PAPER PRESENTATION

ON
DRUG INTERACTIONS

Course title: Pharmacology

Course code: RAD 305

Supervising lecturer:
Mr. Gabriel Kona

Department of Radiography
City university Cambodia

PRESENTER
HASSAN GARBA

2019

Introduction
A drug interaction occurs when a patient’s response to a drug these interactions occur between drugs with
additive or opposing effects. The brain is the organ most commonly compromised by pharmacodynamic
interaction or pharmacokinetic. These interactions generally involve additive, synergistic or antagonistic
effects of drugs acting on the same receptors or physiological systems in terms of absorption, distribution
within the body, metabolism or elimination / excretionThis results in altered plasma concentrations of the
affected drug.
Drug is a chemical substance That brings about change in biological functions through its chemical action
A drug can be said to be substance that is used to diagnose, treat, prevent, or cure a disease condition in
man and animals.

MECHANISMS OF DRUG INTERACTIONS

Drug interactions are usually caused by either pharmacodynamic or pharmacokinetic processes.
Pharmacodynamic interactions: is ‘what the drug does to the body these interactions generally involve
additive, synergistic or antagonistic effects of drugs acting on the same receptors or physiological systems.
Some examples.
The effects of pharmacodynamic interactions can usually be
predicted and managed when the pharmacology of co-administered drugs is known.
Pharmacokinetic interactions is what the body does to the
drug’. These interactions occur when one drug affects the other in terms of its absorption, distribution
within the
body, metabolism or elimination / excretion.
This results in altered plasma concentrations of the affected drug (increased or decreased) or altered
duration of effect (enhanced clearance or accumulation) with the potential for subsequent reduced
efficacy or enhanced toxicity.

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 systemic circulation because the
concentrations in plasma are low.
• Example-oral tetracycline chelates the actions calcium, magnesium, aluminum or iron resulting in
a cation-tetracycline complex that cannot be absorbed

• Also cholestyramine and cholesterol 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, recumbence ,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 microtonal 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 microtonal 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 ,cortisolS 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,

• 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.

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.

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.

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.

Examples

1.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

MAO Is 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

Dysrythmias can occur young healthy individuals taking erythromycin ( or ketoconazole) with
terfenadine- a non sedating antihistamine.

The mechanism of this interaction is the inhibition of the metabolism of terfenadine by erythromycin or
ketoconazole causing increased steady state concentrations of terfenadine, a drug that can prolong
conduction in the heart and cause the potentially lethal dysrtythmia torsardes 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.

Other examples of drugs with narrow therapeutic index;

Anticancer drugs fluorouracil, Immunosuppressive drugs- cyclosporine, antidysrythmic drugs guanidine,

digitalis glycosides dioxin, anticonvulsants phenytoin, oral hypoglycemic drugs-glyburide,
aminglycosides- gentamicin and vancomycin, antiretrovirals- zidovudine, antifungals –amphoterricin B,
Lithium carbonate and Theophylline.

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 e.g timolol eye
drops, and herbal teas.

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 Alzheimer’s
dementia, myasthenia gravis.

In these 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

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.

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 homeostatic
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 favors.

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 preparations, 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 interactions.

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.

5. Be cautious in high risk clinical settings.ICU specialists need to remember interactions all the time.

6. Whenever a patient’s 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.

CONCLUSION
when one medicine falls out with another the outcome can be harmful if the interaction causes an
increase in the toxicity of the drug example, there is a considerable increase in risk of severe muscle
damage if patients on statins start taking azole antifungals monoamine oxidase inhibitor antidepressants
(MAOIs) may experience an acute and potentially. The brain is the organ most commonly compromised
by pharmacodynamic interaction or pharmacokinetic. These interactions generally involve additive,
synergistic or antagonistic effects of drugs acting on the same receptors or physiological systems in terms
of absorption, distribution within the body, metabolism or elimination / excretionThis results in altered
plasma concentrations of the affected drug.
A reduction in efficacy due to an interaction can sometimes be just as
harmful as an increase: patients taking warfarin who are given rifampicin
need more warfarin to maintain adequate and protective anticoagulation

REFFERENCES
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between terbinafine
and amitriptyline. Ther Drug Monit (2005) 27, 680–2.

2. Madani S, Barilla D, Cramer J, Wang Y, Paul C. Effect of terbinafine on the

pharmacokinetics
and pharmacodynamics of desipramine in healthy volunteers identified as
cytochrome P450
2D6 (CYP2D6) extensive metabolizers. J Clin Pharmacol (2002) 42, 1211–18.

3. O’Reardon JP, Hetznecker JM, Rynn MA, Baldassano CF, Szuba MP.
Desipramine toxicity
with terbinafine. Am J Psychiatry (2002) 159, 492. Erratum ibid. 1076.

4. Teitelbaum ML, Pearson VE. Imipramine toxicity and terbinafine. Am J

Psychiatry (2001)
158, 2086.