Neurodegenerative Diseases and Antipsychotics Flashcards

Overview

• Most CNS drugs act by altering neurotransmission.
• Drugs can act presynaptically (production, storage, release, termination of neurotransmitters) or postsynaptically (activating/blocking receptors).
• Key neurodegenerative disorders: Parkinson’s, Alzheimer’s, MS, ALS (Figure 8.1).

Neurotransmission in the CNS

• Basic neuron function in CNS is similar to the autonomic nervous system (ANS).
• Information transmits via neurotransmitters across the synaptic space to receptors on the postsynaptic neuron and trigger intracellular changes.
• CNS differences from ANS:
  • More complex circuitry and greater number of synapses.
  • Powerful inhibitory neuron networks modulate neuronal transmission.
  • Multiple neurotransmitters in the CNS, compared to acetylcholine and norepinephrine in the ANS.

Synaptic Potentials

• In the CNS, receptors at most synapses are coupled to ion channels.
• Neurotransmitter binding opens ion channels, altering the postsynaptic potential.
• This can lead to either depolarization or hyperpolarization.

Excitatory Pathways

• Excitatory neurotransmitters cause depolarization of the postsynaptic membrane.
• Process:
  1. Stimulation releases neurotransmitters like glutamate or acetylcholine.
  2. This increases Na^+ permeability, causing influx.
  3. The influx of Na^+ causes a weak depolarization (EPSP) toward the firing threshold.
  4. Increased stimulation leads to more neurotransmitter release and EPSP depolarization, generating an action potential.
• The nerve impulse reflects activation of synaptic receptors by thousands of excitatory neurotransmitter molecules.
• Figure 8.2 illustrates an excitatory pathway.

Inhibitory Pathways

• Inhibitory neurotransmitters cause hyperpolarization of the postsynaptic membrane.
• Process:
  1. Stimulation releases neurotransmitters like GABA or glycine.
  2. This increases permeability to ions like K^+ and Cl^-.
  3. The influx of Cl^- and efflux of K^+ cause hyperpolarization (IPSP), moving the potential away from its firing threshold.
• This diminishes action potential generation.
• Figure 8.3 shows an inhibitory pathway.

Combined Effects of EPSP and IPSP

• Most CNS neurons receive both EPSP and IPSP input.
• Several neurotransmitters may act on the same neuron, each binding to its receptor.
• The overall action is a summation of individual neurotransmitter actions.
• Neurotransmitters are localized in specific neuron clusters.
• Neuronal tracts are chemically coded, allowing selective modulation of certain pathways.

Neurodegenerative Diseases

• Include Parkinson’s, Alzheimer’s, MS, and ALS.
• Characterized by progressive loss of selected neurons in discrete brain areas.
• Result in disorders of movement, cognition, or both.

Overview of Parkinson’s Disease

• Progressive neurological disorder affecting muscle movement.
• Characterized by tremors, muscular rigidity, bradykinesia, and postural/gait abnormalities.
• Incidence: ≈ 1 in 100 individuals over 65 years.

Etiology

• Cause is unknown for most patients.
• Correlated with the destruction of dopaminergic neurons in the substantia nigra which reduces dopamine actions in the corpus striatum.

Substantia Nigra

• Part of the extrapyramidal system.
• Source of dopaminergic neurons (red in Figure 8.4) terminating in the neostriatum.
• Each neuron makes thousands of synaptic contacts, modulating many cells.
• Dopaminergic projections fire tonically, having a sustaining influence on motor activity.

Neostriatum

• Connected to the substantia nigra by GABA-secreting neurons (orange in Figure 8.4).
• The substantia nigra sends dopamine-secreting neurons back to the neostriatum.
• This mutual inhibitory pathway maintains inhibition.
• In Parkinson’s, substantia nigra cell destruction leads to a degeneration of dopamine nerve terminals in the neostriatum.
• The normal dopamine inhibitory influence on cholinergic neurons is diminished.
• This results in over activity of acetylcholine by stimulatory neurons (green in Figure 8.4).
• The triggering of abnormal signaling leads to loss of muscle movement control.

Secondary Parkinsonism

• Drugs like phenothiazines and haloperidol block dopamine receptors and may produce parkinsonian symptoms (pseudoparkinsonism).
• Use with caution in patients with Parkinson’s disease.

