Galanthamine

Uses

Galanthamine is used for the treatment of mild to moderate dementia of the Alzheimer’s type.

Galanthamine is also used to associated treatment for these conditions: Mild to Moderate Dementia Due to Alzheimer's Disease, Mild Dementia of the Alzheimer's Type, Moderate Alzheimer's Type Dementia

How Galanthamine works

Alzheimer’s disease is characterized by progressive, irreversible degeneration of acetylcholine-producing neurons, cognitive impairment, and the accumulation of neurofibrillary tangles and amyloid plaques. The cholinergic system plays a critical role in memory, alongside other important neural functions such as attention, learning, stress response, wakefulness and sleep, and sensory information. Studies show that acetylcholine (ACh) is involved in the modulation of acquisition, encoding, consolidation, reconsolidation, extinction, and retrieval of memory. The gradual loss of cholinergic neurons in Alzheimer’s disease (AD) may, therefore, contribute to the memory loss exhibited by AD patients.

Acetylcholinesterase is secreted by cholinergic neurons to rapidly hydrolyze ACh at the synaptic cleft to release acetate and choline. Choline is later recycled back into the presynaptic cholinergic neuron via reuptake by the high-affinity choline transporter. There is some evidence demonstrating the potential involvement of the acetylcholinesterase enzyme in the formation of amyloid fibrils. Galanthamine competitively and reversibly inhibits the anticholinesterase enzyme in the CNS (namely in the frontal cortex and hippocampal regions) by binding to the choline-binding site and acyl-binding pocket of the enzyme active site. By blocking the breakdown of ACh, galantamine enhances ACh levels in the synaptic cleft.

Nicotinic acetylcholine receptors (nAChR) in the CNS are mostly expressed at the presynaptic neuronal membrane to control the release of multiple neurotransmitters, such as ACh, glutamate, GABA, dopamine, serotonin, norepinephrine. Agonists of nAChRs improve performance in cognitive tasks, while antagonists of nAChR impair cognitive processes. Some studies show a decrease in the expression and activity of nAChRs in patients with AD, which may explain the reduction in central cholinergic neurotransmission in these patients. Galanthamine binds to nAChRs at the allosteric site, leading to a conformational change of the receptor, increased ACh release, and increased activity of neighbouring glutaminergic and serotoninergic neurons. The modulation of nAChRs facilitates both excitatory and inhibitory cholinergic transmissions in brain tissues and increases receptor sensitivity. The modulated release of other neurotransmitters by galantamine may also contribute to the upregulation of nAChRs and amelioration of behavioural symptoms in AD.

Dosage

Galanthamine dosage

Adults: The recommended starting dose of Galanthamine is 4 mg twice daily (8 mg/day). The dose should be increased to the initial maintenance dose of 8 mg twice daily (16 mg/day) after a minimum of 4 weeks. A further increase to 12 mg twice daily (24 mg/day) should be attempted after a minimum of 4 weeks at 8 mg twice daily (16 mg/day).

Galanthamine tablets should be administered twice daily, preferably with morning and evening meals.

Side Effects

Common side effects are nausea, vomiting, diarrhoea, abdominal pain, dyspepsia; syncope; rhinitis; sleep disturbances, dizziness, confusion, depression, headache, fatigue, anorexia, tremor; fever; weight loss; less commonly arrhythmias, palpitation, myocardial infarction, cerebrovascular disease, paraesthesia, tinnitus, and leg cramps.

Toxicity

The oral LD₅₀ of the active ingredient, galantamine hydrobromide, in rats is 75 mg/kg. Symptoms of overdose are expected to be similar to those of cholinomimetics, which involve the central nervous system, the parasympathetic nervous system, and the neuromuscular junction. Effects of a cholinergic crisis include severe nausea, vomiting, gastrointestinal cramping, salivation, lacrimation, urination, defecation, sweating, bradycardia, hypotension, respiratory depression, collapse, and convulsions. Muscle weakness or fasciculations may also occur, with respiratory muscle weakness having the potential to bring fatal results. In one patient who consumed an oral daily dose of 32 mg developed bradycardia, QT prolongation, ventricular tachycardia and torsades de pointes accompanied by a brief loss of consciousness. In one patient with a history of hallucinations who consumed a daily dose of 24 mg galantamine, hallucinations requiring hospitalization occurred. A patient who ingested 160 mg of galantamine from an oral solution developed sweating, vomiting, bradycardia, and near-syncope one hour following consumption.

