DRUG INTERACTIONS

INTRODUCTION:

      Drug Interaction is a situation in which the effects of  one drug are altered by the prior or concurrent administration of  another drug or by the presence of food, drink or              environmental chemicals.

      The drug whose activity is affected by such an interaction is referred to as the object drug.

      The agent which precipitates such as interaction is referred to as the precipitant drug.

      Drug interactions are generally quantitative whereby the intensity of effect is changed  (for example an increase or decrease) & seldom qualitative.

v  Most interactions are specific types of adverse reactions with altered efficacy of the body.

For example: An enhanced pharmacological activity ( eg: Haemorrhagic tendency of warfarin when phenylbutazone is given subsequently.

Or

Decrease in therapeutic activity resulting in loss of efficacy like that of tetracycline when concomitantly administered with food, antacids or mineral supplements containing heavy metal ions.

v  In some instances, drug interactions may be beneficial.

For example:  Enhancement of activity of penicillins when administered with            probenecid.

THE CAUSES OF DRUG INTERACTIONS 

1. Administration of two or more drugs simultaneously (Multiple pharmacological       effects).
2. Visiting of patients to many doctors (Multiple prescribers).
3. Concurrent use of prescribed and non−prescribed drugs.
4. Patient’s non−compliance.
5. Drug abuse. 

                                         PATIENT VARIABLE

There are many factors that influence the response to a drug in man.

1. AGE

Ø   There is an in­creased incidence of drug interactions in both young and geriatric patients.

Ø   Drug-related problems in young patients are encountered most frequently in newborn     infants. Newborn infants do not have fully developed enzyme systems that are involved in the metabolism of certain drugs, and they also have immature re­nal function.

Ø   Several factors are responsible for increased risk of interactions in the elderly. Most elderly patients have at least one chronic ill­ness (eg, hypertension, diabetes), and this is reflected in the prescribing of a larger number of medications for this patient group.  In addition, there may be aging-related changes in the absorption, distribu­tion, metabolism, and excretion of certain drugs, which in­crease the possibility of adverse events and drug interactions.

2.  GENETIC FACTORS

Ø   These maybe responsible for the development of an unexpected drug response in a particular patient.

Ø   Isoniazid is metabolized by an acetylation process, the rate of which appears to be under      genetic control. Some individuals me­tabolize isoniazid rapidly, whereas others metabolize it slowly, thus necessitating careful dosage adjustment, as the dose that provides satisfactory concentrations in rapid acetylators may cause toxicity in slow acetylators. 

Ø   Eg: Isoniazid causes peripheral neuritis in a number of patients, and this effect has been noted most frequently in slow acetylators.

Ø   It has been observed that isoniazid may inhibit the metabolism of phenytoin, possibly   resulting in the development of adverse events (nystagmus, ataxia, lethargy) of phenytoin.

3.  DISEASE STATES

Ø   A number of disease states, other than the one for which a particular drug is being used may in­fluence patient response to a drug.

Ø   Impaired renal and hepatic function is the most important conditions that may alter drug activity. However, other disorders also may bring about a change in the activity of a drug. 

4.  RENAL FUNCTION

Ø   Renal function is one of the most important determinants of drug activity. If there is renal impairment and the usual dose of a drug that is excreted by the kidney is given, there can be an increased and prolonged effect, since it is not being excreted at the normal rate. As     additional doses are given, serum concentrations will increase, possibly resulting in toxicity.

Ø   Therefore, a need exists for careful dosage adjustment and particular caution when other potentially interacting drugs are added to the therapeutic regimen.

5.  HEPATIC FUNCTION

Ø   Many drugs are metabolized in the liver by a number of mechanisms. Therefore, when there is hepatic damage, these drugs may be metabolized at a slower rate and exhibit a prolonged    effect.

Ø   Although each situation should be evaluated to determine whether a reduction in dosage is neces­sary, it should be recognized that some drugs will be metabolized at the normal rate even though hepatic function is impaired.

Ø    Many therapeutic agents are metabolized by hepatic en­zymes. If other drugs alter the amount and/or activity of these enzymes, a modified response to the drugs that depend on these enzymes for their metabolism might occur.

Ø   Eg:  many agents (eg. barbiturates, rifampin) are known to stimulate the activity of hepatic enzymes (enzyme induction). This results in rapid metabolism and excretion of              concur­rently administered agents that are metabolized by these en­zymes. 

6.  ALCOHOL CONSUMPTION

Ø   Chronic use of alcoholic beverages may increase the rate of metabolism of drugs such as warfarin and phenytoin by increasing the activity of hepatic enzymes.

Ø   Acute use of alcohol by nonalcoholic individu­als may cause an inhibition of hepatic          enzymes.

7.  SMOKING 

Ø   Smoking increases the activity of drug-metabolizing en­zymes in the liver, with the result that certain therapeutic agents (eg, diazepam, propoxyphene, theophylline, olanzapine) are metabolized more rapidly, and their effect is decreased.

8.  DIET

Ø   Food often may affect the rate and extent of absorp­tion of drugs from the gastrointestinal (GI) tract. For example, many antibiotics should be given at least 1 hr before or 2 hr af­ter meals to achieve optimal absorption.

Ø   The type of food is important with regard to the ab­sorption of concurrently administered drugs. Eg: 1.Interaction of milk and other dairy products with tetracycline and

Ø   fluoro­quinolone derivatives.  2.  Certain dietary items contain an appreciable amount of      vi­tamin K. A change in dietary habits that would significantly al­ter the intake of these foods could cause problems in patients on warfarin therapy.

Ø   Diet also may influence urinary pH values. One study has compared the excretion of       amphetamine in two groups of pa­tients maintained on different diets. One group was placed on a balanced protein diet that provided an acidic urine (average pH of 5.9), whereas the other group was put on a low-protein diet that provided an alkaline urine                           (average pH of 7.5). Each group was given a dose of amphetamine, and those with the  acidic urine excreted 23 to 56% of unchanged amphetamine in the first 8 hr and 5 to 13% in the next 8 hr. In comparison, in those with alkalinized urine, there was a 2 to 6% excre­tion in the first 8 hr, followed by a 0.5 to 3% excretion in the next 8 hr.

9.  INDIVIDUAL VARIATION

Ø   Plasma concentrations of certain drugs may vary widely among individuals using the same dosage regimen over the same time period. 

  

TYPES OF DRUG INTERACTIONS

Drug Interactions are of following types:

1. Drug − Drug Interactions.

A) Beneficial Drug Interactions.

B) Adverse Drug Interactions.

      2. Drug − Food Interactions.

3. Drug − Herbal Interactions.

4. Drug − Laboratory Tests Interactions.

DRUG – DRUG INTERACTIONS 

BENEFICIAL DRUG INTERACTIONS

Ø   Some drug interactions may be desirable and intended because of beneficial effects they produce when a combination of medications is given.

Ø   Such a combination produces,  

1.      Improved therapy, 

2.      A greater margin of safety,

3.      More appropriate onset or duration of action,

4.      Lowered toxicity or enhanced potency with diminishing side effects.

Ø   Such an interaction is also termed as Rational Drug Interaction.

DRUG INTERACTION LEADING TO INCREASE IN THERAPEUTIC EFFECTS :

1. In the treatment of Urinary Tract Infections & Pneumocystosis                                (due to microorganism pneumocystis carini ).
2. In the treatment of Parkinsonism, use of Levodopa & Carbidopa.
3. In the treatment of Angina, use of Nitrates + β−blockers.
4. In the treatment of Angina, use of Nitrates + calcium channel blockers.
5. In the treatment of Hypertension, use of Thiazide diuretics + potassium supplements + β−blockers.
6. In the treatment of Hypertension, use of Thiazide diuretics + potassium supplements + α−methyldopa.
7. In the treatment of Hypertension, combination of diuretics (Hydrochlorthiazide +  Triamterene) is used to minimise the K⁺ loss.
8. Use of probenecid to ↑ the serum concentration & prolong the activity of penicillins & some cephalosporins.
9. Amoxicillin with a β−lactamase inhibitor (clavulanic acid or sulbactam) to prevent degradation of Amoxicillin by β−lactamase producing bacteria & to increasing its   antimicrobial spectrum.

