1)Definition
2) Occurrence of drug interaction
a) Multiple pharmacological effects
b) Multiple prescribers
c) Non-prescription drugs
d) Patient non-compliance
e) Drug abuse
3) Physiological factors
1. Age
2.Genetic factor
3.Disease states
4. Alcohol consumption
5.Smoking
6.Hepatic function
7. Renal function
8.Gender
9. Immunological function
10.Pregnancy
11.Lactation
12.Sunlight
13.Circadian variation
14.Stress
15.Infection
16.Fever
17.Starvation
18.Diet
19.Albumin concentration
20.Exercise
TYPES OF DRUG INTERACTION:
-> drug drug interaction
-> drug food interaction
-> drug chemical interaction
-> drug herb interaction
-> drug laboratory interaction
MECHANISM
OF DRUG INTERACTIONS:
A) pharmacokinetics interaction
1) Altered gastrointestinal
absorption
a)
altered pH
b)
altered intestinal bacterial flora
c)
Complexation or chelation
d)
drug induced mucosal damage
e)
altered motility
2)
Alteration of distribution
3) Altered metabolism
4) Altered excretion
B)
pharmacodynamics
interaction
6) ROLE OF PHARMACIST:
1_Identify the Pt risk factor
2_ Take the thorough drug history
3_Be knowledgeable about action of drug
4_Consider therapeutic alternatives
5_Avoide complex therapeutic regimens when possible
6_ Educate thept
7_Monitor therapy
8_ Individual therapy
7)
Significance level of drug interactions
8) Severity
Major
Moderate
Minor
DRUG
INTERACTION:
Definition:-
The pharmacological result either desirable or
undesirable , of drugs interacting with themselves or with other drugs with
endogenous chemical agents, with components of diet or with chemicals used in
or resulting from diagnostic tests.
Occurrence
of Drug Interactions
A number of factors contribute to
the occurrence of drug interactions.
(a) MULTIPLE PHARMACOLOGICAL EFFECTS:-Most
drugs used in current therapy have the capacity to influence many physiological
systems ,therefore two drugs concomitantly administration will often affect some of the same systems.
When considering the same potential for interaction b\w drugs concerned with
the primary effect of the drugs and to overlook the secondary effects
Example: Combined therapy with
. phenothiazine antipsychotice.g chlorpromazine
. TCA e.g amitriptyline
.Antiparkinson agent e.g trihexphenidyl
Each of these agents has different primary effects.
However all three possess
anticholinergic activity. (secondary effect)
(b) MULTIPLE
PRESCRIBERS:-
Whenever there are multiple
prescribers then it is difficult for one prescriber to be aware of all the
medications that have been prescribed by
others.
Example:One physician
may prescribe antihistamine or an opioid analgesic for a patientwhome another
physician has prescribed an antianxiety agent.
The consequence will be an excessive depressant effect.
(c) NON PRESCRIPTION
DRUGS;
Many reports of drug interactions
have involved the concurrent use of prescription drug with non-prescription drug
or use of two or more non-prescription
drugs
Example Many patients have been taking
preparations such as antacids, analgesic, laxatives, dietary supplements and
herbal products in a routine manner that they do not consider them to be important w.r.t
effectiveness and safety of
medicines.
twonon prescription products promoted for different purposes contain the
same active ingredient increasing the risk of an excessive response
e.g diphenhydramine included in many product for its antihistamine action but
also included for sedative effect in many non prescription sleep aid
formulation.
(d) PATIENT NON
–COMPLIANCE:
For a number of reasons many patients do not take medication in the prescribed
manner
Example;
Older patients taking 5-6 medications several times a day can become confused or forget to take
A patient might take tetracycline with food rather than before meals.
Some patient take the missed dose with the next dose
Some assume that if 1-tab partially relieves the pain then two will completely
relieve the pain e.g 1-tab of NIACIN may used to lower cholesterol level but if
a patient takes 2-tablets at a time then it may result in myopathy.
