Modified drug delivery systems, Targeted drug delivery and biopharmaceutical drugs, pk and pd, Drug interactions

MODIFIED-RELEASE DRUG PRODUCTS, TARGETED DRUG
DELIVERY SYSTEMS, BIOTECHNOLOGICAL PRODUCTS,
INTRODUCTION TO PHARMACOKINETICS AND
PHARMACODYNAMICS, DRUG INTERACTIONS
GUIDED BY:
D.VINAY KUMAR SIR
PRESENTED BY:
G.DURGA BHAVANI
M.PHARM-1st YEAR
PHARMACEUTICS
18IS1S0314
JAWAHARLAL NEHRU TECHNOLOGICAL
UNIVERSITY-KAKINADA
1

CONTENTS:
 MODIFIED-RELEASE DRUG PRODUCTS
 TARGETED DRUG DELIVERY SYSTEMS
 INTRODUCTION TO BIOTECHNOLOGICAL PRODUCTS
 INTRODUCTION TO PHARMACOKINETICS AND PHARMACODYNAMICS
 DRUG INTERACTIONS
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MODIFIED-RELEASE DRUG PRODUCTS:
 Modified release drug product are those that alter the timing and/or the rate of release of drug
substance.
 Types of modified release drug products are:
1. Delayed release
2. Extended release
3. Targeted release
4. Orally disintegrating tablet
1. DELAYED RELEASE DRUG PRODUCTS:
 A dosage form that releases a discrete portion/portions of drug at a time other than the promptly
release after administration. An initial portion may be released promptly after administration.
e.g., Enteric-coated dosage forms are common delayed-release products (enteric-coated aspirin and
other NSAID products).
2. EXTENDED RELEASE DRUG PRODUCTS:
 A dosage form that allows at least a twofold reduction in dosage frequency as compared to that drug
presented as an immediate-release (conventional) dosage form.
 It include controlled-release, sustained-release, and long-acting drug products.
3. TARGETED RELEASE DRUG PRODUCTS:
 A dosage form that releases drug at or near the intended physiologic site of action.
 Targeted-release dosage forms may have either immediate- or extended-release characteristics.
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4.ORALLY DISINTEGRATING TABLETS:
 ODTs have been developed to disintegrate rapidly in the saliva after oral administration. It may be
used without the addition of water. The drug is dispersed in saliva and swallowed with little or no
water.
BIOPHARMACEUTIC FACTORS:
 The ER oral drug products remain in the gastro-intestinal (GI) tract longer than conventional,
immediate release, drug products. Thus, drug release from an ER drug product is more subject to be
affected by the anatomy and physiology of the GI tract, GI transit, pH, and its contents such as food
compared to an immediate-release oral drug product.
 In some cases, there may be a specific absorption site or location within the GI tract in which the
extended-release drug product should release the drug.
 This specific drug absorption site or location within the GI tract is referred to as an “absorption
window”. The absorption window is the optimum site for drug absorption.
1. STOMACH
 The stomach receives food or liquids from the oesophagus. It is a “mixing and secreting” organ.
 In the presence of food, the stomach is in the “digestive phase”; in the absence of food, the
stomach is in the “interdigestive phase”.
 If the drug is administered during the digestive phase; Fatty material, nutrients, and osmolality may
further extend the time of the drug staying in the stomach. When the drug is administered during the
interdigestive phase, the drug may be swept along rapidly into the small intestine. The drug release
rates from some extended-release drug products are affected by mechanism of drug release.
 The rate of drug release of various ER formulations can be affected by the composition of the co -
administered meal.
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2. SMALL INTESTINE AND TRANSIT TIME
 The small intestine provides an enormous surface area for drug absorption because of the
presence of microvilli.
 Its transit time of a solid preparation has been concluded to be about 3 hours or less in 95% of the
population.
3. LARGE INTESTINE
 Here, drug transit time is slow. The rectum has a pH of about 6.8–7.0 and contains more fluid
compared to the colon. Drugs are absorbed rapidly when administered as rectal preparations.
 However, the transit rate through the rectum is affected by the rate of defecation. Presumably,
drugs formulated for 24-hour duration must remain in this region to be absorbed.
pH Values against Transit Time at Different Segments of GI Tract:
Fasting condition Food condition
Anatomical
location pH Transition time (h) pH Transition time (h)
Stomach 1-3 0.5-0.7 4.3-5.4 1
Duodenum ~6 <0.5 5.4 <0.5
Jejunum 6-7 1.7 5.4-5.6 1.7
Heum
6.6-
7.4 1.3 6.6-7.4 1.3
Cecum 6.4 4.5 6.4 4.5
Colon 6.8 13.5 6.8 13.5
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DOSAGE FORM SELECTION FOR MRDP:
 The properties of the drug and the size of the required dosage are important in formulating an
extended-release product. These properties will also influence the selection of appropriate
dissolution media, apparatus, and test parameters to obtain in vitro drug release data that will
reflect in vivo drug absorption.
e.g., -Drug with low aqueous solubility generally should not be formulated into a non-
disintegrating tablet, because risk of incomplete drug dissolution is high.
-Drug with low solubility at neutral pH should be formulated as an erodible tablet, so that
most of drug is released before it reaches the colon.
-A drug with high water solubility in acidic pH in stomach but very insoluble at intestine pH
may be difficult to formulate into ER drug product. The osmotic type of controlled drug release
system may be more suitable for this type of drug.
-With too much coating, bioavailability gets reduced.
KINETICS OF EXTENDED-RELEASE DOSAGE FORMS:
 The amount of drug required in an extended-release dosage form to provide a sustained drug level
in the body is determined by the pharmacokinetics of the drug, the desired therapeutic level of the
drug, and the intended duration of action.
 In general, the total dose required (Dtot) is the sum of the maintenance dose (Dm) and the initial
dose (DI) released immediately to provide a therapeutic blood level.
Dtot = DI + Dm
 In practice, Dm (mg) is released over a period of time and is equal to the product of td (the duration
of drug release) and the zero-order rate kr0 (mg/h). Therefore, can be expressed as:
Dtot = DI + kr
0td
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 Ideally, the maintenance dose (Dm) is released after DI has produced a blood level equal to the
therapeutic drug level (Cp). However, due to the limits of formulations, Dm actually starts to
release at t = 0. Therefore, DI may be reduced from the calculated amount to avoid “topping.”
Dtot = DIr − k 0tp+ k r
0td
 It describes the total dose of drug needed, with tp representing the time needed to reach peak drug
concentration after the initial dose.
 For a drug that follows a one-compartment open model, the rate of elimination (R) needed to
maintain the drug at a therapeutic level (Cp) is
R = kVDCp
 where kr0 must be equal to R in order to provide a stable blood level of the drug. it provides an
estimation of the release rate (kr0) required in the formulation. The above equation may also be
written as
R = CpClT
 where ClT is the clearance of the drug. In designing an extended-release product, DI would be the
loading dose that would raise the drug concentration in the body to Cp, and the total dose needed
to maintain therapeutic concentration in the body would be simply
Dtot = DI + C pClTτ
 For many sustained-release drug products, there is no built in loading dose (i.e., DI = 0). The dose
needed to maintain a therapeutic concentration for t hours is
D0 = Cpτ ClT
where, t =dosing interval.
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MODIFIED DRUG DELIVERY PRODUCTS:
 Modified-release drug products are designed for different routes of administration based on the
physicochemical, pharmacodynamic (PD), and pharmacokinetic (PK) properties of the drug and on
the properties of the materials used in the dosage form.
ROUTE OF
ADMINISTRATION DRUG PRODUCT EXAMPLES COMMENTS
Oral drug products Extended release
Diltiazem HCl extended
release Once-a-day dosing.
Transdermal drug Transdermal therapeutic Clonidine transdermal Clonidine TTS is applied every 7 days
delivery systems system (TTS) therapeutic system to intact skin on the upper arm or chest
Ophthalmic drug Insert Controlled-release Elliptically shaped insert designed
delivery pilocarpine for continuous release of pilocarpine
following placement in the cul-de-sac
of the eye.
Intravaginal drug Insert Dinoprostone vaginal insert Hydrogel pouch containing prosta-
delivery glandin within a polyester retrieval
system.
Parenteral drug Intramuscular drug Depot injections Lyophylized microspheres containing
delivery products leuprolide acetate for depot suspension.
Targeted delivery IV injection Daunorubicin citrate Liposomal preparation to maximize
systems liposome injection the selectivity of daunorubicin for
solid tumors in situ.
Implants Brain tumor Polifeprosan 20 with car- Implant designed to deliver carmus-
mustine implant tine directly into the surgical cavity
(Gliadel wafer) when a brain tumor is resected. 8

