Pharmacotherapeutics: Anticonvulsants, Parkinson's, Alzheimer's Drugs PDF
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2024
Dr. Alejandro Baroque
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Summary
These pharmacotherapeutics notes cover anticonvulsant drugs, treatments for Parkinson's disease, and medications for Alzheimer's disease. The document provides information on various topics, including adverse effects, mechanisms of action, and clinical applications, relevant to the three medical conditions.
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#Pha PHARMACOTHERAPEUTICS Anticonvulsants, Drugs for Parkinson's Disease, Drugs for Alzheimer's...
#Pha PHARMACOTHERAPEUTICS Anticonvulsants, Drugs for Parkinson's Disease, Drugs for Alzheimer's Dr. Alejandro Baroque | September 15, 2024 | A.Y. 2024-2025 TABLE OF CONTENTS 1.20.1 ADVERSE EFFECTS........................10 1.21. GABAPENTIN........................................... 10 1. ANTIEPILEPTIC DRUGS...................................... 2 1.22. PREGABALIN........................................... 10 1.1. DEFINITION OF TERMS.............................. 2 1.22.1 ADVERSE EFFECTS OF PREGABALIN & GABAPENTIN...................10 1.2. PATHOPHYSIOLOGY OF SEIZURES..........3 1.23. TOPIRAMATE............................................11 1.3. CELLULAR MECHANISMS OF SEIZURE GENERATION......................................................3 1.23.1. ADVERSE EFFECTS....................... 11 1.4. ANTI-EPILEPTIC MEDICATION................... 4 1.24. LAMOTRIGINE..........................................11 1.5. ETIOLOGY.................................................... 4 1.24.1 ADVERSE EFFECTS........................ 11 1.6. CLASSIFICATION OF SEIZURE TYPES 1.25. ZONISAMIDE............................................ 11 (ONSET)...............................................................4 1.26. LACOSAMIDE........................................... 11 1.7. PATHOPHYSIOLOGY OF SEIZURE............ 4 1.26.1. ADVERSE EFFECTS.......................12 1.7.1 PARTIAL EPILEPSIES.......................... 4 1.27. BENZODIAZEPINES.................................12 1.7.2 GENERALIZED EPILEPSIES............... 5 1.27.1. DIAZEPAM....................................... 12 1.8. MAIN GOALS OF AEDs................................5 1.27.2 MIDAZOLAM..................................... 12 1.9. CLASSIFICATION OF AEDs.........................5 1.27.3 CLONAZEPAM.................................. 12 1.9.1 DECREASED EXCITATION.................. 5 1.28. CONVULSIVE STATUS EPILEPTICUS.... 12 1.9.2 PROMOTE INHIBITION........................ 5 1.28.1 CAUSES............................................12 1.9.3 THE OLDER AEDs................................6 1.29. SUMMARY OF PK DATA OF AEDs.......... 13 1.9.4. NEWER AEDs......................................6 1.30. AEDs IN PREGNANCY.............................13 1.9.5 ACCORDING TO ITS MECHANISM OF 1.31. RISKS FOR SEIZURES DURING ACTION..........................................................6 PREGNANCY.....................................................13 1.10. THE CYTOCHROME P450 ISOZYME 1.32. WHY DO SEIZURES INCREASE DURING SYSTEM...............................................................7 PREGNANCY.....................................................13 1.10.1 HEPATIC ENZYME 1.33. OTHER THERAPEUTIC INDICATIONS OF INDUCERS/INHIBITORS............................... 7 AEDs.................................................................. 13 1.11. AEDs MECHANISM OF ACTION................7 2. DRUGS FOR PARKINSON’S DISEASE............. 14 1.12. CLINICAL SPECTRUM OF ACTIVITY OF 2.1. OVERVIEW ON PARKINSON DISEASE.... 14 AEDs.................................................................... 7 2.1.1. PATHOPHYSIOLOGY OF PARKINSON 1.13. PHARMACOKINETICS OF AED.................7 DISEASE......................................................14 1.14. PHENYTOIN............................................... 8 2.1.2. PHARMACOLOGIC THERAPY IN 1.15. CARBAMAZEPINE......................................8 PARKINSON’S DISEASE.............................15 1.15.1. ADVERSE EFFECTS.........................8 2.1.3. DOPAMINE DEFICIENCY HYPOTHESIS.............................................. 16 1.16. OXCARBAZEPINE......................................9 2.1.4. CLINICAL PRESENTATION...............16 1.17. PHENOBARBITAL...................................... 9 2.1.5. CLINICAL STAGES AND TIME OF 1.17.1. CLINICAL USES................................ 9 COURSE OF PROGRESSION.................... 16 1.17.2. ADVERSE EFFECTS.........................9 2.2. VIDEO ON PARKINSON’S DISEASE......... 17 1.18. VALPROIC ACID.........................................9 2.2.1. MITOCHONDRIA IN PARKINSON’S 1.18.1. ADVERSE EFFECTS.........................9 DISEASE......................................................17 1.19. ETHOSUXIMIDE....................................... 10 2.2.2. GLIAL CELLS IN PARKINSON’S 1.19.1 ADVERSE EFFECTS........................10 DISEASE......................................................18 1.20. LEVETIRACETAM.....................................10 2.2.3. DISEASE PROCESS OF Let's capy-talize on our learning with these awesome notes! | 1 PHARMACOTHERAPEUTICS | Antiepileptic Drugs, Anti-Parkinson Drugs, Drugs for Alzheimer Disease PARKINSON’S DISEASE.............................18 3.5. OTHER DRUGS FOR ALZHEIMER’S 2.2.4. TREATMENT OF PARKINSON’S DISEASE............................................................29 DISEASE......................................................19 3.5.1. SOLANEZUMAB AND 2.3. DRUGS USED IN PARKINSONISM........... 19 BAPINEUZUMAB......................................... 29 2.3.1. LEVODOPA-CARBIDOPA..................20 3.5.2. VERUBECESTAT............................... 29 2.3.2 DOPAMINE RECEPTOR AGONISTS. 22 3.5.2. EPOTHILONE-D................................ 29 2.3.3. AMANTADINE.................................... 