DRUG INTERACTIONS (MECHANISMS OF DRUG-DRUG INTERACTIONS)

DRUG
INTERACTIONS
BY
NADIKATLAANUSHA
M.Pharm

CONTENTS
 INTRODUCTION
 FACTORS CONTRIBUTING TO DRUG INTERACTIONS
 TYPES OF DRUG INTERACTIONS
 MECHANISMS OF DRUG-DRUG INTERACTIONS
 BEHAVIOURAL DRUG-DRUG INTERACTIONS
 PHARMACEUTIC DRUG-DRUG INTERACTIONS
 PHARMACOKINETIC DRUG-DRUG INTERACTIONS
 ABSORPTION INTERACTIONS
Changes in gastrointestinal pH
Changes induced by chelation and adsorption
Changes in gastrointestinal motility
Transporter based interactions
 DISTRIBUTION INTERACTIONS
 METABOLISM INTERACTIONS
Enzyme induction
Enzyme inhibition
 EXCRETION INTERACTIONS
ANUSHA NADIKATLA

 PHARMACODYNAMIC DRUG-DRUG INTERACTIONS
Direct pharmacodynamic interactions.
Indirect pharmacodynamic interactions.
 IMPORTANCE OF CYTOCHROME P450 3A4
 DRUG INTERACTIONS AND OVER-THE-COUNTER (OTC) MEDICINES
 INFLUENCE OF SMOKING ON DRUG INTERACTIONS
 INFLUENCE OF ALCOHOL ON DRUG INTERACTION
 INFLUENCE OF FOOD ON DRUG INTERACTION
 REDUSING THE RISK OF DRUG INTERACTIONS
 CLINICAL RESOURCES FOR DRUG–DRUG INTERACTIONS
 CONCLUSION
 REFERENCES
ANUSHA NADIKATLA

DRUG INTERACTION
ANUSHA NADIKATLA

INTRODUCTION
 A Drug interaction is an interaction between a drug and some other
substance, such as another drug or a certain type of food, which leads
to interaction that could manifest as an increase or decrease in the
effectiveness or an adverse reaction or a totally new side effect that is
not seen with either drug alone that can be severe enough to alter the
clinical outcome.
 Every time a drug is administered with any other prescription
medicine, OTC products, herbs or even food we expose ourselves to
the risk of a potentially dangerous interaction.
 Understanding these potential reactions and their mechanisms help us
to navigate the hazardous effects of combining drugs with other
medicines, food, herbs and vitamins with confidence.
ANUSHA NADIKATLA

Drug interactions are thus:
 Mostly undesirable
 Rarely desirable(beneficial): for eg.,enhancement of activity of
penicillins when administered with probenecid.
The Net effect of a Drug Interaction is:
 Generally quantitative i.e. increased or decreased effect.
 Seldom qualitative i.e. rapid or slower effect.
 Precipitation of newer or increased adverse effect.
Factors contributing to drug interactions
 Multiple drug therapy.
 Multiple prescribers.
 Multiple pharmacological effects of drug.
 Multiple diseases/predisposing illness.
 Poor patient compliance.
 Advancing age of patient.
 Drug-related factors. ANUSHA NADIKATLA

DRUG-DRUG INTERACTIONS.
DRUG-FOOD INTERACTIONS.
CHEMICAL-DRUG INTERACTIONS.
DRUG-LABORATORY TEST INTERACTIONS.
DRUG-DISEASE INTERACTIONS.
TYPES OF DRUG INTERACTIONS
ANUSHA NADIKATLA

DRUG - FOOD / NUTRIENTS INTERACTIONS
• Drug-food/beverage interactions result from drugs reacting with
foods or beverages.
• For example, mixing alcohol with some drugs may cause you to
feel tired or slow your reactions.
• A lack of standardization and contamination further contribute to
these interactions.
• The mechanisms of food-induced interactions are essentially the
same as that of drug interactions, however these occur chiefly due
to alterations in absorption that may impair their nutritional
benefit and to some extent due to altered metabolism.
ANUSHA NADIKATLA

DRUG - DISEASE INTERACTIONS
• Drug- Disease condition interactions may occur when an existing
medical condition makes certain drugs potentially harmful.
• For example, if you have high blood pressure you could experience an
unwanted reaction if you take a nasal decongestant.
• Disease interactions tend to occur when a medication has the potential
to worsen a disease.
• The effect a drug has in certain patients may be unexpected not related
to the drug, but because of the patient’s disease pattern.
• It is important for the physician to know the patients entire disease
profile to plan a suitable therapeutic regimen to avoid drug
interactions carefully balancing the need to ensure that the patient is
given appropriate medicines to cover his ailments.
• This has to be viewed in the context that the patient sub-population
prone to interactions are either frail elderly hospitalized patients or
critically ill patients or those having chronic diseases.
ANUSHA NADIKATLA