CHARACTERISTICS OF EXTENDED RELEASE ORAL DOSAGE FORMS:
 The drugs best suited for incorporation into an extended release product have the following
characteristics:
-They exhibit neither very slow nor very fast rates of absorption and excretion.
-They should uniformly absorbed from the gastrointestinal tract.
-They are administered in relatively small doses.
-Possess a good margin of safety.
-They are used in the treatment of chronic rather than acute conditions.
TYPES OF EXTENDED-RELEASE PRODUCTS:
1. DRUG RELEASE FROM MATRIX:
 A matrix is an inert solid vehicle in which a drug is uniformly suspended. A variety of excipients
based on wax, lipid, as well as natural and synthetic polymers have been used as carrier material in
the preparation of such matrix type of drug delivery systems. The drug release from such matrix
systems is mainly controlled by the diffusion process, concomitant swelling, and/or erosion process.
CLASSIFICATION OF MATRIX TABLETS
 Based on the retarded materials used, matrix tablets can be divided into five types:
a. Hydrophobic matrix (plastic matrix)
b. Lipid matrix
c. Hydrophilic matrix
d. Biodegradable matrix
e. Mineral matrix. 9

EMBEDDING DRUG IN INERT PLASTIC MATRIX
 By this method, the drug is granulated with an inert plastic material such as polyethylene,
polyvinyl acetate, or polymethacrylate, and the granulation is compressed into tablets.
 The drug is slowly released from the inert plastic matrix by diffusion. The inert tablet matrix,
expended of drug, is excreted with the fecus.
EMBEDDING DRUG IN SLOWLY ERODING OR HYDROPHILIC MATRIX SYSTEM
 By this process, the drug substance is combined and made into granules with an excipient material
that slowly erodes in body fluids, progressively releasing the drug for absorption.
 When these granules are mixed with granules of drug prepared without the excipient, the
uncombined granules provide the immediate drug effect whereas the drug-excipient granules
provide extended drug action.
 Matrix system can also be classified according to their porosity situation, including microporous,
and nonporous system. By the usage frequency, matrix tablets can also be categorized as follows:
GUM TYPE MATRIX TABLETS
 Some excipients have a remarkable ability to swell in the presence of water and form a substance
with a gel-like consistency. When this happens, the gel provides a natural barrier to drug diffusion
from the tablet.
 gelatin dissolves rapidly after the gel is formed. Drug excipients such as methylcellulose, gum
tragacanth, Veegum, and alginic acid form a viscous mass and provide a useful matrix for
controlling drug release and dissolution.
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POLYMERIC TYPE MATRIX TABLETS
 The most important characteristic of this type of preparation is that the prolonged release may last
for days or weeks rather than for a shorter duration (as with other techniques).
 An early example of an oral polymeric matrix tablet was Gradumet (Abbott Laboratories), which
was marketed as an iron preparation. The non-biodegradable plastic matrix provides a rigid
geometric surface for drug diffusion, so that a relatively constant rate of drug release is obtained.
2. SLOW RELEASE COATED BEADS, GRANULES OR MICROSPHERES:
 In these systems, the drug is distributed onto beads, pellets, granules, or other particulate systems.
The size of these beads can be very small (microencapsulation) for injections or larger for oral drug
delivery. Several approaches have been used to manufacture beaded formulations including pan
coating, spray drying, fluid-bed drying, and extrusion-spheronization.
 Pan coating is a modified method adopted from candy manufacturing. Cores or nonpareil seeds of a
given mesh size are slowly added to known amount of fine drug powder and coating solution and
rounded for hours to become coated drug beads. The drug-coated beads are then coated with a
polymeric layer, which regulates drug release rate by changing either the thickness of the film or the
composition of the polymeric material.
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3. MICROENCAPSULATED DRUG:
 Microencapsulation is a process of encapsulating microscopic drug particles with a special coating
material, therefore making the drug particles more desirable in terms of physical and chemical
characteristics.
(or)
 It is a process by which solids, liquids, or even gases may be enclosed in microscopic particles by
formation of thin coatings of wall material around the substance.
 The typical encapsulation process usually begins with dissolving the wall material, say gelatin, in
water. The material to be encapsulated is added and the two-phase mixture thoroughly stirred. With
the material to be encapsulated broken up to the desired particle size, a solution of a second
material, usually acacia, is added. This additive material concentrates the gelatin into tiny liquid
droplets.
 One of the advantages of microencapsulation is that the administered dose of a drug is subdivided
into small units that are spread over a large area of the gastrointestinal tract, which may enhance
absorption by diminishing localized drug concentration.
 A common drug that has been encapsulated is aspirin. Aspirin has been microencapsulated with
ethyl cellulose, making the drug superior in its flow.
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4. ION-EXCHANGE PRODUCTS:
 Ion-exchange technique has been popularly applied in water purification and chemical extraction. Ion-exchange
preparations usually involve an insoluble resin capable of reacting with either an anionic or a cationic drug. An
anionic resin is negatively charged so that a positively charged cationic drug may attach the resin to form an
insoluble non-absorbable resin–drug complex.
 It provide protection for very bitter or irritating drugs. Ion exchange has been combining with a coating to obtain a
more effective sustained release product.
PROCESS
 A solution of a cationic drug may be passed through a column containing an ion-exchange resin,
forming a complex by the replacement of hydrogen atoms.
 The resin-drug complex is then washed and may be tableted, encapsulated, or suspended in an
aqueous vehicle. The release of the drug is dependent upon the pH and the electrolyte concentration
in the gastrointestinal tract.
 Release is greater in the acidity of the stomach than in the less acidic environment of the small
intestine.
e.g., Tussionex pennkinetic, an oral suspension containing Hydrocodone polistirex and
chlorpheniramine polistirex suspension and phentermine resin capsules.
 A general mechanism for the formulation of cationic drugs is :
H + + resin − SO3
− drug resin − SO 3
− H+ + drug+
Insoluble drug complex Soluble drug
 For anionic drugs, the corresponding mechanism is:
Cl− + resin − N+ (CH 3 )3 drug resin − N+ (CH 3 )3 Cl− + drug−
Insoluble drug complex Soluble drug
 The insoluble drug complex containing the resin and drug dissociates in the GIT in the presence of
the appropriate counter ions. The released drug dissolves in the fluids and is rapidly absorbed.
.
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TRADE NAME MANUFACTURER GENERIC NAME DESCRIPTION
Acutrim Ciba Phenylpropanolamine Once-daily, over-the-counter appetite
suppressant
Covera-HS Searle Verapamil
Controlled-Onset Extended-Release (COER-
24)
system for hypertension and angina pectoris
Procardia XL Pfizer Nifedipine Extended-release tablets for treatment of
angina and hypertension
Adalat CR Bayer AG Nifedipine An Alza-based OROS system of nifedipine
introduced internationally
5. OSMOTIC DRUG DELIVERY SYSTEMS:
 Osmotic drug delivery systems have been developed for both oral extended-release products known
as gastrointestinal therapeutic systems (GITS) and for parenteral drug delivery as an implantable
drug delivery (e.g., osmotic minipump). Drug delivery is controlled by the use of an osmotically
controlled device in which a constant amount of water flows into the system causing the dissolving
and releasing of a constant amount of drug per unit time.
PROCESS IN OSMOTIC MINIPUMP
 The pioneer oral osmotic pump drug delivery system is the Oros system, developed by Alza.
 The system is composed of a core tablet surrounded by a semi permeable membrane coating have a
0.4 mm diameter hole produced by laser beam.
 The system is designed such that only a few drops of water are drawn into the tablet each hour.
 The rate of inflow of water and the function of the tablet depends upon the existence of an osmotic
gradient between the contents of the bi-layer core and the fluid in the GI tract.
 Drug delivery is essentially constant as long as the osmotic gradient remains constant.
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 Here, The drug release rate may be altered by;
- Changing the surface area,
- The thickness or composition of the membrane,
