Multiple Sclerosis (MS)

• Shorten the acute exacerbation
• Decrease the frequency of acute attacks and delay disease progression
• Relieve the symptoms to maintain the quality of life

Treatment strategies:

• a) Treatment of acute exacerbation
• b) Disease-modifying therapy
• c) Symptomatic treatment
• d) Non-pharmacological treatment

A) Acute exacerbations:

For patients presenting with functional impairment, in acute phase, the recommended first-line treatment is glucocorticoids.

• Methylprednisolone: 1 g/day IV usually for 3-5 days (but can be used up to 10 days). Maybe followed by a tapering dose of oral prednisone (e.g. 100 mg x 1 dose then decrease by 10 mg daily until finished)
• Prednisone: 500-1000 mg PO daily for 3-5 days. Maybe followed by a tapering dose of oral prednisone
• Plasma exchange:  Considered for steroid-resistant exacerbation

B) Disease-modifying therapy:

Indications:

• Relapsing-remitting (RRMS) phase
• Secondary progressive multiple sclerosis (SPMS)
• Primary progressive (PPMS)

Comparison of Oral Disease-Modifying Therapies in MS

Other agents which have been tried but without proven benefit include:

Cyclophosphamide:

• Dose: 700 mg/m² IV; every month along with 1 g of methylprednisolone
• Highly myelosuppressive; monitor absolute neutrophils count for dose adjustment

Other experimental modalities include:

• Hematopoietic stem cell transplantation

Intravenous immunoglobulin (IVIG):

• In the partum or immediate post-partum period
  • Induction with 0.4 g/kg daily for 5 days followed by monthly 1 g/kg

C) Symptomatic treatment:

• Inevitable as disease advances
• Complex due to the widespread compromise of CNS function

1) Spasticity:

Pain and constipation may trigger spasticity. Assess and treat before using antispasmodics.

Treatment:

Baclofen:

• Dose: 5-10 mg PO TID
• Maximum dose: 80 mg/day

Tizanidine:

• Dose: 2-4 mg PO TID
• Maximum dose: 36 mg/day

Gabapentin:

• Dose: Begin at 100 to 300 mg TID
• Effective dose range: 900-1800 mg/daily in 3 divided doses
• Maximum dose: 2400 mg-3600 mg/day

Diazepam:

• Dose: 5-10 mg PO TID PRN

Cannabinoids (delta-9-tetrahydrocannabinol & cannabidiol)

• Dose: Buccal 1 spray every 4 hr, 4-5 sprays/day for MS
• May start initially with 1 spray/day; increase every 1-2 days; Max. ~12 sprays/day

Caution: Abrupt discontinuation of the above agents may cause seizures and withdrawal symptoms.

Botulinum toxin:

• Dose-dependent on site of administration and severity of the disease

2) Fatigue:

May be characterized as:

• Neuromuscular fatigue
• Daytime drowsiness secondary to insomnia
• Fatigue associated with depression

Treatment:

Amantadine:

• Dose: 100 mg PO BID; may improve MS associated lassitude

Modafinil:

• Dose: 100 mg PO BID

Antidepressant:

• For fatigue associated with depression(e.g. fluoxetine)

Fampridine (4 aminopyridines):

• Dose: 10 mg PO daily

3) Pain:

• Acute or chronic pain is a frequent complaint in MS patients affecting the quality of life
• Chronic pain description include burning, squeezing, lancinating or gritty
• Neuropathic pain does not respond to NSAIDs

Treatment:

Gabapentin:

• Dose: Begin at 100 to 300 mg PO TID
• Effective dose range: 900-1800 mg/daily in 3-4 divided doses
• Maximum dose: 2400-3600 mg/day

Carbamazepine:

• Dose: 100-200 mg PO daily
• Increase up to a total daily dosage of 600-1600 mg (divided) as tolerated
• Monitor drug levels, CBC, LFTs

Tramadol:

• Dose: 50-400 mg PO daily as tolerated

Pregabalin:

• Dose: May begin with 25-75 mg PO daily and increase to 150 mg PO BID
• Effective dose range: 900-1800 mg/daily in 3-4 divided doses
• Maximum dose: 600 mg daily in divided doses

Cannabinoids(delta-9-tetrahydrocannabinol & cannabidiol)

