EXPERIMENT NO: 1

DRUG INFORMATION OUERY

INTRODUCTION

The provision of drug information is the most fundamental responsibility of clinical

[Link] information may be specific to an individual patient as an integral part of
pharmaceutical care, or relative to a group of patients, such as in the context of a disease
management programme. The term medicine is used to highlight the services related to
medicinal drugs rather than drug of abuse.

The term drug information was developed in early 1960s. The first drug information centre was
established at the University of Kentucky in 1962. However in India drug information services
and centres are still in their infancy and we have only a few services that qualify as drug
information centre.

Pharmacists have unique range of knowledge and skills which are required for drug information
practice. These include knowledge of pharmaceutics, pharmacology, pharmacokinetics and
pharmacotherapy. All of these are required to optimize the use of drugs in treatment and
prevention of disease.

DEFINITION

Drug information refers to the provision of unbiased , well referenced, and critically evaluated
up- to- date information on any aspect of drug use.

The drug information service (DIS) refers to activities that are part of the overall pharmacy
service or pharmaceutical care process.

Drug information centre (DIC) refers to the specialized facility that provides drug information to
those who need it.

A drug information specialist refers to a new breed of pharmacist who is expert in drug
information monitoring.
OBJECTIVES

 To uplift the profession of pharmacy.

 To improve patient compliance and therapeutic outcome.
 To advise and educate patients for the proper use of drugs.
 To advise and educate patients regarding drug addiction, alcoholism, smoking
hazards and other socio- medical problems.
 Advise on self medication for minor complaints.
 Advise on public health issues.
 Other activities like publishing newsletters or bulletins, conducting seminars,
group discussions, campsigns etc.

PROVIDERSOFDRUGINFORMATION

 Knowledgable about data storage and retrieval methods

 Able to objectively evaluate scientific literature
 Able to apply information to the specific patient situation
 An effective communicator with patients, health care professionals,
admunistrators and the media.

DRUG INFORMATION RESOURCES

Drug information is stored in a variety of media inclufing textbooks, journals,

newsletters, microfiche, optical disks and computer systems. The information regarding
the drugs can be broadly classified into three categories

[Link] resources

Primary literature consists of research studies or clinical experience which has not been
previously published. This includes clinical trials, short reports, case reports and letters to
 the editor which describe clinical events such as adverse drug reactions or unexpected
clinical outcomes. Examples of journal which publish primary literature include:
 Annals of Internal Medicine,
 Lancet,
 The New England Journal of Medicine,
 Journal of American medical Association.

Advantage

 Provide the most current information

 Share opinion with other health professionals
 Keeps abreast of professional news
 Keeps up with the new developments in pathophysiology, diagnostic agents and
therapeutic regimen

Disadvantage

 No guarantee of accuracy
 Inadequacy of articles are common

[Link] resources

Secondary resources provide an overview of previously published work, and include indexing
and abstracting services of the primary literature. Examples of secondary resources include the
sbstracting services like;

 DRUGDEX
 International Pharmaceutical Abstracts
 ClinAlert
 Embase
 Lowa Drug Information System (IDIS) and Medicine. An indexing system provides only
bibliographic information that is indexed by topic and provides the orginal abstract or full
text with no interpretation. On the otherhand, an abstracting service provides content by
interpreting the original reports and creating summaries based on the abstracting service’s
editorial guidelines.
 PubMed from the National Library of [Link] is an examples of online resources

Advantage

 Valuable tools for quick and selective screening of the primary literature for specific
information, data, citation and articles
 Provide sufficient information to serve as references for answering drug information
requests

Disadvantage

 Reviews a finite number of journals

 Usually describe only articles and clinical studies
 Abatracts are general interpretations

3. Tertiary resources
These consist of general literature including textbooks and full-text computer database.
Examples of tertiary resources include
 United States Pharmacopoeia Drugs,
 Remington’s Pharmaceutical Sciences
 Merck Index
 Red Book
 Martindale:
 Tertiary resources are the most commonly used sources of information because they are
easy to use, convenient, concise, and compact.

Advantages

 Provide easy and convenient access to a broad spectrum of related topics

 Background information on drugs and diseases available

Disadvantages

 Gap between recent developments and actual publication of books

 Omission of pertinent data
 Misinterpretation of literature possible

4. Internet

The internet expands the ability to search therapies that have been recently published or
discussed in media. An internet search may be required for the following: company specific
information, issues currently in the news, alternative medicine, or U S government
information. The most popular Web browsers are Mozilla Firefox and Microsoft Internet
Explorer. A variety of search engines, software tools for searching the internet, have been
developed. General search engines (Alta Vista, Google, Yahoo, Ask, Dogpile ) attempt to
index as much of the internet as possible.