- Changing the diameter of the drug release orifice.
- The drug-release rate is not affected by gastrointestinal acidity, alkalinity, fed conditions, or GI
motility.
6. GASTRORETENTIVE SYSTEMS:
 The extended-release drug product should release the drug completely within the region in the GI
tract in which the drug is optimally absorbed. Due to GI transit, the extended-release drug product
continuously moves distally down the GI tract. In some cases, the extended-release drug product
containing residual drug may exit from the body. Pharmaceutical formulation developers have used
various approaches to retain the dosage form in the desired area of the gastrointestinal tract.
 One such approach is a gastro-retentive system that can remain in the gastric region for several
hours and prolong the gastric residence time of drugs.
 Usually, the gastro-retentive systems can be classified into several types based on the mechanism
applied such as
(i) high-density systems
(ii) floating systems
(iii) expandable systems
(iv) super porous hydrogels
(v) mucoadhesive or bioadhesive systems
(vi) magnetic systems
(vii) dual working systems
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7. TRANSDERMAL DRUG DELIVERY SYSTEMS:
 Skin represents the largest and most easily accessible organ of the body. A transdermal drug
delivery sys-tem (patch) is a dosage form intended for delivering drug across the skin for systemic
drug absorption.
 Transdermal drug absorption also avoids presystemic metabolism or “first-pass” effects. It deliver
the drug through the skin in a controlled rate over an extended period of time.
8.CORE TABLETS:
 A core tablet is a tablet within a tablet, the inner core is usually used for the slow-drug-release
component, and the outside shell contains a rapid-release dose of drug.
 Formulation of a core tablet requires two granulations. The core granulation is usually compressed
lightly to form a loose core and then transferred to a second die cavity, where a second granulation
containing additional ingredients is compressed further to form the final tablet.
 The core material may be surrounded by hydro-phobic excipients so that the drug leaches out over a
prolonged period of time. This type of preparation is sometimes called a slow-erosion core tablet,
because the core generally contains either no disintegrant or insufficient disintegrant to fragment the
tablet.
.
TRADE NAME MANUFACTURER GENERIC NAME DESCRIPTION
Catapres-TTS Boehringer Ingelheim Clonidine Once-weekly product for the treatment of
hypertension
Transderm Scop Scopolamine
Prevention of nausea and vomiting associated
with
motion sickness
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9. PROLONG ACTION TABLETS:
 An alternate approach to prolong the action of a drug is to reduce the aqueous solubility of the
drug, so that the drug dissolves slowly over a period of several hours. The solubility of a drug is
dependent on the salt.
 Another application of prolong-action tablets is also called as pulsatile drug delivery system. This
chrono pharmaceutical formulation is usually used in the treatment of circadian rhythm
dysfunction disease.
10. REPEAT ACTION TABLETS:
 Repeat action tablets are prepared so that an initial dose of drug is released immediately followed
later by a second dose. The tablets may be prepared with the immediate release dose in the tablets
outer shell or coating with the second dose in the tablets inner core, separated by a slowly
permeable barrier coating.
 Repeat action dosage forms are best suited for the treatment of chronic conditions requiring
repeated dosing.
The drugs utilized should have low dosage and fairly rapid rates of absorption and excretion.
11. MULTITABLET SYSTEM:
 Small spheroid compressed tablets 3 to 4 mm in diameter may be prepared to have varying drug
release characteristics.
 They may be placed in gelatin capsule shells to provide the desired pattern of drug release.
 Each capsule may contain 8 to 10 minitablets, some uncoated for immediate release and others
coated for extended drug release.
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12. COMPLEX FORMATION:
 Certain drug substances when chemically combined with certain other chemical agents form
chemical complexes that may be only slowly soluble in body fluids, depending upon the pH of the
environment. This slow dissolution rate provides the extended release of the drug.
13.COMBINATION PRODUCT:
 A product comprised of two or more regulated components, that is, drug/device, biologic/device,
drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or
mixed and produced as a single entity.
e.g., Monoclonal antibody combined with a therapeutic drug
14. MODIFIED RELEASE PARENTERAL DOSAGE FORMS:
 It include microspheres, liposomes, drug implants, inserts, drug-eluting stents, and nanoparticles.
 These formulations are designed by entrapment or microencapsulation of the drug into inert
polymeric or lipophilic matrices that slowly release the drug, in vivo, for the duration of several
days or up to several years. Modified-release parenteral dosage forms may be biodegradable or
nonbiodegradable. Nonbiodegradable implants need to be surgically removed at the end of therapy.
EVALUATION OF MODIFIED-RELEASE DRUG PRODUCTS
In vitro/In vivo correlations (IVIVCs)
 IVIVCs is critical to the development of oral extended-release products. Assessing IVIVCs is
important throughout the periods of product development, clinical evaluation, submission of an
application for FDA- approval for marketing, and during post approval for any formulation or
manufacturing changes.
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Three categories of IVIVCs are included;
LEVEL-A
 A predictive mathematical model for the relationship between the entire in vitro
dissolution/release time course.
e.g., the time course of plasma drug concentration or amount of drug absorbed.
LEVEL-B
 A predictive mathematical model of the relationship between summary parameters that
characterize the in vitro and in vivo, time courses.
LEVEL-C
 A predictive mathematical model of the relationship between the amount dissolved in vitro at a
particular time (or T50%) and a summary parameter that characterizes the in vivo time course
(e.g. Cmax or AUC).
DISSOLUTION STUDIES
 Reproducibility of the method
 Proper choice of the medium
 Maintenance of sink condition
 Control of solution hydrodynamics
 Dissolution rate as function of pH, ranging from 1-8
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EVALUATION OF IN-VIVO BIOAVAILABILITY DATA
1. PHARMACOKINETIC PROFILE
 Plasma drug conc.-time curve should adequately define bioavailability of drug from dosage form.
 The bioavailability data should demonstrate the extended release characteristics of the dosage form
compared to reference/immediate release product.
2. STEADY STATE PLASMA DRUG CONCENTRATION
 Fluctuation = C∞ max - C∞ min /C∞ av
 where C∞ av is equal to [AUC]/T
3. RATE OF DRUG ABSORPTION
 For a extended release drug product to claim zero- order absorption, Wagner nelson method is used.
4. OCCUPANCY TIME
 For drugs whose therapeutic window are known, plasma drug conc. Maintained above the minimum
effective drug concentration.
 The time required to obtain plasma drug levels within therapeutic window is known as occupancy
time.
ADVANTAGES OF MRDP:
 Reduction in drug blood level fluctuation.
 Frequency reduction in dosing.
 Patient compliance
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 Reduced adverse side effect.
 Reduction in health care cost.
DISADVANTAGES OF MRDP:
 Dose-dumping
 Less flexibility in accurate dose adjustment.
 Less possibility for high dosage
TARGETED DRUG DELIVERY SYSTEMS:
 Targeted drug delivery system is a special form of drug delivery system where the medicament is
selectively targeted or delivered only to its site of action or absorption and not to the non-target
organs or tissues or cells.
 It seeks to concentrate the medication in the tissues of interest while reducing the relative
concentration of the medication in the remaining tissues.
 This improves efficacy and reduce side effects.
IDEAL CHARACTERISTICS:
 It should be nontoxic, biocompatible, biodegradable, and physicochemical stable in vivo and in
vitro.
 Restrict drug distribution to target cells or tissues or organs and should have uniform capillary
distribution.
 Controllable and predicate rate of drug release.
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 Drug release does not effect the drug action.
 Therapeutic amount of drug release.
 Minimal drug leakage during transit.
 Carriers used must be bio-degradable or readily eliminated from the body without any problem and
no carrier induced modulation of diseased state.
 The preparation of the delivery system should be easy or reasonably simple, reproductive and cost
effective.
REASONS FOR DRUG TARGETING:
23

