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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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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.
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.
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
Salicylates Barbiturates Phenyl butazone Phenyl propionic acids Sulfur and Sulfoxamids Clofibrate Tolbutamide Warfarin
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
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
Enhanced dissolution absorption rate Decreased dissolution hence absorption Decreased dissolution bioavailability
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
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)
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
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
probencecid (acid)
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
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.
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.
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
Barbiturates,carbamazepine,phenytointopira mate Antifungals---- griseofulvin AntiviralsProtease inhibitors(neflinavir,ritonavir), nevirapine Other drugsModafinil,St.Johns wort,Troglitazone
Metabolism Interactions
Co-cyprindiol(Cyproterone/Ethinylestradiol)
ABSORPTION INTERACTIONS
Emergency hormonal
contraceptive(norgestrel/ethinylestradiol) interacts with broad spectrum antibiotics such as penicillins and tetracyclins
Metabolism Interactions
Emergency hormonal contraceptives interact
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.
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
part of your regular visits, and discuss how best to monitor for potential drug interactions. Bring your prescription with you to your appointment.
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.
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
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.