Exam 3 Flashcards
Seizures, opioids, non-cancer pain relief, multiple sclerosis
Drug class of clobazam
Benzodiazepine
Clobazam use
Adjunctive treatment of seizures associated with Lennox Gastsult syndrome in patients 2 years of age and older
Clobazam schedule
4
Clobazam dispensing requirement
Review med guide with every patient or caregiver
Ethosuximibe use
First line for absence seizures
Therapeutic level for ethosuximibe
40-100 mg/L (note: one of the few new AEDs that requires monitoring)
Ezogabine use
Adjunctive agent for partial seizures
Side effects of ezogabine
Dizziness, somnolence, urinary retention
Severe side effect of ezogabine
QT prolongation within 3 hours of administration
Ezogabine dispensing requirement
REMS for urinary retention, medication guide is available
Felbamate use
Reserved for patients not responding to other AEDs
Felbamate side effects
Aplastic anemia and acute liver failure
Felbamate dispensing requirement
Patient or guardian must sign consent form
Gabapentin use
Second line for partial seizures +/- generalizations (also largely used off label)
Off label use for gabapentin
Neuropathic pain, migraines, bipolar disorder
Important counseling point for how to take gabapentin
Do not discontinue abruptly, can cause withdrawal seizures even if not using the medication as AED
Why might gabapentin be adjusted in kidney disease?
Renal elimination, can accumulate and cause additional somnolence
Lacosamide use
adjunctive treatment of partial seizures
Lacosamide schedule
5
Lacosamide side effect
PR internval prolongation
Lacosamide dispensing requirement
Medication guide must be dispensed with each prescription
Important point about lamotrigine that pharmacists should look out for
LOTS of drug interactions
What is one common drug interaction with lamotrigine, what is the effect, and should this combination be avoided?
Valproic acid can increase lamotrigine serum concentrations by 200% (can be used together but need to start lamotrigine doses lower)
Lamotrigine side effect (SEVERE!) and how can we prevent?
Rash due to SJS, start low and go slow especially when given with valproic acid
Levetiracetam absorption and elimination
Completely absorbed after oral administration, renally eliminated
Important pearl about levetiracetam
No induction/inhibition hepatic interactions
T or F: oxcarbazepine is a prodrug of carbamazpine
False (but structurally related
Oxcarbazepine use
Potential 1st line agent for primary generalized convulsions
What makes oxcarbazepine different from carbamazepine? What makes them similar?
No auto-induction, less potent inducer than carbamazepine, possible cross-sensitivity for SJS rash between the two
Oxcarbazepine side effect
Hyponatremia
T or F: the dose of oxcarbazepine and carbamazepine are 1:1 (if F, how would you convert?)
False (CBZ dose per day * 1.5 = OXC dose per day)
Rufinamide use
Adjunctive treatment of generalized seizures of Lennox-Gastaut syndrome
Rufinamide side effect
QT shortening, Contraindicated in patients with familial short QT syndrome
Tigabine use
2nd line agent for partial seizures in patients who failed initial therapy
Important pearl about tigabine
No inhibition or induction of hepatic enzymes, but CYP3A4 substrate
Topiramate use in seizures
First line for partial seizures
Other common use for topiramate
migraine prophylaxis
Topiramate side effects (2 big ones)
CNS effects (psychomotor slowing, somnolence, irritability, slurred speech, confusion), kidney stones 2-4x normal
Vigabatrin use
Adjunctive for patients with really complex seizures
Vigabatrin dispensing requirement
REMS: causes permanent vision loss in infants, children, and adults (Blind as a BAT (vigaBATrin)); DO NOT CRUSH OR CUT; Prescribers and pharmacies must be registered with the program
Zonisamide side effect
SJS (d/c immediately)
Advantage of zonisamide
Long half-life, once daily dosing (others are normally 2-4!)
Role of CBD in seizures
major nonpsychoactive component of marijuana, expected to have anti-seizure properties, Potential alternative for refractory epilepsy in adults and children who do not respond to current medications, Epilepsy is one of 23 approved indications for medical marijuana in PA
Metabolism (enzymes) of medical marijuana
Metabolized by CYP3A4 and CYP2C19
Potential DDIs with medical marijuana
Induced by carbamazepine and phenytoin, Inhibited by ketoconazole
What important safety factor must we look out for with AED use?
Patients on AED have twice the risk of suicidal behavior
Common effect of epilepsy
Sexual dysfunction (caused by many different medications used to treat seizures as well!)
Important note about hormonal contraceptives with AEDs
Need at least 50mcg of ethinyl estradiol (decreases effectiveness)
What AED medication should usually be avoided in pregnancy?
Avoid valproic acid monotherapy or polytherapy in the first trimester
What supplement is important for pregnancy?
Folic acid
What is status epilepticus?
Neurologic emergency that can be associated with brain damage and death
Operational definition of SE
> 5 minutes of continuous seizure or >2 discrete seizures between which there is incomplete recovery of consciousness
Conceptual definition of SE
Condition resulting from either the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms that lead to abnormally prolonged seizures
Can have long term consequences, including neuronal death, neuronal injury, alteration of neuronal networks
2 types of SE and what they look like
Generalized SE: Characterized by repeated primary or secondary seizures that involve both hemispheres of the brain, Associated with persistent postictal state
Nonconvulsive SE: Fluctuating or continuous twilight state that produces altered consciousness and/or behavior
Common causes of SE
Structural lesion (stroke, anoxia, trauma, CNS tumor, hemorrhage) and no structural lesion (withdrawal of AED, alcohol withdrawal, CNS infection)
T or F: elderly patients have a higher mortality associated with SE than children
True
Variables in the mortality of SE
- Time between onset and treatment
- Duration of seizure
- Presence of structural damage
- Patient characteristics: older age, medical comorbidity, high initial APACHE-II scores
Complications of SE
- Rhabdomyolysis
- Lactic acidosis
- Aspiration pneumonitis
- Neurogenic pulmonary edema
- Respiratory failure
First steps in treating SE (before you even start)
- Assess vital signs
- Establish an adequate and protected airway
- Administer oxygen
- Obtain arterial blood gas
- Obtain blood sugar
- Perform an EEG if possible
Non-AED therapy for SE
Oxygen, correct electrolytes, cooling blanket, central IV line, if Wernicke’s encephalopathy (due to alcohol, if you don’t know just give it, it won’t hurt them) give thiamine, dextrose if hypoglycemic (if you don’t know, just give it, it won’t hurt them)
Treating SE: time 0 (3 distinct medications)
- If Wernicke’s encephalopathy is possible (occurs in alcoholics), give IV thiamine
- If hypoglycemia cannot be ruled out, give dextrose IV
- 1st line agents: benzodiazepines
What are the types of benzodiazepines that are used for SE and considerations for route of administration?
