Anti-Asthmatic Drugs Toxicity

Bronchodilators
Beta-adrenergic Agonists
Beta-adrenergic agonists have an important role as cardiac stimulants owing to both
chronotropic and inotropic effects on the heart and are (relatively) rarely used as
bronchodilators today, so their inclusion here may appear incongruous.
Isoproterenol (Isopropylarterenol, Isoprenaline, Isopropylnoradrenaline)
This drug is used to stimulate heart rate in bradycardia or heart block as an
emergency measure, and occasionally for the treatment of asthma. It is readily
absorbed by inhalation and by parenteral administration. It is metabolized in the liver
by catechol-omethyl transferase (COMT). It acts by lowering peripheral vascular
resistance and mean arterial pressure, while increasing cardiac output and relaxing
smooth muscles.
Adverse effects include tachycardia, palpitations, headache, and flushing. Sometimes
arrhythmias or cardiac ischemia may occur.
Dobutamine
Dobutamine resembles dopamine in its structure but possesses an aromatic substitute on
the amino group. It is used for short-term treatment of cardiac decompensation due
to depressed contractility. Infusion of dobutamine in combination with
echocardiography is useful in the non-invasive assessment of patients with coronary
artery disease.
Dobutamine is ineffective orally since it is inactivated by extensive pre systemic
metabolism in the GI mucosa and liver.
The duration of action on IV administration is just 8 to 10 minutes. It has an apparent
volume of distribution of 0.20 to 0.80 L/kg. Dobutamine is metabolized in the liver by
COMT, and by conjugation with glucuronic acid, and excreted in the urine. Dobutamine
is a beta1-adrenergic agonist, and also induces alpha1-adrenoceptor-mediated
vasoconstriction, as well as beta2-adrenoceptor-mediated vasodilation. This results
in an
increase in cardiac output without significantly changing the blood pressure. Unlike
dopamine, it does not cause release of endogenous noradrenaline.
Adverse effects include nausea, tachycardia, palpitations, angina, dyspnea, headache, and
hypotension. Overdose results in hypotension, oliguria, supraventricular tachycardia,
stuffy nose, hoarseness, flushing of skin, tachypnoea, palpitations, anginal pain,
paraesthesias, and urinary incontinence.
Signs and symptoms usually clear within 2 hours.
Treatment consists of symptomatic and supportive measures. The patient must not be
discharged until serial ECGs and cardiac enzymes show no evidence of myocardial
damage.
Beta2-Selective Adrenergic Agonists
Beta2-selective adrenergic agonists are much more useful in the treatment of asthma
than beta-adrenergic agonists, because unlike the latter, they do not stimulate beta1-
adrenergic receptors in the heart that can result in serious cardiac effects. But in
conditions of overdose, such selectivity may be lost. Another advantage is that these
drugs have enhanced oral bioavailability, and hence can be given orally. However,
inhalation of small doses in aerosol form affords best protection against adverse
effects.
Metaproterenol (orciprenaline), terbutaline, albuterol (salbutamol), isoetharine,
isoxsuprine, pirbuterol, bitolterol, fenoterol, formoterol, procaterol, salmeterol and
ritodrine.
Ritodrine is more commonly used for inhibition of uterine contractions (in premature
labour).
Isoxsuprine is used to relieve the symptoms of central and peripheral vascular
diseases such as arteriosclerosis, Buerger’s disease and Raynaud’s disease.