GENERAL CONSIDERATIONS IN TARGETED DRUG DELIVERY
 Considerations in the development of site-specific or targeted drug delivery systems include:
(1) The anatomic and physiologic characteristics of the target site, including capillary permeability
to macromolecules and cellular uptake of the drug.
(2) The physicochemical characteristics of the therapeutically active drug.
(3) Physical and chemical characteristics of the carrier.
(4) Selectivity of the drug–carrier complex.
(5) Any impurities introduced during the conjugation reaction linking the drug and the carrier that
may be immunogenic, be toxic, or produce other adverse reactions.
TARGET SITE:
 The accessibility of the drug–carrier complex to the target site may present bioavailability and
pharmacokinetic problems, which also include anatomic and/or physiologic considerations.
e.g., Targeting a drug into a brain tumor requires a different route of drug administration
(intrathecal injection) than targeting a drug into the liver or spleen.
 Moreover, the permeability of the blood vessels or biologic membranes to macromolecules or drug–
carrier complex may be a barrier preventing delivery and intracellular uptake of these drugs.
SITE-SPECIFIC CARRIERS:
 To target a drug to an active site, one must consider whether there is a unique property of the active
site that makes the target site differ from other organs or tissue systems in the body.
 The next consideration is to take advantage of this unique difference so that the drug goes
specifically to the site of action and not to other tissues in which adverse toxicity may occur.
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 In many cases the drug is complexed with a carrier that targets the drug to the site of action.
e.g., one of the first approved drugs developed using pharmacogenomic principles is Herceptin
(trastu-zumab), a monoclonal antibody designed to bind to the human epidermal growth factor
receptor. This receptor is over expressed on HER-2 positive breast cancer cells. Therefore, the drug
will preferentially bind HER-2 positive breast cancer cells, though other noncancerous cells may
also express the receptor
- Similarly, trastuzumab has also been used as targeting agents for anticancer drug-
encapsulated nanoparticles in clinical studies.
- The successful application of these delivery systems requires the drug–carrier complex to
have both affinity for the tar-get site and favourable pharmacokinetics for delivery to the organ,
cells, and sub cellular target sites.
-An additional problem, particularly in the use of protein carriers, is the occurrence of
adverse immunological reactions—an occurrence that is partially overcome by designing less
immunoreactive proteins.
-Humanized mAbs are an example of a therapeutic protein engineered to be less
immunoreactive.
DRUGS:
 Most of the drugs used for targeted drug delivery are highly reactive drugs that have potent
pharmacodynamic activities with a narrow therapeutic range.
 These drugs are often used in cancer chemotherapy. Many of these drugs may be derived from
biologic sources, made by a semi synthetic process using a biologic source as a precursor, or
produced by recombinant DNA techniques.
25