Disadvantage

 Information obtained may not be peer reviewed or edited before release.

 Information may be only as reliable as the person who posted it and the users who
read and comment on its content.
 A web site should be evaluated by its source (author) of information. The name,
location, and sponsorship should be disclosed.
Drug Information Centre can provide information regarding drugs, their toxicity and
treatment round the clock. In the absence of any available treatment, the centres give
only first aid device and recommend symptomatic treatment. Answering enquiry, or
dealing with request or information forms an integral part of the daily routine for all
pharmacists. For this purpose Drug information request forms are available in the
DIC, which is filled up by the pharmacistwho is in charge.

MODIFIED METHOD TO ANSWER A DRUG INFORMATION

ENQUIRY

There are many types of drug information requests. The most common relate to
therapeutics, adverse drug reactions, dosage and administration, drug interaction and
use of drugs in pregnancy and lactation. Other question may concern aspects of drug
pharmacokinetics, pharmaceutical stability, compatibility, poisoning, toxicity and
drug availability.
There are seven steps to answering an enquiry

STEP 1: Secure demographics of requester

The rewuester’s name, position, training and anticipated knowledge are important to
determine the approach and final response to the question.
For example, an elderly patient and a cardiovascular specialist may each enquire
about the availability of an investigational medication; however each brings a
different frame of reference to the request.
STEP 2 : Obtain background information

The ability to obtain background information is essential for systematic approach.

This has been the most difficult step. Sufficient background information must be
obtained in a limited time period. The background questions should be specific for
the nature of the request. Background information includes the patient’s age, weight,
and sex. In addition, the patient’s diagnosis, other medication such as co- morbidities
and hepatic and renal function are often important to assess. It is also advisable to
find out if the requester has checked any resources previously so as to avoid
duplication of work. Finally the urgency of the request should be ascertained.

STEP 3: Determine and categories the ultimate question

The ultimate question may differ significantly from the original question if the
requester posed a general question, and the pharmacist has used his expertise to
obtain background information. Adequate background information is needed to
determine the ultimate question.

For example: if a doctor is concerned about the safety of prescribing Metronidazole

to a patient taking Simvastatin, the question can be categorized as a drug interaction
query.

STEP 4: Develop search and conduct search

The information resources are selected based on the probability of containing the
desired data. For example given in step 3, standard references on drug interactions
are first-line resources as both simvastatin and metronidazole have been in clinical
use for many years. If one of the drugs was a recently introduced drug, a Medline
search would be more appropriate. The resources may be used based on ease of
access orthe pharmacist’s familiarity with particular resources. The resources used in
answering the question should be documented and this will help in understanding the
usefulness of various resources at times of budget allocation.

STEP 4: Perform evaluation, analysis and synthesis

The information retrieved must be critically reviewed. Application of the techniques

and skill for literature evaluation and knowledge of statistical analysismay be
[Link] the response to be relevant and useful to the requester, the information must
be analysed and synthesized with consideration of the background information
obtained previously. Analysis involves the critical assessment of the nature and merit
of factors which may be relevant to the question. Synthesis involves the careful
integration of critical information abput the patient, disease and medication along
with pertinent background information to arrive at a judgement or conclusion.
Analysis and synthesis together assist in forming opinions, arriving at judgementand
ultimately drawing conclusions.

STEP 6: Formulate and provide response

This involves a series of steps that must be performed completely, objectively and in
a logical sequence. Patient factors, disease factors, medication history and other
relevant background information and special circumferences should be considered .
once this data is collected and carefully assembled it must be critically analysed and
evaluated before providing the final response. The way in which answers are
communicated plays a major role in determining how drug information is accepted
by physician. The response to question must include restarting the request and clearly
identifying the problems, issues and circumstances that are relevant to the question.
Specify recommendation must be scientifically sound and clearly justified. In the
hospital setting the majority of questions will be answered verbally and responses
should be brief, concise and accurate and provided in a timely manner.

