49 MCT Pharmacology Antiparkinsonian Anti-Dementia Drugs PDF

CLASS YEAR 2 COURSE CNS CODE TITLE MCT - PHARMACOLOGY OF ANTI- PARKINSONIAN AND ANTIDEMENTIA DRUGS LECTURER COLIN GREENGRASS, PH.D. DATE DECEMBER 2023  DRUGS THAT TARGET DISEASES OF THE BRAIN – LEARNING OBJECTIVES Describe the mechanism of action and adverse eff...

CLASS YEAR 2 COURSE CNS CODE TITLE MCT - PHARMACOLOGY OF ANTI- PARKINSONIAN AND ANTIDEMENTIA DRUGS LECTURER COLIN GREENGRASS, PH.D. DATE DECEMBER 2023  DRUGS THAT TARGET DISEASES OF THE BRAIN – LEARNING OBJECTIVES Describe the mechanism of action and adverse effects of drugs that target cholinergic neurotransmission in neurodegenerative disease Describe the mechanism of action and adverse effects of drugs that target dopaminergic neurotransmission in neurodegenerative disease Describe the mechanism of action and adverse effects of drugs that target protein aggregation in neurodegenerative disease Describe the mechanism of action and adverse effects of drugs that target excitotoxicity in neurodegenerative disease ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  PARKINSON’S DISEASE CHRONIC PROGRESSIVE NEUROLOGICAL DISORDER SECOND MOST COMMON NEURODEGENERATIVE DISORDER - AFTER ALZHEIMER’S DISEASE 1.5 TIMES MORE COMMON IN MEN MEAN AGE OF ONSET IS 57 YEARS OFTEN IDIOPATHIC NEUROTOXINS, FAMILIAL ARISES SPONTANEOUSLY OR THE CAUSE IS UNKNOWN EARLY ONSET ( entacapone) Severe life-threatening hepatic toxicity (tolcapone – frequent blood monitoring) Cardiovascular risk with Stalevo® (entacapone/caridopa/levodopa) ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  MONOAMINE OXIDASE B INHIBITORS ◉ MAO-B inhibitors prevent breakdown of dopamine secreted by dopaminergic neurons in striatium  DRUG TREATMENT OF PARKINSON'S DISEASE ADDC INHIBITORS COMT INHIBITORS MAOB INHIBITORS COMT INHIBITORS ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  MONOAMINE OXIDASE B INHIBITORS Adverse effects: ◉Nausea, dyskinesia, orthostatic hypotension, sleep disorders ◉Tyramine containing foods? may cause serotonin syndrome which can be life threatening. ◉Selegiline metabolised to amphetamine RCSI-DUB SLIDE (excitement, anxiety, insomnia) ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  ADVERSE EFFECTS OF LEVODOPA – ACUTE COMMON The most common side effects of levodopa are nausea, sleepiness, dizziness, and headache. Side effects can usually be avoided or minimized by starting with a low dose and increasing gradually. ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  LEVODOPA – RARER PSYCHOLOGICAL EFFECTS Confusion Disorientation Insomnia Hallucinations Delusions Agitation These are Psychosis more common in older people ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  LOSS OF EFFECTIVENESS Loss of effectiveness over 2 – 5 years In this study, 15% of patients never responded to levodopa treatment 85% did respond After 5 years 1/3 of those patients still responded 2/3 showed a decreased response to levodopa Hutton JT, Tolosa ES, Capildeo R, Morris JL. Levodopa-Treated Parkinson Disease Has Better Long-term Outcome Than Previously Predicted. Arch Neurol. 2000;57(5):758–759. ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  LEVODOPA (L-DOPA): DYSKINESIA ◉ Long-term use of levodopa is associated with dyskinesias in many patients. ◉ Dyskinesias consist of abnormal involuntary movements that cause rapid jerking or slow muscle spasms Dyskinesias involve abnormal involuntary movement of limbs, trunk, tongue and orofacial regions ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  WHY DOES THIS HAPPEN? LEVODOPA CAUSES HIGH LEVELS OF ACTIVATION WITH INCREASED DOPAMINE RELEASE OVER TIME THIS CAUSES DOWNREGULATION OF RECEPTORS (SPECIFICALLY D1 AND D3) ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  RECEPTORS ARE SEQUESTERED OVER TIME THIS CAUSES DOWNREGULATION OF RECEPTORS WHICH WHEN OCCURRING IN THE NIGROSTRIATAL SYSTEM FURTHER DECREASES DOPAMINE TRANSMISSION ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  LEVODOPA – PSYCHOLOGICAL EFFECTS Dopamine dysregulation syndrome (DDS) is a relatively recently described disturbance that may complicate long-term symptomatic therapy of Parkinson's disease. The prevalence of DDS in patients may be around 3-4%. Patients with DDS develop an addictive pattern of dopamine replacement therapy (DRT) use, administering doses in excess of those required to control their motor symptoms. ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  DOPAMINE DYSREGULATION SYNDROME THE ADDICTIVE POTENTIAL FOR DOPAMINE REPLACEMENT ARISES FROM IT AFFECTING THE MESOLIMBIC SYSTEM INVOLVED IN REWARD ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  LEVODOPA – PSYCHOLOGICAL EFFECTS Impulse Control Disorder (alone or combination with DDS) Amongst the behavioural disturbances associated with DDS are impulse control disorders (ICDs), such as pathological gambling, hypersexuality, compulsive shopping and compulsive eating ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  LEVODOPA (L-DOPA): ‘ON-OFF‘ PHENOMENON ◉ Motor fluctuations are a group of symptoms that include the "wearing off" or "on-off" effect ◉ This occurs when the medication wears off before the next scheduled dose ◉ These fluctuations are called the ‘on-off ‘phenomenon. ◉ ‘On’ time is when levodopa is working well and symptoms are controlled. ◉ ‘Off’ time is when levodopa is no longer active and symptoms such as tremor, rigidity and slow movement re-emerge. ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  LEVODOPA (L-DOPA): ‘ON-OFF‘ PHENOMENON ◉ At the beginning of treatment on-off swings are quite closely related to the timing of dosing for levodopa ◉ Rapid fluctuations in clinical state where hypokinesia and rigidity may suddenly worsen and then improve again. ◉ This hypokinetic period “Off effect” can be very sudden – patient may suddenly stop walking or be unable to rise from chair. ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  LEVODOPA (L-DOPA): ‘ON-OFF‘ PHENOMENON ◉ As Parkinson’s progresses the ‘on-off’ swings become less closely related to the timing of a dose and fluctuations become more pronounced ◉ Instead it is thought that the ‘on-off’ phenomenon is related to other processes in the brain, although these mechanisms are unclear. Early Parkinson's Disease – good motor control Parkinson’s Disease after progression - motor fluctuations ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  LONG-TERM CHALLENGES: CHANGES IN LEVODOPA RESPONSE In more advanced PD, the short-duration response to levodopa predominates. The therapeutic window narrows, and adequate control of symptoms becomes increasingly difficult. Initially this is manifested by an end-of-dose deterioration, where PD symptoms return before the next scheduled medication dose. ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN Obeso et al. 2000  DRUG HOLIDAYS ◉Some patients in long-term PRESYNAPTIC L‐dopa therapy require DOPAMINERGIC TERMINAL PROJECTING FROM SUBSTANTIA NIGRA increasing [L-dopa] ADDITIONAL DOPAMINE PRESYNAPTIC FORMED FROM EXTRA ◉After transient drug withdrawal TERMINAL LEVODOPA parkinsonian syndromes improve markedly for up to 9 months This may work by restoring dopamine sensitivity in the striatum BY UPREGULATING RECEPTORS POSTSYNAPTIC DENDRITE STRIATAL NEURON ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  DOPAMINE AGONISTS Dopamine agonists (DAs) work by PRESYNAPTIC directly stimulating striatal DA receptor DOPAMINERGIC TERMINAL PROJECTING FROM SUBSTANTIA NIGRA Dopamine agonists may be used alone as an initial treatment for some people with early Parkinson disease, especially those who develop symptoms before age 65 years. Also useful in late PD when most nigrostriatal neurons may have degenerated POSTSYNAPTIC DENDRITE STRIATAL NEURON ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  DOPAMINE AGONISTS MAY BE USED LATER IN PD PROGRESSION Continuing loss of DA nerve terminals may limit the long-term effect of L-dopa L-DOPA needs nerve terminals, as this is where it will be synthesised into dopamine DA agonists do not require intact DA neurons ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  APOMORPHINE – A DOPAMINE AGONIST ◉ Apomorphine is used to treat ''off'' episodes (times of difficulty moving, walking, and speaking that may happen as levodopa wears off or at random) ◉ Apomorphine will not work to prevent ''off'' episodes but will help improve symptoms when an ''off'' episode has already begun. 