THERAPEUTICS

Brands

• Akynzeo

Generic?

• No

Class

• Antiemetic

Commonly Prescribed for

(FDA approved in bold)

• Prevention of chemotherapy-induced nausea and vomiting (CINV)

• Nausea and vomiting (gastroenteritis, postoperative)

• Pruritus

How the Drug Works

• Netupitant: selectively inhibits substance P (vomit inducer) at neurokinin 1 (NK1) receptors with long-lasting brain receptor (brainstem, area postrema) saturation after single dose

• Palonosetron: second-generation 5-HT3 antagonist with higher binding affinity and longer plasma half-life. It may trigger 5-HT3 receptor internalization and prolong receptor inhibition

How Long Until It Works

• Typically less than an hour

If It Works

• Use at lowest effective dose

If It Doesn't Work

• Increase dose, or discontinue and change to another agent

Best Augmenting Combos for Partial Response or Treatment-Resistance

• May add D2 antagonist, antihistamine, benzodiazepine, or corticosteroid

Tests

• None required

ADVERSE EFFECTS (AEs)

How the Drug Causes AEs

• Not known

Notable AEs

• Headache, asthenia, dyspepsia, fatigue, constipation, and erythema

Life-Threatening or Dangerous AEs

• Serotonin syndrome

• Hypersensitivity reactions such as angioedema and Stevens-Johnson syndrome have been reported

Weight Gain

• Unusua

Sedation

• Unusual

What to Do About AEs

• Reduce dose or discontinuation

Best Augmenting Agents to Reduce AEs

• Symptomatic management

DOSING AND USE

Usual Dosage Range

• 1 capsule

Dosage Forms

• Capsule: 300mg netupitant and 0.5mg palonosetron

How to Dose

• One capsule 1 hour and dexamethasone 12mg 30 minutes prior to chemotherapy on day 1. Dexamethasone 8mg orally once daily on days 2 to 4 if under highly emetogenic chemotherapy (cisplatin)

Dosing Tips

• Can be taken with or without food. Only for short-term use

Overdose

• May develop drowsiness or headache

Long-Term Use

• Not been studied

Habit Forming

• No

How to Stop

• No need to taper

Pharmacokinetics

• Netupitant: Tmax: 5 hours. Half-life: 80 hours. > 99.5% protein bound. Metabolized by CYP3A4 and inhibits CYP3A4

THERAPEUTICS

Brands

• CellCept, Myfortic

Generic?

• Yes

Class

• Immunosuppressant

Commonly Prescribed for

(FDA approved in bold)

• Prophylaxis of organ rejection in patients with allogenic renal, cardiac, or hepatic transplants

• Myasthenia gravis (MG)

• Chronic inflammatory demyelinating polyneuropathy

• Neurosarcoidosis

• Multiple sclerosis (MS)

• Refractory uveitis

• Churg-Strauss syndrome

• Diffuse proliferative lupus nephritis

• Psoriasis

How the Drug Works

• Prodrug that is actively metabolized to mycophenolic acid, a selective inhibitor of inosine monophosphate dehydrogenase, an important enzyme in de novo synthesis of guanine nucleotide. This alters purine metabolism, which preferentially affects T and B lymphocytes, which depend on this pathway

• Inhibits proliferation of T and B lymphocytes and suppresses antibody formation

• May inhibit recruitment of leukocytes into sites of inflammation and graft rejection

• Does not affect production of interleukins

How Long Until It Works

• In as little as 2–3 weeks, and usually within 6 months

If It Works

• Usually used as a corticosteroid-sparing agent. May allow reduction in dose or discontinuation of corticosteroids. Most MG patients require long-term treatment, but occasionally may remit, allowing careful discontinuation

If It Doesn't Work

• Usually used as an adjunctive agent in conjunction with corticosteroids in MG. Azathioprine, cyclosporine, cyclophosphamide, plasma exchange, and IV immune globulin are alternative longterm treatments. Thymectomy may also be effective for selected patients

Best Augmenting Combos for Partial Response or Treatment-Resistance

• Generally combined with prednisone or other corticosteroids for treatment of MG, allowing eventual decrease in dose, and occasionally combined with other immunosuppressive agents

Tests

• Obtain a CBC when initiating treatment, then weekly in the first month, twice monthly in months 2–3, and monthly through the first year

ADVERSE EFFECTS (AEs)

How the Drug Causes AEs

• Serious AEs are related to immunosupression and neutropenia

Notable AEs

• Diarrhea is most common. Other frequent AEs include abdominal pain, insomnia, nausea, peripheral edema, anxiety, back pain or headache, cough, and mild leukopenia. GI bleeding can also occur

THERAPEUTICS

Brands

• Syprine

Generic?

