Salbutamol + Theophylline (Salbutamolum + Theophyllinum)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
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Clinical and pharmacological group: & nbsp

Beta-adrenomimetics

Adenosinergic agents

Included in the formulation
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    FARMAPEK, ZAO     Russia
    • АТХ:

    R.03.D.B.04   Theophylline in combination with adrenergic agents

    Pharmacodynamics:

    Salbutamol stimulates β2-adrenoreceptors, which are found in membranes of smooth muscle cells of the bronchi, uterus, gastrointestinal tract, detrusor of the bladder, blood vessels (vessels of skeletal muscles, lungs, coronary vessels). In this case, the smooth muscles of the bronchi relax, the tonus and contractile activity of the myometrium, bladder, gallbladder and bile ducts decrease, motor and stomach and intestine tone, blood vessels expand.

    Relaxation of smooth muscles with stimulation of β2-adrenoreceptors, conjugated with Gs-proteins stimulating adenylate cyclase, is associated with an increase in the level of cAMP and activation of cAMP-dependent protein kinase in smooth muscle cells. cAMP-dependent protein kinase A inhibits the kinase of light chains of myosin, as a result, phosphorylation of light chains of myosin is disrupted and its interaction with actin does not occur. cAMP-dependent protein kinase A inhibits phospholampane (an inhibitor of Ca2 + -ATPase), as a result, the activity of Ca2 + -ATPase, transporting Ca2 + from the cytoplasm to the sarcoplasmic reticulum, increases in smooth muscle cells,and the concentration of cytoplasmic Ca2 + decreases. All this leads to a decrease in the tone and contractile activity of smooth muscles. It is possible to increase blood glucose levels, since β2-adrenoreceptors control the glycogenolysis process in the liver and skeletal muscles and insulin secretion in the pancreas, and when stimulated they activate phosphorylase and increase the breakdown of glycogen, resulting in increased blood glucose levels.

    The secretion of insulin with stimulation of β2-adrenergic receptors is increasing.

    The mechanism of bronchodilator action of theophylline is associated with blockade of adenosine A1 receptors of smooth muscle cells, as well as with indiscriminate inhibition of phosphodiesterase (types III, IV). Oppression of phosphodiesterase in bronchial smooth muscle cells (phosphodiesterase IV) leads to accumulation in cAMP cells and a decrease in intracellular Ca2 + concentration, resulting in a decrease in the activity of myosin light chain kinase in cells and the interaction of actin and myosin. This leads to relaxation of the smooth muscles of the bronchi (spasmolytic action). The same way theophylline acts on the smooth muscles of blood vessels, causing vasodilation.Under the effect of theophylline in mast cells, the concentration of cAMP also increases (due to the inhibition of phosphodiesterase IV) and the concentration of Ca2 + decreases. This prevents the degranulation of mast cells and the release of inflammatory mediators and allergies. Inhibition of phosphodiesterase in cardiomyocytes (phosphodiesterase III) leads to the accumulation of cAMP in them and an increase in the concentration of Ca2 + (increase in the force of the heart, tachycardia).

    Theophylline exerts a weak antiplatelet and diuretic action.

    Pharmacokinetics:

    With oral intake, 80-85% is absorbed. The degree of binding of salbutamol with plasma proteins is about 10%.

    Salbutamol is metabolized in the liver and excreted mainly with urine in unchanged form and in the form of phenolic sulfate. The swallowed portion of the inhalation dose is absorbed from the gastrointestinal tract and is subjected to active metabolism during "first passage" through the liver, turning into phenolic sulfate. Unchanged salbutamol and the conjugate is excreted mainly in the urine.

    The half-life of salbutamol is 4-6 hours. It is excreted by the kidneys partially unchanged and partly as an inactive metabolite of 4'-O-sulfate (phenolic sulfate). A small part is excreted with bile (4%), with feces.Most of the dose of salbutamol is excreted within 72 hours.

    Bioavailability of theophylline - 88-100%. Connection with plasma proteins - 40%. Biotransformation in the liver to inactive metabolites (CYP 1A2); caffeine - minor active metabolite in adults. The elimination half-life is 12 hours, smokers 4-5 hours, children 1-9 hours, preterm infants 20-30 hours. The total clearance is reduced in children under 1 year old and over 55 years of age, as well as with high fever , severe respiratory failure, in patients with hepatic and chronic heart failure, with viral infections. Elimination of metabolites by the kidneys, 10% in adults and 50% in children is unchanged. Therapeutic concentrations in serum: for bronchodilator action 5-15 mcg / ml (when the maximum therapeutic concentration is reached, the likelihood of toxic effect increases).

