Medication Related Movement Disorders PDF

Medication related movement disorders  MRMDs represent a diverse group of neurological conditions triggered by the use of certain medications. These disorders can significantly impact an individual's quality of life, often necessitating prompt recognition and management.  Dyskine...

Medication related movement disorders  MRMDs represent a diverse group of neurological conditions triggered by the use of certain medications. These disorders can significantly impact an individual's quality of life, often necessitating prompt recognition and management.  Dyskinesia Derived from Greek: Kinesi refers to motion, movement or action Dys- meaning negation Voluntary muscle control is impaired Dystonia is a movement disorder that causes the muscles to contract involuntarily Akathisia—loss of voluntary muscle control (unable to sit still) History of Drug-Induced Movement Disorders Early in the1960s, doctors were prescribing neuroleptic drugs to treat schizophrenia Noticed patients experienced small, repetitive and compulsive movements (facial muscles) This drug-induced disorder was recognized in 1964 and termed Tardive Dyskinesia History of Drug-Induced Movement Disorders Metoclopramide for acid reflux and gastroparesis Tardive dyskinesia emerged as a side-effect of Metoclopramide treatment Clinical Observations Lead to Common Connection Neuroleptics and Metaclopride common pharmacology, namely Dopamine Correlation of dyskinesia with strength of D2 antagonism PET(A positron emission tomography) images of dopamine D2 type receptors There are high levels of D2 receptors (red color) in deep brain structures and lower levels in the cortex. These include the basal ganglia and thalamus (A) Amygdala and temporal cortex (B) Substantia nigra (C). These regions are concerned with movement, emotion and cognition. The Basal Ganglia The Basal Ganglia The basal ganglia are a group of brain structures linked together, handling complex processes that affect your entire body. Play a role in controlling your body's ability to move Play a role in several other functions, such as learning, emotional processing  The basal ganglia are a cluster of subcortical nuclei deep to cerebral hemispheres. The largest component of the basal ganglia is the corpus striatum which contains the caudate and lenticular nuclei (the putamen, globus pallidus externus, and internus), the subthalamic nucleus (STN), and the substantia nigra (SN). Parkinson Disease (PD)Movement Disorder More than 10 million people worldwide are living with PD. The incidence of Parkinson's disease increases with age, but an estimated four percent of people with PD are diagnosed before age 50. Men are 1.5 times more likely to have Parkinson's disease than women.  Parkinson's Disease (PD) Definition: A neurodegenerative disorder caused by the progressive loss of dopamine- producing neurons in the substantia nigra. Primary Cause: Idiopathic (unknown cause); genetics and environmental factors contribute. Parkinson's Disease (PD) Core Symptoms (Motor):Tremor at rest (often asymmetrical) Rigidity (stiffness) Bradykinesia (slowness of movement) Postural instability (later stages) Parkinson's Disease (PD) Non-Motor Symptoms: Depression, cognitive decline, sleep disturbances, and autonomic dysfunction (e.g., constipation, orthostatic hypotension). Progression: Slow and progressive over years. Treatment: Primarily dopamine replacement therapy (e.g., levodopa) and other medications (e.g., dopamine agonists). Parkinsonism Definition: An umbrella term for conditions that cause symptoms similar to Parkinson’s disease, including tremor, rigidity, and bradykinesia, but have other underlying causes. Parkinsonism Types: Drug-induced Parkinsonism: Caused by medications (e.g., antipsychotics, antiemetics). Atypical Parkinsonism: Includes multiple system atrophy (MSA) and corticobasal degeneration (CBD). Vascular Parkinsonism: Caused by multiple small strokes affecting basal ganglia. Parkinsonism Symptoms: Similar to PD, but may be symmetrical and less responsive to levodopa. Key Differences: Faster progression and often includes additional atypical symptoms (e.g., early falls, dementia, gaze palsy). Treatment: Depends on the underlying cause. Stopping causative drugs or managing underlying disease is often required. Aspect Parkinson’s Disease Parkinsonism Idiopathic, Drugs, strokes, or Cause neurodegeneration other diseases Usually Symmetry of asymmetrical Often symmetrical Symptoms initially Response