• Yes

Class

• Chelating agent

Commonly Prescribed for

(FDA approved in bold)

• Wilson's disease (WD) in patients intolerant of penicillamine

How the Drug Works

• In WD copper accumulates in body tissues (especially the liver and CNS), causing neurological/psychiatric problems and/or liver failure. Trientine binds to (chelates) copper, allowing it to be excreted in the urine

How Long Until It Works

• 6 months or more

If It Works

• Continue treatment, if tolerated. Most patients remain on drug for the rest of their life but if serum copper returns to normal (< 10mcg/dL) consider changing to elemental zinc or zinc sulfate. Monitor for recurrence of symptoms or changes in urinary copper excretion

If It Doesn't Work

• Increase to as much as 2000mg daily for poor clinical response or if free serum copper is above 20mcg/dL. For liver failure or truly refractory patients, liver transplantation is curative

Best Augmenting Combos for Partial Response or Treatment-Resistance

• Change to penicillamine if ineffective. A diet low in copper-containing foods, such as nuts, chocolate, liver, and dried fruit, is recommended

Tests

• Adequately treated patients should have free serum copper below 10mcg/dL. Monitor 24-hour urinary copper excretion every 6–12 months (should be between 0.5 and 1mg)

ADVERSE EFFECTS (AEs)

How the Drug Causes AEs

• Unknown

Notable AEs

• Heartburn, iron deficiency anemia, anorexia, cramps, muscle pain, and epigastric pain have been reported. Rarely muscle spasm or dystonia has occurred. The relationship of these symptoms to trientine is unclear

Life-Threatening or Dangerous AEs

• Myasthenia gravis and systemic lupus erythematosus have been reported

Weight Gain

• Unusual

Sedation

• Unusual

What to Do About AEs

• Discontinue only for serious AEs

Best Augmenting Agents to Reduce AEs

• Most AEs cannot be reduced with the use of an augmenting agent

DOSING AND USE

Usual Dosage Range

• 1000–2000mg/day

Dosage Forms

• Tablets: 250mg

THERAPEUTICS

Brands

• Antivert, Bonine

Generic?

• Yes

Class

• Antiemetic

Commonly Prescribed for

(FDA approved in bold)

• Motion sickness

• Vertigo

How the Drug Works

• Antihistamine and anticholinergic drug

How Long Until It Works

• 30 minutes

If It Works

• Continue to use as needed, especially in shortterm disorders, such as viral labyrinthitis

If It Doesn't Work

• Treat the underlying disorder with appropriate agents for that disorder

• Benzodiazepines (Valium) may be effective for vertigo; antiemetics, such as promethazine, help also treat motion sickness

Best Augmenting Combos for Partial Response or Treatment-Resistance

• Benzodiazepines (Valium) may be effective for vertigo

• Meniere's disease: diuretics, antiemetics, and low-salt diet

• Vestibular rehabilitation may be helpful

Tests

• None

ADVERSE EFFECTS (AEs)

How the Drug Causes AEs

• Antihistamine and anticholinergic actions

Notable AEs

• Dry mouth, sedation are most common

• Paradoxical excitation (nervousness, agitation), blurred vision, rash, tinnitus

• Hypotension, tachycardia

Life-Threatening or Dangerous AEs

• May precipitate narrow-angle glaucoma

• Risk of heat stroke, especially in elderly patients

• Can precipitate tachycardia, cardiac arrhythmias, and hypotension

• May cause urinary retention in patients with prostate hypertrophy

Weight Gain

• Common

Sedation

• Common

What to Do About AEs

• Sedation: give at night or lower dose

• Dry mouth: chewing gum or water

Best Augmenting Agents to Reduce AEs

• Most AEs cannot be reduced with the use of an augmenting agent

DOSING AND USE

Usual Dosage Range

• Vertigo: 25–100mg/day

Dosage Forms

• Tablets: 12.5, 25, 50mg

• Chewable: 25mg

• Capsules: 25mg

How to Dose

• Motion sickness: 25–50mg 1 hour before travel

• Vertigo: 25–50mg 2–3 times daily (maximum 100mg/day)

Dosing Tips

• Taking with meals may reduce AEs

Overdose

• Large overdoses may cause convulsions, hallucinations, or respiratory depression

Long-Term Use

• Unknown, usually a short-term medication

Habit Forming

• No

How to Stop

• No need to taper

THERAPEUTICS

Brands

• Aggrenox

Generic?

• Yes

Class

• Antiplatelet agent

Commonly Prescribed for

(FDA approved in bold)

• To reduce risk of recurrent transient ischemic attack (TIA) or ischemic stroke (IS) due to thrombosis

• Adjunctive prophylaxis of thromboembolism after cardiac valve replacement (adjunctive with warfarin: use dipyridamole only)

How the Drug Works

• Aspirin: by acetylating cyclo-oxygenase-1 (COX-1), aspirin irreversibly inhibits thromboxane synthetase, reducing synthesis of thromboxane A2, a prostaglandin derivative that is a potent vasoconstrictor and inducer of platelet aggregation

• Dipyridamole: inhibits (1) thromboxane synthetase, (2) the cellular reuptake of adenosine into platelets, endothelial cells, and erythrocytes, and adenosine deaminase, which both increase extracellular adenosine levels leading to stimulation of platelet adenylate cyclase and inhibition of platelet aggregation, and (3) phosphodiesterase, augmenting the effect of endothelium-derived relaxing factor (nitric oxide)

How Long Until It Works

• 1–2 hours. Inhibits platelet aggregation for the life of the platelet (7–10 days)

If It Works

• Continue to use

If It Doesn't Work

• Only reduces risk of myocardial infarction (MI) or stroke. Warfarin is superior for cardiogenic stroke. Control all stroke risk factors such as smoking, hyperlipidemia, and hypertension. For acute events, admit patients for treatment and diagnostic testing

Best Augmenting Combos for Partial Response or Treatment-Resistance

• Combinations with other antiplatelet agents are not recommended

Tests

• None required

ADVERSE EFFECTS (AEs)