o Lorazepam considered first line
o Also can use diazepam, midazolam
o Give doses as IV (midazolam must be continuous infusion), IM route not preferred due to delay, can also give diazepam as rectal gel, also have intranasal diazepam (in patients as young as 6 years, weight-based dosing, can give 2 doses per episode) and midazolam (can give 2 doses per episode)
How do benzodiazepines work to stop seizure?
enhancement of GABA actions by helping GABA bind more tightly to the GABA receptor
Benzodiazepine side effects
hypotension, vasodilation, amnesia, drowsiness, headache, confusion
Treating SE: time 10-30 min (when benzo doesn’t work or seizure recurs)
2nd line agents: phenytoin IV or fosphenytoin
Important administration pearl for fosphenytoin (especially useful in SE emergency)
Can be given IM and if no central line is present, less hemodynamic effect
Treating SE: time 60 min
Additional bolus of phenytoin or fosphenyotin
Treating SE: time 90 min
3rd line agents: phenobarbital or valproic acid (most common this one)
Treating SE: refractory (list 3 possible medications and associated ADE)
- Continuous infusion of midazolam
- Continuous infusion of pentobarbital (associated with hypotension, may need pressor support) – not really used
- Propofol (may cause hypotension, bradycardia, hypertriglyceridemia)
Advantages of using newer AED (side effects, monitoring, dosing, DDI)
- Lower ADE rates
- Little or no need for serum monitoring
- QD or BID dosing
- Fewer drug interactions
- Pregnancy category C (not D!)
Important safety consideration for AED
Monitor patients for emergence or worsening of suicidal thoughts or behavior or depression
Phenytoin MOA
inhibition of voltage-dependent sodium channels
Phenytoin use
First line for primary generalized convulsive and partial seizures
Important point about dispensing phenytoin
Differences exist between different salt products (cannot substitute products!!)
How do tube feedings affect phenytoin?
Tube feedings decrease absorption (separate by 2 hours)
Phenytoin oral bioavailability
100%
How does protein binding affect phenytoin? Similarly, how does protein binding of phenytoin affect other drugs?
90% bound to albumin, free phenytoin is the part that causes therapeutic effect (therefore, less albumin, more free drug, more effect), low albumin levels caused by renal failure, malnutrition, burn patients
Drug interactions possible due to drug displacement from albumin (warfarin, valproate)
Volume of distribution consideration for phenytoin
Obesity increases volume of distribution, use adjusted body weight instead
Metabolism of phenytoin (what enzymes and kinetics?)
Extensive hepatic metabolism by CYP2C9/19
Zero order kinetics, metabolism saturates at doses used clinically (at saturation, small increases in dose can result in high serum concentrations)
Phenytoin elimination route
Renal
Loading dose for phenytoin
15-20 mg/kg IV at rate of <50mg/min
Why is there a rate limit for phenytoin administration?
Slow IV to avoid venous irritation, pain, thrombophlebitis, administration related hypotension and arrhythmias
Maintenance dose for phenytoin
300 mg/day (5-6mg/kg/day) in 1-3 divided doses
Concentration dependent ADE of phenytoin
lethargy, fatigue, in-coordination, blurred vision, dizziness, ataxia, nystagmus
Concentration independent ADE of phenytoin (think of the example pictures from lecture)
hypertrichosis, gingival hypertrophy, thickening of facial features, osteomalacia, folate deficiency, hypersensitivity reactions
Monitoring for phenytoin
BP, vital signs, plasma phenytoin, CBC, LFTs
Therapeutic range for phenytoin (and what do we measure?)
Total 10-20 mg/L; free 1-2 mg/L
Trough levels for therapeutic range
When should you obtain trough to test if dose is correct for patient?
Obtain 2-3 weeks after initiation or change of dose, Obtain trough about 30 minutes before next dose (lowest level)
Dose increases for phenytoin based off trough levels
If <7, increase by 100mg/day
If 7-12, increase by 50mg/day
If >12, increase by 30mg/day
If trough is subtherapeutic, but not zero, how should you fix this (and what is the calculation?)
Extra LD (if someone already has drug in the body, and drug level comes back low, don’t need to totally reload the dose, just need to give a little more) to achieve desired serum levels; then use table if normal renal function to change maintenance dose
IV dose (mg/kg)=(Cdesired-Cactual)*0.7
Correction for hypoalbuminemia
Ccorrected= Cobserved/(0.2(Alb+0.1))
Correction for renal failure
Ccorrected= Cobserved/(0.1(Alb+0.1))
T or F: fosphenytoin is a prodrug of phenytoin
True
How is fosphenytoin dosed and what is the loading dose?
Dosed by phenytoin equivalents (PE)
Loading dose: 10-20 mg/kg PE
Major benefit of fosphenytoin over phenytoin
Less infusion site reactions, can also give IM for those without IV access
Carbamazepine MOA
inhibition of voltage-dependent sodium channels, interaction with voltage-gated calcium and potassium channels
Carbamazepine use
First line for partial and primary generalized convulsive seizures who are not in an emergent situation
What pregnancy category is carbamazepine?
