Galantamine
Encyclopedia : G : GA : GAL : Galantamine
Galantamine (trade name Razadyne®, Reminyl®) (2, 3) or galanthamine is an drug used for the treatment of mild to moderate Alzheimer’s disease (1, 2, 3, 4, 5, 6). It is usually used as its hydrobromide. Galantamine in its pure form is a white powder. It is an alkaloid that has been obtained from the bulbs and flowers of Caucasian snowdrop (Voronov’snowdrop), Galanthus woronowii (Amaryllidaceae) and related species. This active ingredient was discovered accidentally by a Bulgarian pharmacologist in 1950s. (6, 7).
Pharmacology
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Galantamine binds to the base of the active site, gorge of the enzyme acetyl-cholinesterase, which spans the acyl binding site and the choline binding site. Galantamine forms two hydrogen bonds to the enzyme acetyl-cholinesterase. The first hydrogen bond is formed between the hydroxyl group of the inhibitor and the Glu-199 Oε1. The second hydrogen bond is formed between the hydroxyl group of Ser-200 bifurcated with His-440 Nε2 and the oxygen of the O-methyl group of Galantamine. It is possible to have another hydrogen bond between the N-methyl group of Galantamine and Asp-72 Oδ2, this is a non-classical hydrogen bond as the methyl group has to carry some of the positive charge of the amine. The active site of acetyl-cholinesterase has a polyethylene glycol (PEG) molecule; the terminal hydroxyl group of PEG interacts with the tertiary amine of Galantamine. (7). All the other interactions between Galantamine and acetyl-cholinesterase is non-polar. The natural substance acetylcholine that binds to acetyl-cholinesterase has a quaternary amine and it interacts with Trp-84 and Phe-330 of the enzyme acetyl-cholinesterase, but Galantamine’s protonated tertiary amine does not interact with these two amino acids of the enzyme. The next methylene in the tetrahydroazepine ring has three interacts with the indole ring of the enzyme. Cyclohexane ring of Galantamine interacts with Trp-84. There is a double bond in the cyclohexane ring that stacks against the pi system of the indole ring of the enzyme. Saturation of this double bond gives rise to lycoramine which can greatly reduce the affinity of Galantamine. In the acyl binding pocket Galantamine’s O-methoxy group interacts with Phe-288 and Phe290 of the enzyme. There are no direct charge to charge interactions between Galantamine and Acetyl-cholinesterase enzyme residues. Galantamine has a bent hinge shape that helps the tight binding of Galantamine to the enzyme. Because of the rigidity of the Galantamine molecule there is a low entropic cost when binding to the enzyme with high affinity. (7)
Absorption, bioavailability and distribution
Absorption of Galantamine is rapid and complete and shows linear pharmacokinetics. In two primary Galantamine efficacy trials, the plasma concentration of Galantamine was measured 10 hours after oral administration. The mean plasma concentration were recorded for different doses, for a 24mg/day oral dose the average plasma concentration was 82-97micrograms/L and for the 32mg/day oral dose the average plasma concentration was 114-126micrograms/L. These concentrations were compared to young healthy volunteers and found that these values are 20% to 30% higher in the trial patients. The absolute bioavailability ranges from 80% to 100%. After an oral administration the maximum time to reach maximum plasma concentration (Tmax) is between 0.5 to 2 hours. Administering Galantamine with food decreases the rate of absorption but it does not affect the extent of the drug absorption. Therefore food does not affect the area under the curve (AUC). However, it has some effect by decreasing the maximum plasma drug concentration (Cmax) by about 25% and also a delaying Tmax by about 1.5 hours. (1, 8, 9, 10)
Galantamine has a large volume of distribution; the mean volume of distribution is about 175L. The volume of distribution at steady state in healthy volunteers is about 2.64 L/kg. This indicates a rapid non-specific distribution of the drug. A study was conducted by intravenously administering Galantamine to mice; the results showed rapid accumulation of drug in tissues, mostly in the kidney, where levels were about 10-fold higher compared to the plasma. However, patients who were administered with 12mg/day or 16mg/day did not show any drug accumulation in tissue. (1, 5, 10)
