Drug interactions

ALEKHYA RAVELLAM PHARMACY(PHARMACOLOGY)

MALLAREDDY INSTITUTE OF PHARMACEUTICAL SCIENCES

An interaction is said to occur when the effects of one drug are changed by the presence of another drug, food, drink or by some environmental chemical agent.

Definition

For convenience the mechanisms of interactions can be subdivided into those which involve the pharmacokinetics of a drug and those which are pharmacodynamic.

Mechanisms of drug interaction

Pharmacokinetic interactions are those which can affect the processes by which drugs are absorbed, distributed, metabolized and excreted (the so-called ADME interactions).

Pharmacokinetic interactions

ALTERATIONS IN ABSORPTION

Complexation/Chelation:

Example:

1)antacids + tetracyclineImpact: tetracycline complexes with divalent cations

forming an insoluble complex

Pharmacokinetic interactions

Effects of changes in gastro intestinal ph:

example:

ketoconazole + antacids proton pump inhibitors

Impact: reduced ketoconazole absorption due to reduced dissolution

Change in gastrointestinal motility:Example:anticholinergics + acetaminophenImpact: delay in absorption of acetaminophen

Induction or inhibition of drug transport proteins:Example:Digoxin is a substrate of p glyco protein and drugs

induce this such as rifampicin,may reduce the bioavailability of digoxin.

Malabsorption caused by drugs:

Example: Neomycin causes malabsorption syndrome.the effect

is to impair the absorption of no of drugs including digoxin and methotrexate.

Protein binding interaction: Example: when patients stabilised on warfarin are given chloral

hydrate because its major metabolite, trichloroacetic acid, is a highly bound compound which successfully displaces warfarin, thereby increasing its anticoagulant effects.

Drug distribution interactions

Changes in first pass metabolism:i)changes in blood flow through liver:

Example:Increase in rate of absorption of dofetilide with

verapamil,which has resulted increase of torsade de pointers.

ii)Inhibition or induction of first pass metabolism:

Example :grape fruit juice induce the cyto chrome p450 isoenzyme cyp3A4 ,which increase the metabolism of calcium channel blockers..

Drug metabolism interactions:

Enzyme induction:Example: phenobarbital + warfarinImpact: phenobarbital increases the metabolism of

warfarin, resulting in reduced anticoagulation.

Enzyme inhibition:Example: cimetidine + theophyllineImpact: cimetidine reduces the clearance of

theophylline causing an increase in adverse effects

Changes in urinary ph:

Thus pH changes that increase the amount in the ionised form (alkaline urine for acidic drugs, acid for bases) increase the loss of the drug, whereas moving the pH in the opposite directions will increase their retention.

Example:changes in the excretion of quinidine and salicylate

due to alterations in urinary pH caused by antacids

Drug excretion interactions

Changes in active renal tubular excretion:

Example: probenecid + penicillin Impact: probenecid prolongs the half-life of penicillin,

allowing single dose therapy. Changes in kidney blood flow : The flow of blood through the kidney is partially

controlled by the production of renal vasodilatory prostaglandins. If the synthesis of these prostaglandins is inhibited (e.g. by indometacin), the renal excretion of lithium is reduced and its serum levels rise as a result.

Additive or synergistic interactions and combined toxicity :

Example: alcohol depresses the CNS and, if taken in moderate

amounts with normal therapeutic doses of any of a large number of drugs (e.g. sedatives, tranquillisers, etc.), may cause excessive drowsiness.

Antagonistic or opposing interactions : Example: the oral anticoagulants can prolong the blood

clotting time by competitively inhibiting the effects of dietary vitamin K.

Pharmacodynamic interactions:

A food-drug interaction can occur when the food you eat affects the ingredients in a medication you are taking, preventing the medicine from working the way it should.

Food-drug interactions can happen with both prescription and over-the-counter medications, including antacids, vitamins, and iron pills.

Food-Drug Interactions:

Drug - grapefruit interactions: 

Drugs which may exhibit increased serum concentrations based on this interaction

amiodarone astemizole alprazolam atorvastatin benzodiazepines  buspirone carbamazepine carvedilol cerivastatin cilostazol 

What you should remember about food-drug interactions:

Read the prescription label on the container. If you do not understand something, or think you need more information, ask your physician or pharmacist.