• Dose: Buccal 1 spray every 4 hr, 4-5 sprays/day for MS
• May start initially with 1 spray/day; increase every 1-2 days; Max. ~12 sprays/day

4) Paroxysmal symptoms:

• Lhermitte sign or barber chair phenomenon (an electrical sensation that radiates down the vertebra on flexion or extension of neck)
• Intermittent vertigo

Treatment:

• Carbamazepine
• Gabapentin

5) Bladder dysfunction:

Bladder spasticity:

• Oxybutynin: 5 mg PO TID or QID
• Tolterodine: 2 mg PO BID
• Imipramine: Usual dose 75 mg PO daily
• Solifenacin: 5 mg PO daily
• Darifenacin: Extended-release 7.5 mg PO daily; may increase to 15 PO daily
• Trospium: 20 mg PO BID
• Intravesicular botox: 200 Units

Denervated bladder treated by:

• Self-catheterization

Nocturia, night-time incontinence/urgency:

• Desmopressin (DDAVP): 0.1-0.4 mg PO once at bedtime

6) Bowel dysfunction:

Constipation: can be treated with the combination of fiber and stool softeners.

• High fiber diet and stool softeners
• Docusate Sodium: 100 mg PO TID
• Stimulants: Senna suppositories 2 tabs at bedtime; digital stimulation sometimes used
• Adopting a bowel regimen may help to regulate urges and incontinence

7) Sexual dysfunction

Erectile dysfunction:

Oral agents:

• Sildenafil* 50-100 mg
• Vardenafil* 5-20 mg
• Tadalafil* 5-20 mg

*Give medication 30 minutes prior to intercourse; caution advised in the elderly and with cardiac disease.

Injectable agents (intracavernous):

• Alprostadil:
  • Begin with 2.5 mcg and titrate by 2.5 mcg increments
  • Initial administered under the supervision
  • Doses exceeding 40 mcg not recommended

Vaginismus:

• Antispasmodics

Vaginal dryness:

• Water-based lubrication

8) Depression

It can be managed through counseling and/or medication.

Tricyclic antidepressant

• Amitriptyline: 75-200 mg/day PO at night or in divided doses
• Imipramine: 75-150 mg/day PO at night or in divided doses
• Nortriptyline: 25-200 mg/day PO at night or in divided doses

Selective serotonin reuptake inhibitors (SSRIs)

• Fluoxetine: 20-80 mg PO once daily
• Paroxetine:
  • 20 mg PO once daily
  • May increase by 10 mg/day to a maximum of 50 mg/day
• Sertraline:
  • 50 mg PO once daily
• Citalopram:
  • 20 mg PO once daily; may increase by 20 mg/week to a maximum of 40 mg/day

Serotonin/norepinephrine reuptake inhibitors (SNRIs)

• Duloxetine:
  • Start 30-60 mg PO once daily; target dose 60 mg/day
  • May titrate dose by 30 mg/day if needed; Max. 120 mg/day
• Venlafaxine:
  • Start 37.5-75 mg daily; may increase by 75 mg/day as tolerated
  • Maximum 225 mg/day

Prognosis

• Variable and unpredictable
• If untreated, more than 50% of patients with multiple sclerosis will develop significant physical disability within 20-25 years from onset
• 70% of patients lead active, productive lives with prolonged remission
• 30% relapse in 1 year, 20% in 5-9 years, and 10% in 10-30 years
• Untreated MS Patients are thought to have an average life expectancy 5-7 years shorter than that of the general population

D) Non-pharmacological treatments

• Minimize exposure to exacerbating factors such as extreme temperature (hot tubs/saunas)
• A cooling vest or cold beverages may help lower body temperature
• Monitor for local sores and ulcers and take preventive measures before they become a source of infection
• Aerobic exercise may help prevent deconditioning
• Stretching exercises to help relieve stiffness
• Assistance with energy conserving techniques e.g. timed rest periods
• Bowel and bladder regimen to assist voiding; increase fiber and fluid intake
• Recommend self-catheterization where required
• Counseling: Psychologist, psychiatrist referral as required

[/cq_vc_tab_item][cq_vc_tab_item tabtitle=”Medication Dose”]MEDICATIONS:

ACUTE EXACERBATION-Medications

Corticosteroids

• Methylprednisolone
• Prednisone

Use: Acute exacerbations

Mechanism:

• Decreases inflammation and the normal immune response through multiple mechanisms, also suppresses adrenal function in higher doses

Doses:

Methylprednisolone

• 1-2 g/day IV usually for 3-5 days (but can be used up to 10 days). Maybe followed by a tapering dose of oral prednisone (e.g. 100 mg x 1 dose then decrease by 10 mg daily until finished)

Prednisone

• 500-1000 mg PO daily for 3-5 days followed by tapering doses

DISEASE MODIFYING-Medications

Interferon

Types:

• Interferon Beta-1a (IFNb-1a)
• Interferon Beta-1b (IFNb-1b)

Use: Immunomodulating therapy

Mechanism:

• Exact mechanism in the treatment of MS is unknown
• Immunomodulatory effects include
  • Enhancement of suppressor T cell activity
  • Reduction of pro-inflammatory cytokines
  • Down-regulation of antigen presentation
  • Reduced trafficking of lymphocytes into the central nervous system

Dose:

Interferon Beta-1a (intramuscular)

• 30 µg once weekly

Note:

• Should be stored in a refrigerator at 2-8°C. Allow to reach room temperature (about 30 minutes) before giving the injection
• Prefilled syringe can be stored at room temperature (between 15-30°C) for up to one week

Interferon Beta-1a (subcutaneous)

• Titrate to 22-44 µg 3 times per week, at least 48 hours apart
• 44 µg titration: 8.8 µg 3 times per week for 2 wks; then 22 µg 3 times per week for 2 wks; followed by 44 µg 3 times per week
• 22 µg titration: Start 4.4 µg 3 times/week for 2 wks; then 11 µg 3 times/week for 2 wks; followed by 22 µg 3 times/week

Note: Interferon Beta-1a new HSA-free formulation liquid in a pre-filled syringe or pre-filled cartridge should be stored at 2-8°C. Allow warming to room temperature prior to use; do not use external heat sources such as hot water. It can also be stored for a limited time period at room temperature (up to 25°C), but not more than 1 month.

• Stored at 2-8°C. Allow to warm to room temperature prior to use, Do not use external heat sources such as hot water
• May be stored for a limited period at room temperature (up to 25°C), but not more than 1 month

General Care:

• Protect injection from light and do not freeze
• Rotate injection site with each injection, to minimize the likelihood of injection site reactions
• NSAIDs, acetaminophen may be used for flu-like symptoms

Interferon Beta-1b

Multiple sclerosis (relapsing)

1. Titration: Increase by 0.0625 mg SC every 2 weeks as follows:
   • Week 1-2 = 0.0625 mg every other day
   • Week 3-4 = 0.125 mg every other day
   • Week 5-6 = 0.1875 mg every other day
   • Then 0.250 mg (target dose) every other day

Multiple sclerosis (secondary-progressive)

• Titration: 0.125 mg SC every other day for 2 weeks as follows; then 0.250 mg every other day

Note: Store between 2-25°C. After reconstitution, if not used immediately, refrigerate solution between 2 and 8°C and use within 3 hours of reconstitution.

IMMUNOMODULATOR

• Glatiramer acetate

Use: Immunomodulating therapy

Mechanism:

• Complete mechanism in the treatment of MS is unknown
• Supported hypothesis
  • Induces and activate T-lymphocyte suppressor cells specific for a myelin antigen
  • Interferes with the antigen-presenting function of certain immune cells opposing pathogenic T-cell function

Dose:

Glatiramer acetate:

• 20 mg SC once daily
• 40 mg SC 3 times per week

Sphingosine 1-phosphate receptor modulator

• Fingolimod

Use: Immunomodulating therapy

Mechanism:

Complete mechanism in the treatment of MS is unknown

• Binds to sphingosine 1-phosphate (S1P) receptors 1, 3, 4, and 5
• It’s binding to S1P receptors on lymphocytes induces S1P receptor down-regulation on lymphocytes, and blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood
• The amount of lymphocytes available to the central nervous system are decreased which reduces central inflammation

Dose:

Fingolimod:

• 0.5 mg PO once daily

Pyrimidine synthesis inhibitor

• Teriflunomide

Use: Relapsing forms of multiple sclerosis (MS)