(e) DRUG ABUSE:
The tendencies of some individuals to abuse or deliberately misuse drugs also
may lead to increased chances of drug interactions.
EXAMPLE:Misuse of antianxiety agents opioids
analgesic are among the agents of most
often abused ,and the anappropriate use of these drugs can result in a number
of problems including an increased potential for drug interactionPHYSIOLOGICAL FACTORS:Because no two people are alike
physiologically and psychologically ,a patient”s response to the drug may vary
greatly depending on these factors.
1- AGE:
Age is an important factor .The
occurrence of drug interactions is highest in young and geriatric patients
Drug related problems in young patients are encountered most frequently in
newborn infants.
Example;.Chloramphenicol causes grey baby syndrome in children.
. Paracetamol resistant hepatotoxicity in children.
In addition, there may be aging –related
changes.
2- Genetic factors:
these may be responsible for the development of an unexpected drug response in
a particular patient.
Example isoniazid inhibits the metabolism of
phenytoin in slow acetylators.
3- Disease states:
A number of disease states other than the one
for which a particular drug is being used
,may influence patient respons to
a drug
Example Beta adrenergic blocking agents can precipitate asthma or COPD .
4- Alcohol
consumption:
Chronic use of alcoholic beverages may
alter the metabolism of certain drugs.
Example
Concurrent use of alcoholic beverages with sedatives and other depressant drugs
could result in excessive CNS depressant response.
5- Smoking:
It increase the activity of drug metabolizing enzymes in the liver.
Example metabolism of theophylline and diazepam increased by smoking so their effects are decreased.
6- Hepatic
Function:
Many drugs are metabolized in liver by a number of mechanisms ,Therefore there is hepatic damage ,these drug may be
metabolized at a slow rate
Many therapeutic agents are metabolized by hepatic enzymes .if other drugs
alter activity of these enzymes a
modified response might occur.
Example
.Barbiturates are enzyme inducers. The
result would be more rapid metabolism and excretion of concurrently administered agents that are metabolized by these enzymes.
. Cimetidine inhibits cytochrome P450
and can slow metabolism of several drugs. (.g warfarin, phenytoin,
theophylline)
7- RENAL FUNCTION:
Renal function is one of the most important determination of drug activity. The
patient,s renal status should be known .
Particularly when drugs that are
excreted primarily in an active
form by the kidney.
Example The ionization of salicylates
decreases reabsorption and increases its
clearance.
8- GENDER:
Some drugs work better in one gender
than in other. Scientist are not sure about this distinictive behavior. But
they do know that differences may occur in pharmacokinetics (PK).
Example
women seem more likely than man to
develop liver damage with certain drugs including halothane , methyl dopa.
Zoloft showed little effect in man with post traumatic stress disorder(PTSD) while the drugs
benefit was clear in the women.
9- IMMUNOLOGICAL
FUNCTION:
Different immunity mediated reactions
may affect the drug response.
Example .sulfamethoxazole induced cutaneous
hypersensitivity.
.
penicillin induced hypersensitivity,
10- PREGNANCY:
Certain drugs are contraindicated in
pregnancy. Example Antimalarials (e.gchloroquine) can cause abortion.11- LACTATION:Certain
drugs should avoid during breast
feeding Example psychoactive drugs (e.g
Alprazolam, Diazepam) drug and metabolites appear in breast milk andcan cause alter CNS functions in infants.12-SUNLIGHT:Drug after appearing in blood transport
to skin . Sunlight can interact with drug molecules in the vessels and can cause certain problems. Example Azithromycin causing photosensitivity
13-CIRCADIAN
VARIATION:
The variation occur in human body in
24-hr may influence the drug response.
Example
Aminoglycoside causes
nephrotoxicity more in mid night.
14- STRESS:
Stress is the disruption of
homeostasis through physical or
psychological stimuli. The individual
responds to stress in ways that affect the individual as well as their
environment,
Example Stress lowers circulating blood
nicotine level.