Plasma protein binding of Galantamine is about 18%, which is relatively low. Although Alzheimer’s patients who received 30mg or 40mg oral doses of Galantamine had 33.8% and 28.3% plasma protein binding respectively. The comparison of plasma protein binding between males and females is insignificant. There was also no correlation with total protein or albumin levels. The total plasma protein binding level of Galantamine is independent of the plasma concentration of the drug within the range of 60µg/L to 228µg/L. Clinical studies have shown that cerebrospinal fluid: acetyl-cholinesterase inhibition was increased from 76.5±10.4 units/mL to 221.5±17.7 units/mL. (1)
Metabolism and excretion
The major route of metabolism for Galantamine is through the liver, this about 75% of the total metabolism of Galantamine. Hepatic cytochrome P450 (CYP) isoenzymes are the active enzymes for this metabolic route. In vitro studies have shown that CYP2D6 and CYP3A4 are involved in Galantamine metabolism. The metabolites of Galantamine are Norgalantamine, Epigalanthamine, Galanthaminone, O-demethyl-galantamine and O-demethyl-norgantamine. (1, 3,)
O-demethyl-galantamine is the major metabolite of Galantamine and it is also called Sanguinine. This metabolite is formed from the activity of enzyme CYP2D6. About 20% of the orally administered Galantamine is metabolised to give Sanguinine, and this metabolite is 3 times more potent than Galantamine in the inhibition of acetyl-cholinesterase. Epigalanthaminone and Galanthaminone also have acetyl-cholinesterase inhibitory activity, but they are 130 times less potent than Galantamine. The other metabolites are clinically not relevant but they are active and show acetyl-cholinesterase inhibition in vitro. (11)
Most of absorbed Galantamine is excreted with urine. After a single dose of Galantamine about 20% of the drug is glucuronidated and excreted unchanged through urine after 24 hours. This represents a renal clearance of about 65mL/min. In a clinical study, 4mg radiolabelled Galantamine was administered orally. The results showed that about 97% of the radioactivity is found in urine and about 2% of the radioactivity is found in faeces. (1, 11).
The mean half-life of elimination (t1/2) for Galantamine ranges from 6-8 hours, and the mean total clearance in healthy individuals is about 0.34 L/h/kg. The mean renal clearance of Galantamine in healthy individuals is about 0.084 L/h/kg which is 20% lower than the total clearance, but this has no clinical relevance. The clearance was reduced by about 25% in patients with reduced activity of CYP2D6 isoenzyme. (1, 11).
Mechanism of Action
Galantamine has two clinically significant mechanisms of actions. These are reversible, competitive inhibition of acetyl-cholinesterase and allosteric modulation of nicotinic acetylcholine receptors. Galantamine is also selective for acetyl-cholinesterase over butyryl-cholinesterase. The drug has shown 53-fold selectivity for human erythrocyte acetyl-cholinesterase over butyryl-cholinesterase. (1, 3).
Acetyl-cholinesterase is the enzyme that hydrolyses acetylcholine at neuro-muscular junction, in the peripheral and central cholinergic synapses and at parasympathetic target organs. The effect of Galantamine is to bind to the acetyl-cholinesterase active site and slow down the catabolism of acetylcholine at the synapse. This inhibitory action results in increased concentrations of acetylcholine in the synapses. IC50 of acetyl-cholinesterase activity for Galantamine was 3.9micromol/L in an in vitro study and 0.41micromol/L in an ex vivo study. (1)
Galantamine is an allosterically potentiating ligand at nicotinic acetylcholine receptors, which enhances their activity. Studies show that Galantamine binds to the alpha subunit of the nicotinic acetylcholine receptor and causes a conformational change in the receptor. In vitro studies have shown that Galantamine non-competitively binds to an allosteric site of the nicotinic acetylcholine receptors and also increases the frequency of opened receptor channels and promotes the agonist activated currents whilst the agonist is bound to the receptor. (1, 7, 11).
Above diagram illustrates the dual mechanism of Galantamine: inhibition of acetyl-cholinesterase (AChE) and allosteric modulation of nicotinic receptors. (9)
It is possible that acetylcholine has an effect on regulation of rapid eye movement (REM) sleep. REM sleep is altered in Alzheimer’s patients. A study was conducted on healthy individuals by administering 10mg or 15mg of Galantamine. The healthy volunteers showed shortened REM latency, increased REM density and reduce slow wave sleep. A three month study showed that Galantamine did not affect the quality of sleep in Alzheimer’s patients. Acetylcholine may also have an effect in electroencephalograph (EEG) desynchronisation. In another study 10mg dose of Galantamine was administered to healthy volunteers and the results showed a synchronising effect on EEG. (1, 13).