DRUG INTERACTIONS PROVIDING ADVANTAGE IN THE MANAGEMENT OF POISIONING & DRUG OVERDOSAGE :

1. In the treatment of Morphine Poisoning & Morphine addiction Naloxone is used.
2. In the treatment of Heparin toxicity, Protamine sulphate (heparin antagonist) is used.
3. In the treatment of Atropine poisoning, physostigmine is used. 
4. To reverse the skeletal muscle relaxant effects of d−tubocurrarine, Neostigmine is used.
5. In the treatment of Methyl alcohol poisoning, Ethyl alcohol is used.
6. In the treatment of Iron poisoning, Deferoxamine is used.

  

                DRUG COMBINATIONS WITH POTENTIAL ADVANTAGES :

Sl.NO	EXAMPLES	POTENTIAL       ADVANTAGE
1	Anti−tubercular drugs (Rifampicin & Isoniazid), Ferrous sulphate &     Folic acid	Improved compliance
2	Triple vaccine (Diptheria , pertussis & tetanus)	Ease of administration
3	Trimethorprim + sulfamethoxazole . Aspirin + codeine.	Synergistic effect
4	Levodopa+ carbidopa	Increased effect
5	antacids (Aluminium salt & magnesium salts)

ADVERSE DRUG INTERACTIONS

      An adverse drug interaction occurs due to error of the patient or physician. And these  interactions are undesirable & unintentional.

      The drug interaction may be Hetergic or Homergic.

      Hetergic : This type of drug interaction occurs when two drugs producing different types of effects are administered.

      Homergic : This type of drug interaction occurs when two drugs producing similar types of effects are administered.

 Adverse Drug − Drug Interactions can happen Invitro or Invivo.

INVITRO ADVERSE DRUG - DRUG INTERACTIONS  :

These interactions occur outside the body and are precisely the “pharmaceutical Interactions” where no pharmacokinetic / pharmacodynamic principles are involved except for chemistry.

Sl.NO	DRUGS	MIXED INTO	RESULT
1	Thiopental + succinyl choline	In the same syringe	Precipitation    (or)          Inactivation
2	Hydrocortisone + Heparin	In the same syringe	Inactivation of Heparin.
3	Hydrocortisone + Penicillin	In the same syringe	Inactivation of         penicillin.
4	Penicillin + Gentamycin	In the same syringe	Mutual Inactivation.
5	Sodium salts of phenytoin, Barbiturates, sulfonamides, Heparin & Penicillins.	In I.v infusion fluid such as 5% dextrose.	Drugs are precipitated in the acidic pH of dextrose solution.

IN VIVO ADVERSE DRUG − DRUG INTERACTIONS:

      In vivo drug-drug interactions occur either due to pharmacokinetic or pharmacodynamic reasons.

      Pharmacokinetic interactions are those in which one agent (the precipitant drug) alters the  absorption, distribution, metabolism, or excretion (ADME) of a second agent (the object drug), with a resultant change in the plasma concentration of the latter agent.  

      pharmacodynamic inter­actions are those in which drugs having similar ((or) opposing) pharmacological effects are administered concurrently and situations in which the sensitivity or responsiveness of the tissues to one drug is altered by another. Simply Pharmacodynamic interactions are situations in which there is a change in drug effect without a change in drug plasma concentration. Although the pharmacokinetic interactions often present challenging clinical problems widely, the pharmacodynamic interactions are encountered more fre­quently. 

PHARMACOKINETIC   INTERACTIONS

A. ABSORPTION

1. ALTERATION OF Gl ABSORPTION

      Due to Interactions, absorption of a drug from the GI tract may change.

      In some situations the absorption of the drug may be reduced, and its therapeutic ac­tivity   compromised. In others, absorption may be delayed, but the same amount of drug is absorbed eventually.

      A delay in drug absorption can be undesirable when a rapid effect is needed to relieve acute symptoms, such as pain. The slower ab­sorption rate also may prolong the effects of a drug and may present difficulty.

      Eg:- If  Effects Hypnotic Drugs are prolonged - the patient may experience excessive      sedation or hangover in the morning. A slower rate of absorption may preclude achievement of effective plasma and tissue concentrations of drugs that are metabolized rapidly and         excreted.

2. ALTERATION OF pH

      Since many drugs are weak acids or weak bases, the pH of the GI contents may influence the extent of absorption.

      The non-ionized form of a drug (the more lipid-soluble) will be absorbed more readily than the ionized form. Acidic drugs exist primarily in the non-ionized form in the up­per region of the GI tract (having a lower pH).

      If a drug such as an antacid is ingested, which will raise the pH of the GI con­tents, it is possible that the absorption of such acidic drugs can be delayed and/or inhibited partially.

v  KETOCONAZOLE - ANTACIDS

      When ketoconazole is administered orally, an acidic medium is re­quired for dissolution of ketoconazole. Drugs like an antacid, a histamine H₂- receptor antagonist   (eg, cimetidine, ranitidine) or a proton pump in­hibitor (eg, lansoprazole, omeprazole) is likely to reduce the dis­solution, absorption, and effectiveness of the antifungal agent.

v  BISACODYL - ANTACIDS

      Laxative bisacodyl when administered orally they cause Gastric Irritation, so formulated as enteric-coated dosage form.

      If concurrent administration of antacid or ingestion of milk leads to increase in the pH of the GI contents and may cause disintegration of the en­teric coating in the stomach,        resulting in release of the drug in the stomach, which cause irritation and vomiting.

3. COMPLEXATION & ABSORPTION

v  TETRACYCLINES-METALS

      Tetracycline can combine with metal ions such as calcium, magnesium, aluminum, iron,  bismuth, and zinc in the GI tract to form complexes that are absorbed poorly.

      Thus, the simulta­neous administration of certain dietary items (eg. milk, other products      containing calcium) or drugs (eg. antacids, iron prepa­rations, products containing calcium salts) with tetracycline could result in a significant decrease in the amount of antibiotic           absorbed.

v  FLUOROQUINOLONES-METALS

      Aluminum and magnesium-containing antacids, as well as certain dietary items (eg. milk, yogurt), reduce the absorption and serum concentrations of fluoroquinolones, as a result of the metal ions complexing with the anti-infective agent.

      Eg: Labeling for Moxifloxacin - is recommended that  Moxifloxacin be taken at least 4 hours before or 8 hours after antacids con­taining magnesium or aluminum, as well as   sucralfate, metal cations such as iron, and multivitamin preparations with zinc.

v  CHOLESTYRAMINE AND COLESTIPOL

      cholestyramine and colestipol, the resinous materials which are not absorbed from the   GI tract and also  bind with bile acids, thyroid hormone, war­farin, digoxin. And thiazide    diuretics and prevent their reabsorption.

      The naturally occurring human bile acid, ursodiol is used in the dissolution of gallstones composed primarily of cholesterol.

      Prolonged administration of cholestyramine and colestipol can decrease the absorption of fat-soluble vitamins such as vitamin K leading to in­creased bleeding tendencies in some patients in whom the vitamin K intake is not increased.

      A newer bile acid-binding agent, colesevelam, appears less likely than cholestyramine and colestipol to interact with other medications or fat-soluble vitamins.

      For the treatment of Rheumatoid arthritis Leflunomide is used. Leflunomide can cause fetal harm if administered during preg­nancy, and it has an active metabolite that can persist in the system for up to 2 years. If a woman of childbearing potential discontinues use of              Leflunomide. It is recommended that cholestyramine (e g. three times a day. for 11 days) be used to accelerate the elimination of the drug and its active metabolite.

v  PENICILLAMINE-METALS

      Aluminum and iron salts   reduce the absorption of penicillamine through chelation and/or adsorption mechanisms.

