72 lectures, 13 tutorials and 66 hours of practical work. (An additional 6 hours of practical work is taught in conjunction with `Pharmacy practice II')
The aim of the subject is to build on the basic physical and organic chemistry taught in `Medicinal chemistry I', and to apply it to aspects of chemistry relevant to pharmacy.
General objectives
In this teaching program students are expected to develop:
understanding of the nomenclature and meaning of terms used to describe the three-dimensional structures (stereochemistry) of drug molecules; spectroscopic methods used in the analysis and structural determination of drugs; the theory and application of thermodynamics; the structural and mechanistic bases for the action of the autonomic neurotransmitters and related agents; factors affecting the physicochemical properties and reactivity of drugs based on aromatic frameworks; factors influencing the three-dimensional structures of proteins; the partition of substances between various phases as applied to both the analysis of drugs and their transport in the body; principles of electrochemistry applied in the analysis of drugs; the chemical principles underlying selected diagnostic aids relevant to pharmacy; the application of radioisotopes in pharmacy; the chemical principles relevant to the activity of selected antiviral compounds;
abilities in the areas of the measurement and recording of data relevant to the understanding of drug structure and reactivity; numerical calculations based on experimental or theoretical data; report writing or oral presentations based on the results of experimental work;
an appreciation of the general chemical principles of enzymatic catalysis; the importance of chemical reactions in determining drug transport and metabolism; the application of the principles of medicinal chemistry to the search for selectivity in therapeutic agents.
Syllabus
Stereochemistry. Molecular geometry, symmetry, isomerism, configuration, conformation, conformational analysis; the use of conformationally restricted analogues in determining receptor structure and the shape of active drugs; preparation of homochiral compounds, implications of stereo-chemistry for drug design and delivery.
Spectroscopy. NMR, IR, UV spectroscopy, mass spectrometry - underlying processes and applications in the pharmaceutical industry; interpretation of spectra; identification of compounds using spectroscopic techniques.
Aromatic chemistry. Differences between aromatic and aliphatic compounds; resonance theory and stabilisation, acid/base properties; linear free-energy relationships, Hammett plots, sigma and rho values, effect of substituents on drug stability; steric effects; structure-activity relationships in local anaesthetics; heterocyclic aromatic compounds - nomenclature and properties, role of heterocyclic compounds in biological systems.
Receptor structure. Chemistry of the peptide bond; factors affecting primary, secondary and tertiary structure of proteins; functional groups involved in binding of drugs to protein; thermodynamics of drug binding, stereochemistry, drug binding and the three-dimensional structure of proteins; techniques involved in determining protein structure.
Chemistry of enzymes. Catalysis of reactions, particularly ester and amide hydrolysis; pH rate profiles; transition-state stabilisation, general acid and general base catalysis, nucleophilic catalysis, metal-ion catalysis, and their role in reactions catalysed by enzymes; pyridoxal phosphate dependent enzymes; enzymes as targets for drugs.
Electrochemistry. Activity, ionic strength, junction potentials; Debye-Huckel theory, Fergusson principle for drug equi-action; ion-selective electrodes, pH measurements, amperometric electrodes, and their role in pharmacy/clinical chemistry; composition of pharmaceutical glasses; biological cell potentials.
Partition and chromatography. Liquid-liquid distribution, extraction efficiency; principles underlying HPLC, gas, gas-liquid, partition and thin-layer chromatography; relationship between pH, drug structure, dissolution medium and drug distribution.
Diagnostic aids. Sampling techniques, clinical stick devices, tests for nitrate, pH, glucose, protein and cholesterol, and their clinical significance; tests for enzymes and lipoproteins; drug interferences in clinical tests.
Radiopharmacy. Types and units of radiation, maximum doses, background radiation; protection required for different forms of radiation; technetium generators and production of isotopes of pharmaceutical interest; preparation of radiopharmaceutical dose forms; X-ray and radio-isotopic imaging; the use of isotopes in sterilisation.
Antivirals. Targets for antiviral therapy and their relationship to structural features of antiviral drugs; structure, mode of action and uses of acyclovir, azidothymidine and ribavirin.
Autonomic nervous system agents. Cholinergic system: muscarinic and nicotinic receptors; structure and activity of acetylcholine and acetylcholinesterase; reversible and irreversible inhibition of acetylcholinesterase; treatment of anticholinesterase poisoning; cholinergic blocking agents and their use as muscle relaxants; degradation of muscle relaxants. Adrenergic system: structure and function of noradrenaline; inactivation of noradrenaline by monoamine oxidase and catecholamine-0-methyl transferase; a- and b-adrenoceptors; chemistry of a-adrenergic antagonists; chemistry and selectivity of b-active agents.
Thermodynamics. Reversible, irreversible and spontaneous processes; disorder, entropy, free energy; equilibrium constants; entropy and enthalpy-driven processes; coupled reactions; measurement of DG; calculation of free-energy changes, van't Hoff plots; applications of thermodynamic concepts to biochemical reactions, conformational equilibria, phase transitions, and drug-receptor interactions.
QSAR. The value of non-traditional approaches to drug design; Hammett, Hansch and Taft constants; use of pKa, partition and hydrolysis data to predict drug stability; multiparameter and non-mathematical approaches.
Practical
66 hours of practical work
Practical classes are designed to reinforce chemical principles taught in the lecture series and to illustrate the analytical bases of quality assurance for pharmaceutical products. Emphasis is placed on technique and general methods. Performance in laboratory classes is taken into account in assessing students' results in this subject.
Textbooks
Recommended texts
As prescribed for `Pharmaceutical chemistry I' and
Griffiths P J F and Thomas J D R Calculations in advanced physical chemistry 3rd edn, Arnold, 1983
Victorian College of Pharmacy Medicinal chemistry II laboratory manual VCP, 1995
Reference books
As prescribed for `Pharmaceutical chemistry I' and
Albert A Selective toxicity 7th edn, Chapman and Hall, 1985
Basset J and others Vogel's 'Textbook of quantitative inorganic analysis' 4th edn, Longman, 1978
Branden C and Tooze J Introduction to protein structure Garland, 1991
Chang R Physical chemistry with applications to biological systems 2nd edn, Macmillan, 1981
Connors K A and others Chemical stability of pharmaceuticals 2nd edn, Wiley, 1986
Delgado I N and Remers W A Wilson and Gisvold's `Textbook of organic medicinal and pharmaceutical chemistry' 9th edn, Lippincott, 1991
Fersht A R Enzyme structure and mechanism 2nd edn, Freeman, 1985
Florence A T and Attwood D Physicochemical principles of pharmacy 2nd edn, Macmillan, 1988
Foye W O Principles of medicinal chemistry 3rd edn, Lea and Febiger, 1989
Furniss B S and others Vogel's 'Textbook of practical organic chemistry' 5th edn, Longman, 1989
Kaplan L A and Pesce A J Clinical chemistry 2nd edn, Mosby, 1989
Martin A N and others Physical pharmacy 4th edn, Lea and Febiger, 1993
Rawn J D Biochemistry N Patterson, 1989
Silverman R B The Organic chemistry of drug design and drug action Academic, 1992
Solomons T W G Organic chemistry 5th edn, Wiley, 1992
Sternhell S and Kalman J R Organic structures from spectra Wiley, 1986
Sykes P A guidebook to mechanism in organic chemistry 6th edn, Longman, 1986
Assessment
Subject assessment will reflect the learning objectives outlined above. Methods of assessment will include :
Mid-year examination (June) (2 hours): 25%
Practical work: 10%
End-of-year examination (3 hours): 65%