DRUG INTERACTIONS

Lecture 1

Dr. Rania Hussein

Fellow, Alexandria University Hospitals
Doctor of public health sciences, HIPH
Pharm D
CPHQ
 Main objective

Enabling the pharmacy students to develop

professional competencies in the recognition of
the pharmacological aspects of drug interactions
and their clinical significance as well as the
application of that knowledge to minimize the
risks and outcomes of these interactions.
 Specific objectives
 Understand the principal mechanisms that cause most common
drug interactions.
 Familiarize students with the major types of drug interactions in
the clinical setting.
 Interpret the clinical significance of various types of drug
interactions.
 Learn how to efficiently access drug interactions information.
 Students will be expected to determine whether a given
interaction is clinically insignificant or required pharmacist
intervention and make scientific recommendations for the
management of drug interactions.
 Definition
Drug interaction is the change in the actions
of a drug as a result of the concurrent or
recent administration of another drug, food,
supplement, or beverage.
Drug interactions are an avoidable cause of
patient harm.

precipitate drug whose purpose i affected by

interaction xrc

object drug
The meta-analysis revealed that 33% of general patients and 67% of
intensive care patients experienced a pDDI during their hospital
stay.
The prevalence of potential drug-drug interactions is high among the
patients on discharge.
Use of drug-drug interactions checker databases before discharge with
computer-based discharge prescriptions is recommended.
Risk Factors contributing to drug interactions
 Multiple drug therapy.
 Multiple [Link] shopping, multiple cormobidity
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 Multiple pharmacological effects of drug.
 Multiple diseases/ predisposing illness.
 Poor patient compliance.
 Age of patient.
 Sex.
 Genetic make up.
 Specific population like obese, critically-ill patient.
 Narrow therapeutic index drugs: Digoxin, Insulin, Lithium , warfarin,
theophylline.
 Drug related factors.
 Types of drug interactions
➢ Drug-drug interactions

➢ Drug -food interactions

➢ Drug-herb interactions

➢ Drug-laboratory test interactions

➢ Drug-disease interactions

➢ Drug-smoking interactions

➢ Drug-alcohol interactions

➢ Drug-Environment Interactions
Classification of drug interactions according to
the mechanism of origin
in vitro outside the body incompatibility
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Pharmaceutical interaction
It occurs when the formulation of one
drug is altered by another before it is
administered.
Examples: alkaline
 Precipitation of sodium thiopentone
and vecuronium within an intravenous
giving [Link]
IV tubing should be thoroughly flushed
after administration of each drug with
NS or glucose.
Pharmaceutical interaction
 Ampicillin, chlorpromazine, barbiturates interact
with dextran in solutions and are broken down.
 Amphotericin precipitates in saline.
 Phenytoin precipitates in dextrose saline.
 Penicillin and aminoglycoside antibiotics inactivate
each other.
 Calcium and ceftriaxone mixed in the same
intravenous solution can cause precipitates. Hence,
ceftriaxone should not be mixed in Ringer’s lactate.
b, pharmacological
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 Pharmacokinetic interactions
 It involves a precipitant drug altering the systemic
concentration of an object drug (ADME interactions).

 These interactions change the magnitude (amount)

and the duration (persistence) of object drug.

 I. Drug absorption interactions
Absorption interactions involve changes in either the rate or
extent of absorption.
In case of long-term drugs for chronic diseases which are taken
as multiple doses, the rate of absorption is unimportant
provided that the total amount of drug is not markedly altered.
A reduction in the rate of absorption (delayed absorption) can
be clinically significant and may result in therapeutic failure
when
 the drug has a short half-life or
 The drug is given as a single dose to be absorbed rapidly,
where a rapidly achieved high plasma concentration is
needed. For example, delayed onset of hypnotic effect of
phenobarbital with antacids.
 I. Drug absorption interactions
The amount of drug that is absorbed to exhibit an effect
is dependent on the bioavailability of the drug.

Oral drugs will have varied bioavailability due to the

extent of first-pass metabolism through the liver,
whereas intravenous drugs will have ? bioavailability as
they bypass the gastrointestinal tract.

Drugs with low oral bioavailability are often affected

while those with high bioavailability are seldom
affected.
 I. Drug absorption interactions
Major mechanisms of absorption interactions:
Alteration in GI pH
Complexation and chelation
Alteration in gut motility
Inhibition or induction of transport
proteins
Alteration of GI microflora
Malabsorption syndrome
 Alteration in GI pH
 The passage of drugs through mucous membranes by

simple passive diffusion depends upon the extent to

which it exists in the non-ionized lipid-soluble form.