4. ALTERATION OF MOTILITY / RATE OF GASTRIC  EMTYING

v  CATHARTICS 

      A cathartic, increases GI motility, enhance the rate of drug passage through the GI tract which leads to decreased absorption of cer­tain drugs.

      Drugs which are absorbed slowly and require prolonged contact with the absorbing sur­face or those that are absorbed only at a particular site along the GI tract. Similar problems might be noted with enteric-coated and controlled-release formulations.

v  ANTICHOLINERGICS

      Anticholinergics decreases GI motility, which causes reduced peristalsis which inturn   retards the dissolution and finally absorption is decreased. And slowing of gastric       emptying may delay absorption from the small intestine.

      If a drug is retained for a longer period of time in the area from which it is optimally    absorbed,so absorption is increased. 

METOCLOPRAMIDE

      Metoclopramide increases motility of the upper GI tract, and may influence the absorption of other drugs adminis­tered concurrently.

5. ALTERATION OF METABOLISM IN G.I. TRACT

The absorption of certain agents is influenced by the extent to which they are metabolized in the GI tract.

MAOIs-TYRAMINE:

      Tyramine is a pressor substance, which is metabolized by MAO (Mono Amino Oxidase ) enzyme  present in the intestinal wall of the liver and protects against  the pressor actions of amines in foods.

      MAO Inhibitors (eg. Isocarboxazid, phenelzine, tranylcypromine) inhibits the MAO (Mono Amino Oxidase) enzyme which results in accumulation of large quantities of                unmetabolized tyra­mine, which acts to release more nor-epinephrine from adrenergic        neurons as a result of MAO inhibition.

      Foods containing the highest tyramine content are aged cheeses, certain alcoholic beverages (eg, Chianti wine), pickled fish (eg. her­ring), concentrated yeast extracts, and broad-bean pods (also known as fava beans or Italian green beans).

GRAPE FRUIT JUICE:

      Consumption of grapefruit juice increases the serum concentration and activity of a number of medications such as certain calcium chan­nel blockers (eg. amlodipine, felodipine, nisoldipine), certain HMG-CoA reductase inhibitors (eg. lovastatin), and cyclosporine.

      The bioavailability of most of these agents is generally low. Primarily as a result of extensive first-pass metabolism.

      Components of grapefruit juice reduce the activity of the cytochrome P-450enzymes (primarily CYP3A4) in the gut wall that is involved in the metabolism of these agents. As a result,               a larger amount of unmetabolized drug is absorbed, and serum concentrations are increased.

6.ALTERATION OF GASTROINTESTINAL FLORA

Antibi­otics can cause changes in the microbial flora of the GI tract & may alter the   production or metabolism of certain agents, which inturn affects the absorption and clinical response.

ANTICOAGULANTS-ANTIBIOTICS

      A number of anti-infective agents enhance the effect of con­currently administered        anticoagulants as a result of inhibiting the production of Vitamin K by the                     mi­croorganisms in the GI tract.  Eg: Broad-spectrum antibiotics such as the tetracyclines.

      Other mechanisms: when sulfonamides and anticoagulants are given concurrently,     anti­coagulant effect is increased, due to displacement of the anticoagulant from            protein-binding sites and/or inhibition of its hepatic metabolism by sulfonamides.

DIGOXIN-ANTIBIOTICS

      In G.I tract, significant portion of the digoxin compound is converted to inactive          metabolites by the bacterial flora of the Intestine.

      When Erythromycin or Tetracycline is administered concurrently, serum concentrations of digoxin are elevated due to inhibition of the bacterial flora.

ORAL CONTRACEPTIVES-ANTIBIOTICS

      The estrogen component of the contraceptive formulation is conjugated to a large extent in the liver and excreted in the bile. Bacteria in the intestine hydrolyses the conjugated form of the estrogen, permitting the free drug to be reabsorbed, and contribute to the     serum concentra­tion of the estrogen.

      Several Antibiotics (eg: Ampicillin ), by reducing the bacterial flora, may interrupt the enterohepatic circulation, with a resultant reduction in serum estrogen concentrations.

MALABSORPTION STATES

   Certain drugs, such as laxatives, colchicine, cholestyramine, and colestipol, have been reported to cause malabsorption prob­lems that result in decreased absorption of vitamins and nutrients from the G.I tract. 

B. DISTRIBUTION

1. ALTERATION OF DISTRIBUTION

Displacement from Protein-Binding Sites

       An interaction of this type may occur when two drugs that are capable of binding to    proteins are administered concurrently. Although they may bind at different sites on the protein, the binding characteristics of one of the drugs may be altered (non­competitive displacement).

       Probably more significant are the situ­ations in which two drugs are capable of binding to the same sites on the protein (competitive displacement). Since there are only a limited number of protein-binding sites, competition will exist, and the drug with the greater    affinity for the binding sites will displace the other from plasma or tissue proteins. 

       The protein-bound fraction of a drug in the body is not pharmacologically active.     However, equilibrium exists between bound and unbound fractions, and as the unbound or free form of the drug is metabolized and excreted, bound drug is released gradually to maintain the equilibrium and pharmaco­logical response.

       The binding of acidic drugs to serum albumin represents the type of drug-protein binding that has been studied most exten­sively. The binding to albumin is readily reversible, and the al­bumin-drug complex essentially serves as a reservoir that re­leases more drug as the free drug is metabolized and/or excreted.

       The importance of the binding of basic drugs (eg, pro­pranolol, lidocaine) to                 Alpha1(α1)-acid glycoprotein (AAG) also has been recognized. Even small increases in the reactant protein con­centration, such as might be associated with infection and           in­flammation, can result in significant changes in the concentra­tion of free drug.

       The risk of an interaction occurring is greatest with drugs that are highly protein-bound (more than 90%) and also have a small apparent volume of distribution. Since only a small frac­tion of the drug ordinarily would be available in the free form, the displacement of even a small percentage of the amount that is bound to proteins could produce a       considerable increase in activity.

       The risk of interactions resulting from protein displacement appears to be greatest during the first several days of concur­rent therapy. It has been suggested that drugs having the greatest capability of displacing a highly bound drug such as warfarin can increase the anticoagulant response within 24 hr and exhibit maximum potentiation in 3 to 5 days.  After this pe­riod the effect levels off since the drug, as a result of greater amounts being available in the unbound form, also is being metabolized more rapidly and excreted. Therefore, the anticoagu­lant usually has a shorter half-life when a displacing agent is given concurrently.

METHOTREXATE

       Salicylates displace the Methotrexate from protein binding sites of plasma proteins to which it is highly bound.

       salicylates also increase the ac­tion of methotrexate by inhibiting its renal excretion.

PHENYTOIN-VALPROIC ACID

       Valproic acid displace phenytoin from plasma protein-binding sites, and also inhibit the metabolism of phenytoin, which leads to increased free phenytoin concentrations and the occurrence of adverse events.

REDUCED ALBUMIN CONCENTRATIONS

       As many drugs are bound extensively to plasma proteins, a de­creased concentration or amount of protein could change the availability of drugs and thus their activity.            Incidence of ad­verse events with certain drugs may be higher in patients with conditions associated with hypoalbuminemia (eg, renal, hep­atic, and GI diseases).

       Eg: A relationship between prednisone dosage, frequency of ad­verse events, and serum albumin concentrations.

       When the serum albumin concentration is less than 2.5 g/100 ml, the frequency of    prednisone adverse events is almost doubled, and this is attributed to an increased      concentration of prednisolone, an active metabolite of prednisone.

       Eg: Incidence of adverse events to phenytoin is greater in hypoalbuminemic patients, due to increased circulating concentrations of un­bound phenytoin.

                                             C. METABOLISM 

1. STIMULATION OF METABOLISM

       Drug metabolism occurs primarily in the liver and most com­monly involves oxidation,       reduction, hydrolysis, and conjuga­tion (eg. with glucuronic acid) reactions.

