Drug Interactions

Definition

 Drug interaction is defined as follows:

“Drug interaction is referred to an altered drug

response produced by the administration of a drug
or co exposure of the drug with another substance,
which modifies the patient’s response to the drug”
Definition

OR
“An interaction is said to occur when the
effects of one drug are altered by the co-
administration of another drug, herbal
medicine, food, drink or other environmental
chemical agents”
Definition

 Much more colorful and informal definitions

by patients are that it is “. . .
 when medicines fight each other. . .”, or “. . .
 when medicines fizz together in the
stomach . . .”, or “. . .
 what happens when one medicine falls out
with another. . .”
Drug-drug interactions may result in
 adverse drug reactions,
 decreased therapeutic benefit, or
 patient harm.
More than 100,000 types of potential drug
interactions have been documented, but most do not
actually lead to adverse effects.
 The risk of dying from a drug-related incident
now exceeds the risk of dying in a traffic
accident. In 2008, 36,500 drug related deaths
were reported.
 Some drug interactions are intentional to
provide improved therapeutic response or to
decrease adverse drug effects.
 E.g. effect of clopidogrel is enhanced by giving
with a cytochrome P450 inducer.
Precipitant and object

 Precipitant:
A precipitant is the drug, chemical or food
element causing the interaction.

 Object:
An object is the drug affected by the
interaction.
Risk Factors for drug interaction
OTC
medication
Narrow
Therapeutic Polypharmacy
Index Drugs

Genetic Multiple
Predispositi Prescribers
on

Morbidity
Classification

 Drug interactions include:

o Drug-drug interactions
o Drug-food interactions
o Drug-herbal interactions
o Pharmacogenetic interactions
o Drug-chemical interactions
o Drug-laboratory tests interactions
Classifications

 Drug interaction occur as:

In vitro or
In vivo

Drug interactions that occur in vivo are

generally classified as:
• Pharmacodynamic interactions
• Pharmacokinetic interactions
Drug-drug Interactions

 A drug-drug interaction maybe defined as the

pharmacologic or clinical response to the
administration of a drug combination
different from that anticipated from the
known effects of the two agents when given
alone.
Drug-drug interactions

 Example:
1. Aminoglycosides and NSAIDs.
• Mechanism
NSAIDs may cause an accumulation of
aminoglycosides by reducing the glomerular
filtration rate.
• Effect
Plasma aminoglycoside concentration maybe
elevated.
Drug-drug interaction

2. Simvastatin and Protease inhibitors:

• Mechanism:
Inhibition of simvastatin first pass metabolism
• Effect:
Simvastatin plasma level elevated
Drug-food interaction

 Food can increase, decrease or not effect the

absorption of drugs.
 Complexation and adsorption of the drug in
the GI tract with another food element is a
common drug interaction that reduces the
extent of drug absorption.
Drug-food interaction

 Example:
1. Calcium (milk based products) and
Quinolones:
• Mechanism:
Complexation
• Effect:
Reduces the extent of drug absorption.
Drug-food interaction
2. Spinach or broccoli and Warfarin:
• Mechanism:
Pharmacodynamic antagonism
• Effect:
Antagonizes the effect of warfarin.
3. Garlic and warfarin:
• Mechanism:
Additive antiplatelet effect
• Effect:
Increase risk of bleeding.
Drug-Herbal interaction

 Herbal preparations are various combinations

of herbs, sometimes being one herb, or a
combination of herbs.
 Many herbal drugs interact at the same
transport, metabolism and receptor sites as
traditional prescription drugs.
 Drug herbal interactions can occur as
pharmacokinetic or pharmacodynamic
interaction
Drug-herbal interaction

 Example:
1. Dong Quai and Beta blockers:
• Mechanism
Inhibition of CYP450 enzyme (CYP 2C9)
• Effect:
Increased level of beta blockers (increased
hypotension)
Drug-disease interaction

 Sometimes, drugs that are helpful in one

disease are harmful in other disorder.

 Drug-disease interaction may occur at any

age group but are common among older
people, who tend to have more disease.
Drug-disease interaction

 Example:
1. Beta blockers and asthma/diabetes
Interaction
Worsens asthma and makes hard for diabetic
patients to tell that their blood sugar is too low.
2. Simvastatin and liver disease:
Interaction
Decreased drug metabolism may lead to
accumulation and increase risk of toxicity.
Drug-lab test interaction

 Drugs often alter laboratory test results, the

literature reports > 40,000 drug effects on
laboratory tests. These effects may cause
misinterpretation of laboratory data and lead
to unnecessary further tests, mislead
diagnosis and additional costs.
Drug-lab test interaction

