DRUG – DRUG INTERACTIONS Department of Pharmaceutics 11/10/2018

The drug whose activity is affected by such an interaction Drug interactions : These are said to occur when the pharmacological activity of a drug is altered by the concomitant use of another drug or by the presence of some other substance. object drug: The drug whose activity is affected by such an interaction Precipitant: The agent which precipitates such an interaction 11/10/2018

Drug interactions include – Drug-drug interactions. Food-drug interactions, for example, inhibition of metabolism of several drugs by grapefruit juice. Chemical-drug interactions, for example, interaction of a drug with alcohol, tobacco or environmental chemicals. Drug-laboratory test interaction, for example, alteration of diagnostic laboratory test results by the presence of drug. Drug-disease interactions, for example, worsening of disease condition by the drug. 11/10/2018

Most interactions are specific types of adverse reactions with altered efficacy of the drug Eg : enhanced pharmacological activity (e.g. haemorrhagic tendency of warfarin when phenylbutazone is given subsequently) decrease in the therapeutic activity resulting in loss of efficacy like that of tetracycline when concomitantly administered with food, antacids or mineral supplements containing heavy metal ions. 11/10/2018

Factors Contributing to Drug Interactions Multiple drug therapy – is very common in most acute and chronic care settings, e.g: Therapy in patient suffering from hypertension and congestive heart failure includes antihypertensives as well as digitalis which together may lead to abnormal heart rhythms. Concurrent use of non-prescription drugs e.g: Aspirin as well as herbal medications also lead to drug interactions 11/10/2018

Multiple prescribers - Some individuals go to more than one physician, eg : one doctor may prescribe an anxiolytic for a patient while another prescribes an antihistamine having sedative properties with the possible consequence of an excessive depressant effect. Multiple pharmacological effects of drug – Most drugs used in current therapy exhibit more than one type of pharmacological action and have the capacity to influence many physiological systems. Therefore, two concomitantly administered drugs will often affect some of the same systems, for e.g. antihistamines (secondary effect is sedation) enhance the sedative effect of tranquillizers. 11/10/2018

Multiple diseases/Predisposing illness – Some patients take several drugs owing to their suffering from more than one disease, e.g. A patient with both diabetes and hypertension. Multiple therapies in such individuals generally result in drug interactions, e.g., oral hypoglycaemics and beta-blockers can result in decreased response to antidiabetic drug resulting in elevated blood sugar levels. Poor patient compliance – this results when a patient does not take medication in the manner intended by the doctor; which may be due to inadequate instructions from the doctor or pharmacist, confusion regarding taking several medicines, etc. all of which may lead to either underdosing or overdosing, and a consequent drug interaction. 11/10/2018

Advancing age of patient – Increased tendency of drug interaction episodes in elderly is generally due to decrease in liver function in such individuals. Drug related factors - Clinically significant interactions are most likely to occur between drugs that have potent effects, a narrow therapeutic index and a steep dose-response curve (e.g., cytotoxic, antihypertensive, and hypoglycemic drugs, digoxin, warfarin, etc.). 11/10/2018

Mechanisms of Drug Interactions Pharmaceutical Interactions Pharmacokinetic Interactions Absorption interactions Distribution interactions Metabolism interactions Excretion interactions Pharmacodynamic Interactions 11/10/2018

Pharmacokinetic Interactions – These interactions are those in which the absorption, distribution, metabolism and/or excretion of the object drug are altered by the precipitant and hence such interactions are also called as ADME interactions. The resultant effect is altered plasma concentration of the object drug. Pharmacokinetic interactions can thus be classified as – Absorption interactions – are those where the absorption of the object drug is altered. Major mechanisms of absorption interactions are – Complexation and adsorption. Alteration in GI pH. Alteration in gut motility. Inhibition of GI enzymes. Alteration of GI microflora. Malabsorption syndrome. 11/10/2018

ABSORPTION INTERACTIONS Object Drug(s) Precipitant Drug(s) Influence on Object Drug(s) ABSORPTION INTERACTIONS 1. Complexation and Adsorption Tetracycline, fluoroquinolones like ciprofloxacin, penicillamine Antacids, food and mineral supplements containing Al, Mg, Fe, Zn, Bi and Ca ions Formation of poorly soluble and unabsorbable complex with such heavy metal ions Cephalixin, sulphamethoxazole, trimethoprim, warfarin and thyroxine Cholestyramine Reduced absorption due to adsorption and binding 11/10/2018

Sulphonamides, aspirin Antacids 2. Alteration of GI pH Sulphonamides, aspirin Antacids Enhanced dissolution and absorption rate Ferrous sulphate Sodium bicarbonate, calcium carbonate Decreased dissolution and hence absorption Ketoconazole, tetracycline, atenolol Decreased dissolution and bioavailability 3. Alteration of Gut Motility Aspirin, diazepam, levodopa, lithium carbonate, paracetamol, mexiletine Metoclopramide Rapid gastric emptying; increased rate of absorption Levodopa, lithium carbonate, mexiletine Anticholinergics (atropine) Delayed gastric emptying; decreased rate of absorption 11/10/2018

5. Alteration of GI Microflora Digoxin Antibiotics (erythromycin, tetracycline) Increased bioavailability due to destruction of bacterial flora that inactivates digoxin in lower intestine Oral contraceptives Antibiotics (ampicillin) Decreased reabsorption of drugs secreted as conjugates via bile in the intestine 6. Malabsorption Syndrome Vitamin A, B12, digoxin Neomycin (and colchicines) Inhibition of absorption due to malabsorption/steatorrhoea caused by neomycin 11/10/2018

