Also known as: Lopidine
Apraclonidine is a relatively selective alpha-2-adrenergic agonist which does not possess significant membrane stabilising (local anaesthetic) activity. When instilled into the eye, apraclonidine has the action of reducing intraocular pressure. Ophthalmic apraclonidine has minimal effect on cardiovascular parameters.
Aqueous fluorophotometry studies in man suggest that the mechanism of the ocular hypotensive action of apraclonidine is related to a reduction in aqueous formation. The onset of action of 5 mg/ml apraclonidine eye drops can usually be noted within one hour and the maximum intraocular pressure reduction usually occurs three to five hours after application of a single dose.
Following topical ocular administration to New Zealand White rabbits, apraclonidine reached peak concentrations after two hours in the aqueous humour, iris, ciliary body and lens. The cornea exhibited the greatest concentration and peaked at the earliest time point (20 minutes). The tissue distribution of apraclonidine from highest to lowest concentration in microgram equivalents per gram of tissue was cornea, iris-ciliary body, aqueous humour, lens and vitreous humour. The elimination half-life of apraclonidine from the aqueous humour was determined to be approximately two hours.
Plasma concentration of apraclonidine following three times daily, bilateral, topical ocular dosing of apraclonidine to normal human volunteers was less than 1.0 ng/ml. A steady state level was attained after five days of dosing. The half-life of the drug was calculated to be eight hours.
Preclinical Safety Data
Administration of apraclonidine intravenously and via the topical ocular route to both cats and monkeys resulted in a reduced anterior segment blood flow, whereas flow to the posterior segment, i.e., retina, choroid or optic nerve head, was not affected. Chronic treatment of primates with apraclonidine hydrochloride 15mg/ml ocularly three times a day for one year did not result in morphologic effects which would be indicative of vasoconstriction of the anterior or posterior segments of the eye. Although ocular blood flow studies have not been conducted in humans, the animal studies provide a basis for the safe use of this drug in the treatment of chronic glaucoma.
The oral LD50 ranged from 5mg/kg (mice) to 64 mg/kg (rats); no lethalities were observed in primates at 55 mg/kg.
Subchronic and Chronic Toxicity
Rats and mice received daily oral doses of up to 1.2 mg/kg and 2 mg/kg, respectively, over a period of 13 weeks. Mortalities occurred from 1.2 mg/kg/day to 1.6 mg/kg/day. Disturbed defaecation, distended abdomen and corneal cloudiness have been observed.
The topical ocular administration of apraclonidine hydrochloride solutions (2 drops instilled at 30 minute intervals into one eye for 6 hours) led to dose-dependent conjunctival and corneal irritation in the rabbit from 5mg/ml.
Rabbits tolerated a solution of 15mg/ml (2 drops t.i.d.) over a period of one month without signs of systemic toxicity. Nevertheless, conjunctival irritation and sporadic minimal corneal cloudiness have been observed.
No drug-related ophthalmic or systemic findings were observed when monkeys received apraclonidine hydrochloride solutions of 5, 10, and 15mg/ml by topical ocular administration t.i.d. for one year.
Assessment of the sensitisation potential in the guinea pig proved apraclonidine hydrochloride to be moderately sensitising.
Mutagenic and Tumorigenic Potential
Mutagenicity testing of apraclonidine hydrochloride using different standard systems all produced negative results. Nevertheless, ocular (keratitis) and renal effects have been reported during these tumorigenic studies.
Although studies performed in rats and rabbits did not suggest any teratogenic action, slight foetal toxicity was observed at 60 times the therapeutic dosage.