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1. Pharmaceuticals, biologics
and biopharmaceuticals
INTRODUCTION TO PHARMACEUTICAL
PRODUCTS
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chemical synthesis plants
finished product pharmaceutical facilities
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HISTORY OF THE
PHARMACEUTICAL INDUSTRY
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THE AGE OF
BIOPHARMACEUTICALS
recombinant DNA technology (geneticengineering)
monoclonal antibody technology
(hybridoma technology)
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It overcomes the problem of source
availability
It overcomes problems of product safety It provides an alternative to direct extraction
from inappropriate/dangerous source
material
It facilitates the generation of engineered
therapeutic proteins displaying some clinicaladvantage over the native protein product
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BIOPHARMACEUTICALS:
CURRENT STATUS AND FUTUREPROSPECTS
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most biopharmaceuticals approved to dateare intended for human use
At least 500 potential biopharmaceuticalsare currently being evaluated in clinical
trials
the first generic biopharmaceuticals are
already entering the market
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TRADITIONAL PHARMACEUTICALS OF
BIOLOGICAL ORIGIN
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Pharmaceuticals of animal origin
The sex hormones
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The androgens
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Oestrogens
stimulation of the growth and maintenanceof the female reproductive system (their
principal effect);
influencing bone metabolism; as is
evidenced from the high degree of bonedecalcification (osteoporosis) occurring inpost-menopausal women;
influencing lipid metabolism.
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Progesterone and progestogens
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Corticosteroids
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Catecholamines
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emergency management of anaphylaxis;
emergency cardiopulmonary resuscitation;
addition to some local anaesthetics (its
vasoconstrictor properties help to prolong
local action of the anaesthetic).
adrenaline
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Prostaglandins
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Pharmaceutical substances
of plant origin
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Pharmaceutical substances of
microbial origin
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generalized penicillin structure
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tetracycline
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aminoglycoside antibiotics
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2. MOLECULAR PROPERTIES
OF DRUGS
pharmacodynamics
pharmacokinetics
drug dose-response profile
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Main molecular properties of drugs
Partition coefficient
Dissociation constant (ionization state)
Solubility
Chemical stability
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ADME Drug administration: How is the drug to be
formulated?
Drug absorption: can the drug pass
through the barrier membranes in the
gastro-intestinal tract? Can it pass throughthe skin barriers?
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Drug metabolism: metabolism increasesthe water solubility of drugs by
enzymatically introducing polar functional
groups so that they can be excreted
Drug excretion: the kidney excretes water-
soluble metabolites.
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Drug action: the shape of the drug, its
chemistry and its compatibility with the
target receptor/enzyme determines the
extent of the response
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PARTITIONING
Affinity for water: HYDROPHILIC (waterloving) or LIPOPHOBIC (lipid hating)
Affinity for oil: LIPOPHILIC (lipid loving) or
HYDROPHOBIC (water hating)
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the partition coefficient
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The standard solvent for partitionmeasurements of medicinal compounds is
octan-1-ol
Positive and negative effects on
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g
log P
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Fragmental constants: quantification
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of substituent effects on partitioning
Aromatic compounds
Benzene: 2.13
Toluene (methylbenzene): 2.79Ethylbenzene: 3.45
Aliphatic compounds
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Exceptions and provisos
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Exceptions and provisos
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For a drug to be administered, it needs todissolve in an aqueous medium if it is to begiven orally or by injection (it needs to be
ionized/charged).
For a drug to be absorbed through a lipidmembrane, it needs to partition from theaqueous to the lipid medium (it needs to beunionized/uncharged and lipophilic).
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For a drug to be transported around the
body, it needs to dissolve in the aqueousplasma (it needs to be ionized/charged).
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Aspirin, pKa = 3.5
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Definitions
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ACIDS ARE PROTON DONORS
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BASES ARE PROTON ACCEPTORS
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THE HIGHER THE pKa VALUE,
THE FURTHER THE EQUILIBRIUM LIES TO THELEFT i.e. THE SPECIES PREFERS TO BEUNDISSOCIATED RATHER THAN DISSOCIATED
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BENZYLAMINE HYDROCHLORIDE
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DIPHENYLAMINE HYDROCHLORIDE
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Benzoic acid has a pKa 4.2. What
t i di i t d i l ti f
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percent is dissociated in a solution of
pH 4.2 ?
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Acids and conjugate acids can have any
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Acids and conjugate acids can have anynumerical value of pKa, but only values
less than 14 will be of any significance in
determining the solubility of acids in waterand only values greater than zero will be
of significance in determining the solubility
of conjugate acids.
