Drug Interactions is common for patient and doctor to prescribe more than one drug and this situation of multiple drug therapy may lead to drug interaction.
- The varied and complex mechanism involved in drug interaction. They can mostly classify as pharmacokinetic interaction and pharmacodynamic interaction.
- In pharmacokinetic interaction, one drug alters the absorption, distribution, metabolism, or elimination of the other drugs.
- In pharmacodynamic interaction, drugs modify the intended and expected action of other drugs.
Definition: Drug interaction results in the quantifiable alteration in response of one drug when administered with another drug, [Interaction including from prescription, nonprescription including complementary medicines drugs, food, alcohol, and smoking of cigarette or diagnostic tests.
- Drug interaction results in increased or decreased efficacy or toxicity of drug which is very dangerous at some time to the patient. There are large numbers of drug interactions associated with the use of anticoagulants, oral hypoglycemic agents, use of cytotoxic drugs, use of digoxin, etc.
Mechanisms of Drug Interactions
Table of Contents
For a better understanding of these complex interactions it is mechanically divided into the following two parts:
- Pharmacodynamic Interactions: In this interaction, agonist drugs act on the same receptor site results in enhancing the drug action while the antagonistic drug blocks the action of the agonist by binding at the same receptor site as of agonist drug.
- Pharmacokinetic Interactions: In this interaction, drugs affect the absorption, distribution, metabolism, or elimination of other drugs.
Pharmacokinetic Interactions
In this interaction, one agent alters the absorption, distribution, metabolism, or elimination of the second agent results in a change in the plasma concentration of the second agent. Different types of pharmacokinetic interaction are as follows:
[I] Alteration of Gastrointestinal Absorption:
Several variables are involved in the alteration of absorption. If there is a delay in the absorption of the drug then there is a decrease in plasma concentration level, reducing therapeutic effect or sometimes prolonged the onset of action.
Variables involved in alteration of absorption are as follows:
- Complexation/Chelation/Adsorption
- Altered Gastric pH
- Altered GI Transit
- Food
- GIT flora
- Inhibition of GI enzyme.
(A) Complexation/Chelation/Adsorption:
Examples of alteration in the absorption process by complexation formation are chelation between antacids and tetracycline; tetracycline with metals. Alteration of absorption is facilitated by the binding or complexation of the drug in the gastrointestinal tract. Tetracycline bind with divalent cations results in insoluble complex formation leading to the decrease in the quantity of tetracycline in the systemic circulation. More examples are given in Table.1.
Table.1: Drug Interactions involving Complexation Mechanism
| Primary Drugs | Secondary Drugs | Influence on Primary Drugs |
| Tetracycline, Penicillamine | Antacids, food, and mineral supplements containing aluminum, magnesium, ferric, and calcium ions | Poorly soluble and unabsorbable complex forms with metal ions. |
| Ciprofloxacin, Norfloxacin | Antacid containing aluminum, magnesium, and calcium ions. | Reduced absorption due to Complexation with metal ions. |
| Cephalexin, Trimethoprim, Sulfamethoxazole, Warfarin | Cholestyramine | Decrease the absorption due to adsorption and binding. |
(B) Altered Gl Transit/Emptying:
Absorption of drugs is also affected by alteration in GI transit or emptying rate. The drugs which affect the GI transit time administered with other influences the absorption process. Example: Administration of acetaminophen with anticholinergics delays in the absorption process of acetaminophen. More examples are given in Table.2.
Table.2: Drug Interactions involving Altered GI Transit Mechanism
| Primary Drugs | Secondary Drugs | Influence on Primary Drugs |
| Aspirin, Diazepam, Levodopa, Lithium carbonate, Paracetamol, Mexiletine | Metoclopramide | Rapid gastric transit increases the rate of absorption. |
| Levodopa, Lithium carbonate, Paracetamol, Mexiletine | Anticholinergic | Delayed gastric transit decreases the rate of absorption. |
(C) Altered Gastric pH:
- Non-ionized drugs (lipid-soluble) get more readily absorbed than ionized drugs (less lipid-soluble).
- In the acidic environment of the stomach, acidic drugs are available in the form of a non-ionized state. So, it is rapidly absorbed, while in an alkaline environment (intestine) acidic drugs become ionized and further absorption gets reduced.
- Basic drugs in contrast and these are readily absorbed from the gastrointestinal tract than from the stomach. Thus, the drugs that alter the pH of GIT may modify the absorption of subsequently administered drugs.
- Example: Administration of H₂ blockers along with ketoconazole decreases the dissolution rate of ketoconazole resulting in reduced absorption.
- Antacids raise the pH, possibly inhibiting or delaying the acidic drug absorption and enhancing the effects of basic drugs. Change in gastric pH may cause premature dissolution of certain drugs e.g. enteric-coated tablets to get dissolved in the stomach rather than intestine if taken after an antacid. More examples are given in Table.3.
