DRUG INTERACTIONS

Dr.Kawooya Francis,Pharm.D
 Definition
 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.

 Interactions can occur by pharmacokinetic or pharmacodynamic mechanisms

Effects of drug interactions

 These can be desirable, adverse or inconsequential.

 Majority of drug interactions are desirable or inconsequential.
 Clinically desirable drug interactions can form part of therapeutic
regimens when two or more drugs with different (e.g to lower
elevated blood pressure.)
Index drug

 When describing adverse drug interactions,

the term index drug is used for the drug
which has its effects cancelled or enhanced
by the interacting drug.Occasionally two
drugs interact with each other to cause
different adverse effects. In such cases , both
drugs are index and both are interacting- a
double adverse drug reaction is the result.
Clinically detectable interactions

 Potential adverse interactions vs clinically detectable adverse drug

interactions;
 Potential adverse interactions occur frequently but clinically detectable
adverse drug interactions occur quite infrequently.
 Why? Because 1.Many interactions lead to small effects on the index drug
and for most index drugs these are clinically unimportant. Example-
Interaction between acetaminophen and isoniazid;
 Isoniazid given 300mgs/ day for 7 days inhibits the microsomal oxidation
of acetaminophen by 70%.However because oxidative metabolism
represents only a minor component of the overall elimination of
acetaminophen,this resulted in only 15% decrease in the total body
clearance of acetaminophen,equivalent to increasing dose of
acetaminophen by 18% a clinically undetectable effect.
 2.Many drugs have a wide therapeutic index. Eg penicillin ,interactions
leading to 2 or 3 fold change in drug concentration may not lead to
adverse effects in most situations
Drug interaction mechanisms

 Mechanisms of drug interactions-pharmacokinetic

and pharmacodynamic.
 Pharmacokinetic
 1.Chemical interactions
 2.Interactions affecting oral availability
 3.Protein binding interactions.
 4.Interactions due to altered biotransformation
 5.Interactions due to altered renal excretion.
Chemical Interactions

 Drugs can react physically or chemically with each other

before they are administered to the patient or in case of
oral preparations before they are absorbed.
 Mixing of drugs before parenteral administration may
cause interaction and thereby and significantly decrease the
activity of one or both drugs.
 Chemical interactions are very unlikely to occur once
drugs reach systmic circulation because the concentrations
in plasma are low.
 Example-oral tetracycline chelates the cations
calcium,magnesium,aluminium or iron resulting in a
cation-tetracycline complex that cannot be absorbed
 Also cholestyramine and colestipol bind some anionic
drugs and decrease their absorption.
Interactions affecting oral
availability
 This can be divided into interactions affecting
gastric emptying,drug absorption and
presystemic elimination.
 1.Gastric emptying-rate of gastric emptying is
important when a rapid onset of effect of the
drug is desired. Eg in rapid relief from pain or
onset of sedation is needed and parenteral drug
administration is not possible.
 What to be done- take drug on an empty stomach
with at least 200cc of water and remain in
upright position.
Gastric emptying

 Slowed gastric emptying occurs in;

 Food, recumbency ,autonomic neuropathy,heavy exercise,
drugs eg antacids, anticholinergic drugs and narcotics
 Enhanced gastric emptying occurs in ;
 Drug administration eg metoclopramide,cisapride,
domperidone.
 This results in earlier and higher peak concentrations of the
index drug.
 Nb- for drugs that are inactivated in the acid milieu of the
stomach eg levodopa and penicillin G ,increased gastric
emptying will lead to increased bioavailability.Increased rate
of GI transit eg in short bowel syndrome,will decrease
absorption of drugs with low dissolution rates or drugs that are
very poorly absorbed(griseofulvin or enteric coated tablets)
Drug absorption

 Most drugs are absorbed in the small intestine by passive

diffusion
 Some drugs eg oral neomycin,antineoplastic drugs can damage
the intestinal absorptive surface and potentially result in
decreased absorption of other drugs ( especially those in which
drug absorption is incomplete)
Presytemic elimination

