Lecture 6 drugs for neurodegenerative diseases by Marc Imhotep Cray, M.D.

DRUGS USED IN DISORDERS OF THE CENTRAL NERVOUS SYSTEM AND TREATMENT OF PAIN Lecture 6:

Drugs for Neurodegenerative Diseases Marc Imhotep Cray, M.D.

Learning Objectives:

CNS Pharmacology Lecture 6

PARKINSONISM AND ITS TREATMENT 1. The presentation of Parkinson’s disease and its underlying pathophysiology 2. The functional circuitry of the nigrostriatal system. 3. The major classes of pharmacotherapy for Parkinson’s Disease and the timeline for their use 4. The indications, mechanism of action, adverse effects and contraindications for the major classes of drugs used in the treatment of Parkinson’s Disease 5. The type and mechanisms of alternative treatments for Parkinson’s Disease. PHARMACOLOGY OF STROKE AND ALZHEIMER’S DISEASE 1. The laboratory and clinical tests for ruling out reversible forms of dementia in the elderly. 2. The drug treatments for the reversible forms of dementia. 3. The current symptomatic and theoretical preventive drug therapies for Alzheimer’s disease. 4. The theoretical drug therapies for Huntington’s disease and ALS. 5. The preventive and symptomatic drug treatments for cerebrovascular disease. Marc Imhotep Cray, M.D.

Classification Schema: Drugs for Neurodegenerative Diseases ANTI-PARKINSON DRUGS Amantadine SYMMETREL Apomorphine APOKYN Benztropine COGENTIN Biperiden AKINETON Bromocriptine PARLODEL Carbidopa LODOSYN Entacapone COMTAN Levodopa (w/Carbidopa) SINEMET Pramipexole MIRAPEX Procyclidine KEMADRIN Rasagiline AZILECT Ropinirole REQUIP Rotigotine NEU PRO Selegiline (Deprenyl) ELDEPRYL Tolcapone TASMAR Trihexyphenidyl ARTANE Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 6

ANTI-ALZHEIMER DRUGS Donepezil ARICEPT Galantamine RAZADYNE Memantine NAMENDA Rivastigmine EXELON ANTI-MULTIPLE SCLEROSIS DRUGS Azathioprine IMURAN Cyclophosphamide CYTOXAN Dexamethasone DECADRON Fingolimod GILENYA Glatiramer COPAXONE Dalfampridine Interferon 1a AVONEX Interferon 1b BETASERON Natalizumab TYSABRI Prednisone DELTASONE ANTI-ALS DRUGS Riluzole RILUTEK

CNS Pharmacology Lecture 6

CNS Neurodegenerative diseases  Neurodegenerative diseases of CNS include:  Parkinson’s disease  Huntington disease  Alzheimer’s disease  Multiple Sclerosis (MS)  Amyotrophic Lateral Sclerosis (ALS)  These devastating illnesses are characterized by progressive loss of selected neurons in discrete brain areas, resulting in characteristic disorders of movement, cognition, or both

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 6

Basal Nuclei (Ganglia) COMPONENTS  Caudate nucleus  Putamen  Globus pallidus GROUPING OF THE BASAL NUCLEI (GANGLIA)  The striatum consists of caudate nucleus and putamen  The lentiform nucleus consists of globus pallidus and putamen  The corpus striatum consists of lentiform nucleus and caudate nucleus

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 6

Striatal (Extrapyramidal) Motor System  Striatal (Extrapyramidal) Motor System plays a role in initiation and execution of somatic motor activity, especially willed movement  It is also involved in automatic stereotyped postural and reflex motor activity (e.g., normal subjects swing their arms when they walk).  Striatal motor system includes the following structures: 1. Neocortex 2. Striatum (caudatoputamen, or neostriatum) 3. Globus pallidus 4. Subthalamic nucleus 5. Substantia nigra (i.e., pars compacta and pars reticularis) 6. Thalamus (ventral anterior, ventral lateral, and centromedian nuclei)

Marc Imhotep Cray, M.D.

The basal nuclei (ganglia)

Fix JD and Brueckner JK. High yield neuroanatomy 4th ed. 2009.

Motor Tracts, Basal Ganglia, and Dopamine Pathways

CNS Pharmacology Lecture 6

ď ą Several major neuronal tracts coordinate somatic motor functions: ď ą One is the pyramidal tract, whose direct motor component goes from precentral gyrus through internal capsule and midbrain and terminates on motor neurons in anterior horn of spinal cord (What is another name for this tract?) ď ą Extrapyramidal tracts (e.g., rubrospinal, reticulospinal, and corticoreticular) are also important for motor control

Marc Imhotep Cray, M.D.