Mechanism:

Exact mechanism of action in MS is unknown

• An immunomodulatory agent that inhibits pyrimidine synthesis by inhibiting dihydroorotate dehydrogenase enzyme
• It also has anti-inflammatory effects

Dose:

Teriflunomide:

• • 7 mg or 14 mg PO once daily (7 mg dose not available in Canada)

• • Drug elimination procedure

Immunomodulator

• Dimethyl Fumarate

Use: Treatment of adults with relapsing-remitting MS

Mechanism:

• Complete mechanism in the treatment of MS is unknown
• It is believed to result from its anti-inflammatory and cytoprotective properties via activation of the Nrf2 pathway

Dose:

Dimethyl Fumarate:

• Initiate 120 mg PO twice daily for 7 days; then increase to 240 mg PO twice daily

Selective Immunomodulators

• Alemtuzumab

Use: Adult RRMS

Mechanism:

• Binds to nucleic acids and inhibits DNA and RNA synthesis
• Replication is decreased by binding to DNA topoisomerase II
• Inhibit the incorporation of uridine into RNA and thymidine into DNA
• Active throughout entire cell cycle (cell-cycle nonspecific)

Dose:

Alemtuzumab:

• 300 mg IV once in 4 weeks

Selective adhesion molecule inhibitor

• Natalizumab

Use: Immunomodulation therapy

Mechanism(s):

Complete mechanism in the treatment of MS is unknown.

• Binds integrins on leukocyte cell walls, preventing migration into inflamed parenchymal tissue (monoclonal antibody)
• Potentially blocks of T-lymphocyte migration into the CNS

Dose:

Natalizumab:

• 300 mg IV infusion over 1 hour every 4 weeks

Immune Modifiers/Monoclonal Antibody

• Ocrelizumab

Use: Relapsing forms of multiple sclerosis (MS), to include

• Clinically isolated syndrome
• Relapsing-remitting disease
• Active secondary progressive
• Early Primary progressive MS

Mechanism:

• Selectively depletes CD20-expressing B cells
  • B cells have been implicated in the pathogenesis of MS
  • CD20 is a surface antigen found in pre-B cells and mature and memory B cells

Dose:

Ocrelizumab:

• Initial dose on day 1: 300 mg (in 250 ml) IV. Follow-up dose on day 15: 300 mg (in 250 ml) IV
• Maintenance: 600 mg (in 500 ml) IV every 6 months

NB: Premedicate 100 mg IV methylprednisolone (or alternative) and antihistamine (e.g. diphenhydramine), +/-  Acetaminophen ~30 minutes prior to each infusion.

NB: All vaccines should be updated at least 4 weeks before starting treatment; hepatitis B screening required. Hepatitis B virus screening. Monitor for allergic reactions, rash, laryngeal edema, dyspnea, infections; increased risk of respiratory infections.

Immune Modifiers/ Sphingosine-1-phosphate receptor modulator

• Siponimod

Use: Secondary Progressive MS (SPMS) with active disease evidenced by relapses or imaging features characteristic of multiple sclerosis inflammatory activity.

Mechanism:

• Retention of lymphocytes (B cells and CD4+ and CD8+ T cells) within lymph nodes and thymus leading to ~ 20% to 30% reduction in circulating lymphocytes and hence reduced lymphocyte transition into the CNS

Dose:

Siponimod:

• Genotype dependent: Treatment is highly dependent on the CYP2C9 genotype defining those with fast, intermediate, or slow metabolizers. Consequently, CYP2C9 genotype needs to be established prior to initiation of treatment
• Assess past and present medical history, including diabetes, ophthalmological disease, concomitant use of immunosuppressive therapy, history of varicella-zoster and cardiac history including the use of antihypertensive agents
• There is a risk of cardiac anomalies including bradyarrhythmias, conduction block, and QTc prolongation that increases as enzyme metabolism decreases, hence the maintenance dose is reduced in intermediate and slow metabolizers and contraindicated in those with the slowest metabolizer genotype (CYP2C9*3*3).  Obtain ECG prior to treatment to assess for pre-existing conduction abnormalities

Immune modifiers/Antineoplastic

• Mitoxantrone

Use: Immunosuppressant therapy

Mechanism:

The mechanism by which it exerts its therapeutic effects in MS is not fully known.