D
Difference in absorption of various formulations of carbamazepine
Erratic from IR tablets due to low water solubility, SR formulations minimize fluctuations
Describe the metabolism of carbamazepine (which enzyme and what makes this drug special)
Hepatic metabolism via CYP3A4, induces hepatic enzymes, auto-induction of its own metabolism
Describe how auto-induction of carbamazepine might affect dosing
Max auto-induction 2-4 weeks after initiation, Re-adjust dose at 3-4 weeks due to auto-induction
Starting dose, weekly increase, and target dose for carbamazepine
o Starting dose: 200 mg BID PO
o Weekly increase: 200 mg/day
o Usual dose: 800-1200 mg/day given in 2-4 divided doses (max 1600-2400 mg/day)
Important counseling point about carbamazepine ER capsules
ER capsules may be opened and sprinkled on food
Concentration dependent ADE of carbamazepine
nystagmus, ataxia, blurred vision, diplopia, vomiting, sedation, dizziness
Concentration independent ADE of carbamazepine
leukopenia, hypersensitivity
Carbamazepine FDA alert (what is it for, who does it affect, how does it affect them)
Screening of patients for Human leukocyte antigen (HLA) B*1052 allele, Present in patients with Asian ancestry
Strong correlation with allele and serious dermatologic reactions with carbamazepine (SJS, toxic epidermal necrolysis)
Patients who are positive should NOT be treated with carbamazepine
Carbamazepine monitoring
CBC with platelet count, serum iron at baseline and periodically, serum level
Therapeutic range for carbamazepine
4-12 mg/L
Valproic acid MOA
potentiate postsynaptic GABA responses, have a direct membrane stabilizing effect, affect potassium channels
Valproic acid use
First line for primary generalized seizures such as myoclonic, atonic, and absence seizures, can be used as monotherapy or adjunctive therapy for partial seizures, useful in patients with mixed seizure disorder
Important dispensing point about valproic acid
DO NOT substitute between dosage forms
DDI with valproic acid
Lots of CYP interactions
Increases carbamazepine
Increases lamotrigine
Increases free phenytoin
Increases phenobarbital
Aspirin increases valproic acid
Carbamazepine, phenytoin, and phenobarbital decrease valproic acid
Loading dose for valproic acid
15-20 mg/kg IV
Starting dose, weekly increase, and target dose for valproic acid
Initial: 10-15 mg/kg/day in 2-3 divided doses
Weekly increase 10 mg/kg/day
Target: 30-60 mg/kg/day in 2-3 divided doses
Dose dependent ADE for valproic acid
GI complaints (take with food), alopecia, thrombocytopenia, platelet dysfunction
Dose independent ADE for valproic acid
hepatotoxicity
Monitoring for valproic acid
baseline and periodically LFTs, CBC with platelets, serum valproate levels
Therapeutic range for valproic acid
50-100 mg/L total
Phenobarbital MOA
elevate seizure threshold by interaction with GABA receptors to facilitate intrinsic chloride channel function, blockade of high voltage calcium channels
Phenobarbital use
Drug of choice for neonatal seizures but is reserved in other situations for patients who have failed therapy with other AEDs, may be useful given IV in refractory SE
Loading dose for phenobarbital
15-20 mg/kg IV
How should we administer the loading dose of phenobarbital?
Avoid rapid administration due to hypotension, Use caution in hemodynamically unstable patients
Maintenance dose for phenobarbital
50-100 mg 2-3 times daily (1-3 g/kg/day in 1-2 doses)
Concentration dependent ADE for phenobarbital
sedation, respiratory depression, hypotension
Concentration independent ADE for phenobarbital
hypersensitivity reactions, hyperactivity, altered concentration, altered learning, depression
Therapeutic level for phenobarbital
15-40 mg/L
When is MS usually diagnosed? Who is at greater risk?
Diagnosed between 15 and 45 years old, women are greater risk than men
T or F: there are both genetic factors and environmental factors that play into the etiology of MS
True
Describe the pathophysiology of MS
Auto-reactive T lymphocytes are activated, cross into CNS, and attack myelin (Damage to myelin and underlying axon, damage to grey and white matter caused by inflammation involving activation of T cells)
T cells differentiate into T helper cells that induce pro-inflammatory response in which cytokines further activate B cells and macrophages
Immune system attacks the myelin sheath of neurons (Forms scar tissue (sclerosis), disrupted signals lead to neurological effects)
Why might MS diagnosis be delayed?
vague, transient symptoms may lead to delay in diagnosis
Primary symptoms of MS
Visual complaints, gait problems, paresthesia, pain, spasticity, weakness, ataxia, speech difficulty, psychological changes, cognitive changes, fatigue, bowel/bladder dysfunction, tremor, heat sensitivity
Describe the importance of heat sensitivity in MS
Many people with MS have worsening symptoms with increased body temperature, cooling may help (cooling vests), but very cold temperatures may cause spasticity
Secondary symptoms of MS
Recurrent UTI, urinary calculi, decubiti, muscle contractures, respiratory infections, poor nutrition
Tertiary symptoms of MS
Financial problems, personal/social problems, vocational problems, emotional problems
Four subtypes of MS (what are they and what are they defined by?)
Relapsing-remitting MS (RRMS): Clearly defined relapses with full recovery or with residual deficit following recovery
Secondary progressive MS (SPMS): Disease progression with or without occasional relapses, minor remissions, or plateau
Primary progressive MS (PPMS): Progressive from onset with occasional plateau and temporary improvements
Progressive relapsing MS (PRMS): Progressive from onset with acute relapses, with or without full recovery, and continuous progression between relapses
Factors for a favorable prognosis of MS
<40 yo, female, optic or sensory symptoms (as opposed to motor or cerebellar), low attack frequency early in disease, relapsing/remitting
Criteria for MS diagnosis (what does this include that was different from before?)