22 3.6. CHOLINESTERASE INHIBITOR THERAPY 2.3.4. MONOAMINE OXIDASE INHIBITORS IN AD..................................................................29 (MAOI)..........................................................23 3.7. GINKGO BILOBA........................................ 29 2.3.5. 3.7.1. DRUG INTERACTIONS AND CATECHOL-O-METHYLTRANSFERASE PRECAUTIONS........................................... 29 INHIBITORS................................................. 23 2.3.6. ACETYLCHOLINERGIC BLOCKERS (MUSCARINIC ANTAGONISTS)..................24 LEGEND 2.3.7. EVIDENCE-BASED COMPARISON OF Reference Book ★ Take Note / Important Info Previous Trans ANTIPARKINSON DRUGS.......................... 24 2.3.8. ECONOMIC BURDEN OF 1. ANTIEPILEPTIC DRUGS PARKINSON’S DISEASE.............................24 Seizures documented 400 BC, saying “a brain disorder due to 2.3.9. PD MEDS INDICATION..................... 25 accumulation of thick humors” Hippocrates 400 BC (Greek Physician) 3. DRUGS FOR DEMENTIA....................................25 ○ Said that seizures are not a sacred/religious disease 3.1. DEMENTIA..................................................25 rather a disorder of the brain ○ He described some physical treatment of epilepsy, stating 3.1.1. CHOLINERGIC HYPOTHESIS IN AD25 it as an incurable chronic illness. Which is not true 3.1.2. SYMPTOM PROGRESSION IN AD... 25 because today, seizures are treatable especially if it is structural in nature. 3.1.3. BRAIN IN ALZHEIMER DISEASE......25 3.1.4. BRAIN IN ALZHEIMER DISEASE......26 3.1.5. CHARACTERISTICS IN ALZHEIMER DISEASE......................................................26 3.1.6. TWO TYPES OF ALZHEIMER’S DISEASE......................................................26 3.1.7. CHOLINERGIC HYPOTHESIS IN AD26 3.2. ACETYLCHOLINESTERASE INHIBITORS 26 3.2.1. TACRINE............................................ 26 3.2.2. DONEPEZIL, RIVASTIGMINE, GALANTAMINE............................................ 26 Fig 1. Prevalence of Seizures. 2019 statistics from WHO 3.2.3. TREATMENT OF AD..........................27 ○ 50 million people in the world suffer from seizures 3.2.4. RIVASTIGMINE PATCH ○ 44 new cases per 100,000 people (in the U.S.) Out of the 50 million people, 80% come from resource-poor PREPARATIONS..........................................27 countries 3.2.5. DRUG INTERACTIONS..................... 27 A significant portion of the chart are unaccounted for ○ Those who are misdiagnosed & those who does not 3.3. NMDA ANTAGONIST..................................28 have the means to have a neurological consultation 3.3.1. NORMAL NMDA RECEPTOR 1% prevalence in the Philippines TRANSMISSION.......................................... 28 Most seizure patients are from younger and older groups ○ Bimodal in pattern 3.3.2. MEMANTINE......................................28 3.3.3. PHARMACOKINETICS...................... 28 1.1. DEFINITION OF TERMS 3.3.4. MEMANTINE IN SPECIAL Seizure: transient occurrence of signs and/or symptoms due to abnormal, excessive or synchronous neuronal activity POPULATIONS............................................ 28 in the brain 3.4. PHARMACOLOGIC TREATMENTS FOR AD. Convulsion: paroxysm of involuntary repetitive muscular 28 contractions ○ Consequence of the seizure Let's capy-talize on our learning with these awesome notes! | 2 PHARMACOTHERAPEUTICS | Antiepileptic Drugs, Anti-Parkinson Drugs, Drugs for Alzheimer Disease ○ Some patients of seizures with metabolic etiology Rapid shift in membrane Oscillatory behavior, Hyponatremia, hypernia, & hypoglycemia potential in depolarizing reciprocal connection, burst ○ Once these metabolic problems are corrected, seizures direction, followed by bursts activities would discontinue, meaning they cannot be of repetitive action Balance of GABA - A and considered as epileptics potentials lasting for several GABA - B conductance Epilepsy: enduring predisposition to generate epileptic hundreds of milliseconds Imbalance between seizures ○ Initial → AMPA GABAergic and Glutamate ○ Occurrence of at least one epileptic seizure ○ Bursts → NMDA T - type calcium channels ○ The patient must have the innate neuronal capacity to ○ Hyperpolarization → Cl - Major modifier generate seizures frequently and not triggered by any and K HCN channels (h - current) - metabolic or physical ailments Modifier Status epilepticus ○ Recurrent seizure activity, behavior and/or electrical, 1.3. CELLULAR MECHANISMS OF SEIZURE GENERATION without recovery (returning to baseline) between seizures Excitatory axonal “sprouting” ○ At 30 minutes, the patient may be in mortally Loss of inhibitory neurons dangerous situation Loss of excitatory neurons “driving” inhibitory neurons to be ○ At around 5 minutes, medication must be started hyperactive Excitation (too much) Etiology of Seizures ○ Ionic–inward Na+, Ca++ currents ○ Idiopathic ○ Neurotransmitter–glutamate No underlying structural brain lesion or other Inhibition (too little) neurological signs & symptoms ○ Ionic–inward Cl-, outward K+ currents ○ Symptomatic ○ Neurotransmitter–GABA Different types of neurological disorders (tumors, subarachnoid hemorrhages, intracerebral hemorrhages) may predispose someone to have irritation of the neurons and produce seizures Clinical types ○ Convulsive ○ Non-convulsive: patient is stuporous, not responding 1.2. PATHOPHYSIOLOGY OF SEIZURES Fig 3. Epileptogenesis (Cellular basis). Normal process of producing an action potential: ○ From the presynaptic cleft, triggering a glutamate exocytosis that goes to glutaminergic receptors, which Fig 2. Pathophysiology of Seizures. once activated will send out action potentials ○ You have to have good balance between excitation and inhibition and that’s where the GABAergic neuron is Excitatory (too much) involved, dampening the neuronal signals. ○ EPSPs Imbalance between excessive excitation transmission and ○ Na+ influx deficiency in inhibitory transmission can happen due to ○ Ca++ Currents disturbances in relationships of the neurotransmitter system ○ Paroxysmal depolarization and cellular membrane integrity Inhibitory (too little) ○ IPSPs Table 2. Epileptogenesis. ○ K+ Efflux Excitatory Process ○ C- Influx Mediated by Glutamate ○ Pumps (degeneration of your sodium-potassium pumps) At rest, the inside is slightly more negative than the outside ○ Low pH (acidic levels in the brain) Action potential starts when voltage-gated sodium channels open, allowing positively charged sodium ions to rush into the Table 1. Types of Seizures. cell, leading to membrane depolarization Types of Seizures Membrane depolarization leads to the opening of high Focal Seizures Generalized Seizures voltage-activated calcium channels, allowing positively Only happens in one part of All parts of the brain are charged calcium ions to enter the neuron the brain hyperactive Causes release of glutamate from the vesicles into the Paroxysmal Depolarizing Thalamocortical synaptic cleft Shift hypersynchronization Glutamate will bind to two types of receptors in the Let's capy-talize on our learning with these awesome notes! | 3 PHARMACOTHERAPEUTICS | Antiepileptic Drugs, Anti-Parkinson Drugs, Drugs for Alzheimer Disease postsynaptic neuron 1.6. CLASSIFICATION OF SEIZURE TYPES (ONSET) ○ AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid Leads to opening of sodium channels ○ NMDA N-methyl-D-aspartate Leads to opening of calcium channels Calcium may also enter the neuron through low voltage-activated calcium channels (T-type calcium channels) ○ Respond to depolarization at or below the levels of resting membrane potential If there is too much glutamate, neurons can become hyperexcitable resulting to a seizure. Inhibitory Process Mediated by GABA Inhibitory neurons prevent too much release of glutamate by releasing the neurotransmitter GABA (gamma-aminobutyric acid) GABA-A binds to GABA-A receptors on the post-excitatory neuron Facilitates opening of chloride channels to allow negatively charged chloride ions to enter, causing the Fig 4. Classification of Seizure Types. membrane potential to be more negative inside relative to the outside (hyperpolarized state). Focal onset This limits the ability of the neurons to respond to further ○ Differentiate if the patient is aware during the epileptic stimulation phase or has impaired awareness Once GABA-A dissociates from the GABA-A receptor, it ○ Check if the patient has motor or non-motor symptoms becomes removed from the synaptic cleft by: ○ A focal seizure may eventually become generalized ○ Reuptake by GABA Transporter 1 (GAT-1) ○ Degraded by GABA-transaminase (GABA-T) ○ Lecture: degraded by GABA-aminotransferase 1.7. PATHOPHYSIOLOGY OF SEIZURE Leads to opening of sodium channels Imbalance between excessive excitation and deficiency in If there is too little GABA, it can allow neurons to be inhibitory signals due to disturbances in the relationships of hyperexcitable, leading to seizures the neurotransmitter system and cellular membrane integrity Summary ○ Paroxysmal depolarizing shift (PDS) Partial/focal seizures Excitatory (Too much) Inhibitory (Too little) ○ Thalamo-cortical hypersynchronization EPSPs IPSPs Generalized seizures Na+ Influx K+ Efflux Abnormal and excessive firing of a population of neurons Ca++ Currents Cl- Influx Low pH and Na-K ATPase 1.7.1 PARTIAL EPILEPSIES Paroxysmal Depolarization degeneration Paroxysmal Depolarization Shift (PDS) ○ Rapid shift in membrane potential in depolarizing direction, followed by bursts of repetitive action 1.4. ANTI-EPILEPTIC MEDICATION potentials lasting for several hundred of milliseconds Pharmacologic Agent that can: Initial: AMPA Decrease frequency and severity of the seizures in people Bursts: NMDA with epilepsy Hyperpolarization: Cl- and K+ ○ Because even those taking medications can get triggered ○ Only one area or region of neurons which are ○ Most common triggers: hyperactive. if they decrease the medications Hyperactive signals may move to the adjacent if they’re not compliant with the medications structures and apparently reach the thalamus Treat the SYMPTOMS, not the underlying epileptic condition where it sends signals to the cortices to become ○ Controlling seizures generalized ○ Prevention of recurrence Thalamus is the relay center towards the cortices ○ Avoiding treatment side effects ○ Maintaining or restoring quality of life 1.5. ETIOLOGY IDIOPATHIC ○ No underlying structural brain lesion or other neurologic signs and symptoms SYMPTOMATIC ○ Result of one or more identifiable structural lesions of the brain that leads to disruption of cellular membranes and electrochemical integrity Let's capy-talize on our learning with these awesome notes! | 4 PHARMACOTHERAPEUTICS | Antiepileptic Drugs, Anti-Parkinson Drugs, Drugs for Alzheimer Disease Fig 8. Generalized seizure neural pathway. ○ Extra excitation in the thalamus will transmit to the cortices through different thalamocortical fibers Fig 5. Abnormal neural firing. 1.8. MAIN GOALS OF AEDs Controlling seizures Prevention of recurrence Avoiding or minimalize treatment of side effects ○ Personalize the treatment Maintaining or restoring quality of life Excitatory (DEC) ○ EPSPs ○ Na+ influx ○ Ca++ currents Fig 6. Focal seizure EEG. ○ Paroxysmal depolarization Inhibitory (INC) Calcium is one the more prominent seizure-genic ○ IPSPs neurotransmitters ○ K+ influx Normal action potential has a depolarization, repolarization, ○ Cl- influx and hyperpolarization phase. ○ Pumps ○ It is the potassium (K+) that is affecting the resting ○ Low pH membrane potential If there is too much calcium coming inside the cell, from a 1.9. CLASSIFICATION OF AEDs depolarization phase it maintains tetani ○ Where paroxysmal depolarization shift happen 1.9.1 DECREASED EXCITATION 1.7.2 GENERALIZED EPILEPSIES DECREASED EXCITATION Thalamocortical Hypersynchrony Action Example ○ Oscillatory behavior, reciprocal connection, burst activities Phenytoin + ○ Balance of GABAA and GABAB conductance Na channel blockers Carbamazepin ○ T-type Calcium channel:- major modifier ○ HCN channels B3 or h-current: modifier