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Pharmacotherapy - Neurology

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أحمد الجويلى

on 28 February 2013

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Transcript of Pharmacotherapy - Neurology

Risk factors Acute event ttt Secondary prevention Neurology Epilepsy Multiple Sclerosis Headache Parkinson's d. Isch. Stroke Classification Diagnosis Treatment 1ry prevention Signs / Symptoms Treatment Types / Definitions Treatment Definitions Treatment Focal seizures Generalized seizures No loss of consciousness / responsiveness With loss of consciousness / responsiveness Evolving to a bilateral, convulsive seizure Was called: Simple partial seizure Was called: Complex partial seizure Was called: Secondarily generalized seizure Absence Myoclonic Tonic-clonic Clonic Tonic Atonic Status epilepticus Nonepileptic seizures Other symptoms Prodrome Aura Physical examination Laboratory tests EKG Magnetic resonance imaging Benzodiazepines Carbamazepine Ethosuximide Ezogabine Felbamate Fosphenytoin Gabapentin Lacosamide Lamotrigine Levetiracetam Oxcarbazepine Phenobarbital Phenytoin Pregabalin Primidone Rufinamide Tiagabine Vigabatrine Topiramate Valproic acid Zonisamide Notes Status epilepticus Special populations Others Surgery Driving When to stop ttt ?? Monitoring Sexual dysfunction Bone death Pregnancy Elderely Treatment principles Acute treatment Long-acting meds Suicidality Non-modifiable Somewhat modifiable Modifiable Less well-documented Reduction of risk factors Patient education Treatment of atrial fibrillation Heparin Streptokinase Tissue plasminogen activator Aspirin Dec. risk factors Carotid endarterectomy Carotid angioplasty Antiplatelet therapy Anticoagulation Aspirin Aspirin/dipyridamole Clopidogrel Cilostazol Cardinal signs Secondary signs Akinesia/hypokinesia Posture/gait abnormalities Tremors Rigidity Cognitive dysfunction Micrographia Speech disturbances Autonomic dysfunction Masked face General principles Special situations Surgery Medications Carbidopa Anticholinergics dopamine agonists Carbidopa/levodopa (sinemet) Levodopa MAO-B inhibitors COMT inhibitors Amantadine Hallucinations/psychosis Usual disorders Cognitive disorders Classic migraine Cluster headache Tension headache Migraine without aura Analgesic rebound headache Cluster headache Migraine Tension headache Prophylaxis Treatment Prophylaxis Treatment Prophylaxis Treatment Symptomatic ttt Acute relapses Disease-modifying therapies IV methylprednisolone IV adrenocorticotropic hormone Fatigue Spasticity (Steroids) Beta interferons Mitoxantrone Fingolimod Glatiramer acetate Natalizumab Walking impairment Relapsing-remitting Secondary progressive Primary progressive Progressive-relapsing 85% of patients at diagnosis 50% of relapsing-remitting patients develop secondary progression within 10 years 10% of patients at diagnosis 5% of patients at diagnosis Oral prednisone 1 g/day as 1 dose or divided doses or divided doses for 3–5 days. 1250 mg/day given every other day for five doses 1st choice Injection site reactions If S.C. rotate injection sites ice injection sites bring a drug to room temperature Flu-like symptoms dissipate in 2–3 months inject the dose in the evening Begin at the 0.25–0.5 dose and slowly increase use ibuprofen or acetaminophen Neutralizing
antibodies 18–24 months after treatment begins frequency and administration route affect
their development may disappear even during continued treatment cross-reactivity with other beta interferons Injection site reactions May involve flushing, chest tightness, palpitations, anxiety, and shortness of breath; this is noncardiac First oral agent for multiple sclerosis treatment Patients must be monitored for bradycardia for 6 hours after the first dose

if therapy is discontinued for more than 2 weeks, patients must be re-monitored. Electrocardiogram is recommended within 6 months for patients using antiarrhythmics (including -blockers and calcium channel blockers), those with cardiac risk factors, and those with slow or irregular heartbeat. Heart rate returns to baseline within 1 month of continued dosing Atrioventricular conduction delays : First- and second-degree block Decrease
in lymphocytes A recent complete blood cell count should be available before starting therapy. Infections may be more common. Discontinue therapy for serious infections; test patients without varicella zoster vaccine or infection history for varicella zoster virus antibodies, and immunize antibody-negative patients (wait 1 month to begin fingolimod). Macular edema Ophthalmologic evaluation at baseline and 3–4 months after fingolimod initiation; a history of uveitis or diabetes mellitus increases risk Respiratory effects Decreases in forced expiratory volume over 1 second and diffusion lung capacity for carbon monoxide can be seen. Elevation of liver enzymes Hypertension – Monitor during treatment Extended effects of drug for up to 2 months after discontinuation require extended monitoring for many adverse effects Drug interactions Ketoconazole – Increased fingolimod Vaccines – Less effective during and 2 months after fingolimod treatment; avoid live attenuated vaccines Avoid pregnancy during treatment and for 2 months after treatment. Indicated for secondary progressive, progressive-relapsing, and worsening-relapsing-remitting multiple sclerosis Because of the potential for toxicity, mitoxantrone is reserved for patients with rapidly advancing disease whose other therapies have failed. Patients taking mitoxantrone should not receive live virus vaccines; other vaccines should be held for 4–6 weeks postdose. Cardiotoxicity is the lifetime dose-limiting toxicity (140 mg/m2); echocardiograms or multiple gated acquisition scans must be performed at baseline and before each infusion.