Strategy of Treatment

• The neostriatum has inhibitory dopaminergic and excitatory cholinergic neurons.
• Parkinsonism symptoms reflect an imbalance between these neurons.
• Therapy aims to restore dopamine in the basal ganglia and antagonize cholinergic neuron effects, and to reestablish the dopamine/acetylcholine balance.

Drugs Used in Parkinson’s Disease

• Aim to maintain constant CNS dopamine levels.
• Provide temporary symptom relief but do not arrest or reverse neuronal degeneration.

Levodopa and Carbidopa

• Levodopa is a metabolic precursor of dopamine (Figure 8.5).
• It restores dopaminergic neurotransmission in the neostriatum.
• In early disease, residual neurons convert levodopa to dopamine.
• Effectiveness declines as neuron numbers decrease.
• Relief is symptomatic and lasts only while the drug is present.
• Carbidopa, a dopamine decarboxylase inhibitor that does not cross the blood-brain barrier, enhances levodopa's effects.

Mechanism of Action

• Levodopa: Actively transported into the CNS and converted to dopamine.
• Carbidopa: Reduces peripheral metabolism of levodopa, increasing its availability to the CNS (Figure 8.5).
  • Lowers the required levodopa dose by four- to fivefold.
  • Decreases side effects from peripherally formed dopamine.

Therapeutic Uses

• Levodopa + carbidopa is effective for Parkinson’s treatment- decreasing rigidity, tremors, and other symptoms.
• Substantially reduces symptoms for the first few years in approximately two-thirds of patients.
• Patients experience decline in response during the 3rd-5th year of therapy.
• Withdrawal from the drug must be gradual.

Absorption and Metabolism

• Rapidly absorbed from the small intestine when empty of food.
• Short half-life (1-2 hours) causes plasma concentration fluctuations.
• This leads to fluctuations in motor response (on-off phenomenon).
• Ingestion of meals, especially high protein, interferes with levodopa transport into the CNS.
• Levodopa should be taken on an empty stomach 30 minutes before a meal.

Adverse Effects

• Peripheral effects: Anorexia, nausea, vomiting (stimulation of chemoreceptor trigger zone), tachycardia, ventricular extrasystoles (dopaminergic action on the heart), hypotension, mydriasis (adrenergic action on the iris), blood dyscrasias, positive Coombs test, brownish saliva/urine (melanin pigment).
• CNS effects: Visual/auditory hallucinations, dyskinesias (overactivity of dopamine), mood changes, depression, psychosis, anxiety.

Interactions

• Pyridoxine (B6) increases peripheral breakdown of levodopa, diminishing its effectiveness.
• Non-selective MAOIs (e.g., phenelzine) can produce a hypertensive crisis (enhanced catecholamine production, Figure 8.7) and avoid concomitant administration.
• Levodopa may exacerbate symptoms in psychotic patients.
• Cardiac patients should be monitored for arrhythmias.
• Antipsychotic drugs are generally contraindicated (block dopamine receptors), but low doses of atypical antipsychotics treat levodopa-induced psychosis.

Selegiline and Rasagiline

• Selegiline selectively inhibits MAO type B (metabolizes dopamine) at low doses.
  • Increases dopamine levels in the brain (Figure 8.8).
  • Enhances levodopa's actions, reducing its required dose, and has little potential for causing hypertensive crises.
  • Metabolized to methamphetamine/amphetamine, whose stimulating properties may cause insomnia if administered late in the day.
• Rasagiline irreversibly inhibits brain MAO type B, with five times the potency of selegiline, and unlike selegiline, it’s not metabolized to an amphetamine-like substance.

Catechol-O-Methyltransferase Inhibitors

• COMT methylates levodopa to 3-O-methyldopa, a minor pathway for levodopa metabolism.
• Carbidopa inhibits peripheral dopamine decarboxylase activity, leading to significant 3-O-methyldopa formation that competes with levodopa for CNS transport (Figure 8.9).
• Entacapone and tolcapone selectively/reversibly inhibit COMT, leading to reduced plasma concentrations of 3-O-methyldopa, increased CNS uptake of levodopa, and increased brain dopamine concentrations.
• Both reduce “wearing-off” phenomena in patients on levodopa/carbidopa.