Ethosuximide Ca++ channel blockers Gabapentin Pregabalin Inhibits synaptic vesicular Levetiracetam protein 2A 1.9.2 PROMOTE INHIBITION PROMOTE INHIBITON Fig 7. Generalized seizure EEG. Action Example Benzodiazepines GABAergics Phenobarbital Valproic acid (VA) Inhibition of excitatory amino Felbamate acids MgSO4 Let's capy-talize on our learning with these awesome notes! | 5 PHARMACOTHERAPEUTICS | Antiepileptic Drugs, Anti-Parkinson Drugs, Drugs for Alzheimer Disease 1.9.3 THE OLDER AEDs MECHANISMS OF ACTION The “Older” AEDs Receptor Drug Drug Brand Name Discovery protein-2 (CRMP-2) Phenobarbital 1912 NMDA Felbamate Phenytoin DilantinTM 1938 Phenytoin Primidone MysolineTM 1954 Carbamazepine Oxcarbazepine Ethosuximide ZarantinTM 1960 TM Voltage-gated Na+ channel Zonisamide Carbamazepine Tegretol 1974 Lamotrigine Valproate DepakateTM 1978 Lacosamide Valproic acid Seizure disorders have been around for more than centuries Ethosuximide ○ Documented 400 BC by Hippocrates Lamotrigine With newer AEDS Voltage-gated Ca+ channel ○ More specificity Gabapentin ○ Less side effects Pregabalin Why is there a need for “new” AEDs? K+ channels Retigabine ○ More effective Phenobarbital ○ Different mechanism of action: more selective AMPA receptors Topiramate Better tolerated Lamotrigine Less side effects Safer ○ Better for women: less teratogenicity Drugs highlighted by Dr. Baroque for the quiz: ○ Less interactions with other drugs ○ Lamotrigine and Lacosamide are also CRN2 inhibitors Have dual activities 1.9.4. NEWER AEDs ○ Lamotrigine has 3 MOAs: Voltage-gated Na+ channels Newer AEDs Voltage-gated Ca++ channel Drug Brand Name Discoverer AMPA receptors ○ Ethosuximide is used in certain types of seizure disorders Felbamate Wallace ○ Retigabine is not always used in practice but may be FelbatolTM asked in exams as it is the only K+ channel blocker NeurontinTM ○ SV2A MOA Gabapentin Pfizer Inhibits vesicle to bind to the membrane to prevent Lamotrigine LamictalTM GSK exocytosis of vesicle-containing neurotransmitters Topiramate TopamaxTM Ortho-McNeil Tiagabine GabitniTM Cephalon Levetiracetam KeppraTM UCB Pharma Oxcarbazepine TrileptalTM Novartis Zonisamide ZonegranTM Elan Pharma Lacosamide VimpatTM Abbott Pharma 1.9.5 ACCORDING TO ITS MECHANISM OF ACTION Fig 10. Different types of Membrane Junctions. GABAergic Interneuron (on the left of figure) Mechanisms to increase GABA inhibitory activity: ○ Block GABA transporter by giving Tiagabine to Fig 9. Mechanism of action of antiepileptic drugs with receptors. prevent GABA reuptake from the synaptic cleft ○ Decrease GABA transaminase by giving Vigabatrin to MECHANISMS OF ACTION prevent breakdown of GABA Receptor Drug ○ Increase GABAA receptor activity by giving Benzodiazepines (DMCL) Synaptic vesicle proteins (SV2A) Levetiracetam Diazepam Collapsin-response mediator Lacosamide Midazolam Let's capy-talize on our learning with these awesome notes! | 6 PHARMACOTHERAPEUTICS | Antiepileptic Drugs, Anti-Parkinson Drugs, Drugs for Alzheimer Disease Clonazepam Lorazepam NMDA receptor antagonism INHIBITION OF Felbamate EXCITATORY AMINO 1.10. THE CYTOCHROME P450 ISOZYME SYSTEM ACIDS OR AMPA and kainate receptor Enzymes most involved with drug metabolism NEUROTRANSMISSION antagonism Enzymes have broad substrate specificity Topiramate Individual drugs may be substrates for several enzymes Principally involved with AED metabolism: INHIBITS SYNAPTIC Levetiracetam ○ CYP2C9 VESICULAR PROTEIN 2A ○ CYP2C19 ○ CYP3A 1.12. CLINICAL SPECTRUM OF ACTIVITY OF AEDs 1.10.1 HEPATIC ENZYME INDUCERS/INHIBITORS GTC & ABSENCE MYOCLONI Inducers AED PARTIAL C ○ Increase clearance of other drugs ○ Decrease steady-state concentration of other drugs PHENYTOIN + 0 0 Inhibitors ○ Decrease clearance of other drugs CARBAMAZEPINE + 0 0 ○ Increase steady-state concentrations of other drugs OXCARBAZEPINE + 0 0 Phenobarbital Phenytoin + + + (may Carbamazepine LAMOTRIGINE worsen in INDUCERS some) Oxcarbazepina (CYP3A4, UGT’s) Lamotrigine (UGT’s) Topiramate (CYP3A4) ZONISAMIDE + ?+ 0 Valproic acid PHENOBARBITAL + 0 + INHIBITORS Oxcarbazepine (CYP2C19) Topiramate (CYP2C19) VALPROATE + + + Gabapentin Levetiracetam TOPIRAMATE + 0 + Ethosuximide Neither inducer nor Zonisamide LEVETIRACETAM + ?+ 0 inhibitor of CYP system Vigabatrin Tiagabine + 0 0 Lacosamide (potential for CYP2C9 inhibition (Adjunct in LACOSAMIDE but no drug interaction noted) partial seizures) Oxcarbazepine and Topiramate can be BOTH inducer and inhibitor depending on the CYP enzyme ETHOSUXIMIDE 0 + 0 ○ bOTh + (in partial 0 0 1.11. AEDs MECHANISM OF ACTION GABAPENTIN seizure) ?+ (in GTC) Carbamazepine Oxcarbazepine + (in partial 0 0 Phenytoin PREGABALIN seizure) REDUCTION OF Na+ ?+ (in GTC) Zonisamide CONDUCTANCE Lamotrigine Primidone CLONAZEPAM + ? + Lacosamide Phenobarbital 1.13. PHARMACOKINETICS OF AED Valproic Acid Most undergo complete/nearly complete absorption when ENHANCEMENT OF given orally Tiagabine POST - SYNAPTIC GABA ○ 80-100% Vigabatrin MEDIATED CURRENT ○ Calcium containing antacids may interfere with BZD (Diazepam, Clonazepam) phenytoin absorption Most (with exceptions) are not highly bound to plasma Gabapentin proteins REDUCTION OF CA++ Cleared chiefly by hepatic mechanisms (with exceptions) Pregabalin CURRENT Many converted to active metabolites with same clearance Ethosuximide Almost all anti-seizure drugs are used as mood stabilizers Has effect in improving mood Let's capy-talize on our learning with these awesome notes! | 7 PHARMACOTHERAPEUTICS | Antiepileptic Drugs, Anti-Parkinson Drugs, Drugs for Alzheimer Disease Exception: Levetiracetam (Aggravates mood changes) ADVERSE EFFECTS: ADVERSE EFFECTS OF PHENYTOIN ○ CNS: sedation, dizziness, ataxia Due to decrease in excitation in the brain → DOSE DEPENDENT DOSE INDEPENDENT somnolence 20 - 30 ug/mL: Gingival hyperplasia, nystagmus and ataxia Hirsutism, Skin rashes 1.14. PHENYTOIN 30 - 40 ug/mL: mental ○ Indicate hypersensitivity Oldest non-sedating drug used for treatment of epilepsy