ENVIRONMENT INDUCED INTERACTIONS
• These interactions are chiefly due to smoking that entails both
pharmacokinetic and pharmacodynamic reactions.
• The carcinogenic polycyclic aromatic hydrocarbons in tobacco smoke
are potent inducers of the CYP4501A1/1A2/and possibly 2E1
enzymes.
• PK interactions with smoking occur with drugs like caffeine,
clozapine, olanzapine, theophylline, haloperidol and imipramine that
are substrates of CYP1A2.
ANUSHA NADIKATLA

DRUG–DRUG INTERACTIONS
• Drug-drug interactions occur when two or more drugs react with each
other.
• This drug-drug interaction may cause you to experience an
unexpected side effect.
• For example, mixing a drug you take to help you sleep (a sedative)
and a drug you take for allergies (an antihistamine) can slow your
reactions and make driving a car or operating machinery dangerous.
• Interactions between drugs (drug–drug interactions) may be beneficial
or harmful.
• Harmful drug–drug interactions are important as they cause 10–20%
of the adverse drug reactions requiring hospitalisation and they can be
avoided.
• Elderly patients are especially vulnerable with a strong relationship
between increasing age, the number of drugs prescribed and the
frequency of potential drug–drug interactions. ANUSHA NADIKATLA

PROBABILITY OF DRUG INTERACTION
 The Drug whose Activity is effected by such an Interaction is called as
a “Object drug.”
 The agent which precipitates such an interaction is refered to as the
“Precipitant”.
ANUSHA NADIKATLA

TOP 10 DRUG-DRUG INTERACTIONS
• Warfarin ~NSAIDs
• Warfarin ~ Sulfa Drugs
• Warfarin ~ Macrolides
• Warfarin ~ Quinolones
• Warfarin ~ Phenytoin
• ACE Inhibitors ~ Potassium Supplements
• ACE Inhibitors ~ Spironolactone
• Digoxin ~ Amiodarone
• Digoxin ~ Verapamil
• Theophylline ~ Quinolones ANUSHA NADIKATLA

MECHANISMS OF DRUG-DRUG INTERACTIONS
BEHAVIOURAL DRUG-DRUG INTERACTIONS: Altered
compliance
Behavioural drug–drug interactions occur when one drug alters the
patient’s behaviour to modify compliance with another drug. For
example, a depressed patient taking an antidepressant may become more
compliant with medication as symptoms improve
PHARMACEUTIC DRUG-DRUG INTERACTIONS: Outside the
body
Pharmaceutic drug–drug interaction is a physicochemical interaction that
occurs when drugs are mixed in i.v. infusions causing precipitation or
inactivation of active principles before it is administered. For example,
precipitation of sodium thiopentone and vecuronium within an
intravenous giving set.
Example:-Ampicillin, chlorpromazine & barbiturates interact with
dextran in solutions and are broken down or from chemical compounds.
ANUSHA NADIKATLA

PHARMACOKINETIC DRUG-DRUG INTERACTIONS: Altered
concentration
Pharmacokinetic drug–drug interactions occur when one drug changes
the systemic concentration of another drug, altering ‘how much’ and for
‘how long’ it is present at the site of action.
PHARMACODYNAMIC DRUG-DRUG INTERACTIONS: Altered
effect
Pharmacodynamic drug–drug interactions occur when interacting drugs
have either additive effects, in which case the overall effect is increased,
or opposing effects, in which case the overall effect is decreased or even
‘cancelled out’
Mechanism: molecular signal (e.g. receptor)
Mode: physiological effect ANUSHA NADIKATLA

PHARMACOKINETIC
DRUG–DRUG INTERACTIONS
• Pharmacokinetics is ‘what the body does to the drug’.
• These interactions occur when one drug (the perpetrator) alters the
concentration of another drug (the object) with clinical consequences.
• “Pharmacokinetic interactions occur when the absorption,
distribution, metabolism or elimination process of the object drug
is altered by the precipitant drug and hence such interactions are
also called as ADME interactions”.
• The resultant effect is altered plasma concentration of the object drug.
ANUSHA NADIKATLA

CLASSIFICATION OF PHARMACOKINETIC DRUG–DRUG INTERACTIONS
ABSORPTION
INTERACTIONS
DISTRIBUTION
INTERACTIONS
METABOLISM
INTERACTIONS
EXCRETION
INTERACTIONS
ANUSHA NADIKATLA

