Pharmacology 1

Poisoning

ethylene glycol

• alcohol dehydrogenase
  • glyceraldehyde
  • glycol acid
    • metabolic acidosis, cytotoxic kidney damage
  • glycoxylic acid
  • oxalic acid
  • calcium oxalate
    • crystals form in brain
• Dx
  • suspicion
  • raised anion gap
  • high lactate on BG but not lab result
  • fluorescing in bodily fluids
• Tx
  • ethanol
    • 100x stronger
  • fomepizole
    • alcohol dehydrogenase antagonist
    • £3000/day
  • filtration

alcohol

• met by alcohol dehydrogenase —> acetaldehyde
  • acetaldehyde dehydrogenase —> acetate

methanol

• toxicity
  • direct CNS depressant
  • met. by alcohol dehydrogenase —> formic acid
    • inhibits cytochrome C oxidase
• Tx. alcohol or fomepizole

pharmacodynamics

laws and principles

• law of mass action = velocity of a chemical reaction is proportional to the concentrations of the reacting components
• Bowman’s principle = the lower the potency, the more drug required, so the higher the concentration gradient and the faster the speed of onset

interactions

• pharmaceutical
  • outside the body
    • e.g. thio and sux form a complex when mixed
    • e.g. paraldehyde reacts with plastic, so needs a glass syringe
  • inside the body
    • e.g. penicillamine chelates heavy metals
• pharmacodynamic
  • direct interaction
    • e.g. flumazenil competes for same binding site as midazolam
  • indirect
    • e.g. anticholinesterases increases Ach, so reducing the effect of NMBs
  • summation
    • effects of two drugs are additive
      • e.g. propofol and midazolam
  • synergism
    • effects of two drugs are more than additive
      • e.g. sulphonamides and trimethoprim are bacteriostatic alone, but bacteriocidal together
  • potentiation
    • effect of an inactive and an active drug together produce more of a response
      • e.g. prolonged action of NMBs with Mg
  • can be demonstrated on an isobologram
• pharmacokinetic
  • absorption
    • e.g. activated charcoal reduces absorption
  • distribution
    • e.g. bisoprolol reduces CO, so slows action of sux
    • e.g. giving 2 highly protein bound drugs - aspirin and phenytoin - doses required will be much lower
  • metabolism
    • CYP450
  • excretion
    • e.g. alkalinising urine with bicarb for aspirin toxicity
• types of antagonism
  • competitive
    • morphine and naloxone
  • non-competitive
    • sux and acetylcholine
  • physiological
    • ephedrine and histamine
    • different physiological actions cancel each other out
  • chemical
    • e.g. penicillamine

equations

• Drug-receptor (KARrR)
  • Kd = [D][R]/[DR]
  • affinity = 1/Kd
  • [RT] = [R] + [DR]
  • r = [DR]/RT = [D]/(Kd + [D])
    • therefore, when the drug concentration is equal to the KD, the occupancy is 50%
  • R = Er = E[D]/Kd + [D]
    • therefore, when the drug concentration is equal to the KD, the response is 50% of maximal
  • Kd= dissociation constant, r = occupancy, RT = total receptors R = response, E= efficacy
• therapeutic index = TD50/ED50
  • digoxin = 2

structure

• basics
  • alkyl = carbon with 3 hydrogens
  • aryl = aromatic group
  • ether = two carbon group separated by an oxygen
  • ester = R-COOH
  • Amine = H2N - R
• isomerism
  • same formula but different structure
  • types
    • structural = different structures
      • tautomerism
        • e.g. midazolam from pH 4 —> 7.4
        • thiopentone
      • chain
        • e.g. butane and isobutene
      • position
        • e.g. isoflurane and enflurane
    • stereoisomers = different 3D configuration
      • optical
        • mirror images
        • enantiomers have the same physicochemical properties but may bind to receptors differently
        • chiral centre surrounded by 4 different groups
        • a racemic mixture contains equal amounts of the two enantiomers
        • e.g. S&R enantiomers of ketamine, ropivacaine and bupivacaine
          • S = So much better
          • except R is better for etomidate!
        • L & D atropine and hyoscine (L is active)
        • Volatiles
          • Except sevo
      • diastereoisomers
        • not mirror images
        • differ in their physicochemical properties
        • geometric
          • molecule has two dissimilar group attached to two atoms linked by a double bond or ring structure
          • cis and trans
          • e.g. mivacurium
            • 60% trans-trans (plus has least activity of the three)
        • more than one chiral centre
          • e.g. atracurium
• Bonding
  • Ionic
    • complete loss or gain of electrons
  • Covalent
    • Stable, produced by electron sharing
  • Hydrogen
    • Rapidly reversible dipole-dipole interactions
  • Dipole-dipole
    • Reversible bond between partially charged molecules