STEP 7: Conduct follow- u and documentation

Follow- up is the process of verifying the appropriateness, correctness,and

completeness of a response after it has been given. When recommendations are
made, follow- up should always be done in a timely manner. This allows pharmacist
to know if the recommendations were accepted and implemented. Patient – specific
requests generally provide opportunities to follow – up. In a hospital setting this may
involve visiting the ward and offering additional advice and information. This type of
follow- up provides opportunitiesfor pharmacists to become involved in direct
patient care, independently of ward round participation or routine patient counselling.
Documentation of the DI query is essential for purposes of quality assurance, budget
allocation, and promotions of the DI service and to minimize liability. The
documentation may be as a simple form or an extensive review and summary of
allprocesses completed.

REFERENCE

1. The Text Book of Clinical Pharmacy Practice by [Link], Karin Nyfort-

Hansen, Milap C Nahata 267-281.
2. Comprehensive Pharmacy by LeonShargel, Seventh Edition, 694-710
 EXPERIMENT NO : II

INVENTORY CONTROL

INRODUCTION

Inventory is the stock of materials kept for sale. Inventory control is the process of
managing inventory in order to meet customer demand at the lowest possible cost and with a
minimum of investment. Unlike many factors in pharmacy, inventory is controllable. The
pharmacy decides how much inventory investment to make, when to record, and in what
quantities.

Inventory control in hospital pharmacy is very essential in a developing country like India.
Drug inventory management stresses on cost containment and improved efficiency.
Inventory is essential to large size inventory for efficient and smooth production and also for
sales operation. Inventory include both ‘expendable’ (medicines, surgical dressing –can be
used only once) and ‘in expendable’ (thermometers, surgical gloves and equipments’) items.

DEFINITION

Inventory control is the operation of continuously arranging receipts and issues in such a way
gas to ensure that stock balance in quantity and the value are adequate to support the current
rate of consumption, at all times, with due regard to economy. The level of inventory is
always optimum that can be economically maintainable and professionally manageable.

OBJECTIVES

The objective of an inventory control system is to make inventory decisions that minimize
the total costs of inventory.
 There are several objectives of inventory control:-

 Determination of the right level of customer service

 Balance of supply and demand
 Minimization of procurement costs and carrying costs.
 Maintenance of an up-to-date inventory control system.

Successful inventory management involves simultaneously attempting to balance the cost of

inventory with the benefits of inventory.

FUNCTIONS OF INVENTORY

 To keep the inventory as low as possible consistent with the market condition
 To forecast market and economic condition of supply as regards availability of materials.
 To maintain a sufficient stock of finished product to meet the reasonable expectations of
customer for prompt delivery of goods.
 To minimize “out of stock” danger, which result in crash purchase at uneconomical rates.

DEMERITS

 Time consuming
 Expensive.

A preliminary step in process of inventory control is to determine the approximate costs of

carrying inventory. These costs include such expenses as storage costs, inventory risks, and the
loss-of-opportunity costs associated with the typing up capital. The cost of capital and
opportunity are the most important of those associated with holding inventory.

METHODS FOR CONTROLLONG INVENTORY

 Open-to-buy(OTB) budget method

 Short list method
 Minimum and maximum method
 Stock record card method
SYSTEMS OF INVENTORY CONTROL

There are two universally organized systems of inventory control

1. Two bin or fixed order quantity system

2. Cyclic system or replenishment system

1. TWO BIN SYSTEM

It is the oldest simplest system of inventory control. It assumes two bins having different
levels for the entire stock of the items, one bin holds the reserve supply of materials equal
to the quantity and quality and the other bin holds the balance of the inventory. The stock
in the first bin is a buffer stock and is like a reserve stock. When the stock in the second
bin is used, it means that it is the time for replenishment and the order is placed based on
the stock position. Here the quantity ordered will be more or less consist. Hence it is
called fixed order quantity system.
Advantage is that it control temporarily out of stock drug considerably well. Drawback is
that it is impossible to control amount tied up in stores.
2. CYCLIC SYSTEM OR REPLENISHMENT SYSTEM

Stock level is reviewed at definite intervals of time. In this order time is fixed but
quantity varies. At the time of placing the order, availability, consumption rate are
considered.