       Quantitatively, the most important hepatic enzymes are the cytochrome P-450 en­zymes, which have been divided into families and subfamilies (eg. CYP3A4) on the basis of the similarity of their amino acid sequences. These enzymes are responsible for the oxidation, hydroxylation.

       Many drug interactions results from, the ability of one drug to stimulate the metabolism of another, most often by in­creasing the activity of hepatic enzymes that are involved in the       metabolism of numerous therapeutic agents. The increased activity probably is due to enhanced enzyme synthesis, resulting in increased amounts of drug-metabolizing enzymes, an effect      frequently referred to as Enzyme Induction.  

       Eg: Barbiturates, phenytoin, carbamazepine, rifampin, & herbal product St John's wort to cause enzyme induction.

       In most situations, drugs are converted to less active, water-soluble metabolites, and enzyme induction usually will result in an increased metabolism and excretion and a reduced        pharmacological action of the agent being metabolized by hepatic enzymes. Less frequently, a drug may be converted to a metabo­lite that is more active than the parent compound, and there may be an enhanced response. However, the initially increased effect may subsequently diminish, since the drug will be ex­creted more rapidly and have a shorter duration of action.

              The stimulation of hepatic enzyme activity is not only a fac­tor in the development of drug     interactions, but also may be re­sponsible for a drug (eg. carbamazepine) stimulating its own metabolism. With continued use, the half-life of the drug will decrease and possibly resulting in a need to increase the dosage.

WARFARIN-PHENOBARBITAL

       Phenobarbital increases the rate of metabolism of warfarin by causing enzyme induction which results in a decreased response of the anticoagulant. As warfarin is being more rapidly         metabolized and excreted, possibly leading to an increased risk of thrombus formation.

ORAL CONTRACEPTIVES

       Phenobarbital, rifampin, and other drugs are known to increase the metabolism of steroid hormones, including estrogens and progestins that are used in oral contraceptive formulations.

              As Phenobarbital, rifampin, and other drugs are capable of causing enzyme induction in­deed may reduce the effectiveness of oral contraceptives, possi­bly resulting in an unplanned      pregnancy.

HIV PROTEASE INHIBITORS

       HIV protease inhibitors (eg, amprenavir, atazanavir, lopinavir, nelfinavir) are extensively   metabolized via CYP3A/3A4 pathways, and the concurrent use of an enzyme inducer could  reduce their action and compromise the effectiveness of the anti-retroviral regimen for HIV     infection/AIDS.

       Ri­fampin is such a strong enzyme inducer, so concurrent use with HIV protease inhibitors is contraindicated.

SMOKING

       In individuals who are heavy smokers, the effects of certain drugs may be decreased, because of increased hepatic en­zyme activity resulting from the action of polycyclic hydrocar­bons that are present in cigarette smoke.  

       Drugs like diazepam, propoxyphene, theophylline, pen­tazocine, & olanzapine, whose         metabolism is increased and therapeutic activity likely to be reduced due to smoking.

       When therapy is given with certain drugs , careful monitoring is done as the drugs are       metabolized by hepatic enzyme systems in patients who are moderate or heavy smokers. And cau­tion also must be exercised if a patient treated with such a med­ication discontinues smoking.

              A sig­nificant risk of toxicity exists when oral contraceptives are used by women who smoke, as  smoking  increases the risk of serious cardiovascular effects (eg. myocardial infarction),             especially in women over 35 years of age.

ALCOHOL

       Alcohol may either stimulate or inhibit the ac­tivity of hepatic enzymes. Rate of metabolism of warfarin and phenytoin is increased in alcoholic patients. This was attributed to increased liver enzyme activity caused by chronic administra­tion of alcohol.

       In contrast, acute use of alcohol by nonalcoholic individuals may cause inhibition of hepatic enzymes. This may decrease the rate of metabolism; thereby increasing the effect of other agents administered concurrently, and may be responsible for the enhanced sedation             experienced when alco­holic beverages and sedative drugs are taken together by individuals who are not alcoholics. 

LEVODOPA-PYRIDOXINE

       Pyridoxine reduces the action of levodopa by accelerating its decarboxy­lation to dopamine in the peripheral tissues. Consequently, less levodopa reaches and crosses the blood-brain barrier, with the result that less dopamine is formed in the brain and the thera­peutic effect is            diminished.

       Doses of pyridoxine of 10 to 25 mg rapidly reverse the effect of the anti-Parkinson drug.

     Sinemet contains both levodopa and carbidopa, the carbidopa acting as an inhibitor of     decar­boxylase enzymes. When levodopa is administered with car­bidopa, the dose of the    levodopa is lowered, as decarboxylation pathway of levodopa is inhibited by carbidopa. The   decrease in dosage often is accompanied by a decreased incidence of adverse effects. Since carbidopa does not cross the blood-brain barrier, it will not hinder the con­version of levodopa to dopamine in the brain.

       Levodopa is metabolized also in the peripheral tissues in a pathway that is catalyzed by       catechol-O-methyl transferase (COMT). When the decarboxylation pathway is inhibited by   carbidopa, the O-methylation pathway becomes the primary path­way through which levodopa is metabolized in the peripheral tis­sues. The COMT inhibitor entacapone was developed to inhibit this metabolic pathway and has been used in conjunction with levodopa and carbidopa.

       Stalevo^®  contains combination of  Levodopa + carbidopa + entacapone.

2. INHIBITION OF METABOLISM

One drug inhibits the metabolism of another, usually resulting in a prolonged and intensified     activity of the latter drug.

ALCOHOL-DISULFIRAM

       Disulfiram is used in the treatment of alcoholism. Disulfiram in­hibits the activity of aldehyde dehydrogenase, thus inhibiting oxidation of acetaldehyde, an oxidation product of alcohol. This results in accumulation of excessive quantities of acetaldehyde and development of the         unpleasant effects characteristic of the disulfiram reaction.

       Disulfiram is not a selective inhibitor of aldehyde dehydro­genase but exhibits several           inhibitory actions that can result in the development of drug interactions. It can enhance the activity of warfarin and phenytoin  by inhibiting their metabolism.

       Another example is reaction be­tween metronidazole and alcohol.

MERCAPTOPURINE OR AZATHIOPRINE – ALLOPURINOL

       Allopurinol is used in the treatment of gout. Allopurinal acts by inhibiting the enzyme xanthine ox­idase , reduces the production of uric acid .

       Xanthine oxidase also has an im­portant role in the metabolism of potentially toxic drugs such as mercaptopurine and azathioprine, and when this enzyme is in­hibited by allopurinol, the     effect of the latter agents can be in­creased markedly.

       When allopurinol is given in doses of 300 to 600 mg/day concurrently with either of these drugs, it is ad­vised that the dose of mercaptopurine or azathioprine be re­duced to about 1/3 to 1/4 the usual dose.

CIMETIDINE

       Cimetidine inhibits hepatic oxidative enzyme systems. So the action of other agents that are metabolized extensively via these pathways will be increased.

       Cimetidine has interactions with carbamazepine, diazepam, phenytoin, theophylline,        warfarin, and other agents. So it is neces­sary to reduce the dosage of these agents when         cimetidine is in­cluded in the therapeutic regimen.

       Ranitidine also binds to a limited extent to the cytochrome P-450 enzymes in­volved in the metabolism of these agents, but it appears to have a lesser affinity for the enzymes than does cimetidine.

              Other Histamine H₂-receptor antagonists (famotidine and nizatidine) are not likely to inhibit oxidative metabolic pathways and to inter­act with other drugs via this mechanism.

THEOPHYLLINE - MACROLIDE ANTIBIOTICS

       Erythromycin increases the serum concentrations of theophylline by inhibiting its hepatic metabolism.

       Patients receiving high doses of theophylline or who are otherwise predisposed to              theophylline toxicity should be monitored closely if erythromycin is administered                 concur­rently. The clarithromycin and telithromycin also inhibit the metabolism of         theophylline, whereas azithromycin is unlikely to interact.

