Master of Pharmacy Degree at King’s College London

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Master of Pharmacy Degreeat Kings College
London
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The College

• Kings is one of the two founding Colleges of the
  University of London a major international
  university in the heart of London with
  approximately 14,000 undergraduate students and
  more than 5,000 postgraduates in nine Schools and
  five campuses.
• School of Biomedical and Health Sciences
• Dental Institute
• School of Humanities
• School of Law
• School of Medicine
• Florence Nightingale School of Nursing
  Midwifery
• School of Physical Sciences Engineering
• Institute of Psychiatry
• School of Social Science Public Policy

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The Department of Pharmacy

• Master of Pharmacy
• Master of Science Programmes
• Biopharmacy
• Pharmaceutical Technology
• Pharmaceutical Analysis Quality Control
• Master of Science / Diploma Programmes
• Primary Care Community Pharmacy
• Supplementary Prescribing
• Research Degrees in the Pharmaceutical Sciences
• Pharmacy Practice

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Pharmaceutical Education Training in the UK

• Master of Pharmacy (MPharm) Degree
• Four Years
• Pre-Registration Training One Year
• Hospital Pharmacy
• Community Pharmacy
• Hospital or Community / Industry or Academic
  Pharmacy
• Professional Examination
• Registration Member of the Royal Pharmaceutical
  Society of GB (RPSGB)

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MPharm 1 Principles of Pharmacy

• Pharmacy orientation course
• (First three weeks)
• Interprofessional Education
• (Throughout the Year)
• Biochemical Basis of Therapeutics
• Pharmacy Practice Biopharmacy
• Physical Pharmaceutics
• Chemistry of Drugs

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• MPharm 2 Pharmacy Therapeutics
• Formulation Analysis of Drugs
• Nervous System
• Respiratory Musculoskeletal Systems
• Cardiovascular Renal Systems
•   

• MPharm 3 Pharmacy Therapeutics
• Medicines Discovery Design
• Gastrointestinal System Skin
• Infection Pharmaceutical Microbiology
• Endocrine System Cancer
• Pharmacy Law Ethics

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MPharm 4 Pharmacy into Practice

• Semester 1 Research Project
• Semester 2 Preparation for Practice
• Electives - Two from
• Chemical Mediators Disease
• Plants Pharmacy
• Drug Development from Natural Sources
• Drug Delivery
• Science of Dosage Form Design
• Drug discovery Design
• Drug Metabolism
• Drug Toxicity

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Department of Pharmacy and Overseas Study
European Union Erasmus-Socrates

• Undergraduate students
• PhD students
• Post-doctoral staff
• Academic staff

• Austria
• University of Vienna
• France
• Joseph Fourier University, Grenoble
• Germany
• Johann Wolfgang Goethe University,
• Frankfurt
• Philipps University, Marburg
• Hungary
• Semmelweis University, Budapest
• Italy
• University of Bologna
• University of Calabria
• University of Padova
• University of Parma
• Poland
• Medical University of Lódz
• Spain

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Stereochemistry Biological Activity

• Andrew J. Hutt
• Department of Pharmacy,
• Kings College London.

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Pharmaceutical Medicinal Chemistry

• No drug was ever used because it had an
• Interesting synthetic pathway
• An unusual stability profile
• Required a particularly sophisticated
• analytical technique.
• Drugs are used because they do something!

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• .. and they do something as a result of
  their molecular structure, which determines
• Physicochemical properties
• Chemical / biochemical reactivity
• Shape
• STEREOCHEMISTRY.

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• Stereochemistry
• Concerned with the three dimensional spatial
  arrangement of the atoms within a molecule.
• Stereoisomers
• Compounds with the same molecular
  connectivity but differ in the spatial
  arrangement of their constituent atoms or groups.

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• Enantiomers
• Stereoisomers which are non-superimposable
  mirror images of one another.
• Diastereoisomers
• Stereoisomers which are not enantiomeric.