 Drugs have the capacity to be absorbed, metabolised or

extracted during transit across the intestinal epithelium into
the portal circulation and during the first pass through the
liver.This is phenomenon is called presystemic elimination or
First pass effect effect.Drugs subject to significant presystemic
elimination and consequently low bioavailability include
propranolol, metoprolol,
chlopromazine,labetalol,amitriptyline,imipramine,felodipine
and morphine.These drugs can compete with each hence
increasing each others bioavailability eg chlopromazine and
propranolol.
 Components of the grape fruit juice can increase
bioavailability of drugs that are substrates of the cytochrome
p450 Isoenzyme ,CYP 3A eg felodipine and cyclosporin.This
occurs by inhibition of the intestinal CYP 3A4 by grape juice
components
Protein binding interactions.

 Drugs that are highly bound in plasma are potentially

subject to displacement from their carrier proteins by
another drug with affinity for the same protein.
 When another highly bound drug is
added,competitive displacement may occur,resulting
in a transient increase in free concentration of the
index drug.
 This is then followed by rapid redistribution of the
index drug,transient increase in the rate of elimination
creating anew equilibrium for both drugs
 This displacement is only likely to cause a clinically
significant effect if the index drug has a small volume
of distribution,narrow therapeutic index and rapid
onset of action.
Interactions due to altered
biotransformation
 Drug metabolism most often occurs in the liver and
involves the conversion of an active non polar drug to
more polar metabolites(- generally less active or inactive)
that are cleared by the kidneys.
 Ocassionally metabolites are pharmacologically active in
ways that are similar or disimilar (including toxicity) to the
progenitor drug.
 Drugs that are extensively metabolized are particularly
susceptible to interactions affecting drug metabolism.
 Most drugs are metabolized by several different pathways,
making prediction of the consequences of metabolic
interactions difficult.
Interactions involving enzyme
inhibition
 Many drugs have the potential to inhibit the metabolism of
other drugs
 A clinically significant interaction may result and is dependent
on 1. the magnitude of decrease in clearance and 2.the
consequences of the resulting increase in the steady-state
serum concentration of the index drug.
 Most clinically significant interactions of this type involve the
hepatic microsomal oxidative enzymes that can be divided
into separate P450 isoenzymes.,eg 1A ,2B, 2C, 2D,2E, and
3A.
 Information regarding the predominant isoenzymes involved
in the metabolism of a drug and whether a microsomal
enzyme inhibitor specifically inhibits a particular isoenzyme is
useful in understanding and predicting this type of drug
interaction.
Enzyme inhibition, cont

 The magnitude of inhibition effect in an individual is variable

because it depends on the specific enzyme or enzymes
inhibited and the quantitative importance of that pathway in
overall clearance of the index drug.
 example;-isoniazid is a potent inhibitor of the microsomal
oxidation of both carbamazepine and acetaminophen.
 With acetaminophen,conjugative metabolic pathways (type 2)
predominate,resulting in a clinically insignificant 15%
decrease in total plasma clearance of acetaminophen.
 With carbamazepine,oxidative metabolic pathways (Type 1)
predominate and isoniazid inhibits total plasma clearance by
45%.This results in increase in steady state serum
concentration of 85% and a significant risk of toxic effects.
Mechanism of enzyme inhibition

 This varies from competitive inhibition to

irreversible inactivation.
 Irreversible inactivation leads to the longest
lasting effects.
 The time course of the change in serum
concentration of an index drug affected by an
inhibitory interacting drug is dependent on the
new half life of the index drug-needing 4-5 t1/2s
to reach a new steady state.
Unpredictability of interactions

