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Neuropharmacology 

Neuropharmacology
Chapter:
Neuropharmacology
Author(s):

Z. Crepeau Amy

and W. Britton Jeffrey

DOI:
10.1093/med/9780190214883.003.0027
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date: 01 October 2020

Introduction

Medications used in the treatment of nervous system disorders typically modulate neurotransmitter function or action potential propagation to result in alterations in neurologic function. This chapter begins with a discussion of principles of pharmacokinetics. Targets for drug action and a basis for understanding how medications exert their action are also discussed. Finally, disease-specific treatments are detailed.

Principles of Pharmacokinetics

Pharmacokinetic principles of neurologic medications are important to understand for the purposes of medication prescribing and ordering (Figure 27.1). Multiple routes of administration—intravenous, sublingual, intramuscular, subcutaneous, rectal, oral, and transdermal—are available for neurologic therapeutic agents. Oral administration is affected by gastric pH, gastric contents, gastric emptying time, transmembrane transport mechanisms, and gastrointestinal tract motility. These factors can be altered by medication coadministration, medical conditions, and age.

Figure 27.1 Principles of Pharmacokinetics.
CYP indicates cytochrome P-450; GI, gastrointestinal; UGT, uridine-glucuronyl transferase.

Figure 27.1 Principles of Pharmacokinetics.

CYP indicates cytochrome P-450; GI, gastrointestinal; UGT, uridine-glucuronyl transferase.

(Used with permission of Mayo Foundation for Medical Education and Research.)

The bioavailability of a drug, once absorbed, or the drug’s distribution is affected by body fat percentage, which varies with age, and protein binding. The volume of distribution is the ratio of total amount of drug in the body to drug blood plasma concentration and reflects how the drug will be distributed throughout the body per dose, based on a number of parameters. The expected serum concentration (Co) after the administration of a specific dose (D) is calculated using the volume of distribution (Vd): Co = D/Vd. Understanding the volume of distribution is important in order to predict duration of drug effect for certain drugs. A common example is comparing the duration of effect of lorazepam and diazepam. Diazepam has a large volume of distribution compared with that of lorazepam. As a result, a bioequivalent dose of diazepam has a shorter duration of anticonvulsant action than lorazepam as it is effectively diluted by its wide distribution after administration.

Factors affecting volume of distribution include body mass, body fat percentage, solubility, and protein binding. Serum proteins that bind drugs include albumin, lipoprotein, glycoprotein, and α‎-, β‎-, and γ‎-globulins. Protein binding is impacted by factors intrinsic to the drug and by serum protein concentration. The latter is affected by age, concurrent illnesses, and other medications taken by the patient (Box 27.1). A decrease in protein binding results in an increased concentration of free drug. Neurologic drugs in which serum protein binding plays an important clinical role include phenytoin, valproic acid, and carbamazepine. Use of serum-free concentrations in monitoring therapy is important with use of these drugs in patients in whom serum protein binding is affected.

Hepatic metabolism of neurologic therapeutics is primarily through the cytochrome P-450 and uridine- glucuronyl transferase enzyme systems. The activity of these systems is influenced by age, genetic factors, and other medications. Renal excretion is heavily influenced by age and renal disease.

Medications that act on the central nervous system (CNS) have the additional challenge of needing to cross the blood-brain barrier. Lipid-soluble molecules are able to cross the blood-brain barrier relatively easily, while water-soluble molecules are often unable to cross the barrier or require the assistance of transport channels. The integrity of the blood-brain barrier is maintained by tight junctions between endothelial cells in the capillaries, choroid plexus, and the meninges. These tight junctions limit the passage of compounds in either direction, particularly for large and water-soluble molecules.

  • Pharmacokinetic principles of neurologic medications are important to understand for the purposes of medication prescribing and ordering.

  • Lipid-soluble molecules are able to cross the blood-brain barrier relatively easily, while water-soluble molecules are often unable to cross the barrier or require the assistance of transport channels.