 Example:
1. Propranolol and thyroxine blood level
tests:
• Mechanism
Increase thyroxine level
2. Amoxicillin and LFTs
• Mechanism:
Increases AST and ALT levels.
Mechanisms of Drug Interactions

 Mechanisms can be classified as:

1. Pharmacokinetic interactions
2. Pharmacodynamic interactions

 Drug interactions often involve more than

one mechanism. There are some situations
where drugs interact by unique mechanisms.
Pharmacokinetic interactions

 Pharmacokinetic interactions are those that

affect the processes by which drugs are
 Absorbed,
 Distributed,
 Metabolized or
 Excreted.
Due to marked interindividual variability in these
processes, these interactions may be expected
but their extent cannot be easily predicted.
Pharmacokinetic interactions

 Such interactions may result in a change in

the drug concentration at the site of action
with subsequent toxicity or decreased
efficacy.
 Pharmacokinetic interactions occurring with
one drug cannot be assumed to occur with
related drugs unless their pharmacokinetic
properties are known to be similar.
1. Absorption

 A number of factors can affect the rate of

absorption or the extent of absorption (i.e.
the total amount of drug absorbed).
 Changes in absorption of a drug more than

20% may be considered significant

• The non-ionized form of a drug is more lipid

soluble and more readily absorbed from GIT

than the ionized form does.
1. Absorption

A. Changes in gastrointestinal pH
 The absorption of a drug across mucous
membranes depends on the extent to which
it exists in the non- ionized, lipid-soluble
form.
 Weakly acidic drugs, such as the salicylates,
are better absorbed at low pH because the
non-ionized form predominates.
1. Absorption
 An alteration in gastric pH due to antacids, histamine
H2 antagonists or proton pump inhibitors therefore has
the potential to affect the absorption of other drugs.

 Antacids transiently (0.5–2 hours) raise gastric pH by 1–

2 units, H2-antagonists (Cimetidine) dose-dependently
maintain gastric pH above 5.0 for many hours, and
proton pump inhibitors (Omeprazole) dose-
dependently raise gastric pH above 5.0 for up to 19
hours.
1. Absorption
 The concomitant administration of these compounds
leads to significant alterations in the extent of
absorption of basic compounds such as certain azole -
antifungals and β-lactam antibiotics.
 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 absorbed at low pH,
1. Absorption

 Hence gastric acidity plays an important part

in this interaction.

Antacids, histamine, H2 antagonists and

omeprazole can significantly decrease the
bioavailability of ketoconazole and
itraconazole, which require gastric acidity for
optimal absorption, but the absorption of
fluconazole and voriconazole is not
significantly altered by changes in gastric pH.
1. Absorption

 The alkalinizing effects of antacids on the

gastro-intestinal tract are transient and the
potential for interaction may be minimized
by leaving an interval of 2–3 h between the
antacid and the potentially interacting drug.
1. Absorption

B. Adsorption, chelation and other complexing

mechanisms:

 Certain drugs react directly within the gastro-

intestinal tract to form chelates and complexes
which are not absorbed.
 The drugs most commonly implicated in this type
of interaction include tetracyclines and the
quinolone antibiotics that can complex with iron,
and antacids containing calcium, magnesium
and aluminium..
1. Absorption

1. Tetracycline and metal cations:

 Tetracyclines can chelate with divalent or trivalent

metal cations such as calcium, aluminium, bismuth
and iron to form insoluble complexes, resulting in
greatly reduced plasma tetracycline concentrations.

 This interaction can however be avoided if the

interval between the medications is at least 2-3
hours.
1. Absorption

2. Bisphosphonates and calcium

supplements:
 Bisphosphonates are often co-prescribed
with calcium supplements in the treatment of
osteoporosis. If these are taken
concomitantly, however, the bioavailability of
both is significantly reduced, with the
possibility of therapeutic failure.
1. Absorption

3. Kaolin-pectin and Digoxin:

Kaolin-pectin suspensions in diarrheal disorders
bind digoxin, when co-administered reducing its
absorption by 30-50%.

4. Antibiotics and GI Flora:

Antibiotics that alter gastrointestinal flora can
reduce the rate of synthesis of vitamin K with a
resultant increase in the effect of oral
anticoagulants due to a competitive mechanism
between them.
1. Absorption

 Most chelation and adsorption interactions

can be avoided if an interval of 2–3 h is
allowed between doses of the interacting
drugs.
 1. Absorption

C. Effects on gastro-intestinal motility:

 Since most drugs are largely absorbed in the upper

part of the small intestine, drugs that alter the rate
at which the stomach empties its contents can
affect absorption.
 Drugs with anticholinergic effects, such as tricyclic
antidepressants,
 phenothiazines and
 some antihistamines,
decrease gut motility and delay gastric emptying.
1. Absorption