• The drug may involve immunomodulation through the depletion and repopulation of lymphocytes

Dose:

Mitoxantrone:

• 5-12 mg/m² IV every 3 months for 2 years, with maximum lifetime cumulative dose of 140 mg/m²

Antineoplastic/Immunosuppressant

• Cyclophosphamide

Use: Immunosuppressant therapy

Mechanism:

• An alkylating agent that prevents cell division by cross-linking DNA strands and inhibiting DNA synthesis
• Interferes with DNA replication and RNA transcription
• It is a cell cycle phase, nonspecific agent and potent immunosuppressive agent

Dose:

Cyclophosphamide

Various treatment protocols exist for cyclophosphamide and methylprednisolone one of them stated below:

• 800 mg/m² IV infusion given once every 4 weeks plus 1 g of methylprednisone. Dose adjustments based on preinfusion and 10 day post-infusion WBC

SYMPTOMATIC TREATMENT-Medications

Antispasmodic

• Baclofen
• Tizanidine
• Cannabinoids

Use: Spasticity

Mechanism:

Complete mechanism of action unknown.

Baclofen

• It inhibits both monosynaptic and polysynaptic spinal reflexes, possibly by hyperpolarization of afferent terminals (resultant relief of muscle spasticity)

Tizanidine

• It is chemically-related to clonidine and other α₂-adrenergic agonists, which acts as a centrally acting muscle relaxant with anti-hypertensive properties
• Presumably, it reduces spasticity by increasing presynaptic inhibition of motor neurons

Dose:

Baclofen

• 5-10 mg PO TID, may increase 5 mg/dose every 3 days; Max. 80 mg/day

Tizanidine

• 2-4 mg PO TID; may increase by 2-4 mg PO as needed to a maximum of 3 doses in 24 hrs, with at least 6-8 hrs interval between doses; Max. 36 mg/day

Dose in renal impairment:

• CrCl <25: Decrease dose (e.g. 2-4 mg PO)

Cannabinoids

• Buccal 1 spray every 4 hr, 4-5 sprays/day for MS, may start initially with 1 spray/day; increase every 1-2 d, Max ~12 sprays/day

Anticonvulsant:

• Gabapentin
• Carbamazepine

Gabapentin

Use: Neuropathic pain, Lhermitte’s, Seizures

Mechanism:

Exact mechanism of action unknown.

• It is structurally related to GABA (gamma-aminobutyric acid)
• It does not affect the synthesis or uptake of GABA
• High-affinity gabapentin binding sites have been located throughout the brain

Dose:

Gabapentin

• Begin at 100 to 300 mg TID; increase as tolerated every 3-7 days. Effective dose range: 900-1800 mg daily in 3 divided doses. Max dose: 2400-3600 mg/day

Dose in renal impairment:

• CrCl 30-60: 200-700 mg twice daily
• CrCl 16-29: 200-700 mg once daily
• CrCl 15: 100-300 mg once daily
• CrCl <15: Decrease dose proportionately to creatinine clearance
• Hemodialysis: Single dose of 125-350 mg as a supplement every 4 hrs of dialysis

Carbamazepine

Use: Neuropathic pain, Lhermitte’s, Seizures

Mechanism:

• Decreases synaptic transmission
• Within CNS by affecting sodium channels in neurons
• It had anticonvulsant, anticholinergic, antineuralgic, antidiuretic, muscle relaxant, antimanic, antidepressive, and antiarrhythmic properties

Dose:

Carbamazepine

• 100-200 mg/day PO; may increase up to a maximum of 600-1600 mg
• Monitor: CBC and risk of bone marrow suppression within the first 2 months of initiating therapy

Analgesic; Neuropathic pain

• Pregabalin
• Cannabinoids

Pregabalin

Primary use: Neuropathic pain may assist with Lhermitte’s; used for partial-onset seizures in some countries

Mechanism:

Exact mechanism of action is unknown.