 Many microsomal inhibitors also have the capacity to induce

microsomal enzymes.
 Therefore depending on the dose, timing or patient settings,
inhibition or induction can be seen.
 Examples –ethanol and isoniazid.
Interactions involving enzyme
induction
 The microsomal enzyme systems in the liver and
other tissues can be induced severalfold by many
drugs and chemicals.
 Enzyme induction occurs by a number of different
mechanisms,but generally leads to increased amounts
of the enzyme and consequently, an increase in the
highest rate (Vmax) of the biotransformation reaction.
 The time course for induction is usually longer than
inhibition and may take 2-3 weeks to become
maximal in humans.
 Inducing agents can be classified as per the specific
P450 isoenzymes induced.
Effects of enzyme induction

 Enzyme induction can enhance the metabolism of the

inducing agent-(auto induction) and/or a variety of other
drugs and some endogenous compounds eg thyroxine
,cortisol and bilirubin.
 Induction can be associated with marked increases in the
clearance of the index drug ,resulting in loss of efficacy.
 Examples;Rifampicin has been implicated as a cause of 1.
graft rejection in patients receiving adequate doses of
prednisone and cyclosporin 2.Failure of effect of oral
contaceptives.
 Example;In patients who are following a methadone
maintenance program,introduction of phenytoin has
precipitated withdrawal symptoms.
Effect of enzyme induction

 If the induction interaction is recognized,the dose

of the index drug can be increased accordingly.
 If the inducing agent is later stopped,the index
drug may have to be reduced to prevent toxicity.
 In some cases,induction of metabolism can result
in increased formation of a toxic metabolite with
serious consequences.
 Example;Administration of isoniazid may
increase the risk of acetaminophen induced
hepatotoxicity by increasing theformation of the
toxic metabolite of acetaminophen.
Agents that alter microsomal
enzyme activity
 Examples of inhibitors
 Ciprofloxacin(1A2),Erythromycin(3A4),Etha
nol (acute),Fluconazole
(3A4),Grapefruit(3A4),Isoniazid(2E1),Itraco
nazole(3A4),Ketoconazole(3A4),Oral
contraceptives,verapamil.
 Examples of Inducers
 Barbiturates(phenobarbital)(2B),Charcoal
broiled
food(1A2),Dexamethasone,Isoniazid(2E1)
Ethanol(chronic)
(2E1),Rifampicin(3A4),Rifabutin(3A4),Toba
cco smoke(1A2)
Interactions due to altered renal
excretion
 Elimination interactions can occur when drugs interfere
with Blood flow to the kidney,active tubular secretion and
kidney tubular fluid Ph.
 Renal blood flow and hence GFR is controlled partially by
renal vasodilatory prostaglandins.If the synthesis of these
prostaglandins is reduced by eg indomethacin,renal
excretion of lithium is reduced with increased lithium
serum concentrations.
 (Mechanism of action of above is not very clear as Aspirin,
a potent prostaglandin synthetase inhibitor, has no effect
on lithium concentrations.)
 Also the clearance of drugs that are excreted entirely by
glomerular filtration are unlikely to be affected by other
drugs.
Altered renal excretion cont.

 In Active Renal tubular secretion,drugs that use

the same active transport system in the kidney
can compete with one another for excretion.
 Example; Probenecid given to increase plasma
penicillin levels by delaying excretion.
 This interaction can also lead to toxicity eg
methotrexate toxicity can be caused by inhibition
of its tubular secretion by salicylate.
Altered renal excretion cont.

 Kidney tubular fluid pH- As with the gut, passive

reabsorption of drugs depends on the extent to which the
drug stays in the non ionized, lipid soluble form.
 Only the non ionized drug is lipid soluble and able to
diffuse back.At alkaline Ph, weak acids exist in the ionized
state and will be excreted.Renal clearance is increased if
the urine is more alkaline.Also at acidic Ph, weak bases
will be excreted.
 Urine acidification causes increased amphetamine
excretion in amphetamine poisoning;
 Urine alkalinization causes increased salicylate excretion
in salicylate poisoning
Pharmacodynamic Interactions

 In pharmacodynamic interactions, the effects

of one drug are changed by the 2nd drug at its
site of action.
 Can involve competition for specific sites but
can also be indirect and involve interferance
with physiological systems.
 Examples1.Synergistic/Additive interactions
2.Antagonistic interactions 3.Serotonin
syndrome 4.Drug or neurotransmitter uptake
interactions
Synergistic interactions

