Theophylline toxicity

Question 1

Theophylline is derived from

Answer 1

methylxanthines alkaloids

Question 2

is used widely for the treatment of

Answer 2

asthma

Question 3

most commonly is used orally in

Answer 3

sustained-release preparations

Question 4

Mode of toxicity

Answer 4

Theophylline has a narrow therapeutic margin (therapeutic dose=10-20 µg/ml).

Mode of theophylline toxicity may be:
Intentional.
Dosing errors: (serum level monitoring during treatment is necessary).

Question 5

Dosing errors include:

Answer 5

• Miscalculation of the dose.
• Change in the frequency of administration.
• Conditions that reduce theophylline clearance:
• Drug interaction with enzyme inhibitors, e.g. erythromycin, cimetidine.
• Liver cirrhosis and CHF.

Question 6

Mechanism of action

Answer 6

Three primary mechanisms have been postulated:
1-Antagonizing the activity of adenosine (adenosine causes constriction of respiratory smooth muscles).
2-Catecholamine release (epinephrine, norepinephrine)
3-Inhibit the activity of the enzyme phosphodiesterase which is responsible for the metabolism of cAMP. As the B-receptors are stimulated, the level of cAMP increase intracellularly and persist

Question 7

Clinical presentation of acute toxicity

Answer 7

I- GIT
Nausea, vomiting, abdominal pain, and may be upper GI bleeding.

II- CNS (due to loss of adenosine anticonvulsant activity)
Agitation, tremors.
Respiratory center stimulation leading to hyperventilation and respiratory alkalosis.

Generalized seizures are the most concerning because they are associated with increased mortality.

Prolonged seizures can contribute to rhabdomyolysis.

Question 8

Clinical presentation of acute toxicity cont.

Answer 8

III- Cardiovascular (due to excessive catecholamine stimulation of the myocardium and aggravated by electrolyte and acid base disturbance).

Tachydysrhythmias:
Sinus tachycardia is the most common, all other types of tachydysrhythmias may be present
Ventricular dysrhythmias as ventricular fibrillation and cardiac arrest may occur.
Hypotension. (B2 effect and worsened by volume depletion).
IV- Metabolic (due to theophylline-induced increase in catecholamine release).

Hypokalemia because of intracellular shift of K+ (B2 adrenergic receptor effect).
Hypomagnesemia (CA stimulation, renal wasting, vomiting)
Metabolic acidosis. (lactic acidosis from convulsion, hypotension)
Hyperglycemia

Question 9

Investigations

Answer 9

*Serum theophylline level: (therapeutic range = 10-20 µg/ml).
*Serum electrolytes, especially K+ level.
*Serum glucose.
*ABG may show
1-Respiratory alkalosis (early)
2-Metabolic acidosis.
*ECG, cardiac monitor.
*Baseline INR, PTT, platelets (should be documented in case that hemodialysis drug removal becomes necessary).

Question 10

Treatment

Answer 10

I- Emergency measures (ABCD).
II- Elimination
GL. It may be delayed in case of SR preparations.
MDAC decreases serum theophylline.
Whole-bowel irrigation ( in cases of SR preparations)
Hemodialysis/hemoperfusion:
Indications:
Peak serum level >90 µg/ml at any time.
Peak serum level >40 µg/ml with clinical manifestations of severe toxicity: seizures, ventricular dysrhythmias, or hypotension unresponsive to fluids.

Question 11

Treatment of dysrhythmias

Answer 11

Supraventricular tachycardia: adenosine

Ventricular dysrhythmias: lidocaine

Question 12

Hypotension

Answer 12

• IV fluids.
• Phenylephrine (vasopressor with alpha receptor activity).
• Non-selective beta-blockers, e.g. propranolol (caution in asthmatic patients).

Question 13

Seizures

Answer 13

• IV benzodiazepine.
• Phenobarbital
• General anesthesia if no response to phenobarbital

Question 14

Hypokalemia

Answer 14

it must not be aggressively treated because redistribution of K+ occurs with decrease of theophylline level.

Question 15

Vomiting must be aggressively controlled with:

Answer 15

Metoclopramide

Serotonin antagonists, e.g. ondansetron