|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.
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
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
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…
Benzenesulfonic acid in atracurium
Mannitol in dantrolene, vecuronium
Glucose in spinal LA solutions
Na metabisulphite in catecholamine solutions: neurotoxicity
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
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
Binding agents: protamine in insulin
Uptake: adrenaline in LA
Flavouring, colouring etc.
d. Outline the variations in generic nomenclature of commonly used drugs.
||Approved name |
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.
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)
f. Describe the process by which new drugs are approved for research and
- 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
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
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.
- 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
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.