McDonald Criteria, includes MRI
CSF evaluation for MS
CNS synthesis of IgG is increased, whereas serum IgG is normal
Electrophoretic studies show oligoclonal bands, present in >90% of patients with clinically definite MS
After initial symptoms, CSF only positive in 30% of patients so analysis reserved for situations where need help to define more definitive diagnosis of MS
> 50x10^6 mononuclear cells in CSF indicated a diagnosis other than MS
What is the instrument used in the clinical evaluation of MS?
Expanded Disability Status Scale (EDSS)
Goals of MS treatment
Reduce the number of relapses, slow the rate of disability, reduce the number of brain lesions and the rate of brain atrophy
When should we start treating MS?
Start therapy immediately after diagnosis, shown to reduce second attacks, but does not suppress disease completely
What are the three categories of treatment of MS?
Acute attacks, disease-modifying therapy, symptomatic therapy
Goal of treating acute attacks of MS, how would you treat, and effect of treatment?
Shorten duration and perhaps severity
If functional decline: IV high dose corticosteroids 3-5 days (Methylpred 500-1000 mg/day)
May decrease edema in area of demyelination, may shorten duration of exacerbation and delay repeat attacks after optic neuritis, has not been shown to affect progression of disease
Goal of disease-modifying therapy and the four different algorithms for treatment
Goals are to decrease frequency and severity of exacerbations, diminish the progression of lesions seen on the brain and spine MRIs, and slow progression of disability over time
Safety (“tried and true”) approach: injection with interferon beta-1a, interferon beta-1b, or glatiramer
“Convenience” approach: oral therapy with dimethyl fumarate, teriflunomide, or fingolimod
“Efficacy” approach: infusion monotherapy with natalizumab or ocrelizumab
Stem cell transplantation: Eliminate and replace pathogenic immune system to achieve long-term remission, only small studies to date
Goal of symptomatic therapy for MS
Improve quality of life (gait difficulties, spasticity, fatigue, tremor, bowel and bladder symptoms, major depression, sensory symptoms, sexual dysfunction)
Treatment for gait difficulties (MOA, CI, ADE, DDI)
Dalfampridine (Ampyra)
CNS potassium blocker indicated to improve walking in patients with MS
Tablets should be take whole
CI: seizures, renal impairment
ADE: UTI, insomnia, dizziness, HA, nausea
DDI: metformin
Treatment for spasticity in MS (goal, non-pharm, 1st-3rd line treatments, ADE and MOA for 1st and 2nd line)
Reduce muscle tone to a degree that function is improved
Non-pharm: physiotherapy, structured exercise, transcranial magnetic stimulation, electromagnetic therapy
1st line: Baclofen
* GABA analog
* ADE: somnolence, confusion, motor weakness, must not be d/c abruptly (hallucinations and seizures)
2nd line: Tizanidine
* Centrally acting alpha-adrenergic agonist
* ADE: sedation, dizziness, dry mouth, hypotension, hepatotoxicity
3rd line: Clonazepam and Dantrium sodium less effective but alternative options
Non-pharm and pharm treatments for fatigue in MS
Non-pharm: aerobic exercise
Amantadine
* Caution with renal insufficiency
Modafinil
* CNS stimulant
* Can reduce hormonal contraception
Treatment for tremor in MS
Propranolol or primidone
Treatment for hyperreflexic bladder, hyporeflexic bladder, and overflow incontinence in MS
Hyperreflexic bladder (inability to store urine)
* Oxybutynin, tolterodine
Hyporeflexic bladder (failure to empty)
* Self-cath, risk of UTIs
Overflow incontinence
* Alpha blockers (terazosin, doxazosin, tamsulosin)
Treatment of constipation in MS
- Increase fiber and hydration
- Laxative or enemas
Treatment of depression in MS
SSRI
With concurrent pain, can use duloxetine
With fatigue, use fluoxetine or bupropion
Treatment of chronic pain in MS
carbamazepine
Treatment of burning sensations in MS
TCAs, carbamazepine, gabapentin
Treatment of neuropathic pain in MS
SNRIs, TCAs, gabapentin, pregabalin
Treatment of sexual dysfunction in MS
Sildenafil, tadalafil, vardenafil
Explain the relationship between vitamin D and MS
Increasing vitamin D levels may decrease severity of symptoms
Consider obtaining vitamin D level or providing supplementation to every patient with MS
Teriflunomide brand and route
Aubagio, oral
Teriflunomide ADE
Hepatotoxicity, pregnancy category X, dose related alopecia, diarrhea, nausea, flu, abnormal LFTs, paresthesia
Less common: lowered WBC, increased BP, severe liver damage, SJS, interstitial lung disease, acute renal failure
Teriflunomide monitoring
Undergoes enterohepatic circulation, so plasma levels are detectable for up to 2 years (can speed up with cholestyramine or activated charcoal)
Check LFTs before start, every month for 6 months
Check CBC before start, monitor for infection
Monitor renal fxn, electrolytes, BP
Many drug interactions (warfarin, CYP2C8, CYP1A2)
Dimethyl fumarate brand and route
Tecfidera, oral
Dimethyl fumarate ADE
Flushing (common, sensation of heat, itching, red blush), GI (N/D, upper GI pain)
Highest in first month, decreases after, taking with food may reduce GI ADE, flushing may be lessened with ASA given 30 min before dose
Dimethyl fumarate monitoring
Baseline CBC with lymphocyte, then Q6months
May cause lymphopenia, interrupt therapy if lymphocyte count less than 0.5x10^9 for more than 6 months
Monomethyl fumarate brand and route
Bafiertam, oral
Diroxemil fumarate brand and route
Vumerity, oral
Diroxemil fumarate ADE
Lower rates of GI ADE compared to dimethyl fumarate
T or F: diroxemil fumarate can be taken at the same time as dimethyl fumarate
False. Converts to same active metabolite as dimethyl fumarate, should not take concurrently but can be started day after ending the other
Fingolimod brand and route
Gilenva, oral
Fingolimod ADE and CI
Increased risk of life-threatening infections and tumor development
