Drug Drug interaction

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DRUG DRUG INTERACTION: A drug interaction has occurred when the administration of one drug alters the clinical effects of another. The result may be an increase or decrease in either the beneficial or harmful effects of the second agent. Although the number of potential interacting drug combinations is very large only a small number are relevant in clinical practice. " Harmful drug interactions are most likely to occur when the affected drug has a:"

> Low therapeutic index meaning that only a small increase in plasma concentration may cause toxic effects
> Steep dose-response curve meaning that a small change in plasma concentration leads to a significant increase in pharmacodynamics effect  (where a small increase in dose results in a large increase in plasma level)
> High first-pass metabolism because these are drugs that are extensively metabolized in the liver or gastrointestinal tract and are therefore sensitive to the effects of metabolic inhibition or induction
> Single mechanism of elimination (e.g. renal clearance, cytochrome metabolism) meaning that the interacting drug can cause a significant increase in plasma concentration.

Drug Interaction Absorption :

" Absorption interactions involve changes in either the rate or extent of absorption. The rate of absorption of most drugs is dependent on gastric emptying into the small bowel. Drugs that either delay (e.g. anticholinergic drugs) or enhance (e.g. prokinetic drugs) the rate at which this occurs will influence the rate of rise in plasma concentration but not the total amount of drug absorbed. The extent of absorption can be influenced by second drugs that bind to form insoluble complexes or chelates (e.g. aluminium containing antacids binding with ciprofloxacin). Drug transport systems, notably the P-glycoprotein (the product of the multidrug resistance gene), are responsible for limiting or enhancing absorption of drugs. It is very likely that these will be the site of drug-drug interactions although most are uncharacterised."

Drug Interaction Distribution

" Distribution interactions occur when drugs are extensively protein-bound and the co-administration of a second can displace it to the non-bound active form. This increases the amount of (unbound) drug available to cause an effect. For example, diazepam displaces phenytoin from plasma proteins, resulting in an increased plasma concentration of free phenytoin and an increased risk of toxicity. The effects of protein displacement are usually short-lived because the metabolism of the affected drug usually increases in parallel with the increased free drug concentration. Distribution interactions can however be significant for drugs that have extremely rapid distribution or narrow therapeutic indices, such as lithium or digoxin.

Drug Interaction Metabolism :

" Many drugs rely on metabolism by different isoenzymes of cytochrome P450 (CYP) in the liver, especially 3A, 2D6, 2C9, 2C19, and 1A2. Interacting drugs have the potential to either increase the rate of metabolism by inducing the formation of more CYP isoenzyme or decrease metabolism by inhibiting isoenzyme activity. Enzyme inducers (e.g. phenytoin, rifampicin) generally reduce plasma concentrations although may enhance conversion of a pro-drug to its active form. Enzyme inhibitors (e.g. clarithromycin, cimetidine, grapefruit juice) have the opposite effect. Enzyme induction effects usually take at least a few days to manifest because of the need to synthesize new CYP enzyme. In contrast, the effects of enzyme inhibition may be rapid with the affected drug quickly reaching a new higher steady state concentration. "

Drug Interaction Excretion :

" Excretion interactions primarily involve changes in renal excretion. This might be due to drug-induced reduction in glomerular filtration rate (e.g. diuretic-induced dehydration, ACE inhibitors, NSAIDs). This can reduce the clearance and increase the plasma concentration of many drugs, including some with a low therapeutic index (e.g. digoxin, lithium, aminoglycoside antibiotics). Less commonly, interactions may be due to competition for a common tubular organic anion transporters (e.g. methotrexate excretion may be inhibited by competition with NSAIDs). In some cases this kind of interaction can be used for therapeutic benefit (e.g. probenecid prolongs the half life of penicillin be competing for tubular excretion). The likelihood of clinically significant excretion interactions increases if a patient has renal impairment.