    Indications:

    Prevention and cupping (including nocturnal) of asthma attacks at bronhospasticheskom syndrome, bronchial asthma; symptomatic treatment (if taken internally) with chronic obstructive pulmonary diseases.

    ICD-10

    X.J95-J99.J98.3   Compensatory emphysema

    X.J95-J99.J98.2   Interstitial emphysema

    X.J40-J47.J43.9   Emphysema (lung) (pulmonary)

    X.J40-J47.J43.8   Other emphysema

    X.J40-J47.J43.2   Centrilobular emphysema

    X.J40-J47.J43.1   Pancreatic emphysema

    X.J40-J47.J43   Emphysema

    X.J40-J47.J46   Asthmatic status [status asthmaticus]

    X.J40-J47.J45.9   Asthma, unspecified

    X.J40-J47.J45.8   Mixed asthma

    X.J40-J47.J45.1   Non-allergic asthma

    X.J40-J47.J45.0   Asthma with predominance of an allergic component

    X.J40-J47.J45   Asthma

    X.J40-J47.J44.9   Chronic obstructive pulmonary disease, unspecified

    X.J40-J47.J44.8   Other specified chronic obstructive pulmonary disease

    X.J40-J47.J44.1   Chronic obstructive pulmonary disease with exacerbation, unspecified

    X.J40-J47.J44.0   Chronic obstructive pulmonary disease with acute respiratory infection of the lower respiratory tract

    X.J40-J47.J44   Other chronic obstructive pulmonary disease

    Contraindications:

    Hypersensitivity to theophylline (including other derivatives of xanthine - caffeine, pentoxifylline, theobromine) and salbutamol; acute myocardial infarction; unstable angina; tachyarrhythmia; extrasystole; cardiac ischemia; chronic heart failure; myocarditis; heart defects, including aortic stenosis; pheochromocytoma; glaucoma; pyloroduodenal constriction; hepatic or renal insufficiency; pulmonary edema; sepsis; gastroesophagealreflux; gastrointestinal bleeding in a recent history; severe arterial hyper- or hypotension; widespread atherosclerosis of blood vessels; hemorrhagic stroke; hemorrhage in the retina of the eye; thyrotoxicosis; Decompensated diabetes mellitus; epilepsy; increased convulsive activity; peptic ulcer of the stomach and duodenum in the stage of exacerbation; pregnancy; children's age till 16 years.

    Carefully:

    With peptic ulcer of stomach and duodenum (in the anamnesis), uncontrolled hypothyroidism (possibility of cumulation), prolonged hyperthermia, prostatic hyperplasia, in old age.

    Pregnancy and lactation:

    Action category for the fetus by FDA - C.

    Animal studies have identified a negative effect of the drug on the fetus, and there have not been proper studies in pregnant women, but the potential benefits associated with the use of this medication in pregnant women can justify its use, despite the risk.

    Dosing and Administration:

    ATafter the meal. Adults take 1 tablet 2 times a day. The maximum daily dose of theophylline should not exceed 12-14 mg per kg of body weight, but not more than 1.2 grams. The maximum daily dose of salbutamol is 32 mg.

    The optimum doses of salbutamol and the duration of the drug are selected by the doctor individually, taking into account the clinical picture of bronchial obstruction and body weight of the patient (starting from the minimum dose of salbutamol), individual drug tolerance, concomitant diseases, simultaneous administration of other medications. The duration of treatment is an average of 1-3 months. With good tolerability and efficacy, a longer duration of prescription is possible.

    Side effects:

    From the nervous system: dizziness, headache, insomnia, nervous tension, agitation, anxiety, irritability, convulsions, tremor.

    From the cardiovascular system: palpitation, tachycardia, arrhythmia, cardialgia, extrasystole, lowering of arterial pressure (BP), collapse, myocardial ischemia, an increase in the frequency of angina attacks, a feeling of "tides" of blood to the skin of the face.

    From the respiratory system: tachypnea, pulmonary edema.