to Good response Poor or no response Levodopa Faster (in atypical Progression Gradual over years forms) Early cognitive or Additional Cognitive symptoms motor symptoms in Symptoms later in disease atypical cases  Parkinson's Disease (PD) Clinical Manifestations Tremor Rest tremor (unlike action tremor when affected limb is being used) Unilateral in hand. Spreads contralaterally as the disease progresses Tremor can be in legs, lips, jaw, tongue, rarely in the head Clinical Manifestations Bradykinesia Slowness of movement (major cause of disability) Starts distally…buttoning clothes, tying shoelaces, double clicking mouse In legs, results in dragging or shuffling steps Levodopa (L-DOPA) Levodopa (L-DOPA) is the mainstay treatment for Parkinson’s disease (PD) and other parkinsonian syndromes. It is the most effective medication for controlling motor symptoms, especially bradykinesia (slowness of movement), rigidity, and tremors. long-term use is associated with complications like motor fluctuations and dyskinesias. Mechanism of Action Levodopa is a dopamine precursor that crosses the blood-brain barrier (BBB), where it is converted into dopamine by the enzyme dopa decarboxylase. Dopamine itself cannot cross the BBB, so levodopa administration is required to increase brain dopamine levels. It restores the depleted dopamine levels in the substantia nigra and striatum in Parkinson’s disease. Pharmacokinetics Absorption: Rapidly absorbed from the small intestine. Distribution: Levodopa crosses the BBB, but only 1-3% reaches the brain if given alone. Metabolism:Peripheral metabolism by dopa decarboxylase and catechol-O- methyltransferase (COMT) reduces levodopa availability in the brain. Co-administration with Carbidopa (a peripheral dopa decarboxylase inhibitor) or Benserazide enhances the availability of levodopa in the CNS. Combination with Carbidopa/Benserazide Levodopa is almost always combined with Carbidopa or Benserazide to prevent its premature conversion to dopamine in peripheral tissues. This combination:Increases the amount of levodopa reaching the brain. Reduces peripheral side effects like nausea and vomiting.Common formulations: Sinemet (Levodopa + Carbidopa), Madopar (Levodopa + Benserazide). levadopa Clinical Uses 1.Parkinson’s Disease – First-line treatment for motor symptoms, especially in older patients. 2.Parkinsonian syndromes (e.g., post-encephalitic parkinsonism, multiple system atrophy). 3.Restless Legs Syndrome (off- label use). Adverse Effects---- levadopa Peripheral Side Effects (due to dopamine outside the brain): Nausea and vomiting: Reduced by using Carbidopa/Benserazide. Orthostatic hypotension: Drop in blood pressure upon standing. Arrhythmias: Rare but possible due to dopamine’s effect on cardiac conduction. Adverse Effects---- levadopa Central Side Effects (due to dopamine in the brain): Dyskinesias: Involuntary, writhing movements occurring with long-term use (peak-dose dyskinesia). Hallucinations and psychosis: More common in elderly patients. Sleep disturbances: Insomnia or vivid dreams. Long-Term Complications —levodopa Motor Fluctuations: Wearing-off phenomenon: Return of symptoms before the next dose. On-off phenomenon: Sudden, unpredictable changes between mobility (“on” periods) and immobility (“off” periods). Dyskinesia:Involuntary movements that typically occur during peak plasma levels of the drug. levodopa Drug Interactions MAO inhibitors (e.g., non- selective MAO inhibitors) can cause hypertensive crisis. Antipsychotics (dopamine antagonists) may reduce the efficacy of levodopa. High-protein meals interfere with levodopa absorption. Levodopa---Precautions and Contraindications Caution in cardiovascular disease: Risk of arrhythmias and hypotension Psychiatric disorders: Risk of exacerbating hallucinations or psychosis. Glaucoma: May increase intraocular pressure in patients with narrow-angle glaucoma. Pregnancy: Levodopa should be used only if the potential benefits outweigh the risks. Strategies to Manage Long-Term Issues 1.Add-on medications: 1.COMT inhibitors (e.g., Entacapone) to prolong levodopa effect. 2.MAO-B inhibitors (e.g., Selegiline, Rasagiline) to reduce motor fluctuations. 2.Switching to controlled-release formulations to reduce "off" periods. 