How the Drug Causes AEs

• Antiplatelet effects increase bleeding risk. Effects on nitric oxide may produce headache

Notable AEs

• Headache, abdominal pain, dyspepsia, nausea/vomiting, diarrhea, arthralgia, hypotension, epistaxis

Life-Threatening or Dangerous AEs

• GI, intracranial, or intraocular bleeding. Rare hepatic failure

Weight Gain

• Unusual

Sedation

• Unusual

What to Do About AEs

• For significant GI or intracranial bleeding, stop drug. For intolerable headaches, switch to 1 capsule at bedtime and low-dose aspirin in the morning for 1 week (headaches usually resolve in 1 week or less)

THERAPEUTICS

Brands

• Clozaril, Clopine, Fazaclo ODT, Versacloz, Denzapine, Zaponex, Leponex Generic?

• Yes

Class

• Antipsychotic

Commonly Prescribed for

(FDA approved in bold)

• Treatment-resistant schizophrenia

• Reducing suicidal behavior in patients with schizophrenia or schizoaffective disorder

• Dyskinesia

• Psychosis in patients with Parkinson’s disease (PD) or dementia with Lewy bodies (DLB)

• Bipolar disorder (treatment resistant)

• Severe psychosis

• Post-traumatic stress disorder

How the Drug Works

• It is a dibenzodiazepine derivative of high affinity for 5-HT2, α1/2, M1–5, and H1 receptors and moderate affinity for D2/4 receptors. The effect is likely from antagonizing D2 receptors (for positive symptoms) and 5-HT2A receptors (for negative symptoms)

How Long Until It Works

• Psychosis: may be effective in days, more commonly takes weeks or months to determine best dose and achieve best clinical effect

If It Works

• Continue to use at lowest required dose with appropriate monitoring. Patients with PD and DLB may improve more than patients with schizophrenia

If It Doesn't Work

• Increase dose

• In psychosis related to PD or DLB, eliminate or reduce dose of offending medications, such as dopamine agonists or amantadine

Best Augmenting Combos for Partial Response or Treatment-Resistance

• PD and DLB: cholinesterase inhibitors may reduce psychotic symptoms

• In dementia, SSRIs may improve behavioral symptoms

Tests

• Obligatory. Prior to starting treatment, obtain CBC, including white count and absolute neutrophil count. Repeat weekly for 6 weeks, then every other week as long as patient is on medication and for 4 weeks after stopping. Also monitor blood sugar periodically

ADVERSE EFFECTS (AEs)

How the Drug Causes AEs

• Motor AEs: blocking of D2 receptors

• Sedation, weight gain: blocking of H1 receptors

• Hypotension: blocking of α1/2-adrenergic receptors

• Dry mouth, constipation: blocking of muscarinic receptors (anticholinergic)

Notable AEs

• Most common: CNS (sedation, dizziness/vertigo, headache, tremor); cardiovascular (tachycardia, orthostatic hypotension, syncope); autonomic (hypersalivation, sweating, dry mouth, visual disturbance, urinary retention); GI reaction (GI hypomotility, constipation, nausea); and fever

THERAPEUTICS

Brands

• Frova, Migard

Generic?

• Yes

Class

• Triptan

Commonly Prescribed for

(FDA approved in bold)

• Migraine

• Menstrual migraine

How the Drug Works

• Selective 5-HT1B/1D/1F receptor agonist. In addition to vasoconstriction of meningeal vessels, its antinociceptive effect is likely due to blocking the transmission of pain signals at trigeminal nerve terminals (preventing the release of inflammatory neuropeptides) and synapses of secondorder neurons in trigeminal nucleus caudalis

How Long Until It Works

• 2 hours or less

If It Works

• Continue to take as needed. Patients taking acute treatment more than 2 days/week are at risk for medication-overuse headache, especially if they have migraine

If It Doesn't Work

• Treat early in the attack: triptans are less likely to work after the headache becomes moderate or severe, regardless of cutaneous allodynia, which is a marker of central sensitization

• Address life style issues (e.g., stress, sleep hygiene), medication use issues (e.g., compliance, overuse), and other underlying medical conditions

• Change to higher dosage, another triptan, another administration route, or combination of other medications. Add preventive medication when needed

• For patients with partial response or reoccurrence, other rescue medications include NSAIDs (e.g., ketorolac, naproxen), antiemetic (e.g., prochlorperazine, metoclopramide), neuroleptics (e.g., haloperidol, chlorpromazine), ergots, antihistamine, or corticosteroid

Best Augmenting Combos for Partial Response or Treatment-Resistance

• NSAIDs or neuroleptics are often used to augment response

Tests

• None required

ADVERSE EFFECTS (AEs)

How the Drug Causes AEs

• Direct effect on serotonin receptors

Notable AEs

• Tingling, flushing, dizziness, palpitations, muscle pain, sensation of burning, vertigo, sensation of pressure, nausea. Transient increase in blood pressure

Life-Threatening or Dangerous AEs

• Rare cardiac events including acute myocardial infaction, cardiac arrhythmias, and coronary artery vasospasm have been reported with frovatriptan

Weight Gain

• Unusual

Sedation

• Unusual

What to Do About AEs

• In most cases, only reassurance is needed. Lower dose, change to another triptan, or use an alternative headache treatment

THERAPEUTICS

Brands

• Comtan, Stalevo

Generic?

