Acetylcholinesterase and Galantamine
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The pharmacist at Marshfield Clinic received an electronic prescription order for a patient for Detrol LA 2 mg extended release oral capsule, which contains the active ingredient tolterodine tartrate. The pharmacist later confirmed that the patient was utilizing this medication to treat an overactive bladder. When verifying the prescription and checking the patient's profile for potential drug-drug interactions, the pharmacist noticed that the patient was also on galantamine 16 mg extended release, brand name Razadyne ER, oral capsule for dementia due to Alzheimer's disease (AD). Being an anticholinergic medication, Detrol LA has an established interaction with galantamine, a competitive acetylcholinesterase inhibitor (AChE-I), resulting in decreased effectiveness of galantamine. Before the patient arrived to pick up the new prescription for Detrol LA, the pharmacist called the doctor to inquire if the prescriber knew that the patient was also taking galantamine, and if so, whether or not he was aware of the interaction. The doctor responded that he was aware that the patient was currently taking galantamine and was also cognizant of the interaction between the two medications. The doctor stated that this potential drug-drug interaction was briefed to the patient. After confirmation with the doctor, the pharmacist felt more assured and the prescription was filled. When the patient arrived to pick up their new medication, the pharmacist consulted the patient on how to utilize the medication, potential side effects to be aware of, how to minimize those adverse effects, as well as reiterated that Detrol LA could make galantamine less effective at managing their symptoms of AD. The pharmacist also informed the patient to contact their doctor if they noticed any changes in their symptoms and to be sure to follow up with their doctor to ensure that the treatment for overactive bladder was working without aggravating the symptoms of their AD. Continuing with this specific patient case, the purpose of this investigation is to explore the drug-drug interaction between galantamine and Detrol LA as well as analyze the galantamine-acetylcholinesterase drug-protein complex interactions. This will be accomplished by viewing these interactions and dissecting them at the molecular level.
According to the Alzheimer's Association, a new person in the United States is diagnosed with Alzheimer's disease (AD) every 70 seconds [1]. AD is a progressive degenerative disease that destroys memory and other cognitive functions [2,3]. AD is characterized by extracellular deposit of beta-amyloid plaque and the presence of intraneuronal neurofibrillary tangles (NFTs)[4]. One main neurotransmitter affected by this disease is acetylcholine (ACh). The neuronal damage has been linked to a decreased expression of acetylcholine and an increase in beta-amyloid plaque [4]. The extent of neuronal damage has been expressed as an up to 70% decrease in nicotine binding sites [5]. Presently, there are no treatments to reverse AD, although there are measures to assist patients suffering from AD to improve their quality of life. These measures are lifestyle modifications such as diet and exercise, but also include drug therapies such as tacrine, donepezil, rivastigmine, and galantamine [2]. These four different cholinergic agents are currently approved by the FDA for managing the symptoms of mild to moderate dementia associated with AD. Since AD is a progressive disease in which early diagnosis is essential, patients who have mild cognitive impairment are often placed on medications such as galantamine, a competitive acetylcholinesterase inhibitor (AChE-I) [2].
Galantamine is a reversible, centrally acting acetylcholinesterase inhibitor (AChE-I) used as a primary treatment of AD [1,3]. It inhibits acetylcholinesterase (AChE), the enzyme responsible for hydrolyzing and degrading ACh by binding to the active site of the enzyme, which is composed of several amino acids; this will result in an increased concentration of ACh in the synaptic cleft. It is theorized that an adequate ACh supply is correlated with slowing the progression of AD, maintaining cognitive function, and reducing memory loss [1]. The amino acids that are within close proximity, defined as less than 5 angstroms, are glycine, tryptophan, serine, histidine, phenylalanine, and tyrosine. Of particular interest is tyrosine 337, abbreviated TYR337, which has been described as a 'swinging gate' that moves out of the active site gorge upon binding. The interaction between TYR337 and N10 of galantamine is critical for the inhibition of the human AChE enzyme [6]. The binding of galantamine in the active site involves an additional hydrogen bond that has formed between the tertiary amine, N10 of galantamine, and TYR337, which is in a different orientation than of those of other AChE substrates [7]).
