Chapter 6 - Drug Interactions

CHAPTER 6 DRUG INTERACTIONS I.

DRUG-DRUG INTERACTIONS

- can occur whenever a patient takes two or more drugs (MORE DRUGS, MORE CHANCES OF INTERACTIONS) - may take multiple drugs to treat a single disorder or multiple disorders - may take OTC drug in addition to prescription medications - may take caffeine, nicotine, alcohol, and other drugs that have nothing to do with their illness - some interactions are both intended and desired - some interactions are both unintended and undesired - some adverse interactions are well known and generally unavoidable, other are yet to be documented A.

CONSEQUENCES OF DRUG-DRUG INTERACTIONS 1. Intensification of Effects potentiative – when a patient is taking two medications, one drug may intensify the effects of the other - interaction that enhances therapeutic effects is clearly beneficial - interaction that intensifies adverse effects is clearly detrimental 2.

Reduction of Effects inhibitory – interactions that result in reduced drug effects - interactions that reduce toxicity are beneficial - interactions that reduce therapeutic effects are detrimental - ex. asthmatic meds and beta blockers

3. Creation of a Unique Response – rarely, the combination of two drugs produces a new response not seen with either agent alone B.

BASIC MECHANISMS

OF

DRUG-DRUG INTERACTIONS

1. Direct Chemical or Physical Interaction – because of their physical or chemical properties, some drugs can undergo direct interaction with other drugs - direct physical and chemical interactions usually render both drug inactive - occur most commonly when drugs are combined in IV solutions which frequently, but not always, produces a precipitate - if precipitate appears, solution should be discarded - direct drug interactions may not always leave visible evidence, so you cannot rely on simple

inspection to reveal all direct interactions - because drugs can interact in solution, never combine two or more drugs in the same container unless it has been established that a direct interaction will not occur - same kinds of interactions that can take place when drugs are mixed together in a bottle can also occur when drugs are mixed together in a patient 2.

Pharmacokinetic Interactions a. Altered Absorption - by elevating gastric pH, antacids can decrease the ionization of basic drugs in the stomach, thereby increasing the ability of basic drugs to cross membranes and be absorbed - laxatives can reduce absorption by accelerating their passage through the intestine - drugs that depress peristalsis (morphine, atrophine) prolong drug transit time in the intestine, increasing the time of absorption - drugs that induce vomiting can decrease absorption of oral drugs - cholestryramine and certain other absorbent drugs (which are administered orally but do not undergo absorption) can absorb other drugs onto themselves, preventing absorption of the other drug into the blood - drugs that reduce regional blood flow can reduce absorption b.

Altered Distribution i. Competition for Protein Binding – when two drugs bind to the same site on plasma albumin, coadminstration of these drugs produces competition for binding - binding of both agents is reduced, causing plasma levels of free drug to rise - increase in free drug can intensify effects - increase in plasma levels of free drug is rarely sustained or significant due to rapid elimination ii. Alteration of Extracellular pH – a drug with the ability to change extracellular pH can alter the distribution of other drugs - ability of drugs to alter pH and thereby alter the distribution of other drugs can be put to practical use in the management of poisoning

c. Altered Metabolism – one of the most important and complex mechanisms by which drugs interact - some drugs increase the metabolism of other drugs by inducing synthesis of hepatic drug metabolizing enzymes - some drugs decrease the metabolism of other drugs by inhibiting hepatic drug metabolizing enzymes - majority of drug metabolism is catalyzed by the cytochrome P450 (CYP) group of enzymes; 5 of which are responsible for the metabolism of most drugs, designated as CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 i.

Induction of CYP Isozymes inducing agents – drugs that stimulate the synthesis of CYP isozymes - ex. is Phenobarbital - can stimulate their own metabolism as well as that of other drugs - can increase the rate of drug metabolism by as much as two- or three-fold - when taken concurrently with another medicine,

dosage of the other medicine may need adjustment - when discontinuing, dosages of other drugs may need to be lowered

ii. metabolism can be

to prevent drug levels from climbing dangerously high as rates of hepatic metabolism decline to their baseline values Inhibition of CYP Isozymes – although inhibition of drug beneficial, as a rule, inhibition has undesirable results - when an inhibitor increases the level of another drug, the outcome is toxicity - when an inhibitor is taken with other medicines, be alert for possible adverse effects

d.

Altered Renal Excretion - renal excretion includes filtration, reabsorption, and active

secretion - glomerular filtration can be decreased by drugs that reduce cardiac output which

decreased renal blood flow, decreases glomerular filtration at the glomerulus, which in decreases the rate of drug excretion - by altering urinary pH, one drug can alter the ionization of another, increasing or decreasing the extent to which that drug undergoes passive tubular reabsorption - competition between two drugs for active tubular secretion can decrease renal excretion of both agents 3. Pharmacodynamic Interactions – may be potentiative or inhibitory and are of great clinical significance a.