changes, lethargy, of the patient to the drug Mechanism of Action: Blocks voltage-gated sodium channels and dysarthria Fetal hydantoin Syndrome ELIMINATION AND METABOLISM 40 ug/mL: stupor ○ Craniofacial abnormality, ○ Nonlinear nail and digital Elimination kinetics shift from first order to zero Others: hypoplasia, order at moderate to high dose levels ○ Osteomalacia microcephaly, mental ○ Enhanced in the presence of inducers of liver ○ Cardiac retardation metabolism (e.g. Phenobarbital, Rifampicin) arrhythmia ○ Inhibited by other drugs (e.g. Cimetidine, Isoniazid) Carbamazepine increases metabolism of phenytoin Most common: Chloramphenicol, dicumarol, isoniazid, disulfiram, cimetidine, and some sulfonamides decrease Diplopia and ataxia metabolism of phenytoin Requires dosage ○ Extensively bound to albumin (90%) adjustment ○ Due to high protein binding, it has a low volume of distribution ○ Prone to displacement by variety of factors: 1.15. CARBAMAZEPINE Hyperbilirubinemia Drugs such as warfarin, valproic acid, phenylbutazone, sulfonamides = these drugs compete with phenytoin for binding to plasma proteins leading to toxicity Fig 12. Carbamazepine structure. Related chemically to tricyclic anti-congestants Drug of choice for trigeminal neuralgia Peak concentration after: 4-8 hours Converted to carbamazepine 10,11 epoxide ○ Has anticonvulsant activity Mechanism of action: reduction of Na+ conductance 1.15.1. ADVERSE EFFECTS Dose related toxicity ○ CNS Fig 11. Effect of Dose on AED Pharmacokinetics. Drowsiness Dizziness NOTE FROM LECTURER: Study the relationship of dose and Diplopia clearance in terms of linearity. Ataxia Nonlinear ○ Mild GI upsets ○ Decreases with dose: phenytoin, valproic acid ○ Hyponatremia ○ Increases with dose: Lamotrigine ○ Water intoxication Linear: Felbamate, Levetiracetam oxcarbazepine, topiramate, Cardiac arrhythmia zonisamide Idiosyncratic reaction ○ Erythematous skin rash ○ Stevens–Johnson syndrome (most common) ○ Blood dyscrasia in elderly patients Aplastic anemia Agranulocytosis ○ Hepatic dysfunction Teratogenicity Let's capy-talize on our learning with these awesome notes! | 8 PHARMACOTHERAPEUTICS | Antiepileptic Drugs, Anti-Parkinson Drugs, Drugs for Alzheimer Disease ○ Carbamazepine 0-2% ○ Phenytoin 9-15% ○ Megaloblastic anemia (responds to folate) ○ Phenobarbital 14% IDIOSYNCRATIC 1.16. OXCARBAZEPINE Skin rash, exfoliative dermatitis (rare); hepatotoxicity A keto-analog of carbamazepine Less potent than carbamazepine Mechanism of action is same as carbamazepine 1.18. VALPROIC ACID Dosage may need to be 50% higher than CBZ to obtain equivalent seizure control 1.17. PHENOBARBITAL Fig 14. Valproic Acid Structure. “Broad spectrum AED” Initially developed for Bipolar Mood Disorders (Dr. Baroque, 2024) Serendipitously discovered Nonlinear pharmacokinetics due to saturable protein binding ○ Similar with phenytoin Fig 13. Model of GABAA receptor-chloride ion channel macromolecular Metabolites have potent antiseizure activity complex. In pregnancy: ○ Neural tube defects (spina bifida) CV, orofacial and Barbituric acid derivative digital abnormalities in offspring Oldest of the currently available antiseizure/antiepileptic ○ HIGHLY Teratogenic drugs (sedating) ○ No longer a first choice in the developed world because 1.18.1. ADVERSE EFFECTS of its sedative properties and many drug interactions INEXPENSIVE DOSE RELATED One of the first line drugs used in status epilepticus ○ “We use the IV preparation, not an oral preparation” (Dr. Transient GI symptoms (most common): anorexia, nausea, Baroque, 2024) vomiting, heartburn Still useful for neonatal seizures CNS: sedation, ataxia, and tremor Oral bioavailability 100% Increase in appetite, weight gain Maintenance doses: do not achieve a steady state level until ○ Weight gain is not from the drug itself but from the 2-3 weeks due to long elimination half life increased appetite. Advise patients to be more active, ○ Even though oral bioavailability is at 100%, the long have more exercise and to eat appropriately half-life may prevent immediate epileptic control – a Hyperammonemia, alopecia problem for most patients and clinicians IDIOSYNCRATIC 1.17.1. CLINICAL USES Useful in the treatment of focal seizures Elevation of hepatic enzymes; hepatotoxicity (fulminant ○ Generalized tonic-clonic seizures hepatitis) ○ Repeat ALT, AST test after 3-6 months or 1 year 1.17.2. ADVERSE EFFECTS depending on their response to medication and hepatic enzymes DOSE RELATED Thrombocytopenia Rash Sedation - most common but tolerance develops with Acute pancreatitis chronic intake Polycystic Ovarian Syndrome Nystagmus and ataxia at excessive dosage Teratogenicity: neural tube defects (spina bifida), CV, Cognitive and behavioral effects orofacial, and digital abnormalities ○ Children: irritability and paradoxic hyperactivity ○ Elderly: agitation and confusion Chronic Use: ○ Osteomalacia with chronic therapy (responds to high doses of vitamin D) Let's capy-talize on our learning with these awesome notes! | 9 PHARMACOTHERAPEUTICS | Antiepileptic Drugs, Anti-Parkinson Drugs, Drugs for Alzheimer Disease 1.19. ETHOSUXIMIDE ○ Behavioral symptoms are commonly seen in elderly patients; MOA for this adverse reaction is poorly understood (Dr. Baroque, 2024) 1.21. GABAPENTIN Fig 15. Ethosuximide Structure. Oral bioavailability 100% Peak concentration after 3-7 hours Not protein bound Fig 16. Gabapentin Structure Completely metabolized to inactive metabolites Not an inducer or inhibitor of CYP enzyme Oral bioavailability is dose dependent Used for treating generalized absence seizures ○ 60% at doses ≤ 1800 mg/day ○ 35% at doses > 3600 mg/day 1.19.1 ADVERSE EFFECTS Not metabolized Does not induce hepatic enzymes (drug-drug interactions DOSE RELATED negligible) Not bound to plasma proteins Gastric distress (pain, nausea, vomiting) - most Commonly used for neuropathic disorders (i.e. anxiety) with common some antiepileptic properties CNS: lethargy, euphoria, hiccup, dizziness, Parkinson-like