Theophylline and Caffeine

Toxicity
Dr.Qayssar Joudah Fadheel
Ph.D.Pharmacology and Therapeutics
 Theophylline

Introduction
Theophylline has been used for the management of pulmonary disorders such as
COPD and asthma, severe persistent asthma, and nocturnal symptoms. The
morbidity and mortality associated with the use of theophylline has risen due to
.the development of sustained-release formulations
 Pharmacology

Theophylline, a methylxanthine, in therapeutic serum concentrations (5–15 mg/L) may

produce beneficial effects in asthma through adenosine antagonism and modulation of

intracellular calcium concentrations. Theophylline is well absorbed from the gastrointestinal

tract. After therapeutic doses, peak serum concentrations are achieved within 2 hours after

regular-release formulations and within 4 to 12 hours after sustained-release formulations.

Absorption is slowed in the overdose setting, and peaks may be delayed for 12 to 24 hours or

longer. The volume of distribution of theophylline is approximately 0.5 L/kg, and it is well

distributed to all body compartments within 45 minutes after dosing . Hepatic metabolism

through the cytochrome P-450 1A2, 3A4, and 2E1 isoenzymes accounts for the majority of

.elimination, with only approximately 10 per cent excreted unchanged in the urine
In the overdose setting, theophylline exhibits saturable pharmacokinetics where

only a constant amount of drug can be eliminated per unit of time, resulting in

prolonged elimination. The three major metabolites in adults are 3 methyl xanthine,

1-methyl uric acid, and 1,3-dimethyluric acid (active metabolite). Neonates

metabolize theophylline slower than children and adults. Neonates metabolize a

consequential amount of theophylline to caffeine by n-methylation, and caffeine

serum concentrations may achieve 25% of theophylline serum concentrations.

Theophylline serum concentrations can increase or decrease depending on changes

in the hepatic microsomal P-450 enzyme activity influenced by age, liver function,

. and drug interactions

 Factors influencing theophylline clearance

Inhibitors(acute ethanol , allopurinol , cimetidine , ciprofloxacin , norfloxacin

, erythromycin , clarithromycin , CHF , liver failure , pulmonary disease ,
verapamil , ticlodipine , propranolol , tacrine)
Enhancers(Rifampin , primidone , carbamazepine , phenytoin ,
.phenobarbital , cigarette smoking)
 Pathophysiology
The nausea and vomiting seen after theophylline poisoning may result from direct
central nervous system (CNS) stimulation of the chemoreceptor trigger zone,
relaxation of lower esophageal sphincter tone, phosphodiesterase inhibition, and
increases in gastric acid secretion. Adenosine receptor antagonism in the brain has
been implicated in the seizures and status epileptics associated with severe
theophylline poisoning. Peripheral adenosine receptor antagonism may also be
partially responsible for the tachycardia and cardiac dysrhythmias seen after
.theophylline poisoning
Theophylline in the overdose setting causes increases in cyclic adenosine
monophosphate through phosphodiesterase inhibition and the release of
catecholamines . These catecholamines, especially epinephrine with resulting
β-adrenergic receptor stimulation, contribute to theophylline-induced
tachycardia, hypokalemia (due to an intracellular shift), lactic acidosis, and
hyperglycemia. Hypophosphatemia and hypomagnesemia may also result,
although these findings are less common. A widened pulse pressure occurs
due to increased β2-adrenergic receptor stimulation, with resultant relaxation
.of arteriolar tone
Increased catecholamines may also contribute to the agitated alert mental status,
seizure activity, and cardiac dysrhythmias (supraventricular and ventricular)
seen after poisoning. Findings in a reported case of theophylline toxicity
suggest myocardial function remains intact but systemic vascular resistance is
low. Other pharmacologic effects apparent after theophylline poisoning
include direct respiratory stimulation, gastric acid secretion, positive cardiac
inotropy and chronotropy, and cerebrovascular vasoconstriction. Direct
.respiratory stimulation causes a respiratory alkalosis
 Clinical Presentation