DRUG ABSORPTION INTERACTIONS
 Absorption interactions are those where the absorption of the object
drug is altered.
 Since the oral route is the one, most frequently used to administer
drugs, interactions influencing absorption are more likely to occur
within the gastrointestinal tract.
 The net effect of such an interaction is:
 Faster or slower drug absorption.
 More or, less complete drug absorption.
 Most clinically significant interactions occur due to the following
factors:
a) Changes in gastrointestinal pH
b) Changes induced by chelation and adsorption
c) Changes in gastrointestinal motility
d) Transporter based interactions ANUSHA NADIKATLA

CHANGES IN GASTROINTESTINAL pH
• Absorption in the gut is governed by the gut pH, lipid solubility and
pKa of the drug, and action of the P-glycoprotein.
• While changes in gastric pH induced by H2 and proton pump blockers
and antacids containing Al/Mg formulations have been shown to
significantly reduce drug bioavailability; in clinical practice the
outcome is a bit uncertain due to other compounding factors such as
chelation and gastric motility.
• However the alteration in pH has certain clinical implications as it can
result in a significant reduction in the absorption of ketoconazole and
itraconazole which are insoluble in water and are only ionized at low
pH, hence gastric acidity plays an important part in this interaction.
Likewise salicylic acid absorption is greater at low pH.
ANUSHA NADIKATLA

CHANGES INDUCED BY CHELATION AND ADSORPTION
• Of the various possible drug interactions that occur due to alterations
in drug absorption the most clinically significant interactions occur
due to chelation or formation of insoluble complexes or when drugs
are bound to resins that bind to bile acids.
• Clinically important interactions relate to use of tetracyclines as well
as ciprofloxacin that can form insoluble chelates with Ca, Al, Bi and
iron, resulting in its reduced antibacterial effects.
• This interaction can however be avoided if the interval between the
medications is at least 2-3 hours.
• Chelation also seems to play an important part in reducing the
bioavailability of penicillamine caused by some antacids.
ANUSHA NADIKATLA

CHANGES IN GASTROINTESTINAL MOTILITY
• Drugs that alter the stomach-emptying rate can affect the rate of
absorption of drugs as most of them are absorbed in the small
intestine.
• Drugs with anticholinergic properties like propantheline or those
altering bowel motility like diphenoxylate may affect the absorption
of other drugs.
• Propantheline increases the absorption of slow dissolving Digoxin by
30% as the reduced gut motility allows a slow dissolving Digoxin
formulation more time to pass into solution making a greater amount
available for absorption but this effect is not seen with fast dissolving
tablets.
• Metoclopramide on the other hand produces the opposite effects on
motility and digoxin absorption.
ANUSHA NADIKATLA

TRANSPORTER BASED INTERACTIONS
• Drug uptake into the enterocyte particularly by the active processes is
mediated by specific drug uptake transport molecules.
• Once the drug enters the enterocyte it could enter the portal
circulation, undergo metabolism or it may get excreted back into the
intestinal lumen resulting in decreased systemic bioavailability.
• Transporter based interactions have of late been recognized much
more than earlier and arise chiefly due to the induction or inhibition of
many identified transporter proteins rather than due to other
mechanisms earlier attributed to protein displacement or enzyme
inhibition or induction.
ANUSHA NADIKATLA

DRUG ABSORPTION INTERACTIONS
OBJECT DRUG PRECIPITANT DRUGS INFLUENCE ON OBJECT DRUG
1.COMPLEXATION & ADSORPTION
Ciprofloxacin, Penicillamine
Antacids, food & minerals
supplements containing al,
mg, fe, zn & ca ions
Formation of poorly soluble and
Unabsorbable complex with such
Heavy metal ions.
2.ALTERATION OF GI PH
Sulphonamides,
Aspirin, Ferrous sulphate
Antacids
Sodium bicarbonate,
calcium carbonate
Enhanced dissolution and
Absorption rate.
Decreased dissolution and
Hence absorption.
3.ALTERATION OF GUT MOTILITY
Aspirin diazepam, levodopa,
mexiletine
Metoclopramide
Rapid gastric emptying,
Increased rate of absorption.
Levodopa, lithium carbonate,
Mexiletine
Anti cholinergics
Delayed gastric emptying;
Decreased rate of absorption.
4.ALTERATION OF GI MICROFLORA
Digoxin Antibiotics
Increased bioavailability
Due to destruction of bacterial flora
That inactivates digoxin in lower
intestine.
5.MALABSORPTION SNDROME
Vitamin A,B12,digoxin Neomycin Inhibition of absorption due to mal.
ANUSHA NADIKATLA

DRUG DISTRIBUTION INTERACTIONS
• Drug 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.
• Many drugs interact by displacement of each others binding to plasma
proteins.
• Acidic drugs are known to have an affinity to bind to plasma proteins,
hence when two or more are given concomitantly, competitive binding
for the same site or receptor may displace one drug from the protein
binding site increasing the amount of the displaced free drug in
plasma and various tissues setting up an interaction leading to an
enhanced potential for toxicity.
ANUSHA NADIKATLA

