بسم الله الرحمن الرحيم Methylxanthines (Theophylline) Toxicity

1. 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

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

3. Pharmacology I- Methylxanthinesare so named because they aremethylated derivatives of xanthine. (purinebase) • Are plant-derived alkaloids: • Caffeine = Cola, Chocolate, Coffee , Tea. • Theobromine=Cocoa (cacao), Chocolate • Theophylline=Tea

4. 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 inbeverages,for their stimulant,mood elevating, and fatigue abating effects.

5. III- Theophylline, or its water-soluble salt aminophylline,israrely 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.

6. Toxicokinetics • Theophylline is 100% bioavailableby 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 ??????????

7. 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

8. 3- Inhibit phosphodiesterase: • ElevatecAMP. • B, adrenergicstimulation. (peripheral vasodilation, myocardial and CNS stimulation)

9. 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.

10. 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.

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

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

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

14. 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”.

15. 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.

16. 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. • Ipecacis 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.

17. Enhancement of Elimination: • MDAC:for all patients with acute or chronic toxicity. • Hemodialysis:in high risk patients: • Serum level  100ug/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.