Drug Interactions

Drug Interactions to Warfarin

March 22, 2017 Drug Informatics, Drug Interactions, Pharmacodynamics, Pharmacokinetics No comments , , , , , , ,

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Drugs may interact with warfarin sodium through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with warfarin sodium are synergism (impaired hemostasis, reduced clotting factor synthesis), competitive antagonism (vitamin K), and alteration of the physiologic control loop for vitamin K metabolism (hereditary resistance). Pharmacokinetic mechanisms for drug interactions with warfarin sodium are mainly enzyme induction, enzyme inhibition, and reduced plasma protein binding. It is important to note that some drugs may interact by more than one mechanism.

Pharmacodynamic:

  • Synergism
  • Competitive antagonism
  • Alteration of vitamin K cycle and metabolism

Pharmacokinetic:

  • Enzyme induction
  • Enzyme inhibition
  • Reduced plasma protein binding

CYP450 Interactions

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CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. The more potent warfarin S-enantiomer is metabolized by CYP2C9 while the R-enantiomer is metabolized by CYP1A2 and 3A4.

  • Inhibitors of CYP2C9, 1A2, and/or 3A4 have the potential to increase the effect (increase INR) of warfarin by increasing the exposure of warfarin.
  • Inducers of CYP2C9, 1A2, and/or 3A4 have the potential to decrease the effect (decrease INR) of warfarin by decreasing the exposure of warfarin.

Examples of inhibitors and inducers of CYP2C9, 1A2, and 3A4 are below in Table 2; however, this list should not be considered all-inclusive.

Drugs that Increase Bleeding Risk

Examples of drugs known to increase the risk of bleeding are presented in Table 3. Because bleeding risk is increased when these drugs are used concomitantly with warfarin, closely monitor patients receiving any such drug with warfarin.

Antibiotics and Antifungals

There have been reports of changes in INR in patients taking warfarin and antibiotics or antifungals, but clinical pharmacokinetic studies have not shown consistent effects of these agents on plasma concentrations of warfarin.

Botanical (Herbal) Products and Foods

More frequent INR monitoring should be performed when starting or stopping botanicals.

Few adequate, well-controlled studies evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and warfarin sodium exist. Due to a lack of manufacturing standardization with botanical medicinal preparations, the amount of active ingredients may vary. This could further confound the ability to assess potential interactions and effects on anticoagulation.

Some botanicals may cause bleeding events when taken alone and may have anticoagulant, antiplatelet, and/or fibrinolytic properties. These effects would be expected to be additive to the anticoagulant effects of warfarin sodium. Conversely, some botanicals may decrease the effects of warfarin sodium. Some botanicals and foods can interact with warfarin sodium through CYP450 interactions (e.g., echinacea, grapefruit juice, ginkgo, goldenseal, St. John’s wort).

The amount of vitamin K in food may affect therapy with warfarin sodium. Advise patients taking warfarin sodium to eat a normal, balanced diet maintaining a consistent amount of vitamin K. Patients taking warfarin sodium should avoid drastic changes in dietary habits, such as eating large amounts of green leafy vegetables.

Make a provider and patient education for levothyroxine

February 13, 2013 Adverse Drug Reactions, Cardiology, Drug Informatics, Drug Interactions, Pharmacokinetics, Pharmacotherapy, Pharmacy Education, Therapeutics 3 comments , , , ,

Today I would like to write something about levothyroxine. My hospital uses levothyroxine often. Everyday there are lots of patients prescribed with levothyroxine. I do believe it is necessary to write below for education, which is not only for patients but also providers. The reference I use comes from U.S. FDA’s official drug information database.

Indications and Usage

Levothyroxine sodium is used for the following indications:

Hypothyroidism – As replacement or supplemental therapy in congenital or acquired hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis. Specific indications include: primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) hypothyroidism. Primary hypothyroidism may result from functional deficiency, primary atrophy, partial or total congenital absence of the thyroid gland, or from the effects of surgery, radiation, or drugs, with or without the presence of goiter.

Pituitary TSH Suppression – In the treatment or prevention of various types of euthyroid goiters, including thyroid nodules, subacute or chronic lymphocytic thyroiditis, multinodular goiter and, as an adjunct to surgery and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid cancer.

Contraindications

Levothyroxine is contraindicated in patients with untreated subclinical (suppressed serum TSH level with normal T3 and T4 levels) or overt thyrotoxicosis of any etiology and in patients with acute myocardial infarction. Levothyroxine is contraindicated in patients with uncorrected adrenal insufficiency since thyroid hormones may precipitate an acute adrenal crisis by increasing the metabolic clearance of glucocorticoids. Finally, levothyroxine is contraindicated in patients with hypersensitivity to any of the inactive ingredients in levothyroxine.

