1. DRUG – DRUG INTERACTIONS
Department of Pharmaceutics
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2. 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
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3. 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.
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4. 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.
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5. 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
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6. 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.
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7. 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.
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8. 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.).
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9. Mechanisms of Drug Interactions
Pharmaceutical Interactions
Pharmacokinetic Interactions
Absorption interactions
Distribution interactions
Metabolism interactions
Excretion interactions
Pharmacodynamic Interactions
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10. 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.
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11. 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
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12. 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
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13. 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
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14. 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
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15. 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
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16. 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
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17. 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
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18. 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
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19. 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.
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20. 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.
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21. REFERENCES :
Milo gibaldi , biopharmaceutics and clinical pharmacokinetics” , “ Gastrointestinal absorption –physic-chemical considerations” , 4th edition ,2010, pg
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
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