DRUG INTERACTIONS
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 132-week (fixed concentration) dietary administration study in rats, clonidine hydrochloride administered at 32 to 46 times the maximum recommended daily human oral dose was unassociated with evidence of carcinogenic potential.
Fertility of male or female rats was unaffected by clonidine hydrochloride doses as high as 150 mcg/kg or about 3 times the maximum recommended daily human oral dose (MRDHD). Fertility of female rats did, however, appear to be affected (in another experiment) at dose levels of 500 to 2000 mcg/kg or 10 to 40 times the MRDHD.
Usage in Pregnancy
Teratogenic Effect
Pregnancy Category C
Reproduction studies performed in rabbits at doses up to approximately 3 times the maximum recommended daily human dose (MRDHD) of clonidine hydrochloride have revealed no evidence of teratogenic or embryotoxic potential. In rats however, doses as low as 1/3 the MRDHD were associated with increased resorptions in a study in which dams were treated continuously from 2 months prior to mating. Increased resorptions were not associated with treatment at the same or at higher dose levels (up to 3 times the MRDHD) when dams were treated days 6 to 15 of gestation. Increased resorptions were observed at much higher levels (40 times the MRDHD) in rats and mice treated days 1 to 14 of gestation (lowest dose employed in that study was 500 mcg/kg). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
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OVERDOSAGE
Clonidine Hydrochloride
The signs and symptoms of clonidine hydrochloride overdosage include hypotension, bradycardia, lethargy, irritability, weakness, somnolence, diminished or absent reflexes, miosis, vomiting and hypoventilation. With large overdoses, reversible cardiac conduction defects or arrhythmias, apnea, seizures and transient hypertension have been reported. The oral LD50 of clonidine in rats was 465 mg/kg, and in mice 206 mg/kg.
The general treatment of clonidine hydrochloride overdosage may include intravenous fluids as indicated. Bradycardia can be treated with intravenous atropine sulfate and hypotension with dopamine infusion in addition to intravenous fluids. Hypertension, associated with overdosage, has been treated with intravenous furosemide or diazoxide or alpha-blocking agents such as phentolamine. Tolazoline, an alpha-blocker, in intravenous doses of 10 mg at 30-minute intervals, may reverse clonidine's effects if other efforts fail. Routine hemodialysis is of limited benefit, since a maximum of 5% of circulating clonidine is removed.
In a patient who ingested 100 mg clonidine hydrochloride, plasma clonidine levels were 60 ng/mL (one hour), 190 ng/mL (1.5 hours), 370 ng/mL (two hours) and 120 ng/mL (5.5 and 6.5 hours). This patient developed hypertension followed by hypotension, bradycardia, apnea, hallucinations, semicoma, and premature ventricular contractions. The patient fully recovered after intensive treatment.
Chlorthalidone
Symptoms of acute overdosage include nausea, weakness, dizziness and disturbances of electrolyte balance. The oral LD50 of the drug in the mouse and the rat is more than 25,000 mg/kg body weight. The minimum lethal dose (MLD) in humans has not been established. There is no specific antidote but gastric lavage is recommended, followed by supportive treatment. Where necessary, this may include intravenous dextrose-saline with potassium, administered with caution.
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