Theophylline in Dextrose

Uses

Dextrose is administered as a parenteral nutrition solution in the treatment of carbohydrate depletion and hypoglycaemic coma. Because of its high dextrose content it is used in the treatment of cerebral edema, shock, circulatory collapse, unconsciousness and to correct hyperkalaemia with or without insulin.

This is used for the symptomatic treatment of reversible bronchoconstriction associated with bronchial asthma, chronic obstructive pulmonary emphysema, chronic bronchitis and related bronchospastic disorders.

Theophylline in Dextrose is also used to associated treatment for these conditions: Arrhythmia, Caloric Deficit, Edema of the cerebrum, Metabolic Alkalosis, Hypoglycemic reaction, Blood Specimen Collection, Electrolyte replacement, Nutritional supplementation, Parenteral Nutrition, Parenteral rehydration therapy, Plasmapheresis, Positive cardiac inotropic effect, Total parenteral nutrition therapy, Urine alkalinization therapy, Fluid and electrolyte maintenance therapyAsthma, Bronchitis, Bronchoconstriction, Bronchospasm, Chronic Obstructive Pulmonary Disease (COPD), Chronic bronchial inflammation, Airway secretion clearance therapy, Bronchodilation

How Theophylline in Dextrose works

Glucose supplies most of the energy to all tissues by generating energy molecules ATP and NADH during a series of metabolism reactions called glycolysis. Glycolysis can be divided into 2 main phases where the preparatory phase is initiated by the phosphorylation of glucose by a hexokinase to form glucose 6-phosphate. The addition of the high-energy phosphate group activates glucose for subsequent breakdown in later steps of glycolysis and is the rate-limiting step. Products end up as substrates for following reactions, to ultimately convert C6 glucose molecule into two C3 sugar molecules. These products enter the energy-releasing phase where total of 4ATP and 2NADH molecules are generated per one glucose molecule. The total aerobic metabolism of glucose can produce up to 36 ATP molecules. This energy-producing reactions of glucose is limited to D-glucose as L-glucose cannot be phosphorlyated by hexokinase. Glucose can act as precursors to generate other biomolecules such as vitamin C. It plays a role as a signaling molecule to control glucose and energy homeostasis. Glucose can regulate gene transcription, enzyme activity, hormone secretion, and the activity of glucoregulatory neurons. The types, number and kinetics of glucose transporters expressed depends on the tissues and fine-tunes glucose uptake, metabolism, and signal generation in order to preserve cellular and whole body metabolic integrity .

Theophylline relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels and reduces airway responsiveness to histamine, methacholine, adenosine, and allergen. Theophylline competitively inhibits type III and type IV phosphodiesterase (PDE), the enzyme responsible for breaking down cyclic AMP in smooth muscle cells, possibly resulting in bronchodilation. Theophylline also binds to the adenosine A2B receptor and blocks adenosine mediated bronchoconstriction. In inflammatory states, theophylline activates histone deacetylase to prevent transcription of inflammatory genes that require the acetylation of histones for transcription to begin.

Dosage

Theophylline in Dextrose dosage

The volume and rate of infusion of dextrose solution will depend upon the requirements of the individual patient and the judgement of the physician.

The maximum rate at which dextrose can be infused without producing glycosuria is 0.5 gm/kg/hr.

The usual recommended flow rate for adult is 10-35 drops per minute infused intravenously.

Intravenous-

Hyperkalaemia:

• Adult: 25-50 g combined with 10 units of regular insulin, administered over 30-60 minutes; may repeat if necessary. Alternatively, 25 g combined with 5-10 units of regular insulin infused over 5 minutes; may repeat if necessary.
• Child and infants: 0.5-1 g/kg (using 25% or 50% solution) combined with regular insulin (1 unit for every 4-5 g dextrose given); infuse over 2 hr, may repeat if necessary.