• No

Class

• Antiparkinson agent

Commonly Prescribed for

(FDA approved in bold)

• Parkinsonism, including Parkinson’s disease (PD)

How the Drug Works

• Highly selective peripherally acting inhibitor of catechol-O-methyltransferase (COMT), an important enzyme in dopamine metabolism. Use with carbidopa-levodopa enables more levodopa to enter the brain and prevents the end-of-dose wearing-off seen in PD. Entacapone has less activity on COMT in the brain, meaning the drug is not considered centrally active

How Long Until It Works

• PD: hours to weeks

If It Works

• PD: a majority (58%) of patients taking 800 mg or more per day of levodopa will lower levodopa dose, on average by 25% of the total after starting entacapone

If It Doesn't Work

• If end-of-dose wearing-off does not improve with entacapone and levodopa, decrease the dosing interval, add a dopamine agonist or monoamine oxidase B (MAO-B) inhibitor, or consider neurosurgical options. For sudden, unpredictable wearing-off, consider apomorphine

Best Augmenting Combos for Partial Response or Treatment-Resistance

• Entacapone is used only as an adjunctive medication in PD with levodopa

• For dyskinesias, lower dose of levodopa or add a dopamine agonist

• Younger patients with bothersome tremor: anticholinergics may help

• For severe motor fluctuations and/or dyskinesias with good “on” time, functional neurosurgery is an option

• Amantadine may help suppress dyskinesias, although benefit is often short-lived

• Depression is common in PD and may respond to low-dose SSRIs

• Cognitive impairment/dementia is common in mid-late stage PD and may improve with acetylcholinesterase inhibitors

Tests

• None required

ADVERSE EFFECTS (AEs)

How the Drug Causes AEs

• COMT inhibition increases the level and duration of action of levodopa

Notable AEs

• (Entacapone alone) diarrhea (usually mild to moderate), dyspnea, weakness. May increase levodopa-related AEs such as dyskinesias, nausea, orthostatic hypotension, and hallucinations

THERAPEUTICS

Brands

• Azilect

Generic?

• Yes

Class

• Antiparkinson agent

Commonly Prescribed for

(FDA approved in bold)

• Parkinson's disease (PD)

How the Drug Works

• Selectively blocks monoamine oxidase type B (MAO-B) and inhibits metabolism of dopamine, increasing its effectiveness. At higher doses, may affect MAO-A as well as MAO-B and inhibit metabolism of norepinephrine, serotonin, and tyramine, as well as dopamine

• It also exerts neuroprotective effects in preclinical studies

How Long Until It Works

• PD: weeks

If It Works

• PD: may require dose adjustments over time or augmentation with other agents. Most PD patients will eventually require carbidopalevodopa to manage their symptoms

If It Doesn't Work

• Bradykinesia, gait, and tremor should improve. If the patient has significantly impaired functioning, consider adding a dopamine agonist and/or carbidopa-levodopa

Best Augmenting Combos for Partial Response or Treatment-Resistance

• For suboptimal effectiveness consider adding a dopamine agonist and/or carbidopa-levodopa with or without a catechol-O-methyl transferase (COMT) inhibitor

• For younger patients with bothersome tremor: anticholinergics may help

• For severe motor fluctuations and/or dyskinesias with good “on” time, functional neurosurgery is an option

• Cognitive impairment/dementia is common in mid- to late-stage PD and may improve with acetylcholinesterase inhibitors

• For patients with late-stage PD experiencing hallucinations or delusions, consider oral atypical neuroleptics (quetiapine, clozapine). Acute psychosis is a medical emergency that may require hospitalization and short-term use of neuroleptics such as low-dose haloperidol

Tests

• Monitor for any changes in blood pressure

ADVERSE EFFECTS (AEs)

How the Drug Causes AEs

• Increases concentration of peripheral and CNS dopamine. At higher doses affects serotonin and norepinephrine levels

Notable AEs

• As monotherapy: flu syndrome, arthralgia, depression, dyspepsia, somnolence, hallucination, psychotic-like behavior, impulse control behaviors

• As adjunctive with levodopa: dyskinesia, accidental injury, weight loss, postural hypotension, vomiting, anorexia, arthralgia, abdominal pain, constipation, dry mouth, abnormal dream, and tenosynovitis

THERAPEUTICS

Brands

• Zanaflex, Sirdalud

Generic?

• Yes

Class

• α2-adrenergic agonist, muscle relaxant

Commonly Prescribed for

(FDA approved in bold)

• Acute and intermittent management of increased muscle tone related to spasticity

• Migraine prophylaxis

• Neck pain/lower back pain

• Myofascial pain

• Trigeminal neuralgia

How the Drug Works

• Central α2-adrenergic agonist (mostly at α2A receptors) that also acts at imidazoline receptors. Both α2A and imidazoline receptors are involved in the supraspinal inhibitory effects on mono- or poly-synaptic reflexes, hence reducing spasticity, which can result from neurological conditions, such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and spinal cord injury. α2A-agonist also increases presynaptic inhibition in locus coeruleus, periaqueductal gray area, and parabrachial nucleus, hence the anesthetic responses. Both receptors are involved in sympatholytic responses

How Long Until It Works

• Hours to weeks

If It Works

• Slowly titrate to most effective tolerated dose

If It Doesn't Work

• Increase to highest tolerated dose. If ineffective, gradually reduce dose and consider alternative medications