INVENTORY CONTROL TECHNIQUES

1. ABC method
2. Vital Essential and Desirable(VED) analysis
3. Lead time
4. Inventory-carrying cost
5. Safety stock
6. Minimum stock level
7. Maximum stock
8. Economic Order Quantity
1. ABC CLASSIFICATION SYSTEM
The ABC method of classifying items or activities is based on their relative importance.
It is basic technique of inventory control. It can be applied to all aspects of material
management like procurement, inspection storage, account keeping, inventory control,
supervision, etc.
ABC categorization is based on the principle of Pareto’s law-“vital few, trivial many”. It
can be applied to any branch of management with success and is considered as ‘Always
Better Control” technique in inventory. It helps to control the best items with maximum
efficiency; hen better items and lastly good and other items. It is based on the cost
criteria.
ABC classification system groups, items according to annual sales volume, in an
attempt to identify the small number of items that will account for the most of the sales
volume and that are the most import ones to control for effective inventory management.
In this system, inventory can be labeled as being A, B or C products. Classifying
merchandise into A, B, and C items allows the pharmacy to better and control items of
greater importance.
A items would be considered the most important to control it covers 10% of the total
inventories. It consumes about 70% of the budget. It requires strict control. It needs
maximum follow up. It must be handled by senior officers.
B items would be somewhere in the middle and their control would depend in the actual
cost of inventory control. It covers about 20% of total inventories. It consumes 20% of
total budget. It requires moderate control. It needs periodic follow up. It can be handled
by middle management. It requires low safety stock.
C items would be considered the least important to control, and not worthy of the more
elaborate system used to control A items. It covers 70% of the total inventory. It
consumes 10% of the total expenditure of inventories. It may require lose control. It
needs close follow up. It can be handled by any official management. It requires high
follow up.
TYPICAL ABC CLASSIFICATION SYSTEM
 ITEMS % ITEMS % OF ANNUAL
CONSUMPTION
A 10 70
B 20 20
C 70 10
ADVANTAGES OF ABC ANALYSIS

1. The investment of inventory can be regulated and funds can be utilized in the best
possible manner.
2. There is a closer and strict control on those items which represented a major portion
of total value.
3. It helps in maintaining enough safety stock of C categories of items
4. The scientific and selective control helps in the maintenance of high stock turnover
rate.
LIMITATIONS OF ABC ANALYSIS
It is based on monetary value and rate of consumption of the item. In a hospital an
item of low monetary value and consumption may be vital or even lifesaving. Their
importance cannot be overlooked simply because they do not appear in category A
LEAD TIME
The lead time is the interval between placing an order receipt of drugs to the
department. The longer the lead time, larger is the safety stock resulting in excess of
investment in inventories.
SAFETY STOCK
Safety stock is the extra units of inventory carried as protection against possible
stock-outs. The safety stock must be carried when the pharmacy is not sure about
either the demand for the drug or the lead time or both.

SAFETY STOCK=(MAXIMUM USAGE-AVERAGE USAGE)x LEAD TIME

REORDER POINT
The reorder point is the inventory level at which it is applicable to replenish stock. It
is used to denote the stock level at which fresh order has to be replaced. By placing at
 the time when stock reaches the re-order level, assure the elimination of stock out
problem.
The calculation is as follow:

REORDER POINT=AVERAGE USAGE PER UNIT x LEAD TIME +SAFETY

STOCK

INVENTRY TURNOVER RATE

One method of assessing the effectiveness of an inventor control system is the
turnover rate. The inventory turnover rate represents the average number of time the
inventory is sold and placed during a given period (usually a year). In general, a high
turnover rate indicates that product usage is “good” relative to the average amount of
inventory kept in stock. A turnover indicates those products are not being used at a
proper rate relative to average inventory.

Annual purchases at cost

INVENTORY TURNOVER RATE=
Avg On−hand inventory

THE ECONOMIC ORDER QUANTITY (EOD)

One of the best known models is for inventory control is the economic order quantity (EOQ).
The purpose of this model is to answer two important questions:

(1) When an item should be recorded ( resulting in replenishment cost)

(2) What quantity should be ordered ( resulting in carrying cost)

This model can be used to determine how much inventory needs can be carried o meet
demand,u not so much that excess costs are incurred.

Procurement costs (replenishment costs)

Procurement costs (replenishment costs) – include costs of making requisitions, writing

orders, receiving and inspecting goods, completing the purchase transaction, and maintaining
inventory records.
 Carry costs – include such items as interest, insurance, taxes, deterioration, spoilage,
obsolescence, handling and warehousing.

EOQ model is based on three basic assumptions:

(1) The firm knows with certainty the annual usage of particular item of inventory.
(2) The rate of usage of inventory does not vary over time; and
(3) Orders placed to replenish the inventory are received at exactly the point in time when
inventory is zero.