 The drugs may also be large macromolecules, such as proteins, and are prone to instability and
inactivation problems during processing, chemical manipulation, and storage.
TARGETING AGENTS:
 Properly applied, drug targeting can improve the therapeutic index of many toxic drugs. However,
monoclonal antibodies are not the “magic bullet” for drug targeting that many people had hoped.
One difficulty encountered is that the large molecule reduces the total amount of active drug that can
be easily dosed (i.e., the ratio of drug to carrier).
 In contrast, conventional carriers or targeting agents that are not specific are often many orders of
magnitude smaller in size, and a larger effective drug dose may be given more efficiently. Antibody
fragments comprised of either the double- or single-chain variable regions are also being tested as
smaller drug targeting agents.
 In addition to employing monoclonal antibodies in liposomes and other delivery systems. The
resulting conjugate can theoretically deliver the drug directly to a cell that expresses a unique surface
marker.
e.g., a tumor cell may over express the interleukin-2 receptor. In this case, a cytotoxic molecule
such as recombinant diphtheria toxin is coupled to an mAb specific for the interleukin-2 receptor
(Ontak). The conjugate delivers the toxin preferentially to these tumor cells. An overall tumor
response rate for Ontak is 38%, with side effects including acute hypersensitivity reaction (69%) and
vascular leak syndrome (27%).
Myoscint is an 111In-labeled mAb targeted to myosin that is used to image myocardial injury
in patients with suspected myocardial infarction. An immune response to mAb drugs may develop,
since mAbs are produced in mouse cells. “Humanized” mAbs are genetically engineered to produce
molecules that are less immunogenic. 26

ORAL IMMUNIZATION:
 Antigens or fragmented antigenic protein may be delivered orally and stimulate gut-associated
lymphoid tissue (GALT) in the gastrointestinal tract. This represents a promising approach for
protecting many secretory surfaces against a variety of infectious pathogens, but products have not
yet reached clinical trials.
 Immunization against salmonella and Escherichia coli in chickens was investigated for agricultural
purposes. Particulate antigen delivery systems, including several types of microspheres, have been
shown to be effective orally inducing various types of immune response. Encapsulation of antigens
with mucosal adjuvants can protect both the antigen and the adjuvant against gastric degradation and
increase the likelihood that they will reach the site of absorption.
ADVANTAGES:
 Drug administration protocols may be simplified.
 Toxicity is reduced by delivering a drug to its target site, there by reducing harmful systemic effects.
 Drug can be administered in a smaller dose to produce the desire effect.
 Avoidance of hepatic first pass metabolism.
 Enhancement of the absorption of target molecules such as peptides and particulates.
 Dose is less compared to conventional drug delivery system.
 No peak and valley plasma concentration.
 Selective targeting to infections cells that compare to normal cells.
27

DISADVANTAGES:
 Rapid clearance of targeted systems.
 Immune reactions against intravenous administered carrier systems.
 Insufficient localization of targeted systems into tumour cells.
 Diffusion and redistribution of released drugs.
 Requires highly sophisticated technology for the formulation.
 Requires skill for manufacturing storage, administration.
 Drug deposition at the target site may produce toxicity symptoms.
 Difficult to maintain stability of dosage form.
E.g.: Resealed erythrocytes have to be stored at 40 C.
 Drug loading is usually low.
E.g. As in micelles. Therefore it is difficult to predict /fix the dosage regimen.
BIOTECHNOLOGICAL PRODUCTS:
 Many diseases occur as a result of variability in the genes involved in producing essential enzymes
or proteins in the body. The genes are coded in deoxyribonucleic acid (DNA), helical double-
stranded molecules folded into chromosomes in the nucleus of cells. The Human Genome Project
was created more than a decade ago to sequence the human genome, This national effort is
continuing to yield information on the role of genetics in congenital defects, cancer, disorders
involving the immune system, and other diseases that have a genetic link.
28

 As a result, biotechnology, or the use of biological materials to create a specific product, in this case
pharmaceuticals, has become an important sector of the pharmaceutical industry and accounts for
the fastest growing class of new drugs in the market. Nucleic acid, protein and peptide drugs, and
diagnostics are the main drug products emerging from the biopharmaceutical industry.
BIOTECHNOLOGICAL DRUGS:
 Pharmaceutical biotechnology consist of the combination of two branch which are “Pharmaceutical
science” and “Biotechnology”.
PHARMACEUTICAL SCIENCE:
 It can be simply define as the branch of science that deals with the formulation compounding and
dispensing of drugs.
BIOTECHNOLOGY:
 Biotechnology drug differ from Pharmaceutical drugs in that they use biotechnology as a means for
manufacturing, which involves the manipulation of microorganism, such as bacteria, or biological
substance, like enzymes, to perform a specific process.
Ex:- Antibiotics, vaccines etc.
BIOTECHNOLOGICAL PRODUCTS:
 Biotechnology can be defined as application of technology using the living organisms to obtain
useful products. The products made by the biotechnology process include, pharmaceuticals
(medicine), food, and water purification, genetic known as biotechnological products.
TYPES OF BIOTECHNOLOGICAL PRODUCTS:
 Industrial and Environmental biotechnology.
29

 Medical / pharmaceutical biotechnology
 Agricultural biotechnology
 Diagnostic research biotechnology
EXAMPLES OF BIOTECHNOLOGICAL PRODUCTS:
1. Proteins and peptides
2. Monoclonal antibodies
3. Oligonucleotides
4. Vaccines (immunotherapy)
5. Gene therapies
1. PROTEINS AND PEPTIDES:
PROTEINS:
 Proteins are the large organic compounds made of amino acids arranged in linear chain and joined
together by peptide bonds.
Protein > 50 amino acids
Molecular weight above 5000
PEPTIDES:
 These are short polymer formed from the linking in a defined order of amino acids.
Peptide < 50 amino acids
Molecular weight less than 5000
30