Principal fiber tracts of spinal cord:

Pyramidal System

CNS Pharmacology Lecture 6

Lateral (crossed) corticospinal tract

Marc Imhotep Cray, M.D.

Motor Tracts, Basal Ganglia, and Dopamine Pathways (2)

CNS Pharmacology Lecture 6

 The basal ganglia (including caudate nucleus, putamen, and globus pallidus) are subcortical masses found between the cerebral cortex and thalamus that, together with the substantia nigra, help to coordinate movement  A major pathway, the nigrostriatal, originates in substantia nigra and connects with basal ganglia and other structures o The substantia nigra receives reciprocal input from these structures plus others

 Efferent pathways (nigrostriatal) are dopaminergic; afferent input is from neurons containing 5-HT, GABA, and substance P  Defects in these pathways lead to motor incoordination or incapacity Marc Imhotep Cray, M.D.

Motor Tracts, Basal Ganglia, and Dopamine Pathways (3)

Horizontal Brain Section Showing Basal Ganglia 12

Motor Tracts, Basal Ganglia, and Dopamine Pathways (4)

Connections of Basal Ganglia

Parkinsonism: Symptoms and Defect

CNS Pharmacology Lecture 6

 Parkinsonism is a progressive neurodegenerative disease that adversely affects motor neuron control:  Major early symptoms are:  tremor at rest  bradykinesia (slowness in initiating and carrying out voluntary movements)  muscle rigidity (cogwheel) and  flat facial affect  If untreated, condition worsens, leading eventually to complete immobility and early mortality

 Prevalence is approximately 2% in persons older than 65 years  A genetic predisposition seems likely, but environmental factors (including viral infections and neurotoxins) may play a role Marc Imhotep Cray, M.D.

Parkinsonism: Symptoms and Defect (2) Modified from: Lippincott Illustrated Reviews-Pharmacology Sixth Edition. 2015

 Most distinctive neuropathologic finding is progressive loss of dopaminergic neurons of the pars compacta of the substantia nigra  Projections of dopaminergic neurons from substantia nigra correlate with motor and cognitive deficits  Degeneration of dopaminergic neurons in the nigrostriatal tract causes loss of inhibitory dopamine action on striatal GABAergic neurons and leads to excessive cholinergic neuron excitation of these striatal neurons  Drugs such as levodopa (increases DA activity) can help 15

Clinical Signs of Parkinsonâ&#x20AC;&#x2122;s Disease:

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 6

Neuropathology of Parkinson Disease:

CNS Pharmacology Lecture 6

ď&#x201A;§ In addition to an abundance of inhibitory dopaminergic neurons, the neostriatum is also rich in excitatory cholinergic neurons that oppose action of dopamine ď&#x201A;§ Many of symptoms of parkinsonism reflect an imbalance between excitatory cholinergic neurons and diminished number of inhibitory dopaminergic neurons

Marc Imhotep Cray, M.D.

PD Strategy of treatment  Treatment aims to replenish dopamine, or at least to reestablish balance between DA and ACh influences on striatal neurons

 Dopamine cannot cross the blood-brain barrier, so its metabolic precursor, levodopa, is used  Most of an oral dose is rapidly converted to dopamine by dopa decarboxylase located in blood vessel walls (thus peripherally)  Approximately 1% to 5% of the dose crosses blood-brain barrier, enters metabolic pathways of dopaminergic neurons, and is converted to DA 18

CNS Pharmacology Lecture 6

Levodopa: Levodopa (L-dopa [Dopar, Larodopa]), the most effective treatment, is metabolized by dopa decarboxylase to DA, which increases availability of DA ( the inhibitory transmitter, in the basal ganglia)  L-Dopa becomes effective in a few weeks, especially for reducing rigidity and akinesia o However, L-dopa is rapidly metabolized in peripheral tissues (bld vessels) , so that only 1% of administered dose reaches CNS • Pyridoxine (vitamin B6) increases this metabolism by activating dopa decarboxylase

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 6

Levodopa (2) L-Dopa should be taken on an empty stomach because large, neutral amino acids will compete with it for absorption from gut and transport across blood–brain barrier (BBB) Carbidopa (Sinemet), a peripheral dopa decarboxylase inhibitor that slows metabolism of L-dopa, is usually combined with L-dopa  L-dopa dosage can then be reduced by 80% without changing effectiveness  Side effects from conversion of L-dopa to DA in periphery are also reduced