• Concomitant administration of warfarin with phenylbutazone or other
highly protein bound drugs leads to increased levels of warfarin, with
the clinical implication of frequent monitoring of INR and PT to
prevent bleeding.
• The drugs most likely to lead to clinically significant interactions are
those that are: 90% or more protein bound, those bound to tissues or
having a small volume of distribution, having a low therapeutic index,
low hepatic extraction ratios, or those that are administered I.V.
• Drugs that are more likely to displace other drugs from protein
binding sites include NSAID’s, phenylbutazone, salicylic acid, and
sulfonamides.
• Altered distribution occurs when the concentration of drug at the site
of action is changed without necessarily altering its circulating
concentration. This is particularly an issue for drugs with intracellular
or central nervous system targets. Some drugs cause significant
changes in the cell membrane transport of other drugs.
ANUSHA NADIKATLA

COMPETITIVE DISPLACEMENT INTERACTIONS
DISPLACED DRUG DISPLACER
Anti
coagulants
Phenylbutazone,
chloral hydrate
Increased clotting time.
increased risk of hemorrhage.
Tolbutamide Sulphonamides Increased hypoglycemic effect.
• For example, verapamil inhibits efflux transporters (e.g. P-
glycoprotein) increasing the concentrations of substrates such as
digoxin and cyclosporin.
• Probenecid inhibits anion transporters (e.g. OAT-1) increasing the
concentrations of substrates such as methotrexate and penicillins.
• Drug interactions involving transport are less well understood than
drug interactions involving metabolism.
ANUSHA NADIKATLA

DRUG METABOLISM INTERACTIONS
• This occurs when the metabolism of the object drug is affected by a
perpetrator drug.
• Recent scientific developments, particularly in the area of the CYP450
enzymes have revolutionized the study of drug interactions resulting
in a deluge of published drug interactions that has bewildered the
practicing physicians.
• The human body is continuously exposed to foreign substances
(drugs) not found naturally in the body that modulate the body
function to achieve a therapeutic end that are modified by a plethora
of enzymes.
• As is well known, the processes by which the enzymes alter an active
drug inside the body to an inactive one or into active or toxic
metabolites are referred to as drug metabolism or biotransformation.
ANUSHA NADIKATLA

Object drugs with a narrow therapeutic index are particularly vulnerable,
as modest changes in concentration may be clinically important.
ANUSHA NADIKATLA

• Perpetrator drugs known to strongly affect drug metabolism are more
likely to cause large concentration changes and hence clinical
consequences.
• Recognising these potential perpetrators of pharmacokinetic drug–
drug interactions is important.
• Metabolism Changes in drug metabolism are the most important
causes of unexpected drug interactions. These occur by changing drug
clearance or oral bioavailability.
• There are several enzyme families involved in drug metabolism, and
the cytochrome P450 (CYP) enzyme family is the most important.
ANUSHA NADIKATLA

• Inhibition of a cytochrome P450 enzyme increases the concentration
of some drugs by decreasing their metabolism.
• For example, clarithromycin is a strong inhibitor of CYP3A-catalysed
simvastatin metabolism, thus increasing the risk of myopathy.
• Drug inhibition of cytochrome P450 enzymes is also used
therapeutically.
• For example, ritonavir, a strong inhibitor of CYP3A, reduces
metabolism of other protease inhibitors thus increasing their
effectiveness in treating HIV (so called ‘ritonavir-boosted’ regimens).
• Induction of a cytochrome P450 enzyme decreases the concentration
of some drugs by increasing their metabolism.
• For example, carbamazepine is a strong inducer of CYP3A that
increases the metabolism of the combined oral contraceptive, thus
increasing the risk of unwanted pregnancy.
ANUSHA NADIKATLA

PRODRUGS
• Some drugs rely on cytochrome P450 enzymes for conversion to their
active form.
• As this is usually dependent on a single enzyme pathway, prodrugs are
particularly vulnerable to changes in metabolism.
• Inhibition of conversion from prodrug to active drug may lead to
inadequate concentrations of the active drug and therapeutic failure.
• For example, tamoxifen is metabolised by CYP2D6 to its active form
endoxifen, and concomitant therapy with the strong CYP2D6 inhibitor
paroxetine has been associated with increased mortality in breast
cancer.
ANUSHA NADIKATLA

MECHANISMS OF METABOLISM INTERACTIONS
Substrate: An agent that is metabolized by an enzyme into a metabolic
end product and eventually excreted.
ENZYME INDUCTION
• Increased rate of metabolism.
• Interfere with the ability of enzyme to metabolize substrate.
• Decreased metabolism → increased concentrations of substrate
• Enzyme inhibitors cause rapid increases (24 hours) in the blood levels
of substrates.
Time to maximal drug interaction determined by:
1. Half-life and time to steady state of the inhibitor drug
2. Time required for the substrate to reach a new steady state.
ANUSHA NADIKATLA

