Pharmacology 10

analgesics

Paracetamol

• PB: 0-5%
• Vd: 1L/kg
• absorbed in small intestine
  • marker for gastric emptying!
• toxicity
  • normally undergoes sulphation and glucoronidation and excreted in urine
    • CAN BECOME SATURATED!
  • 10% oxidised by P450 to NAPQI
    • normally detoxified by conjugation w. glutathione and excreted in urine
    • when glutathione stores are exhausted, NAPQI binds to hepatocellular proteins, causing a cascade of hepatocellular damage, mainly in zone 3 of the centrilobular area
  • Tx: ABC, NAC, methionine (both increase glutathione stores)

NSAIDs

• normally
  • membrane phospholipids
    • phospholipase A2
      • arachidonic acid
        • lipoxygenase
          • leukotrienes
            • bronchoconstriction
        • cycloxygenase
          • PGH
            • platelets
              • thromboxane A2
                • produced in platelets
                • platelet aggregation
                • vasoconstriction
            • vascular endothelium
              • PGI2 (prostacyclin)
                • produced in vascular endothelium
                • inhibits platelet aggregation
                • vasodilation
            • widespread
              • PGE2
                • inflammatory
                • keeps DA open in foetus
              • PGF2alpha (dinoprost)
                • inflammatory
                • used to induce labour/abortion
• COX inhibitors
  • aspirin
    • MOA
      • COX-1 inhibition (mainly side effects)
        • reduce PGI2 and PGE2
          • Gut
            • So less inhibition of acid secretion
          • Kidneys
            • So less vasodilation
        • reduce TXA2 IRREVERSIBLY (PGI2 is only transiently reduced)
          • overall reduction in platelet function
      • COX-2 inhibition (therapeutic effects)
        • reduce PGE2 and PGF2alpha
          • Analgesic, anti-inflammatory, anti-pyretic
      • Increase leukotrienes
        • bronchoconstriction
    • other side effects
      • resp
        • uncouples oxidative phosphorylation
          • increased O2 consumption
          • increased CO2 production
          • resp alkalosis
      • haem
        • may displace warfarin from albumin to increase effect
    • PK
      • BA 70% (due to extensive 1st pass metabolism)
      • PkA 3.5
      • PB 85%
      • Vd 0.1L/kg
      • met: intestinal and hepatic esterase to salicylate, glucoronided and excreted in urine
      • may convert to zero order kinetics
    • OD
      • resp alkalosis
      • followed by met acidosis
      • Tx: ABC

        • 300mg/mL

          • give bicarb - alkalinises urine, therfore ionising salicylates (weak acids) and trapping them in urine

        • 700mg/mL

          • filtration
  • ibuprofen
    • BA 80%
  • diclofenac
    • BA 50%
  • ketorolac
  • benorylate
    • aspirin + paracetamol
  • azapropazone
    • no longer licensed!
  • phenylbutazone
    • aplastic anaemia - no longer licensed!

Opioids

Receptors

• All
  • PRESYNAPTIC Gi GPCR’s
    • Activation ‘CCOKIC’
      • Closure of voltage gated Ca channels
      • Opening of K channels causing hyper polarisation
      • Inhibition of cAMP
• Mu / MOP / OP3
  • Mu1
    • Analgesia
  • Mu2
    • Bradycardia, Resp depression, Reduced gut motility, Euphoria, Miosis
      • BRight GEM
  • Mu3
  • Physical dependence
• Kappa / KOP / OP2
  • Analgesia, sedation, miosis, inhibition of ADP release
  • Sedation, Analgesia, Miosis, Inhibition of ADP release
    • ‘SAMI Damoussi wears Kappa’
  • K1, K2, K3
  • Ketocyclazacine
  • Different kind of dependence
• Delta / DOP / OP1
  • Analgesia, Resp depression
    • ‘RAD’ - analgesia, resp. depression = delta
  • D1, D2
  • Enkephalins
• NOP

Agonists

• Phenyl-piperidines
  • Fentanyl
  • Alfentanyl
  • Remifentanyl
    • Anilino-piperidine
    • Lyophilised white powder with glycine buffer
      • (Not licensed for epidural or intrathecal use due to glycine)
    • Met: non-specific plasma esterases
  • Pethidine
• Phenanthrines
  • Morphine
  • Codeine
    • 10% met to morphine by CYP2D6
• cyclohexanol derivatives
  • tramadol
    • racemic
    • MOA
      • all opioid receptors
      • inhibits re-uptake of NA and 5-HT
      • stimulates presynaptic 5-HT release
      • desmethyltramadol
        • 200x mu affinity

mixed agonist/antagonists

• buprenorphine
• butorphanol
• nalbuphine
  • kappa agonist
    • Analgesia
  • Mu antagonist
    • No resp depression or dependence
  • Does not obtund responses to laryngoscopy and may precipitate withdrawal in addicts
• pentazocine
• ‘B-BNP’

Antagonists

• naloxone
• naltrexone

benzodiazepines

drugs

• short
  • midazolam
    • tautomerism: water soluble ionised ring structure at pH 4, closes above 4 and becomes lipid soluble
    • BA 40%
    • pKa 6.5, 89% unionised at pH 7.4
    • PB 98%
    • T1/2 1-4 hours
    • Cl 6ml/kg/min
    • CYP 3A4
• medium
  • temazepam
    • T1/2: 8 hours
  • lorazepam
    • T1/2: 10 hours
• long
  • diazepam
    • BA 95%
    • PB 99%
    • T1/2: 24 hours

MOA

• bind to separate sites on GABAa receptors and increase their affinity for GABA, opening Cl channels and hyperpolarising the membrane

OD

• ABC
• flumazenil
  • imidazobenzodiazepine derivative
  • binds to same site and antagonises action
  • may cause withdrawal and seizures