 The outcome of the reduced gut motility can

either be an increase or a decrease in drugs
given concomitantly.
1. TCA and Dicoumarol:
 Tricyclic antidepressants can increase
dicoumarol absorption, probably as a result
of increasing the time available for its
dissolution and absorption.
1. Absorption

2. Metoclopramide and Paracetamol:

 Metoclopramide increases gastric emptying
and increases the absorption rate of
paracetamol, an effect which is used to
therapeutic advantage in the treatment of
migraine to ensure rapid analgesic effect.
1. Absorption
3. Propantheline and Digoxin
 Propantheline (is an anticholinergic agent. It
works by decreasing the motion of muscles in
the stomach, intestines, and bladder) 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.
1. Absorption

4. Metoclopramide and Digoxin:

Metoclopramide on the other hand produces
the opposite effects on motility allowing less
time for digoxin absorption.

Prolonged stomach retention

 Can cause excessive degradation of acid-labile

compounds, such as penicillin and erythromycin
1. Absorption

 D. Induction or inhibition of drug transport

proteins:
 The oral bioavailability of some drugs is
limited by the action of drug transporter
proteins, which eject drugs that have diffused
across the gut lining back into the gut.
 At present, the most well-characterised drug
transporter is P-glycoprotein.
1. Absorption

 Digoxin and P-glycoprotein:

Digoxin is a substrate of P-glycoprotein and
drugs that inhibit P-glycoprotein, such as
verapamil, may increase digoxin bioavailability
with the potential for digoxin toxicity.
Rifampicin induces P-gp. activity in the gut
lining thereby ejecting digoxin into the gut with
resultant falls in its plasma levels.
On the other hand Verapamil inhibits P-gp.
activity and raises Digoxin levels.
 1. Absorption
Changes in active and passive transport
 A rapidly expanding field of research is that of intestinal trans-
cellular transport.
 Multiple intestinal transporters located on the brush-border and
baso-lateral membrane of the enterocyte have been identified.
 The potential for competitive inhibition of these transporters
with quinolone antibiotics has been documented.
1. Absorption
 Changes in Pre-systemic Clearance:
 The drug-metabolizing CYP 3A4 and 3A5 (CYP3A4/5) are
expressed at high concentrations in the intestine and
contribute to drug inactivation.
 Determining the relative contributions of intestinal P-
glycoprotein and CYP3A4/ 5 activity to drug
bioavailability and interactions is an active area of
investigation.
1. Absorption

 For example, the benzodiazepine, midazolam

is a specific CYP3A4/5 substrate.
 Potential suicide inhibition of CYP3A4/5
with grapefruit
 Clinical data available for anti-infective–
grapefruit juice. Interactions include the
protease inhibitor saquinavir (anti viral
agent), the antifungal agent itraconazole,
and the macrolide - Clarithromycin.
1.Absorption

 Saquinavir AUC increases 2 fold with a single

400-mL (dose) of grapefruit juice,
itraconazole and clarithromycin AUCs do
not change significantly.
1. Absorption

 Malabsorption:
 Drugs such as neomycin may cause a
malabsorption syndrome leading to reduced
absorption of drugs such as digoxin.

 Most of the interactions that occur within the

gut result in reduced rather than increased
absorption.
1. Absorption

 For drugs that are given chronically on a

multiple dose regimen, the rate of absorption is
usually unimportant provided the total amount
of drug absorbed is not markedly altered.
 On the other hand, delayed absorption can be
clinically significant where the drug affected has
a short half-life or where it is important to
achieve high plasma concentrations rapidly, as
may be the case with analgesics or hypnotics.
2. Drug Distribution

 A drug undergoes distribution to various

tissues including to its site of action.
 Many drugs and their metabolites are highly
bound to plasma proteins.
 Albumin is the main plasma protein to which
acidic drugs such as warfarin are bound,
 Basic drugs such as tricyclic antidepressants,
lidocaine, and propranolol are generally
bound to α1-acid glycoprotein.
2. Drug Distribution

 Drug interactions may occur, principally as a

result of displacement from protein-binding
sites.
 A drug displacement interaction is defined as:
“A reduction in the extent of plasma protein
binding of one drug caused by the presence
of another drug, resulting in an increased
free or unbound fraction of the displaced
drug”.
2. Drug Distribution

 Clinical pharmacokinetic studies suggests,

 for most drugs, once displacement from
plasma proteins occurs,
 the concentration of free drug rises
temporarily,
 but falls rapidly back to its previous steady-
state concentration due to metabolism and
distribution.
2. Drug Distribution