Systolic dysfunction occurs in about 12% of patients; congestive heart failure occurs in about 0.4%. Cardiotoxicity might not be dose-, sex-, or age-related. Therapy-related acute leukemia occurs in about 0.8% of patients Other laboratory tests (complete blood cell count, bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and pregnancy test) must be performed before
each infusion Indicated for relapsing forms of multiple sclerosis but distributed through restricted distribution program because of progressive multifocal leukoencephalopathy risk Hypersensitivity reactions: Itching, dizziness, fever, rash, hypotension, dyspnea, chest pain, anaphylaxis; usually within 2 hours of administration Progressive multifocal leukoencephalopathy: Rapidly progressive viral central nervous system infection; usually results in death or permanent disability.

Patient selection guidelines are for patients with relapsing-remitting disease whose other treatment (efficacy or intolerability) has failed or who have an aggressive initial course; it should not be used in combination with other disease-modifying therapies. Antibodies develop in 9%–12% of patients; they are associated with increased relapses and hypersensitivity reactions Patients may experience fatigue, spasticity, urinary incontinence, pain, depression, cognitive impairment, fecal incontinence, constipation, and sexual dysfunction; treatment should be with standard therapies. Treatment may be nonpharmacologic (rest, assistive devices, cooling strategies, exercise, stress management) or pharmacologic (amantadine, methylphenidate). Therapies must be centrally acting.
i. First line: Baclofen, tizanidine
ii. Second line: Dantrolene, diazepam
iii. Third line: Intrathecal baclofen
iv. Focal spasticity: Botulinum toxin Dalfampridine (Ampyra)
i. Indicated to improve walking in patients with multiple sclerosis by improving walking speed

ii. Potassium channel blocker

iii. Dose: 10 mg orally 2 times/day; extended-release tablets

iv. Contraindicated in patients with a history of seizures or moderate or severe renal impairment

v. Adverse effects: Seizures, urinary tract infections, insomnia One or more fully reversible aura symptoms Aura symptoms for more than 4 minutes
or two or more symptoms occurring
in succession no single aura symptom lasts
more than 60 minutes headache follows aura within 60 minutes At least five attacks of headache lasting 4–72 hours with at least two of the following Unilateral location pulsating quality intensity moderate or severe aggravation by walking stairs or
similar routine physical activity Nausea vomiting photophobia phonophobia At least 10 previous headaches, each lasting from 30 minutes to 7 days, with at least two of the following: pressing/tightening (nonpulsating) quality; intensity mild to moderate; bilateral location; no aggravation with physical activity Several episodes short-lived but severe unilateral, orbital, supraorbital,
or temporal pain Conjunctival injection, lacrimation, nasal congestion, rhinorrhea, facial sweating, miosis, ptosis, or eyelid edema. with one or more of : If patients use analgesics often (usually defined as more than 3 times/week), they may develop analgesic rebound headache chronic daily headache for which they take simple or narcotic analgesics Treatment : withdrawal of all analgesics (but not prophylactic medications) 0.01%–1.5% of population; men/women = 6:1 88% of women; 69% of men 15%–17% of women; 5% of men General principles 2nd choice meds 1st choice meds Used if:
-Migraines are recurrent
-interfere with daily routine
-patient experiences inefficacy or
inability to use acute therapy
-patient prefers prophylaxis as therapy
-cost of acute medications is problematic
-adverse effects with acute therapies occur (a) Use lowest effective dose.

(b) Give adequate trial (2–3 months).

(c) If patient has a coexisting condition, consider prophylaxis choice (e.g., -blockers are contraindicated in patients with asthma but beneficial in hypertension). (a) Amitriptyline
(b) Propranolol
(c) Timolol
(d) Valproic acid
(e) Topiramate (a) Aspirin

