Pharmacology of Analgesics

NSAIDs

• Pharmacokinetics
  • Most well absorbed with/without food
  • Most highly bound to albumin
  • Mostly CYP3A/2C enzymatic metabolism
  • Renal excretion most important but nearly all have some enterohepatic circulation
• Pharmacodynamics
  • Analgesic, anti-inflammatory and anti-pyretic
  • Primarily reversible COX inhibition -> Reduced prostaglandin synthesis
    • Aspirin irreversibly acetylates and blocks platelet COX enzymes
  • All are nephrotoxic
  • Do not alter the natural course of arthritic conditions despite anti-inflammatory effect
  • Adverse effects
    • CNS: Headache, tinnitus, dizziness
    • CVS: Oedema, HTN, CV events
    • GI: Gastritis, dysplasia, vomiting, ulcers and bleeding
    • Haematological: Thrombocytopaenia, neutropaenia
    • Hepatic: Hepatitis
    • Pulmonary: Asthma
    • Skin: Rash
    • Renal: Renal insufficiency, hyperkalaemia
• COX-2 selective inhibitorsApproximately half the risk of GI adverse effects
  • Inhibit COX-2 prostacyclin synthesis in vascular endothelium without inhibiting platelet COX-1 thromboxane synthesis -> Increases CVD risk
  • Similar rates of kidney injury
• Non-selective COX inhibitors
  • E.g. Diclofenac, ibuprofen, indomethacin, ketorolac, naproxen

Aspirin

• Pharmacokinetics
  • pK 3.0
  • Peak plasma level 1-2 hours
  • Half-life 15 min as rapidly hydrolysed to acetic acid and salicylate
  • Alkalinisation of urine increases rate of excretion of free salicylate and water-soluble conjugates
• Pharmacodynamics
  • Irreversible platelet COX inhibition so effect lasts 8-10 days (platelet lifespan)
  • Other effects last 6-12 hours as cells replace their COX enzymes
  • Raye syndrome a risk in children

Paracetamol

• Pharmacodynamics
  • Weak COX-1 and COX-2 inhibitor
  • No anti-inflammatory properties
  • Adverse effects
    • Hepatitis
    • Renal injury
• Pharmacokinetics
  • PO/PR/IV
  • Peak blood concentrations 30-60min
  • Slightly bound to plasma proteins
  • Partially metabolised by hepatic microsomal enzymes to inactive metabolites
  • Minor metabolite (N-acetyl-p-benzoquinone – NAPBQ) accumulates in toxicity
  • Half-life 2-3 hours

Opiates

• Pharmacokinetics
  • Absorption
    • Most well absorbed SC, IM, PO
    • Oral morphine dose undergoes high degree of first-pass metabolism
    • Codeine and oxycodone have less first-pass metabolism
    • IN fentanyl is an option
    • Transdermal also possible
  • Distribution
    • Rapidly distribute to high blood flow organs e.g. brain, lungs, liver, kidney and spleen
      • Main reservoir is skeletal muscle due to size of organ overall
      • Accumulation in fatty tissue can also be a concern after freqeuent dosing or continuous infusions despite lower blood flow
  • Metabolism
    • Mostly glucuronidation in liver
    • Morphine to Morphine-3-glucuronide (neuroexcitatory via GABA) and morphine-6-glucuronide (active with 4-6x more potent analgesic efficacy)
      • Pose problems in renal failure or in high/frequent dosing
    • Esters (e.g. heroin, remifentanil) are rapidly hydrolysed by tissue esterases
    • Phenylpiperidine derivates (fentanyl) undergo hepatic oxidative metabolism
    • Fentanyl has no active metabolites and undergoes N-dealkylation by CYP3A4
    • Codeine and oxycodone undergo metabolism in liver by CYP2D6 to more potent active metabolites
      • Genetic polymorphisms explain differing efficacy of codeine
    • Excretion
      • Metabolites mainly excreted in urine
• Pharmacodynamics
  • Bind to GPCR opioid receptors thus affecting ion channel gating and intracellular protein phosphorylation e.g.
    • Close VG-Ca channels at presynaptic nerve terminals to reduce neurotransmitter release
    • Hyperpolarise and inhibit postsynaptic neurons by opening K channels
  • Primary effects are via mu-receptor agonism
  • Tolerance – Loss of effectiveness with repeated exposure (does not occur for miosis)
  • Physical dependence – Characteristic withdrawal syndrome when drug stopped or antagonist delivered
  • CNS effects: Analgesia, euphoria, sedation, respiratory depression, tolerance, cough suppression, miosis, nausea, vomiting
  • CVS: Hypotensive and cardiac depressant when CVS under stress
  • GI: Constipation, slowed GI transit (no tolerance develops) with subsequent enhanced water absorption in large intestine
  • Renal: Mildly reduced function secondary to reduced renal plasma flow, urinary retention
  • Neuroendocrine: Stimulate release of ADH, prolactin and somatotropin
  • Pruritis
• Indications
  • Acute pain
  • Cough suppression
  • Terminal pain/dyspnoea
  • Diarrhoea e.g. loperamide
  • Shivering
  • Procedural sedation
  • Regional analgesia e.g. epidural
• Strong agonists
  • Phenanthrenes e.g. morphine, heroin
  • Phenylheptylamines e.g. methadone
  • Phenylpiperidines e.g. fentanyl, remifentanil, alfentanil
• Moderate agonists e.g. codeine, oxycodone
• Mixed receptor actions
  • Buprenorphine: Potent long-acting partial mu-agonist and kappa-receptor antagonist
• Miscellaneous
  • Tramadol: Centrally-acting analgesic that acts primarily via serotonin reuptake inhibition. Also inhibits noradrenaline transporter function and weak mu-receptor agonist. Risk of serotonin syndrome, nausea and vomiting.
  • Tapentadol: Most mu-receptor agonism and NA-reuptake inhibition. Weaker binding to serotonin transporter than tramadol. Increased risk of seizures in those with seizure disorders and potential for serotonin syndrome.

Last Updated on August 12, 2021 by Andrew Crofton