Best Augmenting Combos for Partial Response or Treatment-Resistance

• Botulinum toxin is effective, especially as an adjunct for focal spasticity, e.g., post-stroke or head injury affecting the upper limbs. For conditions with multiple areas of spasticity, i.e., cerebral palsy, this combination can be very useful

• May be used carefully in combination with baclofen, although additive sedation can be problematic

• Use other centrally acting muscle relaxants with caution due to potential additive CNS depressant effect

Tests

• Monitor liver and renal function at baseline and at 1, 2, and 3 months. Monitor hepatic enzymes at 6 months and periodically after that

ADVERSE EFFECTS (AEs)

How the Drug Causes AEs

• Related to α2 and imidazoline agonist effect, causing hypotension and increased sedation

Notable AEs

• Dry mouth, weakness, and somnolence are most common. Dizziness, hypotension, and elevation of hepatic transaminases. Hallucinations (usually visual) occur in about 3% of patients

Life-Threatening or Dangerous AEs

• Bradycardia and prolongation of QTc interval with higher doses. Tizanidine withdrawal can cause rebound hypertension

THERAPEUTICS

Brands

• Lyrica, Zeegap

Generic?

• No

Class

• Antiepileptic drug (AED)

Commonly Prescribed for

(FDA approved in bold)

• Partial-onset seizures (adjunctive for adults)

• Neuropathic pain associated with post-herpetic neuralgia

• Neuropathic pain associated with diabetic peripheral neuropathy

• Neuropathic pain associated with spinal cord injury

• Fibromyalgia

• Facial pain

• Panic disorder

• Mania or bipolar disorder

• Generalized anxiety disorder

• Alcohol/benzodiazepine withdrawal

How the Drug Works

• Structural analog of GABA that binds at the α2δ subunit of calcium channel (CACNA2D1) and reduces calcium influx. Modulates calcium channel function but not a channel blocker

• Reduces release of excitatory neurotransmitters, such as glutamate, norepinephrine, and substance P

• Inactive at GABA receptors and does not affect GABA uptake or degradation

How Long Until It Works

• Seizures: 2 weeks

• Pain/anxiety: days to weeks

• Fibromyalgia: often in the first week

If It Works

• Seizures: goal is the remission of seizures. Continue as long as effective and well tolerated. Consider tapering and slowly stopping after 2 years without seizures, depending on the type of epilepsy

• Pain: goal is reduction of pain. Usually reduces but does not cure pain and there is recurrence off the medication. Consider tapering for conditions that may improve over time, e.g., post-herpetic neuralgia or fibromyalgia

If It Doesn't Work

• Epilepsy: consider changing to another agent, adding a second agent, using a medical device, or a referral for epilepsy surgery evaluation. When adding a second agent, keep drug interactions in mind

• Pain: if not effective in 2 months, consider stopping or using another agent

Best Augmenting Combos for Partial Response or Treatment-Resistance

• Epilepsy: no major drug interactions with other AEDs. Using in combination may worsen CNS side effects or weight gain

• Neuropathic pain: TCAs, AEDs (gabapentin, pregabalin, carbamazepine, lamotrigine), SNRIs (duloxetine, venlafaxine, milnacipran, mirtazapine, bupropion), capsaicin, and mexiletine are agents used for neuropathic pain. Opioids (morphine, tramadol) may be appropriate for long-term use in some cases but require careful monitoring. Proven to decrease opioid requirements in patients with post-herpetic neuralgia

THERAPEUTICS

Brands

• Zelapar, Eldepryl, Emsam

Generic?

• Yes (as oral)

Class

• Antiparkinson agent

Commonly Prescribed for

(FDA approved in bold)

• Parkinson's disease (PD)

• Major depressive disorder, treatmentrefractory (patch only)

• Restless legs syndrome

• Anxiety disorders

• Alzheimer's and other dementias

• Migraine

How the Drug Works

• Selectively and irreversibly blocks monoamine oxidase type B (MAO-B) and increases extrastriatal extracellular dopamine levels. MAO-B is inhibited for at least 24 hours and the activity returns to baseline after 2 weeks. At higher doses, starts to affect MAO-A as well as MAO-B and inhibits metabolism of norepinephrine, serotonin, and tyramine, as well as dopamine

How Long Until It Works

• PD: weeks

• Depression, anxiety: usually months

If It Works

• PD: may require dose adjustments over time or augmentation with other agents. Most PD patients will eventually require carbidopa-levodopa to manage their symptoms

If It Doesn't Work

• Bradykinesia, gait, and tremor should improve. If the patient has significantly impaired functioning, add carbidopa-levodopa with or without a dopamine agonist

Best Augmenting Combos for Partial Response or Treatment-Resistance

• For suboptimal effectiveness, add carbidopa-levodopa with or without a catechol-O-methyl transferase (COMT) inhibitor or a dopamine agonist

• For younger patients with bothersome tremor: anticholinergics may help

• For severe motor fluctuations and/or dyskinesias with good “on” time, functional neurosurgery is an option

Tests

• Monitor for any changes in blood pressure

ADVERSE EFFECTS (AEs)

How the Drug Causes AEs

• Increases concentration of peripheral and CNS dopamine. At higher doses affects serotonin and norepinephrine levels

Notable AEs

• Nausea, hallucinations, confusion, lightheadedness, loss of balance, insomnia, orthostatic hypotension, hypertension, weight gain

Life-Threatening or Dangerous AEs

• Hypertensive crisis, especially at higher doses that prevent breakdown of tyramine (via MAO-A mostly). Tyramine-containing foods include aged cheeses, liver, sauerkraut, cured and processed meats, soy, alcohol (especially chianti wine and vermouth), and avocado

THERAPEUTICS

Brands

• Amethopterin, Emthexate, Ledertrexate, Maxtrex, Mexate, MTX, Otrexup, Trexall, Rheumatrex, Metoject

Generic?