(b) Atenolol

(c) Feverfew

(d) Fluoxetine

(e) Gabapentin

(f) Guanfacine

(g) Nonsteroidal anti-inflammatory drugs (h) Magnesium

(i) Metoprolol

(j) Nadolol

(k) Nimodipine

(l) Verapamil

(m) Vitamin B2 (Riboflavine) 3rd choice meds (a) Bupropion

(b) Cyproheptadine

(c) Diltiazem

(d) Doxepin

(e) Fluvoxamine

(f) Imipramine

(g) Mirtazapine (h) Nortriptyline

(i) Paroxetine

(j) Protriptyline

(k) Sertraline

(l) Tiagabine

(m) Trazodone

(n) Venlafaxine Status migranosus Antiemetics Opioids NSAIDs Ergots Triptans Usually effective for only mild to moderate headache pain Sumatriptan and zolmitriptan : good if vomiting exists (SC or intranasal) zolmitriptan and rizatriptan:
good if no access to water (orally disintegrating) contraindicated in patients with CV problems
(coronary artery disease, stroke, uncontrolled hypertension, peripheral vascular disease, ischemic bowel disease) & pregnancy Drug-drug interactions MAO-Is
(within 2 weeks) Ergots
(within 24 hrs) Serotonin meds
(Caution) Propranolol
inc. rizatriptan conc. a 5-mg dose should be used with propranolol, and the maximal dose should not exceed 15 mg/day Dihydroergotamine : good if vomiting exists (SC or intranasal or intranasal) contraindicated in patients with CV problems
(coronary artery disease, stroke, uncontrolled hypertension, peripheral vascular disease, ischemic bowel disease) & pregnancy Butorphanol: good if vomiting exists (intranasal) Prochlorperazine, metoclopramide, chlorpromazine available in
nonoral routes Attack of migraine with headache phase lasting more than 72 hours despite treatment. Headache-free intervals of less than 4 hours (sleep not included) may occur. (a) Corticosteroids: Either intravenous or oral dosing
(b) Dihydroergotamine: Intravenous dosing
(c) Sodium valproate: Intravenous loading Tricyclic antidepressants Botulinum toxin Acetaminophen NSAIDs Verapamil Melatonin Suboccipital injection of betamethasone Lithium efficacious at serum concentrations as low as 0.3 mmol/L Triptans: Subcutaneous and intranasal sumatriptan and intranasal zolmitriptan are effective. Oral formulations usually do not act quickly enough, but oral zolmitriptan had efficacy in one trial Oxygen: One hundred percent oxygen at 6–12 L/minute relieves pain in 50%–85% of patients. Intranasal lidocaine: 20–60 mg as a nasal drop or spray Octreotide and 10% cocaine have been used with some effect. Most common cause of adult disability Third most common cause of death in all developed countries More than 795,000 cases/year in the United States (150,000 deaths) Age Race Sex Low
weight Family
history risk doubles each decade
after 55 years Native americans > african amiericans > white americans Men > women Parental history increases risk Diabetes increases risk 1.8–6 times Hypertension Smoking Oral contraceptives Postmenopausal
hormone therapy Atrial
fibrillation Coronary
heart disease Asymptomatic carotid stenosis Obesity especially abdominal body fat Physical
inactivity Sickle-cell
anemia Peripheral artery
disease Pregnancy the risk remains elevated for the first 6 weeks postpartum. Patent foramen ovale Depression Alcohol abuse (five or more drinks a day), hyperhomocysteinemia, drug abuse (cocaine, amphetamines, and heroin), hypercoagulability, periodontal disease, inflammation and infection, sleep-disordered breathing (sleep apnea and snoring), metabolic syndrome, and
migraine with aura control of hypertension, smoking cessation, control of diabetes, cholesterol reduction Warning signs: Sudden numbness or weakness of the face, arm, or leg, especially on one side of the body; sudden confusion; trouble speaking or understanding; sudden trouble seeing in one or both eyes; sudden trouble walking; dizziness, loss of balance or coordination; sudden, severe headache with no known cause
if not aspirin 75–325 mg/day + Clopidogrel OAC >> if not : aspirin + Clopidogrel OAC >> None or Aspirin 75- 325 mg When oral anticoagulation is recommended ,
this agent is better than warfarin Dabigatran Direct thrombin inhibitor 150 mg 2 times/day dose reduction needed in severe renal dysfunction No antidote (reversal agent)
monitoring Rivaroxaban Factor Xa inhibitor 20 mg/day with evening meal dose reduction needed in renal dysfunction Metabolized by CYP3A4/5, CYP2J2, P-gp, and ABCG2 showed non-inferiority to warfarin N.B.

Give warfarin if patient has atrial fibrillation and mitral stenosis or prosthetic heart valve. not recommended for stroke treatment at therapeutic doses; increases risk of hemorrhagic transformation Should be avoided because of excess mortality Initiate aspirin (160- to 325-mg initial dose with 50- to 100-mg maintenance dose) within 48 hours in patients not eligible for tissue plasminogen activator. Within 4.5 hours of symptom onset Dose 0.9 mg/kg intravenously (maximum = 90 mg) with 10% as a bolus and remainder over 1 hour. Exclusion criteria

i. Minor or rapidly improving stroke signs or symptoms
ii. Intracranial or subarachnoid bleeding (or history)
iii. Other active internal bleeding
iv. Intracranial surgery, head trauma, stroke within 3 months
v. Major surgery or serious trauma within 2 weeks
vi. Gastrointestinal or urinary tract hemorrhage within 3 weeks
vii. Blood pressure greater than 185/110 mm Hg or aggressive treatment required to lower BP
viii. Glucose less than 50 mg/dL or greater than 400 mg/dL
ix. Arterial puncture at a noncompressible site or lumbar puncture within 1 week
x. Seizure at stroke onset
xi. Intracranial neoplasm, arteriovenous malformation, aneurysm
xii. Active treatment with warfarin (INR greater than 1.7), heparin (elevated activated partial thromboplastin time), or platelet count less than 100,000/mm3
xiii. Postmyocardial infarction pericarditis
xiv. Pregnancy
xv. Additional criteria for the 3- to 4.5-hour period
(a) Taking any oral anticoagulant
(b) Baseline National Institutes of Health Stroke Scale score greater than 25
(c) Previous stroke combined with diabetes
(d) Age older than 80 a. Patients with elevated cholesterol (100 mg/dL or greater) or atherosclerosis should be treated with a statin with intensive lipid-lowering effects.

b. Patients with atherosclerotic ischemic stroke without known coronary heart disease should be given statin therapy with intensive lipid-lowering effects.