Major Neurologic Targets

The functions of the neurologic system depend on signaling across synapses and axonal propagation, which allow communication between different brain regions in neural networks. Synaptic and axonal propagation mechanisms provide the target for many neurologic therapeutic agents.

Ion Channels

Electrical signals in the nervous system are propagated by alterations in the resting membrane potential, which is determined by the relative balance of the fluxes of sodium (Na+), potassium (K+), chloride (Cl), and calcium (Ca2+) across the membrane. At rest, the neurons and their processes show a predominance of Na+, Ca2+, and Cl concentrations in the extracellular space, and a higher concentration of K+ in the intracellular space, resulting in a resting membrane potential of −70 mV, reflecting relative negativity in the intracellular region. Increases in Na+ and Ca2+ conductance lead to reductions in the magnitude of negative potential intracellularly, increasing the intracellular potential, until the threshold is reached (the threshold is typically −40 to −55 mV). When the transmembrane potential supersedes the threshold, this triggers the opening of fast-inactivating voltage-gated Na+ channels, leading to rapid membrane depolarization and transient overshoot (transient intracellular positivity). These same voltage-gated channels rapidly inactivate, leading to a reduction in transmembrane potential. In addition, at the threshold, slow-inactivating K+ channels are also opened, leading to K+ efflux. Increasing K+ conductance eventually leads to membrane hyperpolarization, decreasing excitability, and eventually restores the membrane to resting membrane potential. Opening Ca2+ channels also leads to cellular depolarization and excitation. Medications that block voltage-gated Na+ or Ca2+ channels or activate voltage-gated K+ channels decrease neuronal excitability.

γ‎-Aminobutyric Acid

γ‎-Aminobutyric acid (GABA) plays an important role in neuronal inhibition. Ionotropic GABAA receptors reside in synapses, providing quick-acting phasic inhibition, whereas metabotropic GABAB receptors are localized in extrasynaptic regions, giving rise to tonic inhibition.

In the presynaptic neuron, glutamate, an excitatory neurotransmitter, is converted to GABA by glutamic acid decarboxylase. This reaction is dependent on pyridoxine (vitamin B6). GABA is then stored in presynaptic vesicles. When GABA is released and binds to postsynaptic GABAA receptors, Cl flows into the postsynaptic neuron, resulting in hyperpolarization and neuronal inhibition. GABAB receptor activation, in contrast, leads to efflux of intracellular K+, resulting in neuronal hyperpolarization, and thus, inhibition. GABA is taken back up into the presynaptic neuron by GABA transporter and broken down by the enzyme GABA transaminase. GABAergic mechanisms are important in the mechanisms of action of many antiepileptic drugs (AEDs).

Glutamate

Glutamate is the primary excitatory neurotransmitter in the CNS. It is an amino acid, which does not cross the blood-brain barrier but is synthesized within the CNS from glucose from α‎-ketoglutarate in the tricarboxylic acid cycle (Krebs cycle). After glutamate is released into the synapse, it is taken up into glial cells by excitatory amino acid transporters and converted into glutamine by glutamine synthetase. Glutamine is converted back to glutamate by glutaminase. The bidirectional conversion between glutamate and glutamine allows for rapid neurotransmission.

Glutamate acts on a number of ionotropic and metabotropic glutamatergic receptors. The functional classes of the ionotropic subtypes are the N-methyl-d-aspartate (NMDA), α‎-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate receptors. When glutamate binds to one of these receptors, the channel opens, allowing Ca2+ and Na+ influx to the postsynaptic terminal, resulting in depolarization. At membrane potentials more negative than −50 mV, magnesium ions (Mg2+) in the extracellular space block NMDA receptor channels, preventing influx of cations. Activation of NMDA receptors requires concurrent binding of glutamate and glycine. Glutamatergic pathways are important in the mechanisms of seizures and long-term potentiation underlying memory formation.