Patients who acutely overdose with theophylline often present with nausea,
vomiting, and sinus tachycardia .These manifestations begin within 1 hour for
immediate-release preparations (oral regular release tablets, liquid
preparations, and parenteral aminophylline) and within 2 to 4 hours for
sustained-release dosage forms. Patients often complain of feeling jittery. In
addition to tachycardia, vital signs may reveal a widened pulse pressure and
.an elevated respiratory rate
Physical examination is significant for repeated vomiting, tremor, and
hyperreflexia with an intact sensorium. As the theophylline serum
concentration approaches 90 to 100 mg/L, the pulse pressure may further
widen, followed by life-threatening manifestations of toxicity, including
generalized tonic-clonic seizures, status epilepticus, and supraventricular and
ventricular tachydysrhythmias. Seizures secondary to theophylline poisoning
are difficult to manage and often progress to status epilepticus. Hypokalemia,
.hyperglycemia, and an anion gap metabolic acidosis are typically present
Patients develop chronic theophylline toxicity as a result of accumulation secondary
to inappropriate dosing over several days, liver disease, drug-drug interactions, or
other processes that inhibit the elimination of theophylline. The chronically poisoned
patient is typically older, is on concomitant medications, and has some degree of
organ dysfunction. In renal failure patients, the active metabolite, 1,3-dimethyluric
acid, may accumulate to cause toxicity. seizures and cardiac dysrhythmias—at lower
serum concentrations. Gastrointestinal findings may be mild, with anorexia or nausea
occurring in only 50 percent of patients. In one study, seizures were the first
manifestation of toxicity . The most common dysrhythmia seen in patients with
COPD who develop chronic toxicity is multifocal atrial tachycardia. The
catecholamine-mediated hypokalemia and metabolic acidosis classically associated
. with acute toxicity are absent with chronic toxicity, perhaps as a result of tolerance
 Laboratory Studies

Patients with a history of theophylline overdose or who have a toxidrome consistent

with theophylline toxicity should have theophylline serum concentration measured
urgently. If positive, the serum concentration should be repeated every 1 to 2 hours
initially to determine the rate of rise or decline. In cases in which expeditious
laboratory results are not anticipated (within 1 hour) a second theophylline level
should be sent before the results of the first level are received. Theophylline serum
concentrations of 90 to 100 mg/L in acute poisoning (therapeutic, 5–15 mg/L) place
the patient at significant risk for the life-threatening complications related to
theophylline toxicity: seizures, status epilepticus, and cardiovascular collapse.
Rapidly rising levels are also of concern, because they indicate that absorption is
. occurring much faster than elimination
 Treatment

. Syrup of ipecac(Rarely, Early in large ingestions (<1 hr), at home)

. Gastric lavage(ipecac(Rarely, Early in large ingestions (<1 hr) )
Multiple doses of activated charcoal(In all toxic ingestions, unless
contraindicated, Continue until systemic symptoms abate and drug levels fall to
.the therapeutic range)
Whole-bowel irrigation(Early in large ingestions of sustained-release
preparations, With rapidly increasing serum concentrations and when high
levels persist despite multiple doses of activated charcoal or extracorporeal
. removal)
 . Electrolytes(Repeated as indicated)
Antiemetic therapy(For emesis interfering with the administration of activated
.charcoal)

Charcoal hemoperfusion(>90 mg/L for acute intoxication , With levels > 40 mg/L
and significant risk factors in chronic poisoning, With poor response to multiple
. doses of activated charcoal,)
. Hemodialysis(Unavailability of charcoal hemoperfusion)

. Peritoneal dialysis(None)

Exchange transfusion(Infants < 6 mo and neonates requiring extracorporeal

removal who will not tolerate hemodialysis, hemoperfusion, or activated charcoal)
. Plasmapheresis(None)
 Caffeine