3.Adding dopamine agonists (e.g., Pramipexole, Ropinirole) to lower Carbidopa Carbidopa is a peripheral dopa decarboxylase inhibitor, primarily used in combination with Levodopa to enhance its efficacy in the treatment of Parkinson’s disease. Carbidopa plays a critical role in minimizing the peripheral metabolism of Levodopa, thereby increasing the amount of Levodopa that reaches the brain. MOA----CARBIDOPA Inhibits peripheral dopa decarboxylase, the enzyme that converts levodopa into dopamine outside the brain. Carbidopa does not cross the blood-brain barrier, so it only acts in the peripheral tissues, preventing the breakdown of Levodopa. By inhibiting peripheral conversion, Carbidopa:Increases the amount of Levodopa available to cross the blood-brain barrier. Reduces the peripheral side effects of dopamine, such as nausea, vomiting, and hypotension. CLINICAL USES----- CARBIDOPA Parkinson’s Disease:Always used in combination with Levodopa to enhance its therapeutic effect. Dopa-responsive dystonia: In some cases, it is used off-label with Levodopa. Improves Levodopa bioavailability: Reduces the required dose of Levodopa by 70-75%. Reduces side effects:Nausea, vomiting, and cardiovascular side effects (e.g., CARBIDOPA----ADVERSE EFFECTS Dyskinesias (involuntary movements) Hallucinations and psychosis (especially in older patients) Sleep disturbances such as vivid dreams or insomnia Orthostatic hypotension (less common than with Levodopa alone) Drug Interactions--- CARBIDOPA MAO inhibitors: Risk of hypertensive crisis if used with non-selective MAO inhibitors. Antipsychotics: Dopamine antagonists (e.g., haloperidol) reduce the effectiveness of Carbidopa-Levodopa. Pyridoxine (Vitamin B6): Reduces the efficacy of Levodopa if used without Carbidopa by increasing Precautions and Contraindications-- CARBIDOPA Psychiatric conditions: Use with caution in patients with a history of psychosis.Glaucoma: Avoid in patients with narrow-angle glaucoma.Cardiovascular disease: Monitor for hypotension or arrhythmias. Pregnancy and breastfeeding: Carbidopa-Levodopa should only be used if the benefits outweigh the risks. Tolcapone Tolcapone is a catechol-O- methyltransferase (COMT) inhibitor used as an adjunct to Levodopa/Carbidopa therapy in the treatment of Parkinson's disease. It helps prolong the effect of Levodopa by inhibiting its peripheral and central breakdown, thus improving Tolcapone-----MOA COMT is an enzyme responsible for the breakdown of Levodopa into 3-O-methyldopa (3-OMD), both peripherally and centrally. Tolcapone inhibits COMT, increasing Levodopa's plasma half-life and extending the duration of dopamine availability in the brain. Tolcapone----ADVERSE EFFECTS 1. Common Side Effects Nausea, vomiting, diarrhea Dyskinesia (exacerbated by increased Levodopa levels) Orthostatic hypotension Sleep disturbances 2. Severe Side Effects Hepatotoxicity: Tolcapone has been associated with fatal liver failure. Regular liver function monitoring is mandatory. If there is no improvement in symptoms after 3 weeks, Tolcapone should be discontinued to reduce risk. Dopamine Receptor Agonists Dopamine receptor agonists are drugs that mimic dopamine by directly stimulating dopamine receptors in the brain. These agents play a crucial role in the management of Parkinson’s disease (PD), especially in the early stages or as add-on therapy to Levodopa. They are also used to manage motor fluctuations and reduce "off" periods associated with long-term Levodopa Mechanism of Action-- Dopamine agonists bind to dopamine receptors (primarily D2 and D3 receptors) in the striatum, mimicking the effect of dopamine. Classification of Dopamine Agonists Ergot Derivatives Bromocriptine Cabergoline Pergolide (withdrawn in many countries due to cardiac toxicity) Note: Ergot derivatives are less frequently used due to risks of fibrosis (lung, heart valves) and other side effects. 2. Non-Ergot Derivatives (Preferred due to fewer side effects) Pramipexole Ropinirole Rotigotine (transdermal patch) Apomorphine (used for rescue therapy) Dopamine Agonists— CLINICAL USES 1.Parkinson’s Disease 1. Used as monotherapy in early PD, especially in younger patients to delay the use of Levodopa. 2.Add-on therapy with Levodopa to manage motor fluctuations (e.g., "wearing off" and "on-off" phenomena). 