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Stereogenic centre
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Chiros Greek Handed
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Sequence Rule Designation
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Stereoisomers of Ibuprofen
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Stereogenic S P centres
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Stereoisomers of Phenylpropanolamine
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Phenylpropanolamine UK Confusion

• Independent risk factor for hemorrhagic stroke in
  women1
• Withdrawn in the USA (FDA, Oct. 10, 2000)
• ()-norpseudoephedrine in European
  preparations(?)-norephedrine in North
  America(Martindale 32nd Pharm J, Nov. 11, 2000)
• (?)-norephedrine in USA and Europe structure of
  norpseudoephedrine presented in the British
  Pharmacopoeia 2000 (Pharm J, Dec. 2, 2000)

1Kernan WN, et al. N Engl J Med.
20003431826-1832.
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Glyceraldehyde enantiomers
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Stereochemical Designations

• Spatial Arrangement
• R/S
• D/L

• Physical Properties
• d,l
• (),(-)

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Optical Rotation (1)
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Optical Rotation (2)

• Chloramphenicol
• 1R,2R-absolute configuration
• Dextrorotatory in ethanol
• Laevorotatory in ethyl
  acetate
• Moxalactam
• Mixture of two epimeric diastereoisomers both
  of which
  are laevorotatory

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Nomenclature

• Dextro / Dex () Es (S)
• Dexamethasone Esomeprazole
• Dexamfetamine Escitalopram
• Dextromethorpan Eszopictone
• Dextropropoxyphene
• Levo / Lev (-) Ar (R)
• Levamisole Arformoterol
• Levobunolol Arflurbiprofen
• Levodopa
• Levonorgestrel

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D-Glucose
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Amino Acids
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• Differences between stereoisomers are hard to
  detect normally, but become much more marked in
  a chiral environment

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Chiral Biological Macromolecules

• Proteins
• Enzymes
• Structural elements of membranes
• Receptors
• Carbohydrates
• Nucleic acids
• Chiral building blocks of L-amino acids and
  D-carbohydrates.

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Helical structures
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Differences Between Enantiomers Odor

• R S
• Limonene Oranges Lemons
• Carvone Spearmint Caraway

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Differences Between Enantiomers Taste

• D L
• Asparagine Sweet Tasteless
• Leucine Sweet Bitter

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Enantiomeric DiscriminationEasson Stedman
Model (1933)
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Adrenaline Adrenergic Receptors
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Pharmacology Pharmacodynamics

• Stereoselectivity of drug action has been known
  for a number of years.
• Many natural ligands are chiral, eg,
  transmitters, hormones, etc.

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Pharmacodynamic Considerations

• Greatest differences between a pair of
  enantiomers occur at the level of receptor
  interactions.
• Additional Terminology
• Eutomer enantiomer with higher
  affinity/activity.
• Distomer enantiomer with lower
  affinity/activity.
• Eudismic Ratio Ratio of the Eutomer/Distomer
  affinities or activities.
• Eudismic Ratios of 100 to 1000 fold are not
  uncommon.

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Eudismic Ratio

• Terminology applies to a particular activity of a
  drug.
• Dual action drug the Eutomer of one activity may
  be the Distomer for another.
• Propranolol S-enantiomer 40-100 fold more potent
  than the R- as a ß-adrenoceptor antagonist
  similar activity with respect to their membrane
  stabilising properties.
• Eudismic Ratios may also vary with receptor
  subtypes.
• Noradrenaline ER (R/S) a1, 107 a2, 480.
• a-Methylnoradrenaline ER (1R,2S/1S,2R) a1,
  60a2, 550.

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Amosulalol Enantiomer Activity
Eudismic Ratio
Eutomer pA2 (Enantiomer)
Tissue
Receptor

• Adrenoceptor agonist
• Nonspecific ß
• Selective a1

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7.71 (-)
Rat atrium
ß1
Guinea pig trachea
ß2
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7.38 (-)
14
8.31 ()
Rabbit aorta
a1
3
5.36 ()
Rat vas deferens
a2
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Stereoselectivity of TerfenadineH1-Antihistamine.

• Inhibition of mepyamine binding R-, 6.4µM S-,
  7.5 µM.
• Ligand binding at H1-receptors Ki values
• R-, 7.6 S-, 6.81.
• Blockade cardiac K channels R-, 1.19 µM S-,
  1.16 µM.
• Stereogenic centre located in a non critical
  region.

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Sertraline Selective Serotonin Reuptake
Inhibitor
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Formoterol
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Pharmacodynamic Complexity activity resides in a
single enantiomer.

• (S)-?-Methyldopa, antihypertensive.
• (1R,2S)-?-methylnoradrenaline by dopa
  decarboxylase dopamine ß-hydroxylase.