Methods of determination of Economic Order Quantity

1. Tabular determination of EOQ

2. Graphic presentation of EOQ
3. Determination of EOQ by allergic formula

EOQ can be calculated by using formula,

EOQ = 2×12× MONTHLY USAGE × COST ORDERING /UNIT COST×

HOLDING COST

It is calculated once a year where annual requirement is calculated in the beginning of the year
and orders are placed accordingly

VED ANALYSIS

VED analysis is based on critical values and shortage cost of the item. In a drug store, VED
analysis is very useful in controlling and maintaining the stock of various types of formulation of
particular group of drugs.

Based on their criticality, the items could be classified into three categories; vital (V), essential
(E) and desirable (D).
The items critically needed for the survival of the patients and those must be available at all
times were included in V category. The regular supply of these drugs is mandatory in providing
basic health services. It is not essential that all items are costly.

The items with a lower criticality need and those that may be available in the hospital were
included in the E group these are unavoidable for the normal function of store or its service.
These are effective against less severe but nevertheless significant form of illness but are not
absolutely vital in providing basic healthcare.

The remaining items with lowest criticality, the shortage of which would not be detrimental to
the health of the patients, were included in D group. D items are not too important but they are
used for minor or self – limiting illness.

There could be serious functional dislocation of patient care services in hospital when vital drugs
are not available even for a short period. If essential items are not available beyond few days or a
week, the functioning of the hospital can be adversely affected. The storage of desirable items
would not adversely affect patient care or hospital functioning even if shortage is prolonged.

If VED analysis alone is considered, ideal control on the identified vital and/ or essential items,
accounting for 89.52% annual drug expenditure (ADE) of the pharmacy. The comparison with
similar studies in India showed high variation in the percentage of vital, essential and desirable
items.

ABC-VED MATRIX ANALYSIS

The ABC VED matrix was formulated by cross-tabulating the ABC and VED analysis. From the
resultant combination, three categories were classified (I, II and III).

Category I was constituted by items belonging to AV, AE, AD, BV and CV subcategories. The
BE,CE and BD subcategories constituted category II, and the remaining items in the CD
subcategory constituted category III.

In these subcategories the first alphabet denotes its place in the ABC analysis, while the second
alphabet stands for its place in the VED analysis.

CONCLUSION
Pharmacy technicians play a vital role in maintaining the functionality of these systems.
Pharmacy technician’s familiarity with product conditions and uses puts them in a position to
identify quality and care issues that can strengthen the purchasing and inventory control system.
An effective purchasing and inventory control system requires all pharmacy staff understands
and actively participate in the system

REFERENCES

1. PratibaNand, [Link], textbook of hospital pharmacy and clinical pharmacy, first

edition, page no. 49-51
2. [Link], [Link], A Text Book of Pharmacy Practice, first edition, page no.
311-333
EXPERIMENT NO: III

DRUG INTERACTION

DEFINITION

It is the modification of the effect of one drug (the object drug) by the prior concomitant
administration of another (precipitant drug).

TYPES OF DRUG INTERACTIONS

There are essentially two types of drug interactions: pharmacodynamic and pharmacokinetic.

PHARMACODYNAMIC INTERACTION

Pharmacodynamic interactions are those in which the effect of one drug is changed by the
presence of another drug acting at the same biochemical or molecular site (e.g., drug receptor or
second messenger system ), on the same target organ, or on a different target but one that is
associated with a common physiological process essentially when one drug modulates the
pharmacologic effect of another by producing additive, synergistic or antagonistic effects. In
many cases, although not all, pharmacodynamic interactions are generally more intuitive for
those with medical training because the interacting drugs frequently have related actions. For
example, as noted earlier, combining two or more CNS depressants such as benzodiazepines,
opioid analgesics, first –generation antihistamines or alcohol can be additive or synergistic, and
lead to pronounced CNS depression, including respiratory depression, loss of consciousness,
coma or death. Similarly, combining two or more drugs that produce vasodilation can increase
the risk of profound hypotension, syncope or even myocardial infarction. Pharmacodynamic
interactions that involve antagonism generally diminish the therapeutic benefit of one or more
drugs in the mix. A good example would be the use of an anticholinergic drug, such as
oxybutynin, for treating urge incontinence in a patient taking a cholinesterase inhibitor (e.g.,
donepezil) for dementia.
Some pharmacodynamic interactions may not be as easy to predict because the mechanisms of
action and therapeutic targets of the drugs being used are quite different. Often these are
interactions that involve the effects of drugs on different physiological processes that produce
additive or opposing actions at a more systematic level. A prototypical example is the
combination of digoxin and furosemide. Both have different targets (e.g., myocardium versus
renal tubule) and different mechanisms(e.g., Na+/K+ATPase versus Na+Cl- co –transport), yet
the diuretic- induced secondary loss of potassium allows for increased digoxin binding and
related toxicity to the heart. Another that may not be so intuitive is the use of co-trimoxazole in
patients taking angiotensin-converting-enzyme, or ACE, inhibitors or angiotensin II receptor
blockers, or ARBs. Trimethoprim is structurally and pharmacologically similar to potassium –
sparing diuretics and may further increase potassium retention and the risk of hyperkalemia in
those patients.