Conditions that influence the drug activity
If a patient has moderate renal impairment or moderate hepatic impairment, the dose of Galantamine should not exceed 16 mg/day, and if the patient has severe renal or hepatic impairment, administration of Galantamine is not recommended. (14). Patients who use Galantamine also should take precautions if they have peptic ulcer disease, Parkinson’s disease, heart disease, hypotension or if the patient is pregnant. Inhibition of acetyl-cholinesterase may affect the activity of succinylcholine and other muscle relaxants. It also can affect the heart rate and may cause generalised seizures. To minimise the risk of adverse effects, Galantamine should be used with care when it is administered to patients with asthma or obstructive pulmonary disease. Therapeutic monitoring is recommended when treating patients with a risk of developing ulcers. Patients with gastrointestinal or urinary outflow obstruction should not take Galantamine, also it is not recommended for patients recovering from bladder or gastrointestinal surgery. (1, 14). Galantamine falls into category B for use when the patient is pregnant. There are no studies undertaken for human pregnant patients but animal studies show that there are no clinically significant adverse effects. (13).
Adverse effects
The most prominent adverse effect after administration of Galantamine is related to gastrointestinal effects, and is also the major reason for discontinuing the drug. The most frequent adverse effect reported was nausea for duration of 5 to 7 days. Dose escalation period showed most of these effects (13). 1% to 10% of the adverse effects that patients encountered were Dizziness, Anorexia, Bradycardia, weight loss, Diarrhoea, abdominal pain and Tremor. More than 10% of the adverse effects were Nausea and vomiting(3). A randomised double blind placebo controlled trial of patients with mild to moderate Alzheimer’s disease was conducted and the dose escalated from 8mg/day to maintenance dose in a period of 4 to 8 weeks. Results of this trial illustrated in the graph below shows that there are adverse effects occurring at least 5% more than in the Galantamine administrated patients than the placebo patients (1).
Five to six months after treatment significant change in weight loss of patients were observed in a clinical study conducted for 5 months. Patients with a 8mg/day dose had a mean weight loss of 0.5kg, same weight loss for patients with 16mg/day dose and 1.3kg mean weight loss for patients with 24mg/day dose, compared to the placebo group patients who only lost 0.1kg of their mean weight. Another study that was conducted for a period of 6 months, the results showed a mean weight loss of 2.1kg for patients administered with Galantamine 24mg/day and mean weight loss of 2.5kg for patients who had a 32mg/day dose and the placebo group only lost 0.1kg mean weight. It was noticed that the patients who had a large decrease in mean body weight had a higher baseline body weight. The mean body weight lost in patients who took Galantamine was 1.2kg after a period of 12 months. This body weight loss is dose related as explained above and is thought that it is related to gastrointestinal adverse effects. (13, 14, 16).
Gastrointestinal adverse effects are caused by stimulation of intestinal muscarinic receptors and there maybe an autonomic nervous system response to the drug as well. Cardiovascular adverse effects are not common in patients administered with Galantamine, but the few cases reported are result of stimulation of muscarinic receptors in the central compartment and the periphery of the body. Cardiovascular adverse effects could lead to other injuries such as falls. Extensive stimulation of nicotinic receptors is the reason for neuromuscular adverse effects, but the incidence of this adverse effect is very low in patients administered with Galantamine. (1, 16, 17).
Increasing the escalation period has an effect on lowering the incidence of these major adverse effects. Reduction in these symptoms was also observed when Galantamine is administered with food. Use of anti emetic medication and adequate fluid intake also may reduce these symptoms.(1, 4, 17).