 Occur when 2 drugs with similar pharmacological

effects are given together.
 Examples-antidepresants,antiepileptics,antihistamines
when given together lead to excessive drowsiness.
 Example- Drugs with arrythmogenic potential eg
antiarrythmics,neuroleptics,tricyclic antidepressants
and those producing electrolyte imbalances eg
diuretics can lead to ventricular arrthymias and
should be avoided.
Antagonistic Interactions

 This occurs when a drug with agonist action at a particular

receptor site interacts with an antagonist at that site.
 Example;-Beta 2 selective drug salbutamol antagonized by
non selective Beta drug propranolol.
 Example;- Specific antagonists may be used to reverse the
effect of another drug at a specific receptor site eg opioid
antagonist-Naloxone, Benzodiazepine antagonist-
Flumazenil
 Also alpha adrenergic agonists eg metaraminol may be
used in management of priapism induced by alpha
adrenergic antagonists eg phentolamine.
Serotonin syndrome

 Associated with excess of serotonin that results from

therapeutic drugs use,overdose or inadvertent interaction
between drugs.It can occur when 2 or more drugs affecting
serotonin are given at the same time, or one serotonergic
drug is stopped and another started.
 Serotonin syndrome includes
confusion,disorientation,abnormal movements,exaggerated
reflexes,fever,sweating, diarhea,hypotension/hypertension.
 Three or more of the above symptoms are neededto make
a diagnosis when no other cause is seen.
Unrecognized drug interactions

 An interaction can occur and likely to go

unnoticed like when the interacting drug
diminishes the effectiveness of the index drug.
 When a patient takes many drugs,the clinician
may have a difficult task in establishing
continued efficacy and necessity of each
agent.One drug can readily cancel the
effectiveness of another.
 To establish ongoing effectiveness of a drug as
part of a multiple drug regimen, one can stop the
drug in question and to reassess the patient
carefully over time
Drug or Neurotransmitter uptake
interactions
 MAOIs have potential for interactions with other drugs and food.
 Food- drug interactions with irreversible MAOIs are the result of inhibition of
presystemic elimination of tyramine present in various foods.
 The non selective MAOIs eg phenelzine and tranylcypromine inhibit MAO A
in the intestinal wall and liver.This leads to increased oral bioavailability of
tyramine which is not completely metabolized during absorption and the first
pass through the liver.
 When tyramine reaches the systemic circulation,it can cause increased release
of noradrenaline from sympathetic postganglionic neurones.
 POTENTIALLY FATAL HYPERTENSIVE CRISES CAN OCCUR
 In this sympathetic overactivity syndrome, there is hypertension ,headache,
cardiac arrythmias, hyperpyrexia and excitement.Fatal intracranial
hemorrhages and cardiac arrests can also occur.
 The risk of interactions continues for several weeks as new MAOI has to be
synthesized
Interactions involving
unknown/multiple mechanisms
 Many drug – drug interactions involve more
than one mechanism.
 Example –quinidine-digoxin
interaction;when quinidine is given to
patients receiving digoxin,two to three fold
increase in steady state levels of digoxin
occurs.Various mechanisms involved may be
explained by the inhibition of the p-
glycoprotein efflux transporter by quinidine.
Unrecognized drug interactions

 In the late 1990s 16 deaths occurred in

japanese cancer patients being treated for
herpes zoster infection with the new antiviral
drug sorivudine.These patients were taking 5
fluorouracil or other fluoropyrimidine
antineoplastic drugs.
 Sorivudine is a potent inhibitor of
dihydropyrimidine dehydrogenase- the
enzyme responsible for inactivation of
fluoropyrimidines.
 For many new drugs, potential drug
interactions are being predicted and tested
during development
Unrecognized drug interactions

