introduction to biopharmaceutical science

8/13/2019 Introduction to Biopharmaceutical Science

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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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introduction to biopharmaceutical science

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