Drug Interaction Examples :

" Fluoxetine and Phenelzine "

The interaction can result in a central serotonin syndrome.This condition is characterized by mental status changes, agitation, diaphoresis, tachycardia, and death. These symptoms can develop quickly with only 1 or 2 doses of fluoxetine when combined with phenelzine. Serotonin syndrome is possible with any monoamine oxidase inhibitor (MAOI), such as phenelzine or tranylcypromine sulfate, in combination with any drug that increases serotonin levels, such as dextromethorphan, meperidine, and other selective serotonin reuptake inhibitors (SSRIs).It is recommended that fluoxetine be stopped for at least 5 weeks before an MAOI is prescribed because of the long half-life of fluoxetine and its primary metabolite, norfluoxetine. Also, 2 weeks should be allowed after discontinuation of an MAOI before starting SSRI treatment.

" Digoxin and Quinidine "

This significant drug interaction has been known for a long time, yet it continues to be a problem, often with devastating results. The interaction can lead to a marked increase in plasma concentration levels of digoxin in more than 90% of patients.Significant changes in serum digoxin are noticed within 24 hours. The average increase is roughly 2-fold.The effects from this interaction range from nausea and vomiting to death. The primary mechanism for this interaction is a decreased volume of distribution of digoxin, secondary to its displacement from binding sites in body tissues.Quinidine also decreases renal and non renal excretion rates of digoxin, which leads to increased steady-state concentrations of the cardiac glycoside.Ideally, patients taking digoxin should avoid the use of quinidine; however, if the combination is necessary, the patient should be closely watched. Pharmacists should anticipate the need to reduce the digoxin dose by one half.

"Sildenafil and Isosorbide Mononitrate "

Sildenafil may markedly increase the hypotensive effects of isosorbide mononitrate.More than 123 deaths have been reported since 1998, when sildenafil was made available in the United States.Most deaths were among patients with 1 or more risk factors, including obesity, hypertension, and cigarette smoking. Sildenafil was developed as a phosphodiesterase-5 (PDE5) inhibitor. In the presence of PDE5 inhibitors, nitrates can cause intense increases in cyclic guanosine monophosphate and dramatic drops in blood pressure.Patients taking isosorbide mono-nitrate or any nitrate, including nitroglycerin, should be advised not to take sildenafil.

Potassium Chloride and Spironolactone November 2002 Table 2This is another significant drug interaction that has been known for a long time. The combination may result in hyperkalemia.The resulting hyperkalemia can be serious and may lead to cardiac failure and death. Patients with renal impairment are especially prone to this effect. Spironolactone is a competitive antagonist of mineral corticoids, of which aldosterone is a potent example.This mechanism occurs in the kidney at the distal portion of the nephron and leads to the excretion of sodium ions while saving potassium ions.Patients receiving potassium-depleting diuretics, such as amiloride or triamterene, may also experience this interaction. These diuretics can interact with all absorbable forms of potassium?bicarbonate, citrate, acetate, gluconite, and iodide salts.Severe hyperkalemia is dangerous, and thus patients who are prescribed spironolactone must undergo an evaluation of serum potassium levels.

" Clonidine and Propranolol "

The combination may produce a mysterious hypertension that is unrelated to the pharmacology of either agent when administered independently.A sudden withdrawal of clonidine from adjunctive therapy with propranolol may cause fatal rebound hypertension.

Clonidine is a central alpha-2 adrenergic agonist that suppresses the sympathetic nervous system from the brain.This activity leads to a decrease in the norepinephrine amounts available in the synaptic cleft of the adrenergic neuron. Alpha-1 receptors then become sensitized because of less norepinephrine available in the cleft.When clonidine is suddenly withdrawn, the result is a large increase in norepinephrine in the synaptic cleft of the adrenergic neuron. The sensitized alpha-1 receptors are stimulated, leading to an exaggerated vasoconstriction. The body cannot compensate for this response because the beta-2 receptors are blocked when a patient is concurrently taking propranolol. Within 24 to 72 hours, a dramatic rebound hypertension is noticed.