An example of a pharmacodynamic interaction that may not have been so easy to predict and
could lead to diminished therapeutic benefit is nonsteroidal anti-inflammatory drugs, or NSAIDs,
and certain antihypertensive drugs. Since NSAIDs inhibit prostaglandin –mediated vasodilation
and promote salt and water retention, they can compromise the effects of antihypertensive drugs
like ACE inhibitors, ARBs, beta blockers and diuretics, agents whose mechanism depends on
modulating prostaglandins, rennin, or sodium and water balance.

PHARMACOKINETIC INTERACTIONS

Pharmacokinetic interactions are those in which one drug results in an alteration (increase or
decrease) of the concentration of another drug in the system. Different parameters can be
affected by pharmacokinetic interactions, including a drug’s bioavailability, volume of
distribuition, peak level, clearance and half-life. Such changes can lead to changes in drug
plasma concentrations and ultimately increase the risk of side effects or diminish the efficacy of
one or more drugs. 13 Pharmacokinetic interactions are more complicated and difficult to predict
because the interacting drugs often have unrelated actions. Below are a brief summary and some
examples of the four pharmacokinetic processes that may be involved individually or collectively
in various drug interactions.

ABSORPTION
There are three areas in which interactions might occur at the levelof drug absorption. One drug
may affect the rate and /or extent of absorption of other drugs if it alters: GI motility, gastric pH
or chemically binds with other drugs to form insoluble, nonabsorbable complexes.

GI MOTILITY

Drugs that increase gastric emptying or intestinal motility, such as erythromycin or

metoclopramide, may hasten the passage of drugs through the GI tract. These effects might be
expected to increase the initial rate of absorption, or T max, and increase maximal plasma
concentration, or C max, of many orally administered drugs, but ultimately reduce total
bioavailability, or area under curve (AUC). On the other hand, such drugs as the opioids or
anticholinergics that can decrease GI motility may either reduce absorption by retarding
dissolution and slowing gastric emptying, or increase absorption by keeping a drug for a longer
period of time in the area of optimal absorption. Finally, in cases of either increased or decreased
GI motility, enteric – coated and sustained release formulations that rely on normal pH gradients
or residence times in the gut also may be affected.

ALTERATION OF PH

Since many drugs are either weak organic acids or bases, the pH of the GI contents can influence
absorption. Remember, it is the nonionized or uncharged form of a drug that is lipid- soluble and
hence more readily absorbed across the epithelium membranes in the GI tract. Simply stated,
acidic drugs are more likely to be uncharged in an acidic environment, like the stomach, and
basic drugs are more likely to be absorbed along the intestinal tract as the pH rises. Although
formerly not a frequent clinical issue, over the past two decades, the increased availability(e.g.,
OTC and prescription) and widespread use of proton-pump inhibitors, or PPIs, and H2-
antagonists has changed the playing field. Increases in gastric pH can alter the absorption of
medications that are weak acids or bases, as well as those prone to degradation in an acidic or
alkaline environment, or formulated as pH dependent, controlled –release products. For example,
increased gastric pH may lead to decreased drug absorption of weak bases, such as ketoconazole,
cefpodoxime, itraconazole, and such antiretrovirals as delavirdine, indinavir and atazanavir. This
type of interaction represents one in which drug toxicity is not the end result, but the possibility
of treatment failure exists.
Conversely, increases in gastric pH also can lead to enhanced drug absorption by increasing the
dissolution of weak acids, decreasing the ionization of weak bases or simply decreasing the
degradation of acid-labile compounds. Although several studies have demonstrated an increase
in the absorption of digoxin, nifedipine, aspirin, midazolam, didanosine and methadone when
administered with either H2- antagonists or PPIs, the clinical significance of these interactions is
often debated.