15-INFECTION:
Some viral or bacterial infections also
affect the drug response.
Example:Aspirin in children exposed to certain viral infection such as influenza B virus
leads to Reye,s syndrome.
16- FEVER:
Pyrogens inducing fever can affect the
drug response.
Example
Pyrogen induced fever shows a significant
reduction in the half life
of the excretion of the drug metabolites of salicylamide.
17- STARVATION:
Fasting cancer chemotherapy treatment
may significantly enhance the cancer killinf effects of the drug while
protecting healthy cells . A new study
suggests that starvation induce a protective shield around the healthy cells, allowing them to
tolerate a much higer dose of chemotherapy.
18-DIET:
Food may affect the drug response.
Example
tetracyclines administered with
milk produce chelating effect
19- ALBUMIN
CONCENTRATION:
Many drugs bound extensively
to plasma proteins. A decreased amount or concentration of protein could damage the availability of drugs and thus their
activity.
Example
when the serum albumin concentration is less than 2.5g/100ml the
frequency of predisone adverse events is
almost doubled.
20- EXERCISE:
Exercise is one of the factor
that can influence the clearance of
some drugs.
Example
Exercise decreases propranolol half life
and AUC.
TYPES
OF DRUG INTERACTIONS:
Following are some important type
of drug – interactions
Drug
drug interactions
Drug food interactions
Drug chemical interactions
Drug disease interactions
Drug herbal interactions
Drug laboratory interactions
A- DRUG DRUG INTERACTIONS:
Drug drug interaction can be defined
as
The modulation of the pharmacologic
activity of one drug (i.e the object drug) by the prior or concurrent
administration of another drug (i.e the precipitant drug).
TYPES OF DRUG DRUG INTERACTIONS:
Duplication
Opposition (antagonism)
Alteration
Potentiation
Synergism
DUPLICATION:When two drugs with the same effect are taken
their side effects may be intensified .Duplication may occur when people take two drugs ( often at least one is an over the counter
drug) that have the same active
ingredient.
Example A cold remedy (e.gcofcol) and a pain
reliver (e.gparacetamol) both of which
contain Acetaminophen.
OPPOSITION (ANTAGONISM): Two drugs with opposing actions can
interact, thereby reducing the
effectiveness of one or both Example..certain Beta blokers such as propranolol (Inderal) and beta
adrenergic stimulents such as salbutamol
(ventolin)
Both type of drug target the same cell receptors Beta
-2 receptors but one type
block them and other stimulates them.
ALTERATION: One drug may alter how the body absorbs
distributes metabolizes or excretes other drug.
Example NSAIDs reduce excretion of methotrexate
from the body which leads to too
much level of methotrexate in the blood.
POTENTIATION:When drug A boost the effect of drug
B often by increasing the level of drg B
in blood.
Example Aspirin increase the blood sugar lowering the effect of diabetes
Medicines (e.gchlopropamide (diabinese) )
. propranolol potentiate the hypotensive
effect of general anesthetics.
SYNERGISM: Syn – together erg- work i.e working together
Two or more drug work together against
one target . the interaction is
known as synergism
Example Penicillin and gentamicin are
synergistic in their anti pseudomonal
activities.
B- DRUG FOOD
INTERACTIONS: Drug food interactions can modify
the activity of the drug (decrease or increase the effects) or impair the
nutritional benefit of certain food. The most
commonly observed type of drug
food interaction affects drug absorption
.
EFFECT of Food on Drug
Absorption
Presence of
food decreases the absorption of penicillin tetracyciline TCN
levodopa Phenytoin and digoxin.
Drug whose absorption increases when
taken with food include
Spironolactone Griseofulvin and
Itraconazole.
Grape fruit juice increases serum
drug level of benzodiazepines (e.gtriazolam)
C-DRUG CHEMICAL INTERACTIONS:Certain chemicals interact with the drug in different manner
Alcohol -à Alcohol +
sedative = CNS depressant
increase rate of metabolism of
Phenytoin and warfarin when used
with alcohol
Tobacco increase the metabolism rate of
theophylline.