Read directions, warnings, and interaction precautions printed on all medication labels and package inserts. Even over-the-counter medications can cause problems.

Take medication with a full glass of water. Do not stir medication into your food or take capsules apart

(unless directed by your physician). This may change the way the drug works.

Do not take vitamin pills at the same time you take medication - vitamins and minerals can interact with some drugs

Alcohol + Barbiturates

Alcohol and the barbiturates are CNS depressants, which together can have additive and possibly synergistic effects. Activities requiring alertness and good co-ordination, such as driving a car or handling other potentially dangerous machinery, will be made more difficult and more hazardous. Alcohol may also continue to interact the next day if the barbiturate has hangover effects.

Alcoholic drug interactions:

Clinical evidence A study in man of the effects of a single 0.5-g/kg

dose of alcohol, taken in the morning after a dose of amobarbital 100 mg every night for 2 weeks showed that the performance of co-ordination skills was much more impaired than with either drug alone. 1

Mechanisms Both alcohol and the barbiturates are CNS

depressants, and simple additive CNS depression provides part of the effects. 9 Acute alcohol ingestion may inhibit the liver enzymes concerned with the metabolism of the barbiturates. 10

Herbal drug interaction:

Garlic is used for lowering blood cholesterol, triglyceride levels and blood pressure.

Garlic may increase bleeding, especially in patients already taking certain anti-clotting medications.

Ginger is used for reducing nausea, vomiting and vertigo

Ginger may increase bleeding, especially in patients already taking certain anti-clotting medications.

Ginger

St. John's Wort

St. John's Wort is used for mild to moderate depression or anxiety and sleep disorders.

St. John's Wort may prolong the effect of certain anesthetic agents.

Kava-kava Kava-kava is used for

nervousness, anxiety or restlessness; it is also a muscle relaxant.

Kava-kava may increase the effects of certain anti-seizure medications and/or prolong the effects of certain anesthetics. it can enhance the effects of alcohol. It may increase the risk of suicide for people with certain types of depression.

DRUG CATEGORY REASON Astemizole antihistamine serious metabolic drug intxns Bromfenac analgesic hepatotoxicity Dexfenfluramine anorectic cardiovascular tox Felbamate anticonvulsant aplastic anemia Flosequinan vasodilator increased mortality Grepafloxacin antibiotic proarrhythmic Mibefradil Ca channel blocker serious drug intxns Temafloxacin antibiotic severe ADR Terfenadineantihistamine serious drug intxn Travafloxacin antibiotic hepatotoxicity

DRUGS REMOVED FROM THE MARKET DURING THE 1990s

Be on the alert with any drugs which have a narrow therapeutic window or where it is necessary to keep serum levels at or above a suitable level (e.g. anticoagulants, anticonvulsants, antihypertensives, anti-infectives, cytotoxics, digitalis glycosides, hypoglycaemic agents, immunosuppressants, etc.).

Remember those drugs which are enzyme inducing agents (e.g. phenytoin, barbiturates, rifampicin, etc) or enzyme inhibiting agents (e.g. cimetidine).

Think about the basic pharmacology of the drugs under consideration so that obvious problems (additive CNS depression for example) are not overlooked, and try to think what might happen if drugs which affect the same receptors are used together. And don’t forget that many drugs affect more than one type of receptor which results in side-effects.

Keep in mind that the elderly are most at risk because of reduced liver and kidney function on which drug clearance depends.

Conclusion

Fugh-Berman A, Ernst E, Herb-drug interactions: review and assessment of report reliability, British Journal of Clinical Pharmacology 2001, 52(5): 587-595.

Abebe W, Herbal medication: potential for adverse interactions with analgesic drugs, Journal of Clinical Pharmacology and Therapeutics 2002; 27(6): 391-401

.Bailey, D.G., Malcolm, J., Arnold, O. and Spence, J.D. Grapefruit Juice-Drug Interactions, Br. J. Clin. Pharmacol. 1998; 46: p. 101-110.

REFERENCES