HA, diarrhea, back pain, elevated LFTs, cough
Less common: bradyarrhythmia and AV block
CI: recent hx of MI, stroke, TIA, HF, heart block, QTc >500, use with antiarrhythmics (amio or sotalol)
Pregnancy category C
Fingolimod monitoring
Before: CBC, LFTs, ECG, opthalmalogic exam, varicella serology and zoster vaccination if antibody negative
Avoid live attenuated vaccines
Eye exams every 3-4 months
Siponimod brand and route
Mayzent, oral
Siponimod ADE
CI: CYP2C93/3 genotype, recent MI, unstable angina, advanced HF, AV block
HA, HTN, increased transaminase
Dose-dependent decreased lymphocyte counts, infections, macular edema, bradyarrhythmia, liver toxicity
May cause fetal harm, avoid in pregnancy
Siponimod monitoring
Test for CYP2C9 genotype, CBC, LFT, varicella antibodies, ophthalmic, ECG
First dose: monitor for bradycardia and arrhythmias
Monitor LFT and BP during treatment
Ozanimod brand and route
Zeposia, oral
Cladribine brand and route
Mavenclad, oral
Cladribine ADE and CI
URIs, HA, lymphocytopenia
CI: patients with malignancy or active chronic infection
CI in pregnancy, breastfeeding, and for women and men or reproductive potential unless effective contraception for 6 months after last dose
Cladribine monitoring
Screen for infections, malignancy, pregnancy, baseline MRI
Lymphocyte counts before, during, and after treatment
Interferon beta-1a brand and route
Avonex, Rebif, injectable
Interferon beta-1a ADE and CI
Injection site redness and swelling, flu-like symptoms (can take NSAIDs, acetaminophen, steroids)
CI: severe depression, risk of suicide
Counsel on appropriate contraception
Interferon beta-1a monitoring
Baseline CBCs, platelets, LFTs at 1 month, Q3months x 1 year, then Q6months
Interferon beta-1b brand and route
Betaseron, Extavia, injectable
Peginerfon beta-1a brand and route
Plegridy, injectable
Glatiramer acetate brand and route
Copoxone, Glatopa, injectable
Glatiramer acetate ADE
SQ injection, mild pain and pruritus at site
Transient chest tightness, flushing, dyspnea if pt has no CAD, self-limited and benign
NO flu-like sx or depression
Pregnancy category B
Glatiramer acetate monitoring
No lab monitoring required
Ofatumumab brand and route
Kesimpta, injectable
Ofatumumab ADE and CI
URI, HA, injection-related reactions, serious infections
CI: active HBV infection
Females should use effective form of contraception during treatment and 6 months after stopping
Ofatumumab monitoring
HBV and quantitative serum immunoglobulins screening are required
Live vaccines not recommended
Alemtuzumab brand and route
Lemtrada, infusion
Alemtuzumab use
Reserve for patients with inadequate response to two or more MS therapies (safety profile)
Alemtuzumab premedication
Premedicate with corticosteroids, administer antivirals for herpetic prophylaxis
Alemtuzumab black box
Black Box: causes serious and sometimes fatal autoimmune conditions such as immune thrombocytopenia, infusion reactions, and increased risk of malignancies including thyroid cancer, melanoma, and lymphoproliferative disorders
Mitoxantrone brand and route
Novantrone, infusion
Mitoxantrone ADE
Nausea, alopecia, leukopenia
May impart blue-green color to urine, bluish color to sclera
Mitoxantrone monitoring
Ejection fraction (required before each dose), signs of CHF
Natalizumab brand and route
Tysabri, infusion
Natalizumab black box
Black Box: Reports of progressive multifocal leukoencephalopathy (PML) potentially lethal CNS infection caused by JCV, risk increases with number of infusions and also when used with other DMDs
Natalizumab use
Can be used as monotherapy but only in patients who have not responded to or do not tolerate others
Natalizumab ADE
Infusion reaction (rash, drowsiness, fever, chills, nauseas, flushing, decreased BP, SoB), HA, fatigue, UTI, depression, joint pain, abdominal pain
Natalizumab monitoring
JCV antibody every 3-6 months
Ocrelizumab brand and route
Ocrevus, infusion
Ocrelizumab premedication
Premedicate with methylpred and antihistamine
Ocrelizumab ADE
Infusion reactions and infections (upper and lower resp tract, skin infections)
Ocrelizumab monitoring
Hepatitis B screening before each dose
Rituxumab brand and route
Rituxan, infusion
Definition of pain
ill-defined, unpleasant sensation, evoked by an external or internal noxious stimulus
2 components of pain perception
o Nociceptive component
o Affective component
Two pain pathways
ascending and descending
What is transduction in the ascending pain pathway?
stimulation of nerve fibers known as nociceptors
What is conduction in the ascending pain pathway?
nociceptor activation leads to the conversion of a chemical signal into an electrical signal through voltage-gated sodium channels which produce generation of action potentials that are conducted along A-delta and C fibers to the dorsal horn of the spinal cord
What is the difference between the A-delta fiber and the C fiber?
- C fiber – slow conducting (aching, poorly localized, unmyelinated, small diameter)
- A-delta fiber – fast conducting (sharp, well-localized, myelinated, large diameter)
What is transmission in the ascending pain pathway?
nociceptive pain fibers synapse in various layers of the dorsal horn and convert the electrical signals back into chemical signal by releasing excitatory neurotransmitters such as glutamate and substance P. Pain signals reach the brain through a host of ascending spinal cord pathways. The thalamus acts as a relay station within the brain as these pathways ascend and pass the impulses to higher cortical structures
What is modulation in the descending pathway?
transmission can be facilitated by glutamate or substance P to make signals stronger, or the signal can be inhibited by descending pathways that consist of endogenous opioids (enkephalins and Beta-endorphins), GABA, norepinephrine, or serotonin
How do endogenous opioids exert inhibitory effects?