D- DRUG
DISEASE INTERACTION:
Certain drugs have thecapability
to exaeerbate acute or
chronic disorders.
Example Beta
adrenergic blocking agents
can precipitate disease such as
asthma chronic obstructive
pulmonary disorder COPD
E- DRUG HERBAL INTERACTION:The rate of herbal and natural products
is growing significantly every year. Drugs can interact with
different herbs to alter the drug
response.
Because patient generally do not consider these products as drugs, and may not
mention their use during medication
history.
Example Licorice elevate digoxin level 4 fold.
Ginger increased anticoagulant activity
of warfarin
F- DRUG
LABORATORY INTERACTIONS:
These includes the alteration in
diagnostic laboratory test results caused
by the drug
Example Creatinine elevated by ; Aminoglycosides antacids
and
decreased by : Ibuprofen
MECHANISM
OF DRUG INTERACTION:The mechanism by which most interactions develop are
categorized often as:
PHARMACOKINETICS
INTERACTIONS
PHARMACODYNAMIC INTERACTIONS
PHARMACOKINETIC
INTERACTIONS:The interaction in which one agent
(the precipitant drug) alter the absorption
, distribution, metabolism, or excretion (ADME) of a second agent (the object drug) with a resultant change in plasma
concentration of the latter agent are known
as pharmacokinetic interactions.
1- ALTERED GASTROINTESTINAL
ABSORPTION:
Alteration in the G I absorption can
result various mechanisms.
Altered pH
Altered intestinal bacterial flora
Complexation or chelation
Drug induced mucosal damage
Altered motility
a- ALTERED pH:The non ionized form of a
drug is more lipid soluble and more
readily absorbed from GIT into systemic
circulation than the ionized form.
Most drugs are week acids or bases.
Therefore acidic drugs tend to
absorb readily in the upper portion of GI tract where
they are in acidic medium
CLINICAL CONSIDERATIONS: Clinically important interactions occurring by this mechanism are rare . This interaction may be avoided by separating the administration times of each agent by atleast 2 hrs
CLINICALLY IMPORTANT EXAMPLE :ketoconazole abs decrease due to
adm of antacid.
b- ALTERED
INTESTINAL BACTERIAL FLORA: The greatest number of bacteria found
in intestine. Some drug have been shown to be affected by change in intestinal flora.
CLINICAL CONSIDERATION:This mechanism of action
appear to be rare . Drug
interaction due to this mechanism involve those drugs that are incompletely absorbed from the upper
G.I tract. The onset and reversal of
this interaction are delayed, requiring upto several weeks. Thus adjusting
the administration times of two drugs will not do any good.
CLINICALLY IMPORTANT EXAMPLE;Erytheromycin increases the absorption
of Digoxin by altering
the GI bacteria so Digoxin toxicity
may occur.
c- COMPLEXATION OR CHELAT:Certain drugs can combine
with other drugs or food in the GI tract
to form poorly absorbed complexes
CLINICAL CONSIDERATIONS; By lengthening the interval
b/w admn of two drugs by 2-4 hrs will minimize this interaction.
CLINICALLY IMPORTANT EXAMPLE ;Administering aluminium
magnesium hydroxide anacid
with ciprofloxacin may
drastically decrease the
absorption of antibiotic by about 85%
resulting in decrease pharmacological effect.
. Tetracyclines forms insoluble chelate with ion of iron salt decreasing the absorption.
d- DRUG INDUCED MUCOSAL DAMAGE
Drug that damage the GI mucosa may reduce the absorption of certain
drugs
CLINICAL CONSIDERATIONS; Antineoplastic are most commonly implicated.
