways
        
        presynaptic opioid receptors inhibit GABA release
        
        disinhibition → removal of Inhibitory effect on descending pathway!
        
        reduces activity of afferent nociceptivd pathway in dorsal horn
  - - - Pre-synaptic opioid receptors
        
        decreases NT release from nerve terminals of afferent neutrons