Pharmacokinetics

• Oral absorption occurs readily and is not influenced by food.
• Extensively bound to plasma albumin, with a limited volume of distribution.
• Tolcapone has a longer duration than entacapone, requiring less frequent dosing.
• Both are extensively metabolized and eliminated in feces and urine, and dosage may need to be adjusted in patients with moderate or severe cirrhosis.

Adverse Effects

• Similar effects to levodopa-carbidopa: diarrhea, postural hypotension, nausea, anorexia, dyskinesias, hallucinations, sleep disorders.
• Tolcapone is associated with fulminating hepatic necrosis: it should be used only when other modalities have failed with appropriate hepatic function monitoring,
• Entacapone does not exhibit this toxicity and has largely replaced tolcapone.

Dopamine Receptor Agonists

• Include bromocriptine, ropinirole, pramipexole, rotigotine, and apomorphine.
• Have a longer duration than levodopa and used for response fluctuations.
• Associated with less risk of dyskinesias and motor fluctuations.
• Bromocriptine, pramipexole, and ropinirole are effective for Parkinson’s complicated by motor fluctuations and dyskinesias but are ineffective in patients who have not responded to levodopa.
• Apomorphine is an injectable dopamine agonist used in severe/advanced stages to supplement oral medications.
• Side effects limit the utility of these agonists (Figure 8.10).

Bromocriptine

• Ergot derivative with actions similar to levodopa.
• Hallucinations, confusion, delirium, nausea, and orthostatic hypotension are more common, dyskinesia is less prominent, and psychiatric conditions worsen.
• Use with caution in patients with myocardial infarction or peripheral vascular disease.
• Potential to cause pulmonary/retroperitoneal fibrosis.

Apomorphine, Pramipexole, Ropinirole, and Rotigotine

• Nonergot dopamine agonists approved for Parkinson’s treatment.
• Pramipexole and ropinirole are orally active.
• Apomorphine (injectable) is used for acute management of hypomobility off phenomenon.
• Rotigotine (transdermal patch) provides even drug levels over 24 hours.
• Effects: Alleviate motor deficits both in levodopa-naive and advanced Parkinson’s patients; delay levodopa in early Parkinson’s; decrease levodopa dose in advanced Parkinson’s but do not exacerbate peripheral vascular disorders/cause fibrosis.
• Common side effects: Nausea, hallucinations, insomnia, dizziness, constipation, orthostatic hypotension (Figure 8.11); dyskinesias are less frequent than with levodopa
• Pramipexole: Excreted unchanged in urine; dosage adjustments needed in renal dysfunction; cimetidine inhibits renal tubular secretion and increases the half-life.
• Fluoroquinolone antibiotics/CYP450 1A2 inhibitors (e.g., fluoxetine) inhibit ropinirole metabolism, requiring dosage adjustments.
• Figure 8.12 summarizes dopamine agonists' properties.

Amantadine

• Antiviral drug with antiparkinsonian action through increasing dopamine release, blocking cholinergic receptors, and inhibiting NMDA-glutamate receptors.
  *Primary action at NMDA receptors at therapeutic concentrations.
• No effect if dopamine release is already maximal.
• May cause restlessness, agitation, confusion, hallucinations, and acute toxic psychosis at high doses.
• Also: orthostatic hypotension, urinary retention, peripheral edema, and dry mouth.
• Less efficacious than levodopa, tolerance develops rapidly, fewer side effects, and is efficacious in increasing synaptic dopamine levels.

Antimuscarinic Agents

• Less efficacious than levodopa and play an adjuvant role.
• Drugs: benztropine, trihexyphenidyl, procyclidine, and biperiden.
• Blockage of cholinergic transmission produces effects similar to dopamine augmentation, helping Dopamine/Acetylcholine ratio correction (Figure 8.4).
• Adverse effects: mood changes, xerostomia, constipation, visual problems.
• Contraindicated: glaucoma, prostatic hyperplasia, pyloric stenosis.