" Warfarin and Diflunisal "

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as diflunisal, have been shown to increase the risk for gastrointestinal (GI) bleeding and the anticoagulant response of war-farin.Other NSAIDs? such as keto-profen, piroxicam, sulindac, diclo-fenac, and ketorolac?have been shown to have similar interactions with warfarin. In most patients, however, indomethacin has little effect on hypothrombinemic response.Because the interaction between warfarin and diflunisal can lead to GI bleeding or even fatal hemorrhaging, an alternative to diflunisal is suggested. Acetaminophen is the alternative of choice. Yet, if an NSAID is needed, nonacetylated salicylates?such as magnesium salicylate or salsalate?are safer because of minimal effects on platelets and gastric mucosa.

" Theophylline and Ciprofloxacin " Concurrent administration may lead to toxic increases in theophylline.This problem occurs because the hepatic metabolism of theophylline is inhibited by ciprofloxacin via the cytochrome P-450 enzyme system. Theophylline is metabolized by CYP1A2 and to a lesser extent by CYP3A4. Ciprofloxacin and other drugs, including clarithromycin, erythromycin, fluvoxamine, and cimetidine, are all potent inhibitors of CYP1A2. Because they have little effect on CYP1A2, levofloxacin or ofloxacin should be considered as an alternative to ciprofloxacin.Theophylline toxicity is a serious condition; several deaths have been linked with serum concentrations as low as 25 mcg/mL.Signs of theophylline toxicity include headache, dizziness, hypotension, hallucinations, tachycardia, and seizures.

" Pimozide and Ketoconazole "

Pimozide alone can prolong the QT interval, and it has been linked with ventricular arrhythmias (torsades de pointes).When pimozide is combined with ketoconazole, the combination can be deadly. Pimozide is a CYP3A4 enzyme substrate, and ketoconazole is a potent inhibitor of CYP3A4. This leads to marked increases in pimozide serum levels.Other drugs? such as itraconazole, clarithromycin, erythromycin, diltiazem, and nefazodone?are also potent inhibitors of CYP3A4 and should not be administered with pimozide.Fluconazole is weaker, but in larger doses it also inhibits CYP3A4. Terbin-afine is a safer choice because it does not affect CYP3A4.

" Methotrexate and Probenecid "

When probenecid is administered with antineoplastic doses of metho-trexate, the result can be a 2- to 3-fold increase in methotrexate levels.Probenecid acts as an active tubular secretion inhibitor and prevents methotrexate from being excreted, thus potentially causing toxicity. The symptoms of severe methotrexate toxicity include diarrhea, vomiting, diaphoresis, and renal failure, and it may result in death.This interaction with methotrexate also occurs with penicillins (eg, amoxicillin, carbeni-cillin) and salicylates.The risk with low-dose methotrexate (commonly used for arthritis) is lower; in fact, NSAIDs in combination with low-dose methotrexate are often prescribed purposely.

Possible alternatives include aceta-minophen, as opposed to salicylates or NSAIDs. Celecoxib does not affect methotrexate pharmacokinetics and could be an alternative. However, rofecoxib produces some increases in methotrexate serum concentrations and therefore should be avoided.

" Bromocriptine and Pseudoephedrine "

The interaction can lead to severe peripheral vasoconstriction, ventricular tachycardia, seizures, and possibly death.Bromocriptine is an ergot-derived dopamine agonist with several uses, including antiparkinsonian therapy. New treatment guidelines for Parkinson?s disease recommend a first-line therapy change from levodopa to bromocriptine or other dopamine agonists, such as ropinirole, pramipexole, or pergolide.Notable side effects of bromocriptine include thickening of bronchial secretions and nasal congestion.This is significant because it increases the likelihood of a patient taking bromocriptine to self-medicate with an OTC decongestant such as pseudoephedrine. Patients receiving bromocriptine should be advised to avoid all sympathomime-tics.

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