Drug Interactions 10-08-009

DRUG INTERACTIONS

Dr. J. Vijaya RatnaProfessor

AU College of Pharm. SciencesAndhra University Visakhapatnam.

Contents

Types of Drugs Interactions Mechanisms Clinical significance Drug Interactions in Anaesthetic practice Antihypertensives Female hormones Food-Drug Interactions

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Types of Drug Interactions

1. Pharmacokinetic interactions result due to alteration in the rate of absorption, distribution, metabolism or excretion of drugs. Such a change causes altered duration and intensity of pharmacologic action of drug due to altered plasma concentration of drug.

2. Pharmacodynamic interactions result when medications with synergistic or antagonistic pharmacological effects are combined. When two drugs which exert their effect at the same receptor site are given together a pharmacodynamic interaction will result.

3. Pharmaceutical Interactions: They are physicochemical interactions. When two drugs are administered in combination or in rapid succession a precipitation or some physicochemical change may occur.

DURG – TO – DRUG INTERACTIONS

Drugs interact with food and alcohol and they can also interact with each other. Some drugs are given together on purpose for an added effect, like codeine and acetaminophen for pain relief. But other drug-to-drug interactions are unintended and may be harmful. Prescription drugs can interact with each other or with over-the-counter (OTC) drugs, such as acetaminophen, aspirin, and cold medicine. Likewise, OTC drugs can interact with each other.

Drug Interactions

Sometimes the effect of one drug may be increased or decreased. For example, tricyclic antidepressants such as amitriptyline (ELAVIL), or nortriptyline (PAMELOR) can decrease the ability of clonidine (CATAPRES) to lower blood pressure. In other cases, the effects of a drug can increase the risk of serious side effects. For example, some antifungal medications such as itraconazole (SPORANOX) and ketoconazole (NIZORAL) can interfere with the way some cholesterol-lowering medications are broken down by the body. This can increase the risk of serious side effect.

Drug Interactions

Doctors can often prescribe other medications to reduce the risk of drug-drug interactions. For example, two cholesterol-lowering drugs-pravastatin (PRAVCHOL) and fluvastatin (LESCOL), are less likely to interact with antifungal medications. Be sure to tell your doctor about all medications – prescription and OTC – that you are taking.

Pharmacokinetic Interactions

1. Altered absorption due to alteration ina. Gastrointestinal motility and gastric emplying rate.b. Gastrointestinal florac. pH of the GITd. Free drug available in GIT.

2. Altered Distribution due toa. Competitive displacement or bindingb. Reduced plasma protein levels

Drug Interactions

3. Altered biotransformation due toa. Enzyme inductionb. Enzyme inhibition

4. Altered drug excretion due toa. Competition for tubular transportb. Changes in Urinary pHc. Increased fluid flowd. Fluid and electrolyte imbalances.

I. Absorption : 1. Altered absorption : Absorption may be altered by any one of four

mechanisms. a. Gastric motility and gastric emptying rate may be altered. GI absorption slowed by drugs that inhibit gastric emptying

such as atropine or opiates or accelerated by drugs such as metoclopramide.

2. Alteration of pH : antacids, sodium bicarbonate, calcium carbonate may alter the pH of the GIT and thus alter the absorption of drugs whose absorption is dependent on pH such as iron products, aspirin, NSAIDS.

Drug Interactions

3. Alteration of Gastro intestinal flora : Some antibiotics destroy the gastro intestinal flora and thus prevent the absorption of some other drugs.

4. Free available Drug : Calcium and iron form insoluble complex with tetracycline and retards its absorption

Cholestyramine, a bile acid binding resin used to treat hypercholeterolacemia binds drugs such as warfarin and diogoxin.