 The short term rise in the free drug concentration

is generally of little clinical significance,
 but may need to be taken into account in
therapeutic drug monitoring.
 For example,
 if a patient taking phenytoin is given a drug which
displaces phenytoin from its binding sites, the
total (i.e. free plus bound) plasma phenytoin
concentration will fall even though the free
(active) concentration remains the same.
2. Drug Distribution

Warfarin and Diclofenac:

 A typical pharmacological displacement can be
observed when warfarin and diclofenac are co-
administered.
 Warfarin and diclofenac – both have affinity for
albumin - results in displacement of warfarin
from its binding site.
 The increase in plasma concentration of free
warfarin causes the development of serious
hemorrhagic reactions.
3. Drug Metabolism

 Most clinically important interactions involve

the effect of one drug on the metabolism of
another.
 Drug metabolism consists of:
 Phase I reactions such as oxidation,
hydrolysis and reduction, and
 Phase II reactions, which primarily involve
conjugation of the drug with substances such
as glucuronic acid and sulphuric acid.
3. Drug Metabolism

 CORE CONCEPT:
 P450 system
 A set of enzymes (usually hepatic, but not always) metabolize a

wide array of endogenous and exogenous substrates in order to

detoxify them and then eliminate them from the body.

 Involved in phase I, or oxidative, metabolism, as opposed to phase

II conjugation.
 There are more than 40 P450 enzymes.
3. Drug Metabolism
3. Drug Metabolism
3. Drug Metabolism
3. Drug Metabolism
3. Drug Metabolism
 Inter-individual Variability
 Inter-individual variability in enzymatic efficiency
(10- to 30-fold differences in 3A4 function)
 Trends within specific ethnic groups.
 “Poor metabolizers” for the specific P450 enzymes in
question – lack copies of P450 genes.
 “Ultra rapid metabolizers.” individuals who have extra
copies of P450 genes.
 Metabolically normal individuals (called “extensive
metabolizers”) can functionally be converted to “poor
metabolizers” if exposed to inhibitor of specific P450
enzyme – and as long as they are exposed to that agent.
3. Drug Metabolism

CYP2D6
Poor metabolizers
 White 6 – 10%

 Asians 2%

 Afro-Americans more than 10%

Ultra rapid metabolizers

 Middle eastern

 North Africans
3. Drug Metabolism
 Conversely, individuals exposed to an inducer may function as
ultrarapid metabolizers for that P450 enzyme.
 Poor metabolizers/polymorphic individuals will generally have
much higher blood levels of a substrate at a given dose than will
extensive metabolizers.
 Although this is counterintuitive, the rate at which poor
metabolizers/polymorphic individuals metabolize a substrate of
that enzyme is not influenced by introducing an inhibitor of that
enzyme.
3. Drug Metabolism
3. Drug Metabolism

 The effect of a cytochrome 450 isoenzyme on a

particular substrate can be altered by
interaction with other drugs.
 Drugs may themselves be substrates for a
cytochrome 450 isoenzyme and/or may inhibit
or induce the isoenzyme.
 if a drug is metabolized primarily by a single
cytochrome 450 isoenzyme, inhibition or
induction of this enzyme would have a major
effect on the plasma concentrations of the drug.
3. Drug Metabolism

INDUCERS
 An agent that causes the liver (or other target
organ) to produce more of an enzyme,
leading to increased metabolism of the
substrates.

 No more intrinsically active than otherwise;

there is just more of it.
 3. Drug Metabolism

 In the concept of enzymatic stimulation, which

is being considered for 3A4, the enzyme is
rendered more efficient, aside from its
quantity in the liver and/or gut.
Example 1:
Carbamazepine Is Added to Haloperidol
 Carbamazepine induces 3A4, 1A2, and phase
II glucuronidation, and haloperidol is
metabolized by 3A4, 2D6, 1A2, and phase II
glucuronidation.
3. Drug Metabolism
 This increase in the availableamounts of 3A4
and 1A2 (and possibly particular UGTs as
well) leads to more efficient metabolism of
the haloperidol and a resulting decrease in
the blood level of haloperidol.

 This may lead to clinical decompensation.

3. Drug Metabolism

 The most powerful enzyme inducers in clinical use are the

antibiotic rifampicin and antiepileptic agents such as
barbiturates, phenytoin and carbamazepine.

 Some enzyme inducers, notably barbiturates and

carbamazepine, can induce their own metabolism (auto
induction).

 Cigarette smoking, chronic alcohol use and the herbal

preparation St John's wort can also induce drug-
metabolizing enzymes.
3. Drug Metabolism

 Since the process of enzyme induction

requires new protein synthesis, the effect
usually develops over several days or weeks
after starting an enzyme-inducing agent.

