بسم الله الرحمن الرحيم methylxanthines (theophylline) toxicity د/ عبد...

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

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.

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

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.

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.

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 ??????????

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

3- Inhibit phosphodiesterase:

• Elevate cAMPcAMP.• B, adrenergic

stimulation.

(peripheral vasodilation, myocardial and CNS stimulation)

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.

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 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.

Clinical presentationClinical presentation

3- CNS manifestation:3- CNS manifestation: • Irritability, tremors, agitationagitation. • Prolonged refractory seizuresseizures.

4- Metabolic:4- Metabolic: • Hypokalemia………….• Lactic acidosis. ……..

• Rhabdomyolysis. …..• Hyperglycemia……………

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.

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”.

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.

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.

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.