Toxicokinetics
Beta2 agonists can be given orally, by inhalation, or by injection (SC, IM, IV).
Following oral administration, most beta agonists (especially salbutamol and bitolterol)
are well absorbed, with the exception of terbutaline and orciprenaline. Despite adequate
absorption however, the systemic bioavailability of these drugs is generally low, because
of extensive sulfation in the liver and the small intestinal wall. As a result, the oral dose
of beta2 agonists needs to be 5 to 10 times greater than the parenteral dose.
Mode of Action.
■ Bronchodilation.
■ Relaxation of uterine muscle.
■ Peripheral vasodilation.
■ Anti-allergic effect on mast cells causing inhibition of release of bronchoconstriction
mediators (histamine, prostaglandin D2, etc.).
■ Promotion of intracellular shift of potassium from serum, leading to a decrease in
serum potassium concentration.
■ Stimulation of non-pulmonary beta2 receptors, resulting in tachycardia, prolongation of
QTc interval, T wave changes, tremor, and increase in blood glucose.
Adverse Effects
■ Tremor, restlessness, anxiety.
■ Tachycardia, palpitations, hypotension, myocardial ischaemia (especially on systemic
administration).
■ Headache.
■ Hypokalemia.
Drug Interactions
■ Beta blockers inhibit bronchodilator effect.
■ Diuretics and xanthines augment hypokalaemia.
■ Synergistic effect with theophylline and beclomethasone.
■ Potentiation of vascular effects with MAOIs and tricyclics.
Clinical (Toxic) Features
1. CNS: Tremor, agitation, vertigo, headache, mydriasis.
2. CVS: Chest pain, angina, hypotension. ECG changes— Prolongation of QTc interval,
atrial fibrillation, right bundle branch block, and ST-T wave changes. Sinus tachycardia
is said to be the most frequent ECG change seen.
3. General: Nausea, hyperglycemia, hypokalemia, and flushed sweaty skin. Rarely there
may be lactic acidosis, rhabdomyolysis, and acute renal failure.
4. Chronic overdose with salbutamol has led to the development of psychosis.
Treatment
1. Decontamination—Stomach wash may be done if the patient is seen within 4 to 6
hours.
2. Stabilization— a. Admission to intensive care unit and observation for at least 4 to
6 hours. The patient can be discharged if there is normal heart rate, absence of tremor,
and presence of normal blood sugar and serum potassium.
b. For serious cases, cardiac monitoring and oxygen administration are necessary.
c. Hemodialysis may be useful if there is evidence of acute renal failure.
3. Antidote—Some investigators have suggested the use of beta blockers (e.g.
propranolol 0.01 mg/kg) for symptomatic improvement of tremor, tachycardia, and
hypokalemia.
More cardio-selective drugs such as metoprolol may be preferable in order to avoid
precipitation of wheezing in asthmatic patients. However, actual efficacy of such beta
blockers is controversial.
4. Special Measures— a. For serious hypokalemia, administer potassium chloride
cautiously, while repeating serum potassium levels and serial ECGs. In most cases,
hypokalemia reverts to normal spontaneously. Beta blockers may help in speeding the
return to normalcy but must be used with caution in asthmatic patients.
b. In children, it is important to monitor blood glucose levels for several hours to rule
out hyperglycemia.
c Pulmonary oedema may be precipitated if an overdose of b2 agonists has been taken
by a pregnant woman in labor. This should be managed by oxygen, IV diuretics,
and fluid restriction.

CASE STUDY: METHOTREXATE OVERDOSE

History: A 16-year-old female was angry with her mother and ingested a large amount
of the mother’s medication, 30 minutes ago. She now presents to your emergency
department with her mother requesting treatment. Mom has rheumatoid arthritis and
has been placed on methotrexate. She ingested no other medications and is not
currently suicidal.
PMH: None.
Physical Examination:
T: 98.8°F HR: 92 bpm RR: 16 breaths per minute BP: 110/65 mm Hg
General: Alert, tearful and very remorseful.
HEENT: Examination is normal.
Pulmonary: Clear to auscultation.
CV: Regular rate and rhythm without murmur.
Abdomen: Soft and nontender, bowel sounds were normal.
Neurologic: Normal deep tendon reflexes and normal muscle strength.

QUESTIONS

1. What medical concerns do you have?

Methotrexate overdose may result in a wide variety of toxic effects. This patient
requires careful monitoring and aggressive treatment.

2. What symptoms are associated with this type of medication use?

Toxic side effects include gastrointestinal (nausea, vomiting, intestinal bleeding,
stomatitis, mucositis, esophatigits, hematologic (leukopenia, anemia, thrombocytopenia),
hepatic (transaminitis, cirrhosis, hyperbilirubinemia), pulmonary (acute lung injury)
neurologic (hemiparesis, seizures, dysreflexia, encephalopathy, coma) and renal (acute
tubular necrosis).

3. What interventions should be performed?

Leucovorin is a metabolically functional folic acid and can bypass the antifolate
effects of methotrexate. It should be given within 1 hour of ingestion if possible.
It should be given IV and the dose should equal or be greater than the dose of
methotrexate. If dose is unknown then can give 75mg or 10mg/m2/dose in children.
Then 12 mg is repeated every 6 hours for 4 doses. Methotrexate levels can then be
obtained to guide therapy. There are no contraindications for leucovorin use and adverse
side effects includes allergic reaction and possible hypercalcemia. Sodium
bicarbonate and fluids can be used to help prevent nephrotoxicity. Activated
charcoal can be used if patient is protecting their airway and the ingestion is within
1 hour.