• Inhibitors compete with other drugs for a particular enzyme thus
affecting the optimal level of metabolism of the substrate drug, that
then accumulates in the body resulting in toxicity.
• Strong inhibitors achieve a 5 fold increase in plasma AUC or an 80%
decrease in clearance, while moderate inhibitors lead to a 2 fold
increase in AUC and 50-80% decrease in clearance of the substrate
drug.
• Inhibition of enzymes can occur in different ways such as is seen with
ketoconazole, whose nitrogen moiety binds to the heme iron in the
P450 enzyme site preventing the metabolism of concomitantly
administered drugs either by competitive or irreversible inhibition that
is achieved for instance by secobarbital that alkylates and inactivates
the P 450 enzyme permanently.
ANUSHA NADIKATLA

ENZYME INHIBITION
• Decreased rate of metabolism.
• It is the most significant interaction in comparison to other
interactions and can be fatal.
• Increase production of enzyme(s) responsible for metabolizing
substrate
• Increased metabolism → decreased concentrations of substrate.
• Enzyme inducers cause slow change (days to weeks) because it
requires synthesis of the enzyme.
• Maximum effect may not be reached for 2-3 weeks (and take 2-3
weeks to ‘wear off’).
• Inducers, stimulate the production of the CYP isoform, thus increasing
the rate of metabolism and enabling substrate drug to clear out of the
system faster.
ANUSHA NADIKATLA

• This decreases its response, rendering the drug ineffective, as it does
not remain in the system long enough.
• Enzyme induction does not occur quickly, usually taking a week or
two as its maximal effect depends on enzyme synthesis and t1/2 of the
inducing drug, which in the case of phenobarbitone may require a
longer time, while rifampicin with its short t1/2 can manifest its
effects within 24 hours.
• The process of P450 enzyme induction gets initiated by an increase in
the expression of the enzyme chiefly via increased transcription or
decreased degradation.
• Drugs or food gets bound to and activates several xenobiotic receptors
e.g the Pregnane X receptor after entering the liver cells, which then
heterodimerises with the Retinoid X receptor (RXR) to form a
complex with coactivators to initiate transcription of the P450
enzyme.
ANUSHA NADIKATLA

METABOLISM INTERACTIONS
1.ENZYNE INDUCTION
Corticosteroids,
Oral contraceptives,
Coumarins, Phenytoin
Barbiturates
Decreased plasma levels;
decreased efficacy of
object drugs
Oral contraceptives,
Oral hypoglycaemics
Rifamicin Decreased plasma levels
2.ENZYME INHIBITION
Tyramine rich food MAO inhibitors
Enhanced absorption of
Un metabolised
tyramine.
Coumarins
Metranidazole
Phenyl butazone
Increased anti coagulant
activity.
Alcohol
Disulphiram,
Metronidazole
Increased in plasma
acetaldehyde levels
ANUSHA NADIKATLA

IMPORTANCE OF CYTOCHROME P450 3A4
• Phase I reactions are catalysed by a family of mixed function
oxygenases called the ''Cytochrome P 450" class, expressed chiefly
within the microsomal smooth endoplasmic reticulum hepatocytes and
to a lesser extent in other cells.
• The nomenclature for this class of enzyme is usually abbreviated to
‘CYP” followed by an Arabic number indicating the enzyme family
and a capital letter to indicate the enzyme sub family and then an
additional number to describe the specific enzyme e.g. CYP2D6.
• Allelic forms are described with an * and a number or number letter.
• This enzyme complex is so named because it is bound to a membrane
within a cell (Cyto) and contains a hem Pigment (chrome and P) that
absorbs light at a wave length of 450 nm when exposed to Co2.
• The net result is “Cytochrome P 450”.
ANUSHA NADIKATLA

• The interaction starts with the drug binding to the oxidized (Fe)
CYP450 complex which is then reduced in two oxygenation/reduction
steps using a reactive hem ring with an iron atom on the ultimate
electron acceptor donor and NADPH as a necessary co-factor.
• The CYP450 complex is essential for metabolism of drugs and
interactions mediated by it and what is significant is that out of 50
enzymes in this class, each encoded by a different gene, just 6 of them
(CYP1A2, CYP2C8/9, CYP2C19, CYP2D6, CYP2E1 and
CYP3A4/5) together account for 90- 95% of biotransformations; with
the 3A4 and 2D6 sub families being responsible for a large number of
clinically important interactions.
• However, there is a considerable variability in enzyme activity
between patients due to medical, environmental, nutritional and
genetic polymorphisms reasons with polymorphism being specially
significant for CYP2D6, CYP2C9, CYP2C19 and CYP3A4.
ANUSHA NADIKATLA