Dosage and Administration

  • The goal of replacement therapy is to achieve and maintain a clinical and biochemical euthyroid state.
  • The goal of suppressive therapy is to inhibit growth and/or function of abnormal thyroid tissue.

To acheive the two goals above, it depends on variety of factors including the patient’s age, body weight, cardiovascular status, concomitant medical conditions (e.g., pregnancy, concomitant medications, and the specific nature of the condition being treated). As a result Dosing must be individualized and adjustments made based on periodic assessment of the patient’s clinical response and laboratory parameters.

Levothyroxine sodium tablets are administered as a single daily dose.

Table 1 The Indication and Dosages of Levothyroxine

Indication and UsageDosage
1HypothyroidismIndividuals who are at low risk of coronary artery diseaseStarting at 1.7 mcg/kg/day (Full dose). Adjusting dosage in 12.5-25 mcg increments until clinically euthyroid and serum TSH has normalized.
If myxedema coma, administer intravenously rather than orallyIndividuals older than 50 yrs or under 50 yrs with underlying cardiac diseaseStarting from 25-50 mcg/day, with increments of 12.5-25 mcg/day at 6-8 week intervals until clinical euthyroid and the serum TSH has normalized
Elderly individualsStarting from 12.5-25 mcg/day, with increments of 12.5-25 mcg/day at 4-6 week intervals until clinical euthyroid and the serum TSH has normalized
Individuals with severe hypothyroidismStarting from 12.5-25 mcg/day, with increments of 25 mcg/day at 2-4 week intervals until clinical euthyroid and the serum TSH has normalized
Secondary or tertiary hypothyroidismDosage as above but titrated until clinically euthyroid and serum free-T4 level is restored to the upper half of the normal range
2TSH Suppression – various types of euthyroid goiters and thyroid cancerWell-differentiated thyroid cancer> 2 mcg/kg/day (Target: TSH suppressed to <0.1 mU/L)
Contraindicated if the serum TSH is already suppressedWell-differentiated thyroid cancer (high risk)Target: TSH suppressed to <0.01 mU/L
Benign nodules and nontoxic multinodular goiter (controversial)Target: TSH suppressed to between 0.1 to either 0.5 or 1.0 mU/L

 

The adequacy of therapy is determined by periodic assessment of appropriate laboratory tests and clinical evaluation. In adult patients with primary (thyroidal) hypothyroidism, serum TSH levels alone may be used to monitor therapy. The frequence of TSH monitoring during levothyroxine dose titration depends on the clinical situation but it is generally recommended at 6-8 week intervals until normalization.

Monitor (more…)

Clinical Report-Drug Interaction Between Fluoxetin and Mirtazapine

July 23, 2012 Adverse Drug Reactions, Drug Interactions, Entertainment 55 comments , , ,

Clinical Case Report

 

Fluoxetin and Mirtazapine.

Date: July 8 2012

Place: Outpatient Pharmacy, 416 Hospital

Abstract and Introduction:

On the afternoon, July 8 2012 one male patient came to the outpatient pharmacy to take his drug. The phyisican prescribed fluoxetin accompanied by mirtazapine. I checked these two drugs in drug interaction checker and drug interactions were found between fluoxetine and mirtazapine – Potential for dangerous interaction ( may causes serotonin syndrome, although serotonin is rare but is life-threatening). I suggested the patient take these two drugs carefully. I told the man if he have the symptoms or signs of serotonin syndrome he should withdraw both drug immediately and back to hospital for further care if necessary.

Detail:

The Neurology Clinics prescribled fluoxetine accompanied by mirtazapine  to a middle-age man. The dosage and frequency for fluoxetine is 20mg po Qd meanwhile that for mirtazapine is 30mg po Qd.

I checked these two drugs in drug interaction checker and a drug interaction was found between fluoxetine and mirtazapine – Fluoxetine and mirtazapine both increase serotonin levels, potential for dangerous interaction ( may causes serotonin syndrome, although serotonin is rare but life-threatening).