'OFF'' EPISODES ARE BRIEF PERIODS OF HYPOKINESIA AND RIGIDITY ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  DOPAMINE AGONISTS: CLINICAL CONSIDERATIONS ◉Less motor complications (> t1/2 than L-dopa) – used in younger patients However, levodopa may be more suitable in patients requiring fine motor skills ◉Adverse effects similar to levodopa: drowsiness, impulse control disorders, nausea and vomiting, daytime somnolence Gambling, overspending, compulsive eating, hyper sexuality Patients more likely to discontinue dopamine agonists due to adverse effects than levodopa RCSI-DUB SLIDE ◉Dopamine Agonist Withdrawal Syndrome Tapered dose reduction Vigilance for development of depression ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  ACETYLCHOLINE-BLOCKING DRUGS ◉A number of centrally acting antimuscarinic preparations are available ◉They tend to differ in their potency and in their efficacy in different patients. ◉Modest anti-Parkinson activity – reduce tremor and rigidity but little effect on bradykinesia MUSCARINIC RECEPTORS M1 AND M2 DA+ GABAERGIC GABA inhibits + motor and – ACh GABA cognitive function CHOLINERGIC – ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  ACETYLCHOLINE-BLOCKING DRUGS ◉ Adverse Effects ◉ Antimuscarinic drugs have a number of undesirable central nervous system and peripheral effects ◉ They are poorly tolerated by the elderly or cognitively impaired. ◉ Common adverse effects are Dry mouth constipation impaired vision urinary retention ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  ACETYLCHOLINE-BLOCKING DRUGS ◉ Clinical Use ◉ Treatment is started with a low dose of one of the drugs ◉ the dosage gradually being increased until benefit occurs or until adverse effects limit further increments. ◉ If patients do not respond to one drug, a trial with another member of the drug class is warranted and may be successful. ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  OTHER TREATMENT OPTIONS IN PD Amantadine Originally anti-viral; increases dopamine release, anti- cholinergic properties, blocks NMDA receptors Reduced levodopa-induced dyskinesia in advanced disease ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  DEEP BRAIN STIMULATION ◉ Schematic of the chronic deep brain stimulation implant and devices for the treatment of Parkinson’s disease. ◉ An electrode is surgically implanted either in the subthalamic nucleus (STN) or the internal globus pallidus (GPi) and connected to an implanted pulse generator through subcutaneous wires. ◉ The pulse generator is programmed to deliver charge-balanced, voltage- controlled electric pulses. ◉ Image reproduced from (Hickey & Stacy, 2016) 2 under the Creative Commons Attribution License (CC BY). ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN Drug/Treatment Mechanism of Action (MoA) Therapeutic Effect Efficacy Precursor to dopamine; crosses Reduces bradykinesia, rigidity, Highly effective initially; Levodopa (L-DOPA) BBB and converts to dopamine and tremor. Improves motor efficacy may decrease with in the brain. function. long-term use. Inhibits DOPA decarboxylase in Used with Levodopa; reduces Enhances effectiveness of Carbidopa the periphery, increasing L- peripheral side effects of Levodopa by reducing DOPA availability in the brain. Levodopa. peripheral metabolism. Alleviates motor symptoms; Effective, especially in early Dopamine Agonists (e.g., Directly stimulate dopamine can be used in early stages or stages or as adjunct therapy pramipexole, ropinirole) receptors in the brain. with Levodopa in advanced with Levodopa. stages. Inhibit monoamine oxidase B, Improves motor control and Moderate efficacy; more MAO-B Inhibitors (e.g., reducing dopamine can be used as monotherapy in effective in early stages or as selegiline, rasagiline) breakdown. early disease or with Levodopa. adjunct therapy. Inhibit catechol-O- Effective as adjunct therapy COMT Inhibitors (e.g., Reduces “off” periods and methyltransferase, extending with Levodopa, especially in entacapone, tolcapone) prolongs Levodopa’s action. the effect of Levodopa. reducing "off" periods. Antiviral with anti- Reduces dyskinesia associated Modest efficacy; primarily used Amantadine glutamatergic properties; may with Levodopa use and mild for dyskinesia and mild increase dopamine release. anti-parkinsonian effects. symptoms. Primarily reduces tremors; less Limited efficacy; mainly used Anticholinergics (e.g., Inhibit acetylcholine activity to effective for bradykinesia or for tremor control in young trihexyphenidyl, benztropine) balance dopamine deficiency. rigidity. patients.  