Drug–drug interactions
Galantamine antagonise the action of anticholinergic drugs. There is a synergising effect when Galantamine is given with other cholinesterase inhibitors, similar neuromuscular blocking agents and cholinergic agonists; Bethanechol is an example of this action. Cimetidine increases Galantamine bioavailability by about 16% when administered concurrently. Drugs that inhibit CYP3A4 and CYP2D6 isoenzymes increase the AUC of Galantamine, Ketoconazole is a drug that strongly inhibits these enzymes and increases AUC of Galantamine by 30%, Erythromycin is also a drug that inhibits these enzymes, it increases AUC of Galantamine by 10%. Paroxetine is a strong inhibitor of CYP2D6, administration of this drug for 16 days at a 20mg/day dose increases oral bioavailability of Galantamine by 40%. Galantamine could have a pharmacodynamic interaction with drugs that reduce heart rate such as digoxin and beta-blockers, but in a study conducted where 12mg/day of Galantamine administered to patients twice daily did not have any effects on Digoxin or Warfarin. Galantamine potentiates the action of Succinylcholine on muscle relaxation. (1, 4, 14).
Therapeutic applications
Galantamine is used to treat patients with mild to moderate Alzheimer’s disease. Alzheimer’s is a neurodegenerative disease and it is age dependent. Deterioration of memory, judgement and comprehension are common characteristics of Alzheimer’s disease. (1) This disease accounts for about 70% of all dementia reported. The cholinergic hypothesis of Alzheimer’s disease explains that the primary reason for this disease is the cholinergic neurodegeneration in the cortex and the hippocampus of the brain. This condition reduces cholinergic transmission and the level of acetylcholine in patients. There is no cure available for Alzheimer’s disease at the moment but the approaches to treat the disease include administering acetylcholine precursors and augmentation of acetylcholine transferase to increase synthesis of acetylcholine and inhibition of acetyl-cholinesterase to slowdown the hydrolysis of acetylcholine. Inhibition of acetyl-cholinesterase to decrease the acetylcholine degradation in synapses has shown significant improvements in Alzheimer’s patients. Alzheimer’s patients also show decreased number of nicotinic receptors in the temporal cortex, frontal cortex and hippocampus areas of the brain. Nicotinic acetylcholine receptors are also linked to amyloid plaques and neurofibrillary tangles which are associated with Alzheimer’s disease. Galantamine is a drug that complies with both aspects of this disease by inhibiting acetyl-cholinesterase and allosterically modulating nicotinic acetylcholine receptors. Because Galantamine allosterically acts on the nicotinic acetylcholine receptors to increase postsynaptic currents, Galantamine is more effective in early stages of Alzheimer’s disease. Placebo controlled trials have shown that Galantamine improves behavioural symptoms, day to day living activities and provide beneficial effects in cognition. (1, 17)
A post – hoc study of a randomised controlled trial to compare Galantamine treated and Placebo treated, conducted by National Institute of Neurological and Communicative Disorders and Stroke: Alzheimer’s disease and Related disorders Association (NINCDS-ADRDA). 24mg/day dose was administered to 831 patients with mild to moderate Alzheimer’s and 839 patients were randomized to the placebo group. These patients were assessed using Alzheimer’s disease Assessment Scale (ADAS-cog), Clinician’s Interview-Based Impression of Change plus caregiver input (CIBIC-plus), Activities of Daily Living (ADL) and Disability Assessment for Dementia (DAD). The mean ADAS-cog scores were significantly improved in Galantamine treated patients than the placebo patients in a six month period, the scores increased from 3.7 to 4.1. ADL scores were also favouring the Galantamine treated patients compared to the placebo group. The graph below summarises the overall results from this study. (1, 17)
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Regulatory issues
Galantamine is marketed for Alzheimer’s Diseases as Galantamine Hydrobromide tablets or solution, by the trade names of Reminyl or Razadyne. Food and Drug Administration (FDA) granted the approval to Janssen Pharmaceutica to sell this drug in the market in February 2001. The extended release tablet was approved by the FDA on December 2004. (19). Galantamine has received regulatory approval in 29 countries including: Argentina, Australia, Canada, Czechia, the European Union (except for The Netherlands), Iceland, Korea, Mexico, Norway, Poland, Singapore, South Africa, Switzerland, Thailand, and the United States. (19).
