بسم الله الرحمن الرحيم methylxanthines (theophylline) toxicity د/ عبد...
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الرحيم الرحمن الله بسم
Methylxanthines(Theophylline) Toxicity
مدبولى/ جودة المنعم عبد دالسموم و الشرعى الطب دكتوراة
األكلينيكية,, األكلينيكية السموم و الشرعى الطب مدرس
الجامعى بنها بمستشفى التسمم عالج استشاري
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ObjectivesObjectives 1.1. Therapeutic uses.Therapeutic uses.
2.2. Toxicokinetics.Toxicokinetics.
3.3. Mechanism of toxicity.Mechanism of toxicity.
4.4. Clinical presentation.Clinical presentation.
5.5. Diagnosis & DD.Diagnosis & DD.
6.6. Treatment.Treatment.
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PharmacologyPharmacology
I- Methylxanthines are so named because they are methylated derivatives of xanthinemethylated derivatives of xanthine.
(purine base)
– Are plant-derivedplant-derived alkaloids:
1. Caffeine = Cola, Chocolate, CoffeeCola, Chocolate, Coffee , Tea.
2. Theobromine == CocoaCocoa (cacao), ChocolateChocolate
3. Theophylline == TeaTea
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II- II- Theophylline is a bronchodilatorbronchodilator and respiratory respiratory stimulant.stimulant.
• Used to treatUsed to treat::
1. Asthma, chronic obstructive pulmonary dis.
2. Neonatal apnea syndrome.
3. A weight-loss agent.
Used, most commonly in beveragesbeverages, for their stimulant, mood elevating, and fatigue abating effects.
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III-III- Theophylline Theophylline, or its water-soluble salt aminophyllineaminophylline, is rarelyrarely used to treat respiratory conditions.
• ButBut more selective B. agents selective B. agents with fewer side effects, such as albuterolalbuterol and other selective B, adrenergic agonistsselective B, adrenergic agonists, are now more commonly used.
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ToxicokineticsToxicokinetics• Theophylline is 100% bioavailable by oral route ??????
• Theophylline is rapidly absorbed butbut may be delayed in sustained- release preparation or if bezoars ??????????
• The VD is 0.6 L/kg0.6 L/kg, and 36% is protein bound ??????????
• It is metabolized hepatically, undergoes entero-hepatic 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 ??????????
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Mechanism of toxicityMechanism of toxicity::
1- 1- Adenosine antagonist:Adenosine antagonist:– Adenosine modulates histamine releasehistamine release and cause
bronchoconstriction. – Adenosine antag. results in nor- epinephrine releasenor- epinephrine release.
IN therapeutic dose ------ BronchodilatorBronchodilator
IN overdose ---------------- CNS manifestationsCNS manifestations
2- +++ release of endog. Catecholamines:2- +++ release of endog. Catecholamines:
– --------------------- CARDIAC CARDIAC & & CNS symptomsCNS symptoms
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3- Inhibit phosphodiesterase:
• Elevate cAMPcAMP.• B, adrenergic
stimulation.
(peripheral vasodilation, myocardial and CNS stimulation)
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4- Stomach:• Increase gastric acidacid secretion• Smooth muscle relaxationrelaxation • Stimulation of chemoreceptor trigger zonechemoreceptor trigger zone.
5- Increase striated muscle contractility:5- Increase striated muscle contractility:• increase intracellular calciumcalcium content.• increase muscle oxygenoxygen consumption • increase the basal metabolic ratebasal metabolic rate. • These effects are sought by users of methylxanthines to
enhance or improve athletic performance or lose athletic performance or lose weightweight.
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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.
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Clinical presentationClinical presentation
1- GIT manifestations:1- GIT manifestations: • Prominent and early features of toxicity. • NauseaNausea and vomitingvomiting.
2- C.V.S manifestations2- C.V.S manifestations: • Sinus tachycardiaSinus tachycardia ---------- tachyarrhythmia. • HypotensionHypotension
• HypovolemiaHypovolemia secondary to vomiting.
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Clinical presentationClinical presentation
3- CNS manifestation:3- CNS manifestation: • Irritability, tremors, agitationagitation. • Prolonged refractory seizuresseizures.
4- Metabolic:4- Metabolic: • Hypokalemia………….• Lactic acidosis. ……..
• Rhabdomyolysis. …..• Hyperglycemia……………
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DiagnosisDiagnosisHistory: • Type of preparation, Co-ingestant drugs.• Underlying diseases.
Clinical presentation. …………………………..
Serum theophylline concentration: • Correlates with the severity of acute toxicityacute toxicity as follows: - 5-155-15 ug/ml …… therapeutic level. - 20-4020-40 ug/ml ….. mild toxicity. - 40-7040-70 ug/ml ….. moderate toxicity. - 70 70 ug/ml …... severe toxicity.
• Blood gas analyses, serial electrolytes, blood glucose level, ECG.
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TreatmentTreatment
Stabilization of the ABC & Emergent therapy:Stabilization of the ABC & Emergent therapy:
1- Tachyarrhythmia: • Non selective - blockers- blockers e.g. propranololpropranolol … may
precipitate bronchospasm.
• So EsmololEsmolol, selective B1- blocker safe to use in patient with asthma.
• LidocaineLidocaine for ventricular tachycardia, If unstable, use
cardioversioncardioversion.
2- Hypotension: I.V. fluid and/or vasopressors (PhenylephrinePhenylephrine “α” or noradrenaline “α > β”.
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3- Seizures: • Diazepam is the initial choice • Phenobarbital • Skeletal muscle relaxant. • General anesthesia.
• No role for phenytoinNo role for phenytoin…………. هااام
4- Hypokalemia: k supplementation k supplementation بالك بالك خللى . . …… خللى
5- Metabolic acidosis: I.V. sodium bicarbonate.
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GIT decontamination:GIT decontamination:• Activated charcoal and a cathartic can be added only once.
• Whole bowel irrigationWhole bowel irrigation: in sustained- release preparation.
• Surgical decontaminationSurgical decontamination to remove a bezoars formation.
• IpecacIpecac is contraindicatedcontraindicated because:1. it may exacerbate the vomiting. 2. It also complicates the use of activated charcoal which is known to
decrease the serum theophylline level.
Gastric lavage: Gastric lavage: large size tablets ??????large size tablets ??????If refractory vomiting: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.
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Enhancement of EliminationEnhancement of Elimination:: • MDAC: for all patients with acute or chronic toxicity.
• Hemodialysis: in high risk patients: • Serum level level 100 100 ug/ml• Older or chronic pt. with level 30 ug/ml. 30 ug/ml. • Rising serum level despite MDACdespite MDAC.• Life threatening toxicityLife threatening toxicity which includes: prolonged seizures,
uncontrollable Dysrhythmias and persistent hypotension.
• Charcoal hemoperfusion:Charcoal hemoperfusion: Provides a higher Provides a higher clearance of theophylline than hemodialysisclearance of theophylline than hemodialysis.