2.Restless Legs Syndrome (RLS) 1.Pramipexole and Ropinirole are FDA- approved for treating moderate to severe RLS. 3.Prolactinomas and Hyperprolactinemia 1.Bromocriptine and Cabergoline are used to lower elevated prolactin levels. Advantages of Dopamine Agonists Delay the need for Levodopa in younger patients with Parkinson’s disease. Reduce "off" time and motor fluctuations when combined with Levodopa. Have longer durations of action than Levodopa, providing smoother symptom control. Adverse Effects Common Side Effects Nausea and vomiting Orthostatic hypotension Drowsiness and fatigue Peripheral edema Adverse Effects Serious Side Effects Impulse control disorders (ICDs): Pathological gambling, hypersexuality, binge eating, and compulsive shopping. Most common with Pramipexole and Ropinirole. Hallucinations and psychosis: More frequent in elderly patients. Ergot derivatives: Risk of fibrosis (e.g., pulmonary, cardiac valve fibrosis). Pergolide was withdrawn due to these risks. Precautions and Contraindications Psychiatric disorders: Use cautiously in patients with a history of psychosis. Impulse control disorders: Monitor for behavioral changes (e.g., gambling, hypersexuality). Cardiac and pulmonary disease: Avoid ergot derivatives in patients with valve disease or pulmonary fibrosis. Orthostatic hypotension: Caution in patients prone to hypotension. Drug Interactions Antipsychotics: Dopamine antagonists can reduce the efficacy of dopamine agonists. Levodopa: When combined, the dose of Levodopa may need to be reduced to avoid dyskinesia. CNS depressants: Concomitant use may increase the risk of sedation. Amantadine:- antiviral drug. It Increases the release of dopamine from Nigrostriatal neurons and also inhibit the reuptake of dopamine by these neurons. Used to treat mild cases of Parkinson’s disease with combination of L-dopa. Less effective than dopamine agonists. Acetylcholine Receptor Antagonists Acetylcholine receptor antagonists, also known as anticholinergics, are a class of drugs used in the management of Parkinsonism help restore the balance between dopamine and acetylcholine in the basal ganglia. These drugs are especially useful for tremor- predominant Parkinson's disease, but their use is limited due to cognitive side effects. MOA---- Acetylcholine Receptor Antagonists In Parkinson’s disease, the loss of dopamine-producing neurons leads to an imbalance between dopamine and acetylcholine, resulting in tremors and other motor symptoms. Anticholinergic drugs block muscarinic acetylcholine receptors (M1 subtype) in the basal ganglia, thereby reducing excess cholinergic activity. This action helps improve tremor and rigidity, although they are less effective against bradykinesia. Commonly Used Acetylcholine Receptor Antagonists 1.Trihexyphenidyl 2.Benztropine 3.Biperiden 4.Procyclidine Clinical Uses 1.Parkinson’s Disease 1.Particularly effective for tremor- predominant Parkinsonism. 2.Used in younger patients to manage tremor and rigidity. 2.Drug-Induced Parkinsonism (Extrapyramidal Symptoms) 1.Used to counteract extrapyramidal side effects (EPS) caused by antipsychotics (e.g., haloperidol, risperidone). 3.Dystonic Reactions 1.Acute dystonia, a form of EPS, is managed with Benztropine or Procyclidine.  1.Central Nervous System Side Effects Cognitive impairment (memory problems, confusion) Sedation and drowsiness Hallucinations and delirium (particularly in elderly patients) 2. Peripheral Side Effects Dry mouth Blurred vision (due to mydriasis and cycloplegia) Constipation Urinary retention Tardive Dyskinesia Tardive Dyskinesia (TD) is a neurological disorder characterized by involuntary, repetitive movements, primarily affecting the face, tongue, and other extremities. These movements often manifest as grimacing, lip smacking, and tongue Tardive Dyskinesia TD is associated with prolonged use of certain medications, particularly antipsychotics, and can be challenging to manage Tardive Dyskinesia TD is most commonly associated with the use of , especially the antipsychotic medications first-generation (typical) antipsychotics like haloperidol and the second-generation (atypical) antipsychotics such as risperidone and olanzapine. The precise mechanism leading to TD is not fully understood, but it is thought to involve dopamine receptor supersensitivity and alterations in neurotransmitter pathways. Tardive Dyskinesia Clinical Features Involuntary Movements: Repetitive, purposeless movements such as facial grimacing, tongue protrusion, and lip smacking. Body Regions Affected: While the face and mouth are commonly affected, TD can also involve the limbs and trunk, leading to choreiform or athetoid movements. Late-Onset: TD often develops after prolonged use of neuroleptic medications, typically after months to years of treatment. Irregular Pattern: Movements in TD may be continuous, but they can also occur intermittently or in a patterned manner. Risk Factors Antipsychotic Use: Long-term use