 Similarly, the effect generally persists for a

similar period following drug withdrawal
3. Drug Metabolism

 Enzyme-inducing drugs with short half-lives

such as rifampicin will induce metabolism
more rapidly than inducers with longer half-
lives.
 For example,
 phenytoin, because they reach steady-state
concentrations more rapidly.
3. Drug Metabolism

 Enzyme induction usually results in a decreased

pharmacological effect of the affected drug.
 However, if the affected drug has active
metabolites, this may lead to an increased
pharmacological effect.
 The effects of enzyme induction vary
considerably between patients and are
dependent upon age, genetic factors,
concurrent drug treatment and disease state.
3. Drug Metabolism

 Increased CYP activity via induction - less of

an immediate concern than inhibition
because induction occurs gradually rather
than rapidly and generally leads to
compromised therapeutic goals rather than
profound toxicity.
 Enzyme induction does not occur quickly,
usually taking a week or two
3. Drug Metabolism

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.
3. Drug Metabolism

 Once the drugs responsible for induction

are stopped, their effects take an equally
long time to disappear and this can result
in major toxicity.

 Can also increase the activity of phase II

metabolism processes such as
glucuronidation
3. Drug Metabolism

 INHIBITORS
 Enzyme inhibition is responsible for many
clinically significant interactions. Many drugs
act as inhibitors of cytochrome 450 enzymes.
 Concurrent administration of an enzyme
inhibitor leads to reduced metabolism of the
drug.
 Enzyme inhibition appears to be dose
related.
3. Drug Metabolism

 Example 1:

If erythromycin (an inhibitor of CYP3A4) is

taken by a patient being given carbamazepine
(which is extensively metabolized by CYP3A4),
this may lead to toxicity due to higher
concentrations of carbamazepine.
3. Drug Metabolism

Example 2:
Paroxetine Is added to Nortriptyline
 Nortriptyline is a 2D6 substrate, and

paroxetine is a 2D6 inhibitor.

 The addition of paroxetine impairs the ability

of 2D6 to metabolize nortriptyline, leading to

an increase in the blood level of nortriptyline
3. Drug Metabolism

 Effects of enzyme inhibition on drug

metabolism

Inhibition and Pro-drugs

 Pro-drugs require enzyme activation to

produce their effect, hence enzyme inhibition

results in a reduced activity of the drug.

3. Drug Metabolism

 The analgesic effect of codeine results from

its conversion to morphine by CYP2D6,

hence its inhibition decreases codeine’s
therapeutic effect.
4.Elimination

Drug interactions by elimination employs different

mechanisms, such as :
 Competition at active transport sites,

 Alterations in Glomerular Filtration,

 Passive renal tubular reabsorption

 Active secretion

 Urinary pH.
4. Elimination
Glomerular Filtration Rate
 Rates of glomerular filtration can be affected by changes in renal
blood flow, cardiac output, and extent of protein binding.
 With highly protein-bound drugs (e.g., >80%), a significant
increase in the unbound fraction can lead to an increase in
glomerular filtration and subsequent increased drug elimination.
 Conversely, with transporter saturation and renal elimination at
maximal, elimination rates may decrease significantly with
increased free drug.
4. Elimination

1. Changes in urinary pH:

 As with drug absorption in the gut, passive
reabsorption of drugs depends on the extent
to which the drug exists in the non-ionized
lipid-soluble form.

 Only the non-ionized form is lipid soluble and

able to diffuse back through the tubular cell
membrane.
4. Elimination

Alkaline pH and weakly acidic drugs:

 Thus, at alkaline pH, weakly acidic drugs (pKa

3.0–7.5) largely exist as ionized lipid-insoluble
molecules which are unable to diffuse into
the tubule cells and will therefore be lost in
the urine.
 The renal clearance of these drugs is
increased if the urine is made more alkaline.
4. Elimination

Acidic urine and weakly basic drugs:

 At acidic pH, weakly basic drugs largely exist
as ionized lipid insoluble form, thus
increasing their clearance.

 Strong acids and bases are virtually

completely ionized over the physiological
range of urinary pH and their clearance is
unaffected by pH changes.
4. Elimination

 This mechanism of interaction is of very

minor clinical significance because most
weak acids and bases are inactivated by
hepatic metabolism rather than renal
excretion.