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Pharmacodynamic Complexity Both enantiomers have
similar activity.

• Promethazine antihistamine enantiomers have
  similar pharmacological toxicological profiles.
• Flecainide antiarrhythmic activity effect on
  cardiac sodium channels similar no significant
  pharmacokinetic differences.

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Pharmacodynamic Complexity Both enantiomers
marketed with different therapeutic indications.
Propoxyphene
CH2NMe2
CH2NMe2
Me
H
H
Me
C6H5
EtCOO
C6H5
OOCEt
CH2C6H5
CH2C6H5
(-)-2S,3R Antitissive NOVRAD
()-2R,3S Analgesic DARVON
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Pharmacodynamic Complexity Enantiomers have
opposite effects at the same receptor.

• Picenadol
• Opioid analgesic
• ()-(3S,4R) enantiomer is agonist
• (-)-(3R, 4S) enantiomer is antagonist
• (?)-(3RS, 4RS) partial agonist

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Pharmacodynamic Complexity One enantiomer
antagonises the side effects of the other.

• Indacrinone
• Loop diuretic, evaluated for treatment of
  hypertension and congestive heart failure
• Racemate administration results in elevated uric
  acid
• R-enantiomer diuretic, t½ 10 12
  hS-enantiomer uricosuric, t½ 2 5 h
• Mixture SR 41 isouricemic SR 81
  hypouricemic

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Pharmacodynamic Complexity Required activity
resides in one or both enantiomers, adverse
effects predominantly associated with one
enantiomer

• Ketamine, general anaesthetic with analgesic
  properties.
• S-enantiomer ca 3-fold greater affinity for the
  NMDA receptor
• 2-4 selectivity for µ- and ?-opioid receptors.
• Post-anaesthesia emergence reactions
• hallucinations, vivid dreams, agitation,
• mainly associated with the R-enantiomer.
• Chiral Switch, the S-enantiomer being available
  in Germany.

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Configuration Activity
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Pharmacology Pharmacokinetics

• Absorption active transport
• Distribution active/selective uptake, protein
  binding
• Metabolism numerous examples
• Excretion active secretion or reabsorption

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Stereoselective drug absorption
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Stereoselectivity in plasma protein binding

• Acidic drugs Unbound () Ratio
• S-enantiomer
  R-enantiomer (S/R)
• Flurbiprofen 0.048 0.082 0.59
• Ibuprofen 0.64 0.42 1.5
• Indacrinone 0.3 0.9 0.33
• Pentobarbitone 26.5 36.6 0.72
• Phenprocoumon 0.72 1.07 0.67
• Warfarin 0.9 1.2 0.75
• Basic drugs
• Bupivacaine 4.5 6.6 0.68
• Chloroquine 33.4 51.5 0.64
• Disopyramide 22.2 34 0.64
• Methadone 9.2 12.4 0.74
• Mexiletine 28.3 19.8 1.4
• Propafenone 2.5 3.9 0.64
• Sotalol 62 65 0.95
• Verapamil 11 6.4 1.7

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Drug metabolismProchiral to chiral
transformation
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Drug metabolismChiral to chiral
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Drug metabolismChiral to diastereoisomers
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Drug metabolismChiral Inversion of
2-Arylpropionic Acid NSAIDs
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Enantiomeric Differences in Pharmacokinetic
Profile
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Use of Racemates

• Isomeric ballast
• Clean drugs
• Polypharmacy

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FDA

• The Agency is impressed by the possibility that
  the use of single enantiomers may be
  advantageous (1) by permitting better patient
  control, simplifying dose-response relationships
  (2) by reducing the extent of interpatient
  variation in drug response.

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Potential Advantages of Single Isomer Products

• Less complex and more selective pharmacological
  profile
• Potential for an improved therapeutic index
• Less complex pharmacokinetic profile
• Reduced potential for complex drug interactions
• Less complex relationships between plasma
  concentration and effect

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Racemates vs Enantiomers

• No requirement from any regulatory authorities
  for marketing single isomers
• Choice of stereoisomeric form must be justified
  on scientific grounds

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Racemates vs Enantiomers (Contd)

• Configurational stability
• Preparation not technically feasible on a
  commercial scale
• Enantiomers have similar pharmacological and
  toxicological profiles
• One enantiomer is shown to be inactive and not
  provide an additional body of burden
• The use of a racemate produces a therapeutic
  effect superior to that of the individual
  enantiomers