CHELATION AND ADSORPTION

Tetracyclines, fluoroquinolones, levothyroxine and the bisphosphonates can combine, or

“chelate” with certain divalent ions (e.g., Ca, Mg, Al, Fe, and Zn) in the GI tract to form poorly
absorbable complexes. Thus, certain foods (e.g., milk) or drugs (e.g., antacids; products
containing Mg, Al, and Ca salts; or Fe preparations) can significantly decrease the absorption of
those drugs and in some cases lead to treatment failure. For example, studies have shown that
taking calcium carbonate within four hours of levothyroxine might decrease the hormone’s and
Mg containing products than with products containing Ca, Fe, or Zn; however, the resulting
decrease in fluoroquinolone absorption with all these products is potentially significant and
increases the possibility of therapeutic failure. Even multivitamin preparations that contain lower
concentrations of minerals should be avoided. Similar adverse effects on fluoroquinolone
absorption were observed with concomitant administration of ferrous sulphate, with decreases in
bioavailability of the antibiotic of 19% to 66%. 26 Although it is usually recommended that
concomitant intake of calcium –rich foods(e.g., milk) be avoided because of the potential for
chelation effects, the actual influence of diary products on fluoroquinolone absorption varies.

Complex formation through the process of adsorption also may occur with the bile –acid
sequestrants (e.g., cholestyramine and colestipol). In addition to binding with and preventing
reabsorption of bile acids, these agents can bind with with certain drugs in the GI tract and
reduce their systematic bioavailability. The binding resins have the greatest affinity for acidic
drugs, including thyroid hormones, warfarin, propanolol, tetracycline , pencilin G, estrogens and
progestins, furosemide, thiazides, methotrexate,digoxin and others. They also may bind to fat-
soluble vitamins, such as vitamin A, vitamin D, vitamin E and vitamin K (see below under drug
induced nutrient depletions).
DISTRIBUTION

Competition for protein binding, in particular with serum albumin, is another potential source of
drug interactions. Although this type of interaction has increasingly come under fire as having
little clinical significance, for drugs that are very highly bound ( greater than 90%) and have a
narrow therapeutic index, the possibility of clinically significant interactions does increase.
Furthermore, these types of interactions may be more likely to occur in those with alcoholics.
Drugs that have high affinity for, and extensive binding to, serum albumin are generally acidic
drugs and include warfarin, NSAIDs (including COX-2 inhibitors), phenytoin, lorazepam,
valproic acid and sulfamethoxazole. A good clinical example of this is the COX-2 inhibitor
celecoxib. Since celecoxib by itself doesnot affect platelet function or bleeding time, it is an
appropriate anti-inflammatory /analgesic treatment option for patients taking warfarin. However,
shortly after its introduction, a number of studies found that celecoxib (protein bound 97%)
could significantly elevate the international normalized ratio, or INR, in patients taking warfarin
(99% bound) and that it was most likely due to a drug displacement interaction.

METABOLISM

Most interactions occur with phase –I metabolic processes, namely cytochrome P450 or
CYP450. Of the 18 different human CYP450 families, the majority of drugs are metabolized by
one or more of six isoforms: CYP3A4, CYP2D6, CYP2C9, CYP2C12, CYP1A2, CYP2E1.
While these enzymes are located primarily in the liver, there also is a significant concentration of
the metabolism and clearance of a vast number of drugs, particularly fat –soluble, orally
administered drugs. Interactions related to drug metabolism are the most likely of the
pharmacokinetic interactions and certainly among the most difficult to predict. Furthermore,
such patient factors as genetics, diet, age, lifestyle, health state, comorbidities and more can
produce a wide variation in the clinical response of CYP450- related drug interactions.

Drug metabolism also can be mediated by non –P450 enzymes, the most significant of which are
flavin- containing monooxygenase, monoamine oxidase, alcohol dehydrogenase, aldehyde
dehydrogenase, aldehyde oxidase and xanthine oxidase. In some cases, a few of these pathways
can produce the same metabolites as those generated by P450,while most of the other enzymatic
pathways generate different metabolites from CYP450. Obviously, anyone reading this article is
familiar with monoamine oxidize, or MAO, and the potential for significant interactions between
MOA inhibitors and a vast array of noradrenergic, dopaminergic and serotonergic drugs, as well
as dietary tyramine. Other than that and the inhibition of aldehyde dehydrogenase by disulfiram (
and possibly metronidazole) there are few interactions on record related to non-glucuronic acid,
sulfate and other moieties plays a very important role in drug metabolism and clearance, there is
little or no direct role in clinically relevant drug interactions.