DEEP BRAIN STIMULATION ACTIVATES DOPAMINERGIC NEURONES CORTEX GLUTAMATERGIC MUSCARINIC RECEPTORS M1 AND M2 + GABAERGIC Now, GABA + greatly inhibits – ACh GABA motor and cognitive Deep brain CHOLINERGIC –DA function DOPAMINERGIC stimulation DOPAMINERGIC RECEPTORS D1 AND D2 activates SUBSTANTIA NIGRA CORPUS STRIATUM dopaminergic neurone bundles ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  DEEP BRAIN STIMULATION WILL NOT WORK FOR ALL PATIENTS GUIDELINES RECOMMEND THAT TO CONSIDER DBS IN PD: PRESENCE OF MOTOR OFF FLUCTUATIONS OR TREATMENT-INDUCED DYSKINESIA PRESENCE OF TREMOR, WHICH CANNOT BE SATISFACTORILY TREATED WITH MEDICATION LEVODOPA-CAN STILL INDUCE REDUCTION OF MOTOR SYMPTOMS BY >33% OF THE UNIFIED PARKINSON DISEASE RATING SCALE (UPDRS) ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  DEEP BRAIN STIMULATION ONLY PROVIDES TEMPORARY RELIEF However, over CORTEX time these fibres degenerate so GLUTAMATERGIC MUSCARINIC RECEPTORS + GABAERGIC much, that even M1 AND M2 Now, GABA + greatly inhibits deep brain – ACh GABA motor and cognitive stimulation is no CHOLINERGIC –DA function DOPAMINERGIC longer effective at DOPAMINERGIC RECEPTORS D1 AND D2 producing SUBSTANTIA NIGRA CORPUS STRIATUM inhibition of the GABA neurons ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  INITIAL TREATMENT STRATEGY FOR PARKINSON'S DISEASE ◉ Treatment Approach Symptom control with mono-therapy No single universal first-line agent ◉ Common First-line Medications Levodopa + Dopa Decarboxylase Inhibitor Non-Ergot Dopamine Agonists (oral or transdermal) Monoamine Oxidase B (MAO-B) Inhibitors ◉ Factors Influencing Drug Choice Efficacy and side-effect profile Disease stage and symptomatology Patient-specific factors: age, comorbidities, cognitive status ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  SUMMARY: TREATMENT OPTIONS IN EARLY PD Initial therapy for PD First line option Symptom Risk of Side Effects Control Motor Other Levodopa YES +++   Dopamine agonists YES ++   MAO-B inhibitors YES +   Anti-cholinergics NO minor Anticholinergic Anticholinergic effects effects Amantadine NO Reduced levodopa- Lack of evidence Lack of evidence induced dyskinesia +++ Good degree of symptom control, ++ moderate degree of symptom control, + limited degree of symptom control ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN UNDER INVESTIGATION | NEURAL TRANSPLANTATION, GENE THERAPY AND BRAIN STIMULATION NEURAL TRANSPLANTATION OF FOETAL NEUROBLASTS TRANSPLANTATION TO REPLACE LOST NEURONES – some successes AIMED AT INCREASING NEUROTRANSMITTER GENE THERAPY SYNTHESIS AND GROWTH FACTORS NEUROTROPHIC DIRECT INFUSION OF GROWTH FACTORS INTO GROWTH FACTOR PUTAMEN TO RESCUE DYING CELLS (GNGF) ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  QUESTION 1 Which of the following, knowing the pathology of neurodegeneration in PD, is ◉ the last therapy which could still have some efficacy? THE ANSWER IS A dopamine agonist A. Higher dose of Levodopa B. Levodopa with a MAOI such as seligiline C. A dopamine agonist D. Deep brain stimulation E. An acetylcholinesterase inhibitor such a neostigmine ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  QUESTION 2 ◉ This diagram represents the pathology of PD in a late stage. If deep brain stimulation could be precise enough which target of the following sites would be a possible therapeutic target to treat PD? A. glutamatergic neurons B. Dopaminergic neurons C. Cholinergic neurons D. GABAergic neurons E. None of these ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  QUESTION 2 ◉ This diagram represents the pathology of PD in a late stage. If deep brain stimulation could be precise enough which target of the following sites would be a possible therapeutic target to