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Penicillamine

• Originally introduced for the treatment of
  Wilsons disease
• Animal toxicity weight loss, intermittent fits,
  death in rats L gtgt D
• Mutagenicity L gt D
• Optic neuritis with racemate in man, drug
  withdrawn (USA)

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Dopa
decarboxylation
L-Dopa
Dopamine (natural neurotransmitter)

• Side effects nausea, vomiting, anorexia, mental
  effects,involuntary movements, granulocytopenia

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Thalidomide
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Thalidomide Enantiomers

• Both are sedative in the mouse, only
  (S)-thalidomide is teratogenic.
• Mouse is a poor model for teratogenicity.
• Both are teratogenic in NZW rabbits.
• Enantiomers undergo rapid racemization in vivo
  and in vitro.
• In man following administration of the R- and
  S-enantiomers ca 25 and 43 of the total AUC is
  due to the alternative stereoisomer.

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Drug Chirality The 1980s
Non chiral 6
Sold as single isomer
Naturalsemisynthetic 475
461
Chiral 469
Sold as racemate
Drugs 1675
8
Sold as single isomer
Non chiral 720
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Synthetic 1200
Chiral 480
Sold as racemate
422
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New Chemical Entities Assessed by the UK
Medicines Control Agency (MCA/MHRA) between
1996-2000
Non-chiral 2
Naturalsemisynthetic 19
Single isomer 16
Chiral 17
NCEs 95
Racemate 1
Non-chiral 31
Synthetic 76
Single isomer 30
Chiral 45
Racemate 15
Shah Branch, 2003.
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Racemate to Enantiomer Racemic or Chiral
Switches

• Drug Name Class Approval Status
• Dexfenfluramine Anoretic Withdrawn
• Levofloxacin Antimicrobial Japan, UK, USA
• Dilevalol ?-blocker Development stopped
• Dexibuprofen NSAID Austria (1994), Switzerland,
  EU (2005)
• Dexketoprofen NSAID Spain, UK
• Levobupivacaine Local anesthetic UK
• (S)-Ketamine Anesthetic Germany
• Esomeprazole H-pump inhibitor UK, USA
• (R)-Salbutamol ?2-agonist USA
• (R)-Fluoxetine Antidepressant Development stopped
• Cisatracurium Neuromuscular blockade UK,
  USALevocetirizine Antihistamine UK,
• (R,R)-Methylphenidate ADHD USA
• Escitalopram Antidepressant UK, USA
• (S)-Amlodipine Dihydropyridine India
• Eszopiclone Insomnia USA
• Arformoterol ?2-agonist USA (April 2007)
• Armodafinil Antinarcoleptic USA (Approvable
  letter, April 2007)

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Body of Evidence

• Im not sure I get it, Marino said, rubbing his
  eyes. How can compounds be the same but
  different?
• Think of dextromethorphan and levomethorphan as
  identical twins, I said. Theyre not the same
  people, so to speak, but they look the same
  except one is right-handed and the other
  left-handed. One is benign, the other strong
  enough to kill. Does that help? Dr Kay
  Scarpetta
• Patricia Cornwell, 1991

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Further Reading

• A. Slovakova A.J. Hutt (1999) Chiralne
  zluceniny a ich farmakologicke ucinky. Czech
  Slovak Pharmacy, 48, 107-112.
• A.J. Hutt J. Valentová (2003) The chiral
  switch the development of single enantiomer
  drugs from racemates. Acta Facultatis
  Pharmaceuticae Universitatis Comenenianae, 50,
  7-23.
• R. Cižmáriková, J. Valentová A.J. Hutt (2004)
  Blokátory ß-adrenergických receptorov skupina
  chirálnych liecivenantioseparácie v skupine
  ß-blokátorov. Czech Slovak Pharmacy, 53, 9-17.
• J. Valentová A.J. Hutt (2004) Chirálni zámena
  chiral switch cisté enantiomery léciv místo
  racemických smesí. Czech Slovak Pharmacy, 53,
  285-293.
• R. Cižmáriková, J. Valentová, A.J. Hutt S.
  Sedáková (2005) Blokátory ß-adrenergických
  receptorov skupina chirálnych lieciv
  stereoselektivna syntéza ß-blokátorov. Czech
  Slovak Pharmacy, 54, 201-206.

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