c. Goal of low-density lipoprotein cholesterol is a 50% reduction or less than 70 mg/dL. if 70%–99% stenosis. For 50%–69% stenosis, carotid endarterectomy recommendation depends on age, sex, and comorbidities; use aspirin 50–100 mg/day and statin therapy before and after the procedure. Carotid angioplasty and stenting may be an alternative to carotid endarterectomy in some patients. Between 75 and 100 mg/day .. If the patient has an additional stroke while taking aspirin, there is no evidence that increasing the aspirin dose will provide additional benefit i. Capsule contains dipyridamole extended-release pellets (200 mg) and aspirin tablet (25 mg).
ii. Dose: 1 capsule orally 2 times/day
iii. Most common adverse effects: headache, nausea, and dyspepsia; can increase liver enzymes i. Inhibits adenosine diphosphate–induced platelet aggregation

ii. Dose: 75 mg/day orally

iii. Very low incidence of neutropenia (0.04% severe)

iv. Rarely, thrombotic thrombocytopenic purpura has been reported.

v. Efficacy similar to that of aspirin/dipyridamole

vi. Combining aspirin with clopidogrel increases hemorrhage in patients with ischemic stroke and should not be recommended (outside the setting of atrial fibrillation, as detailed above)

.vii. Partially metabolized by CYP2C19; there may be interactions with inhibitors of CYP2C19, notably proton pump inhibitors, or genetic polymorphisms of this enzyme. The FDA has issued an alert on this topic i. Inhibits cyclic AMP phosphodiesterase III–inducted platelet aggregation

ii. Dose: 100 mg orally 2 times/day on an empty stomach

iii. Metabolized extensively by CYP3A4 and CYP2C19

iv. Adverse effects: Headache, palpitation, diarrhea, and dizziness; rarely thrombocytopenia or agranulocytosis. Contraindicated in patients with congestive heart failure.

v. Monitoring: Complete blood cell count with differential every 2 weeks for 3 months; periodically thereafter. Thus, used infrequently Warfarin (Athrombin-K, Coumadin, Jantoven, Panwarfin)
a. Prevention of second ischemic event, if patient has atrial fibrillation, rheumatic mitral valve disease, mechanical prosthetic heart valves, bioprosthetic heart valves, or left ventricular mural (along the artery wall) thrombus formation
b. Target INR of 2.5 (3.0 for mechanical prosthetic heart valves) No med. can stop progression .. so only symptomatic In patients who require initiation of dopaminergic treatment, either levodopa or a dopamine agonist may be used. The choice depends on the relative impact of improving motor disability (better with levodopa) compared with the lessening of motor complication (better with dopamine agonists) for each individual patient

i.e. acc. to dominant symptoms Treatment may be initiated with rasagiline as well, but the effects are not robust (not strong) Treatment with several different classes of medications simultaneously is common Selegiline Rasagiline (a) Loses selectivity for MAO-B at doses greater than 10 mg/day

(b) Contraindicated with meperidine

(c) Dose: 5 mg orally 2 times/day (tablets; usually morning and noon); 1.25–2.5 mg/day (orally disintegrating tablets)

(d) Adverse effects: Nausea, hallucinations, orthostatic hypotension, insomnia (metabolized to amphetamine)

(e) Dosage forms: Tablets, orally dissolving tablets, and patches. The patches are FDA indicated for depression; they should not usually be used to treat Parkinson disease. Selectivity for monoamine oxidase type B has not been definitively established.

(1) Contraindicated with meperidine

(2) Do not administer with propoxyphene, tramadol, methadone, dextromethorphan, sympathomimetics, fluoxetine, or fluvoxamine.

(3) Ciprofloxacin can double the concentration of rasagiline (through CYP1A2 inhibition).

(b) Dose: 0.5–1 mg/day orally Improvement of disability and possibly mortality Greatest effect on bradykinesia and rigidity; less effect on tremor and postural instability Combined in fixed ratios with levodopa Prevents some of the peripheral conversion of levodopa to dopamine by inhibiting peripheral dopa decarboxylase; therefore, levodopa is available to cross the blood-brain barrier A total of 75 mg/day is usually required to inhibit peripheral decarboxylase activity. High-protein diets decrease absorption. Immediate-release half-life 60–90 minutes Orally disintegrating tablet available; not absorbed sublingually Slow-release considerations: Fewer daily doses; less plasma fluctuations; delay to effect; cannot crush; can divide. No measurable effect on “freezing” Acute adverse effects: Nausea/vomiting, orthostatic hypotension, cardiac arrhythmias,
confusion, agitation, hallucinations Long-term adverse effects Wearing-off On-off Involuntary movements (Dyskinesia) It describes the period of time between the end of the effect of one dose of medication, and the beginning of the next one. ttt: add dopamine agonist, add a monoamine oxidase type B inhibitor, add a catechol-O-methyl transferase inhibitor, or increase the frequency/dose of levodopa. Unpredictable loss of action of levodopa , that may come suddenly ttt: adding entacapone, rasagiline, ramipexole, ropinirole, apomorphine, and selegiline or redistributing dietary protein ttt: decrease the levodopa dose or add amantadine as an antidyskinetic drug. Therapy initiation :

(a) Standard formulation: 25/100 1 tablet orally 3 times/day

(b) Controlled-release formulation: 1 tablet orally 2 or 3 times/day

(c) Titration always necessary

(d) A combination of formulations may be required (e.g., 0.5 tablet of Sinemet 25/100 on awakening and 1 tablet of Sinemet CR 25/100 3 times/day). Bromocriptine (Parlodel), pramipexole (Mirapex), ropinirole (Requip)
Bromocriptine is an ergot-derived product: Very rarely, adverse effects such as cardiac fibrosis have been attributed to it; regular monitoring of the ECG is recommended.
Dosing: Always titrate to final dose. Adverse effects: Nausea, vomiting, postural hypotension, hallucinations, hypersexuality, compulsive behaviors