 Absorption is therefore governed by pKa of the drug, its

lipid solubility, and the pH of the contents of the gut.

 Rises in pH due to antacids, proton pump inhibitors, H2

receptor antagonists can markedly reduce the absorption

of acidic drugs which are readily absorbed from upper

GIT.
 Alteration in GI pH
weak acid
Examples:
ionised
➢ Atazanavir and omeprazole: Atazanavir AUC ↓ by 94%
➢ Fosamprenavir and omeprazole: absorption is reduced
➢ Raltegravir and omeprazole: Raltegravir AUC ↑ by 3-fold basic
➢ Erlotinib and omeprazole: Erlotinib AUC ↓≈ 50%
Retrospective review of patient records found concurrent treatment
was significantly associated with shorter survival time (12.9m vs. 16.8m)*
➢ A reduction of the protective properties of alendronate with reference
to avoiding hip fractures was observed when PPI were given at the
same time.
➢ Itraconazole and ketoconazole, whereas absorption of fluconazole and
voriconazole is not significantly altered by changes in gastric pH due to
their high bioavailability.
➢ Bisacodyl
➢ Aspirin

*Chu, M. P., et al. (2015). Gastric Acid suppression is associated with decreased erlotinib efficacy in
non-small-cell lung cancer. Clinical lung cancer, 16(1), 33–39.
[Link]
 Adsorption, chelation and complexation
The extent of absorption can be influenced by second drugs that
bind to form insoluble complexes or chelates.
➢ Activated charcoal is an adsorbing agent for the treatment of
drug overdose or other toxic materials, but it can also affect the
absorption of drugs like acetaminophen and citalopram.
➢ Tetracyclines, quinolones, and levothyroxine can chelate with
a number of divalent and trivalent metallic ions such as calcium,
aluminum, bismuth, magnesium, and iron, to form complexes
that are poorly absorbed and with reduced effects (e.g.
aluminum-containing antacids binding with ciprofloxacin).
➢ Cholestyramine binds to some drugs as digoxin, warfarin, and
levothyroxine, thereby reducing their absorption.
➢ Bisphosphonates used in osteoporosis, such as alendronate, have
a very low bioavailability of only 0.5% to 2%. Calcium ions may
reduce this markedly still further.
Alteration in GI motility
 Alteration in GI motility
Drugs with anti-cholinergic effects, such as TCAs, phenothiazines and
some antihistamines decrease gut motility and delay gastric emptying into
the small bowel leading to either an increase or a decrease in absorption
of drugs given concomitantly.
 For example, TCAs can increase dicoumarol absorption, probably as a
result of increasing the time available for its absorption.
 Anti-cholinergic agents reduce the bioavailability of levodopa by 50%
due to increased gastrointestinal transit time due to the reduction of
motility, thereby increasing the gastric degradation of levodopa and
reducing the amount available for absorption in the small intestine .
 Diarrhea and Laxatives decrease absorption of vitamins and nutrients.
 Alteration in GI motility
 Opioids such as diamorphine and pethidine strongly inhibit gastric
emptying and greatly reduce the absorption rate of paracetamol, without
affecting the extent of absorption.

 Metoclopramide increases the GI motility resulting in lesser time for

paracetamol to reach the small intestine (absorption site) and, hence,
producing a quick analgesic effect, an effect which is used as therapeutic
advantage in the treatment of migraine.

It also accelerates the absorption of propranolol, lithium and ciclosporin.

 Metoclopramide with digoxin: decreases the rate and extent of

absorption. metoclopramide is prokinetic increases gastric
empting ,
but digoxin req low gastric emptying,
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Modulation of Drug transport systems
(transport proteins)
in intestinal lumen

 Uptake and efflux transporters in the

gut can be inhibited or induced by
drugs and may ↓ or ↑ bioavailability of
drugs that rely on those proteins.
 Of the many gut transporters, only 2
have been associated with clinical DDIs
P-glycoprotein (P-gp)
Breast cancer resistance protein (BCRP)
Inhibition or induction of transport proteins
in intestinal lumen
Example:
❑ Digoxin requires a transport protein. Verapamil is an inhibitor of P-gp,
thus increasing digoxin toxicity.
❑ Dabigatran co-administration with verapamil increases bioavailability
and can result in an increased risk of bleeding.
❑ P-gp inhibitors can be used with antibiotics and can extend the lifetime
of the antibiotics, improving therapeutic efficacy. These inhibitors
increase bacterial susceptibility to antimicrobial agent by enhancing
their accumulation inside the cell.
Clinical P-gp inhibitors include verapamil, quinidine,
cyclosporine, erythromycin, itraconazole.
• Drugs which induce P-glycoprotein, such as rifampicin, can reduce the
bioavailability of some other drugs as digoxin, decreasing its plasma
levels.
Alteration of GI microflora
Antibiotics can alter the GI flora
necessary for the metabolism of some
drugs:
increased digoxin
 Digoxin + tetracycline
toxicity