CLINICALLY IMPORTANT EXAMPLE; Reduced GI absorption
of Digoxin by chemo therapy
regimens (e.g cyclophosphamide ,
Vincristine)
e- ALTERED MOTILITY: Changes in GI motility may increase or decrease absorption. Increase GI
motility may decrease
absorption by reducing the time
that an orally administered drug is in contact with the absorbing surface
CLINICAL CONSIDERATIONS;
Interactions occurring as a result
of altered GI motility result from
systemically administrating the precipitant drug. Therefore separating the administration time of interacting drugs would not prevent this
interaction.
CLINICALLY IMPORTANT EXAMPLE;Increased GI motility by metoclopramide decreases the
absorption of orally
administered digoxin.
2- ALTERATION OF
DISTRIBUTION
DISPLACED PROTEIN BINDING; An interaction of this type
may occur when two drugs that
are capable of binding to proteins are administered concurrently. The
drug having highest affinity for binding
sites will displace the drug with lower association constant. Once the object
drug is displaced from protein binding
site it will not be able to exert
its pharmacological action and also the
other drug becomes available for metabolism , excretion, and redistribution to
other tissues.
CLINICAL CONSIDERATIONS; Clinically important drug
interactions involving
displacement from protein binding are
uncommon once the object drug is displaced from plasma proteins ,
it is rapidly cleared from body.
CLINICALLY IMPORTANT
EXAMPLE; Highly protein bound
drugs include phenytoin 90%
warfarin 99%
valporic acid displaces phenytoin
from plasma-protein binding sites and also may
inhibit the metabolism of
phenytoin.
3- ALTERED
METABOLISM Drug metabolism mainly occur in liver and most commonly involved oxidation,
reduction, hydrolysis, conjugation
reactions. The hepatic enzymes are cytochrome p450 enzymes which have been divided
into families and sub-families
a- INCREASED METABOLISM
( Enzyme induction) This interaction mechanism result from
increased production of drug metabolizing enzymes .
CLINICAL CONSIDERATIONS; This mechanism of interaction has slow onset because protein synthesis
is involved and may take up several
weeks before the maximum effect seen.
CLINICALLY IMPORTANT EXAMPLES; Phenobarbital (enzyme inducer) causes the warfarin to be more quickly
and thus to be less effective
b- DECREASED METABOLISM (Enzyme inhibition)
Enzymes
inhibition usually result from competition between the presipitant and object drugs for for binding sites on the enzymes. The
enzymes involved most often are monooxegenase enzymes.
CLINICAL CONSIDERATIONS;
Enzymes inhibition is one of the most common mechanism of drug interactions. The onset and reversal of this interaction often occur with in 24 hrs . This interaction usually produce an
increase in serum drug concentration ,
resulting in a possible
augmentations of both the
pharmacological and adverse effects of object drug.
CLINICALLY IMPORTANT EXAMPLE
Erythromycin inhibit
metabolism of astemizole and increasing serum concentration of antihistamine
4-ALTERD EXCRETION
The renal excretion of one drug
may be increased or decreased by
co-administring another drug .
ALTERATION OF
URINARY pH: A change in urinary pH will influence the ionization
of week acids and week bases and
thus affect the extent to which
these agents are reabsorbed
and excreted. When a drug
in its non ionized form it wwill
diffuse more readily from urine back
into blood. So the effects may be intensified ,
CLINICAL CONSIDERATION; Interferences with renal elimination
may be clinically important if
the fraction of unmetabolized drug is large.
CLINICALLY IMPORTANT EXAMPLE; Chronic antacid therapy with a mganesium
and aluminium hydroxide combination has been associated with increased salicylate clearance and 30 -70% decrease in serum salicylate levels.
b- ALTERATION
OF ACTIVE TUBULAR SECRETION
Active tubular secretion of drug molecules occur in the proximal
portion of the renal tubule.
In oder for the drug to pass from the
systemic circulation to the tubular
lumen, the drug is transported by
combining with a protein.
Although each protein has a unique
affinity for an anion or cation drug that use as a similar system for transport appear to interact by competitive
inhibition of transport proteins.
CLINICAL CONSIDERATION;
Interaction resulting from this type of
mechanism tends to occur rapidly. Plasma concentration of the object drug may
be increased producing an increase
in therapeutic and toxic effects.