• CYP3A4 is responsible for the metabolism of more than 50%
of medicines.
• CYP3A4 activity is absent in new-borns but reaches adult
levels at around one year of age.
• The liver and small intestine have the highest CYP3A4
activity.
• Some important CYP3A4 interactions are due to intestinal
rather than hepatic enzyme inhibition ( eg: grapefruit).
• There is considerable variability in CYP3A4 activity in
population.
• Women have higher CYP3A4 activity than men.
• Potent inhibitors of CYP3A4 include clarithromycin,
erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir,
verapamil, goldenseal and grapefruit.
• Inducers of CYP3A4 include phenobarbital, phenytoin,
rifampicin, St. John’s Wort and glucocorticoids.
ANUSHA NADIKATLA

Phase II conjugation/hydrolysis:
These reactions provide a second set of mechanisms for modifying
compounds for excretion wherein large water soluble metabolites are
acted upon by non P450 enzymes such as N-acetyl and glucuronyl
transferase systems which render them inactive or less active water
soluble metabolites.
ANUSHA NADIKATLA

DRUG ELIMINATION REACTIONS
• Drug elimination reactions are those where the excretion pattern of the
object drug is altered.
• The major routes for elimination of drugs remain the kidney and bile,
but there are no significant drug - drug interactions through bile
elimination, but only drug-disease ones.
• Some drugs are excreted from the body unchanged in the active form,
usually in the urine or via the biliary tract in the faeces.
• Drugs that are chiefly excreted by the kidneys can get involved in
drug interactions by different mechanisms such as Competition at
active transport sites, or alterations in Glomerular Filtration, passive
renal tubular reabsorption or active secretion and urinary pH.
• Changes in renal drug clearance may occur due to effects on renal
tubular function or urine pH.
• For example, probenecid reduces the renal clearance of anionic drugs
such as methotrexate and penicillin. ANUSHA NADIKATLA

Major mechanisms of excretion interactions are:
 Alteration in renal blood flow
 Alteration of urine PH
 Competition for active secretions
 Forced diuresis
EXCRETION INTERACTIONS
1.CHANGES IN ACTIVE TUBULAR SECRETION
Pencillin,cephalospori
ns,nalidixic acid
Probenicid
Elevated plasma levels of acidic
drugs
2.CHANGES IN URINE PH
Amphetamine
Antacids, thiazides,
Acetazolamide
Increased passive reabsorption of
basic drugs, Increased risk of
toxicity
3.CHANGES IN RENAL BLOOD FLOW
Lithium bicarbonate NSAIDS
Decreased renal clearance of
lithium, Risk of toxicity
ANUSHA NADIKATLA

PHARMACODYNAMIC DRUG–DRUG INTERACTIONS
• Pharmacodynamic drug–drug interactions can be managed based on
anticipating known drug effects and monitoring the patient for those
effects.
• They are often intentional.
• Unintentional harmful interactions are particularly common with
multiple drugs acting on the central nervous system.
• Pharmacodynamics is ‘what the drug does to the body’.
• These interactions occur between drugs with additive or opposing
effects.
• The brain is the organ most commonly compromised by
pharmacodynamic interactions.
• Pharmacodynamic interactions are relatively common in practice and
occur when a precipitant drug alters the clinical effects of the object
drug at its site of action. ANUSHA NADIKATLA

• One drug may alter the normal physiological environment whereby it
can increase or decrease the effects of another drug as is exemplified
by the interaction produced by diuretic induced hypokalemia with the
concurrent use of digoxin that results in digoxin toxicity.
• In a similar situation of diuretic usage concurrently with anti-
arrhythmics like quinidine or sotalol a much more serious toxicity in
the form of Torsade de pointes can occur resulting in fatal ventricular
arrhythmias.
• Pharmacodynamic interactions between drugs with additive effects
may be intentional, for example when combining antihypertensives, or
unintentional, for example serotonin syndrome caused by adding
tramadol to a selective serotonin reuptake inhibitor (SSRI).
• Conversely, combining drugs with opposing effects can result in loss
of drug effect, for example reduced bronchodilation by a beta2 agonist
prescribed with a non-selective betablocker. Considering drug effects
by organ is a useful way to recognise pharmacodynamic interactions.
• This approach allows you to consider interactions between drugs with
different modes of action, for example an anticholinergic and a
benzodiazepine. ANUSHA NADIKATLA

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
a. Antagonism.
b. Addition or summation.
c. Synergism or potentiation.
Antagonism: The interacting drugs have opposing actions
Example: Acetylcholine and noradrenaline have opposing effects on
heart rate.
ANUSHA NADIKATLA