Drugs Used in Alzheimer’s Disease

• Alzheimer's is characterized by senile plaques (β-amyloid accumulations), neurofibrillary tangles, and the loss of cortical neurons, particularly cholinergic neurons.
• Current therapies are palliative with modest short-term benefit.
• They improve cholinergic transmission or prevent excitotoxic actions from NMDA-glutamate receptor overstimulation.
• Available therapeutic agents do not alter the underlying neurodegenerative process.

Acetylcholinesterase Inhibitors

• Progressive loss of cholinergic neurons is associated with memory loss.
• Inhibition of AChE improves cholinergic transmission in functioning neurons.
• Reversible AChE inhibitors: donepezil, galantamine, rivastigmine with selectivity for the CNS.
• Galantamine may augment acetylcholine action at nicotinic receptors.
• Provide a modest reduction in the rate of loss of cognitive function.
• Rivastigmine (transdermal formulation) manages dementia associated with Parkinson’s disease, hydrolyzed by AChE to a carbamylate metabolite and has no interactions with drugs that alter the activity of CYP450 enzymes.
• Other agents are substrates for CYP450 and have potential interactions.
• Common adverse effects: nausea, diarrhea, vomiting, anorexia, tremors, bradycardia, muscle cramps (Figure 8.13).

NMDA Receptor Antagonist

• Glutamate receptor stimulation is critical for memory formation.
• Overstimulation, particularly of the NMDA receptor type, leads to excitotoxic effects on neurons.
• Binding of glutamate to the NMDA receptor opens an ion channel for Ca^{2+} entry, leading to neuron damage/apoptosis due to excessive intracellular Ca^{2+} .
• Memantine: NMDA receptor antagonist for moderate to severe Alzheimer’s, limiting Ca^{2+} influx.
• Well-tolerated with few dose-dependent adverse events.
• Often given with an AChE inhibitor due to different mechanisms of action and possible neuroprotective effects.
• Expected side effects (confusion, agitation, and restlessness) are indistinguishable from the symptoms of Alzheimer’s disease.

Drugs Used in Multiple Sclerosis

• MS: Autoimmune inflammatory demyelinating disease of the CNS.
• Variable course: acute episodes to chronic, relapsing, or progressive disease.
• Historically, corticosteroids (e.g., dexamethasone, prednisone) treat acute exacerbations and chemotherapeutic agents (e.g., cyclophosphamide, azathioprine).

Disease-Modifying Therapies

• Decrease relapse rates or prevent disability accumulation.
• Major target: modify the immune response through WBC-mediated inflammatory processes.

Interferon β1a and Interferon β1b

• Immunomodulatory effects diminish inflammatory responses that lead to demyelination of axon sheaths.
• Adverse effects: depression, local injection site reactions, hepatic enzyme increases, and flu-like symptoms.

Glatiramer

• Synthetic polypeptide that resembles myelin protein and may act as a decoy to T-cell attack.
• Some patients experience a self-limiting postinjection reaction (flushing, chest pain, anxiety, itching).

Fingolimod

• Oral drug that alters lymphocyte migration, resulting in fewer lymphocytes in the CNS.
• May cause first-dose bradycardia and is associated with an increased risk of infection and macular edema.

Teriflunomide

• Oral pyrimidine synthesis inhibitor that leads to a lower concentration of active lymphocytes in the CNS.
• May cause elevated liver enzymes but should be avoided in pregnancy.

Dimethyl Fumarate

• Oral agent that may alter the cellular response to oxidative stress to reduce disease progression.
• Flushing and abdominal pain are the most common adverse events.

Natalizumab

• Monoclonal antibody for MS in patients who have failed first-line therapies.

Mitoxantrone

• Cytotoxic anthracycline analog that kills T cells and may also be used for MS.

Symptomatic Treatment

• Classes of drugs manage symptoms like spasticity, constipation, bladder dysfunction, and depression.
• Dalfampridine (oral potassium channel blocker) improves walking speeds in patients with MS (first drug approved for this use).

Drugs Used in Amyotrophic Lateral Sclerosis

• ALS is characterized by the progressive degeneration of motor neurons, resulting in an inability to initiate or control muscle movement.
• Riluzole, an NMDA receptor antagonist, is the only drug for ALS management.
• It inhibits glutamate release and blocks sodium channels.
• Riluzole may improve survival time and delay the need for ventilator support.