Thursday, October 29, 2009

Carbimazole and Thyroxine in the Treatment of Graves' Disease

A 43-year-old Malay woman, AS, has been diagnosed with Graves Disease 4 years ago. She is under follow up at a specialist clinic and has been on t. carbimazole 15 mg tds and t. levothyroxine 0.1 mg od (levothryroxine was added 4 months ago). [Note: this is an actual case at a district hospital]

Issue of interest:

In Graves’ disease, hyperthyroidism results from the action of thyroid stimulating antibodies directed against the thyrotropin receptor on the surface of the thyroid cells. These immunoglobulin G (Ig G antibodies) bind to the surface of thyroid cells and stimulate those cells to overproduce thyroid hormones.

Carbimazole is a thionamide that blocks thyroid hormone synthesis; on the other hand, levothyroxine is the drug of choice for hormone replacement therapy in the treatment of hypothyroidism.
What is the rationale of adding levothyroxine to carbimazole in AS?


Carbimazole is given 20-60 mg/day as 2-3 divided doses until patient becomes euthyroid (usually after 4-8 weeks). For maintenance dose, the dosage of carbimazole is gradually reduced to maintain normal thyroid activity. Therapy is usually continued for 12-18 months.

The evidence that high doses of antithyroid drug have an immunosuppressive effect has led to implementation of block-replacement regimen by some clinicians. In this regimen, the dose of carbimazole is maintained at initially high level (20-60 mg/day) and supplemental thyroxine (50-150 mcg/day) is given in order to prevent an underactive thyroid induced by the high carbimazole dosage. (prevention of iatrogenic hypothyroidism). Therapy is usually continued for 12-18 months.

A systematic review of 12 trials that compared a Block-Replace regimen (requiring a higher dose of anti-thyroid drug treatment) with a Titration regimen showed that there was no significant difference between the regimens for relapse of hyperthyroidism (relative risk (RR) = 0.93, 95% confidence interval (CI) 0.84 to 1.03). Participants were more likely to withdraw due to adverse events with a Block-Replace regimen (RR = 1.89, 95% CI 1.25 to 2.85).

In 8 out of the 12 studies, the ant-thyroid drug used was carbimazole, the dose ranged between 30 and 60 mg/day in the Block-Replace arms of all these studies except for one study, where a dose of 100 mg/day was used.

  1. DiPiro J et al. Pharmacotherapy handbook. 6th ed. USA: McGraw-Hill; 2006, p. 196-200.

  2. Lucas A, Salinas I, Rius F, Pizarro E, Granada ML, Foz M, and Sanmartl A. Medical therapy of Graves’ disease: Does thyroxine prevent recurrence of hyperthyroidism? Journey of Clinical Endocrinology and Metabolism 1997 [cited 28 October 2009]; 82(8): 2410-2413. Available from: URL:

  3. Lexi-Comp Drug Information Handbook. 18th ed.

  4. BNF 57.

  5. Abraham P, Avenell A, Park CM, Watson WA, and Bevan JS. A systematic review of drug therapy for Graves’ hyperthyroidism. European Journal of Endocrinology 2005 [cited 28 October 2009];153 (4): 484-498. Available from: URL:

Vancomycin : Pharmacokinetic and Pharmacodynamic

Vancomycin is a commonly used drug esp in MRSA infection. However there is a lot of grey-zone in the pharmacokinetic and pharmacodynamic of vancomycin.

Lets go through some of the recommendation made by the Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists (2009) (articles below are directly coded from the Rybak MJ, Lomaestro BM, Rotschafer JC et al. Vancomycin Therapeutic Guidelines: A Summary of Consensus Recommendations from the Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. Clin Infect Dis 2009; 49: 325-7)

1. Dosage. Initial vancomycin dosages should be calculated on the basis of actual body weight, including for obese patients. Subsequent dosage adjustments should be based on actual serum concentrations, to achieve targeted therapeutic concentrations. Continuous infusion regimens are unlikely to substantially improve patient outcome, compared with intermittent dosing. (Level of evidence, II; grade of recommendation, A.)

2. Peak versus trough concentrations. Trough serum vancomycin concentrations are the most accurate and practical method of monitoring the effectiveness of vancomycin. Trough serum concentrations should be obtained just before the fourth dose, at steady-state conditions. (Level of evidence, II; grade of recommendation, B.)
3. Avoidance of development of resistance. On the basis of the evidence suggesting that S. aureus exposure to trough serum concentrations of !10 mg/L can produce strains with vancomycin–intermediately susceptible S. aureus (VISA)–like characteristics, it is recommended that trough serum vancomycin concentrations always be maintained at 110 mg/L to avoid the development of resistance. (Level of evidence, III; grade of recommendation, B.)
4. Recommended trough serum concentrations and dosage adjustments. On the basis of the potential to improve penetration, to increase the probability of optimal target serum concentrations, and to improve clinical outcomes of complicated infections, such as bacteremia, endocarditis, osteomyelitis, meningitis, and hospital-acquired pneumonia caused by S. aureus, trough serum vancomycin concentrations of 15–20 mg/L are recommended. Trough serum vancomycin concentrations in that range should achieve an AUC/MIC of 1400 for most patients if the MIC is !1 mg/L. (Level of evidence, III; grade of recommendation, B.)