The metabotropic glutamate receptors activate a G-protein–coupled reaction, which either leads to release of postsynaptic Ca2+ vesicle stores, leading to apoptosis, or inhibition of cyclic adenosine monophosphate (cAMP) formation, leading to inhibition of neurotransmitter release and a decrease in neuronal excitability.

Monoamines

The monoamines norepinephrine, epinephrine, and dopamine are neurotransmitters which are synthesized from tyrosine through a shared pathway. Tyrosine hydroxylation of tyrosine to levodopa is the rate-limiting step in monoamine synthesis. Levodopa in turn is converted by 3,4-dihydroxyphenylalanine (dopa) decarboxylase to dopamine. Dopamine then undergoes hydroxylation to norepinephrine, which undergoes methylation to epinephrine. The rate-limiting step in monoaminergic synthesis is the hydroxylation of tyrosine to levodopa.

Five dopamine receptor subtypes are further categorized into 2 main dopamine receptor families, the D1-like families (D1 and D5), which lead to increased cAMP activity, and D2-like families (D2, D3, and D4), which lead to reduction in cAMP activity. D1 and D2 are located primarily in the corpus striatum and frontal lobes, and D3 and D4 in the frontal cortex, hippocampus, amygdala, and nucleus accumbens. D1 and D2 play a crucial role in modulating motor activity in the basal ganglia. D2 agonists lead to presynaptic inhibition of neurotransmitter release and decreased neuronal excitation. Dopamine agonists are used in the treatment of Parkinson disease (PD). Conversely, dopamine antagonists are used in the treatment of schizophrenia, which may lead to parkinsonism and tardive dyskinesia.

Norepinephrine is synthesized in preganglionic neurons and stored in vesicles with the assistance of vesicular monoamine transporter (VMAT) proteins. Inhibition of norepinephrine production or its ability to bind with α‎- and β‎-adrenergic receptors results in decreased activity in the sympathetic nervous system, an effect which is commonly exploited in the treatment of hypertension, cardiac disease, and urinary retention. Adrenergic receptor antagonists and α‎2-receptor presynaptic agonists such as prazosin, which lead to reduced presynaptic norepinephrine release, may cause orthostatic hypotension–related presyncope and dizziness, which may necessitate a neurology consultation. Conversely, agonists of α‎-receptors, such as modafinil, lead to increases in blood pressure and are used in the management of neurogenic orthostatic hypotension, such as in multiple system atrophy (Shy-Drager syndrome).

Serotonin

Serotonin is synthesized from the amino acid tryptophan. Serotonergic neurons are located in the dorsal raphe nuclei in the midbrain, which project to the cerebral cortex, medulla, spinal cord, and forebrain structures. Serotonin is stored in vesicles for eventual release with the assistance of VMATs. After release, serotonin reuptake is modulated by the serotonin transporter (SERT). SERT blockage allows for prolonged serotonergic activity. Serotonin is broken down to 5-hydroxyindolacetic acid (5-HIAA) by monoamine oxidase (MAO), and in the pineal gland, it is converted to melatonin.

Medications to enhance serotonin activity through inhibition of serotonin uptake (selective serotonin reuptake inhibitors or SSRIs) are widely used in the treatment of depression. Serotonin receptor agonists are used in the treatment of migraine. Drugs that inhibit norepinephrine and serotonin reuptake (selective noradrenergic reuptake inhibitors or SNRIs) are also used in the treatment of depression.

Acetylcholine

Acetylcholine (ACh) is widely distributed in the CNS and has many roles related to memory, attention, induction of rapid eye movement (REM) sleep, regulation of behavior, and muscle excitation and in the functioning of the autonomic nervous system.

ACh is synthesized by the binding of acetyl coenzyme A and choline by choline acetyltransferase. It is subsequently broken down to acetate by acetylcholinesterase intrasynaptically. There are 2 main types of ACh receptors: nicotinic and muscarinic.