of antipsychotic medications, especially older agents, is a major risk factor for TD. Age: Older individuals are at a higher risk of developing TD. Duration of Medication Use: The longer an individual has been on antipsychotic medications, the greater the risk of TD. Underlying Mental Health Conditions: Certain psychiatric disorders, such as schizophrenia, for which antipsychotics are commonly prescribed, may increase the risk of TD. Diagnosis Clinical Assessment: Diagnosis is primarily based on clinical evaluation, focusing on the presence of characteristic involuntary movements. History: A thorough patient history, including medication use, duration, and dosage, is crucial. Standardized Rating Scales: Various rating scales, such as the Abnormal Involuntary Movement Scale (AIMS), are used to assess the severity of TD. Management and Treatment Medication Adjustment: In some cases, reducing the dosage or discontinuing the offending medication may alleviate symptoms. Switching Medications: Changing to a lower-risk antipsychotic or one less likely to cause TD may be considered. Clozapine: This atypical antipsychotic is associated with a lower risk of TD and may be considered in certain cases. Vitamin E: Some studies suggest that vitamin E may have a protective effect or reduce the severity of TD. Tardive Dyskinesia-specific Medications: Certain medications, such as valbenazine and deutetrabenazine, have been approved for the Prevention of TD Regular Monitoring: Patients on long- term antipsychotic medications should be regularly monitored for signs of TD. Individualized Treatment Plans: Healthcare providers should strive to use the lowest effective dose of antipsychotic medications and consider alternatives when appropriat Akathisia Akathisia is a movement disorder characterized by a subjective feeling of inner restlessness and an irresistible urge to move. It is often accompanied by visible motor symptoms, such as pacing, rocking back and forth, or fidgeting. Akathisia can be a side effect of certain medications, particularly antipsychotics and other drugs that affect the dopaminergic system. Types of Akathisia Acute Akathisia: Develops shortly after initiating or increasing the dose of a medication. Chronic Akathisia: Persists over an extended period and may continue even after discontinuing the causative medication. Tardive Akathisia: Appears after prolonged use of certain medications, similar to tardive dyskinesia. Etiology The exact cause of akathisia is not fully understood, but it is believed to involve dopaminergic imbalances in the central nervous system. Medications that block dopamine receptors, especially in the basal ganglia, are common triggers for akathisia. Clinical Features Restlessness: Individuals with akathisia often experience an intense inner restlessness and a compelling need to move. Motor Symptoms: Observable motor manifestations include pacing, shifting weight from foot to foot, leg swinging, and constant movement. Anxiety: Akathisia can be associated with heightened anxiety, agitation, and emotional distress. Subjective Distress: Patients may describe a sense of "crawling out of their skin" or an inability to sit or stand still comfortably. Risk Factors Medications: Antipsychotic medications, antiemetics (e.g., metoclopramide), and certain antidepressants, especially SSRIs, are common culprits. Dose Increases: Higher doses of triggering medications increase the risk of developing akathisia. Individual Susceptibility: Some individuals may be more Diagnosis Clinical Assessment: Diagnosis is primarily clinical, relying on the patient's reported symptoms and observable motor behavior. Akathisia Rating Scales: Rating scales, such as the Barnes Akathisia Rating Scale, may be used to quantify the severity of akathisia. Management Medication Adjustment: Lowering the dose or discontinuing the causative medication is a primary intervention. Switching Medications: Changing to a different medication with a lower risk of akathisia may be considered. Benzodiazepines: These medications can provide symptomatic relief by calming the central nervous system. Beta-Blockers: Propranolol and other beta-blockers may be effective in managing the physical symptoms of akathisia. Anticholinergic Medications: In some cases, anticholinergic drugs may be prescribed to alleviate symptoms. Prognosis The prognosis for akathisia is generally good if the underlying cause (medication) is identified and appropriately managed. Symptoms usually improve with