Pharmacology 8

emesis

antiemetics

• D2 antagonists
  • phenothiazines
    • propylamines
      • chlorpromazine
        • also muscarinic, alpha, histamine and 5HT antagonist
          • ‘pretty SMAHD’
        • BA 30%, PB 95%, 160 metabolites!
    • piperidines
      • thioridazine
    • piperazines
      • prochlorperazine
        • alpha blockade: orthostatic hypotension, anti-cholinergic, extrapyramidal side effects (e.g. oculogyric crisis)
  • benzamides
    • metoclopramide
      • also blocks 5HT3 receptors
      • also prokinetic and increases oesophageal sphincter tone
      • SE’s
        • neuroleptic malignant syndrome
        • dystonia
        • CVS: hypotension, arrythmias
        • increased prolactin
  • butyrophenones
    • droperidol
    • domperidone
      • does not cross BBB (can use in Parkinson’s)
• 5HT3 antagonists
  • ondansetron
    • carbazole derivative
    • PK
      • A: BA 60%
      • D: PB 76%
      • M: liver
      • E: T1/2 3hrs
    • SE’s
      • QT prolongation
  • gravisetron
• H1 antagonists
  • cyclizine
    • piperazine derivative
    • also has some antimuscarinic activity
    • PK
      • A: BA 80%
      • D
      • met. N-demethylation to inactive norcyclizine
      • E: T1/2 10hrs
• anti-cholinergics
  • atropine
  • hyoscine
  • may cause cholinergic crisis in Parkinson’s
  • reduce intragastric pressure, bronchodilate
• others
  • NK1 antagonists
  • dexamethasone
  • propofol
  • benzodiazepines
  • IV fluids
  • hypnotism, acupuncture

receptor locations

• labyrinths
  • H1
• vestibular + cerebellar nuclei
  • Ach
  • H1
• pain
  • H1
• CTZ
  • direct input
    • GIT
      • 5HT-3
    • emetics
  • 5-HT3
  • opioid
  • D2
  • ‘SOD’
  • area postrema on the floor of the 4th ventricle, outside the BBB
• GIT
  • Ach and NA
• chemo + baroreceptors
  • 5-HT3
  • H1
  • ‘SH’

local anaesthetics

esters

• cocaine
  • vasoconstriction
  • PB: 98%
• amethocaine
  • PB: 75%
• procaine
• issues
  • all may be met. to PABA - may cause allergy

amides

• lidocaine
  • Toxic concs (ug/mL)
    • 4
      • Circumoral tingling
    • 10
      • LOC, convulsions
    • 15
      • Coma
    • 20
      • Arrythmias, resp arrest
    • 25
      • Cardiac arrest
  • PK
    • 3mg/kg (7 with adrenaline)
    • pKa 7.9
    • unionised 25%
    • partition coefficient 3
    • PB 65%
    • Vd 1L/kg
    • CYP 3A4 to active mets
• bupivacaine
  • 2mg/kg max
  • pKa 8.1
  • unionised 15% (slower onset)
  • partition coefficent 28 (more potent)
  • PB 95% (longer acting, more toxic)
• levo-bupivacaine
• ropivacaine
  • pKa 8.1
  • partition coefficient 10
  • PB 95%
• prilocaine
  • met to O-toluidine —> methaemoglobinaemia

creams

• ameTOP choice!
  • 4% amethocaine
  • eythema due to mild histamine release (ESTER) and vasodilation
• EMLA
  • eutectic = 2 compounds mixed to produce a substance with different characteristics
  • 2.5% lidocaine + 2.5% prilocaine
  • cons
    • risk of methaemoglobinaemia (o-toluidine metabolite)
    • must wait 60 mins
    • avoid on mucous membranes
    • avoid with class-1 anti-arrythmics - additive effect
    • skin blanching & vasoconstriction

toxicity

• descending risk (IIC LBC)
  • IV
  • intercostal
  • caudal
  • lumbar
  • brachial plexus
  • S/C
• Tx:ABC
  • arrested
    • ALS, 1.5mL/kg 20% intralipid, then infusion of 15mL/kg/hr. Can give 2 further boluses and increase to 30mL/kg/hr
  • not-arrested
    • consider intralipid