 Warfarin + tetracycline reduced warfin due to lack of

vitk

 OCs + tetracycline conjugated ocs increase and not converted tto free
form unconjugated hence theraputic failure
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 Malabsorption syndrome
Alteration of absorption due to drug, food, or nutritional
supplement.
 Neomycin causes malabsorption syndrome and reduces the
absorption of digoxin.
 Orlistat is a specific long-acting inhibitor of gastric and
pancreatic lipases, thereby preventing the hydrolysis of
dietary fat to free fatty acids and triglycerides, leading to
reduced absorption of fat-soluble drugs co-administered
with orlistat.
There has been recent concern about potential decreased
absorption of levothyroxine and anti-epileptic drugs such as
valproate sodium and lamotrigine.
 Drug absorption interactions
Delayed absorption can be clinically
significant with:
 The drug affected has a short half-life,
 When it is important to achieve high plasma
concentrations rapidly, as the case with
analgesics or hypnotics (single dose).
The extent of absorption can be clinically
significant with: drugs with low oral
bioavailability.
Interactions can often be avoided by allowing an
interval of 2–3 h between administration of the
interacting drugs.
 II. Drug distribution interactions
Protein binding interactions
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.
Only unbound molecules are free and pharmacologically active while
those that are bound form a circulating but pharmacologically
inactive reservoir.
Examples of highly protein-bound drugs
are phenytoin (90%), tolbutamide
(96%), and warfarin (99%).
 Drug distribution interactions
 Depending on the concentrations and
their relative affinities for the binding
sites, one drug may compete with
another and displace it.

 A drug that reduces the binding from

99% to 95% would increase the
concentration of free active drug from
? to ? (a ? increase).
 Drug distribution interactions
 Only drugs with a low Vd are affected.
e.g. phenytoin, warfarin, sulfonylureas,
methotrexate, valproate.

 Another important factor is clearance,

clinically important protein binding
interactions are present only if a small
proportion of the drug is eliminated (low
extraction ratio drugs).
 Drug distribution interactions
Example:
A patient is taking phenytoin was given a drug
that displaced it from its binding sites. The
amount of free phenytoin would rise but this
would be quickly eliminated by metabolism and
excretion, thereby keeping the amount of free
active phenytoin the same. However, the total
amount of phenytoin would be reduced.
Therefore, if phenytoin was monitored using an
assay looking at total phenytoin levels, it may
appear to be subtherapeutic and that the dose
needs to be increased. However, as the amount
of active phenytoin is unchanged, this may be
dangerous.
 Drug distribution interactions
Measuring the total concentration of the drug in
the blood might not provide an accurate
representation of its pharmacologically active
form if protein binding is altered.
Reactions are not problematic as drug will fall
rapidly to its steady state concentration due to
metabolism and excretion.
This short-term rise in free drug concentration is
of little clinical significance but is important in
TDM (monitoring of free drug concentrations) in
case of a drug with narrow therapeutic index.
Instances where clinically important consequences do occur on introducing
a drug that displaces another from tissue binding sites are due to additional
actions of the second drug on elimination of the first. For instance,
 Quinidine displaces digoxin from tissue binding sites, and can cause digoxin
toxicity, but only because it simultaneously reduces the renal clearance of
digoxin by a separate mechanism.
 Phenylbutazone (an NSAID currently reserved for ankylosing spondylitis
unresponsive to other drugs) displaces warfarin from binding sites on
albumin, and causes excessive anticoagulation, but only because it also
inhibits the metabolism of the active isomer of warfarin (S-warfarin),
causing this to accumulate at the expense of the inactive isomer.
 Indometacin (NSAID) displaces warfarin from binding sites on albumin but
does not inhibit its metabolism and does not further prolong prothrombin
time in patients treated with warfarin, although it can cause bleeding by
causing peptic ulceration and interfering with platelet function.
 Altered distribution: transport proteins
 Transport proteins play a role in the distribution of drugs to organ systems
protected by blood organ barriers (brain, placenta, kidneys).

 Induction or inhibition can result in altered distribution of the substrate.