DRUG INTERACTIONS

Dr. J. Vijaya Ratna Professor AU College of Pharm. Sciences Andhra 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 in a. Gastrointestinal motility and gastric emplying rate. b. Gastrointestinal flora c. pH of the GIT d. Free drug available in GIT. 2. Altered Distribution due to a. Competitive displacement or binding b. Reduced plasma protein levels

Drug Interactions
3. Altered biotransformation due to a. Enzyme induction b. Enzyme inhibition 4. Altered drug excretion due to a. Competition for tubular transport b. Changes in Urinary pH c. Increased fluid flow d. 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. 2. 3. 4. 5. 6. 7. 8.

Salicylates Barbiturates Phenyl butazone Phenyl propionic acids Sulfur and Sulfoxamids Clofibrate Tolbutamide Warfarin

Microsomal Enzyme Inducers

1. 2. 3. 4. 5.

Alcohol Chloral hydrate Cortisone Nicotine Prednisone

6. Phenytoin 7. Chlordiazepoxide 8. Imipramine 9. Phenobarbital 10. Testosterone

Microsomal Enzyme Inhibitors

1. 2. 3. 4. 5.

Allopurinole Oral antidiabetics Disulfiram Metronidazole Inhibitors Oral anti coagulants

6. Anabolic agents 7. Chloramphenicol 8. Isonizid 9. Monoamine Oxidase 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, Antacids, food and Formation of poorly soluble penicillamine mineral supplements and unabsorbable complex ciprofloxacin, containing Al, Mg, with such heavy metal ions norfloxacin Fe, Zn, Bi and Ca Reduced absorption due to cephalexin, ions complexation with metal sulfamethoxazole Antacids containing Al, ions , trimethroprim, Mg and Ca and Reduced absorption due to warfarin and sucralfate absorption and binding thyroxine cholestryamine

ABSORPTION INTERACTIONS
2. Alteration of GI pH

sulfonamides, aspirin ferrous sulfate ketoconazole, tetracycline, altenolol

antacids sodium bicarbonate, calcium carbonate antacids

Enhanced dissolution absorption rate Decreased dissolution hence absorption Decreased dissolution bioavailability

and and and

3. Alteration of Gut Motility aspirin, diazepam, levodopa, lithium carbonate, paracetamol, mexiletine levodopa, lithium carbonate, mexiletine metoclopramide anticholinergics (antropine, homatropine) rapid gastric emptying; increased rate of absorption delayed gastric emptying; decreased rate of absorption

4. Inhibition of GI Enzymes (see metabolism interactions) 5. Alteration of GI Microflora digoxin antibiotics (erythromycin, Tetracycline) increased bioavailability due to destruction of bacterial flora that inactivates digoxin in lower intestine

PHARMACOKINETIC DRUG INTERACTIONS

Object Drug(s) oral contraceptives Precipitant Drug(s) antibiotics (ampicillin) Influence on Object Drug(s) decreased reabsorption of drugs secreted as conjugates via bile in the intestine

6. Malabsorption Syndrome vitamin A, digocin B12, neomycin colchicines) (and Inhibition of absorption due to malabsorption/steatorrhea caused by neomycin

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

phenylbutazone, chloral hydrate, salicylates sulfonamides sulfonamides, salicylic acid valproic acid

increased clotting time; increased risk of hemorrhage increased hypoglycemic effect increased methotrexate toxicity phenytoin toxicity

METABOLISM INTERACTIONS 1. Enzyme Induction corticosteroids, oral contraceptives, coumarins, phenytoin, tolbutamide, tricyclics corticosteroids, oralcontraceptives theophylline, cyclosporin oral contraceptives, oral hypoglycemics, cumarins antibiotics (erythromycin, Tetracycline) phenytoin rifampicin increased bioavailability due to destruction of bacterial flora that inactivates digoxin in lower intestine -do-do-