Table.3: Drug Interactions involving Altered Gastric pH Mechanism
| Primary Drugs | Secondary Drugs | Influence on Primary Drugs |
| Sulphonamide | Antacid | Dissolution and absorption rate enhanced. |
| Ferrous sulfate | Sodium bicarbonate | Dissolution and absorption rate decreased. |
Food:
- In the stomach, the presence of food influence the absorption of several drugs. The food also reduces the absorption of the drug by binding with it or by changing the pH of Gl content or changing the dissolution rate of drugs.
- The presence of food in the stomach reduces the absorption of Penicillamine, erythromycin, rifampicin. So, it is recommended that antibiotics should be given at least two hours after or one hour before the meals to achieve optimum absorption.
Gastrointestinal Flora:
Certain antibiotics may enhance the response of anticoagulants by altering the gastrointestinal flora and thus interfering with vitamin K synthesis and resulting in alteration in the efficacy of anticoagulants. Other examples are given in Table.4.
Table.4: Drug Interactions by affecting GI Flora
| Primary Drugs | Secondary Drugs | Influence on Primary Drugs |
| Oral Contraceptives | Erythromycin, Tetracycline | Diminished the reabsorption of the drug via bile in the intestine |
| Digoxin | Ampicillin | Bioavailability increased due to demolition of bacterial flora in GI results in inactivation of digoxin in the lower part of the intestine |
Alteration of GI Enzyme:
The absorption of certain drugs depends on their metabolism by the enzyme. If these enzymes are inhibited then the absorption of drugs also decreases.
Example: Administration of folic acid along with phenytoin decreases the absorption of folic acid. In the diet, folic acid is present in the formula of polyglutamate which is poorly soluble. During absorption of folic acid, a polyglutamate form of folic acid is converted into monoglutamate form by using intestinal conjugase enzyme. Subsequent administration of phenytoin inhibits the enzyme conjugate and thus results in a deficiency of folic acid.
[II] Alteration in Distribution
Alterations in Plasma Protein Binding:
- These types of interactions are more significant when the 2 drugs are capable of binding to a similar site on the protein. The drug which has a greater affinity for binding positions will dislocate the other from plasma protein.
- Example: In the administration of phenytoin along with valproic acid, protein binding of valproic acid is reduced and total steady-state concentration decreased. Other examples are given in Tables.5.
Table.5: Drug Interaction affecting Protein Binding of Drug
| Bound Drug | Greater Affinity for Binding Sites (Displacing Drug) | Effects |
| Salicylates | Tolbutamide | Hypoglycemic |
| Barbiturates, Phenylbutazone | Warfarin | Hemorrhage |
| Phenyl propionic acid, Methotrexate | Sulphonamide | Agranulocytosis |
| Thiopentone | sulphonamide | Prolonged anesthesia |
[III] Alteration in Hepatic Metabolism
(A) Induction of Metabolism:
One drug enhances the metabolism of other drugs usually by stimulating the production of the hepatic enzyme involved in drug metabolism. Due to enzyme induction may cause rapid metabolism of the drug resulting in a decrease in the pharmacological action of a subsequent drug.
Example: When phenobarbital is administered with warfarin, there is an increase in the metabolism of warfarin, resulting in reduced anticoagulation.
(B) Inhibition of Metabolism:
A drug that inhibits the microsomal enzyme production may raise the blood level of the drug resulted to increase drug effect and longer duration of action.
Example: When cimetidine is administered with theophylline, cimetidine increases the plasma concentration of theophylline results in an increase in adverse effects. Table.6 indicates the examples of drugs that either induce or inhibits microsomal enzymes. While table.7 shows more examples of drug interactions involving metabolic mechanisms.
Table.6: Drug Induces and Inhibits Microsomal Enzyme
| Drug Induce Microsomal Enzyme | Drug Inhibit Microsomal Enzyme |
| Alcohol Cortisone Rifampicin Testosterone Phenytoin Imipramine Nicotine Phenobarbitone | Isoniazid Cimetidine Erythromycin MAO inhibitors Ciprofloxacin Diltiazem Propoxyphene |
Table.7: Drug Interactions Affecting Drug Metabolism
| Primary Drugs | Secondary Drugs | Influence on Primary Drugs |
| (A) Enzyme Induction | ||
| Corticosteroid, Oral contraceptives, Theophylline, Cyclosporine | Barbiturates, Phenytoin | Decreased the plasma level and efficacy of primary drugs because of enzyme induction. |
| (B) Enzyme Inhibition | ||
| Tyramine rich food | MAO inhibitor | Increased pressure activity. |
| Tricyclic antidepressant | Chlorpromazine, Haloperidol | Increased plasma half-life. |
| Coumarin | Metronidazole, Phenylbutazone | Increased anticoagulant activity, risk of hemorrhage. |
| Oral hypoglycemic drugs | Chloramphenicol Phenylbutazone | Hypoglycemia gets precipitate. |
| Alcohol | Metronidazole, Disulfiram | Increased the activity. |
| Benzodiazepine, warfarin, theophylline | Cimetidine | Increased blood level. |
[IV] Alteration in Renal Clearance
(A) Increased in Renal Blood Flow: Drug which increases the rate of renal clearance increases the excretion of another drug. Example: When hydralazine is administered with digoxin, there is an increase in the renal clearance of digoxin.