Endogenous opioids exert inhibitory effect on pain transmission through substantia gelatinosa
Sensory A-beta fibers stimulate release of met-enkephalin from interneurons of substantia gelatinosa and block pain transmission
How do exogenous opioids work?
Agonist (fentanyl, morphine, etc.) binding –> conformational changes in the GPCR (inhibition of adenyl cyclase, stimulation of K+ current, inhibition of voltage-gated calcium channels) –> decreased release of neurotransmitter (substance P, neurokinin A, neurokinin B, glutamate) –> hyperpolarization and relieves pain
Opioid classes and receptor type
Class –> Receptor type
Endorphins –> Mu
Enkephalins –> Delta
Dynorphins –> Kappa
Opioid receptor coupling and effects
Major opioid receptors are coupled to their effectors via G proteins
* Affect ion channel gating
* Modulate intracellular calcium disposition
* Alter protein phosphorylation
What are the two well established direct G-protein coupled actions on neurons and what is the effect?
Closure of voltage gated Ca+ channels –> on presynaptic nerve terminals, reduction and inhibition of neurotransmitter release
Opening of K+ channels –> inhibition of postsynaptic neurons
What is tolerance
With frequently repeated therapeutic doses of morphine, there is a gradual loss of effectiveness, larger dose must be administered
How does the body maintain normal sensitivty of recetors
Maintenance of normal sensitivity of receptors requires reactivation by endocytosis and recycling
Endogenous ligands result in this endocytosis followed by resensitization
Morphine fails to induce endocytosis
In contrast, methadone does induce receptor endocytosis
Structure activity relationship of endogenous opioids
the relationship between chemical structure and pharmacological activity for a series of compounds
What are the two regions of endogenous opioids
Message region: confers recognition at opioid receptors –> common sequence is Tyr – Gly – Gly – Phe
Address sequence: substype selectivity (mu, kappa, delta)
Metabolism steps for fentanyl
Fentanyl –> dealkylation (phase I rxn) –> norfentanyl
Biological activity of norfentanyl
Norfentanyl has no significant biological activity at the mu opioid receptor, “nor”= loss of functional group
Metabolism steps for codeine
Two pathways
Codeine –> N-demethylation –> Norcodeine (inactive)
Codeine –> O-demethylation –> morphine (active)
Morphine either then undergoes phase I demethylation to become normorphine or phase II reactions to become other morphine substrates
Metabolism steps for methadone
Two pathways
Methadone –> reduction –> methadol –> dealkylation –> normethadol –> dealkylation –> dinormethadol (active)
Methadone –> alkylation –> normethadone –> dealkylation –> dinormethadone –> reduction –> dinormethadol (active)
Explain the difference between methadone, buprenorphine, and naltrexone for medication assisted treatment (MAT) for opioids addiction
Methadone (full agonist) fully replacing the effect of whichever opioid the person is addicted to
Buprenorphine (partial agonist) partially replacing the effect of whichever opioid the person is addicted to
Naltrexone (antagonist) block the effects of opioids
What dose of morphine is associated with acute morphine poisoning?
> 50 mg, lethal dose is 250 mg
How to treat acute morphine poisoning?
Positive pressure respiration, IV fluids, gastric lavage, naloxone
How does naloxone work? How do we administer it?
Mu, kappa, and delta antagonist
Can reverse opioid overdose
If first dose does not work, can administer 2nd
Takes 2-5 minutes to take effect
Stays in system for one hour
* Shorter half-life than heroin
* Can go back into overdose after the hour
What is pain?
unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage
What is chronic pain?
pain lasting >12 weeks or >3 months
Describe the 3 different types of pain syndrome (include the definition and descriptors)
Somatic Pain: Pain arising from damage to muscle, bone, or skin; well localized; Sharp, intense, throbbing, localized
Visceral Pain: Pain arising from damage to organs; not well localized, can be referred; Gnawing, cramping, squeezing, diffuse, distant
Neuropathic pain: Pain arising from a lesion or disease of the somatosensory nervous system; Shooting, burning, numb, tingling, enhanced sensitivity to heat/cool
What are the parts of pain assessment?
P: precipitating/palliating
Q: quality (what kind of pain?)
R: region/radiating
S: severity
T: timing/temporal
U: utilization (what have you tried?)
V: values
What is osteoarthritis? Where is it most common?
Common degenerative disorder of the joints leading to hypertrophic bone changes
Most common in hands, knees, hips, and spine (asymmetric)
Symptoms of osteoarthritis
persistent joint pain, stiffness, locomotor restriction
Treatment algorithm for osteoarthritis
- Non-pharm (regular exercise, bracing, splinting)
- Topical NSAID –> systemic NSAID
- Consider opioids, but monitor for dependence
- Intraarticular injections
- Surgery
What is diabetic neuropathy?
Nerve damage caused by poorly controlled diabetes that leads to numbness in extremities
Most common microvascular complication of diabetes
What are the symptoms of diabetic neuropathy?
unprompted numbness, tingling, burning, shooting (symmetrical)
What are the risk factors of diabetic neuropathy?
poor blood sugar control, longer duration of diabetes, kidney disease, obesity, cigarette smoking
What is the treatment algorithm for diabetic neuropathy? Include which agents are first and second line.
- Non-pharm (optimize glycemic control)
- 1st line: antidepressants (duloxetine) and anticonvulsants (pregabalin and gabapentin)
- 2nd line: antidepressants (venlafaxine and amitriptyline), topical (lidocaine patch and capsaicin), opioid (tramadol and tapentadol)
What is fibromyalgia?
