(Theophylline) Toxicity د/ عبد المنعم جودة مدبولى بسم الله الرحمن الرحيم Methylxanthines (Theophylline) Toxicity د/ عبد المنعم جودة مدبولى دكتوراة الطب الشرعى و السموم الأكلينيكية, مدرس الطب الشرعى و السموم الأكلينيكية, استشاري علاج التسمم بمستشفى بنها الجامعى

Objectives Therapeutic uses. Toxicokinetics. Mechanism of toxicity. Clinical presentation. Diagnosis & DD. Treatment.

Pharmacology I- Methylxanthines are so named because they are methylated derivatives of xanthine. (purine base) Are plant-derived alkaloids: Caffeine = Cola, Chocolate, Coffee , Tea. Theobromine = Cocoa (cacao), Chocolate Theophylline = Tea

II- Theophylline is a bronchodilator and respiratory stimulant. Used to treat: Asthma, chronic obstructive pulmonary dis. Neonatal apnea syndrome. A weight-loss agent. Used, most commonly in beverages, for their stimulant, mood elevating, and fatigue abating effects.

III- Theophylline, or its water-soluble salt aminophylline, is rarely used to treat respiratory conditions. But more selective B. agents with fewer side effects, such as albuterol and other selective B, adrenergic agonists, are now more commonly used.

Toxicokinetics Theophylline is 100% bioavailable by oral route ?????? Theophylline is rapidly absorbed but may be delayed in sustained- release preparation or if bezoars ?????????? The VD is 0.6 L/kg, and 36% is protein bound ?????????? It is metabolized hepatically, undergoes entero-hepatic circulation ????????????? Rapidly diffuses into the total body water and all tissues, readily crosses the blood-brain barrier and is secreted into breast milk ??????????

Mechanism of toxicity: 1- Adenosine antagonist: Adenosine modulates histamine release and cause bronchoconstriction. Adenosine antag. results in nor- epinephrine release. IN therapeutic dose ------ Bronchodilator IN overdose ---------------- CNS manifestations 2- +++ release of endog. Catecholamines: --------------------- CARDIAC & CNS symptoms

3- Inhibit phosphodiesterase: Elevate cAMP. B, adrenergic stimulation. (peripheral vasodilation, myocardial and CNS stimulation)

5- Increase striated muscle contractility: 4- Stomach: Increase gastric acid secretion Smooth muscle relaxation Stimulation of chemoreceptor trigger zone. 5- Increase striated muscle contractility: increase intracellular calcium content. increase muscle oxygen consumption increase the basal metabolic rate. These effects are sought by users of methylxanthines to enhance or improve athletic performance or lose weight.

6- Metabolic effects: Severe hypokalemia = B. Shift Metabolic acidosis: Ms. Activity, BMR Hyperglycemia: is common and occurs in 75% of acute theophylline overdoses. Hyperthermia: caused by increased metabolic and muscle activity.

Clinical presentation 1- GIT manifestations: Prominent and early features of toxicity. Nausea and vomiting. 2- C.V.S manifestations: Sinus tachycardia ---------- tachyarrhythmia. Hypotension Hypovolemia secondary to vomiting.

Clinical presentation 3- CNS manifestation: Irritability, tremors, agitation. Prolonged refractory seizures. 4- Metabolic: Hypokalemia…………. Lactic acidosis. …….. Rhabdomyolysis. ….. Hyperglycemia……………

Diagnosis History: Clinical presentation. ………………………….. Type of preparation, Co-ingestant drugs. Underlying diseases. Clinical presentation. ………………………….. Serum theophylline concentration: Correlates with the severity of acute toxicity as follows: - 5-15 ug/ml …… therapeutic level. - 20-40 ug/ml ….. mild toxicity. - 40-70 ug/ml ….. moderate toxicity. -  70 ug/ml …... severe toxicity. Blood gas analyses, serial electrolytes, blood glucose level, ECG.

Treatment Stabilization of the ABC & Emergent therapy: 1- Tachyarrhythmia: Non selective - blockers e.g. propranolol … may precipitate bronchospasm. So Esmolol, selective B1- blocker safe to use in patient with asthma. Lidocaine for ventricular tachycardia, If unstable, use cardioversion. 2- Hypotension: I.V. fluid and/or vasopressors (Phenylephrine “α” or noradrenaline “α > β”.

No role for phenytoin…………. هااام 3- Seizures: Diazepam is the initial choice Phenobarbital Skeletal muscle relaxant. General anesthesia. No role for phenytoin…………. هااام 4- Hypokalemia: k supplementation خللى بالك … . 5- Metabolic acidosis: I.V. sodium bicarbonate.

GIT decontamination: Activated charcoal and a cathartic can be added only once. Whole bowel irrigation: in sustained- release preparation. Surgical decontamination to remove a bezoars formation. Ipecac is contraindicated because: it may exacerbate the vomiting. It also complicates the use of activated charcoal which is known to decrease the serum theophylline level. Gastric lavage: large size tablets ?????? If refractory vomiting: Ranitidine 50 mg I.V. Metoclopramide 10mg I.V. Avoid: - Cimitidine because it decrease theophylline metabolism - Phenothiazine because it decrease seizure threshold.

Enhancement of Elimination: MDAC: for all patients with acute or chronic toxicity. Hemodialysis: in high risk patients: Serum level  100 ug/ml Older or chronic pt. with level  30 ug/ml. Rising serum level despite MDAC. Life threatening toxicity which includes: prolonged seizures, uncontrollable Dysrhythmias and persistent hypotension. Charcoal hemoperfusion: Provides a higher clearance of theophylline than hemodialysis.