Distribution

Distribution of the drug in the body is effected by plasma protein binding and displacement interactions or tissue and cellular interactions

1. Plasma Protein binding and displacement :

Some highly protein bound drugs

1. Salicylates

2. Barbiturates

3. Phenyl butazone

4. Phenyl propionic acids

5. Sulfur and Sulfoxamids

6. Clofibrate

7. Tolbutamide

8. Warfarin

Microsomal Enzyme Inducers

1. Alcohol 6. Phenytoin

2. Chloral hydrate 7. Chlordiazepoxide

3. Cortisone 8. Imipramine

4. Nicotine 9. Phenobarbital

5. Prednisone 10. Testosterone

Microsomal Enzyme Inhibitors

1. Allopurinole 6. Anabolic agents2. Oral antidiabetics 7. Chloramphenicol3. Disulfiram 8. Isonizid4. Metronidazole 9. Monoamine Oxidase

Inhibitors5. Oral anti coagulants 10. Climetidine

Urinary Alkalinizaers

Acetazolamide Diuretics Potassium Citrate Sodium Acetate Sodium Bicarbonate Sodium Citrate

Urinary Acidifiers

p-amino salicylate Ascorbic acid Fatty acids Phenyl butazone Ammonium Chloride Calcium Chloride

List of Some of the Important Pharmacokinetic (ADME) Interaction

Object Drug(s) Precipitant Drug(s) Influence on Object Drug(s)

ABSORPTION INTERACTIONS

1. Complexation and Absorption

tetracycline,penicillamineciprofloxacin,

norfloxacincephalexin,

sulfamethoxazole, trimethroprim,

warfarin and thyroxine

Antacids, food and mineral supplements containing Al, Mg, Fe, Zn, Bi and Ca ions

Antacids containing Al, Mg and Ca and sucralfate

cholestryamine

Formation of poorly soluble and unabsorbable complex with such heavy metal ions

Reduced absorption due to complexation with metal ions

Reduced absorption due to absorption and binding


2. Alteration of GI pH

sulfonamides,aspirinferrous sulfateketoconazole,tetracycline,altenolol

antacidssodium bicarbonate,calcium carbonateantacids

Enhanced dissolution and absorption rate

Decreased dissolution and hence absorption

Decreased dissolution and bioavailability

3. Alteration of Gut Motility

aspirin, diazepam,levodopa, lithiumcarbonate,

paracetamol,mexiletinelevodopa, lithiumcarbonate, mexiletine

metoclopramideanticholinergics(antropine, homatropine)

rapid gastric emptying;increased rate of absorptiondelayed gastric emptying;decreased rate of absorption

4. Inhibition of GI Enzymes (see metabolism interactions)

5. Alteration of GI Microflora

digoxin antibiotics(erythromycin,Tetracycline)

increased bioavailabilitydue to destruction of bacterial

flora that inactivates digoxin in lower intestine

PHARMACOKINETIC DRUG INTERACTIONS


oral contraceptives antibiotics(ampicillin)

decreased reabsorption of drugs secreted as conjugates via bile in the intestine

6. Malabsorption Syndrome

vitamin A, B12, digocin

neomycin (and colchicines)

Inhibition of absorption due to malabsorption/steatorrhea caused by neomycin

DISTRIBUTION INTERACTIONS(resulting from altered P-D binding)1. Competitive Displacement InteractionsDisplaced drug(s) Displacer(s)

phenylbutazone,chloral hydrate,salicylatessulfonamidessulfonamides,salicylic acidvalproic acid

increased clotting time;increased risk of hemorrhageincreased hypoglycemic effectincreased methotrexatetoxicityphenytoin toxicity

METABOLISM INTERACTIONS

1. Enzyme Induction

corticosteroids,oral contraceptives,coumarins, phenytoin, tolbutamide, tricyclicscorticosteroids, oralcontraceptivestheophylline,

cyclosporinoral contraceptives,

oral hypoglycemics, cumarins

antibiotics(erythromycin,Tetracycline)phenytoinrifampicin

increased bioavailabilitydue to destruction of bacterial

flora that inactivates digoxin in lower intestine

-do--do-


2. Enzyme Inhibition

tetracycline, rich food(cheese, liver,yeast products)folic acidtricyclic antidepressantscoumarinsoral hypoglycemicsalcoholazathiporine,mercaptopurinealcohol,

MAO inhibitors (phenelzine, pargyline, etc.)