THEOPHYLLINE-FLUOROQUINOLONES

       Ciprofloxacin increase the plasma concentrations and activity of theophylline by inhibiting its hepatic metabolism, and concurrent use is best avoided.

              Certain other fluoroquinolones, such as levofloxacin, are not likely to inhibit hepatic enzyme systems and interact with theophylline.

MAOIs

              There have been many reports of drug interactions involving use of an MAOI with another drug or with certain di­etary items. It is likely that MAOIs enhance the effect of drugs such as the barbiturates and opioid analgesics by inhibiting hepatic enzyme systems involved in their metabolism. How­ever, other mechanisms are involved in some of the more publi­cized problems with these compounds and are considered else­where in this chapter.

CALCIUM CHANNEL BLOCKING AGENTS

       Calcium channel blocking agents (eg. Diltiazem, nifedipine, vera­pamil) interact with a number of drugs, although the mechanisms through which these interactions oc­cur are not completely defined.

       It has been suggested that vera­pamil and diltiazem may inhibit the hepatic metabolism of      carbamazepine, thereby increasing the activity of the latter agent. Because the calcium channel blocking agents are metabolized themselves in the liver, they may interact with certain drugs be­cause they are competing for the same metabolic pathways.

                                             D.  EXCRETION

1. ALTERATION OF EXCRETION

       Although some therapeutic agents are eliminated via other mechanisms, most drugs and their metabolites are excreted via  kidneys. The most important clinical im­plications of         altering renal excretion involve the use of drugs that are excreted in their unchanged form or in the form of an active metabolite. Thus, substances with pharmacological activity are    being reabsorbed or excreted to a greater extent when renal excretion is altered.

       In contrast, when only inactive metabolites are being excreted, changes in therapeutic    activity are less likely to be associated with the use of other drugs that can influence renal excretory pathways.

2. ALTERATION OF URINARY pH

SALICYLATES-ACIDIFYING AND ALKALINIZING AGENTS

       A change in urinary pH will influence the ionization of weak acids and weak bases and thus affect the extent to which these agents are reabsorbed and excreted. When a drug is in its non-ionized form it will diffuse more readily from urine back into blood. Therefore, for an acidic drug, there will be a larger pro­portion of drug in the non-ionized form in  acid urine than in alkaline urine where it will exist primarily as an ionized salt. The result is that from acid urine more of an acidic drug will diffuse back into the blood and       produce a prolonged, and perhaps intensified, activity.

       Salicylate dosage regimen that provided a serum concentration of 20 to 30 µg/mL in a patient when the urinary pH was ap­proximately 6.5 produced serum concentrations that were ap­proximately twice as high when the urinary pH was decreased to 5.5. The risk of a significant interaction is greatest in patients who are taking large doses of salicylates (eg, for arthritis).

AMPHETAMTNES-ALKALINIZING AGENTS

       The excretion of a dose of basic drug like dex­troamphetamine at urinary pH values of approximately 5 & 8. when the urinary pH was maintained at approxi­mately 5,  54.5% of the dose of dextroamphetamine was excreted within 16 hr, compared with a 2.9%        excretion in the same period when the urinary pH was maintained at approximately 8.

        For basic drug like quinidine, quinidine toxicity is observed when urine becomes        alkaline, since excretion of quinidine is decreased considerably as urinary pH was raised.

       For pseudoephedrine, when the urinary pH was increased to about 8 with sodium        bicarbonate, the plasma half-life of pseudoephedrine was approximately double that in nor­mal subjects. When urinary pH in the same subjects was de­creased to 5.2. using    ammonium chloride, the plasma half-life decreased markedly from control values.

  3. ALTERATION OF ACTIVE TRANSPORT

PENICILLINS-PROBENECID

       A number of organic acids undergo active transport from the blood into the tubular urine and vice versa. In some situations these agents interfere with the excretion of each other.

       Probenecid increase serum concentrations and prolong ac­tivity of penicillin derivatives by blocking their tubular secre­tion. 

       Probenecid also   decreases renal excre­tion of other agents, including methotrexate.

METHOTREXATE - NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

       Nonsteroidal anti-intlammatorydrugs(NSAIDs) increase the activity and toxicity of     methotrexate.  Methotrexate toxicity is seen in patients receiving ketoprofen, as it inhibits the active renal tubular secretion of methotrexate.

 LITHIUM - NONSTEROIDAL ANTIINFLAMMATORY DRUGS

       The serum concentrations and incidence of adverse effects of lithium salts are increased by the concurrent administration of anti-inflammatory agents such as ibuprofen,

indomethacin and piroxicam.

       It is suggested that the renal clearance of lithium is reduced as a result of the action of these anti-inflammatory agents to inhibit renal prostaglandin synthesis.

 4. ALTERATION OF DRUG TRANSPORT

       P-glycoprotein has more importance in the absorption, distribution, metabolism, and   excretion of certain drugs. P-glycoprotein functions as a trans­port system that may act as a barrier for certain agents and as a pump that facilitates the transport of certain agents across membranes.

       For example, it limits cellular uptake of certain drugs from the blood into the brain and from the intestinal lu­men into epithelial cells.

       The role of P-glycoprotein in the over­all absorption of a drug that is administered orally in high mil­ligram doses is not clinically important because this transport system is    quickly saturated by the high concentra­tions of drug in the intestinal lumen. However, its role may be important in the absorption of drugs that are administered orally in very small doses (eg, digoxin).

       There are numerous substrates for P-glycoprotein including  drugs such as cyclosporine, digoxin, diltiazem, verapamil, atorvastatin, lovastatin, simvastatin, doxorubicin,

pacfitaxel, HIV protease inhibitors, and loperamide.

       There is overlapping substrate specificity between P-glycoprotein and CYP3A4, and many of the drugs that inhibit or in­duce CYP3A4 also inhibit or induce P-glycoprotein. Therefore, drug interactions that result from inhibition or induction of CYP3A4 often   also involve inhibition or induction of P-glyco­protein. 

       Inhibitors of P-glycoprotein are clarithromycin, erythromycin, itraconazole,                 ketoconazole, quinidine, and verapamil. Inducers include such agents as ri­fampin and    St John's wort.

DIGOXIN-QUINIDINE OR VERAPAMIL

       Concurrent use of quinidine or verapamil with digoxin results in greater serum digoxin concentrations.

       Both quini­dine and verapamil are inhibitors of P-glycoprotein which results in increased absorption, de­creased elimination, and higher concentrations of digoxin. 

       Inducers of P-glycoprotein such as rifampin and St John's wort also decrease serum    concentra­tions of digoxin.

LOPERAMIDE-P-GLYCOPROTEIN

       Antidiarrheal agent loperamide, cause central nervous sys­tem adverse events because    P-glycoprotein prevents it from crossing the blood-brain barrier and gaining access to the central nervous system.

       If a patient using loperamide is also treated with a P-glycoprotein inhibitor, CNS effects that are characteristic of the opioids may be experienced.   

PHARMACODYNAMIC   INTERACTIONS

DRUGS HAVING OPPOSING PHARMACOLOGICAL EFFECTS

Interactions resulting from the use of two drugs with opposing effects should be among the easiest to detect. However, these sometimes are due to the secondary effects of certain drugs and this and other factors may preclude early identification of such situations.

DIURETICS

       The  thiazides and certain other diuretics elevate  blood glucose concentrations. When the diuretic is prescribed for a diabetic patient being treated with insulin or one of the oral antidiabetic agents, this ac­tion may partially counteract the glucose-lowering action of the antidiabetic drug, necessitating an adjustment in dosage.

       Simi­larly, many diuretics produce hyperuricemic effect. Ther­apy in patients with gout should be monitored closely, as the hy­peruricemic action of a diuretic may necessitate an adjustment in dosage of the agent being used in the treatment of gout.