INDUCTION

A number of drug interactions result from the ability of one drug (or other non drug agents ) to
stimulate the liver to produce greater amounts of one or more cytochrome P450 isoforms. With
few exceptions, the clinical impact of induction is that those drugs metabolized by the “induced”
CYP450 isoforms will be cleared faster, and their systematic concentrations could become less
efficacious or sub therapeutic in the absence of appropriate dosage adjustments. The time
required for CYP450 to reach a new, elevated steady state level following the introduction of an
inducer may range from a few days to few weeks, depending on the half-life of the drug and the
degradation half-life of the enzyme. Furthermore, the induction phenomenon is reversible. Upon
discontinuing an inducer , it may take between two to four weeks for CYP450 levels to return to
baseline concentrations.

While most induction – related interactions typically compromise therapeutic efficacy of one or
more drugs, there is one important case in which induction may increase the risk of drug toxicity.
Ethanol is an inducer of the CYP2E1, the P450 isoform that plays a role not only in the clearance
of ethanol and certain gaseous anesthetics, but also in the conversion of acetaminophen into its
toxic metabolite, NAPQI, with resultant hepatic damage. Chronic alcohol consumption increases
the risk that the use of acetaminophen, even at normal therapeutic doses, may produce hepato
toxicity.

INHIBITION

Inhibition of the CYP450 system can occur by 1- of-3 mechanisms. The first and most common
mechanism is competitive inhibition simply put, there are a finite number of molecules of a
particular cytochrome P450 isoform in hepatocytes. The more drugs that need to be metabolized,
the more competition there is for that fixed number of enzymes most CYP450 inhibitors also are
substrates for the enzyme and hence can become competitive inhibitors. The extent of inhibition
of one drug by another depends on their relative affinities for the P450 enzyme (km,ki), the
concentration of substrate required for inhibition (IC50) and the half- life of inhibiting drug. On
occasion, some drug metabolites also can be inhibitors of cytochrome P450, as is the case for nor
fluoxetine, the active metabolite of fluoxetine.

In addition to competition for the CYP450 catalytic site, a few drugs (e.g., nifedipine and
medroxyprogesterone) have been reported to produce a noncompetitive inhibition by binding to
neighboring allosteric site(s) in the CYP2C9 isoform and causing a change in its conformation or
physical structure. Of greater clinical importance, furanocoumarins, found predominantly in
grape fruit flesh, exhibit a mechanism – based inhibition in which a reactive metabolite is formed
and covalently binds to the CYP3A4 enzyme, resulting in irreversible inhibition appears to affect
CYP3A4 in the gut wall to a much greater extent than in the liver. The onset of this interaction
can occur quickly ( i.e., within 30minutes) following intake of a single glass grape fruit juice,
and the inhibition can last up to 3 days following the last administration of grape fruit juice.

Unlike induction, which may take days to appear and weeks before it reaches its maximal effect,
the effects of CYP450 inhibitors can be observed after administration of the first dose of an with
inducers, there are some drugs that can inhibit several different isoforms of P450 (with differing
potencies), such as ketoconazole, fluconazole, amiodarone and ritonavir. However, with few
exeptions, when it comes to clinically relevant CYP450 inhibition, most drugs that are inhibitors
are selective for one particular CYP isoform.

RISK FACTORS OF DRUG INTERACTION

HIGH RISK DRUGS- These are the drugs that show a narrow therapeutic index e.g.,
corticosteroids, rifampin, oral contraceptives, quinidine, lidoquine

HIGH RISK PATIENTS- These are the groups of patients that should be treated with caution
due to a specific health condition e.g., pregnant women, malignant cases, diabetic patients,
patients with liver or kidney disorders asthmatic patients and cardiac disorders.
PREVENTION OF DRUG INTERACTION

 Monitoring therapy and making adjustments

 Monitoring blood level of some drugs with narrow therapeutic index e.g., digoxin,
anticancer agents…etc
 Monitoring some parameters that may help to characterize the early events of
interaction or toxicity e.g., with warfarin administration, it is recommended to monitor
the Prothrombin time to detect any change in the drug activity.
 Increase the interest of case report studies to report different possibilities of drug
interaction.

REFERENCE

 Stockley’s drug interactions 8th edition, page no. 1-9

 A text book of clinical pharmacy practice by G Parthasarathi, Karin Nyfort, 2 nd
Edition; page No: 123-134