phenytoinchlorpromazine, haloperidolmetronidazole,phenylbutazone

enhanced absorption of ummetabolized tyramine; increased pressor activity, potentially fatal risk of hypertensive crisis

decreased absorption of folic acid due to inhibition of an enzyme responsible for its efficient absorption

azathiporine,mercaptopurinealcohol,

benzodiazepines, warfarin, phenytoin,

theophylline, phenobarbital

phenylbutazone,sulfaphenazole,chloramphenicoldisulfiram, metronidazole,tinidazolexanthine oxidaseinhibitors (allopurinol)cimetidine

increased plasma half-life of tricyclics; increased risk of sudden death from cardiac disease in such patients

increased anticoagulant activity; risk of hemorrhage

hypoglycemia may be precipitateddisulfiram like reactions due to

increase in plasma acetaldehyde levels

increased toxicity of antineoplastics

increased blood levels of object drugs

EXCRETION INTERACTIONS1. Changes in Active Tubular Secretion

penicillin, PAS,cephalosporin,

nalidixic acid, methotrexate, dapsome

probencecid (acid) elevatede plasma levels of acidic drugs; risk of toxic reactions

Pharmacodynamic Interactions

Direct Pharmacodynamic interaction: drugs having similar or opposing pharmacologic effects are used concurrently.

a. Antagonism : Interacting drugs have opposing actions.b. Addition or Summation : Interacting Drugs have similar actions

and the result is the sum of individual drug responses.c. Synergism or Potentiation : Enhancement of action of one by

another, 1+1=3. Indirect Pharmacodynamic Interactions : Object and precipitant

drugs have unrelated effects but the latter alters the effects of the former

Pharmaceutical Interactions

Incompatibilities occur when drugs are mixed in intravenous infusions causing precipitation or inactivation of the active principles

Deleterious Drug Interactions in Anaesthetic Practice

G Shorten

Department of Anaesthetics, University Hospital, Cork

Pharmaceutical

When administered in combination or in rapid succession, sodium thiopentone and either vecuronium or pancuronium form a white precipitate which can occlude intravenous tubing. Formation of this precipitate can result in patient awareness with or without muscle relaxation. It was demonstrated that the precipitate was thiopentone acid (not a combination of thiopentone and vecuronium) and that it is extremely insoluble in plasma. The potential therefore exists that this precipitate could occlude narrow blood vessels or even cause pulmonary infraction.

Metabolism interactions

Bartkowski et al (3) reported a case of a 32yr, 80kg man who underwent exploratory laparotomy for persistant lower abdominal pain. During the 24hr prior to surgery, he received erythromycin 1g three times, and intraoperatively (over 2hr and 15min) received alfentanil 260 (μg/kg/). Twice postoperatively, he required administration of naloxone because he was unrounsable and hypoventilating or apneic.

Inducers and inhibitors of cytochrome P450 enzymes

Inducers Inhibitors

BarbituratesPhenytoinPrimidoneCarbamezapineTobacco smokeEthanolRifampicin

IsoniazidErythromycinTroleandromycinCimetidineOmeprazolePropofolKetoconazoleItraconazoleDiltiazemVarapamil

Pharmacodynamic

Synergism (i.e a supra-additive effect) has been demonstrated for several drugs commonly administered in combination by anaesthetists (e.g opioids and benzodiazepines). Whether such effects are beneficial or deleterious depends upon whether the anaesthetist takes the interaction into account when choosing the doses to be administered.