 DRUGS HAVING SIMILAR PHARMACOLOGICAL  EFFECTS

An excessive response attributable to the concurrent use of drugs having similar actions is the type of interaction that occurs most often, and these potential problems warrant particular  atten­tion.

CNS DEPRESSANTS

       Concurrent use of two or more drugs ex­hibiting a depressant action results in an          excessive CNS depressant ef­fect.  Pa­tients experience effects such as sedation and      dizziness are at increased risk of falls and injuries, such as hip fractures.

       In considering multiple drug regimens, agents (eg, sedative-hypnotics, antipsychotics, tricyclic antidepressants, opioid analgesics, and most antihistamines) that can exhibit a depressant effect that will be at least additive to the effect con­tributed by other drugs. 

ALCOHOI - OTHER   CNS   DEPRESSANTS 

       In patients who take alcoholic beverages, CNS depressant effect of the drug prescribed is increased.

DRUGS HAVING ANTICHOLINERGIC ACTIVITY

       Drugs that differ considerably in their primary pharmacologi­cal actions may exhibit the same secondary effects.

       Some pa­tients being treated with antipsychotic agents such as chlorpromazine are given an antiparkinson agent such as trihexyphenidyl to control the extrapyramidal effects of the chlorpromazine. In addition, a number of these patients experience symp­toms of     depression, and a tricyclic antidepressant such as amitriptyline might be added to the   therapy.

       Each of these three agents possesses anticholinergic activity, and the addi­tive effect could result in side effects such as dryness of the mouth, blurred vision, urinary retention,           constipation, and ele­vation of intraocular pressure.

       The patient experiencing persis­tent dryness of the mouth as a side effect and when              nitroglycerin tablets were administered sublingually for the management of exertional angina, the relief of the symptoms is delayed because of the slower dissolution of the sublingual  tablets.

       An excessive anticholinergic effect can cause an atropine like delirium, particularly in      geriatric patients. This effect could be misinterpreted as an increase in psychiatric symptoms, which might be treated by increasing the dosage of the therapeutic agents that are actually   responsi­ble for causing the problem. This example points out the diffi­culty that often can exist in distinguishing between the symp­toms of the condition(s) being treated and the effects of the drug(s) being employed as therapy.

       The blurring of vision, which also may be associated with the use of drugs having                 anticholinergic activity, may be especially distressing for older patients, particularly those whose physical activities may be limited and for whom reading ­is a favorite ac­tivity.

              Patients taking phenothiazine-antiparkinson combinations & exposed to high environmental tem­perature and humidity severe hyperpyrexia is observed. As combinations interfere with the ther­moregulatory system of the body, So for physi­cians it is recommended that patients treated in hot and humid climates should min­imize outdoor exposure of patients receiving high doses of these agents.

  DRUGS EXHIBITING HYPOTENSIVE EFFECTS

       Certain antihypertensive drugs as well as some other classes of medications                         (eg. tricyclic antidepressants) can cause ortho­static hypotension, resulting in symptoms such as dizziness, lightheadedness, and in more severe cases syncope.

       Older pa­tients are more susceptible to this type of response and the as­sociated risks such as falls and injuries, and appropriate pre­cautions should be exercised whether these agents are given alone or in combination.

       The use of sildenafil, tadalafil, and vardenafil in the treat­ment of erectile dysfunction is  contraindicated in patients treated with nitrates because these agents may potentiate the   hypotensive effect of the nitrates.

NSAIDs

       Some patient un­knowingly may  take several different products that con­tain the same NSAID. An arthritic patient whose condition who take ibuprofen obtained through prescription  may purchase an ibuprofen product available without a prescription for pain/discomfort not           associated with the arthritis, without recognizing that the two products contain the same drug and that there is an increased risk of adverse effects.

3.ALTERATION OF ELECTROLYTE CONCENTRATIONS

Several important drug interactions occur as a result of the ability of certain therapeutic agents to alter the concentration of electrolytes such as potassium and sodium.

DIGOXIN – DIURETICS:

       Diuretics (eg, the thiazide derivatives) cause an excessive loss of potassium.

       Particular caution is necessary in patients being treated with digoxin, many of whom  would be candidates for diuretic therapy. If potassium depletion remains uncor­rected, the heart may  become more sensitive to the effects of the cardiac glycoside and arrhythmia may result.

       When both digoxin & diuretic therapy is given, alternately potassium supplementation  are  given but sometimes it may leads to risk of hyperkalemia , such risk is more   in patients with diminished renal function.

       In addition to the diuretics, other agents also cause potassium depletion. Prolonged therapy with cathartics and corticosteroids may cause potassium depletion,   not likely to occur as quickly or to the same extent as with diuretics.

       Diuretic therapy may lead to development of magnesium de­pletion, and as observed when     potassium is depleted, the activ­ity of digoxin may be increased and possibly result in toxicity.

              In some patients with digoxin toxicity, low serum-magnesium concentrations may coexist with normal potassium values.

ANGIOTENSIN CONVERTING ENZYME INHIBITORS - POTASSIUM SPARING         DIURETICS

       ACE inhibitors (eg, enalapril, lisinopril, ramipril) may cause an elevation of serum potassium concentrations.

       Potassium-sparing diuretics (amiloride, spironolactone, and triamterene) or potassium supplements should be used concurrently with caution, because of the risk of hyperkalemia and associated complications. Salt substitutes containing potassium also should be used with caution.

LITHIUM-DIURETICS

       Sodium depletion is known to increase lithium toxicity.

       So it has been recommended that lithium salts should not be used in patients on diuretic    therapy or on a sodium-restricted diet. Even pro­tracted sweating or diarrhea can cause       sufficient depletion of sodium to result in decreased tolerance to lithium.

       The sodium depletion caused by diuretics reduces the renal clearance and increases the      activity of lithium.

4. INTERACTIONS AT RECEPTOR SITES

MAO INHIBITORS - SYMPATHOMIMETIC AGENTS

       MAO metabolizes the catecholamines such as nor-epinephrine. When the enzyme is        inhibited, the concentrations of nor-e­pinephrine within adrenergic neurons increase, and a drug that can stimulate its release can bring about an exaggerated response.

       Exaggerated response is due  to interactions between MAO Inhibitors and indirectly acting sympathomimetic amines (eg. am­phetamine) is seen.  The effects due to these interactions are severe headache, hyper­tension (possibly a hypertensive crisis), and cardiac arrhyth­mias. 

       Although most sympathomimetic amines, such as am­phetamine, are available only by     prescription, others such as phenylephrine, which also interact simi­larly with MAOIs, are found in many nonprescription cold and allergy preparations. It is important that patients being treated with MAOIs avoid using products containing these agents.

MAO INHIBITORS - TRICYCLIC ANTIDEPRESSANTS

       Concurrent use of MAO Inhibitors with a tricyclic antidepressant (eg, amitriptyline,             imipramine) results in severe atropine-like reac­tions, tremors, convulsions, hyperthermia, and vascular col­lapse.

MAO INHIBITORS - SELECTIVE SEROTININ REUPTAKE INHIBITORS

       Serious consequences may result from the com­bined use of an MAO Inhibitors and selective serotonin reuptake inhibitors (SSRI) (citalopram, escitalopram, fluoxetine,     fluvoxamine, paroxetine, sertaline). So concurrent use or use within 14 days before or after most of these agents is contraindicated.

       Because of the long half-lives of flu­oxetine and its active metabolite, it is recommended that at least 5 weeks should elapse between discontinuation of fluoxe­tine and initiation of therapy with an MAOI.

       It should be noted that the antineoplastic procarbazine and the anti-infective furazolidone and linezolid, also can inhibit MAO enzymes, and warnings applying to the use of other MAOIs should be heeded for these drugs also.

 GUANETHIDINE-TRICYCLIC ANTIDEPRESSANTS

       Guanethidine is transported to its site of action within adrener­gic neurons by a transport system that also is responsible for up­take of nor-epinephrine, as well as several indirectly acting sympathomimetic amines such as ephedrine and the am­phetamines. Concentration of       guanethidine in these neurons is necessary for its antihypertensive action.

