DRUG INTERACTIONS

MSC TID 1
Nyakundi BM
April 21st 2010
 Definition

• A drug interaction is defined as a

measurable ( modification in magnitude or
duration) of the action of one drug by prior
or concomitant administration of another
substance (including prescription and non
prescription drugs,food or alcohol)
• 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 and 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),Ethanol
(acute),Fluconazole
(3A4),Grapefruit(3A4),Isoniazid(2E1),Itraconazol
e(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),Tobacco 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