Nicotinic ACh receptors are located at neuromuscular junctions, adrenal medulla, and CNS and in the preganglionic synapses in the autonomic nervous system. Activation of these ionotropic receptors results in influx of Na+ and Ca2+, depolarizing the postsynaptic target.

Muscarinic ACh receptors are located in the postganglionic synapses of the parasympathetic autonomic nervous system, peripheral tissue, and CNS. Many medications, such as tricyclic antidepressants, have antagonistic effects on muscarinic ACh receptors which lead to reduced parasympathetic activity resulting in symptoms such as urinary retention, xerostomia, constipation, and erectile dysfunction.

Deactivation of ACh activity occurs through degradation of ACh by acetylcholinesterase. Inhibitors of acetylcholinesterase are used to enhance ACh activity in the treatment of neurologic diseases such as Alzheimer disease, which is associated with reductions in ACh due to degeneration of cholinergic neurons in the basal forebrain, and myasthenia gravis, which is due to antibody blockage of postsynaptic nicotinic ACh receptors.

  • Ionotropic GABAA receptors reside in synapses, providing quick-acting phasic inhibition, whereas metabotropic GABAB receptors are localized in extrasynaptic regions, giving rise to tonic inhibition.

  • The monoamines norepinephrine, epinephrine, and dopamine are neurotransmitters which are synthesized from tyrosine through a shared pathway.

  • Five dopamine receptor subtypes are further categorized into 2 main dopamine receptor families, the D1-like families (comprising D1 and D5), which lead to increased cAMP activity, and D2-like families (D2, D3, and D4), which lead to reduction in cAMP activity.

  • Dopamine agonists are used in the treatment of Parkinson disease. Conversely, dopamine antagonists are used in the treatment of schizophrenia, which may lead to parkinsonism and tardive dyskinesia.

  • Serotonin receptor agonists are used in the treatment of migraine. Drugs that inhibit norepinephrine and serotonin reuptake (selective noradrenergic reuptake inhibitors or SNRIs) are also used in the treatment of depression.

  • Inhibitors of acetylcholinesterase are used to enhance ACh activity in the treatment of neurologic diseases such as Alzheimer disease, which is associated with reductions in ACh due to degeneration of cholinergic neurons in the basal forebrain, and myasthenia gravis, which is due to antibody blockage of postsynaptic nicotinic ACh receptors.

Disease-Specific Medications

Epilepsy

AEDs function generally through decreasing neuronal excitation or increasing neuronal inhibition. Some AEDs have a single mechanism of action, while others are known to have more than one. In some AEDs, the anticonvulsant mechanism remains unclear.

Selection of an AED takes into account a number of factors in addition to its mechanism of action. Seizure type is often the first consideration (Table 27.1). Pharmacokinetics also need to be considered carefully, particularly in patients on multiple medications and with concurrent medical ailments, such as liver and renal disease, because AEDs have a relatively narrow therapeutic range, and these factors can affect serum concentrations. Finally, the potential adverse effects of particular medications may be especially important in the management of certain patients. Considering these 3 factors, the complete list of AED options can usually be pruned to a few preferences for an individual patient (Table 27.2).

Table 27.1 Antiepileptic Drug Selection by Seizure Type

Seizure Type

Drug

Focal epilepsy

Phenytoin

Carbamazepine

Oxcarbazepine

Lamotrigine

Valproic acid

Levetiracetam

Lacosamide

Gabapentin

Pregabalin

Tiagabine

Vigabatrin

Topiramate

Zonisamide

Felbamate

Ezogabine

Perampanel

Primarily generalized tonic clonic

Valproic acid

Felbamate

Lamotrigine

Levetiracetam

Topiramate

Zonisamide

Generalized atonic or tonic

Lamotrigine

Rufinamide

Topiramate

Clobazam

Felbamate

Valproic acid

Absence

Ethosuximide

Valproic acid

Lamotrigine

Myoclonic

Levetiracetam

Valproic acid

Zonisamide

Infantile spasms

Adrenocorticotropic hormone

Vigabatrin

Topiramate

Clonazepam

Valproic acid

Corticosteroids

Table 27.2 Commonly Used Antiepileptic Drugs

Drug

Mechanism of Action

Half-life, h

Metabolism/Excretion

Major Adverse Effects

Phenytoin

Blocks sodium channels

14–22

Hepatic

Long-term use: gingival hyperplasia, peripheral neuropathy

Carbamazepine or oxcarbazepine

Inhibits rapid firing of sodium channels

12–17

Hepatic

Hyponatremia, dizziness

Lamotrigine

Blocks voltage-dependent sodium channels, inhibits glutamate release

12–70

Hepatic

Stevens-Johnson syndrome, insomnia

Lacosamide

Inhibits slow firing of sodium channels

13

Hepatic

Dizziness, imbalance, prolonged PR interval

Rufinamide

Modulates voltage-dependent sodium channels

6–10

Hepatic

Nausea, shortened QT interval

Zonisamide

Blocks voltage-dependent sodium channels, T-type calcium channels, weak carbonic anhydrase inhibitor

63–105

Hepatic or renal

Somnolence, mental slowing, nephrolithiasis

Phenobarbital

Increases duration of GABAA receptor opening

48–168

Hepatic

Sedation, mental slowing

Valproic acid

Enhances GABA activity

9–16

Hepatic

Weight gain, sedation, tremor, pancreatitis, hepatotoxicity

Clobazam

Increases frequency of GABAA receptor opening

36–42

Hepatic

Sedation, tolerance

Vigabatrin

Irreversibly binds to GABA transaminase

7–7.5

Renal

Drowsiness, loss of peripheral vision

Tiagabine

Inhibits GABA transporter-1

7–9

Hepatic or renal

Dizziness, emotional lability

Topiramate

Inhibits AMPA receptors, weak carbonic anhydrase inhibitor

21

Renal or hepatic

Cognitive blunting, paresthesias, decreased appetite, nephrolithiasis

Felbamate

Blocks NMDA receptors, voltage-dependent calcium channels

13–23

Hepatic

Insomnia, decreased appetite, aplastic anemia, hepatic failure

Perampanel

AMPA receptor antagonist

66–90

Hepatic

Dizziness, somnolence, headache

Ethosuximide

Blocks T-type calcium channels

40–60a

Hepatic

Nausea, abdominal upset

Gabapentin

Inhibits opening of voltage-dependent calcium channels, enhances GABA

5–7

Renal

Sedation, dizziness, ataxia

Pregabalin

Inhibits opening of voltage-dependent calcium channels, enhances GABA

6.3

Renal

Sedation, dizziness, weight gain

Ezogabine

Potassium channel opener

7–11

Hepatic

Urinary retention

Levetiracetam

Binds to SV2A transport protein

6–8

Renal

Irritability, emotional lability

Abbreviations: AMPA, α‎-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA, γ‎-aminobutyric acid; NMDA, N-methyl-d-aspartate; SV2A, synaptic vesicle glycoprotein 2A.

a Duration is for adults.

Parkinson Disease

The symptoms and signs of PD are related to loss of dopaminergic activity due to loss of dopaminergic neurons in the substantia nigra. The primary goal of current PD treatment is to increase dopaminergic activity in the CNS. This is accomplished pharmacologically by drugs that increase production or decrease degradation of dopamine or through stimulation of dopamine receptors by synthetic dopamine agonists. Levodopa, a precursor of dopamine, which unlike dopamine can cross the blood-brain barrier, is considered the gold standard of PD treatment.

Some pharmacokinetic factors are important to keep in mind with use of levodopa. Levodopa is converted to dopamine by dopa decarboxylase in dopaminergic neurons. To prevent peripheral conversion of levodopa to dopamine by peripheral dopa decarboxylase, which would markedly decrease the amount of levodopa available for transport across the blood-brain barrier and lead to elevated systemic dopamine levels resulting in nausea and other adverse effects, levodopa is usually coadministered with carbidopa or a benserazide, both dopa decarboxylase inhibitors. Also, levodopa has amino acid properties and is transported to the blood from the gut via amino acid transporters in the mucosa. As a result, coadministration of levodopa with a protein meal can interfere with levodopa absorption.

Levodopa leads to indiscriminant increases in dopamine levels. Therefore, its dopaminergic effects are nonselective, leading to agonism of all CNS and peripheral dopaminergic receptor subtypes. This leads to adverse effects of nausea, orthostatic hypotension, and hallucinosis. Because levodopa leads to increased dopamine production, the serum half-life of levodopa is generally unimportant in selecting dose intervals early in the course of PD. As the disease progresses and the number of dopaminergic neurons declines, the duration of effect of every levodopa dose often shortens considerably, and the frequency of administration increases.

Dopamine agonists do not require conversion to dopamine but bind directly to dopamine receptors. While more selective than levodopa in terms of affected dopaminergic receptor subtypes, dopamine agonists still can lead to orthostatism and hallucinosis because of activation of dopaminergic receptors.

Monoamine oxidase type B (MAO-B) inhibitors block degradation of dopamine, increasing the half-life of dopamine. These are distinct from monoamine oxidase type A (MAO-A) inhibitors used in the treatment of depression. Catechol O-methyltransferase (COMT) inhibitors prevent degradation of levodopa, increasing its duration of action.

Anticholinergic medications are also used in PD primarily as a preferential treatment for tremor. Amantadine, an antiviral medication, was serendipitously found to be effective in decreasing tremor and dyskinesias in PD. The primary mechanism of action is the enhancement of dopamine release from presynaptic terminals, but it is postulated that amantadine has a neuroprotective effect by way of acting as an NMDA receptor antagonist (Table 27.3).

Table 27.3 Treatment of Parkinson Disease

Drug

Major Adverse Effects

Levodopa

Nausea, hypotension, dyskinesias

Dopamine agonists

   Bromocriptine

Nausea, orthostatic hypotension, vasospasm

   Pramipexole

Nausea, orthostatic hypotension, hallucinations, compulsive behaviors

   Ropinirole

Nausea, orthostatic hypotension, hallucinations, compulsive behaviors, sudden sleep attacks

   Apomorphine

Hypotension, somnolence

Monoamine oxidase type B inhibitors

   Selegiline

Insomnia, dizziness, nausea, hallucinations, chorea, potential for serotonin syndrome

   Rasagiline

Insomnia, anorexia, nausea, hallucinations, chorea, potential for serotonin syndrome

Catechol O-methyltransferase inhibitors

   Entacapone

Diarrhea, orange discoloration of bodily fluids

   Tolcapone

Hepatic failure

Anticholinergics

   Trihexyphenidyl

Dizziness, anxiety, disrupted sleep, delirium, constipation, dry mouth

   Benztropine

Dizziness, anxiety, delirium, constipation, dry mouth

Dopamine release enhancer

   Amantadine

Mood changes, nausea, dizziness

Migraine

Treatment of migraine headaches is divided into acute and preventive strategies. A number of medication classes have been used in migraine prevention. These include AEDs (valproic acid, topiramate); antidepressants (nortriptyline, amitriptyline); β‎-blockers (propranolol); calcium channel antagonists (verapamil); and neurotoxins (onabotulinumtoxinA). These classes have various mechanisms, and the exact method by which they prevent migraines is not completely understood.

Triptans are selective agonists of 5-hydroxytryptamine receptor 1B (5-HT1B) and 5-hydroxytryptamine (serotonin) receptor 1D (5-HT1D) used in the acute treatment of migraine. The postulated mechanisms of action of the triptans are intracranial vasoconstriction (5-HT1B), inhibition of peripheral pain signal transmission and neuropeptide release (5-HT1D), and presynaptic dorsal horn stimulation (5-HT1D), inhibiting central pain transmission. There is a risk of serotonin toxicity if triptans are taken in conjunction with SSRIs, and they are contraindicated in patients with a history of unstable coronary artery disease, stroke, and uncontrolled hypertension.

Ergot alkaloids are less specific serotonin receptor agonists that can also be used in the acute treatment of migraine. Intravenous dihydroergotamine (DHE) is indicated for status migrainosus and can be effective in migraines that have failed to respond to other acute treatments, including triptans. Intravenous DHE is given every 6 to 8 hours, until the migraine has abated. The drug is associated with severe nausea, and pretreatment with an antiemetic is required. It should not be administered within 24 hours of triptan use because of concerns about vasoconstriction. As a class, ergots interact with multiple receptor types, resulting in multiple potential adverse effects. The primary adverse effects are nausea and vasoconstriction, and thus, ergots are contraindicated in patients with vascular disease, hypertension, and pregnancy (Table 27.4).

Table 27.4 Migraine-Specific Acute Treatment

Medication

Tmax, h

Half-life, h

Route of Administration

Triptans

   Sumatriptan

2–2.5 (oral), 1–1.75 (intranasal), 0.2 (subcutaneous)

3

Oral, intranasal, subcutaneous

   Rizatriptan

1–2.5

2–3

Oral

   Eletriptan

2

4

Oral

   Zolmitriptan

1

3

Oral, intranasal

   Almotriptan

1–3

3–4

Oral

   Frovatriptan

2–4

26

Oral

   Naratriptan

2–3

6

Oral

Ergots

   Dihydroergotamine

(0.2

9–10

Intravenous, intranasal

Multiple Sclerosis

Medications used in multiple sclerosis are distinct from those used in other neurologic diseases because they do not exert their action through alterations of neural transmission but rather act to alter immune function in the nervous system. Injectable disease-modifying therapies promote an anti-inflammatory state by decreasing type 1 helper T cell (TH1) (proinflammatory) activity and increasing type 2 helper T cell (TH2) (anti-inflammatory) activity. Natalizumab and fingolimod have different mechanisms of limiting lymphocyte entry into the CNS. Teriflunomide inhibits pyrimidine synthesis, inhibiting rapidly dividing cells. All the medications currently in use struggle to balance immunosuppression and immunomodulation, with adverse effects associated with these alterations (Table 27.5).

Table 27.5 Treatment of Multiple Sclerosis

Drug

Mechanism of Action

Route of Administration

Dosing Frequency

Major Adverse Effects

Glatiramer acetate

Promotes suppressor cells of TH2

Subcutaneous

Daily

Injection site reaction, chest pain, palpitations, flushing

Interferon beta-1a

Promotes shift of TH1 to TH2

Intramuscular or subcutaneous

Weekly or 3 times per week

Flulike symptoms, leukopenia, elevated LFTs

Interferon beta-1b

Antiviral/anti-inflammatory action

Subcutaneous

Every other day

Flulike symptoms, elevated LFTs

Mitoxantrone

Antineoplastic action

Intravenous

Every 3 mo

Congestive heart failure, leukemia

Natalizumab

Prevents entry of T cells into the CNS

Intravenous

Every 4 wk

Increased risk of progressive multifocal leukoencephalopathy

Fingolimod

Modulates sphingosine-1-phosphate receptors, sequestering lymphocytes in lymph nodes

Oral

Daily

Headache, fatigue, herpesvirus infection, bradycardia

Teriflunomide

Pyrimidine synthesis inhibitor

Oral

Daily

Hepatotoxicity, peripheral neuropathy

Abbreviations: CNS, central nervous system; LFT, liver function test; TH1, type 1 helper T cell; TH2, type 2 helper T cell.

Common symptoms in multiple sclerosis require additional symptomatic treatment. Spasticity is treated with muscle relaxants, including baclofen, tizanidine, and diazepam. Trigeminal neuralgia commonly occurs in multiple sclerosis and is typically treated with carbamazepine, gabapentin, or pregabalin. Fatigue may be treated with amantadine or modafinil or with paroxetine or sertraline when depression is a factor. Bladder spasticity can be treated with oxybutynin or bethanechol.

Dementia

Dementia, both as a group of diseases and as individual neurodegenerative diseases, lacks definitive treatment. Medications approved for use in dementia aim either to improve memory and attention or to protect neurons from excitotoxicity (Table 27.6).

Table 27.6 Alzheimer Disease

Drug

Mechanism of Action

Major Adverse Effects

Donepezil

Cholinesterase inhibitor

Nausea, anorexia, bradycardia, vivid dreams

Galantamine

Cholinesterase inhibitor

Nausea, anorexia, abdominal discomfort

Rivastigmine

Cholinesterase inhibitor

Nausea, vomiting

Memantine

NMDA receptor antagonist

Confusion, dizziness, insomnia, agitation

Abbreviation: NMDA, N-methyl-d-aspartate.

Cholinesterase inhibitors are available in both oral and transdermal forms for use in Alzheimer disease, which is associated with degeneration of cholinergic neurons in the basal forebrain. Rivastigmine is available as a transdermal patch, which has been shown to increase compliance. The slow release from a transdermal patch allows for steady dosing of the medication and has been associated with fewer adverse effects, particularly abdominal upset.

Behavioral adverse effects in dementia often require symptomatic treatment. Antipsychotic medications can be used to treat agitation or hallucinations, although caution needs to be taken in patients with Lewy body dementia because of the drugs’ antagonistic effects on dopamine receptors. Clozapine has minimal dopamine receptor binding, decreasing the risk of extrapyramidal adverse effects, but it carries a risk of agranulocytosis and seizures. The use of antipsychotic medications in elderly patients with dementia has been associated with increased mortality, with greater risk when using first-generation, as opposed to second- and third-generation antipsychotics.

  • Levodopa has amino acid properties and is transported to the blood from the gut via amino acid transporters in the mucosa. As a result, coadministration of levodopa with a protein meal can interfere with levodopa absorption.

  • Levodopa causes indiscriminant increases in dopamine levels. Therefore, its dopaminergic effects are nonselective, leading to agonism of all CNS and peripheral dopaminergic receptor subtypes. This leads to adverse effects of nausea, orthostatic hypotension, and hallucinosis.

  • Triptans are selective agonists of 5-hydroxytryptamine receptor 1B (5-HT1B) and 5-hydroxytryptamine (serotonin) receptor 1D (5-HT1D) used in the acute treatment of migraine. The postulated mechanisms of action of the triptans are intracranial vasoconstriction (5-HT1B), inhibition of peripheral pain signal transmission and neuropeptide release (5-HT1D), and presynaptic dorsal horn stimulation (5-HT1D), inhibiting central pain transmission.

  • Antipsychotic medications can be used to treat agitation or hallucinations, although caution needs to be taken in patients with Lewy body dementia because of the drugs’ antagonistic effects on dopamine receptors.

Notes:

Abbreviations: ACh, acetylcholine; AED, antiepileptic drug; AMPA, α‎-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; cAMP, cyclic adenosine monophosphate; CNS, central nervous system; COMT, catechol O-methyltransferase; DHE, dihydroergotamine; dopa, 3,4-dihydroxyphenylalanine; GABA, γ‎-aminobutyric acid; 5-HIAA, 5-hydroxyindolacetic acid; 5-HT1B, 5-hydroxytryptamine receptor 1B; 5-HT1D, 5-hydroxytryptamine (serotonin) receptor 1D; MAO, monoamine oxidase; MAO-A, monoamine oxidase type A; MAO-B, monoamine oxidase type B; NMDA, N-methyl-d-aspartate; PD, Parkinson disease; REM, rapid eye movement; SERT, serotonin transporter; SNRI, selective noradrenergic reuptake inhibitors; SSRI, selective serotonin reuptake inhibitor; TH1, type 1 helper T cell; TH2, type 2 helper T cell; VMAT, vesicular monoamine transporter