Drug Interaction for diploma in pharmacy

health

1. Drug Interaction

2. Introduction: Drug interaction refers to the process of alteration in effect of one drug that occurs after co-administration of the another drug . It is an adverse or seldom a beneficial drug response produced . The effects of drugs may be modified by food, smoking, alcohol or environmental pollutants. The components of a drug interaction are: Precipitant drug: The drug which causes the interaction . Object drug: The drug which is affected by the interaction .

3. Causes of Drug Interactions (DIS) Improper knowledge of health care practitioner Inappropriate dose; high, low and both Polypharmacy Use of non prescriptive medicine Drug abuse Patient non-compliance Multiple prescriber. Multiple pharmacological effects. Individual variation of patients: Age, Genetic factor, Sex, Disease state, Renal function, Hepatic functions, Alcohol consumption, Smoking, Diet, Environment factor, Individual variation etc.

4. Factors affecting drug interaction Drug related factor Narrow therapeutic index Drug formulation (presence of interacting excipients) Drugs chemical and physiochemical properties Drug potency Duration of therapy Drug dosage Drug concentration in blood and tissue Timing and sequence of administration of interacting drug Route of administration Rate and extent of drug metabolism Degree of protein binding of interacting drugs Volume of distribution of affected drug

5. Patient-Related Factors Body weight and size Quantity and activity of specific drug-metabolizing enzymes Inherent inter- and intraindividual variability in pharmacokinetics and pharmacological response Age Gender Race Habit; Tobacco and Alcohol use Diet Underlying disease states and their severity Malfunction and disease of organs of drug elimination ( eg , liver,kidney ) Polypharmacy

6. Classification of DIs A. Consequence wise 1. Beneficial drug interactions Frequency and severity of the object drug related side effects is decreased, while the therapeutic effect is enhanced by the co-administration Aspirin + Acetaminophen This combination is used for more antipyretic effect. ( Levodopa + Carbidopa ) Carbidopa is used along with levodopa to minimize the systemic effect of levodo and to increase the anti parkinsonian action. Co- trimoxazole ( Sulfamethoxazole + Trimethoprim ) This combination is used because microbes resistant to one can be susceptible to the combination

7. Antihypertensives : Beta-blockers and diuretics are given in combination, as they are more effective when in combination. Antitubercular drug therapy: Combination therapy has proved to be much effective and is treating tuberculosis. Isoniazid + Ethambutol + Rifampicin + Pyrazinamide Local Anesthetics Minerals Iron is given in combination with Vitamin C since it increases the absorption of Iron Antidotes These are given for antagonizing the drugs in over dosage/toxicity cases.

8. 2. Adverse drug interactions Undesirable, unwanted and harmful alteration in the effect of one drug by the presence of another drug, food, drink or chemical agent

9. B) Site wise 1. In-vitro drug interactions These interactions occur during formulation and mixing of drug and usually termed as incompatibilities. I. Physical Interaction When two or more different chemicals/drugs are mixed, their physical state or color may be changed, changes may occur to all the constituents mixed together or of one component mixed. E.g. Heparin and Protamine when mixed together, such kind of interactions are observed. II. Chemical interaction During mixing of two or more chemicals/drugs produce altered product due to chemical reaction among them. E.g. Dopamine and Sodium bicarbonate, Furosemide and Ascorbic acid are mixed together, such kind of interactions are observed.

10. 2. In-vivo drug interactions Pharmacokinetic drug interactions I. Drug interaction due to absorption a. Adsorption, Chelation and other Complexing mechanisms Tetracycline and Antacids,Ca+ion forming insoluble complexes, chelates that can't be absorbed from the mucosal layer of GIT. Some adsorbents may also cause the reduction in the absorption of drugs e.g. Kaolin, Charcoal, Anion exchange resins. b. Change in Gl - pH Weakly acidic drugs are best absorbed at low pH e.g. Salicylates . Antacids, Proton-pump inhibitors, H, blockers affect the absorption of other drugs.