INTRODUCTION
Many people depend on stimulants to keep them alert and improve their
productivity. Coffee alone is consumed in an estimated 80–98 percent of U.S.
homes with one out of every three persons consuming an average of 200 mg of
caffeine per day. Caffeine is commonly accepted and is not usually perceived as
a drug by most people. It is found in chocolate, carbonated sodas, and coffee as
well as in over-the-counter oral analgesics, migraine treatments, and products
. promoting alertness
 Pharmacokinetics
Caffeine is rapidly absorbed and in adults undergoes both oxidation and N-
demethylation, with approximately 1 per cent excreted unchanged in the urine.
Caffeine is metabolized to theophylline by the cytochrome P-450 enzyme
system. However, in neonates approximately 85 percent of a dose is excreted
unchanged in the urine. Decreased elimination and a prolonged half-life may
increase caffeine toxicity in neonates and premature infants .The metabolism
of a child approaches that of an adult at the approximate age of 8 months.
Elimination Half-Life of Caffeine in Premature Infants(65–102 hr),
. Neonates(82 hr) , Children(14.4 hr), Adults(3-7.5 hr)
 Pathophysiology

Caffeine has many effects in the body. The three most commonly documented
effects are (1) adenosine receptor antagonism, (2) phosphodiesterase inhibition,
and (3) enhanced intracellular calcium levels . Adenosine receptor antagonism
leads to vasoconstriction, hypertension, tremor, and agitation. These effects are
.frequently seen in caffeine overdose
Caffeine inhibits phosphodiesterases, causing increased levels of cyclic AMP,
which results in increased levels of catecholamines. Muscle contractility is
enhanced through increased intracellular calcium levels and increased
permeability of the sarcoplasmic reticulum to calcium. Stimulation of gastric
acid and intestinal secretions and lowering of lower esophageal sphincter tone
.by caffeine commonly result in diarrhea and abdominal cramping

Beneficial effects of caffeine include bronchodilation and vasodilation in the

treatment of apnea in premature infants. Although caffeine-induced vasodilation
may lower blood pressure, caffeine-induced medullary stimulation and
.increased catecholamine release offset this effect
 Clinical Presentations
Acute Toxicity

In adults, ingestion of 500–1000 mg of caffeine may result in nausea, vomiting,

diarrhea, tremors, and agitation. Most patients have sinus tachycardia and a mild
hypertension. Increases in cardiac output and glomerular filtration rate (GFR) can
increase urine production. Dehydration and hypokalemia are common. Death due to
caffeine overdose is rare but can result from the spontaneous vomiting that occurs
with ingestion of large amounts. Caffeine-related deaths from dysrhythmias,
seizures, and neurologic effects have been reported .The estimated lethal dose of
caffeine in an untreated adult is 5–10 g,] and in children 78 mg/kg has caused
serious symptoms. This may be due to the slower elimination of caffeine by
. children
 Chronic Toxicity

Chronic excessive ingestions of caffeine frequently result in tachycardia,

hypertension, and palpitations, Myocardial infarction, vasculitis,
cardiomyopathy, and dysrhythmias (paroxysmal atrial tachycardia, premature
ventricular contractions , ventricular tachycardia, and ventricular fibrillation)
. have been reported in large and chronic overdoses
 Laboratory Studies
diagnosis or the agent ingested, but do not routinely correlate with symptoms and
are not readily available . Electrocardiogram (ECG) and chest radiograph may be
indicated if cardiac dysrhythmias or cardiomyopathy are suspected. Electrolytes
should be monitored because vomiting and diarrhea can lead to fluid and
electrolyte imbalances. Rhabdomyolysis, hypokalemia, and lactic acidosis have
been reported. A creatine kinase level greater than five times the normal range
indicates significant rhabdomyolysis . Other laboratory tests required to evaluate
conditions listed in the differential diagnosis can be performed as needed. A
computed tomographic (CT) scan of the head is indicated if intracranial
.hemorrhage is suspected
 Treatment

. Decontamination(Activated charcoal )
Dysarrythmias (Benzodiazepines(Diazepam, Lorazepam)
Esmolol, lidocaine ,procainamide
.Hypertension(Benzodiazepines(Diazepam,Lorazepam )

.Sodium nitroprusside
. Seizures(Benzodiazepines(Diazepam,Lorazepam )

. Phenobarbital
Nausea/vomiting(Rehydration if necessary(Titrate crystalloids to maintain
. urine output )

. Potassium/electrolyte replacement(Replace electrolytes as needed)

. Antiemetics (Metoclopromide)

. Ondansetron
Thank You