CLINICALLY IMPORTANT EXAMPLE:
Probenecid appears to impair the tubular secretion of methotrexate result in three to four fold
increase in serum concentration of methotrexate.
B. Pharmacodynamic interactions:
the interactions in which the drug having
similar or opposing pharmacological
effects are administered concurrently
and in which the responsiveness of the tissues to one drug is altered by
another.
Pharmacodynamicinteractions also have
been viewed as situations in which there is a change in drug effect
without a change in plasma
concentration . it include:
Antagonistic
pharmacodynamics effects
Additive
pharmacodynamics effects
a- ANTAGONISTIC
PHARMACODYNAMIC EFFECTS:
Two drug with opposing actions
can interact thereby reducing the
effectiveness of one or both .These
interactions involve drugs acting on
the same organ system . These type of interactions are sometimes due to secondary effects of certain drugs.
CLINICALLY IMPORTANT EXAMPLE;
The ability of thiazide
and certain other diuretics to elevate blood glucose concentration is well known. So dosage adjustment is required for diabetics
using antidiabetic medicines and
diuretics concurrently.
inhibition of the response to benzodiazepines by the concurrent use of theophylline
ADDITIVE PHARMACODYNAMIC EFFECTS:
When two or more drug with
similar pharmacodynamics effects are given
the additive effect may result in
excessive response and toxicity.
CLINICAL CONSIDERATION;
This is the most common
mechanism by which drug interaction
occur.
CLINICALLY IMPORTANT EXAMPLE :
Propranolol and verapamil have synergistic or
additive cardiovascular effects. Both
drug have negative inotropic and chronotropic effects
ROLE OF PHARMACIST:
Following guidelines are
offered to reduce and manage drug
interactions
1-IDETIFY THE PATIENT RISK FACTORS:- Factors such as age nature of pt,s
medical problems , dietary habits and
problems like alcoholism will
influence the effect of certain drugs
and should be considered during the initial patient interview.2- TAKE A THOROUGH DRUG HISTORY:A complete record of
prescription and non-prescription
drugs should be taken to avoide drug
interactions.3-BE KNOWELDGEABLE ABOUT
ACTIONS BEING USED; The knowledge of the properties and the primary and secondary pharmacological
action of each of the agent used is essential..4- CONSIDER THERAPEUTIC ALTERNATIVES:In most cases two drugs that are known to interact can be administered concurrently
as long as adequate precautions are
taken however in those situation in which another agent with similar therapeutic properties and a lesser risk of interacting is available
it should be used.5- AVOID
COMPLEX THERAPEUTIC REGIMENS WHEN POSSIBLE:The number of medications used should be kept to a minimum
6- EDUCATE THE PATIENT:
Patients often know little about their illnesses so
council the patient about his illness and the use of medications.
7- MONITOR THERAPY:
The risk
of drug related problems warrants
close monitoring not only the possible
occurance of drug interactions but also
for adverse effects occurring with individual agents and
noncompliance.
8- INDIVIDUAL THERAPY:
It is difficult to predict the
response of many therapeutic agents when they
are given alone. The challenge and
limitations in anticipating the response with a multiple drug regimen are even greater,
therefore priority should be assigned to the needs and clinical response of the individual
patient rather than to the usual dosage recommendations and standard treatment and monitoring guideline,SIGNIFICANCE
LEVEL OF DRUG INTERACTIONS: A number 1 through 5 will be assigned to each interaction
monograph based on the Editorial group ,s
assessment of the interactions
severity and documentationSEVERITY:The potential severity of the
interaction is important in assessing the risk vs benefit of therapeutic alternatives.Major :The effects are potentially life threating or
capable of causing permanent
damage.Moderate ;The
effects may cause a deterioration in a patient ,s clinical status
Additional treatment, Hospitalization may be necessary.Minor: The effects are usually mild ,
consequences may be bothersome or
unnoticeable