In multiple studies, many randomized placebo controlled trials (RCT) have shown the efficacy of galantamine is slowing the progression of AD. A study in 2000 published in the British Medical Journal, demonstrated in a RCT of 653 patients with mild to moderate AD that galantamine significantly improved cognition over placebo [8]. This study was conducted mainly in Europe and Canada with one of the authors representing Galantamine International -1 Study Group. There was another study conducted in the same year in the US that showed that a 5-month RCT with 978 patients with mild to moderate AD that concluded with the same results [9]. Finally, a withdrawal study following patients with at least three months of galantamine usage to demonstrate the impact of galantamine on AD progression showed in a double blind RCT that withdrawal of galantamine was associated with a decline in cognition [10]. Cognition following discontinuation of galantamine deteriorated towards levels observed in patients who continuously received placebo [10]. Overall, while there are drugs such as galantamine currently available to help treat the symptoms of dementia associated with AD, there is still presently no effective means for slowing or changing the disease process [2].
The patient would need to determine whether controlling their overactive bladder or treating their symptoms of dementia associated with AD would take precedence. Considering the adverse effects for each medication may play a role in this decision. Adverse effects include headache, constipation and dry mouth for Detrol LA and galantamine adverse effects include nausea, vomiting, dizziness and headache [21,22]. Keeping the drug-drug interaction in mind, the patient and the health care providers may determine it is acceptable for the patient to take both Detrol LA and galantamine with adjustment of doses.
Galantamine hydrobromide stands apart from the other cholinergic agents in that it treats AD due to its alkaloid structure. It is extracted from a bulb of a daffodil, the Narcissus pseudonarcissus, but was originally obtained from the Caucasian snowdrop (Voronov's snowdrop) and related species [11]. It is a phenantherene derivative and tertiary amine that crosses the blood brain barrier (BBB) in order to exert a cholinergic effect centrally. Galantamine binds in the active site of AChE through its P321 ligand shown by cocrystallization via dimer formation [11]. Increased concentrations of ACh have been shown to reduce the positive presentation of AD and sustain cognitive function, however, the use of cholinergic agents does not cure the underlying cause of dementia or cure the progression [12].
Another interesting aspect of galantamine's mechanism of action is that in addition to increasing serum ACh, it also binds allosterically to nicotinic acetylcholine receptors (nAChR), potentiating their activity and therefore, counteracting the down-regulated receptors secondary to neuronal damage in AD [10]. Finally, it also exerts an anti-amyloid property [13]. A recent study investigating the interaction between galantamine and beta-amyloid found that galantamine disrupts key pi-pi stacking between aromatic rings of Phe19 on Chain A and Phe19 of Chain B as well as intermolecular hydrogen bonds seen in unbound peptide dimers [13]. It was noted that the tertiary nitrogen of galantamine stabilized the dimer conformation due to close proximity to the backbone of Leu34 [13]. The result was interruption in interactions between beta- strands and promotes conformations of beta-amyloid 1-40 to prevent the formation of neurotoxic oligomers[13].
Galantamine is also selective for AChE; it is 50 times more effective against human AChE than butyrlcholinesterase at therapeutic doses [14]. Its serum half-life is 4-6 hours, making it longer acting than tacrine but shorter than donepezil [14]. X-ray analysis shows that the oxygen moiety on the methoxy group is in close proximity to SER200 and HIS440 of the catalytic triad in AChE [14]. The catalytic trial involves SER200, HIS440 and GLU 327. This interactions support its ability to inhibit the hydrolysis of ACh. The positively charged amine on galantamine interacts with the hydroxyl of the Tyrosine 337. Although we understand that galantamine asserts its mechanism of action on AChE, the mechanism by which it potentiates nAChr activity is still unknown [12].
To prevent unwanted activation of neighboring muscle cells and neurons as well as to ensure proper timing of signaling at the postsynaptic neuron, acetylcholine (ACh) is degraded by cholinesterase. As previously mentioned, acetylcholinesterase (AChE) is the primary enzyme responsible for this task, degrading about 400,000 ACh molecules per minute [15]. In several theories related to AD, it is believed that deteriorating cognitive function and memory is due to decreasing amount of ACh molecules in neuronal synaptic clefts of the brain. Recalling that galantamine is a reversible, competitive AChE inhibitor, its mechanism of action, although not entirely known, is predicted to be through blocking the actions of AChE [16,17]. By essentially inhibiting the ACh degrader, AChE, it allows more ACh molecules to accumulate in the synaptic cleft and to constantly stimulate ACh receptors on the post synaptic neurons in the brain. As a result this maintains a higher concentration of ACh in the synaptic cleft which patients diagnosed with AD lack. By keeping a higher amount of ACh in the synaptic cleft, this increased ACh supply is linked with slowing the progression of dementia associated with AD [18]. However, having the adequate ACh supply is only half of the equation; having adequate, functional receptors completes the other half.