So due to this drug interaction, when I was dispensing these two to him, I asked him whether he was also taking or had recently taken any other psychotropic medications such as antidepressants, MAOIs, SSRIs or some drugs such as analgesics and so on, which also increase serotonin levels and may cause serotonin syndrome if they are coadministered. He told me negative. So I told him that he could take these two medications in combination, but should take with caution due to the drug interaction between fluoxetine and mirtazapine. And the most important is that I taught him how to identify serotonin syndrome. Simply that the general symptoms and signs of serotonin syndrome are clonus, agitation or diaphoresis, tremor and hyperreflexia or hypertonia, temperature above 100.4°F (38° C) and I said if he have any symptoms or signs of serotonin syndrome both drugs should be withdrawed immediately and he should go back to hospital for further care if necessary, I told him.

Finally the patient told me he knew what he should and took both drugs home.

Discussion:

Serotonin is a neurotransmitter that is synthesized from the amino acid L-tryptophan. Synthesis is necessary in the central and peripheral nervous system because serotonin cannot cross the blood-brain barrier. Once synthesized, serotonin is either stored in neuronal vesicles or metabolized by monoamine oxidase (MAO) to 5-hydroxyindoleacetic acid. Serotonin binds 1 of 7 postsynaptic 5-hydroxytryptophan (5-HT) receptors. The hyperstimulation of the 5-HT receptors in the brain and/or spinal cord is the cause of serotonin syndrome. So what is serotonin syndrome? Serotonin syndrome, characterized by mental status changes, neuromuscular dysfunction, and autonomic instability, is thought to be secondary to excessive serotonin activity in the spinal cord and brain. Serotonin syndrome is a potentially life-threatening set of symptoms caused by serotonin toxicity, and usually involves a combination of psychotropic medications that increase serotonergic transmission. That means specific drug interactions can be the reason for serotonin syndrome. Serotonin syndrome can ensue after the addition of a second serotonergic drug to an existing drug regimen or with administration of a serotonergic drug before allowing an inadequate washout period after discontinuation of another serotonergic drug. Potential mechanisms and corresponding agents of serotonin syndrome include:

  1. Increasing production of serotonin by providing increased amount of precursors – L-tryptophan-containing substances;
  2. Prevention of metabolism of stored serotonin – Monoamine oxidase inhibitors (MAOIs);
  3. Increased release of stored serotonin – Amphetamine, cocaine, fenfluramine, methylenedioxymethamphetamine (MDMA or ecstasy), or meperidine;
  4. Prevention of reuptake of serotonin released into the synapse – SSRIs, tricyclic antidepressants (TCAs), MDMA, dextromethorphan, meperidine, or St John’s Wort;
  5. Direct stimulation of serotonin receptors – Buspirone, lysergic acid, diethylamide (LSD);
  6. Unknown mechanism – Lithium.

I summarize the drugs which are implicated in serotonin syndrome. They are in  Table 1.

Categories

Drugs

Amphetamines and their derivativesEcstasy Dextroamphetamine, Methamphetamine and Sibutramine
AnalgesicsCyclobenzaprine, Fentanyl, Meperidine, Tramadol
Antidepressants/Mood stabilizersBuspirone, Lithium
Monoamine Oxidase InhibitorsPhenelzine
SSRIsFluoxetine
Serotonin-Norepinephrine Reuptake InhibitorsVenlafaxine
Serotonin 2A Receptor BlockersTrazodone
St. John’s Wort
Tricyclic Antidepressants
AntiemeticsMetoclopramide, Ondansetron
Antimigraine Drugscarbamazepine, ergot alkaloids, triptans, and valproic acid

Table 1 Drugs that are potential to serotonin syndrome.

Other drugs if used in combination that may cause serotonin syndrome include cocaine, dextromethorphan, linezolid, l-tryptophan, and 5-hydroxytryptophan. (more…)

Nine agents in one Rx. and twenty drug interactions found (Not finished)

July 20, 2012 Anticoagulant Therapy, Cardiology, Drug Interactions 2 comments , , , ,

This afternoon I met a perscription that consist of nine different agents, which have twenty drug interactions. Many of them are cardiovascular drugs. They are  Beta-Blockers, Electrolytes, Statins, ARBs, Inotropic Agents, Thiazide, Calcium Channel Blockers, and Benzodiazepines. I list them and their dosage below.