symptoms 1.22. PREGABALIN ○ Parkinson-like symptoms: rigidity, tremors, bradykinesia, sometimes postural instability IDIOSYNCRATIC (Rare) Skin rash Stevens-Johnson Syndrome Blood dyscrasia 1.20. LEVETIRACETAM Rapidly and completely absorbed, unaffected by food Peak plasma concentration 1.3 hours Fig 17. Pregabalin Structure Linear kinetics Not metabolized by Cytochrome P450, excretion mainly Structural analogue of Gabapentin (same MOA) renal ○ “Cousin of Gabapentin” Devoid of known interactions with other antiepileptics ○ Greater potency in animal models of epilepsy, pain and Excellent seizure control for almost all kinds of seizures anxiety except for absence seizures ○ Better bioavailability 90% Not metabolized; Not an inducer or inhibitor (same as 1.20.1 ADVERSE EFFECTS Gabapentin) Not bound to plasma proteins DOSE RELATED No drug-drug interactions Excreted unchanged in urine Somnolence Dizziness 1.22.1 ADVERSE EFFECTS OF PREGABALIN & GABAPENTIN Ataxia DOSE RELATED IDIOSYNCRATIC Headache Behavioral symptoms, particularly common in children Dizziness ○ Emotional lability, depression, anxiety, aggression, Somnolence agitation, hostility, oppositional behavior Ataxia Fatigue Let's capy-talize on our learning with these awesome notes! | 10 PHARMACOTHERAPEUTICS | Antiepileptic Drugs, Anti-Parkinson Drugs, Drugs for Alzheimer Disease 1.23. TOPIRAMATE GI Symptoms: Nausea vomiting CNS: Dizziness, headache, diplopia, somnolence NON-DOSE RELATED Skin rash, Stevens-Johnson Syndrome Aplastic anemia → Pancytopenia 1.25. ZONISAMIDE Fig 18. Topiramate Structure Rapidly absorbed with 80% bioavailability Linear kinetics No active metabolites, renal excretion Uses: other seizure types such as Lennox-Gastaut syndrome, West’s syndrome, Migraine headaches 1.23.1. ADVERSE EFFECTS DOSE RELATED Fig 20. Zonisamide Structure Somnolence, dizziness, fatigue Sulfonamide derivative Cognitive slowing, confusion Almost completely absorbed after oral administration Weight Loss Good bioavailability ○ Can be differentiated from other medications that Linear kinetics cause increase in appetite Does not interact with other antiepileptic drugs Paresthesias Urolithiasis 1.25.1 ADVERSE EFFECTS IDIOSYNCRATIC DOSE RELATED Angle-closure glaucoma Drowsiness, somnolence, ataxia Myopia Difficulty concentrating, word finding difficulty Anorexia, Nausea, Vomiting Renal Calculi 1.24. LAMOTRIGINE IDIOSYNCRATIC Skin rash Blood dyscrasia 1.26. LACOSAMIDE Fig 19. Lamotrigine Structure Completely absorbed from the GIT Drug Interactions ○ With enzyme inducers: ½ life DECREASED to 13-15 hours Fig 21. Lacosamide Structure ○ With enzyme inhibitors: ½ life INCREASED to 60 hours 100% Oral bioavailability Linear Kinetics Linear pharmacokinetics Half-life: 13 hours 1.24.1 ADVERSE EFFECTS Time to Steady State: 2-3 days Not associated with any significant pharmacokinetic DOSE RELATED interactions Low protein binding Metabolites not pharmacologically active Let's capy-talize on our learning with these awesome notes! | 11 PHARMACOTHERAPEUTICS | Antiepileptic Drugs, Anti-Parkinson Drugs, Drugs for Alzheimer Disease 1.26.1. ADVERSE EFFECTS 1.28. CONVULSIVE STATUS EPILEPTICUS STATUS EPILEPTICUS (pp. 433, Katzung) COMMON Clinically defined as abnormally prolonged or repetitive seizures. CNS: Drowsiness, Headache, Balance disorder, Memory Presents in several forms: impairment, Somnolence, Tremor, Nystagmus ○ Convulsive status epilepticus: consisting of repeated Eyes: Diplopia, blurred vision generalized tonic-clonic seizures with persistent postictal GI Symptoms: Nausea, vomiting, constipation, flatulence depression of neurologic function between seizures Depression life-threatening emergency that requires immediate treatment defined as more than 30 minutes of either CARDIAC continuous seizure activity or more sequential seizures without full recovery of consciousness INCREASED PR Interval between seizures ○ Especially with co-administration with carbamazepine, ○ Nonconvulsive status epilepticus: persistent change in lamotrigine, and pregabalin behavior or mental processes with continuous ○ Even if pregabalin may not induce/inhibit metabolism epileptiform EEG but without major motor signs of other drugs, it still may increase PR interval ○ Focal status epilepticus, with or without altered awareness. Treatment should be begun when the seizure duration 1.27. BENZODIAZEPINES reaches 5 minutes for generalized tonic-clonic seizures and ★ MECHANISM OF ACTION: Enhancement of postsynaptic GABA 10 minutes for focal seizures with or without impairment of consciousness. Table 3. Pharmacokinetics and Pharmacodynamics of Benzodiazepines Initial treatment of choice: benzodiazepine DRUG PEAK ELIMINATION PLASMA ○ intravenous lorazepam or diazepam BLOOD ½ LIFE PROTEIN ○ intramuscular midazolam LEVEL (hrs) BINDING Lorazepam (hrs) ○ is less lipophilic than diazepam and does not undergo as Parent drug rapid redistribution from brain to peripheral tissues as (24-48) does diazepam. Diazepam 1-2 99 N-desmethyl 1.28.1 CAUSES diazepam If possible: get blood glucose and electrolytes ○ To know if the seizure is due to hypo- or hyperglycemia 60 hrs ○ Most important lab test: CBC, Urinalysis, and Na Midazolam 1-3 1-9 95 Hyponatremic patients may have seizures ○ Note: low potassium levels causes weakness and does Clonazepam 1-4 20-60 (30) 86 not normally alter sensorium Lorazepam 1-6 10-20 (14) 85-90 5 TO 20 MINS: INITIAL THERAPY PHASE Choose ONE of the following 1.27.1. DIAZEPAM Intramuscular Midazolam N-desmethyldiazepam, major metabolite less active than Intravenous Lorazepam parent drug; may behave as partial agonist Intravenous Diazepam Widely distributed to tissues Not given intramuscularly: causes problems in the skin and Effective for status epilepticus (IV) but short duration of muscle action due to rapid redistribution of the drug from the Give 5 mg for the first 5 mins brain Max: 20 - 30 mg/DAY (if max dose is reached, it won’t be ○ First line drug for status