Addition or summation: The interacting drugs have similar actions and
the resultant effect is the some of individual drug responses
Example: CNS depressants like sedatives and hypnotics,…etc
Synergism or potentiation: It is an enhancement of action of one drug
by another
Example: Alcohol enhances the analgesics activity of aspirin.
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: salicylates decrease the ability of the platelets to aggregate thus
impairing the Homeostasis if warfarin indused bleeding occurs.
ANUSHA NADIKATLA

DRUG INTERACTIONS AND OVER-THE-COUNTER (OTC)
MEDICINES
• Over-the-counter (OTC) drug labels contain information about
ingredients, uses, warnings and directions that is important to read and
understand.
• The label also includes important information about possible drug
interactions.
• Further, drug labels may change as new information becomes known.
• That’s why it’s especially important to read the label every time you
use a drug.
ANUSHA NADIKATLA

1. The “Active Ingredients” and “Purpose” sections list:
 The name and amount of each active ingredient.
 The purpose of each active ingredient
2. The “Uses” section of the label:
 Tells you what the drug is used for
 Helps you find the best drug for your specific symptoms
3. The “Warnings” section of the label provides important drug
interaction and precaution information such as:
 When to talk to a doctor or pharmacist before use
 The medical conditions that may make the drug less effective or not
safe
 Under what circumstances the drug should not be used
 When to stop taking the drug
ANUSHA NADIKATLA

4. The “Directions” section of the label tells you:
 The length of time and the amount of the product that you may safely
use .
 Any special instructions on how to use the product .
5. The “Other Information” section of the label tells you:
 Required information about certain ingredients, such as sodium
content, for people with dietary restrictions or allergies.
6. The “Inactive Ingredients” section of the label tells you:
 The name of each inactive ingredient (such as colorings, binders, etc.)
7. The “Questions?” or “Questions or Comments?” section of the
label (if included):
 Provides telephone numbers of a source to answer questions about the
product. ANUSHA NADIKATLA

INFLUENCE OF SMOKING ON DRUG INTERACTIONS
Particulate matter of tobacco smoke consists of:
a) Water-soluble compounds: nicotine
b) Fat soluble compounds: polycyclic aromatic hydrocarbons.
• Smoking increases the activity of drug metabolizing enzymes in the
liver, with the result that certain therapeutic agents
• Example: Diazepam, propoxyphene, theophylline, olanzapine are
metabolized more rapidly, and their effect is decreased.
• Chronic smoking increases the metabolism of nicotine, phenacetin,
antipyrine, theophylline, imipramine, propranolol.
ANUSHA NADIKATLA

CHLORDIAZEPOXIDE: Drowsiness is reported in
 10% nonsmokers
 6% light smokers
 3% heavy smmokers
PROPOXYPHENE is ineffective for the relief of mild to moderate pain
or headache in
 10% nonsmokers
 20% heavy smokers
 Of 7 reported adverse effects to propoxyphene, 6 occurred in
nonsmokers
 Reduced efficacy of propoxyphene in smokers is consistent with
enhanced metabolism.
ANUSHA NADIKATLA

DIAZEPAM: Drowsiness is reported in
 8% nonsmokers or light smokers
 3% heavy smokers
THEOPHYLLINE: The increased metabolism of theophylline in
smokers seems to be associated with reduced toxicity during clinical use.
Incidence of theophylline toxicity was-
 13% nonsmokers
 7% smokers
 For smokers who are taking theophylline chronically, their dose of
theophylline will need to be reduced by ¼ to 1/3 after brief tobacco
abstinence.
ANUSHA NADIKATLA

INFLUENCE OF ALCOHOL ON DRUG INTERACTION
• Chronic use of alcohol beverages may increases the rate of
metabolism of drugs such as warfarin and phenytoin, probably by
increasing the activity of hepatic enzymes.
• Use of alcoholic beverages with sedatives and other depressants drugs
could result in an excessive depressant response.
• Chlordiazepoxide elimination after i.v. administration was
determined before and after acute injection of ethanol, 0.8 g/kg
followed by 0.5 g/kg every 5hr for 30 hr.
• Plasma clearance of chlordiazepoxide fell about 1/3 from 27 ml/min
in control period to 17 ml/min during ethanol intoxication. Ethanol
also decreased the plasma protein binding of drug.
ANUSHA NADIKATLA

• Ethanol not only inhibits but also stimulates drug metabolism.
• Regular administration of ethanol for one month to alcoholic and
nonalcoholic subjects resulted in an enhanced elimination of
meprobamate, phenobarbital, and ethanol itself.
DRUG
HALF LIFE-
ALCOHOLIC
HALF LIFE-
NONALCOHOLIC
MEPROBAMATE
Reduced from 17 to
7hrs
Reduced from 14 to
8hrs
PHENOBARBITAL -
Reduced from 35 to
26hrs
ANUSHA NADIKATLA