  1. Alprazolam 0.4 mg po Qd
  2. Metoprolol 12.5 mg po Bid
  3. Potassium Chloride 1 g po Bid
  4. Simvastatin 20 mg po Qn
  5. Irbesartan 0.15 g po Qd
  6. Irbesartan/Hydrochlorothiazide 1 tablet po Qd
  7. Digoxin 0.125 mg po Qd
  8. Amlodipine 5 mg po Qd
  9. Warfarin 2.5 mg po Qd

I check these nine drug in Multi-Dug Interaction Chechker and find there are twenty drug interactions between these nine drugs. They are:

Serious – Use alternative

Amlodipine + Simvastatin. Amlodipine increases levels of simvastatin by Other (See comment). Possible serious or life-threatening interaction. Monitor closely. Use alternatives if available. Comment: Benefits of combination therapy should be carefully weighed against the  potential risks of combination. Potential for increased risk of myopathy/rhabdomyolysis. Limit simvastatin dose to no more than 20 mg/day when used concurrently.

Significant – Monitor Closely

Hydrochlorothiazide + Digoxin. Hydrochlorothiazide increases effects of digoxin by pharmacodynamic synergism. Significant interaction possible, monitor closely. Hypokalemia increases digoxin effects.

Potassium Chloride + Hydrochlorothiazide. Potassium chloride increases and hydrochlorothiazide decreases serum potassium. Effect of interaction is not clear, use caution. Potential for dangerous interaction. Use with caution and monitor closely.

Simvastatin + Warfarin. Simvastatin, warfarin. Either increases effects of the other by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Significant – Monitor Closely. Competition by each drug for CYP3A4-mediated metabolism may result in increased INR and increased risk of rhabdomyolysis.

Simvastatin + Digoxin. Simvastatin will increase the level or effect of digoxin by P-glycoprotein (MDR1) efflux transporter. Significant – Monitor Closely.

Digoxin + Hydrochlorothiazide. Digoxin will increase the level or effect of hydrochlorothiazide by basic (cationic) drug competition for renal tubular clearance. Significant – Monitor Closely.

Metoprolol + Irbesartan. Metoprolol, irbesartan. Mechanism: pharmacodynamic synergism. Significant – Monitor Closely. Risk of fetal compromise if given during pregnancy.

Alprazolam + Digoxin. Alprazolam increases levels of digoxin by unknown mechanism. Significant – Monitor Closely.

Metoprolol + Digoxin. Metoprolol increases effects of digoxin by pharmacodynamic synergism. Significant – Monitor Closely. Enhanced bradycardia.

Metoprolol + Amlodipine. Metoprolol and amlodipine both increase anti-hypertensive channel blocking. Significant – Monitor Closely.

Irbesartan + Potassium Chloride. Irbesartan and potassium chloride both increase serum potassium. Significant – Monitor Closely.

Metoprolol + Potassium Chloride. Metoprolol and potassium chloride both increase serum potassium. Significant – Monitor Closely.

Potassium Chloride + Digoxin. Potassium chloride and digoxin both increase serum potassium. Significant – Monitor Closely.

Irbesartan + Metoprolol. Irbesartan and metoprolol both increase serum potassium. Significant – Monitor Closely.

Irbesartan + Digoxin. Irbesartan and digoxin both increase serum potassium. Significant – Monitor Closely.

Irbesartan + Hydrochlorothiazide. Irbesartan increases and hydrochlorothiazide decreases serum potassium. Effect of interaction is not clear, use caution. Significant – Monitor Closely.

Metoprolol + Digoxin. Metoprolol and digoxin both increase serum potassium. Significant – Monitor Closely.

Metoprolol + Hydrochlorothiazide. Metoprolol increases and hydrochlorothiazide decreases serum potassium. Effect of interaction is not clear, use caution. Significant – Monitor Closely.

Digoxin + Hydrochlorothiazide. Digoxin increases and hydrochlorothiazide decreases serum potassium. Effect of interaction is not clear, use caution. Significant – Monitor Closely.

Irbesartan + Irbesartan/Hydrochlorothiazide (Not listed in the multi-drug interaction checker. I add this interaction by myself). Both Irbesartan and Irbesartan/Hydrochlorothiazide increase the level or effects of each other. The combination use of these two drugs is repeated administration and may enhance adverse effects of Irbesartan. I think this combination use should be avoid absolutely.

I alysis these twenty drug interactions. These twenty drug interactions include ten refered to  potassium disorder, three refered to pharmacodynamic synergism, one refered to myopathy/rhabdomyolysis, one hepatic/instestinal enzyme, one MDR1 (P-gp), one renal tubular excretion, one unknown, one anti-hypertension channel, and one repeated administration.

I think the next thing to do is to modify this pharmacotherapy regimen as there are many drug interactions in this regimen.

Management of serotonin syndrome reviewed

July 8, 2012 Adverse Drug Reactions, Drug Interactions, Pharmacokinetics, Pharmacology, Therapeutics No comments , , ,

May 10, 2010 — Prevention, diagnosis, and management of serotonin syndrome are described in a review for family physicians published in the May 1 issue of the American Family Physician.