 Scientific advances in molecular and cell biology have resulted in the development of two new
biotechnologies.
-The first utilizes RECOMBINANT DNA to produce protein product.
-The second technology is HYBRIDOMA TECHNOLOGY. Various protein and peptide drug are
epidermal growth factor, tissue plasminogen activator.
2. MONOCLONAL ANTIBODIES:
 Antibody or immunoglobulin's are protein molecules produced by a specialized group of cells
called B-lymphocytes in mammals.
 An antibody is a protein produced by white blood cells and used by the immune system to identify
and neutralize foreign objects like bacteria, viruses and foreign substances. Each antibody
recognizes a specific antigen unique to its target.
- Monoclonal antibodies (mAb) are antibodies that are identical because they were produced by
one type of immune cell, all clones of a single parent cell.
- Polyclonal antibodies are antibodies that are derived from different cell lines.
 The power of mAb lies in their highly specific binding of only one antigenic determinant. As a
result, mAb drugs, targeting agents, and diagnostic are creating new ways to treat and diagnose.
 Monoclonal antibodies can also target and deliver toxin specifically to cancer cells and destroy
them while sparing normal cells and important detectors used in laboratory diagnostics.
MAB PRODUCT(target name) TARGET INDICATION
Muromonab-CD3
transplant rejection
CD3 on T cells Reversal of acute kidney
Orthoclone OKT3
31

3. OLIGONUCLEOTIDES:
 Antisense drugs consist of nucleotides linked together in short DNA or RNA sequence known as
oligonucleotides.
 Antisense oligonucleotides drugs, are drugs that seek to block DNA transcription or RNA
translation in order to moderate many disease processes.
 Oligonucleotides are chemically synthesized by using phosphoramidite. The oligonucleotide chain
proceeds in the direction of 3’ to 5’ terminus.
 These are the molecules made of synthetic genetic material, which interact with the natural genetic
material that codes the information for production of proteins.
 Antisense RNA prevents protein translation of certain mRNA strands by binding to them.
 Antisense DNA can used to target a specific complementary RNA.
e.g.,Mipomersen for high cholesterol.
4. VACCINES (IMMUNOTHERAPY):
 A vaccine is a biological preparations that improves immunity to a particular disease.
 A vaccine typically contains an agent that resembles a disease causing microorganism and is often
made from weakened or killed forms of the microbe, its toxins or one of its surface proteins.
 Vaccines are dead or inactivated organisms or purified product derived from them.
 The different types of vaccines are:
A) TRADITIONAL VACCINES:
1. Killed 2. Live, attenuated 3. Toxoid 4. Subunit
32

B) INNOVATIVE VACCINES:
1. Conjugate vaccines 2. Recombinant vector vaccine 3. T-cell receptor peptide vaccine 4. Valence 5.
Heterotypic
5. GENE THERAPHY:
 A technique for correcting defective genes that are responsible for disease development.
 In this use of DNA as a pharmaceutical agent to treat disease.
 The most common form of gene therapy involves using DNA that encoded a functional, therapeutic
gene to replace a mutated gene.
 Approaches for gene therapy:
1.Gene modification
a. Replacement therapy
b. Corrective gene therapy
2.Gene transfer
a. Physical (Microinjection, Gene gun, naked DNA, Electroporation)
b. Chemical (Liposomes, Cationic liposomes, Oligonucleotides etc.)
c. Biological (Viral vector , mammalian artificial chromosomes)
3. Gene transfer in specific cell lines
a. Somatic gene therapy
b. Germ line gene therapy
4.Eugenic approach(gene insertion)
33

INTRODUCTION TO PHARMACOKINETICS AND PHARMACODYNAMICS:
 The purpose of studying pharmacokinetics and pharmacodynamics is to understand the drug
action, therapy, design, development and evaluation.
PHARMACOKINETIC STUDY:
 It is a branch of Pharmacology which deals with the study of Absorption, Distribution,
Metabolism, Excreation/Elimination.
 Pharmacokinetics is the study of “What the body does to the drug”
PHARMACODYNAMIC STUDY:
 In Greek, Pharmcon – Drug Dynamics – Action.
 Pharmacodynamics is the study of biochemical and physiologic effect of drug. It is the study of
“What the drug does to the body”
34

PHARMACOKINETICS:
 It involves Four Processes: 1. Absorption 2. Drug distribution 3. Metabolism 4. Drug elimination
1.ABSORPTION:
 It is the process of entry of drug from site of administration into systemic circulation.
 The bioavailability of the drug depends on the extent of the absorption.
35

 Bioavailability is the percentage of drug that reaches the systemic circulation in an unchanged
form and becomes available for biological effect following administration by any route.
 Bioequivalence occurs when two formulations of the same compound have the same
bioavailability and the same rate of absorption.
FACTORS INFLUENCING ABSORPTION:
1.FACTORS RELATED TO DRUG:
a) Physicochemical properties
-Degree of ionization, Degree of solubility, Chemical nature, valence.
-High lipid / water partition coefficient increases absorption
b) Pharmaceutical form of drug
e.g., Absorption of solutions is better than suspensions or tablets.
2. FACTORS RELATED TO PATIENT:
a) Route of administration
-absorption is faster from i.v.> inhaled >i.m. > oral > dermal Administration.
b) Area and vascularity of absorbing surface
-Absorption is directly proportional to both area and vascularity. Thus absorption of the drug
across the intestine is more efficient than across the stomach, as Intestine has more blood flow
and much bigger surface area than those of the Stomach.
c) State of absorbing surface
e.g. atrophic gastritis and mal-absorption syndrome decrease rate of absorption of drugs.
36

d) Rate of general circulation
e.g. in shock, peripheral circulation is reduced and I.V. route is used.
e) Presence of other drugs and other Specific factor
e.g. intrinsic factor of the stomach is essential for vitamin B12 absorption from lower ileum and
adrenaline induces vasoconstriction so delay absorption of local anaesthetics.
3. FIRST-PASS EFFECT (pre-systemic metabolism):
 where drugs must pass through gut mucosa and liver before reaching systemic circulation.
a) Gut first-pass effect:
e.g. benzyl penicillin is destroyed by gastric acidity, insulin by digestive enzymes
b) Hepatic first-pass effect:
e.g. lidocaine (complete destruction so not effective orally) and propranolol (extensive
destruction)
2.DISTRIBUTION:
 Distribution is the movement of drug from the central compartment (blood) to peripheral
compartments. Here the concentration gradient is being the driving force for the movement from
plasma to tissues.
 It depends on;
- Ionization
- Molecular size
- Binding to plasma proteins
- Differences in regional blood flow Presence of tissue-specific transporters.
37

