1. Drug-Induced Diseases

2. A drug-induced disease is the unintended effect of a drug that results in mortality or morbidity with symptoms sufficient to prompt a patient to seek medical attention and/or to require hospitalization. Drug-induced disease can result from unanticipated or anticipated drug effects. Disease also can occur from product impurities, as was the case with deaths attributed to the use of contaminated heparin in 2008. Vigilance on the part of regulatory authorities, drug manufacturers, clinicians, and patients is necessary to minimize the potential for harm that is inherent in drug use. In everyday clinical practice, adverse events associated with the use of medical products can lead to hospitalization, permanent disability, and even death. Physicians and other health professionals should be aware of the extent and spectrum of drug-induced disease. Monitoring for and reporting adverse events can save lives and spare others from illness.

3. Pharmacokinetic and pharmacodynamic factors: Toxic or exaggerated responses to normal drug doses can lead to drug-induced diseases and other adverse events for two reasons. First, excessively high concentrations of unbound drug or metabolite at the site of action may occur as a result of unusual pharmacokinetics (absorption, distribution, metabolism, excretion) of the drug or metabolites. Second, response to a given concentration of unbound drug or metabolite at the site of action (pharmacodynamics) may be exaggerated or unusual because of many factors, including changes in the number and/or binding affinity of target receptors as well as alternations in signal-transduction pathways.

4. The pharmacokinetic and pharmacodynamic behaviours of drug may be influenced by factors 1.Concurrent Diseases; 2.Physiologic Conditions; 3. Drug-drug interactions ; 4. Drug-Food Interactions ; 5. Lifestyle Factors; 6. Genetic Variability; 7.Adherence To Prescribed Therapy; 8.Medication Errors

5. Concurrent Diseases For drugs or drug metabolites that are highly dependent on the kidney or liver for elimination, usual does produce higher-than-normal serum drug concentrations in patients with kidney or liver disease respectively. This results in an exaggerated response, particularly for drugs with narrow therapeutic index. Cardiovascular diseases, such as acute myocardial infarction or heart failure, may reduce hepatic and/or renal blood flow and decrease the elimination of drugs that are normally highly extracted by the liver. Serum concentrations and response are increased if such drugs are administered intravenously. Hypothyroidism may be associated with a decrease in both hepatic and renal drug clearances.

6. Many diseases can also decrease the serum protein binding of drugs. For example, kidney and liver diseases have been associated with decreased albumin binding of some drugs. Misinterpretation of total serum drug concentrations of highly protein-bound drugs that are routinely monitored may lead a clinician to inappropriately increase the dose, thus resulting in toxicity. Concurrent diseases may also be associated with enhanced pharmacodynamic responses to drugs for a variety of reasons. For example, The incidence of skin rashes and serious dermatologic adverse effects such as Stevens-Johnson syndrome is increased in patients with human immunodeficiency virus (HIV) infection who are taking trimethoprim-sulfamethoxazole Concurrent Diseases (continue…)

7. 2.Physiologic Conditions The pharmacokinetics of a drug may be affect by age, pregnancy, and sex. In general, the rate of elimination of a drug is impaired in premature newborns, increases in early childhood to more efficient rates than those in adults, and then progressively declines with advancing age. In addition, early patients may also suffer from decreased mental status or diminished physical function. When these physiologic conditions are compounded by decreased elimination of some drugs, the patient is more susceptible to drug-induced falls or physical injury (i.e., benzodiazepines).

8. 2.Physiologic Conditions(Continue..) A variety of physiologic changes during pregnancy may affect the pharmacokinetics of drugs, but no consistent patterns have been identified. The higher serum concentrations of digoxin reported in pregnant patients may be caused by increased bioavailability resulting from decreased gastric emptying time. Women have a higher risk of drug-induced adverse events as compared with men, which has been attributed to the fact that they take more drugs than men, have lower activity of drug- metabolising enzymes, and have estrogen-related effects on drug receptors, as in the case of drug-induced torsades de pointes.

9. 3.Drug-drug interactions Drug-drug interactions may cause altered pharmacokinetics (bioavailability, distribution, clearance) or altered pharmacodynamics by additive or antagonistic effects. Such interactions have been extensively reviewed and are more often a predictable and preventable cause of morbidity and mortality. By far the most frequent contributing factors to drug-induced disease resulting from drug interactions are those that affect bioavailability and drug elimination. A large number of important interactions occur in the liver and gastrointestinal tract because of decreases in the rate of a drug’s metabolism or transport caused by other drugs that are inhibitors of these systems.