• Binds to alpha₂-delta subunit of voltage-gated calcium channels within the CNS, inhibiting excitatory neurotransmitter release
• Produces antinociceptive and antiseizure effects

Dose:

Pregabalin

• 75-150 mg PO BID; Max. dose 600 mg daily in 2-3 divided doses

Dose in renal impairment:

Cannabinoids

• Buccal 1 spray every 4 hr, 4-5 sprays/day for MS, may start initially with 1 spray/day; increase every 1-2 d, Max. ~12 sprays/day

Benzodiazepine

• Diazepam

Use: Spasticity, anxiety, sedation

Mechanism:

• Binds to benzodiazepine receptors and enhances GABA effects
• Depresses the CNS, produces skeletal muscle relaxation, has anticonvulsant properties due to enhanced presynaptic inhibition

Dose:

Diazepam

• 5-10 mg PO TID PRN; can be given as monotherapy or in combination

Dopamine agonist

• Amantadine

Use: Fatigue

Mechanism: Unclear

Dose:

Amantadine

• 100 mg PO BID; Max. 300 mg PO daily in divided doses

Central nervous system stimulant

• Modafinil

Use: Fatigue in MS

Mechanism:

Exact mechanism of action is unknown.

• It may exert its stimulant effects by decreasing GABA-mediated neurotransmission

Dose:

Modafinil:

• 100 mg PO BID

Selective serotonin reuptake inhibitors (SSRIs)

• Fluoxetine

Use: MS induced fatigue, depression

Mechanism:

• Inhibits the presynaptic reuptake of neurotransmitters and increases synaptic serotonin concentration and potentiates its effect
• Little effect on the reuptake of norepinephrine or dopamine
• Does not significantly bind to alpha-adrenergic, histamine, or cholinergic receptors

Dose:

Fluoxetine

• Start 20 mg/PO daily every morning; may increase dose gradually after several weeks if inadequate response; Max. 80 mg/day

Potassium channel blocker

• Fampridine – Approved by Health Canada
• Dalfampridine – Approved by FDA

Use: Help to improve walking in patients with MS

Mechanism:

Exact mechanism of action is unknown.

• Inhibits potassium channels
• Delay repolarization and prolongs the duration of action potentials, improves conduction of action potentials in demyelinated axons

Dose:

Fampridine/Dalfampridine

• 10 mg PO every 12 hr

Opioid analgesic

• Tramadol

Use: Pain management

Mechanism:

The precise mechanism is unclear but may be related to:

• The binding of its active metabolites to mu-opioid receptors in the CNS which inhibits the reuptake of serotonin and norepinephrine
• The binding causes inhibition of ascending pain pathway which in turns alter the perception of and response to pain

Dose:

Tramadol

• 50-400 mg PO daily as tolerated

Anticholinergic

• Oxybutynin
• Tolterodine
• Solifenacin
• Darifenacin
• Trospium

Use: Urinary incontinence

Mechanism:

• Antagonizes the action of acetylcholine at postganglionic receptors
• Relaxes bladder smooth muscle, inhibits involuntary detrusor muscle contractions

Dose:

Oxybutynin

• 5 mg PO BID or TID; Max. of 5 mg PO 4 times a day

Tolterodine

• 2 mg PO BID

Solifenacin

• 5 mg PO daily, if tolerated may increase to 10 mg once daily
• Note: Maximum 5 mg/day if on potent CYP3A4 inhibitor

Darifenacin

• 7.5 mg PO daily; may increase if required at least after 2 weeks to 15 mg PO daily

Trospium

• Immediate-release: 20 mg PO BID
• Extended-release: 60 mg PO daily

Neuromuscular blocking agent, (Botulinum toxin)

• Botox

Use: Muscle spasticity, Urinary incontinence

Mechanism:

• Blocks neuromuscular conduction by binding to receptor sites on motor nerve terminals, inhibits the release of acetylcholine and produces a state of denervation that could last for weeks-months

Dose:

Botox (intramuscular)

• Exact dosage and number of injection sites are based on patient size, extent and location of muscles involved, severity of spasticity, presence of local muscle weakness, and response to prior treatment

Botox (intravesical)

• Recommended dose is 200 Units
• Treatment benefits usually last a minimum of three months.