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ONLY THE UNIONISED FORM OF A DRUG
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ONLY THE UNIONISED FORM OF A DRUGCAN PARTITION ACROSS BIOLOGICAL
MEMBRANES (providing the unionized form
is lipophilic) [required for drug absorptioninto the body]
THE IONISED FORM TENDS TO BE MORE
WATER SOLUBLE [required for drug
administration and distribution in plasma]
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RCOOH, pKa = 4.0
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a basic drug, pKa = 7.0
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pH at roughly equal distribution
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pH at roughly equal distribution
RCOOH, pKa = 4.0; P = 200
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Papp = 198 in the
stomach
FACTORS AFFECTING ACID
AND BASE STRENGTH
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AND BASE STRENGTH
The ability of a compound to exist as anacid depends on the ability of the anion
formed by dissociation to stabilise the
negative charge !
Carboxylic acids
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Effect of R on pKa?
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inductive effect of alkyl groups
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mesomeric effects
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Phenols
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Sulphonamides
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Sulphonic acids
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Molecular Structures of Bases
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no drug is basic without nitrogen in its
structure
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Aromatic Amines
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Amides
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Amidines and Guanidines
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Diacidic bases (two nitrogens
without charge sharing)
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-Amino Acids
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zwitterion
Heterocycles
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- deficient heterocycles
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' -excessive' heterocycles
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ANALYTICAL MEASUREMENT IN
MEDICINE AND DRUG
DEVELOPMENT
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The Control Of Errors In Analysis
A batch of paracetamol tablets are stated to contain
500 mg of paracetamol per tablet. Four students
carry out a spectrophotometric analysis of an
extract from the tablets and get the following
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extract from the tablets and get the following
percentages of stated content for the repeat
analysis of paracetamol in the tablets:
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Accuracy And Precision In
Analytical Measurement
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Dilutions And Weights And
MeasuresA sodium chloride infusion is diluted as follows
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A sodium chloride infusion is diluted as follows.
5 ml to 100 ml followed by 5 ml to 250 ml. The
sample is then analysed and is found to
contain 1.03 mg/100 ml of sodium chloride.
Calculate:
1. The concentration of sodium chloride in
the original solution in % w/v.
2. The amount of sodium chloride in mgpresent in 5 ml of the original solution.
APPLICATIONS OF
SPECTROPHOTOMETRY IN
BIOPHARMACEUTICAL SCIENCE
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Spectrophotometry is a group of analytical
techniques that are used to provide
information about the nature (i.e. the
identity) and composition (i.e. amount) of
substances in a sample.
Ultraviolet/visible absorption
spectrophotometry
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the measurement of the amount of light
absorbed by the drug substance in
solution in the ultraviolet and visible
regions of the spectrum
What Is Electromagnetic Radiation?a form of energy whose behavior is described by
the properties of both waves and particles
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Red: 780 nm, Orange: 620 nm, Yellow: 585 nm, Green: 570 nm,Blue: 490 nm, Indigo: 440 nm, Violet: 420 nm
blue is minus yellow
green is minus magenta
red is minus cyan
yellow is minus bluemagenta is minus green
cyan is minus red
Quantitative UV-Vis
Spectrophotometry
When making a quantitative
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g q
spectrophotometric measurement of asolution of a substance at a particular
wavelength, two light intensities are
measured, viz. the intensity passing into thesolution (Io) and the (reduced) intensity (It)
transmitted from the solution after absorption
of some of the light has occurred.
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The Beer Lambert Law
A = abc
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whereA: the absorbance,
a: the ABSORPTIVITY (a
proportionality constant),b: the pathlength
c: the concentration of the solution
A = b c
where c is in moles/l and b is in cm
: the molar absorptivity
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p y
A =A(1%, 1cm) b cwhere c is in g/100 ml and b is in cm
A(1%, 1 cm): the specific absorbance
What is the absorbance at a particularwavelength if the % transmittance of a
solution is 10% at that wavelength?
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solution is 10% at that wavelength?
What % of the light at a particular
wavelength is absorbed by a solutionhaving an absorbance of 0.5 at that
wavelength?
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What Happens When Light Is
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Absorbed In The UV-Vis Region?
UV/Vis Spectra for Molecules Energy quantification of a molecule
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with Eelec >Evib>Erot
The absorption of UV/visible radiation occursthrough the excitation of electrons within themolecular structure to a higher energy state;
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These transitions occur from the lowestvibrational state in the electronic ground
state of the molecule to any one of a numberof higher vibrational levels in the electronicexcited state.
What Type of Molecules Absorb
UV/Visible Radiation?
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Extended Chromophores
A CHROMOPHORE is group that is
composed of a series of double bonds (at
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composed of a series of double bonds (at
least two) separated by single bonds
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The Benzene Ring Chromophore
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Auxochromes
Groups containing nitrogen and oxygen,
which have non-bonding electron pairs, also
interact with an extended chromophore
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interact with an extended chromophore
such as the benzene ring.
To create bathochromic/hyperchromic shiftsauxochromes have to be attached directly
to the system i.e. directly on one of the
double bonds in the extendedchromophore.
