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Factor Effect

Physical alteration

Diet

Increase elimination Low carbohydrate, high-protein diet

Charcoal-broiled meat

Decrease elimination High-carbohydrate,

low-protein diet

whereas large quantities of dietary

xanthines may slow elimination ( there are of

clinical importance only if change in usual

eating patterns is sustained and extreme)

Factors altering theophylline metabolism

Hendeles,et al. J Pediatr 1992; 120(2):177-83.

Factor Effect

Physical alteration

Diet

Increase Low carbohydrate, high-protein diet

Charcoal-broiled meat

Decrease High-carbohydrate,

low-protein diet

whereas large quantities of dietary

xanthines may slow elimination ( there are of

clinical importance only if change in usual

eating patterns is sustained and extreme)



Factor Effect

Bronchopulmonary dysphasia

Fever,

if sustained for> 24 hrs

Heart failure

Hyperthyroidism

Hypothyroidism

Liver disease

Decreases elimination variably; may be profound

Slow theophylline elimination by an average of ~50%


Increases elimination by an average of 20%

Decreases elimination by an average of 40%




Factor EffectDrug Interaction Allpurinol (high)

Cimetidine

Ciprofloxacin

Contraceptive pills

Carbamazepine

Slow elimination by average of 25%

Decreases elimination by average of 50%


Decreases elimination by average of 30% (may be less with low dosage)

Increases elimination by average of 60%



Factor EffectDrug Interaction Erythromycin

Interferon (recombinant interferon α)

Methotrexate

Mexiletine

Propranolol

Thiabendazole

Troleandomycin






Decreases elimination by average of about 65%

Decreases elimination average of 50% ( 25% on low dosage)



Factor Effect Drug Interaction

Rifampin

Smoking

(cigarette or marijuana)

Isoproterenol

(intravenous infusion)

Phenobarbital

Phenytoin


Increases elimination by average of about 50%(effects of low tar-low nicotine cigarettes may be less)



Increases elimination by average of 75%(additionally theophylline appears to inhibit absorption of phenytoin)



Clinician’s concern“Non-effect to high toxicity”

Theophylline plasma

concentration mcg/ml

Clinical Consequence

≤ 5 Absence of therapeutic effect

6-10 Sub-optimal therapeutic effect

10-20 Traditionally accepted ther.Window

>15 Anxiety, insomnia (possible)

>15 Gastro-intestinal disturbances(possible)

>20 “Toxic effect” (CVS,GI &CNS)

>30* Severe cardiac arrhythmias, *Fatal

>40* Seizures,coma. *Fatal

*Sessier CN, Am j med.1988 Allegra L,Giom It Mal Tor 2006

Initial dosageAdults and children >1 yr or age:

12-14 mg/kg/day up to a maximum of 300 mg/day

Initial dosageAdults and children >1 yr or age:

12-14 mg/kg/day up to a maximum of 300 mg/day

After 3 days, if tolerated, ,increase dose to

Incremental increaseAdults and children > 45 kg : 400 mg/day

Children <45 kg : 16 mg/kg/day up to maximum of 400 mg/day

Incremental increaseAdults and children > 45 kg : 400 mg/day


Final dosage before serum concentration measurementAdults and children > 45 kg : 600 mg/day


Final dosage before serum concentration measurementAdults and children > 45 kg : 600 mg/day


After 3 days, if tolerated, increase dose to:

Check serum concentration ~4 hours after a morning dose of most slow-release products or 8 hours after a dose of a very slowly absorbed product given once every 24 hours, when no doses have been missed, added, or taken at unequal intervals for 3 days

i

Dosage adjustment based on serum concentration

Peak serum concentration

<7.5 µg/ml

7.5 to 9.9 µg/ml

10 to 14.9 µg/ml

15 to 19.9 µg/ml

Directions

Increased dose about 25%. Recheck serum theophylline concentration for guidance in further dosage adjustment.

If tolerated, increase dose ~25%

If tolerated, maintain dose. Recheck serum theophylline concentration at 6 to 12 mo. intervals

Consider 10% decrease in dose to provide greater margin of safety.


Dosage adjustment based on serum concentration

Peak serum concentration

20 to 24.9 µg/ml

25 to 30 µg/ml

> 30 µg/ml

Directions

Decrease dose 10% to 25%. Recheck serum concentration after 3 days

Skip next dose and decrease subsequent doses at least 25%. Recheck serum theophylline concentration after 3 days

Skip next 2 doses and decrease subsequent doses at least 50%. Recheck serum theophylline concentration for guidance in further dosage adjustment


Side-effects

• Most common

- anorexia

- nausea/vomiting

- headache

Side-effects• May occur - CNS stimulation, seizures - palpitations - tachycardia - arrhythmia - abdominal pain, diarrhea - GERD - rarely gastric bleeding

Side-effects

• Changes in mood and personality, impaired school performance has been reported.

(Furukawa CT,et al. Lancet 1984;1:621,J allergy Clin Immunol 1988;81:83-8)

• Children with asthma receiving theophylline attain scores on standardized achievement tests that, on average, match those of their non-asthmatics siblings

(Lokshin,et al.Ann Allergy 1991; 66:65.)

(Lindgren S,et al. New Engl J Med 1992;327:926-3)

Theophylline toxicity in children

• 65 cases of theophylline toxicity,aged <17 yo. were reviewed at Johns Hopkins U. 1974-1985

• Mean age 7.4 yo. (3 mo.-16 yo.)• Most common manifestations :- vomiting,

tachycardia, CNS excitation• Seizures – 4 cases with serum conc. < 70

mcg/ml• Hallucinations – 2 cases associated with

high serum conc.

Baker MD.J Pediatr 1986; 109:538-42

Dosage

• > 1 yr. = 12-14 mg/d max 300 mg/dGINA 2006:- start 5 mg/d – 10mg/d• < 1 yr. dose = (0.2)×(age in weeks) + 5.0 (mg/d)

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