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 6

Levodopa (3) ď&#x201A;§ Catechol-O-methyltransferase (COMT) inhibitors prevent methylation of L-dopa in a side pathway o This side pathway becomes significant when dopa decarboxylase is inhibited by carbidopa i. Entacapone (Comtan) requires frequent dosing but is least toxic COMT inhibitor ii. Tolcapone (Tasmar) is longer acting but can cause fulminating hepatic necrosis

Remember: Entacapone and tolcaponeâ&#x20AC;&#x201D;prevent peripheral L-dopa degradation to 3-O-methyldopa (3-OMD) by inhibiting COMT Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 6

Side effects from L-dopa  Side effects from L-dopa include:  Nausea, vomiting, and anorexia induced by stimulation of chemoreceptor trigger zone  severity of nausea is reduced by gradually increasing t dose into therapeutic range and by combining L-dopa with carbidopa  Postural hypotension  Arrhythmias from actions of DA on the heart  Choreiform movements due to excessive actions of DA on basal ganglion  Psychological disturbances that can lead to insomnia and delirium

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 6

On–Off effects of L-Dopa Tx of PD  On-Off effects often develop after a year or more  These are indicative of the “wearing-off phenomena” at end of dosage intervals and erratic effectiveness  Patients typically have a decline in response after a few years of therapy

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 6

Contraindications for L-dopa:  Contraindications for L-dopa include:  Treatment with MAO inhibitors, because the combination can lead to a hypertensive crisis  Glaucoma, because L-dopa can induce mydriasis  Psychiatric disorders (PD), especially those disorders being treated with antipsychotic drugs, which are DA antagonists; o However, SSRIs or mirtazapine can be tried in PD patients who are also depressed

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 6

DA receptor agonists: nonselective  DA receptor agonists have effects and side effects that are similar to L-dopa  They are often used with L-dopa and carbidopa to reduce the ON– OFF effects o However, they are not active in patients who have no response to L-dopa i. Bromocriptine (Parlodel) and Pergolide (Permax) are nonselective DA agonists  Because they are ergot derivatives, they can cause pulmonary and retroperitoneal fibrosis

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 6

DA receptor agonists: D2 selective ii. Pramipexole (Mirapex) and ropinirole (Requip) are selective D2agonists, which are very effective and have fewer side effects Pharmacokinetics:  Pramipexole is cleared by renal tubular secretion o Its half life is increased by cimetidine, which interferes with secretion of organic bases (cations)

Remember: Dopamine agonists Ergots—bromocriptine and pergolide Non-ergot (preferred) —pramipexole, ropinirole Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 6

Anticholinergics:  The anticholinergics (e.g., trihexyphenidyl [Artane]), benztropine [Cogentin]) reduce cholinergic excitatory tone in basal ganglia  They are most frequently used in combination with antipsychotic drugs to reduce extrapyramidal symptoms from antipsychotic drugs (see note box below)  Side effects are due to central and peripheral cholinoceptor blockade Secondary parkinsonism: Drugs such as the phenothiazines and haloperidol, whose major pharmacologic action is blockade of dopamine receptors in the brain, may produce parkinsonian symptoms (also called pseudoparkinsonism). These drugs should be used with caution in patients with Parkinson’s disease. Marc Imhotep Cray, M.D.

Other Drug Used to Tx PD:

CNS Pharmacology Lecture 6

 Amantadine (Symmetrel) is an antiviral drug (Tx influenza A and rubella) that reduces symptoms of Parkinson’s disease  It increases DA release, decrease DA reuptake, blocks ACh receptors, and inhibits N-methyl-D-aspartic acid (NMDA) glutamate receptors (NMDAR)  Tolerance to this therapeutic effect often develops within 6 months  Adverse events ataxia, livedo reticularis  Selegiline (Eldepryl) blocks conversion of dopamine into 3-MT by selectively inhibiting MAO-B  This enzyme metabolizes L-dopa, but not 5-HT or NE  The selective decrease of DA metabolism enhances effectiveness of L-dopa with less risk of a hypertensive crisis compared to MAO-A (Metab. 5-HT, EPI, NE)  It can be used in combination with L-dopa, making it possible to lower the Ldopa dosage  Antihistamines, such as diphenhydramine (Benadryl) have some weak therapeutic effects, which are probably due to anticholinergic actions of these drugs Marc Imhotep Cray, M.D.

