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You are in Home >> Exams >> Mitchell Anaesthetic Notes

Pharmaceutical aspects

Created: 21/4/2006
a. Define shelf life and outline factors that may influence drug potency during storage.

The period over which a drug loses 10% of its potency or its guarantee of sterility when stored according to the manufacturer’s specifications.

b. Describe methods of preserving shelf-life of drugs

Suitable method depends on the nature of the reactions which would degrade the drug.

    Sealed containers 
        Refrigeration or freezing to reduce the rate of degrading reactions; e.g. sux, 
        atracurium, blood products 
        Dark or opaque containers minimize light-induced changes; e.g. halothane, nitroprusside
        Dried to powder to reduce reaction rates; e.g. thiopentone, vecuronium, many antibiotics

    Controlled pH 
        Many drugs in solution have NaOH or HCl and buffer added 
    Reducing or oxidizing agents in solution 
        Usually reducing agents, may cause reactions (e.g. sulfites, nitrites) 
    Reaction with or adsorption to a carrier 
        Sugar glasses in phase IIb trials for a1-antitrypsin 
    Controlled atmosphere (N2) or vacuum 
        Thio, some antibiotics

    Pretreatment to sterilize drug 
        Heat, radiation, ethylene oxide 
    Risk of contamination minimized by physical and chemical methods which remove water
    (and oxygen) 
        added to many oral agents; e.g. alcohol, benzalkonium chloride

c. Describe the mechanisms of action and potential toxic effects of buffers, antioxidants, anti-microbials and solubilizing agents added to drugs.

        Commonly NaOH, KOH, HCl used to control pH 
        Carbonate buffers in LA solutions, methohexitone, thio… 
        Phosphate buffers 
        Benzenesulfonic acid in atracurium 
    Osmolal agents 
        Mannitol in dantrolene, vecuronium 
        Glucose in spinal LA solutions 
    Stabilizing agents 
            Na metabisulphite in catecholamine solutions: neurotoxicity 
        Other agents 
            Thymol in halothane prevents light inactivation 
            N2 atmosphere in thiopentone 
        Methylparabens used in multidose vials, cause hypersensitivity 
        Methyl- and propyl-hydroxybenzoate in topical and IV solutions 
        Benzalkonium chloride in nebulizer solutions 
        Benzyl alcohol in some water preparations 

    Solubilizing agents
        Lipid solutions 
            Cremaphor EL: polyoxyethylated castor oil, hypersensitivity 
            Intralipid: soybean oil, egg phospholipid, glycerol 
                High omega-6-fa content 
            Propylene glycol & alcohols solution e.g. diazepam 
            Polyethylene glycol in temazepam gelcaps (phlebitis if injected) 
            Chlorofluorocarbons in inhalers may be replaced with other agents; e.g. N2
    Pharmacokinetic alteration 
            Binding agents: protamine in insulin 
            Uptake: adrenaline in LA
            Flavouring, colouring etc.

d. Outline the variations in generic nomenclature of commonly used drugs.

Not approved Approved name
acetaminophen paracetamol
albuterol salbutamol
aminoacetic acid glycine
aminoacridine aminacrine
amobarbital amylobarbitone
aneurine thiamine
anthralin dithranol
asparaginase colaspase
azidothymidine zidovudine
calciferol ergocalciferol
carvomenthenol terpineol
chlormethin mustine
cortisol hydrocortisone
cromolyn cromoglycate
dextrose glucose
dibucaine cinchocaine
epinephrine adrenaline
ergonovine ergometrine
furosemide frusemide
glyburide glibenclamide
hexamurium distigmine
isoprotenerol isoprenaline
laevulose fructose
levarterenol noradrenaline
levothyroxine thyroxine
lidocaine lignocaine
meperidine pethidine
mephobarbital methylphenobarbitone
methenamine hexamine
niacin nicotinic acid
nitroglycerine glyceryl trinitrate
norephedrine phenylpropanolamine
norepinephrine noradrenaline
norethinderone norethisterone
omadine pyrithione
penicillin G benzylpenicillin
penicillin V phenoxymethylpenicillin
phytonadione phytomenadione
pizotyline pizotifen
propoxyphene dextropropoxyphene
pyrilamine mepyramine
tetracaine amethocaine
trolamine triethanolamine
tromethamine trometamol