INFLUENCE OF FOOD ON DRUG INTERACTION
• Food effects the rate and extent of absorption of drugs from the GI tract.
• Example: Many antibiotics should be given atleast 1hr before or 2hr after
meals to achieve Optimal absorption.
• The type of food may be important with regard to the absorption of
concurrently administered Drugs.
• Example: Dietary items such as milk and other dairy products that contain
calcium may decrease the absorption of tetracycline and flouroquinolone
derivatives.
• Diet also may influence urinary pH values.
• Certain vegetables, including Brussels sprouts, cabbage, turnips, broccoli,
cauliflower, & spinach, contain chemicals that include aryl hydrocarbon
hydroxylase enzyme activity.
LEVODOPA: The mean % of the time patients were responding satisfactorily
to levodopa was
• 51% for high-protein diet
• 67% for low-protein diet over 3 meals,
• 77% for low-protein diet restricted to evening meal.
ANUSHA NADIKATLA

REDUSING THE RISK OF DRUG INTERACTIONS
1) Knowledge of the pharmacological effects of drugs and of patient
physiology together allows recognition of potential pharmacodynamic
drug– drug interactions.
2) Identify the patient’s risk factors.
3) Take thorough drug history. Any interactions between existing drugs in a
given patient have already occurred.
4) Be knowledge about the actions of the drugs being used. Drugs with a
narrow therapeutic index are particularly susceptible to pharmacokinetic
drug–drug interactions
5) Consider therapeutic alternatives.
6) Avoid complex therapeutic regiments when possible.
7) Starting or stopping a drug is a prescribing decision that may cause a drug
interaction.
8) Monitoring patients for drug toxicity or loss of efficacy is part of routine
care.
9) Checking for changes in symptoms, biomarkers of effect, or drug
concentrations soon after prescription changes helps identify drug
interactions early and can reduce harm.
10) Educate the patient. ANUSHA NADIKATLA

CLINICAL RESOURCES FOR DRUG–DRUG INTERACTIONS
• Individual drug monographs in formularies, such as the Australian
Medicines Handbook, are a useful starting point for learning about
new drugs.
• Tables listing the major perpetrators of pharmacokinetic drug–drug
interactions are available in the Australian Medicines Handbook or
online (www.pkis.org)
• Prescribing and dispensing software mostly generates alerts from
tables of information about drug pairs. The time involved and the
amount of irrelevant information retrieved may cause ‘alert fatigue’
and limit their clinical utility.
• Drug information services have access to reference information such
as Stockley’s Drug Interactions and Micromedex.
ANUSHA NADIKATLA

CONCLUSION
It has been projected that the possibility of drug
interactions increase almost exponentially with the number of
drugs used. Drug interactions may cause either adverse effects
or sometimes therapeutic failure. It is desirable to understand
the basic pharmacology of drugs so as to avoid giving drugs
that are additive in nature or those acting on the same or
multiple sites as well as to remember the important inducers of
metabolism. The prescriber and also the patient should take
care while taking any OTC, natural products and food during
the medication.
ANUSHA NADIKATLA

REFERENCES
• Sloan RW. Drug Interactions. Am Fam Physician 1983;27:229
• Boston Collaborative study Programme Adverse Drug interaction. JAMA 1972;220:1238-39
• Malone DC et al: Assessment of potential drug-drug-interactions with a prescription claims
database. Am J Health-System Pharm, 2005;62:1983-91
• Durrence CW et al: Potential drug interactions in surgical patients. Am J Hosp Pharm
1985;42:1553-55
• Pirmohamed M, James S, Meakin S, Green C, Scott AK, Walley TJ, et al. Adverse drug
reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ
2004;329:15-9.
• Merlo J, Liedholm H, Lindblad U, Björck-Linné A, Fält J, Lindberg G, et al. Prescriptions
with potential drug interactions dispensed at Swedish pharmacies in January 1999: cross
sectional study. BMJ 2001;323:427-8.
• Polasek TM, Lin FP, Miners JO, Doogue MP. Perpetrators of pharmacokinetic drug-drug
interactions arising from altered cytochrome P450 activity: a criteria-based assessment. Br J
Clin Pharmacol 2011;71:727-36.
• Fallowfield JM, Marlow HF. Propranolol is contraindicated in asthma [letter]. BMJ
1996;313:1486.
• Hilmer SN, Mager DE, Simonsick EM, Cao Y, Ling SM, Windham BG, et al. A drug burden
index to define the functional burden of medications in older people. Arch Intern Med
2007;167:781-7.
• Isaac T, Weissman JS, Davis RB, Massagli M, Cyrulik A, Sands DZ, et al. Overrides of
medication alerts in ambulatory care. Arch Intern Med 2009;169:305-11.
ANUSHA NADIKATLA

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