 Urine alkalinisation or acidification has been

used as a means of increasing drug
elimination in poisoning with salicylates and
amphetamines, respectively.
4. Elimination

2. Changes in active renal tubule excretion:

 Drugs that use the same active transport
system in the kidney tubules can compete
with one another for excretion.
 Such competition between drugs can be used
to therapeutic advantage.
For Example:
 Probenecid may be given to increase the
plasma concentration of penicillins by
delaying renal excretion.
4.Elimination

 Probenecid inhibits the renal secretion of

many other anionic drugs via organic anion
transporters.
 Increased methotrexate toxicity, sometimes
life-threatening, has been seen in some
patients concurrently treated with salicylates
and some other non-steroidal anti-
inflammatory drugs (NSAIDs) (due to
decreased renal clearance) and PPIs delay
MTX clearance via transport protein inhibition.
4. Elimination

3. Changes in renal blood flow:

Blood flow through the kidney is partially
controlled by the production of renal
vasodilatory prostaglandins.
 Lithium and indomethacin:
Synthesis of prostaglandins is inhibited by
drugs such as indomethacin, the renal
excretion of lithium is reduced with a
subsequent rise in plasma level.
4. Elimination

4. Biliary excretion and the enterohepatic

shunt:
 A number of drugs are excreted in the bile,
either unchanged or conjugated, for
example, as the glucuronide. Some of the
conjugates are metabolized to the parent
compound by the gut flora and are then
reabsorbed.
4. Elimination

 This recycling process prolongs the stay of

the drug within the body but if the gut flora
are diminished by the presence of an
antibacterial, the drug is not recycled and is
lost more quickly.
 This mechanism has been postulated as the
basis of an interaction between broad-
spectrum antibiotics and oral
contraceptives.
4. Elimination

 Antibiotics may reduce the enterohepatic

circulation of ethinyloestradiol conjugates,
leading to reduced circulating oestrogen
levels with the potential for therapeutic
failure.
4.Elimination

Drug transport protein:

 Drugs and endogenous substances are now known to
cross biological membranes not just by passive
diffusion but by carrier-mediated processes, often
known as transporters.

 Significant advances in the identification of various

transporters have been made and although their
contribution to drug interactions is not yet clear, they
are now thought to play a role in many interactions
formerly attributed to cytochrome 450 enzymes.
4. Elimination

 P-glycoprotein (P-gp) is a large cell

membrane protein that is responsible for the
transport of many substrates, including
drugs.

 P-glycoprotein is found in high levels in

various tissues including the renal proximal
tubule, hepatocytes, intestinal mucosa, the
pancreas and the blood–brain barrier.
4. Elimination

 The pumping actions of P-glycoprotein can

be induced or inhibited by some drugs.

 For example, concomitant administration of

digoxin and verapamil, a P-glycoprotein
inhibitor, is associated with increased digoxin
levels with the potential for digoxin toxicity.
Pharmacodynamic interactions

 These interactions generally involve

 additive,
 synergistic or
 antagonistic effects of drugs acting on the
same receptors or physiological systems.

 Pharmacodynamic interactions are common

but not always recognized.
Pharmacodynamic interactions

 Sometimes these interactions involve

competition for specific receptor sites but
often they are indirect and involve
interference with physiological systems.

 They are much less easy to classify than

interactions with a pharmacokinetic basis.
Pharmacodynamic interactions

 Potentiation
Potentiation occurs when two drugs are taken
together and one of them intensifies the action
of the other. This could be expressed by a +b= B.
As an example, Promethazine, Phenergan(R),
an antihistamine, when given with a painkilling
narcotic such as Meperidine Demerol(R)
intensifies its effect, there by cutting down on
the amount of the narcotic needed.
Pharmacodynamic interaction

 Synergism
Synergism is similar to potentiation. If two drugs
are taken together that are similar in action, such
as barbiturates and alcohol, which are both
depressants, an effect exaggerated out of
proportion to that of each drug taken separately
at the given dose may occur. This could be
expressed by 1+1= 5. An example might be a
person taking a dose of alcohol and a dose of a
barbiturate.
Pharmacodynamic interaction

 Additive Effect
Additive effect is the term used when two or
more drugs are taken at the same time and the
action of one plus the action of the other
results in an action as if just one drug had been
given. This could be represented by 1+1= 2. An
example would be a barbiturate and a
tranquilizer given together before surgery to
relax the patient.
Pharmacodynamic interaction

1. Additive or synergistic interactions

 If two drugs with similar pharmacological effects
are given together, the effects can be additive.
Although not strictly drug interactions, the
mechanism frequently contributes to ADR.
 For example:
I. the concurrent use of drugs with CNS depressant
effects such as antidepressants, hypnotics,
antiepileptics and antihistamines may lead to
excessive drowsiness, yet such combinations are
frequently encountered.
Pharmacodynamic interactions

ii. Platelet-related interactions:

It is generally known that simultaneous administration
of NSAIDs increases the COX-1-mediated inhibition of
thromboxane synthesis and hence the risk of
gastrointestinal bleeding in a synergistic manner.

iii.Drugs with arrhythmogenic potential:

Combinations of drugs with arrhythmogenic potential
such as antiarrhythmics, neuroleptics, tricyclic
antidepressants and those producing electrolyte
imbalance (e.g. diuretics) may lead to ventricular
arrhythmias and should be avoided.
Pharmacodynamic interactions

iv.Nephrotoxicity with synergism:

Likewise the simultaneous use of two
nephrotoxic drugs can aggravate renal
damage, where the dose of either drug may
have been insufficient to produce toxicity -
Amphotericin and pentamidine administered
concomitantly result in nephrotoxicity.
Pharmacodynamic interactions

v. Bone marrow suppression with synergism:

 Gancyclovir and Zidovudine given together
increase the risk of bone marrow depression.
vi. Hyperkalemia:
The simultaneous prescription of potassium
supplements to patients already on
spironolactone or triamtrene and those on ACE
inhibitors leads frequently to severe hyperkalemia.
Pharmacodynamic interactions

2. Antagonistic interactions:
 It is to be expected that a drug with an
agonist action at a particular receptor type
will interact with antagonists at that receptor.
 For example,
i. the bronchodilator action of a selective β2-
adrenoreceptor agonist such as salbutamol
will be antagonized by β-adrenoreceptor
antagonists.
Pharmacodynamic interactions

 There are numerous examples of interactions

occurring at receptor sites, many of which are
used to therapeutic advantage.
 Specific antagonists may be used to reverse
the effect of another drug at receptor sites;
ii. Examples include the opioid antagonist
naloxone and
iii. the benzodiazepine antagonist
flumazenil.
Pharmacodynamic interactions

iv. Acetaminophen overdoses may be treated

with a drug called acetylcysteine, which
prevents the toxic effect on the liver by
eliminating toxic metabolites (breakdown
products) of acetaminophen.

Antagonistic drug interactions are often

unwanted, for example, caffeine may reduce
the effect of sleep aids.
Pharmacodynamic interactions

 Antihypertensive medication is likely to be

less effective when taken with many herbal
weight loss products.
 These products often contain the stimulant
bitter orange (synephrine) and various forms
of caffeine such as guarana, which can
increase blood pressure.
Pharmaceutical drug interactions

 This type of interaction can occur during the

formulation of an active drug substance.

 During the addition of the drugs to existing

formulations (eg. Additives to intravenous
fluids), or
 simply during storage of a formulation in a
plastic containers.
Pharmaceutical drug interactions

Pharmaceutical drug interactions can be

divided in to chemical and physical reactions.

1. Chemical Drug-Drug Interaction:

An example of a chemical reaction is the

incompatibility of potassium phosphate and
calcium chloride in total parenteral nutrition
preparations, also known as TPNs.
Pharmaceutical drug interactions

 The two drugs may interact to form calcium

phosphate, which will result in a precipitate
(“snow”) in the intravenous (IV) fluid bag.

 Two commonly used anticonvulsant drugs,

Phenytoin and Lorazepam, become
ineffective if mixed together in the same IV
bag or syringe.
Pharmaceutical drug interactions

2. Physical Drug-Drug Interaction:

One drug can alter the formulation of another

drug, such as the combination of diazepam
with the emulsion propofol. Diazepam
destabilizes the propofol emulsion, causing it
to “oil out” and making it dangerous to
administer intravenously.
Pharmaceutical drug interactions

 Environmental conditions can adversely

affect drugs.

 Light can cause some drugs to degrade and

become less effective. This is why medicine
bottles are usually amber or opaque.
 Humidity can have a similar effect on drugs.
Management of Drug Interactions

 The pharmacist, along with the prescriber has

a duty to ensure that patients are aware of
the risk of side effects and a suitable course
of action should they occur.
 With their detailed knowledge of medicine,
pharmacists have the ability to relate
unexpected symptoms experienced by
patients to possible adverse effects of their
drug therapy.
Management of Drug Interactions

 Avoiding the combination entirely:

For some drug interactions, the risk always
outweighs the benefits, and the combination
should be avoided. Because drug classes are
usually heterogeneous with regard to drug
interactions, one can often select a no
interacting alternative for either the object
drug or the precipitant drug.
Management of Drug Interactions

 Adjusting the dose of the object drug:

Sometimes, it is possible to give the two
interacting drugs safely as long as the dose of
the object drug is adjusted.
Management of Drug Interactions

 Spacing dosing times to avoid the

interaction:
For some drug interactions involving binding in
the gastrointestinal tract, to avoid the
interaction one can give the object drug at least
2 h before or 4 h after the precipitant drug.
In this way, the object drug can be absorbed
into the circulation before the precipitant drug
appears.
Management of Drug Interactions

 Monitoring for early detection:

In some cases, when it is necessary to
administer interacting drug combinations, the
interaction can be managed through close
laboratory or clinical monitoring for the
evidence of the interaction.
In this way, the appropriate dosage changes
can be made, or the drugs discontinued if
necessary.
Management of Drug Interactions