e. Define isomerism, provide a classification with examples and explain its

Isomers are molecules having the same empirical formula but different structures.
Chemical isomers have completely different atom to atom bonds, for example enflurane and isoflurane or edrophonium and ephedrine HCl. Stereoisomers or enantiomers have the same bond arrangements but differ in three-dimensional structure due to the presence of chiral centres (atoms bonded to four different groups) which may exist in two mirror-image arrangements or bonds without rotational freedom such as unsaturated carbon-carbon bonds with the two carbon atoms each bonded to different groups.

Chiral centres are present in all amino-acids and many other organic compounds including sugars. They are usually designed D- or L- or d- or l- or R- or S- or (+) or (-)
isomers according to their configuration or effect on the polarization of light. Unsaturated bonds are present in many lipids and other molecules and are designated cis- or transisomers (Z- or E-) according to whether the major functional groups on the carbon atoms involved are on the same or opposite sides.

A chiral carbon

Many organic compounds include multiple chiral centres (e.g. atracurium) or unsaturated bonds (e.g. retinoic acid), yielding multiple optical isomers. As the isomers are different in three dimensional structure, they often bind with different affinities to receptor sites with specific three-dimensional structure and are degraded by enzymes at different rates.

Examples (optical isomers) 
  • Isomers equally active
  • Isomers have slightly different potencies and metabolism, e.g. atracurium, ropivacaine
  • Isomers have different actions, e.g. quinine/quinidine
  • One isomer is active and drug is administered as a racemic mix, e.g. verapamil makes blood levels misleading (active L-verapamil is cleared more rapidly)
  • One isomer is active and is administered alone, e.g. l-DOPA
f. Describe the process by which new drugs are approved for research and
clinical use in Australia and outline the phases of human drug trials.

Safety tests in animals/tissue culture     
  • Acute toxicity: LD50 in animals (2 species, 2 routes), “no effect” dose
  • Subacute toxicity: up to 6 months use in three dose ranges in 2 species
  • Chronic toxicity: 1-2 years if prolonged use is planned in humans
  • Specific testing: reproduction, carcinogenesis, mutagenicity (Ames test), investigative toxicology
Human evaluation     
  • Phase I: establish dose-effect relationship in healthy volunteers or diseases volunteers; not blinded, establishes predictable adverse effects and pharmacokinetics
  • Phase II: small single-blind trials in diseased patients with placebo and positive controls
  • Phase III: large, usually multicentre, double-blind or crossover trials
  • Phase IV: ongoing surveillance for adverse effects during marketing 
    Phases I trials often start more than 4 years after initial synthesis and phase III may not be completed until 8 years after initial synthesis. Some drugs are made available for life-threatening or serious diseases without completion of phase III or even phase II trials, e.g. some antiretrovirals.

Australian approval is distinct from overseas approval and applies similar criteria of safety and efficacy as in the US and UK. PBS listing and approval for hospital pharmacopoeia availability depends on cost-effectiveness as well.

The detection of rare adverse effects requires more subjects than are available in phase III trials. For example, to detect the doubling in incidence of a 1/1000 adverse effect requires 18000 subjects (beta=0.20, alpha=0.05). Thus most rare or unpredictable adverse effects will not be detected prior to marketing.

List the plants from which commonly used drugs are derived.

Claviceps purpurea                 Ergotamine
Erythroxylon coca                   Cocaine
Papavertum somniferum          Morphine, codeine, thebaine, papaverine etc.
Digitalis purpurea                    Lantana digoxin
Rauwolfia serpentina               Reserpine
Atropa belladonna                   Atropine
Hyocyamus niger                    Hyoscine

Kindly provided by Dr James Mitchell from his pharmacodynamics series.

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