    From the digestive system: a feeling of heaviness in the stomach, gastralgia, nausea, vomiting, dry mouth, gastroesophageal reflux, heartburn, peptic ulcer, diarrhea, with prolonged intake - decreased appetite.

    Allergic reactions: skin rash, itching, angioedema.

    Laboratory indicators: albuminuria, hematuria, hyperglycemia, increased concentration in the blood of free fatty acids, hypokalemia.

    Other: increased sweating.

    Overdose:

    Symptoms: gastralegia, diarrhea, nausea, vomiting (including with blood), gastrointestinal bleeding, tachypnea, facial skin hyperemia, tachycardia, ventricular arrhythmias, headache, hallucinations, insomnia, motor agitation, anxiety, photophobia, tremor, convulsions . In severe poisoning, epileptic seizures may develop (especially in children aged 16 to 18 without any precursors), hypoxia, metabolic acidosis, hyperglycemia, hypokalemia, decreased blood pressure, necrosis of skeletal muscles, confusion, renal insufficiency with myoglobinuria.

    Treatment: cancellation of the drug, gastric lavage, intake of activated carbon, laxative drugs, intestinal washing with a combination of polyethylene glycol and electrolytes, forced diuresis, hemosorption, plasmasorption, hemodialysis (efficacy is low, peritoneal dialysis is not effective), symptomatic cardioselective therapy β-adrenoblockers with tachycardia.If seizures occur, maintain airway patency and conduct oxygen therapy. For arresting seizures - in / in diazepam, 0.1-0.3 mg / kg (but not more than 10 mg). With severe nausea and vomiting, metoclopramide or ondansetron (intravenously).

    Interaction:

    Theophylline increases the likelihood of side effects of glucocorticosteroids, mineral corticosteroids (hypernatremia), funds for general anesthesia (increases the risk of ventricular arrhythmias), drugs that excite the central nervous system (increases neurotoxicity).

    Antidiarrhoeal drugs and enterosorbents reduce the absorption of theophylline.

    Rifampicin, phenobarbital, phenytoin, isoniazid, carbamazepine, sulfinpyrazone, aminoglutethimide, oral estrogen-containing contraceptives and moracisin, as inducers of microsomal liver enzymes, increase the clearance of theophylline, which may require an increase in its dose.

    When used simultaneously with cytochrome P 450 inhibitors, macrolide group antibiotics, lincomycin, allopurinol, cimetidine, isoprenaline, enoxacin, small doses of ethanol, disulfiram, fluoroquinolones,recombinant interferon-alpha, methotrexate, mexiletine, propafenone, thiabendazole, ticlopidine, verapamil, and when vaccinated against influenza, the intensity of theophylline may increase, which may require a reduction in its dose.

    Theophylline increases the effect of beta-adrenomimetics and diuretics (including by increasing glomerular filtration), reduces the effectiveness of lithium and beta-blockers.

    Theophylline is compatible with antispasmodics. It is not used together with other xanthine derivatives, with caution prescribed simultaneously with anticoagulants.

    Salbutamol enhances the effect of stimulants of the central nervous system, cardiotropic thyroid hormones.

    Salbutamol increases the likelihood of glycoside intoxication, reduces the effectiveness of antihypertensive drugs, nitrates.

    Xanthines with simultaneous application with salbutamol increase the likelihood of developing tachyarrhythmias; means for inhalation anesthesia, levodopa - severe ventricular arrhythmias.

    Monoamine oxidase inhibitors and tricyclics, enhancing the effect of salbutamol, may lead to a sharp decrease in blood pressure.

    Salbutamol is incompatible with nonselective beta-blockers.

    Simultaneous use of salbutamol with anticholinergic agents (including inhalation) can promote increased intraocular pressure.

    Diuretics and glucocorticosteroids increase the hypokalemic effect of salbutamol.

    Special instructions:

    The effectiveness of the action of theophylline may decrease in smokers.

    Be careful when consuming large quantities of caffeine-containing foods or drinks during the treatment period.

    Given the profile of side effects, it is not recommended when administering the drug to drive vehicles and engage in other potentially hazardous activities requiring increased concentration of attention and speed of psychomotor reactions.

    Treatment with prolonged forms is carried out with periodic monitoring of theophylline concentration in the blood.

    Drugs of prolonged action significantly reduce the likelihood of a dose-dependent side effect.

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