5. To achieve rapid attainment of this target concentration for seriously ill patients, a loading dose of 25–30 mg/kg(based on actual body weight) can be considered. (Level of evidence, III; grade of recomm endation, B.) A targeted AUC/MIC of 1400 is not achievable with conventional dosing methods if the vancomycin MIC is >2 mg/L for a patient with normal renal function (i.e., creatinine clearance, 70–100 mL/ min). Therefore, alternative therapies should be considered. Vancomycin dosages of 15–20 mg/kg (based on actual body weight) given every 8–12 h are required for most patients with normal renal function to achieve the suggested trough serum concentrations when the MIC is about 1 mg/L.

6. It should be noted that currently available nomograms were not developed to achieve these targeted end points. individual pharmacokinetic adjustments and verification of achievement of target serum concentrations are recommended. When individual doses exceed 1 g (e.g., 1.5 and 2 g), the infusion period should be extended to 1.5–2 h. (Level of evidence, III; grade of recommendation, B.)

7.Vancomycin toxicity. There are limited data suggesting a direct causal relationship between toxicity and specific serum vancomycin concentrations. There are also conflicting data characterized by confounding nephrotoxic agents, inconsistent and highly variable definitions of toxicity, and the inability to examine the time sequence of events surrounding changes in renal function secondary to vancomycin exposure. A patient should be considered to have vancomycin-induced nephrotoxicity if multiple (at least 2 or 3 consecutive) high serum creatinine concentrations (increase of 0.5 mg/dL or 150% increase from baseline, whichever is greater) are documented after several days of vancomycin therapy in the absence of an alternative explanation. (Level of evidence, II; grade of recommendation,B.). Available evidence does not support monitoring of peak serum vancomycin concentrations to decrease the frequency of nephrotoxicity. (Level of evidence, I; grade of recommendation,

  • A.) Monitoring of trough serum vancomycin concentrations to reduce nephrotoxicity is best suited for patients receiving aggressive dose targeting to produce sustained trough serum concentrations of 15–20 mg/L or who are at risk of toxicity, such as patients receiving concurrent treatment with nephrotoxins. (Level of evidence, III; grade of recommendation, B.) Monitoring is also recommended for patients with unstable renal function (either deteriorating or significantly improving function) and for patients receiving prolonged courses of therapy (13–5 days). (Level of evidence, II; grade of recommendation)

  • B.) All patients receiving prolonged courses of vancomycin treatment should have at least 1 steady-state trough serum concentration measured just before the fourth dose. Frequent monitoring (11 measurement of trough concentration before the fourth dose) for short-course therapy (!5 days) or for lower-intensity dosing (targeted to attain trough serumvancomycin concentrations of !15 mg/L) is not recommended. (Level of evidence, II; grade of recommendation, B.) There are limited data to support the safety of sustained trough serum vancomycin concentrations of 15–20 mg/L. When this target range is desired, once-weekly measurements of trough concentrations for hemodynamically stable patients is recommended. Frequent (in some instances, daily) monitoring of trough concentrations is advisable to prevent toxicity in hemodynamically unstable patients. The exact frequency of monitoring is often a matter of clinical judgment. (Level of evidence, III; grade of recommendation, B.)

8. Data on comparative vancomycin toxicity for continuous versus intermittent administration are conflicting, and no recommendation can be made.

9. Monitoring of serum vancomycin concentrations to prevent ototoxicity is not recommended, because this toxicity is rarely associated with monotherapy and does not correlate with serum vancomycin concentrations. Monitoring may be more important when other ototoxic agents, such as aminoglycosides, are administered. (Level of evidence, III; grade of recommendation, B.)

(This page is authored by Mai and is reproduced at

Monday, October 5, 2009

Drugs to be Taken on Empty Stomach

Drugs to be taken on empty stomach should be taken either 1 hour before or 2 hours after meals. However, in the hospital scenario, in order not to confuse patients, we usually cancel the 'selepas' for the label to read 'sebelum makan'.

Here are some common examples of drugs to be taken on empty stomach and the reasons for doing so.

where the oral bioavailability of the drug is reduced by more than 20% by food
  • 6-mercaptopurine

  • alendronate

  • atenolol

  • azithromycin

  • captopril

  • ferrous fumarate

  • indinavir (heavy/large meals only)

  • d-penicillamine (take with food if GI upset)

  • dicloxacillin

  • didanosine

  • erythromycin base (erythromycin estolate, erythromycin stearate: take with food as drugs may cause a signicicant incidence of gastric side effects)

  • flucloxacillin

  • gemfibrozil

  • isoniazide

  • perindopril

  • rifampicin

  • tacrine

  • tetracycline

  • lansoprazole

As gastric acid secretion is maximally stimulated by food ingestion, maximal efficacy of proton pump inhibitors (e.g. omeprazole, pantoprazole, lansoprazole) should be achieved when they are taken before a meal.

where the presence of food reduces the effectiveness of the preparation but is unrelated to absorption
  • bismuth subcitrate

  • sucralfate (theoretical)

where the rate of absorption of the drug is significantly reduced by food and clinical effect is related to rapid absorption
  • bumetanide

  1. The Dispensing Guide 2001, The Pharmaceutical Society of New Zealand