Drug Interaction in Antihypertensives

1. Drugs that inhibit Beta-Blocker MetabolismAmiodaroneCimetidineFluvoxamineVerapamilChlorpromazineCiprofloxacin

2. Drugs that induce Beta-Blocker metabolismRifampicin

3. Drugs whose metabolism is inhibited by Verapamil and Diltazem

CyclosporinCarbamazepineImipramineTheophylline

4. Drugs that affect Calcium channel blocker metabolisma. Drugs that induce metabolism:

CarbamazepinePhenytoinRifampicinPhenobarbitonePrimidone

Metabolism Interactions

b. Drugs that inhibit metabolism

Azole antifungals

Erythromycin

Ritonavir

Cimitidine

Grape fruit juice

Drugs that reduce effects of HRT ABSORPTION INTERACTIONS

Antibacterials--------Rifabutin, Rifampicin Anticonvulsants—

Barbiturates,carbamazepine,phenytointopiramate

Antifungals---- griseofulvin Antivirals—Protease

inhibitors(neflinavir,ritonavir), nevirapine Other drugs—Modafinil,St.John’s

wort,Troglitazone


Co-cyprindiol(Cyproterone/Ethinylestradiol) interacts with enzyme inducing drugs


Emergency hormonal contraceptive(norgestrel/ethinylestradiol) interacts with broad spectrum antibiotics such as penicillins and tetracyclins


Emergency hormonal contraceptives interact with enzyme inducing drugs like rifampicin and some anticonvulsants


Enzyme inducing drugs interact with menopausal HRT.

Case: A 28 year old woman taking oral conjugated oestrogens (Premarin) 1.25mg daily after ovidectomy , had a dramatic increase in the incidence of hot flushes when she began to take phenytoin 300mg daily. Her estrone and estradiol levels were found to be very low and they subsequently increased four to six fold after the phenytoin was stopped at which point the incidence of hot flushes stopped.

Pharmacodynamic Interaction

The rare failure of a copper IUD to prevent pregnancy may be due to a interaction with a corticosteroid, aspirin or NSAID.

Mechanism: part of the efficacy of copper IUDs may be based on local inflammatory effects and that anti- inflammatory drugs might reduce this.


Oral contraceptives interact with antibacterials

Mechanism: Suppression of intestinal bacteria which results in reduced enterohepatic recirculation of ethinylestradiol and a fall in serum levels is the explanation for interaction.

GUIDELINES TO HELP PREVENT DRUG INTERACTIONS

Brown Bag Medicine Checkup – each time you see your health care provider, put all your medications, including over-the-counter and complimentary products, in a bag have your physician conduct a personalized review of your medicine for safety, appropriateness, compatibility and instruction for use.

Each time you are prescribed a new medication, ask your physician if it can be combined safely with your other therapies.

Talk to your health care provider about making a medicine checkup part of your regular visits, and discuss how best to monitor for potential drug interactions. Bring your prescription with you to your appointment.

ARTHRITIS AND PAINANALGESIC / ANTIPYRETIC

They treat mild to moderate pain and fever. An example is : Acetaminophen / TYLENOL, TEMPRA Interactions Food : For rapid relief, take on an empty stomach because food

may slow the body’s absorption of acetaminophen. Alcohol : Avoid or limit the use of alcohol because chronic

alcohol use can increase your risk of liver damage or stomach bleeding. If you consume three or more alcoholic drinks per day talk to your doctor or pharmacist before taking these medications.

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS)

NSAIDS reduce pain, fever, and inflammation. Some examples are: aspirin / BAYER, ECOTRIN ibuprofen / MOTRIN, ADVIL naproxen / ANAPROX, ALEVE, NAPROSYN ketoprofen / ORUDIS nabumetone / RELAFEN Interaction Food : Because these medications can irritate the stomach, it is

best to take them with food or milk.

ALLERGIES

Antihistamines are used to relieve or prevent the symptoms of colds, hay fever, and allergies. They limit or block histamine, which is released by the body when we are exposed to substances that cause allergic reactions. Antihistamines are available with and without a prescription (over-the-counter). These products vary in their ability to cause drowsiness and sleepiness.

ANTIHISTAMINES Some examples are: Over the Counter :

brompheniramine / dimetane, bromphenchlorpheniramine / chlor-trimetondiphenhydramine / benadrylclemastine / tavist

Prescription :fexofenadine / allegroloratadine / claritincetirizine / zyrtecastermizole / Hismanal

Interaction Food : it is best to take prescription antihistamines on an empty

stomach to increase their effectiveness. Alcohol : Some antihistamines may increase drowsiness and slow

mental and motor performance. Use caution when operating machinery or driving.