Pramipexole and ropinirole also have FDA indications for restless legs syndrome ( irresistible urge to move one's body to stop uncomfortable or odd sensations)

Ropinirole and pramipexole are available as an extended-release formulation. Apomorphine Indications Short-acting dopamine receptor agonist Contra-indications Kinetics Adv. effects Dosing Acute, intermittent treatment of “off” episodes associated with advanced Parkinson disease Use with Serotonin-3 antagonists (ondansetron, granisetron, dolasetron, palonosetron, and alosetron) causes profound hypotension; sulfite sensitivity/allergy When given orally, poorly bioavailable and extensive first-pass metabolism; used as subcutaneous injection in a pen self-injector (1) Severe nausea and vomiting

(A) Treat with trimethobenzamide 300 mg 3 times/day for 3 days before starting treatment and for at least 6 weeks during treatment.
(B) About 50% of patients can discontinue trimethobenzamide after 2 months.
(C) Thirty-one percent nausea and 11% vomiting WITH trimethobenzamide

(2) Hypotension

(3) Hallucinations

(4) Injection site reactions

(5) Dyskinesias (1) Must be titrated in a setting where BP can be monitored
(2) In the off state, the patient should be given a 0.2-mL (2 mg) test dose.
(3) Supine and standing BP taken predose; 20, 40, and 60 minutes postdose
(4) If tolerated, begin with a 0.2-mL dose as needed; increase by 0.1 mL if necessary.
(5) Doses greater than 0.6 mL, more than 5 times/day, or greater than 20 mg/day have limited experience.
(6) If first dose is ineffective, do not re-dose.
(7) If patients do not dose for more than 1 week, restart at a 0.2-mL dose. The most potent antiemetic that does not have effects on the serotonergic, dopaminergic, or histaminergic systems, so it has a lower likelihood of causing undesired side effects Trihexyphenidyl (Artane), benztropine (Cogentin)

Most useful for tremor

Initial dosing :
(a) Trihexyphenidyl 0.5 mg 1 tablet orally 2 times/day
(b) Benztropine 0.5 mg 1 tablet orally 2 times/day

Adverse effects: Dry mouth, urinary retention, dry eyes, constipation, confusion Symptomatic benefits and may reduce dyskinesias caused by levodopa or dopamine agonists

Dosing: 100 mg 1 tablet orally 2 or 3 times/day; caution in renal dysfunction

Adverse effects: Dizziness, insomnia, anxiety, livedo reticularis, nausea, nightmares i. Prevent breakdown of dopamine, more levodopa available to cross blood-brain barrier

ii. Tolcapone (Tasmar): Severely restricted because of hepatotoxicity; must sign consent form

iii. Entacapone (Comtan)
Dosing: 1 tablet with each carbidopa/levodopa dose; maximum of 8 times/day; there is a dosage form (Stalevo) that includes carbidopa, levodopa, and entacapone 200 mg

Must use with carbidopa/levodopa

Adverse effects: Dyskinesias, nausea, diarrhea (may be delayed for up to 2 weeks after initiation or dose increase), urine discoloration (orange), hallucinations/vivid dreams may be caused by either Parkinson disease or treatment.

i. Discontinue/reduce Parkinson disease medications as tolerated.

ii. If an antipsychotic is required, use quetiapine or clozapine as the first choice.

iii. Avoid typical antipsychotics, risperidone, and olanzapine because they may worsen Parkinsonsymptoms. i. Discontinue/reduce Parkinson disease medications as tolerated.

ii. Rivastigmine has an FDA indication for treatment; other cholinesterase inhibitors may have efficacy. Sleep disorders, depression, agitation, anxiety, constipation, orthostatic hypotension, seborrhea, can be seen in Parkinson disease; treat as usual. With observable motor or autonomic components .. Involving subjective sensory (e.g., visual, auditory, olfactory, gustatory sensations) or psychic phenomena only (corresponds to the aura) Typical absence seizures are brief and abrupt, last 10–30 seconds, and occur in clusters.
Absence seizures usually result in a short loss of consciousness, or the patient may stare, be motionless, or have a distant expression on his or her face. Electroencephalograms performed during seizure activity usually show three Hz spike-and-wave complexes. Consist of brief, lightning-like jerking movements of the entire body or the upper and occasionally lower extremities. Myoclonic seizures can be further classified as myoclonic atonic or myoclonic tonic. Typically, there are 5 phases of a primary tonic-clonic seizure: flexion, extension, tremor, clonic, and postictal (very deep info) The length of the entire seizure is usually 1–3 minutes. After the seizure, the patient may be postictal. During this time, the patient can be difficult to arouse and/or very somnolent. Before the seizure, a patient may experience a prodrome, but not an aura. Only the clonic phase of a tonic-clonic seizure; rhythmic, repetitive, jerking muscle movements Only the flexion and/or extension phases of a tonic-clonic seizure Characterized by a loss of muscle tone. Atonic seizures are often described as drop attacks in which a patient loses tone and falls to the ground any seizure that lasts more than 20 minut es OR recurrent seizures of sufficient frequency that the patient does not regain consciousness between episodes. paroxysmal nonepileptic episodes resembling epileptic seizures that can be organic or psychogenic. Awareness of an impending seizure before it occurs. The prodrome may consist of headache, insomnia, irritability, or feeling of impending doom (3azab washeek) !! A focal seizure consisting of sensory or autonomic symptoms that may precede evolution to a bilateral, convulsive seizure. Patients may experience feelings of fear, embarrassment, or déjà vu. Automatic behavior (automatism) and psychic symptoms may occur. Automatisms may include lip smacking, chewing, swallowing, abnormal tongue movements, scratching, thrashing of the arms or legs, fumbling with clothing, and snapping the fi ngers. Psychic symptoms include illusions, hallucinations, emotional changes, dysphasia, and cognitive problems. may include examination of the head, vision, cranial nerves, motor function, cerebellar function, and sensory function metabolic causes of seizures are common, serum glucose, electrolytes, calcium, complete blood cell counts, and renal function tests may be required. A toxicology screen may also be prudent. The best time to perform an electroencephalogram is while the patient is having seizures. useful in finding brain lesions when magnetic resonance imaging cannot be performed in a timely fashion. can sometimes drastically reduce the number of seizures; possible surgeries include removal of the seizure focus, corpus callosotomy, or vagus nerve stimulators. i. Ascertain ABCs (airway, breathing, and circulation).
ii. Give a rapidly acting drug to stop the seizure immediately.
iii. Follow with a longer-acting drug to prevent the recurrence of seizures.
iv. In general, all drugs for status epilepticus should be given parenterally.
v. Neuromuscular blocking drugs do not stop seizures; they stop only the muscular response to the brain’s electrical activity. i. Lorazepam: Drug of choice
(a) Rapid onset (2–3 minutes)
(b) Dosage 0.05–0.1 mg/kg for 30 seconds; may repeat every 10–15 minutes to a maximum of 4 mg Diazepam
(a) Rapid onset, short duration
(b) Dosage 0.2–0.3 mg/kg for 2–3 minutes. May repeat every 15–20 minutes
(c) Rectal gel formulation can be given in absence of intravenous access. i. Phenytoin: Dosage 20 mg/kg; administration rate less than 50 mg/minute