• Yes

Class

• Antineoplastic agent, immunosuppressant

Commonly Prescribed for

(FDA approved in bold)

• Treatment of malignancies, including non-Hodgkin lymphoma, gestational choriocarcinoma, head and neck epidermoid cancer, and lung and breast cancer

• Psoriasis

• Rheumatoid arthritis

• Inflammatory myopathies: polymyositis (PM) and dermatomyositis (DM)

• Vasculitis, including Wegener’s granulomatosis

• Relapsing-remitting or chronic progressive multiple sclerosis (MS)

• Primary CNS lymphoma

• Ulcerative colitis or Crohn's disease

• Systemic lupus erythematosus

• Psoriatic arthritis

How the Drug Works

• Inhibits dihydrofolic acid reductase. Prevents synthesis of purine nucleotides and thymidylate. This interferes with DNA synthesis, repair, and replication

How Long Until It Works

• Within a week, but effect on neurological diseases may take months

If It Works

• DM/PM: improves strength, and may allow discontinuation or reduced dose of corticosteroids. Corticosteroids are tapered first. Taper slowly over 6 months if clinical remission occurs

• MS: may reduce relapses and new lesions on MRI

• Other disorders: Improves symptoms and clinical markers of the disease

If It Doesn't Work

• DM/PM: question the diagnosis (inclusion-body myositis, hypothyroidism, muscular dystrophy), rule out corticosteroid-induced myopathy, and evaluate for undiagnosed malignancy (especially in DM). Change to azathioprine

• MS: if clearly not helpful, change to another agent

Best Augmenting Combos for Partial Response or Treatment-Resistance

• Usually used in combination with corticosteroids (to reduce corticosteroid dose) in DM and PM. Occasionally combined with other treatments for the treatment of MS

Tests

• Obtain CBC, liver and renal function tests, and chest x-ray at baseline and at dosage adjustments, or for any clinical symptoms. Use serum level and WBC to assess response to treatment

ADVERSE EFFECTS (AEs)

How the Drug Causes AEs

• Folic acid antagonism

Notable AEs

• Ulcerative stomatitis, nausea, abdominal distress

• Malaise, fatigue, chills and fever, dizziness

• Headache, speech impairment, convusions, encephalopathy

• Rash or photosensitivity

• Elevated liver function tests (up to 15%)

THERAPEUTICS

Brands

• Mestinon, Mestinon Timespan, Regonal

Generic?

• Yes

Class

• Cholinesterase inhibitor

Commonly Prescribed for

(FDA approved in bold)

• Myasthenia gravis (MG)

• Reversal of non-depolarizing muscle relaxants

• Orthostatic hypotension

How the Drug Works

• It is a quaternary amine that reversibly inhibits the cholinesterase enzyme and improves the neuromuscular transmission in MG. It is poorly absorbed in the gut and does not cross the BBB

How Long Until It Works

• Orally about 30 minutes, IM form within 15 minutes, IV within 5 minutes

If It Works

• Continue to use to reduce symptoms of MG. Often combined with disease-modifying therapy such as immunosuppression or thymectomy

If It Doesn't Work

• Increase to the maximal dose: if no effect, question the diagnosis of MG. Remove potential offending medications. If not controlled at 240–360mg daily, consider immunomodulating treatment

Best Augmenting Combos for Partial Response or Treatment-Resistance

• Generally not combined with other symptomatic treatments. For refractory MG, add immunotherapy

Tests

• None

ADVERSE EFFECTS (AEs)

How the Drug Causes AEs

• Cholinergic properties of the drug

Notable AEs

• Muscarinic AEs include diarrhea, abdominal cramps, nausea, increased salivation, miosis, increased bronchial secretions, rash, worsening of bronchial asthma, and diaphoresis. Nicotinic AEs, including fasciculation and muscle cramping, are less bothersome

Life-Threatening or Dangerous AEs

• Bradycardia – possibly leading to hypotension – is most common with IV use

• Cholinergic crisis – worsening weakness, usually with overdose of drug and severe cholinergic AEs – is very rare

Weight Gain

• Unusual

Sedation

• Unusual

What to Do About AEs

• Lower to tolerable dose, take with food

Best Augmenting Agents to Reduce AEs

• Treat GI AEs with anticholinergics that do not affect nicotinic receptors (so no weakness): glycopyrrolate 1mg, propantheline 15mg, or hyoscyamine sulfate 0.125mg. Use 3 times a day or take with each pyridostigmine dose. For diarrhea try loperamide or diphenoxylate hydrochloride-atropine. To prevent bradycardia and excessive secretions with IV form, use atropine 0.6–1.2mg IV immediately prior

THERAPEUTICS

Brands

• Savaysa

Generic?