 Provide information on patient risk factors that

increases the chance of an adverse outcome:
Clinical experience and literature evidences suggest
that most patients who take interacting drug
combinations do not manifest adverse consequences.
The risk of statin-induced myopathy increases with
increasing serum concentrations of the statin.
Accordingly, it has been recommended that
simvastatin should not exceed 20 mg daily in patients
receiving verapamil concurrently.
Management of Drug Interactions

 Improve computerized screening systems:

It is clear that computerized drug interaction
screening systems have not been as successful as
one hoped.
 Excessive number of drug interactions on the
systems:
Many pharmacists find that computerized drug
interaction screening systems detect a large
number of DDIs of questionable clinical
significance.
Drug class differences not handled
correctly

Almost all drug classes interaction seems heterogeneous with

in the class
 A good example, because simvastatin and lovastatin are
extensively metabolized by CYP3A4, atorvastatin is
moderately metabolized by CYP3A4, fluvastatin is
metabolized by CYP2C9, and pravastatin and rosuvastatin
are not metabolized by cytochrome P450 isozymes.
 Thus, combining all members of this drug class together
is rarely justified when considering drug interactions.
Drug class differences not handled
correctly
 Nonetheless, it is common for reviews and
computer systems to include all statins
together as interacting with CYP3A4
inhibitors, even though the risk is primarily
limited to lovastatin, simvastatin, and to a
lesser extent, atorvastatin.
Case Study

 Mrs. C is a 62-year-old woman with a history

of hypertension, atrial fibrillation and type 2
diabetes. She is a non-smoker and obese. Her
current medication comprises flecainide 100
mg twice a day, aspirin 75 mg daily,
simvastatin 40 mg and diltiazem 180mg daily.
Mrs. C is suffering from a respiratory tract
infection and her primary care doctor has
prescribed a 5-day course of clarithromycin.
Case Study

 Questions:

1. Are there likely to be any clinically significant

drug interactions?
2. What advice do you give?
Case Study
 Answers:
1. There is potential for interaction between simvastatin
and diltiazem and between simvastatin and
clarithromycin. Some statins, particularly simvastatin
and atorvastatin, are metabolized by cytochrome
P450 (CYP3A4) and co-administration of potent
inhibitors of this enzyme may particularly increase
plasma levels of these statins and so increase the risk
of dose-related side effects, including rhabdomyolysis.
Clarithromycin is a potent inhibitor of CYP3A4 and
diltiazem is a less potent inhibitor.
Case Study

2. Current advice is that diltiazem and simvastatin may

be given together provided the simvastatin dose
does not exceed 40 mg daily, so it is reasonable for
this therapy to be continued. However,
clarithromycin should not be given together with
simvastatin. Myopathy and rhabdomyolysis have
been reported in patients taking the combination.
Mrs. C should be advised not to take her simvastatin
while she is taking clarithromycin and to start taking
it again after she has completed the course of
antibiotic.
Case Study 2

A 19-year-old woman is on long-term treatment

with minocycline 100 mg daily for acne. She wishes
to start using the combined oral contraceptive and
her doctor has prescribed a low-strength pill
(containing ethinyloestradiol 20 μcg with
norethisterone 1 mg).
The doctor contacts the pharmacist for advice on
whether the tetracycline will interfere with the
efficacy of the oral contraceptive.
Case Study 2

Question:
Is there a clinically significant
interaction in this situation?
Case Study 2

 Answer:
Contraceptive failure has been attributed to
doxycycline, lymecycline, oxytetracycline,
minocycline and tetracycline in about 40
reported cases, seven of which specified long-
term antibacterial use. There is controversy
about whether or not a drug interaction occurs
but if there is one it appears to be very rare.
Case Study 2

 Controlled trials have not shown any effect of

tetracycline or doxycycline on contraceptive
steroid levels. The postulated mechanism is
suppression of intestinal bacteria resulting in
a fall in enterohepatic recirculation of
ethinyloestradiol. Overall, there is no
evidence that this is clinically important.
Case Study 2

 In the case of long-term use of tetracycline's

for acne, a small number of cases of
contraceptive failure have been reported.
Nevertheless, the only well-designed, case–
control study in dermatological practice
indicated that the incidence of contraceptive
failure due to this interaction could not be
distinguished from the general and
recognized failure rate of oral contraceptives.
Case Study 2

 The UK Family Planning Association advises

that women on long-term antibiotic therapy
need only take extra precautions for the first
3 weeks of oral contraceptive use because,
after about 2 weeks, the gut flora becomes
resistant to the antibiotic. In addition, there is
some evidence that ethinyloestradiol may
accentuate the facial pigmentation that can
be caused by minocycline.