Intravenous-

Hypoglycaemia:

• Adult: 10-25 g (40-100 ml of 25% solution or 20-50 ml of 50% solution). Doses may be repeated in severe cases.
• Child: ≤6 mth: 0.25-0.5 g/kg/dose; >6 mth: 0.5-1 g/kg/dose. Doses may be repeated in severe cases. Max: 25 g/dose.

Oral-

Hypoglycaemia:

• Adult: 10-20 g as single dose; may repeat in 10 min if needed.
• Child: >2 yr: 10-20 g as single dose; may repeat in 10 min if needed.

Dosages are adjusted to maintain serum theophylline concentrations that provide optimal relief of symptoms with minimal side effects. Most of the controlled release preparations may be administered every 12 hours in adults while administration every 8 hours may be necessary in some children with markedly rapid hepatic metabolism of theophylline. The recommended dosages for achieving serum theophylline concentrations within the accepted therapeutic range is as follow:

• 1-6 months: 10mg/Kg/day
• 6 months-1 year: 15mg/Kg/day
• 1-9 years: 24mg/Kg/day
• 10-16 years: 18mg/Kg/day
• Adults: 10-15mg/Kg/day

It should not be administered by SC or IM route. Dextrose should be infused through the largest available peripheral vein.

Side Effects

Venous thrombosis, phlebitis, hypovolemia, hypervolemia, dehydration, oedema, fever, mental confusion, unconsciousness, hyperosmolar syndrome, hyperglycaemia, hypokalaemia, acidosis, hypophosphataemia, hypomagnesemia, polyuria, glycosuria, ketonuria, nausea, diarrhoea, polydipsia, vein irritation, tissue necrosis, pulmonary oedema, tachypnoea.

The following side effects have been observed:

Gastrointestinal: Nausea, vomiting, epigastric pain and diarrhoea.

Central nervous system: Headache, irritability, restlessness, insomnia, muscles twitching.

Cardiovascular: Palpitation, tachycardia, hypotension. circulatory failure.

Respiratory: Tachypnoea.Renal: Potentiation of diuresis.

Others: Alopecia, hyperglycemia, rash etc.

Toxicity

Oral LD50 value in rats is 25800mg/kg. The administration of glucose infusions can cause fluid and/or solute overloading resulting in dilution of the serum electrolyte concentrations, over-hydration, congested states, or pulmonary oedema. Hypersensitivity reactions may also occur including anaphylactic/anaphylactoid reactions from oral tablets and intravenous infusions.

Symptoms of overdose include seizures, arrhythmias, and GI effects.

Precaution

Concentrated dextrose solution should not be infused rapidly or for a long period. It may be hazardous in patients with impaired hepatic or renal function and severe sepsis.

Care should be taken to avoid circulatory overload, particularly in patients with cardiac insufficiency. Caution must be exercised in the administration of these injections to patients receiving corticosteroids or corticotropin. These injections should be used with caution in patients with overt or subclinical diabetes mellitus.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and seal is intact.

Careful consideration is needed for various interacting drugs and physiologic conditions that can alter Theophylline clearance. Dosage adjustment is required prior to initiation of Theophylline therapy, prior to increases in Theophylline dose, and during follow up. The dose of Theophylline selected for initiation of therapy should be low and, if tolerated, increased slowly over a period of time.

Interaction

There is no drug drug interaction and none well documented.

Allopurinol, cimetidine, norfloxacin, ciprofloxacin, erythromycin, oral contraceptives and propranolol increase serum theophylline levels. Phenytoin, methotrexate and rifampicin lead to decreased serum theophylline levels

Volume of Distribution

The mean volume of distribution after intravenous infusion is 10.6L.

• 0.3 to 0.7 L/kg

Elimination Route

Polysaccharides can be broken down into smaller units by pancreatic and intestinal glycosidases or intestinal flora. Sodium-dependent glucose transporter SGLT1 and GLUT2 (SLC2A2) play predominant roles in intestinal transport of glucose into the circulation. SGLT1 is located in the apical membrane of the intestinal wall while GLUT2 is located in the basolateral membrane, but it was proposed that GLUT2 can be recruited into the apical membrane after a high luminal glucose bolus allowing bulk absorption of glucose by facilitated diffusion . Oral preparation of glucose reaches the peak concentration within 40 minutes and the intravenous infusions display 100% bioavailability.

Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form.

Half Life

The approximate half-life is 14.3 minutes following intravenous infusion. Gut glucose half-life was markedly higher in females (79 ± 2 min) than in males (65 ± 3 min, P < 0.0001) and negatively related to body height (r = -0.481; P < 0.0001).

8 hours

Clearance

The mean metabolic clearance rate of glucose (MCR) for the 10 subjects studied at the higher insulin level was 2.27 ± 0.37 ml/kg/min at euglycemia and fell to 1.51±0.21 ml/kg/ at hyperglycemia. The mean MCR for the six subjects studied at the lower insulin level was 1.91 ± 0.31 ml/kg/min at euglyglycemia.

• 0.29 mL/kg/min [Premature neonates, postnatal age 3-15 days]
• 0.64 mL/kg/min [Premature neonates, postnatal age 25-57 days]
• 1.7 mL/kg/min [Children 1-4 years]
• 1.6 mL/kg/min [Children 4-12 years]
• 0.9 mL/kg/min [Children 13-15 years]
• 1.4 mL/kg/min [Children 16-17 years]
• 0.65 mL/kg/min [Adults (16-60 years), otherwise healthy non-smoking asthmatics]
• 0.41 mL/kg/min [Elderly (>60 years), non-smokers with normal cardiac, liver, and renal function]
• 0.33 mL/kg/min [Acute pulmonary edema]
• 0.54 mL/kg/min [COPD >60 years, stable, non-smoker >1 year]
• 0.48 mL/kg/min [COPD with cor pulmonale]
• 1.25 mL/kg/min [Cystic fibrosis (14-28 years)]
• 0.31 mL/kg/min [Liver disease cirrhosis]
• 0.35 mL/kg/min [acute hepatitis]
• 0.65 mL/kg/min [cholestasis]
• 0.47 mL/kg/min [Sepsis with multi-organ failure]
• 0.38 mL/kg/min [hypothyroid]
• 0.8 mL/kg/min [hyperthyroid]

Elimination Route

Glucose can be renally excreted.

Theophylline does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver. Renal excretion of unchanged theophylline in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults.

Pregnancy & Breastfeeding use

Pregnancy Category C. Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Pregnancy: It is not known whether Theophylline can cause foetal harm when administered to pregnant woman.Xanthines should be given to a pregnant woman only if clearly needed.

Nursing mother: Theophylline is excreted into breast milk and may cause irritability or other signs of mild toxicity in nursing human infants. Serious adverse effects in the infant are unlikely unless the mother has toxic serum Theophylline concentrations.

Contraindication

Concentrated dextrose solution is contraindicated in patients with Glucose-Galactose Malabsorption Syndrome and severe hydration. The infusion of hypertonic dextrose injections is contraindicated in patients having intracranial or intraspinal hemorrhage, in patients who are severely dehydrated, in patients who are anuric, and in patients in hepatic coma. Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products.

Hypersensitivity to xanthine derivatives. It is also contraindicated in patients with active peptic ulcer disease and in individuals with underlying seizure disorders (unless receiving appropriate anti-convulsing medication).

Theophylline should not be administered concurrently with other xanthine. Use with caution in patients with hypoxemia, hypertension, or those with history of peptic ulcer. Do not attempt to maintain any dose that is not tolerated.

Acute Overdose

Reevaluate patient's condition and institute appropriate symptomatic treatment.

Symptoms may include nausea, vomiting, gastrointestinal irritation, cramps, convulsions, tachycardia & hypotension. The stomach contents should be emptied & supportive measures employed to maintain circulation, respiration & fluid & electrolyte balance. Electrocardiographic monitoring should be carried out & in severe poisoning charcoal haemoperfusion should be used.

Storage Condition

Store at 25°C.

Store in a cool and dry place, protect from light and moisture. Keep out of the reach of children

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