• No

Class

• Anticoagulant

Commonly Prescribed for

(FDA approved in bold)

• To reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF)

• Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5–10 days of initial therapy with a parenteral anticoagulant

• Prevention of DVT and PE

• Treatment of cerebral venous thrombosis

How the Drug Works

• Edoxaban is a selective inhibitor of the enzyme factor Xa (Stuart-Prower factor), which is the first member of the final common pathway of coagulation. It does not require antithrombin III for antithrombotic activity. It inhibits free factor Xa, and prothrombinase activity and inhibits thrombin-induced platelet aggregation. Inhibition of factor Xa in the coagulation cascade reduces thrombin generation and reduces thrombus formation

How Long Until It Works

• Peak effect in 1–2 hours

If It Works

• Monitor for signs of bleeding. Assess renal function periodically as clinically indicated

If It Doesn't Work

• Correct the underlying disorder. Use a higher dose or switch to different anticoagulant

Best Augmenting Combos for Partial Response or Treatment-Resistance

• Combining with antiplatelet agent may not always improve efficacy but definitely increases bleeding risk

Tests

• The degree of anticoagulation does not need to be assessed; PT, aPTT highly variable

• Assess renal function (CrCl) regularly

ADVERSE EFFECTS (AEs)

How the Drug Causes AEs

• Reduced coagulation due to inhibited thrombin formation

Notable AEs

• Bleeding, nausea/vomiting, constipation, abnormal liver function test, rash

Life-Threatening or Dangerous AEs

• From clinical trials, the yearly incidence of major bleeding is 3.1%, intracranial hemorrhage is 0.5%, GI bleeding 1.8%, and fatal bleeding (mostly intracranial hemorrhage) is 0.2%. Non-major bleeding 9.4%

Weight Gain

• Unusual

Sedation

• Unusual

What to Do About AEs

• Discontinue treatment, supportive care. Activated charcoal may reduce absorption

• Not effective: vitamin K, protamine sulfate, tranexamic acid, and hemodialysis

THERAPEUTICS

Brands

• Temodar, Temodal, Temcad, Methazolastone

Generic?

• No

Class

• Antineoplastic agent

Commonly Prescribed for

(FDA approved in bold)

• Refractory anaplastic astrocytoma

• Newly diagnosed glioblastoma multiforme (GBM) combined with radiotherapy

• Malignant prolactinoma

• Oligodendroglioma

• Primary CNS lymphoma

• Melanoma

How the Drug Works

• An alkylating agent prodrug whose clinical actions are due to metabolite methyl triazeno imidazole carboxamide (MTIC). The metabolites methylate DNA guanine bases, resulting in apoptosis of tumor cells. Treatment success is more likely in tumors with silencing of the O-6-methylguanine- DNA methyltransferase (MGMT) gene, which is important in demethylation

How Long Until It Works

• Used to prolong survival. Clinical benefits may be difficult to determine for weeks to months

If It Works

• May be continued for up to 6 cycles

If It Doesn't Work

• Discontinue treatment, consider alternative salvage chemotherapy such as bevacizumab or dexamethasone depending on clinical situation

Best Augmenting Combos for Partial Response or Treatment-Resistance

• Most patients will receive co-treatment with radiotherapy

• One small study shows potential benefit when combined with chloroquine. Another with the topoisomerase-1 inhibitor irinotecan

• O-6-Benzylguanine may be useful in those with treatment-resistant anaplastic glioma, but does not appear to be effective against GBM

Tests

• CBC before and during treatments, especially in elderly patients

• Chest radiographs in those at risk for Pneumocystis jiroveci pneumonia (PCP)

ADVERSE EFFECTS (AEs)

How the Drug Causes AEs

• Similar to other alkylating dugs, AEs are related to its effects on rapidly dividing cells

Notable AEs

• Most common: nausea/vomiting, constipation, alopecia, fatigue, anorexia, lymphopenia, thrombocytopenia

• Less common: rash, diarrhea, thrombocytopenia

Life-Threatening or Dangerous AEs

• Severe neutropenia and thrombocytopenia

• Toxic epidermal necrolysis and Stevens- Johnson syndrome have been rarely reported

• Opportunistic infections including PCP

• Rarely may cause respiratory failure

Weight Gain

• Unusual

THERAPEUTICS

Brands

• Banzel, Inovelon

Generic?

• No

Class

• Antiepileptic drug (AED)

Commonly Prescribed for

(FDA approved in bold)

• Adjunctive therapy for Lennox-Gastaut syndrome (LGS) in patients 4 years and older

• Tonic or atonic seizure

• Refractory bipolar disorder

How the Drug Works

• The exact mechanism is unknown but likely related to modulation of sodium channel activity and membrane stabilization. Rufinamide prolongs the inactive state of the sodium channel

How Long Until It Works

• Seizures: should decrease by 2 weeks

If It Works

• Seizures: goal is the remission of seizures. Continue as long as effective and well tolerated

If It Doesn't Work

• Increase to highest tolerated dose

• Epilepsy: consider changing to another agent, adding a second agent, using a medical device, or a referral for epilepsy surgery evaluation. When adding a second agent, keep drug interactions in mind

Best Augmenting Combos for Partial Response or Treatment-Resistance

• Generally used adjunctively in combination with other AEDs for refractory epilepsy

Tests

• No regular blood tests are recommended

ADVERSE EFFECTS (AEs)