Widespread soft tissue pain affecting muscles, ligaments, tendons with no obvious objective abnormalities
What are the symptoms of fibromyalgia?
diffuse musculoskeletal pain present for >3 months, often accompanied by fatigue, headache, cognitive disturbance, and sleep disturbance
Treatment algorithm for fibromyalgia
- Non-pharm
- Pharm –> target bothersome symptoms
For sleep disturbances, use amitriptyline, cyclobenzaprine, pregabalin, gabapentin
For depression/anxiety, use duloxetine, milnacipran, amitriptyline, pregabalin
What is post herpetic neuralgia
Pain in a dermatomal distribution caused by nerve damage secondary to an inflammatory response induced by viral replication (herpes zoster) within a nerve sustained for at least 90 days after acute herpes zoster
What are the symptoms of postherpetic neuralgia
burning, shock-like pain, may be associated with allodynia (pain from stimuli which are not normally painful) or hyperalgesia (abnormally heightened sensitivity to pain)
What are the risk factors of post herpetic neuralgia?
immunosuppression, advanced age, female, underlying diabetes
Treatment algorithm for post herpetic neuralgia
1st line: gabapentin, pregabalin, lidocaine patch, capsaicin cream
2nd line: TCAs
3rd line: opioids (not preferred)
What is acetaminophen used for? How is it used?
OA
max dose 3000mg OTC, 4000mg Rx
What are NSAIDs used for and how are they used?
OA
Topical or systemic Q6-12H
Diclofenac gel: 2-4g, 4x/day, max 32 g/day
Which NSAID is hardest on the GI tract? Which can be used?
Ketorolac, use celecoxib/ibuprofen
Which NSAID should be used with CV risk factors? Which should be avoided?
Use naproxen, avoid celecoxib/diclofenac
Which NSAID should be used with renal risk factors?
Use celecoxib/diclofenac, avoid naproxen (opposite CV risk factors)
What is the order of NSAIDs from most COX-2 selective to most COX-1 selective?
My Crazy Dad Is Not In the Kitchen
Meloxican, celecoxib, diclofenac, ibuprofen, naproxen, indomethacin, ketorolac
What are topicals used for?
Neuropathic, OA
Which topical is used for diabetic neuropathy? How long do they take to work?
capsaicin patches and cream, helpful for pain that responds to heat, see relief in 2-4 weeks
Which topical is used for post herpetic neuralgia?
Lidocaine patches
What type of pain are antidepressants used for?
Neuropathic pain
Which antidepressants are used for diabetic neuropathy? For fibromyalgia? For post herpetic neuralgia?
Diabetic: venlafaxine, duloxetine, amitriptyline, nortriptyline, desipramine
Fibromyalgia: duloxetine, milnacipran, amitriptyline
Post herpetic neuralgia: amitriptyline, nortriptyline, desipramine
How long does it take to see results from antidepressants for pain?
4 weeks
What pain syndromes are anticonvulsants used for?
Neuropathic pain
What type of anticonvulsants are gabapentin and pregabalin?
Calcium channel blockers
How long does it take to see pain improvement with anticonvulsants?
1-2 weeks (shorter for pregabalin)
Advantages of pregabalin over gabapentin
Faster onset, higher bioavailability, dose can be titrated more rapidly, BID dosing
Disadvantages of pregabalin
Higher risk of peripheral edema, schedule IV, more expensive, dose reduction for renal impairment (gabapentin needs this too)
What type of pain are skeletal muscle relaxants used for? How are they used?
Muscle spasms, TID PRN
What is the role of opioids in non-cancer pain?
LAST line, use lowest effective dose
6 A’s for monitoring of opioid use
analgesia, affect, activities, adjuncts, ADE, aberrant behavior
What is a seizure? How are they triggered?
Seizure: disorder viewed as a symptom of disturbed electrical activity in the brain
Disruption of homeostasis of neurons and their stability, which may trigger hyperexcitability
Describe the occurrence of first seizure in terms of likelihood based on age
Bimodal distribution of first seizure occurrence (either infants or elderly usually)
What is epilepsy?
chronic disorder of recurrent, unprovoked seizures
List characteristics for increased seizure risk
Genetic mutations
Patients with cerebral palsy, head injury, strokes
Factors that may precipitate seizures
Hyperventilation, sleep deprivation, stress, hormonal changes, puberty, menses, photo-stimulation
Medications
Sub-therapeutic anti-epileptic drug (AED) levels
Withdrawal of CNS depressants
Antibiotics (penicillin, cephalosporins, ciprofloxacin, carbapenems)
Bupropion
SSRIs (if serotonin syndrome develops)
Theophylline
Meperidine (especially with renal dysfunction)
Overdose (Effexor, TCAs, salicylates, tramadol)
What are seizures in terms of pathophysiology?
Seizures result from excessive excitation of a large population of cortical neurons
Normal membrane conductance and inhibitory synaptic currents break down
Mechanisms that contribute to hyperexcitability
Alterations in the distribution number, type, and biophysical properties of ion channels in the neuronal membranes
Biochemical modifications of receptors
Modulation of second messaging systems and gene expression
Changes in extracellular ion concentrations
Alterations in neurotransmitter uptake and metabolism
Modifications in the ratio and function of inhibitory circuits
Mechanisms of control of abnormal neuronal activity (how do the AEDs work?)
Elevating the threshold of neurons to electrical or chemical stimuli
* Involves stabilization of neuronal membranes
Limiting the propagation of the seizure discharge from the origin
* Depression of synaptic transmission and reduction of nerve conductance
How are seizures classified? (what is looked at clinically?)
EEG and symptoms
What is a partial (focal) seizure? How does it manifest?
Begin in one hemisphere and result in asymmetric motor manifestation
Can manifest as changes in motor function, sensory, or somatosensory symptoms, or automatisms (brief set of unconscious behaviors like lip smacking or finger rubbing)
What are the 3 types of partial seizure?