CASE STUDY: PHENYTOIN POISONING

History: A 19-month-old male presents to your emergency department with his

parents after ingesting 35 mL of phenytoin suspension. Parents relate
that he appears to be “wobbly” and “sleepy”. He has had no vomiting and
no seizure activity.

PMH: Brain aneurysm, seizure disorder, feeding disorder.

Physical Examination:
T: 100.4°F HR: 132 bpm RR: 30 breaths per minute BP: 110/70 mm Hg
General: He appears very sleepy but is arousable and has an intact gag reflex.
HEENT:
Examination reveals horizontal and vertical nystagmus. Mouth
examination reveals gingival hyperplasia.
Pulmonary: Clear to auscultation.

CV: Regular rate and rhythm without murmur, capillary refill normal.

Neurologic: GCS = 15, cranial nerves II-XII intact. Truncal ataxia is present.
Hyperreflexia present, all DTR’s.

QUESTIONS

1. What are the usual signs of acute phenytoin toxicity?

 CNS effects are the most common symptoms of acute phenytoin ingestion. The
minimum oral toxic dose is 20 mg/kg. Mild to moderate intoxication causes
horizontal nystagmus, ataxia, ophthalmoplegia, dysarthria, hyperreflexia,
hyperglycemia, irritability and altered mental status. Severe intoxication causes
stupor, coma and respiratory arrest. While phenytoin toxicity can produce
paradoxical seizures, this finding should prompt a search for other causes as this
is a rare finding. Death from phenytoin poisoning is also rare.
Serum phenytoin levels can be obtained and it is generally recommended that
repeated levels are determined because of potential for slowed absorption. The
therapeutic range is 10-20 mg/L. At levels under 10 mg/L, systemic
manifestations are rare. at levels 10-20 mg/L, mild nystagmus may be present.

At levels between 20-30 mg/L nystagmus is common, and ataxia may occur. At
levels between 30-40 mg/L patients often develop ataxia and slurred speech. At
levels between 40-50 mg/L patients may develop lethargy, confusion and
combativeness. At levels above 50 mg/L patients also develop choreoathetoid
movements and opisthotonic posturing. Survival has been reported in three
patients with levels greater than 100 mg/L. Although cardiovascular effects occur
after rapid intravenous administration of phenytoin, due to the propylene glycol
excipient, these effects do not occur after chronic or acute oral exposures
In some instances, the patient's serum phenytoin level may seem discordant with
their symptoms. In these situations, a serum albumin level might be helpful as
higher free phenytoin concentrations are seen in the setting of
hypoalbuminemia.
Because it is the free phenytoin concentration that determines toxicity, but the
total level that is reported, hypoalbuminemic patients may exhibit significant
symptoms in the setting of only mildly elevated levels. Free phenytoin
concentrations can be obtained; however they are generally not measured
unless there is clinical uncertainty of the diagnosis.
 choreoathetoid movements

opisthotonic posturing

2. What initial therapy should be instituted?

Initial management is focused on stabilizing the airway, breathing and circulation.

Patients with ataxia should have precautions taken to prevent injury from fall.
Since the child has a seizure disorder, it is important not to drop the
anticonvulsant level to a subtherapeutic range. If seizures occur, treat in the
usual way and search for other causes. In the appropriate situation, activated
charcoal may be administered. If the level is very high and the patient has
significant symptoms, multi-dose activated charcoal can be given to enhance
phenytoin elimination but is not necessary and may increase aspiration risk in
symptomatic patients. Physicians should weigh the benefits of multidose
activated charcoal in patients in need of chronic phenytoin therapy for seizure
control.
3.What are the signs and symptoms of chronic phenytoin toxicity?

Patients on long term phenytoin therapy can develop gingival hyperplasia, which is
the most common adverse effect in adults and children. Chronic phenytoin toxicity may
result in phenytoin encephalopathy. Other adverse effects include hyperglycemia
secondary to impaired insulin secretion, hypothyroidism, osteomalacia, aplastic
anemia, malignant lymphoma, hemorrhagic disease of the newborn (responsive to
vitamin K), and megaloblastic anemia secondary to decreased folate absorption and
altered folate metabolism (responsive to folic acid).