treat PD? A. 1 – glutamatergic neurons B. 2 – Dopaminergic neurons C. 3 – Cholinergic neurons D. 4 – GABAergic neurons E. None of these ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  PATHOGENESIS OF ALZHEIMER’S DISEASE ◉ AD is associated with brain shrinkage and loss of neurons in many brain regions, but especially in the hippocampus and basal forebrain. ◉ The loss of cholinergic neurons in the hippocampus and frontal cortex is a feature of the disease ◉ It is thought to underlie the cognitive deficit and loss of short-term memory in Alzheimer's disease ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  ALZHEIMER’S DISEASE Prevalence rises sharply with age, from about 2% in those aged 65–69 to 20% in those aged 85–89. COMMON SYMPTOMS OF AD ARE DIFFICULTY REMEMBERING NAMES AND RECENT EVENTS, LOSS OF EXECUTIVE FUNCTIONING, APATHY AND DEPRESSION. SYMPTOMS OF THE DISEASE ONLY BECOME OBVIOUS AFTER THE UNDERLYING PATHOLOGY HAS PROGRESSED TO QUITE AN ADVANCED STAGE ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN PATHOGENESIS OF ALZHEIMER’S DISEASE ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN PATHOGENESIS OF ALZHEIMER’S DISEASE ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  AMYLOID PRECURSOR PROTEIN (APP) APP is a 770-amino acid membrane protein Amyloid plaques consist normally expressed by many cells, including CNS of overproduced neurons. The APP gene resides on chromosome 21 fragments of APP ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  ALZHEIMER'S DISEASE CURRENT PHARMACOLOGICAL THERAPY ◉ Loss of cholinergic neurons Although changes in many transmitter systems have been observed, a selective loss of cholinergic neurons in the basal forebrain nuclei is characteristic of Alzheimer's disease Muscarinic receptor density is not affected Nicotinic receptor density particularly in the cortex, is decreased ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  CLINICAL USE OF DRUGS IN DEMENTIA – ACETYLCHOLINESTERASE INHIBITORS Acetylcholinesterase inhibitors are used in mild to moderate Alzheimer’s disease. Donepezil Galantamine Rivastigmine Anticholinesterase inhibitors block the enzyme AChE There is an increase in Ach in the synaptic cleft ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  CHOLINESTERASE INHIBITORS: CLINICAL CONSIDERATIONS DONEPEZIL, RIVASTIGMINE, GALANTAMINE Address loss of cholinergic neurotransmission and ACh synthesizing neurons in subcortical nuclei of the forebrain Used for moderate to severe Alzheimer's disease Improved cognition, behavior, and functional ability BUT only in about 20% of patients, and only delay cognitive deterioration by about one year (benefit still controversial) Adverse Effects Cholinergic side effects such as nausea, anorexia, vomiting, and diarrhea ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  CHOLINESTERASE INHIBITORS: HOW DO THEY WORK? DONEPEZIL, RIVASTIGMINE, GALANTAMINE Mechanism: Inhibits acetylcholinesterase, increasing acetylcholine Donepezil levels in the brain.  acetylcholine availability in synaptic cleft. Mechanism: Dual inhibition of acetylcholinesterase and Rivastigmine butyrylcholinesterase.  acetylcholine availability in synaptic cleft. Mechanism: Inhibits acetylcholinesterase and modulates nicotinic Galantamine acetylcholine receptors.  acetylcholine availability in synaptic cleft. Clinical Effect: Helps mitigate cognitive decline by compensating for Overall Impact cholinergic neuron loss. ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  ADVERSE EFFECTS – ACETYLCHOLINESTERASE INHIBITORS ◉Unwanted cholinergic effects may be troublesome ◉Efficacy is monitored periodically in individual patients ◉ Administration is continued only if the drugs are believed to have an effect in slowing functional and cognitive deterioration is judged to outweigh adverse effects. ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN Cholinesterase Inhibitors: How do they work? Donepezil, Rivastigmine, Galantamine Cerebral Cortex and Hippocampus These regions are vital for memory formation and cognitive functions. Cholinesterase inhibitors boost acetylcholine levels helping to mitigate the decline in cognitive functions. The hippocampus, is one of the first regions affected in Alzheimer's, particularly benefits from increased acetylcholine, which aids in memory consolidation and retrieval. Basal Forebrain This area contains cholinergic neurons that project to the cortex and hippocampus, playing a key role in cognitive and memory processes. ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  NMDA ANTAGONISTS: HOW DO THEY WORK? MEMANTINE Target: NMDA Receptors on Neurons Action: Non-competitive antagonist that binds to NMDA receptor-calcium channels. Effect: Prevents excessive calcium influx caused by abnormal glutamate activity without hindering normal neurotransmission. Result: Protects neurons from excitotoxicity, potentially slowing neurodegeneration and preserving cognitive functions in Alzheimer's disease. ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  MEMANTINE Memantine, an orally active weak antagonist at NMDA receptors currently approved for the treatment of ad It’s action at NDMA would indicate potential inhibition of excitotoxicity. However, instead it produces a modest cognitive improvement in Alzheimer's disease Protects neurons from excitotoxicity, potentially slowing neurodegeneration ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  ADVERSE EFFECTS OF NMDA ANTAGONISTS ◉ NMDA ANTAGONISTS HAVE SIGNIFICANT ADVERSE EFFECTS AND ARE OF LIMITED USE CLINICALLY. ◉ MEMANTINE IS VERY WEAK BINDING AND ONLY BLOCKS THE CHANNEL FOR A SHORT PERIOD C. G. Parsons, A. Stöffler, W. Danysz Neuropharmacology (2007) ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  NMDA ANTAGONISTS: HOW DO THEY WORK? MEMANTINE It is approved for moderate to severe Alzheimer's symptoms and clinical studies have shown that it can improve cognition, social behaviour, and functional ability in a subset of patients. It is thought to work via dampening noise in NMDA activity to allow normal activity to be detected ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  NMDA ANTAGONISTS: WHERE DO THEY WORK? MEMANTINE Widespread Effect Across the Brain: Memantine particularly affects areas with glutamate overactivity, which is broadly distributed. This can be widespread in Alzheimer's disease. Cerebral Cortex and Hippocampus: Memantine also impacts the cerebral cortex and hippocampus by preventing excitotoxicity, it helps protect neurons in these areas from damage ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  NMDA ANTAGONISTS: CLINICAL CONSIDERATIONS MEMANTINE Used for moderate to severe Alzheimer's disease Clinical studies show improved cognition, social behavior, reducing behavioural symptoms like agitation, and functional ability (60-70% response rate) Recently re-evaluated (benefit controversial) Memantine in Combination Therapy Often used in conjunction with cholinesterase inhibitors (ChEIs) for synergistic effect. Meta-analyses show improved cognitive and behavioral outcomes when combined with ChEIs, especially in moderate to severe AD. May enhance overall therapeutic efficacy and slow disease progression ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  NMDA ANTAGONISTS: ADVERSE EFFECTS MEMANTINE Adverse Effects: Side effects can include dizziness, headache, constipation, and confusion. Memantine is generally well tolerated ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  ADUCANUMAB Binding to Plaques Aducanumab crosses the blood-brain barrier. Binds specifically to aggregated amyloid-beta (Aβ), including soluble oligomers and insoluble fibrils. Prefers pathological Aβ forms over normal monomers. Immune System Recruitment Ad Binding flags plaques for destruction. Microglia, the brain’s immune cells, are recruited. Activates immune response against Aβ plaques. Phagocytosis and Clearance Microglia engulf and digest Aβ plaques. Phagocytosis leads to the clearance of plaques. Aims to reduce amyloid burden and slow disease progression. ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN ANTI-AMYLOID MONOCLONAL ANTIBODIES ADUCANUMAB AND LACANEMAB ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  ADUCANUMAB VS. LECANEMAB Aducanumab (2021) Ad Le Ad Targets both soluble oligomers and insoluble fibrillar forms of amyloid- beta (Aβ). Insoluble forms deposit later in AD Theoretical potential to be active in later stages due to ability to target established insoluble plaques. Aducanumab reported a 22% slowing on the Clinical Dementia Rating (CDR-SB) in early AD Lecanemab (2023) Le Primarily targets soluble highly toxic Aβ oligomers, more prevalent in early stages, not insoluble plaques. Ad Efficacy might be more pronounced in early stages of Alzheimer's disease. Lecanemab reported a 27% slowing on the Clinical Dementia Rating (CDR-SB) in early AD ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN WHY ARE THEY LIKELY NOT EFFECTIVE IN LATER STAGE AD? Amyloid-beta (Aβ) Plaques are too dense to clear later in AD ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  EXCITOTOXITY AND NEURODEGENERATION ◉ Neurodegenerative diseases in which excitotoxicity is believed to play a part in the progression of the disease include: 1. Alzheimer's Disease 2. Amyotrophic Lateral Sclerosis (ALS) 3. Huntington's Disease 4. Parkinson's Disease (PD) 5. Multiple Sclerosis (MS) 6. Frontotemporal Dementia 7. Prion Diseases (such as Creutzfeldt-Jakob disease) 8. Certain forms of spinocerebellar ataxia ◉ In these conditions, the excessive activation of glutamate receptors leads to calcium influx and subsequent neuronal damage. ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  EXCITOTOXICITY ◉ Excitotoxicity across various neurodegenerative conditions is generally caused by the overactivation of receptors for the excitatory neurotransmitter glutamate. 2+ ◉ This overactivation leads to excessive calcium (Ca ) influx into neurons, usually through NMDA receptors (with AMPA involved) and subsequent cell damage or death. ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  EXCITOTOXICITY Glutamate Receptor Overactivation Overstimulation of NMDA and AMPA receptors on Excessive glutamate remains in the synaptic cleft. postsynaptic neurons. Calcium Influx and Enzyme Activation Activation of damaging enzymes such as proteases, lipases, Excessive Ca2+ enters neurons. and endonucleases. Oxidative and Nitrosative Stress Overproduction of reactive oxygen species (ROS) and nitric Mitochondrial dysfunction and release of apoptotic signals. oxide (NO). Inflammatory Response Attraction and activation of microglia. Release of pro-inflammatory cytokines by astrocytes. Disruption of Cellular Processes Apoptotic cell death pathways are activated. Chronic alterations in neuronal calcium homeostasis. ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  DRUGS TO COUNTERACT EXCITOTOXICITY Drug Class Mechanism of Action Specific Drugs Used in Conditions Adverse Effects Approval Status (UK) Alzheimer's Disease, NMDA Block NMDA receptors to Dementia with Lewy Dizziness, headache, Receptor prevent excessive calcium Memantine Approved bodies, Mixed dementia, constipation, confusion Antagonists influx. CBD AMPA Block AMPA receptors to Drowsiness, dizziness, Likely off-label for Epilepsy (off-label for Receptor inhibit excitatory Perampanel fatigue, behavioral neurodegenerative diseases; neurodegeneration) approved for epilepsy Antagonists neurotransmission. changes Glutamate Nausea, dizziness, Reduce presynaptic Amyotrophic Lateral Release Riluzole elevated liver enzymes, Approved release of glutamate. Sclerosis (ALS) Inhibitors weakness ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  RILUZOLE – MECHANISM OF ACTION Enhances Glutamate Reuptake EAAT-1 Activation: Riluzole may boost EAAT-1 function, facilitating the clearance of glutamate and reducing excitotoxicity. Reduces Extracellular Glutamate xCT Inhibition: By inhibiting the cystine/glutamate antiporter, Riluzole decreases extracellular glutamate levels, mitigating excitotoxic damage. Impacts Antioxidant Synthesis GSH Synthesis: Inhibition of xCT affects cystine uptake, potentially reducing intracellular glutathione, an essential antioxidant. Modulates Neurotransmission GRM1 Receptor: The impact on this glutamate receptor subtype suggests a role in regulating neuronal signaling and cell proliferation. ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN  BIBLIOGRAPHY THESE BOOKS WERE USED IN THE PREPARATION OF THIS LECTURE ROYAL COLLEGE OF SURGEONS IRELAND | MEDICAL UNIVERSITY OF BAHRAIN