As in any case of overdose, general supportive measures should be initiated. Tertiary anticholinergics such as intravenous atropine may be used to reverse the cholinergic effects of galantamine. The recommended initial dose of atropine intravenously administered for galantamine overdose ranges from 0.5 to 1.0 mg. It is not known whether galantamine can be removed by dialysis.

Precaution

Caution should be taken in patients with cardiac disease; electrolyte disturbances; susceptibility to peptic ulcers; asthma, chronic obstructive pulmonary disease, pulmonary infection. Galanthamine should be avoided in urinary retention and gastro-intestinal obstruction.

Interaction

ay antagonise the effect of other cholinomimetics (e.g. donepezil, neostigmine, systemic pilocarpine). Pharmacodynamic interaction w/ drugs that significantly reduce the heart (e.g. digoxin, β-blockers, certain Ca-channel blocking agents and amiodarone). May exaggerate succinylcholine-type muscle relaxation during anaesth, esp in pseudocholinesterase deficiency.

Food Interaction

• Take with food. Food delays the rate of absorption but not the extent.

Galanthamine Drug Interaction

Moderate: metoprolol, metoprololUnknown: aspirin, aspirin, calcium / vitamin d, calcium / vitamin d, omega-3 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, memantine, memantine, clopidogrel, clopidogrel, acetaminophen, acetaminophen, cyanocobalamin, cyanocobalamin, ascorbic acid, ascorbic acid, cholecalciferol, cholecalciferol

Galanthamine Disease Interaction

Major: bradycardia, bronchospasm, PUDModerate: hepatic impairment, renal impairment

Volume of Distribution

The mean volume of distribution is 175 L. About 52.7% of galantamine is distributed to blood cells, the blood to plasma concentration ratio of galantamine is 1.2. Galanthamine penetrates the blood–brain barrier.

Elimination Route

Over a dose range of 8-32 mg/day, galantamine exhibits a dose-linear pharmacokinetic profile. The oral bioavailability of galantamine ranges from 90-100%. Following oral administration, the Tmax is about 1 hour. Following 10 hours of administration, the mean galantamine plasma concentrations were 82–97 µg/L for the 24 mg/day dose and 114–126 µg/L for the 32 mg/day dose.

Half Life

Galanthamine has a terminal half-life of about 7 hours.

Clearance

The renal clearance is 65 mL/min and the total plasma clearance is about 300 mL/min.

Elimination Route

Renal clearance accounts for about 20–25% of total plasma clearance of the drug in healthy individuals: the elimination of galantamine has been shown to be decreased in subjects with renal impairment. Following oral or intravenous administration, approximately 20% of the dose is excreted as unchanged in the urine within 24 h. In a radiolabelled drug study, about 95% and 5% of the total radioactivity was recovered in the urine and feces, respectively. Of the dose recovered in the urine, about 32% was in the unchanged parent compound, and 12% was in the glucuronide form.

Pregnancy & Breastfeeding use

Pregnancy category B. Galanthamine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It should not be used during breast-feeding. However, if its use is unavoidable, then breast-feeding should be discontinued.

Contraindication

Galanthamine is contraindicated in patients with renal impairment; breast feeding and known hypersensitivity to the active substance or to any of the excipients

Special Warning

Children: Galanthamine is not recommended in children.

Hepatic impaired patients: In patients with moderately impaired hepatic function, the total daily dose should generally not exceed 16 mg/day. The use of Galanthamine in patients with severe hepatic impairment is not recommended.

Renal impaired patients: For patients with moderate renal impairment the dose should generally not exceed 16 mg/day. In patients with severe renal impairment (creatinine clearance <9 mL/min), the use of Galanthamine is not recommended.

Acute Overdose

Symptoms: Muscle weakness or fasciculations, severe nausea, vomiting GI cramping, salivation, lacrimation, urination, defecation, sweating, bradycardia, hypotension, collapse and convulsions.

Management: General supportive measures. Anticholinergics such as atropine (with initial dose of 0.5-1 mg IV) may be used as general antidote.

Storage Condition

Store in a cool and dry place. Protect from light.

Innovators Monograph

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