ii. Fosphenytoin: Administration rate less than 150 mg of phenytoin equivalent per minute

iii. Phenobarbital: Dosage 20 mg/kg

iv. Valproic acid: Dosage 15–30 mg/kg at 3–10 mg/kg/minute; does not have FDA-labeled approval for status epilepticus

v. Levetiracetam: Has been successfully used in case reports (doses of 500–3000 mg/day) and one small study of adults (dose of 2500 mg), one small study of elderly individuals (dose of 1500 mg), and two retrospective studies of children (dose of 6.6–89 mg/kg); does not have FDA-labeled approval for status epilepticus

vi. Lacosamide: has been successfully used in one case report (200 mg); does not have FDAlabeled approval for status epilepticus

vii. Pentobarbital coma: Load 15 mg/kg for 1 hour; follow with a 1- to 2-mg/kg/hour infusion

(a) Only if unresponsive to other measures
(b) May have severe hypotension requiring treatment with vasopressors; should have continuous BP measurement
(c) Must be on ventilator

viii. Midazolam: Load a 0.2-mg/kg slow intravenous bolus; follow with a 0.75-mcg/kg/minute infusion. Only if unresponsive to other measures
ix. Propofol: Load a 1- to 2-mg/kg intravenous bolus for 30–60 seconds; follow with a 50-mcg/kg/minute infusion.
(a) Only if unresponsive to other measures
(b) Some reports of seizure exacerbation with propofol Pharmacokinetic changes in the elderly that may affect antiepileptic medications include the following:
i. Carbamazepine: Decreased clearance
ii. Phenytoin: Decreased protein binding if hypoalbuminemic or in renal failure
iii. Valproic acid: Decreased protein binding
iv. Diazepam: increased half-life
v. Phenylethylmalonamide (active metabolite of primidone): Decreased clearance if creatinine clearance is decreased
vi. Lamotrigine: Decreased clearance
vii. Antiepileptic drugs with renal elimination must be adjusted on the basis of creatinine clearance. During reproductive years, women with epilepsy should:

(a) Take the best drug for their seizure type
(b) Be treated with monotherapy, if possible
(c) Discuss the possible decrease in hormonal contraceptive effectiveness if taking enzyme inducing medications. If hormonal contraceptives are chosen, a formulation containing at least 50 mcg of ethinyl estradiol or mestranol should be chosen
(d) Use folic acid supplementation with no less than 0.4 mg/day. Limiting the dose of valproic acid or lamotrigine during the first trimester, if possible, should be considered to lessen the risk of major congenital malformations.

(d) Avoiding the use of phenytoin, carbamazepine, and phenobarbital, if possible; may be considered to reduce the risk of cleft palate (phenytoin), posterior cleft palate (carbamazepine), cardiac malformations (phenobarbital), and poor cognitive outcomes (phenytoin, phenobarbital).

(e) Women with epilepsy taking antiepileptic drugs during pregnancy probably have an increased risk of small for gestational age babies and 1-minute Apgar scores less than 7.

(f) Monitoring of lamotrigine, carbamazepine, and phenytoin serum concentrations during pregnancy should be considered.