VOLUME OF DISTRIBUTION(Vd):
 It is defined as the volume of fluid required to contain the total amount of drug Q in the body at
the same concentration as that present in the plasma, Cp
Vd = Q/Cp
IMPORTANCE OF Vd:
 It helps in estimating the total amount of drug in body at any time.
Amount of drug = Vd x plasma concentration of drug at certain time
 Vd is important to determine the loading dose.
Loading dose = Vd x desired concentration
3. METABOLISM (BIOTRANSFORMATION):
 Biotransformation means chemical alteration of the drug in the body.
 It is needed to render non-polar (lipid-soluble) compounds polar (lipid insoluble) so that they are
not reabsorbed in the renal tubules and are excreted.
 The primary site for drug metabolism is liver; others are-kidney, intestine, lungs and plasma.
 Phases of biotransformation:
- Phase I (Non-synthetic) reactions - A functional group is generated or exposed-metabolite may
be active or inactive.
- Phase II (Synthetic) reactions – Mostly a conjugation reaction - Metabolite is mostly inactive
(except few drugs).
38

Phase I (Non-synthetic) Reactions
 Introduction or unmasking of functional group by oxidation, reduction hydrolysis, Cyclization,
Decyclization
 These reactions may result in ;
1.Drug inactivation (most of drugs)
2.Conversion of inactive drug into active metabolite (cortisone→ cortisol)
3. Conversion of active drug into active metabolite (phenacetin→ paracetamol)
4.Conversion to toxic metabolite (methanol → formaldehyde)
Phase II (Synthetic) Reactions
 Functional group or metabolite formed by phase I is masked by conjugation with natural
endogenous constituent as glucuronic acid , glutathione, sulphate , acetic acid, glycine or methyl
group.
 These reactions usually result in drug inactivation with few exceptions.
e.g. morphine-6-conjugate is active
 Most of drugs pass through phase I only or phase II only or phase I then phase II.
 Some drugs as isoniazid passes first through phase II then phase I (acetylated then hydrolyzed to
isonicotinic acid).
FACTORS AFFECTING DRUG METABOLISM
a) DRUGS
 One drug can competitively inhibit the metabolism of another if it utilizes the same enzyme or
cofactors either by Enzyme induction or by Enzyme inhibition.
39

b) GENETIC VARIATION
 The most important factor is genetically determined polymorphisms.
e.g., Isoniazid is metabolized in the liver via acetylation. There are two forms (slow and fast) of
the enzyme responsible for acetylation (N-acetyl transferase ), thus some patients metabolize the
drug quicker than others. Slow acetylators are prone to peripheral neuritis while fast acetylators
are prone to hepatic toxicity.
c) NUTRITIONAL STATE
 Conjugating agents are sensitive to body nutrient level.
e.g., low protein diet can decrease glycine.
d) DOSAGE
 High dose can saturate metabolic enzyme leading to drug accumulation. If metabolic pathway is
saturated due to high dose or depletion of endogenous conjugate, an alternative pathway may
appear.
e.g. paracetamol may undergo N-hydroxylation to hepatotoxic metabolite.
e) AGE
 Drug metabolism is reduced in extremes of age (old patients and infants)
4. ELIMINATION OR EXCRECTION:
 Elimination-Termination of Drug Action by which a drug or metabolite is eliminated from the
body. Drugs and their metabolites are excreted in Urine, Faeces, Exhaled air, Saliva and sweat.
-Two-stage kidney process (filter, absorption)
-Metabolites that are poorly reabsorbed by kidney are excreted in urine. 40

-Some drugs have active (lipid soluble) metabolites that are reabsorbed into circulation (e.g., pro-
drugs)
-Other routes of elimination: lungs, bile, skin
TERMINOLOGIES IN PHARMACOKINETICS
 Elimination Half-Life = time required for drug blood levels to be reduced by 50%
 Volume of Distribution = dose/Plasma Concentration
(theoretical volume that would have to be available for drug to disperse)
 Clearance = Volume of blood cleared of drug per unit time.
PHARMACODYNAMICS:
 Pharmacodynamics refers to the relationship between drug concentration at the site of action and
the resulting effect, including the time course and intensity of therapeutic and adverse effects.
 The effect of a drug present at the site of action is determined by that drug’s binding with a
receptor.
 The concentration at the site of the receptor determines the intensity of a drug’s effect.
 Drug Action: Four major types of bio- macromolecular targets of drug action is there,
(A) Enzyme
(B) Transmembrane ion channel
(C) Membrane bound transporter
(D) Receptor
41

FACTORS AFFECTING DRUG RESPONSE:
 Density of receptors on the cell surface.
 The mechanism by which a signal is transmitted into the cell by second messengers.
 Regulatory factors that control gene translation and protein production may influence drug effect.
DOSE-RESPONSE CURVES:
 Individual responses to varying doses;
-Threshold: Dose that produces a just-noticeable effect.
-ED50: Dose that produces a 50% of maximum response.
-Ceiling: Lowest dose that produces a maximal effect.
DOSE-RESPONSE FUNCTIONS:
 Efficacy ED50 = median effective dose
 Lethality LD50 = median lethal dose
 Therapeutic Index = LD 50 /ED 50 = toxic dose/effective dose
 This is a measure of a drug’s safety
-A large number = a wide margin of safety
-A small number = a small margin of safety
DURATION OF EFFECT:
 Duration of effect is determined by a complex set of factors, including;
-The time that a drug is engaged on the receptor
-Intracellular signalling
-Gene regulation.
42

 Time Course Studies important for ;
-Predicting dosages/dosing intervals
-Maintaining therapeutic levels
-Determining time to elimination
TOLERANCE:
 The effectiveness can decrease with continued use is referred to as tolerance.
 Tolerance may be caused by;
-The pharmacokinetic factors, such as increased drug metabolism, that decrease the concentrations
achieved with a given dose.
-The pharmacodynamic factors like when the same concentration at the receptor site results in a reduced
effect with repeated exposure.
DRUG INTERACTION:
 Drug interaction may be defined as an alteration in the effects of one drug by prior or concurrent
administration of another drug.
-Drug that precipitates the interaction - Precipitant drug
-Drug whose action is affected - Object drug
TYPES OF DRUG INTERACTIONS:
1.Drug-drug interactions.
2.Drug-food interactions.
3.Chemical-drug interactions.
4.Drug-laboratory test interactions.
5.Drug-disease interactions.
43