10. 3.Drug-drug interactions (continue….) Drugs that displace other drugs from serum protein-binding sites without affecting their metabolism cause only transient increases in unbound drug concentration, and hence do not generally result in adverse effects. Serious drug-drug interactions may also occur when drugs produce additive effects through different mechanisms. Examples include: the combined blood-pressure- lowering effects of calcium channel-blockers and β -blockers An example of a drug-drug interaction involving active or toxic metabolites is the potentiation of acetaminophen hepatotoxicity in patients receiving enzyme inducer such as rifampin, presumably by increasing the formation of toxic acetaminophen metabolites.

11. 4. Drug-Food Interactions Drug-food interactions have been extensively reviewed. A large dietary intake of tyramine (or a dietary intake of tyramine while taking MAO inhibitors ) can cause the tyramine pressor response, which is defined as an increase in systolic blood pressure of 30 mmHg or more. The displacement of norepinephrine (noradrenaline) from neuronal storage vesicles by acute tyramine ingestion is thought to cause the vasoconstriction and increased heart rate and blood pressure of the pressor response. In severe cases, adrenergic crisis can occur. The salt, protein, or vitamin content of the diet also may affect the renal excretion of drugs. For example, a patient taking lithium who initiates a low-salt diet for treatment of hypertension or heart failure excretes less lithium, resulting in higher serum lithium concentrations and potential toxicity, given this drug’s narrow therapeutic range. A low- protein diet is associated with decreased renal clearance of oxypurinol, apparently through enhanced reabsorption efficiency by the uric acid transporter system.

12. 5. Lifestyle Factors Alcohol and caffeine consumption can affect both the pharmacokinetics and the pharmacodynamics of other drugs, leading to serious drug-induced diseases. There are many examples of alcohol exaggerating the central nervous system depressant effects of drugs, including benzodiazepines, phenothiazines, tricyclic antidepressants, opiates, and anthistamines. Caffeine has an additive and potentially dangerous stimulant effect when taken with ephedrine in herbal weight-loss and athletic performance- enhancing supplements.

13. 6. Genetic Variability As a result of the rapidly evolving field of pharmacogenomics, inter individual differences in drug related toxicity and therapeutic response are not always considered to be “idiosyncratic” responses. Rather, it is widely recognized that genetic makeup is responsible for a significant portion of drug-induced diseases. Many genes that encode metabolic enzymes or drug transporters are polymorphic, meaning that some groups of patients with certain gene variants have relatively inactive enzymes or transporters, while others have unusually active forms. In addition, the proportion of patients with active or inactive forms may differ among racial groups. Patients with low N-acetyltransferase activities, known as “slow acetylators,” are more likely to suffer from peripheral nerve damage when administered standard isoniazid doses as compared with fast acetylators. Severe and potentially fatal hematologic toxicity occurs in the small percentage of patients receiving azathioprine or mercaptopurine who have a genetic deficiency in the thiopurine methyltransferase enzyme

14. 7.Adherence To Prescribed Therapy Noncompliance implies that the patient is intentionally or willfully not following directions for medication use, which may or may not be the case. For this reason, some prefer the term non adherence, because it places no blame on either the patient or the health care professional. Common causes of non adherence are listed in Table 1. Regardless of the cause, non adherence can lead to drug-induced disease. Patients may take more or less drug than prescribed or recommended, modify medications in an inappropriate fashion (e.g., crush a sustained- release tablet), or continue to take a prescribed drug even though the underlying medical condition for which the drug was originally prescribed has resolved. Any of these actions can put patients at increased risk for drug-induced disease.

15. 7.Adherence To Prescribed Therapy (continue..) Unfortunately, health care providers typically are unable to identify patients at risk for non adherence. Patient age, sex, race, intelligence, and educational background have not been shown to be predictive of adherence or non adherence to a prescribed drug regimen. Until the most effective strategy or strategies to improve adherence can be identified, it is recommended that healthcare professionals keep drug regimens simple, provide clear and complete instructions, encourage medication adherence by scheduling regular appointments, respond clearly and promptly to patients’ questions and concerns, and reinforce adherence with the prescribed regimen at every opportunity.