The function of Detrol LA, an oral prescription anti-cholinergic agent, is to antagonize muscarinic ACh receptors on the postsynaptic neurons throughout the body. Since ACh binding to muscarinic receptors can stimulate contraction of detrusor muscles and relaxation of urinary sphincters, this medication is indicated for treating overactive bladder [19]. This medication, however, is not selective for muscarinic receptors in the periphery and thus can also block ACh receptors located in the brain. As such, the off target non-specificity of Detrol LA can competitively bind to the ACh receptors on post synaptic neurons of the brain, leading to limited available site for ACh molecules binding, and therefore can lead to decreased efficacy of galantamine [17]. Thus far, the drug-drug interaction only identifies that Detrol LA decreases the effect of galantamine but there are none exploring how galantamine affects Detrol LA. From a mechanistic standpoint, although galantamine does not directly affect the ACh receptors, it does generate more ACh available for binding. The authors of this paper hypothesize that increased concentration of ACh will increase the probability of ACh rather than Detrol LA binding to the ACh receptor, thus indirectly decreasing the efficacy of Detrol LA. To avoid this interaction, it would best serve the patient to switch to a different agent for bladder control such as tamsulosin, which is a selective alpha-1 adrenergic receptor blocker [20].
In our specific patient case, the patient was previously on galantamine for mild to moderate dementia associated with AD and was then prescribed Detrol LA. Based on the mechanisms of the two drugs aforementioned, we would anticipate a drug-drug interaction, resulting in decreased efficacy of the patient's anti-AD agent, galantamine. With galantamine efficacy being decreased by concurrent use with Detrol LA, it would be highly recommended for patient, pharmacist, and prescriber to follow up with one another to assess whether the current galantamine dose is adequately addressing the patient's AD symptoms. For example, our patient is currently on one 16 mg extended release oral capsule once daily. This gives some prescribing flexibility, as galantamine is also readily available in a higher dose. If the 16 mg therapy is not adequately managing symptoms of dementia associated with AD even after 4 weeks of exposure, a prescriber can opt to increase therapy to once daily dosing of a 24 mg extended release formulation of galantamine. Although not currently commercially available, one clinical trial suggests that there is improved efficacy without significant increase in adverse effects at doses up to 32 mg of galantamine per day [8]. Since the interaction of these two medications would result in decreased efficacy of galantamine, an increased dose of galantamine to 24 mg per day may be appropriate in this patient to counteract this drug-drug interaction 21,22. Lastly, another plausible option for this patient would be to discontinue Detrol LA therapy altogether if their overactive bladder is being sufficiently managed without needing this drug therapy. In summary, by viewing and dissecting galantamine and AChE interactions on a molecular level, one can see how Detrol LA can lower the effectiveness of galantamine in managing dementia related to AD. However, as healthcare providers, we must also realize that we are not working with a conglomeration of molecules, but rather working to treat a patient as a whole. After weighing the benefits versus risks, with proper monitoring, this patient can safely take their new Detrol LA along with their previously prescribed galantamine.
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We would like to acknowledge and thank Dr. Frank Dailey for his help in developing and revising our topic paper. We would also like to recognize the following preceptors for participating in discussions about this project and contributing to the development of our knowledge of pharmacy practice: Erica Wesolowski, RPh, Marshfield Clinic - Eau Claire Center, Eau Claire, WI; Bill Ross, RPh, Ye Olde Pharmacy, Glendale WI; Nathan Smith, Froedtert Hospital, Milwaukee WI; Laura Alar, RPh, Columbia St. Mary's Ozaukee, Mequon, WI; Jim Englemeier, RPh, CVS, Whitefish Bay, WI; Justin Graff, PharmD, Wheaton Franciscan-St. Joseph, Milwaukee, WI."
This paper would not have been possible without several helping hands. Special thanks to Bradley Betts and Jennifer Dettmer for writing the case synopsis and help with final revisions; Brian Nguyen and Michael Vineburg for producing and editing the Jmol images, helping with portions of the drug-drug interactions, and sections of the medicinal chemistry; Brian Trinh and Michael Sitzman for writing about drug background, development, and portions of the medicinal chemistry; Mathew Letizia and Peter Jackson for composing the discussion section, writing about drug-drug interactions and side effects; Nhan Vu for compiling the individual contributions, references, citations, and for making the final revisions."