(B) Decreased Renal Blood Flow: Drug which decreases the rate of renal clearance decreases the excretion of other drugs results in a risk of toxic effects. Example: When NSAIDs are administered with lithium, NSAIDs decrease the clearance of lithium results in an increase in the risk of toxicity.
(C) Inhibition of Active Tubular Secretion: When Penicillin/PAS/Cephalosporin/Nalidixic acid/Methotrexate/Dapsone is administered with Probenecid (Acid), Probenecid prolongs the half-life of Penicillin and other drugs by increasing the plasma concentration thus allowing single-dose therapy for preventing toxic reactions.
(D) Alterations in Tubular Reabsorption: Alteration in tubular reabsorption affected the renal clearance process. Example: When antacids are administered with aspirin, there is a reduction in the reabsorption of salicylate from tubules through an increase in the pH of urine.
Pharmacodynamic Interactions
Combinations of drugs often are used as therapeutic advantages because their beneficial effects are additive or synergistic. According to their effects i.e. beneficiary or adverse interactions they are classified as follows:
(A) Drug having Similar/related Pharmacological Effects:
- Drugs acting at the same site or influencing the same physiological system cause a synergistic effect.
- The excessive pharmacological actions are seen due to the use of a drug that has similar pharmacological action. The examples are given in Table.8.
Table.8: Drug Interactions showing Similar Pharmacological Effects
| Primary Drug | Interacting Drug | Mechanism of Primary Drug | Mechanism of Interacting Drug | Effects |
| Nitroglycerin, related nitrate | Sildenafil, Tadalafil, Vardenafil | Nitrate produce vasodilation by elevation of cyclic GMP | Inactivation of cyclic GMP due to inhibition of phosphodiesterase in the vasculature | Profound hypotension |
| Oral anticoagulant warfarin | Non-steroidal anti-inflammatory drugs. e.g. aspirin | Inhibition of clot formation | Inhibiting platelet aggregation | Risk increases by fourfold for GIT bleeding |
| Warfarin | Antibiotics | Inhibition of clot formation | Alter the intestinal flora reduce the bacterial synthesis of vitamin K | Enhancing the effect of warfarin |
| Alcohol | Barbiturates, Antihistamines | CNS depressant | CNS depressant | Increased CNS depressant activity of alcohol |
(B) Drug having Opposite Pharmacological Effects:
The interaction occurs due to the use of two drugs which having an opposite pharmacological effect. These effects observe due to secondary effects of certain drugs. The examples are given in Table.9.
Table.9: Drug Interactions showing Opposite Pharmacological Effects
| Primary Drug | Interacting Drug | Mechanism of Primary Drug | Mechanism of Interacting Drug | Effects |
| ACE-inhibitors, Angiotensin receptor antagonists, and β-Adrenergic receptor antagonists | NSAIDs (Indomethacin, Ibuprofen, Piroxicam, COX- 2 inhibitors) | Hypotensive action | Increase the B.P. by PG mediated (Hypertension) | Antagonize the action of primary drug (raise the blood pressure) |
| Antidiabetic agents | Diuretics (Thiazide) | Hypoglycemic action | Elevated the blood glucose level | Counteract the action of hypoglycemic agents |
(C) Interactions at Receptor Site:
- The drug effects are seen as a result of binding to specialized areas on the receptor site. When drugs are concurrently administered, they may interact at the same receptors or different receptors but physiologically related sites.
- Administration of both the drugs Morphine and Nalorphine act at the same receptors site but the effect of Morphine such as respiratory depression is antagonized by Nalorphine.
(D) Alteration of Electrolyte Level:
- When the drugs alter the electrolyte level then it is important to monitor the effect when they are included in the therapeutic regimen.
- Example: Thiazide diuretics can cause loss of potassium at an extreme level. If digoxin is administered without correcting the level of potassium in the thiazide used patient, the heart becomes more sensitive to the response of digoxin, and arrhythmia may occur. Other drugs which alter the electrolyte level are Lithium/ NSAIDS/Sodium intake, ACEIs, A2-antagonists/K, K-sparing, Diuretics, K supplement, NSAIDS/antihypertensive agents.
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