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Instrumentation in the UV/Visible
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Applications of UV/Visible
Spectrophotometry in
Pharmaceutical Analysis
Quantification Based on Comparison with
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a Standard Solution (i.e. solution of knownconcentration)
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Some Calculations Using Standard A (1%
1cm) Values of the Drug
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Determine pKa of Drug Substances
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The absorbance of a fixed concentration of
phenylephrine at 292 nm is found to be
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1.224 in 0.1 M NaOH and 0.02 in 0.1 MHCl. Its absorbance in buffer at pH 8.5 is
found to be 0.349. Calculate the pKa value
of its acidic phenolic hydroxyl group.
Determine Partition Coefficients
A sample of a neutral drug (5 mg) is
dissolved in 5 ml of water and then the
t i h k ith 5 l f t l A
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water is shaken with 5 ml of n-octanol. Aportion of n-octanol (2 ml) and is withdrawn
and is diluted to 50 ml with methanol. The
absorbance reading for the diluted sampleis 0.657. If the A(1%,1cm) value for the
drug is 181 calculate its n-octanol/water
partition coefficient.
The Effect of pH on Partitioning
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CHEMICAL STABILITY OF
PHARMACEUTICALS
Decomposition products of the drug may
b f t i t th ti t th it
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be far more toxic to the patient than itsparent drug
Significant decomposition of the drug in its
dosage form (e.g. tablets) will reduce the
effective dose to the patient
Up to 10% degradation may be acceptable
provided the decomposition products arenot toxic to the patient !
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hydrazine (< 0.05%)
Isoniazid
expiry date: the Medicines Act 1968
The limiting factor in the setting of the
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The limiting factor in the setting of theexpiry date is the chemical stability or
other component of the medicine
adverse conditions
Heat
Light
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Light
Moisture
For substances affected by water, the effectof pH will also be investigated
Air (oxygen)
HYDROLYSIS OF ESTERS
The general reaction for acid-catalysed or
base catalysed hydrolysis:
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base-catalysed hydrolysis:
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saponification
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Lactides and lactones
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Rates of Hydrolysis
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HYDROLYSIS of AMIDES
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AUTOXIDATION
Autoxidations are usually radical-induced
chain reactions
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Typical pharmaceutical
examples
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Adrenaline
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Inhibition of Oxidation
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5. Use an antioxidant
Oxygen scavengers
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Ascorbic acid
Chain terminators
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T i l ti id t th l b t l t d
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Typical antioxidants: thymol, butylated
hydroxyanisole, butylated hydroxytoluene,propyl gallate, octyl gallate and dodecyl gallate
THE SHAPES OF ORGANIC
MOLECULES
drug molecules interact with optically active,
asymmetric biological macromolecules suchas proteins, polynucleotides, or glycolipids
ti t
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acting as receptors,
stereochemical specificity
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constitutional isomers: the order of atomic
connections that defines a molecule
Stereoisomers: different in the three
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Stereoisomers: different in the three
dimensional arrangement of atoms in space
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Configuration
The configuration of a molecule of defined
constitution is the arrangement of its
atoms in space without regard toarrangements that differ only after rotation
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g y
about single bonds.
Geometric isomers are configurational isomers
that result from the presence of double bonds or
rings that impose rigidity on the molecule thus
preventing free rotation about certain bonds
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Configurational isomers that are mirror
images of each other are termed
enantiomers
Chirality
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Optical activity
Enantiomers have identical physical
properties except in one respect, they rotate
the plane of polarized light in opposite
directions
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Molecules that rotate polarized light are said
to be 'optically active
indicated by (+) or (-) before the name ofthe substance
asymmetric atoms: tetrahedrally bonded to
four different atoms or groups (chiralcentre)
Racemic: equal amounts of enantiomeric
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Racemic: equal amounts of enantiomeric
molecules are present together
Importance of Chirality in
Drug Therapy
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Exercises!
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INTRODUCTION TO
PHARMACOKINETICS AND
PHARMACODYNAMICS
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Drugs may be defined as chemicals thatalter physiological or biochemical
processes in the body in a manner that
makes them useful in the treatment,
prevention, or cure of diseases.
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the onset, intensity, and duration of
therapeutic effects for a particular disease
condition
dose frequency of administration route of
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dose, frequency of administration, route of
administration
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PHARMACODYNAMICS
Drug Effects at the Site of Action
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Interaction of a Drug with Its Receptor
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Postreceptor Events
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Agonists, Antagonists, and
ConcentrationResponse Relationships
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A drug that mimics the endogenous
receptor ligand to activate the receptor is
referred to as an agonist
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A drug that binds to a receptor but does
not activate it is referred to as an
antagonist
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The goal of pharmacokinetics
Identifying the drug and patient factors that
determine the rate and extent of each
process
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Identifying a way to quantify or summarize
each process in ADME using a singleparameter
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Pharmacokinetic Representations ofAbsorption, Distribution and
Elimination
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One-Compartment Open Model:Intravenous Bolus Administration
DB: drug in body
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DB: drug in bodyVD: apparent volume of distribution;
k: elimination rate constant.
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Volume of Distribution
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