epilepticus while stabilizing effective → switch to Midazolam) patient Not useful as an oral agent for seizure disorder If first line drugs are not available, choose one of the ff: ○ Due to tolerance and dependence Intravenous phenobarbital ★ Preparation: tablet, IV, rectal (for children) ➤ Patient should be intubated first 1.27.2 MIDAZOLAM Rectal Diazepam Preparation of IV form Intranasal Midazolam Normally reserved until the end 20 TO 40 MINS: SECOND THERAPY PHASE ★ Diazepam → anti-epileptic drugs with IV preparation → IV fosphenytoin Midazolam drip ○ 20 mg/kg, max: 1,500 mg/dose Drip used so the brain is silent IV valproic acid ○ 40 mg/kg, max: 3,000 mg/dose 1.27.3 CLONAZEPAM IV levetiracetam Avoided as much as possible due to increased tendency in ○ 60 mg/kg, max: 4,500 mg/dose dependence and tolerance IV phenobarbital ○ 15 mg/kg, single dose 40 TO 60 mins: THIRD THERAPY PHASE Let's capy-talize on our learning with these awesome notes! | 12 PHARMACOTHERAPEUTICS | Antiepileptic Drugs, Anti-Parkinson Drugs, Drugs for Alzheimer Disease Repeat 2nd line therapy or anesthetic doses of either 1.30. AEDs IN PREGNANCY thiopental, midazolam, phenobarbital, or propofol For women with epilepsy (WWE) taking AEDs, no substantial ○ With continuous ecg monitoring increased risk ○ Cesarean delivery ○ Late pregnancy bleeding ○ Premature contractions ○ Premature labor and delivery ○ Status epilepticus, pre-eclampsia, pregnancy-related hypertension, or spontaneous abortion Rate of remaining seizure free during pregnancy if WWE are seizure free for at least 9 months to 1 year prior to pregnancy is probably 84-92% Major congenital malformations ○ 20% for valproic acid - neural tube defects (spina bifida), facial clefts, hypospadias ○ 11% for phenytoin - cleft palate ○ 8.0% for carbamazepine - posterior cleft palate ○ 6.1% for phenobarbital - cardiac malformation ○ 1.0% for lamotrigine 1.31. RISKS FOR SEIZURES DURING PREGNANCY About ⅔ of the women were seizure free during their pregnancy Seizure frequency is unchanged in the majority (70%) of the women during pregnancy Approximately 12% have fewer seizures and a slightly higher percentage have more seizures during pregnancy 1.32. WHY DO SEIZURES INCREASE DURING PREGNANCY Clearance of older medications (Pb, PHT, CBZ, and VA) increases during pregnancy by 10-55% Oxcarbazepine levels also tend to increase during pregnancy however carbamazepine levels do not ○ Carbamazepine is preferred over oxcarbazepine Of the new anti-seizure medications, lamotrigine and levetiracetam are the most widely used due to their known safety during pregnancy Fig 22. Proposed Algorithm for Status Epilepticus. ★ Best anti AED for pregnant women: Levetiracetam 1.29. SUMMARY OF PK DATA OF AEDs 1.33. OTHER THERAPEUTIC INDICATIONS OF AEDs NEUROPATHIC Gabapentin PAIN Pregabalin Carbamazepin Valproate MIGRAINE Topiramate Gabapentin Levetiracetam Phenytoin BIPOLAR Carbamazepine DISORDERS Valproate Lamotrigine ★ Note: in mood or bipolar disorders, almost all anti seizure medications can be used as a mood stabilizing agent EXCEPT levetiracetam DIABETES Carbamazepine INSIPIDUS Fig 23. Summary of Pharmacokinetic Data of AEDs. ANXIETY Gabapentin DISORDERS Pregabalin Let's capy-talize on our learning with these awesome notes! | 13 PHARMACOTHERAPEUTICS | Antiepileptic Drugs, Anti-Parkinson Drugs, Drugs for Alzheimer Disease PATHWAY medial neurons that project to different output structures Believed to have opposite effects on movement Substantia nigra transiently produces excitatory inputs into the caudate and the putamen Transiently inhibitory projections of the caudate and the putamen project to tonically active inhibitory neurons in the internal segment of the globus pallidus ○ In turn, projects into the ventro-anterior and ventrolateral complex of the thalamus Followed by transient excitatory inputs projected to the premotor cortex ★ It may seem complicated but this is the target Fig 24. Summary of mode of action (AEDs). of the pharmacologic interventions because the problem in Parkinson’s is dopaminergic 2. DRUGS FOR PARKINSON’S DISEASE which comes from the substantia nigra 2.1. OVERVIEW ON PARKINSON DISEASE Also known as paralysis agitans Transiently active inhibitory neurons from Neurologic disorder that results in progressive loss of the caudate and the putamen project to coordination and movement (neurodegenerative) tonically active inhibitory neurons of the Micrographia external segment of the globus pallidus which ○ 1919 - Hitler’s condition was apparent by the lack of is short-circuiting the internal segment of the movement in his left arm globus pallidus ○ 1943 - Dr. Abraham Lieberman studied about 300 hours Influence of nigral dopaminergic inputs to of videos on Hitler and declared that the first symptom of neurons in the indirect pathway is inhibitory Hitler’s condition was apparent in 1934 (age 45) INDIRECT Globus pallidus externa projects to the ○ 1944 - Around 1940 (age 51), Hitler was diagnosed by his PATHWAY subthalamic nucleus which also receives doctors as having Parkinson Disease strong excitatory input from the cortex. ○ Many neurologists believe that Hitler had lost the ability to The subthalamic nucleus projects into the reason and grasp quickly due to his disease and this in globus pallidus interna where its transiently part contributed to the down of Germany excitatory drive acts to oppose the disinhibitory action of the direct pathway 2.1.1. PATHOPHYSIOLOGY OF PARKINSON DISEASE The indirect pathway modulates the effects of Basal Ganglia System the direct pathway ○ A collection of neurons, which does not generate movements but rather modulates them ○ It consists of the: Caudate nucleus (GABA, Inhibitory) Putamen (GABA, Inhibitory) Globus pallidus interna and externa (GABA, Inhibitory) Subthalamic nucleus (Glutamate, Stimulatory) Substantia nigra (Dopamine) D1 receptor - Stimulatory D2 receptor - Inhibitory ○ Subcortical nuclei which control voluntary actions ○ Target of the