Simple partial: WITHOUT loss or change of consciousness
Complex partial: WITH loss or change of consciousness
Secondary: partial onset which evolves into generalized tonic-clonic seizure
What is a generalized seizure? How does it manifest?
Clinical manifestations that indicate involvement in both hemispheres
Bilaterally symmetrical without local onset
Loss of consciousness
What are the 6 types of generalized seizures?
Absence, myoclonic, clonic, tonic, tonic-clonic, atonic
Describe absence seizures
Sudden onset, interruption of ongoing activities, blank stare, possibly brief upward rotation of the eyes
Commonly occurs in young children
Describe myoclonic seizures
Brief shock-like contractions of the face, trunk, and extremities
Describe clonic seizures
Contraction of muscles into a rigid position
Describe tonic-clonic seizures
Sudden sharp contractions followed by a period of rigidity
Patients may moan, cry, lose sphincter control, bite the tongue, develop cyanosis
Describe atonic seizures
Sudden loss of muscle tone
Head drop, dropping of a limb, slumping to the ground
Patients often wear protective head gear
What are idiopathic seizures?
no identifiable cause
What are secondary seizures caused by?
Infections, fever, intracranial events, toxins, metabolic
What are febrile seizures? Who are they most common in?
Occurs primarily in children between 6 months and 6 years
Seizures develop as the temperature is increasing rapidly but may develop as the fever is declining
Can occur during both viral and bacterial infections
Majority have the seizure on the first day of illness, often first sign child is sick
T or F: only high temperatures lead to febrile seizures
False
T or F: febrile seizures require daily AED
False
T or F: usually children who have a febrile seizure will not have another
False, children with febrile seizures are at risk for developing recurrent febrile seizures
What is the most important cause of symptomatic epilepsy in people 15-24 years old?
TBI (traumatic brain injury)
T or F: the less severe the injury, the longer the patient is at risk for late seizures
False. More severe the injury, longer the patient is at risk for late seizures
Mild TBI at risk for 5 years, moderate for 10 years, severe for 20+ years
What is the difference between early seizures after TBI and late seizures after TBI?
Early seizures (within 7 days of TBI): Acute symptomatic events with a low likelihood of recurrence, prophylaxis with antiepileptic drugs is used to prevent early post-traumatic seizures (has been shown to reduce number of early seizures)
Late seizures: represent epilepsy
T or F: AED are always initiated after the 1st seizure
False, started after the 2nd seizure, not usually initiated after 1st seizure unless:
Abnormalities on EEG
Remote symptomatic cause
Abnormal neurologic examination
T or F: we should always try to use multiple AED for patients with epilepsy
False, monotherapy is preferred, but we often need multiple AED
How often should drug levels of AED be checked? Why is this useful? What might cause them to flucutate?
Drug levels should be checked at least yearly (in patients not having seizures, not undergoing medication changes)
Useful to…
* Establish individual therapeutic concentration when a patient is in remission
* Assist in the diagnosis of clinical AED toxicity
* Assess compliance
* Guide dose adjustments
But drug concentrations may fluctuate in compliant patients
* Lab errors
* Generic substitution
* Drug interactions
* Variable pill potency (where was the medication stored?)
T or F: AED are lifelong medications
False, discontinuation may be considered after 2-4 year seizure-free interval
How should AED be discontinued?
Gradual tapering (25% monthly, can be tapered faster for ADE)
If on more than one, stop the medication that is less appropriate for the seizure type or the agent responsible for the ADE
What can happen if AED are abruptly discontinued? What are factors that increase this risk?
Withdrawal seizures
Factors that increase the risk of seizure recurrence
* History of high frequency seizures
* Repeated SE episodes
* Combination of seizure types
* Development of abnormal mental functioning
* Identifiable brain disease
* Abnormal neurologic examination
* Seizure onset after the first decade
* Poor initial response to treatment
* Combination therapy
* Selected epilepsy syndromes
* Abnormal EEG
* Family history of epilepsy
Why is it important to dose adjust AED in the elderly? (think of ADME)
Drug interactions (CYP3A4)
Hypoalbuminemia is common in elderly
* Many drugs are bound, more free, active drug
Body mass changes during aging (affects drug distribution)
Declining renal or hepatic function
Pharmacodynamic response can change and become more sensitive to neurocognitive ADEs
Why is it important to dose adjust AED in infants? (think of ADME)
Increase in total body water to fat ratio
Decrease in serum albumin
Decreased renal and hepatic function
Past 2-3 years of age, children may have greater hepatic activity than adults, may require higher doses
Role of estrogen in seizures
seizure-activating effect
Role of progesterone in seizures
seizure-protecting effect
When are women at highest risk for seizures?
Just before and during menstruation
At ovulation (Related to progesterone withdrawal, Changes to estrogen : progesterone ratio)
Peri-menopausal period can be associated with worsening seizure (fluctuations of sex hormones)
How is hormonal contraceptive affected by AED? If we use hormonal contraceptive in these patients, what should we use?
Enzyme induction of oral contraceptive metabolism by AEDs
Associated with decreased estrogen and progesterone levels
Suggest alternative form of contraception
Often recommend contraceptive with at least 50 mcg of estrogen
Relationship between pregnancy and seizures
25% of women have increased seizures during pregnancy
Relationship between AED and pregnancy
Congenital malformation occurs in infants born to women with epilepsy
* 90% of pregnancies have successful outcomes
* Congenital heart malformations, orofacial clefs, spina bifida, neural tube defect
* Thought to be due to folate insufficiency associated with AEDs
* Many teratogenic effects can be prevented with adequate folate intake
Pregnancy category D (phenytoin, carbamazepine, valproic acid, phenobarbital)
Which AED are inducers?
carbamazepine, phenytoin, phenobarbital
Which AED are inhibitors?
Valproic acid
Which AED are both inducers and inhibitors?
Felbamate, oxcarbazepine, topiramate