       Tricyclic antidepres­sants inhibit the uptake of guanethidine into the neuron termi­nal, thereby preventing its concentration at these sites and re­ducing its activity.

       Antipsychotic agents such as chlorpromazine and haloperidol can act similarly to the             tricyclic antidepressants in reducing the antihypertensive effect of guanethidine.

  

DRUG - FOOD INTERACTIONS

Ø   It is known that food can influence the absorption of a number of drugs. In some        situations, absorption may be delayed but not reduced, whereas in other circumstances the total amount of drug absorbed may be reduced.

Ø   The effect of food in influencing drug absorption sometimes is due to its action in   slowing gastric emptying. However, food also may affect absorption by binding with drugs, decreasing the access of drugs to sites of absorption, altering the dissolution rate of drugs, or altering the pH of the GI contents.

ANTI INFECTIVE AGENTS - FOOD:

Ø   The presence of food in the GI tract will reduce the absorption of many anti-infective agents. Although there are some exceptions (eg. peni-cillin V, amoxicillin, doxycycline, minocycline), it generally is rec-ommended that the penicillin and tetracycline           derivatives as well as certain other anti-infective agents be given at least 1 hr before meals or 2 hr after meals, to achieve optimum absorption.

Ø   Erythromycin stearate formulations should be administered at least 1 hr before meals or 2 hr after a meal, whereas formu­lations of erythromycin ethyl succinate may be given without regard to meals.

 CAPTOPRIL – FOOD :

Ø   The presence of food in the GI tract has been reported to reduce the absorption of captopril by 30 to 40%.  Food does not appear to alter the absorption of most of the other                         angiotensin-converting enzyme inhibitors (eg, enalapril, lisinopril).

Ø   ALENDRONATE AND RISEDRONATE-FOOD:

Food and even orange juice, coffee, and mineral water reduce the bioavailability of alendronate and risedronate and it is recommended that these drugs be administered soon after arising at least 1/2 hr before any food, beverage, or medication, with plain water only.

 ARBOSE & MIGLITOL - FOOD:

The maximum effectiveness of acarbose (an antidiabetic drug) is attained when the drug is taken immediately at the start of each meal (not ½ hr befor or after), because it delays the carbohydrate absorption (from the meal) and reduce the eleva­tion of blood    glucose concentrations by inhibiting the enzyme α- glucosidase.

Ø   SOME OTHER INTERACTIONS ARE :

1. Several tyramine food containing foods (eg: matured cheese, red wines, riped         bananas, yoghurt, shrimp paste, salami) are capable of producing hypertensive crisis in patients taking MAO Inhibitors.
2. Food can pharmacodynamically antagonise the effect of many drugs. For example, spinach & brocoli provide dietary source of vitamin K which antagonises the effect of warfarin .
3. Tetracyclines complex with calcium found in milk products.
4. Food increases the bioavailability of griseofulvin, metoprolol , propronolol, phenytoin ,     dextropropoxyphene , & dicumarol.
5. Food delays or reduces the bioavailability of NSAIDS, tetracycline, ethanol &         didanosine (antiviral drug).
6. Grape fruit and oranges inhibit CYP 3 A 4 isoenzyme system, increases  the     bioavailability   of indinavir , saquinavir , midazolam , nimodipine , nifedipine , lovastatin ,            carbamazepine & verapamil.
7. Rich protein diet results in acidic urine (pH 5.9), which Promotes excretion of basic drugs (like amphetamines) while low protein diet provides alkaline urine (pH 7.5) which promotes excretion of acidic drugs (eg: aspirin).
8. The rate of metabolism of theophylline is increased in individuals consuming large amounts of charcoal broiled beef because of enzyme inducing effects of polycyclic hydrocarbons (introduced in this cooking process).

BAL INTERACTIONS DRUG - HER

Ø  The nature of herb-drug interactions is not a chemical interaction between a drug and an herb component to produce something toxic. Instead, the interaction may involve having an herb component cause either an increase or decrease in the amount of drug in the blood stream.

Ø  A decrease in the amount of drug could occur by herb components binding up the drug and preventing it from getting into the blood stream from the gastrointestinal tract, or by stimulating  the production and activity of enzymes that degrade the drug and prepare it for elimination from the body.

Ø  An increase in the drug dosage could occur when an herb component aids absorption of the drug, or inhibits the enzymes that breakdown the drug and prepare it for   elimination. A decrease in drug dosage by virtue of an interaction could make the drug ineffective.

Ø  An increase in the drug dosage could make it reach levels that produce side effects.

Ø  Alternatively, an herb might produce an effect that is contrary to the effect desired for the drug, thereby reducing the drug effect; or , an herb might produce the same kind of effect as the drug and give an increase in the drug effect(without increasing the amount of the drug).

v  DUE TO THE HERB-DRUG INTERACTIONS, THE HERB MAY

·         Increase or decrease the effect of a blood thinner such as warfarin and lead to  either a bleeding episode or formation of dangerous clot.

·         Decreasing the effect of a blood pressure medication, leading to high blood pressure and a stroke.

·         Decreasing the effect of an anti-infection agent, letting the infection get out of control; or

·         Increasing the effect of an anti-diabetes drug and plunge blood sugar to        dangerously low levels.

v  EXAMPLE OF CERTAIN HERBS AND ITS EFFECT ON CERTAIN DRUG

·         Aloe Vera’s latex has laxative properties & lowers blood sugar. Hence,        concurrent use of laxatives and hypoglycaemic agents should be avoided. It may also decrease  the intestinal absorption of vitamin k and thus may potentiate    anticoagulant effects of warfarin.

·         Asian / Chinese ginseng potentiates the effects of anticoagulants, antiplatelet drugs, sympathomimetics, caffeine, MAO Inhibitors & CNS stimulants      (“ginseng abuse syndrome” with diarrhoea, hypertension & tremors). It          decreases the effects of                    antihypertensive drugs, cardiac glycosides & hormone replacement therapy.

·         Ginkgo biloba increases the bleeding tendency with concurrent use of             antiplatelet and        anticoagulant drugs.

·         Kava – Kava has summative effects with benzodiazepines & other         CNS depressants drugs. Use of antipsychotics is levodopa may potentiate dystonias.

·         St.John’s wort leads to phototoxicity when used with  tetracyclines,                sulfonamides & proton pump inhibitors & summation effects with                CNS depressants; decreases plasma      concentration  of digoxin , cyclosporin , warfarin , & protease inhibitors.

·         Administration of garlic with anticoagulant & antiplatelet drugs should be avoided because of the risk of bleeding. Garlic decreases the effectiveness of gastrokinetic drugs such as cisapride , metoclopramide & domperidone.

·         Ginger also, increases the risk of bleeding when used concomitantly with        antiplatelet /       anticoagulant drugs.

Ø  In China it is common for herbs to be combined with drugs. Their combination is sometimes incidental, but is often intentional and based on a prevalent favourable theory about using herbs and drugs.

Ø  The openion of Chinese doctors is that herbs reduce the side effects of drugs and help them to perform their function better, inturn drugs with an herb formula work more strongly and quickly. Together, herbs and drugs may produce a more desirable result than either taken alone. But little attention has been paid to adverse herb-drug          interaction.

Ø  In the West, the drugs were more reliable than herbs. The reintroduction of herbs bring with it suspicions and concerns about their unreliablity and the lack of adequate knowledge about them.

Ø  The “ xanthines”, such that the caffeine containing herbs(eg: coffee and tea) could counteract the action of sedatives or excessive stimulation with stimulant drugs.

Ø  The “coumarine containing” which makes reference to the fact that sum herbs contain coumarins which might act along with warfarin, a coumarine(binary coumarine, much more potent than coumarins) or along with other blood thinners.