Galantamine greatly reduces costs for patients with mild to moderate Alzheimer’s disease, because the drug improves the quality of life for the patients the full time care is not needed till the disease is severe. Estimated cost for Alzheimer’s per year in United States is about $US100 billion. (1). Studies conducted using data from Sweden, The Netherlands and Canada showed that each country gives patients net saving in overall treatment when Galantamine is used. Alzheimer’s disease is affected 17 to 25 million people world wide and estimated 4 to 6 million people affected in United States.(1). The prevalence of this disease doubles about every five years after 65 years old. Industrialised countries have a prevalence of about 5%, United States currently have about 100000 deaths per year related to Alzheimer’s disease and it is predicted that the number of people affected by Alzheimer’s disease is about 14 million people by the year 2050. Galantamine is not subsidised in New Zealand and costs about $NZ200 to $NZ260 for a month’s supply. (20, 21).
Total synthesis
- Main article: Galanthamine total synthesis
References
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3. Lexi-Comp Inc., American Pharmaceutical Association. Drug information for mental health. Hudson, Ohio [Washington, D.C.]: Lexi-Comp ; American Pharmaceutical Association; 2001.
4. Mosby Inc. Mosby's drugconsult. St. Louis [Mo.]: Mosby; 2002.
5. Tatro DS, Borgsdorf LR. A to Z drug facts. 6th ed. St. Louis, Mo.: Facts and Comparisons; 2005.
6. Sweetman SC, Martindale W. Martindale : the complete drug reference. 34th / ed. London ; Chicago: Pharmaceutical Press; 2005.
7. Greenblatt HM, Kryger G, Lewis T, Silman I, Sussman JL. Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 A resolution. FEBS Lett 1999;463(3):321-6.
8. Lacy C. Lexi-Comp's Drug information handbook international : with Canadian and international drug monographs. Hudson, Ohio: Lexi-Comp; 2005.
9. Farlow MR. Clinical pharmacokinetics of galantamine. Clin Pharmacokinet 2003;42(15):1383-92.
10. Bickel U, Thomsen T, Fischer JP, Weber W, Kewitz H. Galanthamine: pharmacokinetics, tissue distribution and cholinesterase inhibition in brain of mice. Neuropharmacology 1991;30(5):447-54.
11. Jann MW, Shirley KL, Small GW. Clinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors. Clin Pharmacokinet 2002;41(10):719-39.
12. Orgogozo JM, Small GW, Hammond G, Van Baelen B, Schwalen S. Effects of galantamine in patients with mild Alzheimer's disease. Curr Med Res Opin 2004;20(11):1815-20.
13. Gauthier S. Cholinergic adverse effects of cholinesterase inhibitors in Alzheimer's disease: epidemiology and management. Drugs Aging 2001;18(11):853-62.
14. Drugdex [database on the Internet]. Vol. 121 expires 9/2004. Greenwood Village (CO): Thomson Micromedex; 2003. Available from the University of Auckland Library LEARN website: http://www.library.auckland.ac.nz/databases/learn_database/public.asp?record=micromedex
15. Lanctot KL, Herrmann N, Yau KK, Khan LR, Liu BA, LouLou MM, et al. Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis. Cmaj 2003;169(6):557-64.
16. Wilcock GK, Lilienfeld S, Gaens E. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: multicentre randomised controlled trial. Galantamine International-1 Study Group. Bmj 2000;321(7274):1445-9.
17. Bruno Vellas, Luís Cunha, Hermann-Josef Gertz, Peter Paul De Deyn, Keith Wesnes, Gerry Hammond. Early onset effects of Galantamine treatment on attention in patients with Alzheimer’s disease. Galantamine International-28 Study Group. Current Medical Research And Opinion 2005:21(5):1423-1429
18. Lyseng-Williamson KA, Plosker GL. Galantamine: a pharmacoeconomic review of its use in Alzheimer's disease. Pharmacoeconomics 2002;20(13):919-42.
19. Alzheimer’s Disease Mild to Moderate Treatment Information [Internet website]. Last Updated: May 23, 2005, Available from: http://www.razadyne.com/html/raz/pd_main.xml?article=media_releases.jspf
20. Alzheimer’s New Zealand Home Page, ‘Frequently Asked Questions’ Available from: http://www.alzheimers.org.nz/faqs.php#faq07
21. Information for health professionals, Data sheet for Reminyl, Last Updated: 8 February 2005. Available from: http://www.medsafe.govt.nz/Profs/Datasheet/r/Reminyltab.htm
External links
- [Razadyne] (manufacturer's website)
- [Galantamine] (patient information)
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