(g) Having MHD (levetiracetam and oxcarbazepine) serum concentrations monitored during pregnancy may be considered. criteria for withdrawal:

i. Patient should be seizure free for 2–5 years on antiepileptic drug;

ii. Patient should have a single type of partial or primary generalized tonic-clonic seizures;

iii. Patient should have a normal neurologic examination

iv. Patient’s electroencephalogram should have become normalized with antiepileptic medication treatment. If a drug is discontinued, it is usually tapered for several months; a typical regimen would reduce the dose by one-third for 1 month, reduce it by another one-third for 1 month, and then discontinue it. a. Number of seizures: The goal number of seizures is always zero.
b. Signs of toxicity
c. Laboratory values: Specific for each drug
d. Blood concentrations: Available for many of the medications, commonly used for carbamazepine, phenobarbital, phenytoin, and valproic acid. The International League Against Epilepsy has a position paper on therapeutic drug monitoring, giving situations in which serum concentrations are most likely to be of benefit: i. When a person has attained the desired clinical outcome, to establish an individual therapeutic concentration that can be used subsequently to assess potential causes for a change in drug response
ii. As an aid in the diagnosis of clinical toxicity
iii. To assess adherence, particularly in patients with uncontrolled seizure or breakthrough seizures
iv. To guide dosage adjustment in situations associated with increased pharmacokinetic variability (e.g., children, the elderly, patients with associated diseases, drug formulation changes
v. When a potentially important pharmacokinetic change in anticipated (e.g., in pregnancy, or when an interacting drug is added or removed)
vi. To guide dose adjustments for antiepileptic medications with dose-dependent pharmacokinetics, particularly phenytoin may be induction of CYP isoenzymes to increase testosterone metabolism, increased hepatic synthesis of sex hormone–binding globulin, or induction of aromatase, which converts free testosterone to estradiol.

Sexual dysfunction has been reported with carbamazepine, phenobarbital, phenytoin, pregabalin, topiramate, and zonisamide.

Improved sexual functioning has been reported with lamotrigine and oxcarbazepine. all antiepileptic medications may contribute to osteopenia or osteoporosis.

Proposed mechanisms: Hepatic induction of CYP isoenzymes leads to increased vitamin D catabolism; impaired calcium absorption; calcitonin deficiency; vitamin K interference; and direct detrimental effect on bone cells.

Proposed treatments: High-dose (4000 IU/day for adults and 2000 IU/day for children) vitamin D improved bone mineral density compared with low doses; estrogen may be helpful for women but may also trigger seizures in some women. FDA required a warning and a medication guide for all antiepileptic medications