FACTORS CONTRIBUTING TO DRUG INTERACTIONS:
1.Multiple drug therapy.
2.Multiple prescribers.
3.Multiple pharmacological effects of drug.
4.Multiple diseases
5.Poor patient compliance.
6.Drug-related factors.
7.Advancing age of patient
MECHANISM OF DRUG INTERACTIONS:
 The three mechanisms by which an interaction can develop are;
A. Pharmaceutical interactions.
B. Pharmacokinetic interactions.
C. Pharmacodynamic interactions.
A. PHARMACEUTICAL INTERACTIONS:
 Also called as incompatibility. It is a physicochemical interaction that occurs when drugs are
mixed in i.v . Infusions causing precipitation or inactivation of active principles .
e.g., Ampicillin ,chlorpromazine & barbiturates interact with dextran in solutions and are broken
down or from chemical compounds.
B. PHARMACOKINETIC INTERACTIONS:
 “These interactions are those in which ADME properties of the object drug is altered by the
precipitant and hence such interactions are also called as ADME interactions”.
44

 The resultant effect is altered plasma concentration of the object drug. These are
classified as:
1.Absorption interactions
2.Distribution interactions
3.Metabolism interactions
4.Excretion interactions
1. ABSORPTION INTERACTIONS:
 Are those where the absorption of the object drug is altered. The net effect of such
an interaction is:
• Faster or slower drug absorption.
• More, or, less complete drug absorption.
Major mechanisms of absorption interactions are:
1.Complexation and adsorption.
2.Alteration in GI pH.
3.Alteration in gut motility.
4.Inhibition of GI enzymes.
5.Alteration of GI micro flora.
45

2. DISTRIBUTION INTERACTIONS:
 Are those where the distribution pattern of the object drug is altered.
 The major mechanism for distribution interaction is alteration in protein-drug binding.
3.METABOLISM INTERACTIONS:
 Are those where the metabolism of the object drug is altered.
 Mechanisms of metabolism interactions include;
a. Enzyme induction:
- Increased rate of metabolism.
b. Enzyme inhibition:
-Decreased rate of metabolism. It is the most significant interaction in comparison to other
interactions and can be fatal.
47

4.EXCRETION INTERACTIONS:
 Are those where the excretion pattern of the object drug is altered.
 Major mechanisms of excretion interactions are;
- Alteration in renal blood flow
-Alteration of urine PH
-Competition for active secretions
-Forced diuresis
48

C. PHARMACODYNAMIC INTERACTIONS:
•Are those in which the activity of the object drug at its site of action is altered by the precipitant.
Such interactions may be direct or indirect.
•These are of two types:
1.Direct pharmacodynamic interactions.
2.Indirect pharmacodynamic interactions.
1. DIRECT PHARMACODYNAMIC INTERACTIONS:
•In which drugs having similar or opposing pharmacological effects are used concurrently.
•The three consequences of direct interactions are :
49

a. Antagonism.
b. Addition or summation.
c. Synergism or potentiation
a. SYNERGISM:
 When the therapeutic or toxic effects of two drugs are greater than the sum of effects of individual
drugs.
 It is an enhancement of action of one drug by another.
E.g.: Combination of sulfamethoxazole and trimethoprim is used as antimicrobial agent.
Alcohol enhances the of analgesics activity aspirin.
b. ADDITIVE EFFECT:
 Net effect of two drugs used together is equal to the sum of the individual drug effects.
E.g.: Combination of thiazide diuretic and beta adrenergic blocking drug is used for the treatment
of hypertension.
c. ANTAGONISM:
 The effects of one drug can be reduced or abolished by the presence of another drug.
 The interacting drugs have opposing actions
E.g.: Blockade of antiparkinsonian action of levodopa by neuroleptics and metoclopramide having
anti dopaminergic action.
Acetylcholine and noradrenaline have opposing effects on heart rate
2.INDIRECT PHARMACODYNAMIC INTERACTION:
 In which both the object and the precipitant drugs have unrelated effects but latter in some way
alerts the effects of the former.
Example : morphine and nalorphine.
50

DRUG-FOOD INTERACTIONS:
GARLIC
 when combined with diabetes medication could cause dangerous decrease in blood sugar level.
 Some garlic sensitive individuals may experience heart burn and flatulence. It also has anti-
clotting properties (interaction with anticoagulants).
ORANGE JUICE
 It must not be consumed with antacids containing aluminium.
 The juice increases the absorption of aluminium and leads to severe constipation.
MILK
 It contains elements like Mg and Ca which chelate antibiotics like tetracycline and hence decrease
its absorption and effect.
GRAPEFRUIT JUICE
 It inhibits CYP3A4; increasing levels of antidepressants (sertraline), benzodiazepines, verapamil.
VITAMIN K
 Vit.k rich foods reduce the effectiveness of anticoagulants (such as warfarin), increasing the risk
of clotting.
Fiber in OATMEAL and other cereals
 when consumed in large amounts, can interfere with the absorption of digoxin.
ALCOHOLIC BEVERAGES
 It tend to increase the depressive effect of medications such as benzodiazepines, antihistamines,
51

antidepressants, antipsychotics, muscle relaxants and narcotics.
 Disulfiram like reaction with metronidazole.
 Increase metabolism of warfarin and phenytoin.
SMOKING
 It increases activity of drug metabolizing enzymes in the liver.
 Diazepam, Theophylline, Olanzapine are metabolized rapidly and their effect is decreased.
DRUG-DISEASE INTERACTIONS:
 Drug – Condition interaction occurs when a drug worsens or exacerbates an existing medical condition.
-Nasal decongestants + Hypertension… ↑ Blood Pressure
-NSAIDs + Asthmatic Patients … Airway obstruction
-Nicotine + Hypertension … ↑ Heart Rate
-Motorman + Heart failure … ↑Lactate level
CONDSEQUENCES OF DRUG INTERACTIONS:
 The consequences of drug interactions may be:
Major: Life threatening.
Moderate: Deterioration of patients status.
Minor: Little effect
REDUCING THE RISK OF DRUG INTERACTIONS:
1. Identify the patients risk factors.
2. Take through drug history.
3. Be knowledge about the actions of the drugs being used.
4. Consider therapeutic alternatives.
5. Avoid complex therapeutic regiments when possible.
6. Educate the patient.
7. Monitor therapy.
52

REFERENCES:
 Shargel leon, WU Pong Susanna, B.C. YU Andrew, Applied Bio pharmaceutics and
Pharmacokinetics, 5th edition, rights by McGraw-Hill, page no.-516-551.
 S. P. Vyas and V. K. Dixit, “Pharmaceutical Biotechnology”, CBS Publication, page no. 402-409.
 http://en.m.wikipedia.org  http://www.youtube.com  http://www.google.com.
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