Interactions at the Same Receptor – almost always inhibitory - inhibition occurs when an antagonist drug blocks access of an agonist drug to its receptor - some reduce therapeutic effects and are undesirable - some reduce toxicity and are beneficial - ex. morphine and narcan b.

Interactions Resulting from Actions at Separate Sites - even though two drugs have different mechanisms of action and act at separate sites, if both drugs influence the same physiologic process, then one drug can alter responses produced by the other 4.

Combined Toxicity - common sense tells us that if drug A and drug B are both toxic to the same organ, then taking them together will cause more injury than if they were not combined - unfortunately, when treating certain illness (tuberculosis, HIV/AIDS), the combination is essential, and hence can’t be avoided C.

CLINICAL SIGNIFICANCE OF DRUG-DRUG INTERACTIONS - it should be clear that drug interactions have the potential to affect the outcome of therapy - interactions that increase therapeutic effects or reduce toxicity are desirable - interactions that reduce therapeutic effects or increase toxicity are detrimental - risk of serious drug interaction is proportional to the number of drugs that a patient is taking, SO

ALWAYS BE ALERT - interactions are especially important for drugs that have a low therapeutic index - interactions that produce a modest increase in drug levels can cause toxicity - interactions that produce a modest decrease in drug levels can cause therapeutic failure - if a patient develops unusual symptoms, it is wise to suspect that dug interaction may be the cause Ways to Minimize Adverse Interactions: - minimize the number of drugs a patient receives - take a thorough drug history that identifies all drugs the patient is taking to allow the prescriber to adjust the regimen accordingly ***NOTE: illicit drugs or OTC preparations may fail to be reported*** - adjust the dosage when an inducer of metabolism is added to or deleted from the regimen - adjust the timing of administration to minimize interference with absorption - monitor for early signs of toxicity when combinations of toxic agents cannot be avoided

II.

DRUG –FOOD INTERACTIONS - drug-food interactions are both important and poorly understood - important because they can result in toxicity or therapeutic failure - poorly understood because research has been sorely lacking

A.

IMPACT OF FOOD ON DRUG ABSORPTION 1. Decreased Absorption - frequently decreases the rate of drug absorption which merely delays the onset of effects - peak effects are not lowered - occasionally decreases the extent of absorption which reduces the intensity of peak responses - high fiber foods can reduce absorption of some drugs - interaction between calcium-containing foods and tetracycline antibiotics is the classic example of food reducing drug absorption - tetracyclines bind with calcium to form an insoluble and nonabsorbable complex causing absorption to be reduced and antibacterial effects may be lost 2.

Increased Absorption - with some drugs, food increases the extent of drug absorption - when this occurs, peak effects are heightened

B.

IMPACT

FOOD ON DRUG TOXICITY - drug-food interactions sometimes increase toxicity - most dramatic example is the interaction between monoamine axidase (MAO) inhibitors (family of antidepressants) and food rich in tyramine (e.g., aged cheese, yeast extracts, Chianti wine) - combining an MAO inhibitor with these foods can raise blood pressure to a life-threatening level - other examples include: Theophylline (an asthma medicine) plus caffeine, can result in excessive CNS excitation Potassium-sparing diurectics (e.g., spironolactone) plus salt substitutes, can result in dangerously high potassium levels Aluminum-containing antacids (e.g., Maalox) plus citrus beverages (e.g., orange juice), can result in excessive absorption of aluminum C.

IMPACT

D.

TIMING

OF

OF FOOD ON DRUG ACTION - although most drug food interactions concern drug absorption or drug metabolism, food may also (rarely) have a direct impact on drug action

DRUG ADMINISTRATION WITH RESPECT TO MEALS - administration of drugs at the appropriate time with respect to meals is an important facet of drug therapy - absorption of some drugs can be significantly decreased by food; these drugs should be administered on an empty stomach - absorption of other drugs can be increased with food; these drugs should be administered with meals - drugs may cause stomach upset when taken without food – if food does not reduce their absorption, administer with meals; however, if it does reduce absorption: administer with food and reduce stomach upset (good news) but reduce absorption (bad news) OR administer without food and improve absorption (good news) but increase stomach upset (bad news) no obvious choice - to administer with meals means shortly after a meal - to administer on an empty stomach means either 1 hour before or 2 hours after a meal OF

- medication orders frequently fail to indicate when a drug should be administered with respect to meals - if you are uncertain, ASK the prescriber

III.

DRUG-HERB INTERACTIONS

- herbal supplements are used widely in the U.S. creating the potential for frequent and significant interactions with conventional drugs - of greatest concern are the interactions that reduce beneficial responses to conventional drugs and interactions that increase toxicity - reliable information about herbal supplements is largely lacking – including information on interactions with conventional agents