Old trials prove it
New trials deny it Augment gamma -aminobutyric acid–mediated chloride influx Tolerance may develop: Usually used as adjunctive, short-term therapy Most commonly used drugs: Chlorazepate (Tranxene), clobazam (Onfi), clonazepam (Klonopin), lorazepam (Ativan) Non-epileptic indications: Chlorazepate – anxiety disorders, anxiety; clonazepam – panic disorder with or without agoraphobia; lorazepam – anxiety disorders, anxiety anxiety in situations where the sufferer perceives the environment as being difficult to escape or get help Fast sodium channel blocker Enzyme inducer, autoinduction Adv. effects Rash (occurs after a delay of 2–8 weeks) syndrome of inappropriate ADH release aplastic anemia, thrombocytopenia, anemia, leukopenia Extended-release tablets (Tegretol XR) 100, 200, and 400 mg; extended-release capsules (Carbatrol) 100, 200, and 300 mg available. Dosing is still twice daily. Do not crush or chew. Extended-release capsules (Carbatrol) can be opened and sprinkled on food. Ghost tablets can be seen in the stool with the extended-release tablets (Tegretol XR). Patients with HLA-B*1502 are at a 10 times increased risk of Stevens-Johnson syndrome.
(a) Testing is recommended for Asians (including Indians).
(b) More than 15% of populations in Hong Kong, Malaysia, the Philippines, and Thailand have this allele. Non-epileptic indication: Trigeminal neuralgia T-type calcium current blocker Useful only for absence seizures Potassium channel opener Adverse effects: Urinary retention, hallucinations, QT prolongation Blocks glycine site on N-methyl-d-aspartate receptor Hepatotoxicity, aplastic anemia. Patient or guardian must sign consent form Prodrug for phenytoin; fast sodium channel blocker Parenteral formulation for loading or maintenance dosing in place of phenytoin; statusepilepticus Enzyme inducer, nonlinear kinetics 1 mg of phenytoin = 1.5 mg of fosphenytoin = 1 mg of phenytoin equivalent. Adverse effects: Hypotension, perianal itching, other adverse effects of phenytoin Advantages over phenytoin:
(a) Intramuscular or intravenous dosing(b) Phlebitis is minimized.(c) Infusion can be up to 150 mg of phenytoin equivalents per minute.(d) Can deliver in normal saline solution or D5W (5% dextrose [in water] injection) Inhibition of voltage-dependent calcium channels Not metabolized, eliminated renally; adjustments may be necessary for renal dysfunction and hemodialysis for treatment of postherpetic neuralgia pain Doses often exceed product info.
maximum of 3600 mg/day. Non-epileptic indication – Postherpetic neuralgia Slow sodium channel blocker Maximal dose of 300 mg/day with creatinine clearance of 30 mL/minute or less or with mild to moderate hepatic impairment Adverse effects: PR-interval prolongation/first-degree atrioventricular block Controlled substance schedule V because of euphoric effects Parenteral formulation: FDA indication only for replacement of oral formulation Decreases glutamate and aspartate release, delays repetitive firing of neurons, blocks fast sodium channels Rash is a primary concern; lamotrigine must be titrated slowly to avoid a rash Valproic acid decreases lamotrigine metabolism; this interaction requires even slower titration and lower final doses. Non-epilepsy indications: Maintenance treatment of bipolar I mood disorder prevent hypersynchronization of epileptiform burst firing and propagation of seizure activity Not metabolized largely, adjust dose in renal dysfunction, no drug interactions with other antiepileptic drugs Parenteral use: Currently indicated by the FDA only for replacement of oral dosing; however, sometimes used for status epilepticus Extended-release tablets (500 mg) are available for once-daily dosing. Fast sodium channel blocker Active metabolite 10-monohydroxy oxcarbazepine; enzyme inducer, no autoinduction Hyponatremia more common than with carbamazepine (increased dose and increased age increase risk of hyponatremia); blood dyscrasias less common than with carbamazepine; 25%–30% of patients with hypersensitivity to carbamazepine will have hypersensitivity to oxcarbazepine; rash Increases gamma-aminobutyric acid–mediated chloride influx Enzyme inducer Adverse effects: Hyperactivity, cognitive impairment Non-epilepsy use: Anxiety Fast sodium channel blocker Enzyme inducer, nonlinear kinetics Administration considerations:
(a) Intravenous formulation: Very basic product. Thus, phlebitis and extravasation are oncerns; hypotension; maximal infusion rate of 50 mg/minute. Can prepare only in normal saline solution
(b) Oral suspension: Must be shaken well; adheres to feeding tubes and is bound by enteral nutrition products Dose-related adverse effects: Nystagmus, ataxia, drowsiness, cognitive impairment Non–dose-related adverse effects: Gingival hyperplasia, hirsutism, acne, rash, hepatotoxicity, coarsening of facial features Inhibits voltage-dependent calcium channels Not metabolized, renally excreted, reduce dose in renal dysfunction Adverse effects: Drowsiness, blurred vision, weight gain, edema, angioedema, creatine kinase elevations (three reports of rhabdomyolysis), rash Schedule V controlled substance: Insomnia, nausea, headache, diarrhea reported after abrupt discontinuation Non-epileptic indications: Neuropathic pain associated with diabetic neuropathy, postherpetic neuralgia, and fibromyalgia Increases gamma -aminobutyric–mediated chloride influx Metabolized to phenobarbital and phenylethylmalonamide all have antiepileptic action. Enzyme inducer Also used for essential tremor Fast sodium channel blocker Absorption increased by food (should be administered with food); metabolized by hydrolysis rather than through cytochrome P450 (CYP) enzymes Decreases concentrations of ethinyl estradiol and norethindrone FDA indication only for Lennox-Gastaut syndrome Slightly shortens the QT interval and therefore should not be used in patients with familial short QT syndrome Blocks gamma-aminobutyric reuptake in the presynaptic neuron Associated with new onset seizures and status epilepticus in patients without epilepsy Fast sodium channel blocker, enhances gamma-aminobutyric activity, and antagonizes AMPA (-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)/kainate activity, weak carbonic anhydrase inhibitor Not extensively metabolized, eliminated in urine Adverse effects: Drowsiness, paresthesias, psychomotor slowing (titrate slowly), weight loss, renal stones, acute angle-closure glaucoma, metabolic acidosis, and hyperthermia (associated with decreased perspiration—oligohidrosis) Non-epilepsy indication: Prophylaxis of migraine headaches Blocks T-type calcium currents, blocks sodium channels, increases -aminobutyric production Pharmacokinetics: Enzyme inhibitor Parenteral use: Has FDA indication only for replacement of oral dosing; however, sometimes
used for status epilepticus, especially if absence status epilepticus Adverse effects: Hepatotoxicity, nausea/vomiting, weight gain, interference with platelet aggregation, pancreatitis, alopecia, tremor Available in immediate-release (valproic acid [Depakene]) capsules for 3–4 times/day dosing; delayed-release (divalproex sodium [Depakote]) capsules and tablets for twice-daily dosing; and extended-release (divalproex sodium [Depakote ER]) tablets for once-daily dosing Non-epilepsy indications: Manic episodes associated with bipolar disorder, prophylaxis of migraine headaches Irreversible inhibition of gamma-aminobutyric acid transaminase Pharmacokinetics: Induces CYP2C9; renal elimination Adverse effects: Fatigue, somnolence, nystagmus, tremor, blurred vision, vision impairment, weight gain, arthralgia, abnormal coordination, and confusional state Serious adverse effect: Vision loss; increased risk with higher total dose and duration; periodic vision testing required; (Vigabatrine) Fast sodium channel blocker, blocks T-type calcium currents, weak carbonic anhydrase inhibitor Non-arylamine sulfonamide: Avoid in sulfa-sensitive individuals; it is sometimes used in individuals with nonserious sulfa allergies, particularly when non-acrylamides (i.e., sulfonylureas) have been used successfully. Long half-life Adverse effects: Depression, rash, psychomotor slowing, paresthesias, kidney stones, blood dyscrasias, hyperthermia (associated with decreased perspiration—oligohidrosis) Administration considerations:
(a) Intravenous formulation: Very basic product. Thus, phlebitis and extravasation are concerns; hypotension; maximal infusion rate of 50 mg/minute. Can prepare only in normal saline solution
(b) Oral suspension: Must be shaken well; adheres to feeding tubes and is bound by enteral nutrition products Dose-related adverse effects: Nystagmus, ataxia, drowsiness, cognitive impairment Non–dose-related adverse effects: Gingival hyperplasia, hirsutism, acne, rash, hepatotoxicity, coarsening of facial features T-type calcium current blocker Useful only for absence seizures Conjunctival injection lacrimation nasal congestion rhinorrhea facial sweating miosis ptosis eyelid edema
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