Object Drug(s) 2. Enzyme Inhibition tetracycline, rich food (cheese, liver, yeast products) folic acid tricyclic antidepressants coumarins oral hypoglycemics alcohol azathiporine, mercaptopurine alcohol,

Precipitant Drug(s)

Influence on Object Drug(s)

MAO inhibitors (phenelzine, enhanced absorption of pargyline, etc.) ummetabolized tyramine; phenytoin increased pressor activity, chlorpromazine, potentially fatal risk of haloperidol hypertensive crisis metronidazole, decreased absorption of folic acid phenylbutazone due to inhibition of an enzyme responsible for its efficient absorption

azathiporine, mercaptopurine alcohol, benzodiazepines, warfarin, phenytoin, theophylline, phenobarbital

phenylbutazone, sulfaphenazole, chloramphenicol disulfiram, metronidazole, tinidazole xanthine oxidase inhibitors (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 precipitated disulfiram like reactions due to increase in plasma acetaldehyde levels increased toxicity of antineoplastics increased blood levels of object drugs

EXCRETION INTERACTIONS 1. 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
 a. b. c. 

Direct Pharmacodynamic interaction: drugs having similar or opposing pharmacologic effects are used concurrently. Antagonism : Interacting drugs have opposing actions. Addition or Summation : Interacting Drugs have similar actions and the result is the sum of individual drug responses. 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 ( g/kg/). Twice postoperatively, he required administration of naloxone because he was unrounsable and hypoventilating or apneic.

Inducers and inhibitors of cytochrome P450 enzymes

Inducers Barbiturates Phenytoin Primidone Carbamezapine Tobacco smoke Ethanol Rifampicin Inhibitors Isoniazid Erythromycin Troleandromycin Cimetidine Omeprazole Propofol Ketoconazole Itraconazole Diltiazem Varapamil

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 Metabolism Amiodarone Cimetidine Fluvoxamine Verapamil Chlorpromazine Ciprofloxacin Drugs that induce Beta-Blocker metabolism Rifampicin

 2.

 3.

Drugs whose metabolism is inhibited by Verapamil and Diltazem Cyclosporin Carbamazepine Imipramine Theophylline Drugs that affect Calcium channel blocker metabolism a. Drugs that induce metabolism: Carbamazepine Phenytoin Rifampicin Phenobarbitone Primidone

 4.

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,phenytointopira mate  Antifungals---- griseofulvin  AntiviralsProtease inhibitors(neflinavir,ritonavir), nevirapine  Other drugsModafinil,St.Johns wort,Troglitazone

Metabolism Interactions
 Co-cyprindiol(Cyproterone/Ethinylestradiol) 

interacts with enzyme inducing drugs

ABSORPTION INTERACTIONS
 Emergency hormonal

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

Metabolism Interactions
 Emergency hormonal contraceptives interact

with enzyme inducing drugs like rifampicin and some anticonvulsants

Metabolism Interactions
 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.

ABSORPTION INTERACTIONS
 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 PAIN ANALGESIC / 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 bodys 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, bromphen chlorpheniramine / chlor-trimeton diphenhydramine / benadryl clemastine / tavist Prescription : fexofenadine / allegro loratadine / claritin cetirizine / zyrtec astermizole / 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.

INFECTIONS ANTIOBIOTICS 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.

ANTIBACTERIALS PENICILLIN
 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, SUMYCIN doxycycline / VIBRAMYCIN minocycline / 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 medications 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 6709 2225 2730 1463 1041 1726 3152 2541 6847

DRUG GROUP

PERCENTAGE OF PATIENTS

ANALGESIC ANTACID ANTIARRHYTHMIC ANTICOAGULANT ANTIHYPERTENSIVE ANTIINFLAMATORY ANTIMICROBIAL DIURETIC SEDATIVE-TRANQUILIZER

2% 3% 4% 11% 12% 3% 6% 3% 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% of pa 20tie nt s 15wit h re 10ac tio ns 50-5 16-20 6-10 11-15 number of drugs

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 sedativestranquilizzers). (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.Johns 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.