INFECTIONSANTIOBIOTICS AND ANTIFUNGALS

Many different types of drugs are used to treat infections caused by bacteria and fungi. Some general advice to follow when taking any such product is:

Tell your doctor about any skin rashes you may have had with antibiotics or that you get while taking this medication. A rash can be a symptom of an allergic reaction, and allergic reactions can be very serious.

Tell your doctor if you experience diarrhea. If you are using birth control, consult with your health care

provider because some methods may not work when taken with antibiotics.

Be sure to finish all your medication even if you are feeling better.

Take with plenty of water.

ANTIBACTERIALSPENICILLIN

Some examples are:

penicillin V / VEETIDS

amoxicillin / TRIMOX, AMOXIL

ampicillin / PRINCIPEN, OMNIPEN Interaction Food : Take on an empty stomach, but if it upsets your stomach,

take it with food.

QUINOLONES

Some examples are:

ciprofloxacin / CIPRO

levofloxacin / LEVAQUIN

ofloxacin / FLOXIN

travafloxacin / TROVAN Interaction Food : Take on an empty stomach one hour before or two hours

after meals. If your stomach gets upset, take with food.

TETRACYCLINES

Some examples are :tetracycline / ACHROMYCIN, SUMYCINdoxycycline / VIBRAMYCINminocycline / MINOCIN

Interaction Food : Take on an empty stomach one hour before or two hours

after meals. If your stomach gets upset, take with food. However, it is important to avoid taking tetracycline / ACHROMYCIN, SUMYCIN with dairy products, antacids and vitamins containing iron because these can interfere with the medication’s effectiveness.

NITROIMIDAZOLE

An example is : metronidazole / FLAGYL Interaction Alcohol : Avoid drinking alcohol or using medications that

contain alcohol or eating foods prepared with alcohol while you are taking metronidazole and for at least three days after you finish the medication. Alcohol may cause nausea, abdominal cramps, vomiting, headaches and flushing.

ANTIFUNGALS

Some examples are: fluconazole / DIFLUCAN griseofulvin / GRIFULVIN ketoconazole / NIZORAL itraconazole / SPORANOX Interaction Food : it is important to avoid taking these medications with

dairy products (milk, cheeses, yogurt, ice cream), or antacids.

TOTAL PATIENTS

DRUG GROUP PERCENTAGE OF PATIENTS

6709 ANALGESIC 2%

2225 ANTACID 3%

2730 ANTIARRHYTHMIC 4%

1463 ANTICOAGULANT 11%

1041 ANTIHYPERTENSIVE 12%

1726 ANTIINFLAMATORY 3%

3152 ANTIMICROBIAL 6%

2541 DIURETIC 3%

6847 SEDATIVE-TRANQUILIZER 2%

Percentage of hospitalized patients, categorized by drug group, who experienced adverse drug reactions. (Data from May, F.E., Stewart, R.B., and Cluff, L.E.)

25-

20-

15-

10-

5-

0-5 6-10 11-15 16-20 number of drugs

%

of

pa tie nt s wit h

re ac

tio ns

Effect of the total number of drugs received by the patient on the percentage of patients experience as an adverse drug reaction to a specific drug group. Key : (●) antihypertensives; (O) anticoagulants; () other drug groups (including analgesics, antacids, antiarryhythmic, anti-inflammatories, antimicrobial agents, diuretics and sedatives-tranquilizzers). (Data from May, F.E., Stweart R.B., and Cluff, L.E.)

c. Over-the-counter (OTC) drugs and herbal preparations can also be involved in CYP450 isoenzyme metabolism and can cause serious drug- herbal interactions. For example, St.John’s wort may induce CYP3A4 isoenzyme and decrease cyclosporine to subtherapeutic levels.

d. Foods may also interfere with hepatic drug metabolism. For example, grapefruit juice is a powerful inhibitor of the CYP3A4 isoenzyme, and will increase blood levels of saquinavir if taken together.

Drug Interactions 10-08-009

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