11. c. Alteration in gastric motility Opiates (Morphine, Codiene , Pethidine ) reduce gastric motility thus decrease absorption of another drug by decreasing gastric emptying Metocloperamide increases gastric emptying thus increase absorption of another drug d. Alteration in normal flora of GIT 10% Digoxin is inactivated by gut bacteria. Introduction of broad-spectrum antibiotics decrease the gut bacteria, hence increasing the levels of Digoxin

12. II. Drug interaction due to distribution a. Drug displacement/Protein binding interaction Reduction in the extent of plasma protein binding of one drug caused by the presence of another drug, resulting in an increased free or unbound fraction of the displaced drug If a patient taking Phenytoin is given another drug that displaces it from its binding sites, free or unbound drug increases. b. Receptor binding Binding sites are significant in interactions e.g. Quinidine displaces Digoxin from binding sites in skeletal muscle increasing serum concentration of Digoxin

13. III. Drug interaction due to Metabolism The concurrent administration of more than one drug may lead to an alteration in metabolic rates. Enzyme Induction Certain drugs induce enzyme systems causing more metabolism of drug Approximately 400 drugs and chemicals are enzyme inducers in animals and humans. Phenobarbital, Phenytoin , Carbamazepine , Rifampicin are enzyme inducers of clinical significance Enzyme Inhibition Certain drugs inhibit enzyme system causing less metabolism of drug, This likely results in increased serum concentration of the object drug and if the drug has narrow therapeutic index, the toxicity occurs very soon Ciprofloxacin and Norfloxacin inhibit CYP1A2 and ha been reported to increase plasma Theophyllin levels.

14. IV. Drug interaction due to Elimination Most drugs are eliminated either through the bile or through urine. Interactions occur when drugs interfere with kidney pH, active transport mechanism or blood flow. Changes in urinary pH A change in glomerular filtration rate (GFR), tubular secretion, reabsorption , urinary pH etc can alter elimination of the same drug. Urine alkalization and acidification is used as a mean of increasing the elimination of drug in the poisoning with Salicylates & Amphetamine Changes in active renal tubular excretion Competition at the same active transport system in tubules may occur with certain drugs Methotrexate toxicity is seen in patients concurrently treated with NSAIDs due to this process

15. II. Pharmacodynamic drug interactions In this process one drug induces a change in patient's response towards drug without altering the object drug's pharmacokinetics, are known as pharmacodynamic drug interactions. Types of pharmacodynamic drug interactions I. Additive reactions (A+A= 2A) If the effect of one drug doubles, on co-administering the similar dose of another drug, it is said to be showing additive effect. Two drugs with similar pharmacological effects when given together, the effect may be additive II. Synergestic reactions (A+A=>2A) If the effect of one drug becomes more than double, on co-administering the similar dose of another drug, it is said to be showing synergistic effect.

16. III. Antagonistic reactions (A + A =<A) If the effect of one drug becomes less than the effect of the single drug, on co administering the similar dose of another drug, Agonist and antagonist competition for the same receptor site antagonists may be used to reverse the effect of another drug at the receptor site e.g. Opioid vs. Naloxone , Benzodiazepine vs. Flumezinil IV. Indirect pharmacodynamic interactions There are many indirect pharmacodynamic interactions of potential clinical significance. Eg . MAOIS and SSRIS, MAOIS and TCAS are responsible for serotonin syndrome. It is caused by excessive serotonin activity in CNS which causes confusion, fever, shivering, ataxia, diarrhea,

17. Clinical Significance of DIs  Drugs that have small therapeutic index so that relatively small quantitative changes at the target site, will lead to substantial changes in effect, eg lithium Drugs that are exhibit saturable metabolism when small interference with kinetics may lead to large alteration of plasma concentration, eg phenytoin Drugs that are used long-term, where precise plasma concentrations are required, egantiepilepsy drugs, lithium When drugs that may interact are used to treat the same disease, for this increases their chance of being given concurrently, e.g. theophylline and salbutamol given for asthma may cause cardiac arrhythmia In patients with significantly impaired liver or kidney function, for these are the principal organs that terminate drug action In the elderly, for they tend to have multiple pathology, may receive several drugs concurrently, and are specially susceptible to adverse drug effects