Antidiuretic

• Desmopressin

Use: Nocturia

Mechanism:

• Increases cyclic adenosine monophosphate (cAMP) in renal tubular cells with an increase in water permeability in distal tubules and collecting ducts leading to decreased urine volume and increased urine osmolality
• Increases plasma levels of von Willebrand factor, factor VIII, and t-PA

Dose:

Desmopressin

• 0.1-0.4 mg PO daily at bedtime

Antidepressants

• Tricyclic antidepressant (TCAs)
• Selective serotonin reuptake inhibitors (SSRIs)
• Serotonin/norepinephrine reuptake inhibitor (SNRIs)

Tricyclic antidepressants (TCAs)

• Amitriptyline
• Imipramine
• Nortriptyline

Use: Depression

Mechanism:

• Inhibits the presynaptic reuptake of neurotransmitters, increases synaptic serotonin and/or norepinephrine
• Also has significant anticholinergic properties

Dose:

Amitriptyline

• Start 25-50 mg/day; may increase dose gradually; usual effective dose 75 to 200 mg PO daily or in divided doses; Max. 300 mg/day

Imipramine

• Start 75 mg/day and increase dose gradually to 150 mg PO daily or in divided doses; Max. 200 mg/day

Nortriptyline

• 25-50 mg/day PO; may increase gradually to 200 mg/day, if needed

Selective serotonin reuptake inhibitors (SSRIs)

• Fluoxetine
• Paroxetine
• Sertraline
• Citalopram

Use: Depression

Mechanism:

• Inhibits the presynaptic reuptake of neurotransmitters, increases synaptic serotonin concentration
• Little effect on the reuptake of norepinephrine or dopamine
• Does not significantly bind to alpha-adrenergic, histamine, or cholinergic receptors

Dose:

Fluoxetine

• Start 20 mg PO daily in the morning; may increase dose gradually after several weeks if inadequate response; Max. 80 mg/day

Paroxetine

• Immediate-release: Start 20 mg PO daily in the morning; may increase dose gradually by 10 mg/day after at least 1 week of interval; Max. 50 mg/day
• Controlled-release (CR): Start 25 mg PO daily in the morning; may increase dose gradually by 12.5 mg/day after at least 1 week of interval; Max. 62.5 mg/day

Sertraline

• Start 50 mg PO in the morning or at bedtime once daily; may increase dose gradually after at least 1 week of interval; usual dose 50-100 mg/day; Max. 200 mg/day

Citalopram

• Start 20 mg PO in the morning or at bedtime once daily; may increase dose gradually after at least 1 week of interval; usual dose 20-40 mg/day; Max. 60 mg/day

Serotonin/Norepinephrine reuptake inhibitors (SNRIs)

• Duloxetine
• Venlafaxine

Use: Depression, pain

Mechanism:

Exact mechanism of action is unknown.

• A potent serotonin and norepinephrine reuptake inhibitor
• Weakly inhibits dopamine reuptake

Dose:

Duloxetine

• 30-60 mg PO once daily; target dose 60 mg/day; may titrate dose by 30 mg/day if needed; Max. 120 mg/day

Venlafaxine

• 37.5-75 mg PO daily; may increase in ≤75 mg/day increments at intervals of ≥4 days as tolerated (maximum daily dose: 225-375 mg)

Stool softener

• Docusate sodium

Use: Stool softener

Mechanism:

• Facilitates mixture of stool fat and water
• May also promote electrolyte and water secretion into the colon

Dose:

Docusate sodium

• 100 mg PO TID

Phosphodiesterase type 5 inhibitors (PDE5 inhibitors)

• Sildenafil
• Tadalafil
• Vardenafil

Use: Erectile dysfunction

Mechanism:

• Does not directly cause penile erections
• Inhibits the enzyme phosphodiesterase type 5 (PDE5), which inactivates cGMP
• Enhances the effects of nitric oxide released during sexual stimulation
• Nitric oxide activates guanylatecyclase enzyme and increases cGMP level which leads to smooth muscle relaxation of corpus cavernosumhence promotes increased blood flow and subsequent erection

Dose:

Sildenafil

• 50-100 mg PO, prior to intercourse (~1 hour before)

Tadalafil

• 5-20 mg PO, prior to intercourse (at least 30 minutes)

Vardenafil

• 5-20 mg PO, prior to intercourse (~1 hour before)

Prostaglandin

• Alprostadil

Use: Erectile dysfunction

Mechanism:

• Vasodilator – relaxes arterial smooth muscle and dilates cavernosal arteries

Dose:

Alprostadil

• 2.5-40 mg intracavernosal injection

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