dose reduction or discontinuation of the offending medication. Drug-Induced Tremors Drug-induced tremors refer to involuntary rhythmic movements of one or more body parts caused by the use of certain medications. Tremors are characterized by repetitive oscillations of a body part and can range from subtle to severe. Identifying the specific medication causing the tremor is crucial for management. Common Medications Associated with Tremors Stimulants: Drugs like amphetamines and caffeine can induce tremors, especially at higher doses. Antidepressants: Some antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), may cause tremors. Bronchodilators: Medications used to treat respiratory conditions, such as albuterol, can lead to tremors. Common Medications Associated with Tremors Lithium: Used to manage bipolar disorder, lithium is known to cause tremors in some individuals. Antipsychotics: Certain antipsychotic medications, especially first-generation (typical) antipsychotics, may induce tremors. Immunosuppressants: Drugs used to suppress the immune system, like tacrolimus and cyclosporine, can cause tremors. Clinical Features Characteristics: Tremors may manifest as rhythmic shaking, usually involving the hands, but can also affect the head, voice, or other body parts. Aggravating Factors: Stress, anxiety, and certain postures or movements may exacerbate drug-induced tremors. Rest Tremor vs. Action Tremor: Tremors can be classified as occurring at rest or during voluntary movement. Pathophysiology The mechanism -- - not fully understood. It may involve the modulation of neurotransmitters, such as dopamine or serotonin, or the direct impact on muscle function. Diagnosis Clinical Evaluation: Diagnosis is primarily based on a thorough clinical assessment, including a detailed medical history and medication review. Neurological Examination: A neurological examination helps identify the characteristics and distribution of tremors. Exclusion of Other Causes: Other potential causes of tremors, such as neurological disorders or metabolic conditions, should be ruled out. Management Medication Adjustment: Adjusting the dosage or discontinuing the causative medication is a primary intervention. Alternative Medications: In some cases, switching to an alternative medication with a lower risk of inducing tremors may be considered. Symptomatic Treatment: Medications like beta- blockers (e.g., propranolol) may be prescribed to help alleviate tremors. Physical Therapy: Occupational or physical therapy can be beneficial in managing functional limitations associated with tremors. Dystonia Dystonia is a neurological movement disorder characterized by sustained muscle contractions, leading to repetitive or twisting movements and abnormal postures. These movements are often involuntary and can affect one or more body parts Etiology The exact cause of dystonia is not always clear, but it is thought to involve abnormalities in the basal ganglia, a group of structures deep within the brain that play a crucial role in motor control Clinical Features Involuntary Movements: Repetitive, twisting, or writhing movements that may be sustained or intermittent. Abnormal Postures: Twisting or contorting of affected body parts, leading to abnormal postures. Pain: Dystonia can be associated with pain, particularly when sustained muscle contractions lead to discomfort. Functional Impairment: Dystonia can significantly impact daily activities and quality of life. Common Types of Dystonia Cervical Dystonia (Spasmodic Torticollis): Involuntary contractions of neck muscles, leading to abnormal head postures. Writer's Cramp: Dystonia affecting the hand and forearm, particularly during writing. Blepharospasm: Involuntary closure of the eyelids, often leading to functional blindness. Oromandibular Dystonia: Involuntary contractions of the muscles of the lower face and jaw. Management Botulinum Toxin Injections: A common and effective treatment for focal dystonias, involving the injection of botulinum toxin into affected muscles to temporarily paralyze them. Oral Medications: Medications such as anticholinergics, benzodiazepines, or muscle relaxants may be prescribed to manage symptoms. Physical and Occupational Therapy: Therapies focused on improving muscle function, reducing pain, and adapting to functional limitations. Deep Brain Stimulation (DBS): In severe cases, DBS may be considered, involving the surgical implantation of electrodes in the brain to modulate abnormal neural activity.