How the Drug Causes AEs

• CNS AEs are probably caused by effects on sodium channels

Notable AEs

• Somnolence, fatigue, coordination abnormalities, anorexia, nausea/vomiting, headache, dizziness, tremor, nasopharyngitis, influenza

Life-Threatening or Dangerous AEs

• Suicidal ideation

• Blood dyscrasias including leukopenia

• Bundle branch and first-degree AV block infrequently occurred in clinical trials but the relationship of this to rufinamide is unclear

• Multi-organ hypersensitivity syndrome

Weight Gain

• Unusual

Sedation

• Not unusual

What to Do About AEs

• Decrease dose

• Taking drug in fasting state will lower absorption and may reduce both AEs and effectiveness

Best Augmenting Agents to Reduce AEs

• Most AEs cannot be reduced by use of augmenting agent

DOSING AND USE

Usual Dosage Range

• Epilepsy: 1600–3200mg/day in adults

Dosage Forms

• Tablets: 200 or 400mg

THERAPEUTICS

Brands

• Sabril

Generic?

• No

Class

• Antiepileptic drug (AED)

Commonly Prescribed for

(FDA approved in bold)

• Refractory complex partial seizures in patients ≥ 10 years of age, as adjunctive therapy in patients who have responded inadequately to several alternative treatments

• Infantile spasms: monotherapy in infants 1 month to 2 years of age

• Panic disorder

• Cocaine or methamphetamine dependence

How the Drug Works

• Inhibits catabolism of GABA by inhibiting GABA transaminase (GABA-T). This increases synaptic levels of GABA but does not act directly on GABA receptors. May decrease levels of excitatory neurotransmitters (glutamate, aspartate, glutamine) in the brain

How Long Until It Works

• Seizures: by 2 weeks

If It Works

• Seizures: goal is the remission of seizures. Continue as long as effective and well tolerated

• Monitor vision every 3–6 months

If It Doesn't Work

• Increase to highest tolerated dose

• Epilepsy: consider changing to another agent, adding a second agent, using a medical device, or a referral for epilepsy surgery evaluation. When adding a second agent, keep drug interactions in mind

Best Augmenting Combos for Partial Response or Treatment-Resistance

• Often used in combination with other AEDs. Lack of significant drug interactions makes it easier to use than many other AEDs

Tests

• No regular blood tests are recommended

ADVERSE EFFECTS (AEs)

How the Drug Causes AEs

• CNS AEs are probably caused by changes in GABA levels

Notable AEs

• Somnolence, fatigue, weight gain, headache, dizziness, anxiety, depression, ataxia, hyperactivity (children), psychosis (adults), upper respiratory tract infection

Life-Threatening or Dangerous AEs

• Retinal atrophy and visual field defects in about one-third of patients, peaking at 1 year but occurring as soon as a few weeks. Visual field loss may be irreversible

Weight Gain

• Not unusual

Sedation

• Not unusual

THERAPEUTICS

Brands

• Sativex

Generic?

• No

Class

• Cannabinoid

Commonly Prescribed for

(FDA approved in bold)

• Spasticity and spastic pain in multiple sclerosis (MS)

• Neuropathic pain

• Advanced cancer pain

• Pain in fibromyalgia, rheumatoid arthritis

How the Drug Works

• It is composed of 1:1 mixture of 2 cannabinoids: cannabidiol (CBD) and 9-δ- tetrahydrocannabinol (THC)

• THC, a partial agonist of both cannabinoid receptors (CB1, CB2) in brain and spinal cord, reduces spasticity but causes sedation and psychotropic side effects. Its action also involves analgesia, muscle relaxation, antiinflammation, neuroprotection, and anxiolysis

• CBD reduces sedation and psychotropic side effects

How Long Until It Works

• Minutes to hours

If It Works

• Takes weeks to months for full effect. Usually within 4 weeks

If It Doesn't Work

• Treat underlying conditions. Consider addition of other agents

Best Augmenting Combos for Partial Response or Treatment-Resistance

• For spasticity, may consider use of other centrally acting muscle relaxant or botulinum toxin

• For neuropathic pain, many consider use of TCAs, SNRIs, AEDs, and opioids

Tests

• None

ADVERSE EFFECTS (AEs)

How the Drug Causes AEs

• Related to CB1 and CB2 agonist effect in peripheral tissues, such as sympathetic ganglia, adrenal gland, heart, lung, reproductive tissues, urinary bladder, GI tract, immune cells

Notable AEs

• Sedation, dizziness, dry mouth, nausea, headache. Administration site irritation

Life-Threatening or Dangerous AEs

• Cardiac arrhythmia, myocardial infarction

• Operational hazard (driving, heavy machinery)

• Psychosis and dependence

Weight Gain

• Not unusual

Sedation

• Common

What to Do About AEs

• Lower the dose and titrate more slowly

Best Augmenting Agents to Reduce AEs

• Most AEs cannot be reduced by an augmenting agent

DOSING AND USE

Usual Dosage Range

• 5–12 sprays per day

Dosage Forms

• Buccal spray: THC 27 mg/mL and CBD 25 mg/mL

How to Dose

• First day: 1 spray every 4 hours, maximum 4 sprays

• Titrate: spread out the doses throughout the day. Watch for adverse reactions. Titrate to a tolerated dosage with acceptable pain relief

• Maximum: 12 sprays per day