“Serotonin syndrome is a potentially life-threatening set of symptoms caused by serotonin toxicity, and usually involves a combination of drugs that increase serotonergic transmission,” write Adrienne Z. Ables, PharmD, and Raju Nagubilli, MD, from Spartanburg Family Medicine Residency Program in Spartanburg, South Carolina. “This syndrome was first described in the literature during the 1960s in studies of single and combination therapy with antidepressant medications. Potential mechanisms of serotonin syndrome include increased serotonin synthesis or release; reduced serotonin uptake or metabolism; and direct serotonin receptor activation.”

Symptoms of excessive serotonergic activity in the nervous system include mental status changes, autonomic instability, and neuromuscular hyperactivity, usually caused by exposure to multiple serotonergic drugs or excessive exposure to a single serotonin-augmenting drug.

Intentional self-poisoning with serotonergic agents has also been reported, as well as serotonin syndrome occurring when drugs that inhibit the cytochrome P450 2D6 and/or cytochrome P450 3A4 isoenzymes are added to therapeutic regimens of selective serotonin reuptake inhibitors (SSRIs).

Specific agents that may be implicated in serotonin syndrome include amphetamines and their derivatives (ecstasy, dextroamphetamine, methamphetamine, and sibutramine), analgesics (cyclobenzaprine, fentanyl, meperidine, tramadol), antidepressants/mood stabilizers (buspirone, lithium), monoamine oxidase inhibitors (such as phenelzine), SSRIs (such as fluoxetine), serotonin-norepinephrine reuptake inhibitors (such as venlafaxine), serotonin 2A receptor blockers (such as trazodone), St. John’s wort, tricyclic antidepressants, antiemetics (metoclopramide, ondansetron), and antimigraine drugs (carbamazepine, ergot alkaloids, triptans, and valproic acid).

Miscellaneous agents that may cause serotonin syndrome include cocaine, dextromethorphan, linezolid, l-tryptophan, and 5-hydroxytryptophan.

Criteria for Identifying Serotonin Syndrome

It is important for clinicians to be able to recognize serotonin toxicity because the prognosis is favorable if complications are managed appropriately. The term serotonin syndrome usually is reserved for severe toxicity.

The Hunter Serotonin Toxicity Criteria are used to diagnose serotonin syndrome. Diagnosis by these criteria requires at least 1 of the following characteristic features or groups of features:

  • Spontaneous clonus;
  • Inducible clonus with agitation or diaphoresis;
  • Ocular clonus with agitation or diaphoresis;
  • Tremor and hyperreflexia; or
  • Hypertonia, temperature above 100.4°F (38° C), and ocular or inducible clonus.

Differential diagnosis of serotonin syndrome includes anticholinergic syndrome, malignant hyperthermia, and neuroleptic malignant syndrome.

Most cases of serotonin syndrome are mild, and patients usually respond to withdrawal of the offending agent and supportive care. Agitation and tremor may be treated with benzodiazepines, and cyproheptadine may be used as an antidote.

For moderate or severe cases of serotonin syndrome, patients should be hospitalized, and neuromuscular paralysis, sedation, and intubation may be indicated for critically ill patients.

Key Recommendations for Practice

Specific key clinical recommendations for practice, and their accompanying level of evidence rating, include the following:

  • To prevent serotonin syndrome, clinicians must be aware of the toxic potential of serotonergic agents (level of evidence, C). Education and use of drug interaction software may help promote awareness.
  • Serotonin syndrome should be identified and diagnosed with use of established criteria (level of evidence, C). Compared with Sternbach’s criteria, the Hunter Serotonin Toxicity Criteria are more sensitive and specific in diagnosing serotonin syndrome.
  • First-line treatment of serotonin syndrome is to withdraw the offending drugs and to provide supportive care (level of evidence, C).
  • On the basis of case reports, moderate to severe cases of serotonin syndrome may be treated with cyproheptadine (level of evidence, C).

“The incidence of serotonin syndrome is rising, reflecting the growing number of serotonergic drugs available and the increased use of these agents in clinical practice,” the review authors write. “The reported incidence may also reflect an increasing diagnostic awareness of the syndrome…. Prevention of serotonin syndrome begins with awareness by physicians and patients of the potential for toxicity from serotonergic drugs.”

The review authors have disclosed no relevant financial relationships.

Am Family Physician. 2010;81:1139-1142. Abstract