CHINESE HERBS

Ø  The possible interaction of minor bupleurum combination(Xiao Chaihu Tang; in     Japan;  Sho Saiko To) with interferon in treatment of hepatitis to cause an immune   response leading to lung damage.

Ø  The possible interaction of saliva (Danshen) and warfarin, leading to excessive    thinning.

Ø  Th e possible interaction of aristolochic acid and diuretic drugs(or others) to cause   renal failure.

HERBALS AND DRUG INTERACTION

Name of Herb	Some common uses	Possible side effects or drug interactions
Cayenne	Extenal: used for muscle spasam and sourness Internal: GI tract disorders	External:potential for skin          ulceration and blistering with greaterthan two days  of use. Internal: overuse may cause severe hypothermia.
Echinacea	Echinacea boosts the immune   system helps fight colds and flu. Aids wound healing.	Echinacea may cause inflamation of the liver if used with certain other medications, such as anabolic steroids, methotrexate or others.
Ephedra	Ephedra is also called Ma-huang. It is used in many over-the-counter diet aids as an appetite             suppressant. It is also used for  asthama or bronchitis.	Ephedra may interact with certain antidepressant medications or     certain high blood pressure     medications to cause dangerous elevation in blood pressure or heart rate. It could cause death in certain individuals.
Feverfew	Feverfew is used to ward off     migrane headache and for arthritis, rheumatic disease and allergies.	Feverfew may increase bleeding, especially in patients already taking certain anti-clotting medications.
Garlic	Garlic is used for lowering blood cholesterol, triglyceride levels and blood pressure.	Garlic may increase bleeding,     especially in patients already taking certain anti-clotting medications.
Ginger	Ginger is used for nausea,        vomiting and vertigo.	Ginger may increase bleeding,    especially in patients already taking certain anti-clotting medications.
Ginkgo	Ginkgo, also called Ginkgo       billoba, it is used for increasing blood circulation and oxigenation and for improving memory and mental alertness.	Ginkgo may increase bleeding    especially in patients already taking certain anti-clotting medications.
Ginseng	Ginseng increases physical     stamina and mental concentration.	Ginseng may cause decreased effectiveness of certain anti-clotting medications.Persons using Ginseng see increased heart rate or high blood pressure. It may cause bleeding in women after menopause.
Goldenseal	Goldenseal is used as a mild   laxative and also reduces           inflamation.	Goldenseal may worsen swelling and or high blood pressure.
Kava-Kava	Kava-Kava is used for            nervousness, anxiety or restlessness, it is also a muscle relaxant.	Kava-Kava may increase the effects of certain anti-seizure medications and or prolong the effects of certain anesthetics. It can enhance the    effects of alcohol. It may increase risk of suicide for people with    certain types of depression.
Licorice	Licorice is used for treating Stomach ulcers.	Certain licorice compounds may cause high blood pressure, swelling or electrolyte imbalance.
Saw Palmetto	Saw Palmetto is used for enlarged prostate and urinary inflamations.	People using Saw Palmetto may see effects with other hormone      therapies.
St. John’s Wort	St. John’s Wort is used for mild to moderate depression or anxiety and sleep disorders.	St. John’s Wort may prolong the effect of anesthetic agents.
Valerian	Valerian is used as mild sedative or sleep aid. It is also a muscle  relaxant.	Valerian may increase the effects of certain anti-seizure medications or prolong the effects of certain      anesthetic agents.

 DRUG INTERACTIONS WITH HERBAL PRODUCTS:

Herbal Product	Interacting Drugs
Ginkgo biloba	Asprin,warfarin(Coumadin),ticpidine(Ticid),clopidogrel(Plavix),dipyridamole(Persantine)
St. John’s wort	Antidepressants
Ephedra	Caffeine,decongestants,stimulants
Ginseng	Warfarin
Kava	Sedatives, sleeping pills, anitpsychotics, alcohol

Ø  Some herbs, including garlic, ginkgo, ginseng and St. John’s Wort, have a significant influence on concurrently administered drugs.

Ø  Herbal medicines may mimic, decrease, or increase the action of prescribed drugs. This can be especially important for durgs with narrow therapeutic windows and in sensitive patient populations such as older adults, the chronically ill, and those with compromise immune system.

Activity	Commonly Used Herbs*
Anti-coagulant	Chamomile,dong quai(tang-kuei),horse chestnut
Anti-platelet	Bilberry, bromelain, cayenne, feverfew, flaxseed oil, garlic, ginger, ginkgo, ginseng, green tea, meadowsweet,motherwort, and turmeric
Pro-coagulant	Goldenseal,Oregon grape root,shepherd’s purse
*To expand the list of anticoagulant and antiplatelet herbs, the following are         mentioned in Pharmacology and Applications of Traditioinal Chinese Medicine(#):  White atracytlodes,cnidium(chuanxiong), salvia, garlic, zedoaria, pueraria, carthamus, lysimachia, cinnamon bark, tien-chi(sanqi), and capillaris(also listed:tang-kuei and turmeric).

DRUG LABORATORY TESTS INTERACTIONS 

Sometimes misinterpretation of laboratory test results & consequently wrong diagnosis may result due to drug interference in test values. Some examples are cited below:

1. Occurrence of a false positive test for urinary glucose after cephalosporin               administration.
2. Cephalosporin also produce spurious serum creatinine levels due to interference with common laboratory test procedures.
3. Diuretics can affect electrolyte (Na⁺, K⁺⁾ test results.
4. Alcohol increases γ-glutamyl transpeptidase values.
5. Iodohydroxy quinoline & radiocontrast media, being iodinated compounds, cause an increase in the real values of I¹³¹ uptake and protein bound iodine.
6. Salicylates, nalidixic acid & vitamin C provide a false positive test of urine sugar if performed by Benedict’s solution or Clintest reagents.
7. Spironolactone causes decreases in the renal values of digoxin plasma levels if       performed by radioimmunoassay.
8. Use of estrogens (in contraceptive pills) causes an increase in serum thyroxine values due to hyperproteinaemia (resulting from estrogens).
9. Use of MAO Inhibitors causes the decreases in the levels of urinary VMA due to     reduced   metabolism of nor-epinephrine.

REDUCING THE RISK OF DRUG INTERACTION

The guidelines to reduce and manage drug interactions are:

       Identify the Patient Risk Factors Factors such as age, the nature of the patient's medical  problems (eg. impaired renal function), dietary habits, smoking, and problems like alcoholism will influence the effect of certain drugs.

       Take a Thorough Drug History of a Patient.

       Be Knowledgeable about the Actions of the Drugs being used.

       Consider Therapeutic Alternatives.

       Avoid Complex Therapeutic Regimens.

       Educate the Patient about benefits and problems that could result from drug therapy.

       Monitor Therapy :

The risk of drug-related problems warrants close monitoring, not only for the possible  occurrence of drug interactions but also for adverse events occurring with individual agents and noncom­pliance.

       Individualize Therapy

§  As wide variations in the response of patients to the same dose of certain individual drugs, priority should be assigned to the needs and clinical response of the individual patient, rather than to the usual dosage rec­ommendations and standard treatment and monitoring guidelines.

§  The pharmacist will be involved actively in the observance of the guidelines and to maintain complete and current patient medication records, and also to supervise and monitor drug therapy more closely.

  

SUMMARY

v  It is impossible to remember all drug interactions, so medical pracitioners should be alerted to take appropriate steps to minimize their occurrence.

v  If the combination of potentially interacting drugs is unavoidable, the dose of any drug likely to have increased effects as a result of the interaction should be reduced and the  patient is monitored for toxic effects using clinical variables or plasma drug levels for at least 2 weeks or until these are stable.

v  Drugs that are likely to have reduced effects as a result of the interaction, the patient similarly should be monitored for therapeutic failure for at least 2 weeks or until    stable, and the dose is increased if necessary.

v  Treatment is given with the drug which does not interact.

v  Patients should be advised to seek guidance about their medication if they plan to stop smoking or start a herbal remedy, as they may need close monitoring during the   transition.\