Parkinson’s disease Tx approach:

CNS Pharmacology Lecture 6

 Order of efficacies of available drugs for PD disease is the following: L-dopa  bromocriptine amantadine  anticholinergics  A common approach is to use low-efficacy drugs (e.g., selegiline, amantadine, anticholinergics) during early stages of Parkinson’s disease and reserve L-dopa with carbidopa and dopaminergic agonists for later stages

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 6

Final Points on PD Tx:  A loss of GABA or increase DA in basal ganglia can lead to the choreiform movements that are characteristic of Huntington’s disease  As a result, L-dopa and anticholinergics are an inappropriate combination  Some reduction of symptoms can be induced by DA depleters, antipsychotics (DA blockers), or cholinesterase inhibitors  These treatments are largely palliative and do not cure syndrome (choreiform movements) Note: METHYLPHENYLTETRAHYDROPYRIDINE (MPTP)-INDUCED PARKINSONISM MPTP is an analog of meperidine (Demerol). It destroys dopaminergic neurons in the substantia nigra Marc Imhotep Cray, M.D.

PD treatment strategies encapsulated:

CNS Pharmacology Lecture 6

Levodopa, Carbidopa, and Other Drugs Class and Drug

Mechanism of Action

Dopamine prodrugs  Levodopa  Levodopa + carbidopa

Are rapidly converted to dopamine by dopa decarboxylase (which is inhibited by carbidopa)

Direct-acting dopamine agonists  Bromocriptine, Pergolide, Pramipexole, Ropinirole

Bind to dopamine receptors and mimic the action of dopamine

Indirect-acting dopamine agonist  Amantadine

Increases dopamine release and reduces dopamine reuptake into dopaminergic nerve terminals of substantia nigra neurons (by unknown mechanism)

MAOI  Selegiline

Inhibits only type B isozyme

Muscarinic antagonists:  Benztropine, Biperiden, Orphenadrine, Trihexyphenidyl

Have central activity (brain) as anticholinergic agents

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 6

PD treatment strategies summary schematic

Marc Imhotep Cray, M.D.

LE, T et al. First Aid for the USMLE Step 1 2015

Huntington Disease and Tourette Syndrome

CNS Pharmacology Lecture 6

ď ą Various tremors (rhythmic oscillations around a joint), tics (repetitive, sudden, coordinated, abnormal movements), and chorea (irregular, unpredictable, involuntary muscle jerks) are components of disorders of coordinated movement ď ą Gilles de la Tourette syndrome (which includes involuntary verbal outbursts) is a disorder of unknown cause ď&#x201A;§ Current therapy consists primarily of haloperidol and other dopamine D2 receptor antagonists

Marc Imhotep Cray, M.D.

Huntington Disease and Tourette Syndrome (2)

CNS Pharmacology Lecture 6

 Huntington disease is a dominantly inherited disorder characterized by progressive chorea and dementia  disorder is traced to a single gene defect on chromosome 4  It is typically associated with an adult onset and a shortened lifespan  GABA and enzymes for ACh and GABA synthesis are deficient in basal ganglia  Current therapy consists usually of amine-depleting drugs, such as tetrabenazine, or haloperidol or other dopamine D2 receptor antagonists  adverse drug effects: hypotension, depression, sedation, restlessness, and parkinsonism are most common Marc Imhotep Cray, M.D.

Alzheimer Disease: Symptoms, Course, and Pathology

CNS Pharmacology Lecture 6

 Alzheimer disease is a neurodegenerative disorder characterized by progressive impairment of short-term memory and other memory, language, and thought processes  Functions are typically lost in reverse order in which they were attained  In advanced stages, patients cannot perform simple activities of daily life  Diagnosis is usually made 3 years or more after symptom onset, and life expectancy is approximately 7 to 10 years after diagnosis

Marc Imhotep Cray, M.D.

Alzheimer Disease: Symptoms, Course, and Pathology (2)

CNS Pharmacology Lecture 6

 Gross brain atrophy accompanies progression of disease, with characteristic high numbers of neuritic plaques (fragments of insoluble amyloid, type Aβ, protein) and neurofibrillary tangles (abnormal τ microtubule complexes), particularly in hippocampus and posterior temporoparietal lobe areas  Predisposing factors include aging and genetics, with a possible contribution from environmental toxins  The neurodegeneration results in loss or dysfunction of neurotransmitter pathways Marc Imhotep Cray, M.D.