Distribution interactions – are those where the distribution pattern of the object drug is altered. The major mechanism for distribution interaction is alteration in protein-drug binding. Competitive Displacement Interactions Displaced drug(s) Displacer(s) Anticoagulants (warfarin) Phenylbutazone, chloral hydrate, salicylates Increased clotting time; increased risk of haemorrhage Tolbutamide Sulphonamides Increased hypoglycaemic effect Methotrexate Sulphonamides, salicylic acid Increased methotrexate toxicity Phenytoin Valproic acid Phenytoin toxicity 11/10/2018

METABOLISM INTERACTIONS Metabolism interactions – are those where the metabolism of the object drug is altered. Mechanisms of metabolism interactions include – Enzyme induction – increased rate of metabolism Enzyme inhibition – decreased rate of metabolism. It is the most significant interaction in comparison to other interactions and can be fatal. METABOLISM INTERACTIONS 1. Enzyme Induction Corticosteroids, oral contraceptives, coumarins, phenytoin, tolbutamide, Barbiturates Decreased plasma levels; decreased efficacy of object drugs Corticosteroids, oral contraceptives, theophylline, cyclosporin Phenytoin -do- Oral contraceptives, oral hypoglycaemics, coumarins Rifampicin 11/10/2018

Tyramine rich food (cheese, liver, yeast products) 2. Enzyme Inhibition Tyramine rich food (cheese, liver, yeast products) MAO inhibitors (phenelzine, pargyline, etc.) Enhanced absorption of unmetabolised tyramine; increased pressor activity; potentially fatal risk of hypertensive crisis Drugs that undergo extensive first-pass hepatic metabolism (e.g. propranolol, calcium channel blockers, etc) Grapefruit juice Enhanced absorption of drugs; increased risk of toxicity Folic acid Phenytoin Decreased absorption of folic acid due to inhibition of an enzyme responsible for its absorption Coumarins Metronidazole, phenylbutazone Increased anticoagulant activity; risk of haemorrhage Oral hypoglycaemics Phenylbutazone, sulphaphenazole, Hypoglycaemia may be precipitated Alcohol Disulphiram, metronidazole, tinidazole Disulphiram like reactions due to increase in plasma acetaldehyde levels 11/10/2018

EXCRETION INTERACTIONS Excretion interactions – are those where the excretion pattern of the object drug is altered. Major mechanisms of excretion interactions are – Alteration in renal flood flow Alteration of urine pH Competition for active secretion EXCRETION INTERACTIONS 1. Changes in Active Tubular Secretion Penicillin, cephalosporin, nalidixic acid, PAS, methotrexate, dapsone Probenicid (acid) Elevated plasma levels of acidic drugs; risk of toxic reactions Procainamide, ranitidine Cimetidine (base) Increased plasma levels of basic object drugs; risk of toxicity Acetohexamide Phenylbutazone Increased hypoglycaemic effect 2. Changes in Urine pH Amphetamine, tetracycline, quinidine Antacids, thiazides, acetazolamide Increased passive reabsorption of basic drugs; increased risk of toxicity 3. Changes in Renal Blood Flow Lithium bicarbonate NSAIDs (inhibitors of prostaglandin synthesis; the latter control renal blood flow partially by vasoconstriction) Decreased renal clearance of lithium; risk of toxicity 11/10/2018

Pharmacodynamic Interactions – are those in which the activity of the object drug at its site of action is altered by the precipitant. Such interactions may be direct or indirect. Direct pharmacodynamic interaction is the one in which drugs having similar or opposing pharmacological effects are used concurrently. The three consequences of direct interactions are – a)Antagonism: The interacting drugs have opposing actions, e.g. acetylcholine and noradrenaline have opposing effects on heart rate. b)Addition or Summation: The interacting drugs have similar actions and the resultant effect is the sum of individual drug responses, e.g. CNS depressants like sedatives, hypnotics, etc. c)Synergism or Potentiation: It is enhancement of action of one drug by another, e.g. alcohol enhances the analgesic activity of aspirin. Indirect pharmacodynamic interactions are situations in which both the object and the precipitant drugs have unrelated effects but the latter in some way alters the effects of the former, for example, salicylates decrease the ability of the platelets to aggregate thus impairing the haemostasis if warfarin induced bleeding occurs. The resultant effect of all pharmacodynamic interactions is thus altered drug action without a change in plasma concentration 11/10/2018

Reducing the Risk of Drug Interactions The consequences of drug interactions may be Major – life threatening Moderate – deterioration of patient’s status Minor – bothersome or little effect. The following are guidelines to reduce and manage drug interactions. Identify patient risk factors such as age, the nature of the patient's medical problem (e.g., impaired renal function), dietary habits, smoking, and problems such as alcoholism influence the effect of certain drugs. Take thorough drug history and maintain complete patient medication records. Keep knowledge about actions (both primary and secondary pharmacological actions) of drugs being utilized. 11/10/2018

Avoid complex therapeutic regimens where possible. Educate the patient to comply with instructions for administering medications. They should be encouraged to ask questions about their therapy and to report any excessive or unexpected responses. Monitor therapy: Any change in patient behavior should be suspected as drug-related until that possibility is excluded. Individualize therapy: priority should be assigned to the needs and clinical response of the individual patient, rather than to the usual dosage recommendations, standard treatment, and monitoring guidelines. 11/10/2018

REFERENCES : Milo gibaldi , biopharmaceutics and clinical pharmacokinetics” , “ Gastrointestinal absorption –physic-chemical considerations” , 4th edition ,2010, pg 40-60. D.M.Brahmankar , Sunil .B .jaiswal , “ Biopharmaceutics and pharmacokinetics” physic-chemical factors affecting drug absorption”, 5th edition ,2009. Biopharmaceutics and pharmacokinetics 2nd edition ,V.Venkateswarlu 11/10/2018

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