pharmacologic action Two circuits of the Basal Ganglia Function: Direct nd Indirect Pathways ○ Direct Pathway = “Dance”; it makes you move ○ Indirect Pathway = Inhibitory; makes you stop moving Has a connection from subthalamic nucleus of Luy’s and substantia nigra Fig 25. Direct and indirect pathway of the Basal Ganglia System. ★ The problem with PD is in the substantia nigra pars (PowerPoint slides of Dr. Baroque) compacta ○ Produces dopamine Dopaminergic neuronal degeneration ○ Affected by the inhibitory pathway ○ at the site of the substantia nigra ○ decreased activity in the direct pathway and increased Table 4. Pathways of basal ganglia activity in the indirect pathway ○ thalamic input to the motor area of the cortex is reduced TWO CIRCUITS OF THE BASAL GANGLIA FUNCTION Mnemonic: TRAP ○ T - Tremor: shaking, usually starting on one side DIRECT Originates from distinct populations of striatal ○ R - Rigidity: stiffness of the limbs, neck, and trunk Let's capy-talize on our learning with these awesome notes! | 14 PHARMACOTHERAPEUTICS | Antiepileptic Drugs, Anti-Parkinson Drugs, Drugs for Alzheimer Disease ○ A - Akinesia: loss or impairment power of voluntary movement ○ P - Posture and balance 2.1.2. PHARMACOLOGIC THERAPY IN PARKINSON’S DISEASE Tyrosine → L-Dopa → Dopamine Dopamine is then released in the synaptic cleft where it is either degraded or undergoes reuptake ○ Medications for Parkinson’s disease targets the DA synthesis, degradation, receptor site, or reuptake Fig 28. Histological findings of brain tissues in normal and pathologic case. Fig 28 explanation: The presence of Louis bodies gives the pathologic diagnosis of parkinsonism Comparing the substantia nigra from a gross specimen of a normal versus a diseased state, the substantia nigra is much paler in the case of the latter. Healthy patients: Substantia nigra (black arrows, Image A) is seen as darkly-stained areas. ○ Histologically, numerous healthy neurons are observed (Image C). Parkinson's Disease Patient (Image B): Previously darkly stained substantia nigra are no longer observed due to the accelerated degeneration of the substantia nigra neurons ○ Accumulation of alpha-synuclein in Lewy Bodies (Image Fig 26. Parkinson Disease Pathophysiology (Kaztung). E) Products of metabolic activities of the cells which are Fig 26 explains that no dopamine signals comes from the supposed to be cleared. substantia nigra Due to genetic influences, there is accumulation in ○ Cholinergic effects if ACh dominates excessive amounts causing stress to the neurons and promoting premature death (apoptosis). Fig 29. Accumulation of Alpha-Synuclein. Fig 27. Balance of acetylcholine and dopamine in the CNS. In Parkinson Disease, there is an abnormal deposition of Fig 27 explanation: alpha-synuclein B: Since there is a decrease in dopamine, there is a ○ Alpha-synuclein - cause of the premature death of subsequent increase in acetylcholine. Since acetylcholine is neurons in substantia nigra (molecular graveyard) increased, that would trigger tremors and worsen rigidity Lewy bodies (inclusion bodies containing C: the goal of antiparkinson drugs is to increase dopamine to alpha-synuclein) in fetal dopaminergic cells decrease Ach binding in the receptor site transplanted into the brain of patients with Parkinson’s suggest that it may be a prion disease Alpha-synuclein nucleopathy: exaggerated levels of the protein = Parkinson’s disease Let's capy-talize on our learning with these awesome notes! | 15 PHARMACOTHERAPEUTICS | Antiepileptic Drugs, Anti-Parkinson Drugs, Drugs for Alzheimer Disease and modulate motor activity The projections follow a pathway to the striatum, know as the “nigrostriatal pathway” Motor symptoms appear after approximately 50% loss of the neurons in this region “Parkinsonism” - mimic Parkinson Disease not a neurodegenerative disease (e.g. stroke in the basal nuclei) Dopamine is known to be the neurotransmitter most critically involved in PD 2.1.4. CLINICAL PRESENTATION Parkinsonism is a clinical syndrome and typically when the condition appears to be idiopathic and responsive to levodopa therapy, is referred to as Parkinson’s disease Fig 30. Accumulation of Alpha-Synuclein. The Four Cardinal Features of Parkinsonian syndrome are: (TRAP) Several factors may lead to accumulation: ○ Resting Tremor ○ Reactive oxygen species: CNS events ○ Muscular Rigidity Head injury: most common mechanism; increases ○ Akinesia/Bradykinesia ROS = inc in a-synuclein ○ Postural instability and gait impairment Paraquat These features are not always observed in every patient, at Permethrin any given time Dieldrin Cognitive decline occurs in many patients as the disease Metals advances Pathogen ○ Non-motor symptoms include: ○ Aging - inhibits proper clearance and promote more Affective disorders (anxiety and depression) aggregation Confusion ○ Genetic factors - are important especially when disease Cognitive impairment occurs more than 50 years old. Genetic mutations Personality changes include: Apathy Fatigue Mutations of the alpha-synuclein gene at 4q21 or Abnormalities of autonomic function (sphincter or duplication and triplication of the normal synuclein sexual dysfunction, dysphagia and choking, sweating gene - referred to as synucleinopathy abnormalities, sialorrhea, or disturbances of blood Mutations of the leucine-rich repeat kinase 2 pressure regulation) (LRRK2) gene at 12cen, and the UCHL1 gene may ○ Sleep disorders also cause autosomal dominant parkinsonism ○ Sensory complaints or pain - Incurable, progressive and Mutations in the parkin gene (6q25.2-q27) cause leads to increasing disability early-onset autosomal recessive, familial ○ Pharmacologic treatment may relieve motor parkinsonism, or sporadic juvenile-onset ○ symptoms and improve quality of life parkinsonism 2.1.5. CLINICAL STAGES AND TIME OF COURSE OF PROGRESSION In diagnosing patients with Parkinson Disease, it takes 10 - 20 years before symptoms show up Types of Parkinsonism. ○ Young onset:
