Neuropharmacology is a small piece of the overall management of the person with a brain injury. This chapter touches on a few elements of brain injury pharmacology but should not overshadow the necessary work of obtaining an adequate history, performing a thorough examination, discussing the goals of treatment, and applying the correct therapies and interventions. Furthermore, administration of any medication should occur only by brain injury physicians who have had adequate training and who understand the potential benefits, risks, and potential interactions of said medication. In addition, the authors of this book highly recommend consultation with a clinical pharmacist when appropriate.
Analgesics
Issues of pain are common after a traumatic brain injury (TBI). (Dobscha) This chapter is not the appropriate place to explore complementary or alternative options to pain management, but they should not be ignored by the brain injury physician.
Modalities
The authors of this chapter recommend nonpharmacological treatment of pain whenever possible in the TBI population. Table 59.1 has some of the possible modalities.
| Modality | Type of Pain Typically Treated |
|---|---|
| Heat conduction | Subacute and chronic pain |
| Convection heat | Subacute pain, limited neuropathic pain |
| Conversion heat | Subacute muscular pain |
| Deep heat | Deep muscle pain, chronic muscle pain |
| Cold | Acute pain and inflammation-related pain |
| Electrical stimulation/TENS | Subacute pain, limited neuropathic pain |
| Traction | Acute joint pain |
Nonopioid analgesics
Acetaminophen
Mechanism of action (MOA) (Micromedex), (Lexicomp Online): Proposed analgesia through the activation of descending serotonergic inhibitory pathways in the central nervous system (CNS); inhibits the cyclooxygenase (COX) isoenzyme, particularly the COX-2 isoform, by acting as a reducing cosubstrate at the peroxidase site
Side effects (SEs) : Minimal; monitor Liver Function Test with long-term use
Comments: used alone to treat mild pain and in combination with opioid to treat mild and moderate to severe pain
- •
Advantage: pain relief with little cognitive effect
- •
Advantage: first line for posttraumatic headache (Watanabe)
Nonsteroidal antiinflammatory drugs
MOA: block prostaglandin synthesis resulting in analgesic, antipyretic, and antiinflammatory properties
Examples: ibuprofen (COX-1 and 2 inhibitor), meloxicam (COX-1 and 2 inhibitor), celecoxib (COX2 inhibitor)
SEs: peripheral edema, dyspepsia, increased liver enzymes, nephrolithiasis
- •
Advantage: pain relief with little cognitive effect
- •
Disadvantage: cardiovascular thrombotic events, serious gastrointestinal (GI) bleeding, ulcerations, and GI perforation possible
Opioid analgesics
- •
Advantage: strong pain relief
- •
Disadvantage: sedation and risk of addiction
- •
Opioids are also mentioned later in this chapter under Problematic Medications.
Pure agonists
MOA: bind to mu opioid receptors in CNS and inhibit ascending pain pathways; opioids alter the perception of and response to pain
Examples: morphine, oxycodone, hydrocodone
SEs: drowsiness, headache, nausea, constipation, respiratory and CNS depression
- •
Disadvantage: active metabolites of morphine can accumulate in renal impairment.
Partial agonists
MOA: bind to mu opioid receptors in aŁŁ CNS; partial mu agonist and weak kappa antagonist activity
Example: buprenorphine
SEs: similar to
- •
Advantage: useful similar to pure agonist in addiction because partial mu agonist properties are such that at high doses behaves as an antagonist
Central agonists
Tramadol
MOA: bind to mu opiate receptors in the CNS and inhibits ascending pain pathways; inhibit norepinephrine and serotonin reuptake
SEs: dizziness, vertigo, constipation, nausea, dyspepsia, respiratory depression
Comments: risk of seizures when taken alone; increased risk of seizure when taken with other medications known to lower seizure threshold
- •
Disadvantage: risk of seizure
Tapentadol
MOA: binds to mu opiate receptors in the CNS, inhibiting ascending pain pathways; inhibits norepinephrine
Adjuvants/alternative pain medications
Antiepileptic medications
- •
Discussed further in the Anticonvulsants section
- •
Used off label to assist in pain management
MOA: medication specific
Examples: gabapentin, pregabalin, carbamazepine, topiramate
SEs: peripheral edema, somnolence, weight gain, fatigue, dizziness, hepatic dysfunction, hyponatremia, thrombocytopenia, rash
- •
Advantage: Some individual antiepileptics have specific uses in pain. Common examples:
- •
Carbamazepine: trigeminal neuralgia
- •
Gabapentin: neuropathic pain
- •
Valproic acid: headache
- •
Tricyclic antidepressants
- •
Discussed further in the Antidepressants section and Table 59.2
TABLE 59.2
Tricyclic Antidepressants
Amitriptyline
Amoxapine
Desipramine
Doxepin
Imipramine
Maprotiline
Nortriptyline
Protriptyline
Trimipramine
- •
Used off label for years to treat neuropathic pain
MOA: inhibit serotonin and/or norepinephrine reuptake in CNS
SEs: anticholinergic: constipation, xerostomia, blurred vision, urinary retention
- •
Advantage: individual medications have specific uses:
- •
Nortriptyline: fewer anticholinergic properties than other tricyclic antidepressants (TCAs)
- •
Amitriptyline: posttraumatic headache
- •
Serotonin-norepinephrine reuptake inhibitors
- •
Discussed further in the Antidepressants
MOA: inhibit reuptake of serotonin and norepinephrine and weak inhibitor of dopamine reuptake
Examples: duloxetine, venlafaxine
SEs: insomnia, dizziness, drowsiness, nausea, headache, fatigue
Local anesthetics
MOA: medication specific
Examples: lidocaine, capsaicin, diclofenac
SEs: exfoliation of skin, papule formation, skin edema, localized erythema, pruritus, rash, xeroderma, increased serum transaminases, dizziness
Anticonvulsants/antiepileptic medications
Prophylaxis versus treatment
- •
Based largely on the work of Dikmen and Temkin, various recommendations have been given for seizure treatment and prophylaxis after moderate to severe TBI without penetrating injury.
- •
Full summary of this topic is not possible within this chapter, but a generalized evidence-based approach is present in the organization of this section.
- •
Please see Chapter 28 for more information.
Type of posttraumatic seizure
- •
Consider 7 days of prophylactic medications in all cases (Temkin)
- a.
Immediate seizure
- i.
Seizure occurs within 24 hours of injury.
- ii.
Treat acute seizure as appropriate.
- iii.
Recommend 7 days of prophylactic medication only.
- i.
- b.
Early seizure
- i.
Seizure occurs within 24 hours to 7 days post injury.
- ii.
Treat acute seizure as appropriate.
- iii.
Recommend 3 to 6 months of further medication.
- i.
- c.
Late
- i.
Seizure occurs 1 week or more postinjury.
- ii.
Treat acute seizure as appropriate.
- iii.
Recommend long-term antiepileptic management.
- iv.
Late seizures typically reflect more permanent structural damage and require long-term treatment.
- i.
- a.
Medication options
Carbamazepine
MOA: limits influx of sodium ions across cell membrane
SEs: sedation, dizziness, hepatic dysfunction, hyponatremia, thrombocytopenia, rash
Gabapentin
MOA: membrane stabilizer that blocks voltage gated calcium channels. It is structurally similar to the neurotransmitter gamma aminobutyric acid (GABA), but it has no effects on GABA receptors
SEs: Somnolence, sedation, dizziness, peripheral edema
- •
Advantage: commonly used for neuropathic pain as discussed in section A
- •
Advantage: may help with paroxysmal sympathetic hyperactivity
- •
Disadvantage: generally not considered primary antiepileptic
Lamotrigine
MOA: inhibits the release of glutamate and inhibits voltage-sensitive sodium channels and calcium channels stabilizing neuronal membranes
SEs: nausea, peripheral edema, insomnia, skin rash
- •
Disadvantage: must be slowly titrated to prevent life-threatening skin rashes
Levetiracetam
MOA: The mechanism of action is unknown but may involve inhibition of calcium channels.
SEs: drowsiness, aggression, irritability, anorexia, dizziness
- •
Advantage: Typically the drug of choice for seizure prophylaxis
Phenobarbital
MOA: long-acting sedative hypnotic; suppresses high-frequency firing in neurons through actions on sodium channels
SEs: bradycardia, hypotension, respiratory depression
- •
Disadvantage: requires slower administration rate
- •
Disadvantage: very sedating and typically used as last line as an anticonvulsant because of its slow rate of administration
Phenytoin
MOA: stabilizes neuronal membranes, decreasing seizure activity through changes in sodium, potassium, and calcium conductance and membrane potentials
SEs: bradycardia, cardiac arrhythmia, nausea, vomiting, nystagmus, tremors, gingival hyperplasia
- •
Disadvantage: significant cognitive deficits in TBI patients
- •
Disadvantage: serum levels should be checked frequently
Valproic acid
MOA: increases availability of GABA to neurons; blocks sodium channels and therefore decreases repetitive neuronal firing
SEs: headache, drowsiness, nausea, thrombocytopenia, diplopia
- •
Advantage: mood stabilizing; see Anxiolytics/Mood Stabilizers
- •
Advantage: may have few cognitive side effects
Topiramate
MOA: blocks sodium channels and enhances GABA A activity
SEs: drowsiness, memory impairment, nausea, diarrhea
- •
Disadvantage: There are some case reports of hyperammonemia when used with valproic acid.
Antispasticity agents
Spasticity often follows TBI, especially in the severe TBI population. The use of the medications in this section is an option but is often limited by their side effects.
Gaba agonists
Baclofen
MOA: acts as GABA agonist, hyperpolarizes afferent fiber terminals, reducing release of excitatory transmitters in brain and spinal cord
SEs: drowsiness, confusion, headache, nausea, vomiting, hypotension, urinary retention, weakness
- •
Advantage: oral and intrathecal formulations available
- •
Disadvantage: abrupt withdrawal of intrathecal baclofen can be fatal
- •
Symptoms of withdrawal include hyperpyrexia, altered mental status, muscle rigidity, multiple organ failure, death.
Benzodiazepines
MOA: binds to GABA receptors and enhance the inhibitory effect of GABA; enhances inhibitory effect of GABA through increased neuronal permeability to chloride ions
Examples: alprazolam, clonazepam, diazepam, lorazepam
SEs: drowsiness, hypotension, dizziness, amnesia, disinhibition, agitation, respiratory depression, dependency/abuse, confusion, hypotension
- •
Disadvantage: usually avoided in patients with brain injury because of CNS depression, worsening cognitive impairments
Alpha antagonists
Clonidine
MOA: an alpha-2 adrenergic agonist; it controls symptoms of autonomic dysfunction through decreased sympathetic outflow from CNS
SEs: decrease in peripheral resistance, muscle relaxation, hypotension, bradycardia, and renal vascular resistance
- •
Disadvantage: less commonly used in spasticity given the side effects
Tizanidine
MOA: a central alpha-2 adrenergic agonist; increases presynaptic inhibition, reducing facilitation of spinal motor neurons
SEs: hypotension, drowsiness, dizziness, xerostomia, bradycardia
- •
Disadvantage: requires monitoring of liver function, blood pressure, renal function
Calcium channel
Dantrolene
MOA: interferes with excitation-contraction coupling in the muscle fiber by preventing release of calcium and thereby decreasing catabolic processes and spasticity
SEs: flushing, drowsiness, dysphagia, nausea, vomiting, hepatitis
- •
Disadvantage: has potential for hepatotoxicity and requires regular liver function tests
Marijuana/tetrahydrocannabinol
- •
Animal studies have identified activation of cannabinoid type 1 receptor, resulting in reduction in glutaminergic transmission and thus in reduction of spasticity.
- •
In humans, the data for use in spasticity is inconsistent and confounded by the multiple cannabinoid products; future studies are required to adequately assess the usefulness in spasticity.
Neurotoxins
Botulinum toxin A
MOA: binds to the c-terminus of the SNAP-25 protein
Examples: onabotulinum toxin A, incobotulinum toxin A, abobotulinum toxin A
SEs: weakness, anaphylaxis
- •
Advantage: works locally with few if any systemic side effects
- •
Disadvantage: effects last 2 to 6 months
Antibiotics
The use of antibiotics in the TBI population requires understanding of a few special principles. Those issues are described here:
- •
Beta-lactams (e.g., penicillins and cephalosporins) can lower seizure thresholds at high doses that penetrate the CNS or in patients with renal failure. The mechanism is thought to be through interfering with the inhibitory effects of GABA. The overall risk is thought to be low.
- •
Carbapenems readily penetrate the CNS and have an increased risk of seizure over the other beta-lactams through the same mechanism. In addition, they can significantly decrease valproic acid serum levels; therefore, their concomitant use is not recommended or an additional antiseizure medication should be administered.
- •
Fluoroquinolones have been implicated in seizure risk in patients with renal dysfunction. Fluoroquinolones have also been known to cause encephalopathies and delirium, which can be difficult to separate from posttraumatic confusion.
Sedatives/hypnotics
There are a number of possible reasons for the administration of these medications in the TBI population. Specific medications that are commonly used are described here.
Benzodiazepines
MOA: bind to GABA receptors and enhance the inhibitory effect of GABA; enhance inhibitory effect of GABA through increased neuronal permeability to chloride ions
Examples: lorazepam, diazepam, alprazolam, clonazepam
SEs: drowsiness, hypotension, dizziness, amnesia, disinhibition, agitation, respiratory depression, dependency/abuse, confusion, hypotension
- •
Disadvantage: relatively contraindicated in brain injury patients because of high risk of delirium, memory impairment, falls, and neurological recovery delay
Beta blockers
MOA: antagonize beta receptors
Examples: propranolol, carvedilol
SEs: Hypotension, bradycardia, dizziness, fatigue
- •
Advantage: Propranolol is considered first-line treatment for posttraumatic agitation/aggression; its CNS effects are a result of its highly lipophilic nature thus allowing it to readily cross the blood-brain barrier; the desired clinical effect for posttraumatic agitation often requires higher doses (200–400 mg/day).
- •
Advantage: Propranolol may also improve autonomic dysfunction in patients with severe TBI and paroxysmal sympathetic hyperactivity.
Doxepin
MOA: tricyclic antidepressant that has potent histamine (H1) antagonist effects at very low doses.
SEs: nausea, xerostomia, dizziness, hypertension, orthostatic hypotension, cardiac arrhythmias, extrapyramidal symptoms
GABA A–positive allosteric modulators or “Z drugs”
MOA: GABA A receptor agonist (specific sedating effects are induced via the α1 subtype)
Examples: zolpidem, zaleplon, zopiclone, eszopiclone
SEs: nausea, vomiting, drowsiness, anxiety, confusion complex sleep-related behavior, hallucinations, possible amnesia
- •
Advantage: similar to benzodiazepines, but they bind to GABA A receptors in a different manner; this reduces the risk of tolerance, dependence, and/or withdrawal; potential for complications remains however
- •
Advantage: Immediate-release formulations have a duration of action of 2 to 4 hours and facilitate sleep initiation more so than sleep maintenance.
- •
Advantage: The controlled-release formulations’ duration of action is 6 to 8 hours and therefore be more effective for sleep maintenance.
Melatonin
MOA: acts on melatonin receptors (MT1 and MT2) in the suprachiasmatic nucleus to induce sleep and facilitate normal circadian rhythms
SEs: usually benign, can cause nightmares, hallucinations, confusion, and vertigo
- •
Disadvantage: optimal dosing in the brain injury population is unclear; the unregulated and variable dosing of over-the-counter (OTC) formulations further complicates this issue
Prazosin
MOA: alpha-1 blocker; alpha-1 adrenergic receptor antagonist
SEs: Dizziness, headaches, drowsiness, weakness
- •
Mixed research on benefit for PTSD
Ramelteon
MOA: melatonin receptor (MT1 and MT2) agonist
SEs: drowsiness, dizziness
Suvorexant
MOA: antagonizes orexin 1 and orexin 2 receptors (dual orexin receptor antagonist), thereby facilitating both sleep initiation and maintenance
SEs: headaches, dizziness, abnormal dreams, diarrhea, xerostomia, cough, upper respiratory infection
Trazodone
MOA: at low doses, it acts as an effective sleep aid through its antagonism of serotonin (5HT2A), histamine (H1), and adrenergic (α1) receptors. ,
SEs: orthostatic hypotension, nausea, vomiting, QT prolongation, priapism
Neurostimulants/cognitive enhancers
There remains tremendous optimism in the rehabilitation field for medications to improve cognition or aspects of cognitive function after a TBI. As best described by Wortzel and Arciniegas, pharmacological interventions should be “best regarded as adjunctive to nonpharmacologic interventions.” Nonpharmacological cognitive interventions are prioritized given that most of the studies involving pharmacological interventions for cognition are rather small and somewhat underwhelming.
Amantadine
MOA: increases pre- and postsynaptic dopamine, dopamine receptor agonist, and uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist
SEs: orthostatic hypotension, dizziness, hallucinations, xerostomia, livedo reticularis, congestive heart failure exacerbation, neuroleptic malignant syndrome (with abrupt discontinuation)
- •
Advantage: often used in the TBI population for hypoarousal, akathisia, parkinsonism, impaired cognition, and posttraumatic agitation.
- •
Advantage: The best evidence lies in the disorders of consciousness population in which a randomized clinical trial found improvements in patients who were vegetative or minimally conscious.
- •
Disadvantage: A study of TBI patients who did not have a disorder of consciousness found no consistent cognitive improvement with amantadine.
- •
Disadvantage: must be renally adjusted based on creatinine clearance
Bromocriptine
MOA: D2 receptor agonist
SEs: dizziness, nausea, diarrhea, hypotension, hypoglycemia
- •
Advantage: Improves executive function in TBI patients
- •
Advantage: Due to its propensity to lower blood pressure, it is a good neurostimulant option for patients who are experiencing dysautonomia.
- •
Disadvantage: may result in orthostatic hypotension in some patients
Dextroamphetamine/amphetamine
MOA: promotes the release and inhibits the reuptake of norepinephrine and dopamine
SEs: hypertension, tachycardia, irritability, insomnia, appetite suppression
- •
Advantage: similar indications as methylphenidate but with less research
Donepezil
MOA: acetylcholinesterase inhibitors
SEs: nightmares, anorexia, nausea, vomiting
- •
Advantage: Donepezil may help with attention, working memory, and executive dysfunction, so it is often used in TBI. ,
- •
Advantage: Donepezil works centrally with minimal peripheral activity and may have fewer side effects than rivastigmine.
- •
Advantage: It is often given in the morning to improve performance during the day and limit nightmares.
Levodopa/carbidopa
MOA: Levodopa crosses the blood-brain barrier and serves as a dopamine precursor; carbidopa inhibits the peripheral metabolism of levodopa by inhibiting decarboxylation thereby increasing plasma levodopa levels.
SEs: orthostasis, nausea, hallucinations
- •
Advantage: can be used as a neurostimulant and/or for parkinsonism following brain injury
Memantine
MOA: strong NMDA receptor antagonist
SEs: tiredness, body aches, joint pain, dizziness, nausea, vomiting, diarrhea, constipation
- •
Advantage: benefit may have more to do with slowing secondary damage than improving the function in TBI
Methylphenidate
MOA: promotes the release and inhibits the reuptake of norepinephrine and dopamine
SEs: Hypertension, tachycardia, irritability, insomnia, appetite suppression
- •
Advantage: Studies in TBI population have demonstrated improvement in attention, poor initiation, hypoarousal, aphasia, executive dysfunction, depression, and apathy in TBI samples.
- •
Advantage: also has antidepressant properties as described in the Antidepressants section
- •
Advantage: Methylphenidate is not found to increase the risk of seizures in the TBI population.
Modafinil
MOA: exact mechanism not clear; increases dopamine by blocking dopamine transporters
SEs: dizziness, anxiety, insomnia
- •
Advantage: Food and Drug Administration (FDA)–approved indications are obstructive sleep apnea, narcolepsy, and shift work-related sleep disorder.
- •
Advantage: commonly used off label for hypoarousal and disorders of consciousness in the brain injury population
- •
See the Antifatigue Agents section for more information.
Rivastigmine
MOA: an acetylcholinesterase inhibitor
SEs: Anorexia, nausea, vomiting
- •
Advantage: Rivastigmine is typically tasked with improving attention, working memory, and executive dysfunction in TBI.
- •
Disadvantage: It may have more side effects than donepezil.
Antidepressants
Selective serotonin reuptake inhibitors
Selective serotonin reuptake inhibitors (SSRIs)are indicated for various neuropsychiatric disorders that may arise following a brain injury, including depression, anxiety, emotional lability, pathological laughing and crying, and posttraumatic agitation.
Among the SSRIs, there is considerable overlap in terms of side effect profiles, all possessing a sizeable risk of dizziness, insomnia, diarrhea, syndrome of inappropriate antidiuretic hormone secretion (SIADH), QT prolongation, and sexual dysfunction. Platelet inhibition and hemorrhage is another known effect, however the clinical implications vis-à-vis intracranial hemorrhage are not clear.
Each individual SSRI is noted to have distinct secondary pharmacological properties that result in additional unique therapeutic and adverse effects.
Citalopram
- •
Advantage: generally well tolerated
- •
Disadvantage: It has a high (maybe the highest) risk of QT prolongation of all SSRIs.
Escitalopram
- •
Advantage: It is considered to have the most favorable SE profile of all SSRIs.
- •
Disadvantage: likely prolongs the QT interval (Ojero-Senard)
Fluoxetine
- •
Advantage: the most activating of the SSRIs
- •
Advantage: It has demonstrated neurorecovery properties in stroke patients.
- •
Advantage: low risk of withdrawal symptoms upon abrupt discontinuation because of very long half-life
- •
Disadvantage: many drug interactions because of CYP450 inhibition
Paroxetine
- •
Disadvantage: It has limited utility in the brain injury population because of anticholinergic effects.
Sertraline
- •
Advantage: may be somewhat activating
- •
Advantage: well studied in TBI population , (Fann)
- •
Advantage: may help with aggression and irritability after TBI
- •
Disadvantage: lower risk of QT prolongation compared with other SSRIs
Serotonin-norepinephrine reuptake inhibitors
- •
Serotonin-norepinephrine reuptake inhibitors (SNRIs) are covered also in the Analgesics section.
Duloxetine
MOA: potent serotonin and norepinephrine reuptake inhibition; weak dopamine reuptake inhibition
SEs: nausea, headaches, fatigue
- •
Advantage: FDA approved for a variety of pain syndromes
- •
Advantage: less sedating than most other agents used for neuropathic pain
Venlafaxine
MOA: potent serotonin and norepinephrine reuptake inhibition, weak dopamine reuptake inhibition
SEs: nausea, insomnia, dizziness, hypertension
- •
Advantage: The extended-release formulation is better tolerated than the immediate-release formulation.
- •
Advantage: Metabolically, venlafaxine is converted into the active metabolite desvenlafaxine (another SNRI).
Tricyclic antidepressants
Although very effective antidepressants because of their serotonin and norepinephrine reuptake inhibition, tricyclic antidepressants (TCAs) should be used with caution after a TBI because of the anticholinergic, antihistaminic, and alpha-1 adrenergic effects; see Table 59.2 for a list of tricyclic antidepressants.
- •
TCAs are associated with an increased risk of cardiac arrhythmias and seizures.
- •
Amitriptyline has been used in TBI-related agitation and for posttraumatic headaches.
- •
TCAs are also covered in the Analgesics section.
Other antidepressants
Bupropion
MOA: several proposed mechanisms: norepinephrine-dopamine reuptake inhibitor (NDRI) or dopaminergic and serotonergic agonist
SEs: insomnia, headache, agitation, dizziness, xerostomia, weight loss, seizures
- •
Disadvantage: contraindicated in patients with history of seizures, which limits utility in the severe brain injury population
Methylphenidate
MOA: promotes the release and inhibits the reuptake of norepinephrine and dopamine
SEs: hypertension, tachycardia, irritability, insomnia, appetite suppression
- •
Advantage: Methylphenidate is proven to be an effective antidepressants in the TBI population, especially as an augment to SSRIs.
- •
Covered in the Neurostimulants/Cognitive Enhancers section.
Mirtazapine
MOA: noradrenergic and specific serotonin antidepressant (NaSSA); blocks presynaptic alpha-2 adrenergic receptors, thereby increasing the release of serotonin and norepinephrine; also blocks serotonin and histamine receptors
SEs: drowsiness, xerostomia, weight gain
- •
Advantage: can also be used as an effective appetite stimulant at low doses (typically 7.5 mg)
Agents for pathological laughing and crying
Pathological laughing and crying (PLC) or pseudobulbar affective disorder (PSA) are well recognized after TBI. SSRIs should be considered first line for PLC given effectiveness and rapid onset (often within a few days). TCAs, neurostimulants (amantadine, methylphenidate), and dextromethorphan/quinidine are also reasonable options.
Antipsychotics
Typical (first-generation) antipsychotics
- •
The typical antipsychotics act via widespread blocking of D2 receptors; very effective at controlling the positive symptoms of psychosis
- •
These drugs are associated with numerous undesirable side effects, including sedation, cognitive impairment, apathy, akathisia, hyperprolactinemia, anticholinergic effects, and movement disorders/extrapyramidal symptoms.
- •
These drugs may be used in the setting of acute agitation/aggression but are otherwise of very limited utility in the brain injury population.
- •
Haloperidol is the most commonly used typical antipsychotic.
- •
The authors of this chapter encourage you to use these medications as little as possible.
Haloperidol
MOA: widespread blocking of D2 receptors
SEs: Sedation, cognitive impairment, apathy, akathisia, hyperprolactinemia, anticholinergic effects, and movement disorders/extrapyramidal symptoms
- •
Disadvantage: likely prolongs the duration of posttraumatic amnesia (PTA) and may slow recovery ,
Atypical (second-generation) antipsychotics
- •
Like the typical antipsychotics, the atypical antipsychotics are effective at managing psychosis by blocking D2 receptors.
- •
Unlike the typical antipsychotics, however, these drugs also possess serotonin receptor antagonist activity that affords a lower risk of extrapyramidal symptoms and hyperprolactinemia.
- •
Atypical antipsychotics are more likely than the typical antipsychotics to cause cardiometabolic problems, including weight gain, hypertension, diabetes, elevated lipids, etc.
- •
Each of the specific agents within this class has unique properties and actions that may be useful for certain neurobehavioral sequelae after brain injury.
Aripiprazole
- •
Advantage: Unique MOA (partial D2 agonist) may help with depression.
Clozapine
- •
Advantage: may improve aggression and psychosis in TBI
- •
Disadvantage: hematological risk of life-threatening agranulocytosis and sedation
Olanzapine
- •
Advantage: may improve post-TBI psychosis ,
- •
Disadvantage: sedating and typically causes weight gain
Quetiapine
- •
Advantage: may decrease irritability, aggression, and psychosis
- •
Advantage: Questionable improvement in cognitive function
- •
Advantage: dose-dependent effect: sedative, antidepressant, antipsychotic
- •
Disadvantage: sedation and weight gain common
Risperidone
- •
Disadvantage: high risk of hyperprolactinemia
- •
Disadvantage: high risk of extrapyramidal syndrome
Ziprasidone
- •
Advantage: may help with rapid deescalation of aggressive behavior
- •
Disadvantage: increased risk of QT prolongation (Addiow)
Anxiolytics/mood stabilizers
Because anxiety and labile mood are often present after brain injury, neuropharmacological management is often attempted. This section will mention a few of the more common medications that can be used, but it should be stressed that the first-line approach should be psychological interventions, counseling, environmental strategies, and meditation.
Buspirone
MOA: unknown but likely related to its affinity for serotonin (5-HT1A) receptors
SEs: dizziness, nausea, headache, nervousness, lightheadedness, drowsiness, feeling tired, blurred vision
Divalproex
MOA: increases availability of GABA to neurons, blocks sodium channels and therefore decreases repetitive neuronal firing
SEs: headache, drowsiness, nausea, thrombocytopenia, diplopia
- •
Advantage: Although also used for seizures and migraine, divalproex and its cousin valproic acid are often used as mood stabilizers in TBI.
Lithium
MOA: unknown, but lithium interacts throughout the CNS and is thought to decrease norepinephrine release and increase serotonin synthesis
SEs: tremor, increased thirst, increased urination, diarrhea, vomiting, weight gain, impaired memory
Valproic acid
MOA: increases availability of GABA to neurons, blocks sodium channels and therefore decreases repetitive neuronal firing
SEs: headache, drowsiness, nausea, thrombocytopenia, diplopia
- •
Advantage: Serum levels can be checked to assist in preventing toxicity.
- •
Advantage: Wroblewski presented a case series that demonstrated improvements in depression and mania in TBI patients
- •
Advantage: In a study by Dikmen et al, valproate did not result in changes in cognition in a TBI sample; this may make valproic acid a good choice for those working on cognitive improvement
- •
Advantage: potent antiepileptic as discussed in the Anticonvulsants/Antiepileptic Medications section
Antifatigue agents
Fatigue is a common complaint after TBI, but there has been little success with pharmacological interventions.
Modafinil
MOA: exact mechanism not clear; increases dopamine by blocking dopamine transporters
SEs: dizziness, anxiety, insomnia
- •
Disadvantages: often used to assist with somnolence and posttraumatic narcolepsy; research with TBI populations is inconsistent (Castriotta) (Kaiser) (Jha)
- •
See section L for more information
Zolpidem
MOA: GABA A receptor agonist (specific sedating effects are induced via the alpha-1 subtype)
SEs: nausea, vomiting, drowsiness, anxiety, confusion, complex sleep-related behavior, hallucinations, possible amnesia
- •
Disadvantage: Despite evidence for improving consciousness in patients with disorders of consciousness, there is no evidence for improvement in fatigue or other psychological complaints (nonsleep issues) in TBI.
Problematic medications
Histamine-2 blockers
Histamine-2 blockers, including cimetidine, famotidine, nizatidine, ranitidine, and others, are often used to assist with gastroesophageal reflux disorder, gastritis, and gastrointestinal prophylaxis. There is a risk of worsening delirium and confusion with these medications.
Metoclopramide
Metoclopramide is often used for poor gastric motility. It has been observed to cause cognitive deficits and extrapyramidal side effects.
Opioids
Opioids are available in too numerous in formulation to name. Opioids are covered briefly in the Analgesics section. Although often necessary to control pain, they may cause somnolence, dizziness, and addiction. Recent epidemiological research indicates that TBI may make addiction more likely, thus the need to monitor closely.
Tricyclic antidepressants
Covered in the tend to have anticholinergic properties and should be avoided if possible.
Benzodiazepines
Benzodiazepines are thought to worsen cognitive deficits after TBI and increase somnolence. Please see the Hypnotics section for more information.
Anticholinergic medications
Anticholinergic medications are covered in various earlier sections. All medications with anticholinergic properties may cause anticholinergic side effects. There are peripheral anticholinergic effects such as decreased salivation, decreased bronchial secretions, and increased heart rate. There are central effects such as impaired concentration, confusion, attention deficit, and memory impairment. It is the central effects that are often problematic in the TBI population. See Table 59.3 for a list of anticholinergic medications.
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