 Dysrythmias can occur young healthy individuals

taking erythromycin ( or ketoconazole) with
terfenadine- a non sedating antihistamine.
 The mechanism of this interation is the inhibition
of the metabolism of terfenadine (CYP3A4) by
erythromycin or ketoconazole causing increased
steady state concentrations of terfenadine, a drug
that can prolong coduction in the heart and cause
the potentially lethal dysrtythmia torsardes des
pointes.
High Risk Clinical Setting

 Physicians may not know or recall ALL the

documented or potential interactions.Since the risk is
small in most clinical settings,the astute clinician can
reduce the risk to the patient by being aware of the
clinical settings in which the risk of adverse drug
interactions is increased.
 These include 1.Index drugs with a narrow
therapeutic index.Care must be taken when adding/
removing a drug in patients taking a drug with a low
toxic/therapeutic ratio.
 Classical example is warfarin.
High risk clinical setting

 Other examples of drugs with narrow therapeutic

index;
 Anticancer drugs-5
fluoruracil,Immunosuppressive drugs-
cyclosporin,antidysrythmic drugs-
quinidine,digitalis glycosides-
digoxin,anticonvulsants- phenytoin,oral
hypoglycemic drugs-glyburide,aminglycosides-
gentamicin and vancomycin,antiretrovirals-
zidovudine,antifungals –amphoterricin
B,Lithium carbonate and Theophylline.
High risk clinical setting

 2.Patients taking many drugs

 As the number of drugs taken increases, the risk of drug
interaction increases disproportionately.
 This increased risk of adverse drug interactions can be from OTC
drugs,topical drugs eg timolol eye drops ,herbal teas.
High risk clinical setting

 3. Critically ill patients;

 These patients have lost their physiological reserve in one or
more systems and often require multiple drugs.
 Examples include patients with renal,
hepatic,respiratory,cardiac or autonomic failure;alzheimers
dementia,myasthenia gravis.
 In this patients, a drug which usually has a wide therapeutic
index when given to a relatively healthy individual may have a
low therapeutic index.
 Opioids may be given safely to healthy patients with a
toothache but not to patients with respiratory failure.
 Deterioration in critically ill patients should increase ones
vigilance and check on interactions.
High risk clinical setting

 4.Patients with HIV

 They have a high incidence of skin reactions to sulphur drugs
than the general population and also at risk of organ failure from
a multitude of infections.
 They also receive large numbers of new and toxic combinations
of drugs.
High risk clinical setting

 5.The passive patient

 Passive patients often do not know the reason for
taking many of their medications.These are the
elderly and psychiatric patients.
 The elderly are also prone to adverse drug
interactions because of a deterioration of
homoestatic mechanisms leading to a lower
margin of safety for many drugs.
 Active patients can sometimes demand that the
benefit /risk ratio of the given drugs to be
substantially in their favour.
High risk clinical setting

 6.Drug abusers
 People who abuse drugs are likely to consume alcohol,
Tobacco,illegal recreational, prescription and OTC drugs often in
large doses.
 They are also frequently erratic in their drug taking behaviours-
hence drug interactions are more likely to result in adverse effects
Prevention of adverse drug
interactions
 The principles include
 1.Document all drugs including herbal prearations,
OTC,recreational drugs that the patient is taking.
 2.Understand the pharmacokinetics and
pharmocodymics of the drugs given ,keeping in mind
the important mechanisms of drug interations.
 3.Minimize the number of drugs given to any patient
and try to ensure that the benefits outweigh the risks
for each.
 4.Be particularly vigilant with patients taking low
therapeutic index drugs.
Prevention of adverse drug
interactions cont.
 5.Be cautious in high risk clinical settings.ICU
specialists need to remember interactions all the time.
 6.Whenever a patients course deteriorates, look out
for a possible adverse drug interaction.IF the
deterioration is due to drug therapy,it probably is
reversible.
 7.Use textbooks of drug interactions or modern
software programs to search for possible drug
induced effects you may not have considered.
 8.Always be vigilant for previously undescribed
interations,particularly when prescribing new or
unfamiliar drugs.
end

 END