Alzheimer Disease: Cholinergic Involvement and Drugs

CNS Pharmacology Lecture 6

 Although many NT systems become disrupted in Alzheimer disease, cholinergic pathways become especially damaged  Functional cholinergic deficits, such as impairment in short-term memory, become apparent even in early stages of disease  (SDL, Study NIP, Plates 3-21 , 3-22 and 3-23)  Medication strategies to ameliorate the decline in cholinergic function include the administration of precursors (eg, lecithin); directacting cholinergic receptor agonists; and indirect acting cholinomimetics  Indirect-acting agents, specifically cholinesterase inhibitors, such as donepezil, galantamine, and rivastigmine, are currently the most commonly used Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 6

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 6

Drugs Used in Multiple Sclerosis (MS)  MS is an autoimmune inflammatory demyelinating disease of the CNS (effects both sensory and motor function)  The course of MS is variable:  For some, MS may consist of one or two acute neurologic episodes  In others, it is a chronic, relapsing, or progressive disease that may span 10 to 20 years  Historically, corticosteroids (for example, dexamethasone and prednisone) have been used to treat acute exacerbations of the disease  Chemotherapeutic agents, such as cyclophosphamide and azathioprine, have also been used Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 6

MS Tx-Disease-modifying therapies  Drugs currently approved for MS are indicated to decrease relapse rates or in some cases to prevent accumulation of disability  Major target of these medications is to modify the immune response through inhibition of white blood cell–mediated inflammatory processes that eventually lead to myelin sheath damage and decreased or inappropriate axonal communication between cells

Marc Imhotep Cray, M.D.

MS Tx-Disease-modifying therapies (2)

CNS Pharmacology Lecture 6

 Interferon β1a and interferon β1b: The immunomodulatory effects of interferon help to diminish inflammatory responses that lead to demyelination of the axon sheaths  Adverse effects may include depression, local injection site rxns, hepatic enzyme increases, and flulike symptoms  Glatiramer: a synthetic polypeptide that resembles myelin protein and may act as a decoy to T-cell attack  Adverse effects some patients experience a postinjection reaction that includes flushing, chest pain, anxiety, and itching  It is usually self-limiting  Fingolimod: an oral drug that alters lymphocyte migration, resulting in fewer lymphocytes in the CNS  Adverse effects may cause first-dose bradycardia and is associated with an increased risk of infection and macular edema Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 6

MS Tx-Disease-modifying therapies (3) 4. Teriflunomide: an oral pyrimidine synthesis inhibitor that leads to a lower concentration of active lymphocytes in CNS ď&#x201A;§ Adverse effects may cause elevated liver enzymes, should be avoided in pregnancy 5. Dimethyl fumarate: an oral agent that may alter cellular response to oxidative stress to reduce disease progression ď&#x201A;§ Adverse effects flushing and abdominal pain are most common 6. Natalizumab: a monoclonal antibody indicated for MS in patients who have failed first-line therapies

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 6

MS-Symptomatic treatment ď ą Many different classes of drugs are used to manage symptoms of MS such as spasticity, constipation, bladder dysfunction, and depression ď&#x201A;§ Dalfampridine an oral potassium channel blocker, improves walking speeds in patients with MS o First drug approved for this use

Marc Imhotep Cray, M.D.

Drugs Used in Tx of Amyotrophic Lateral Sclerosis (ALS)

CNS Pharmacology Lecture 6

 ALS is characterized by progressive degeneration of motor neurons, resulting in inability to initiate or control muscle movement (pure motor disease (vs MS that is motor and sensory)  Riluzole an NMDA receptor antagonist, is currently the only drug indicated for management of ALS  It is believed to act by inhibiting glutamate release and blocking sodium channels  Riluzole may improve survival time and delay need for ventilator support in patients suffering from ALS Marc Imhotep Cray, M.D.

THE END

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 6

Further study (SDL):

CNS Pharmacology Lecture 6

MedPharm Digital Guidebook: Unit 3-Drugs Used for CNS Disorders Companion eNotes: CNS- Central Nervous System Pharmacology Textbook Reading: Aminoff MJ. Pharmacologic Management of Parkinsonism & Other Movement Disorders In: Katzung BG, ed. Basic & Clinical Pharmacology. 12th ed. Pgs. 483-98 Online resource center: Medical Pharmacology Cloud Folder

Lectures/discussions to follow: 7. Anesthetics 8. Analgesics 9. Drugs of Abuse

Marc Imhotep Cray, M.D.