Seizure

Glutamate

Seizure

GABA

is the major inhibitory transmitter

Epilepsy

Seizures

Symptoms

Seizures

Onset

Usually unpredictable- may be preceded by an aura.

Causes of Seizures

1. Metabolic: hypoglycemia, hyponatremia, fever (only under 5 yo) , alkolosis.

2. Structural: tumor

3. Genetic: inborn error of metabolism.

4. Idiopathic: insufficient data to classify

5. Drug induced. (camphor, theophylline/aminophylline, tricyclic antidepressanys, cocaine, barbiturate withdrawal, petit mal is made worse by carbamazepine, phenytoin, or phenobarbital and alcohol withdrawal- when you stop a medication can cause a seizure)

Therapy for Seizures

Goal

Seizures

Treatment modalities

-Correct the underlying metabolic problem

-Consider possibility of poison, remove poison

-Drugs Pregnancy Category (Phenytoin-D, Phenobarbital-D, Carbamazepine-C, Valproic Acid- D, Ethosuximide- C, Primidone- D, Diazpam-D, Clonezepam-D, Felbamate-C, Gabapentin-C, Lamotrigine-C. BRIGGS

Ketogenic Diet

Seizure

Educating the patient

1.Include the whole family.( impacts everyone)

2. Keep a log

3. Wear a medical alert tag.

4. Explain the importance of good compliance

5. Discuss side effects patient should watch for.

6. Tell patient that the dose and/or the drug may have to be changed to find the best one for them. ( set the stage, they m

1. Narrow therapeutic index

2. Blood levels have a known correlate to either therapeutic effect or toxic effect. ( Example: don't measure levels, measure a patients BP)

3. A rapidly changing physiological effect is not avaliable to be monitored.

4. There is a large variation in doses among patients needed to acheive the same steady state serum concentration (can't predict it)

Exact time Administered

It is important to clearly note when the blood level was drawn in relation to the administration of the dose

Trough Level

Seizure

If possible, we want a patient to be controlled on...

Monotherapy. One drug is selected and allowed to get into the therapeutic range, if control is inadaquate, a second drug is tried. The second drug should be added and allowed to attain therapeutic concentrations before the first drug is disconintued slowly over several weeks. DONT ABRUPTLY STOP ANTICONVULSANTS. RAPID WITHDRAWAL OF ANY ANTICONVULSANT DRUGS MAY PRECIPITATE SEIZURES.

Anticonvulsant therapy may be completeley withdrawn in some patients

Good candiates fit the following criteria:

1. Seizure onset was between 2 and 35 years of age.

2. Normal EEG (now)

3. Seizure free for 2 to 5 years.

If all co-exist.

Anticonvulsant therapy may be completeley withdrawn in some patients

Good candiates fit the following criteria:

How slowly should therapy be discontinued?

Phenytoin

(Dilantin)

PHT

Mechanism of action

inactivate fast Na+ channels leading to decreased release of glutamate and increased release of GABA

Phenytoin

(Dilantin)

PHT

Therapeutic Range

Normal dose is 10-20 mcg/ml

it is normally 90% protein bound. it's protein binding is decreased in the setting of hypoalbuminemia or renal dysfunction (secondary to uremia) As a result, the therapeutic range in a patient with a creatinine clearance <10 ml/min OR with hypoalbuminemia is 5-10 mcg/ml. In a patient with BOTH renal function and hypoalbumnemia the theraputic concentraton goes down to 3-5 mcg/ml. Good to closely monitor patients with increased unbound drug

Phenytoin

(Dilantin)

PHT

Administration

Accumulation Kinetics

its half-life gets longer as the serum concentration gets higher. As a result, if this drug is doubled than the new steady state is more than doubled. Th resulting increase is not easy to predict. increase the dose in small increments.

(increase no more than 30-50 mg per day when concentration is greater than 10 mcg/ml) system becomes saturated.

Phenytoin

(Dilantin)

PHT

Administration

A loading Dose

necessary to achieve a therapeutic drug concentration rapidly. If an oral loading dose is used, the following regimen will minimize GI upset (adult dosing): give 1000 mg in 3 seperate doses. Calculate your loading dose based on the patients weight.

Phenytoin

(Dilantin)

PHT

Administration

IM /IV

The parenteral solution contains propylene glycol (40%) and is buffered to a pH of 12 to solumbilize the very insoluble phenytoin AVOID IM injection. Absorption is incomplete, delayed and may cause significant local irritation.

IV: do no exceed 25-50 mg/min. Can be mixed in NS. Rapid injection mayy precipiatate cardiac arrhythmias, wat are in part caused by propylene glyol. Monitor BP and EKG.

Phenytoin

(Dilantin)

 PHT

Administraton

Intravenous

are possible if guidelines are closely followed. Mix only in NS. Do not refrigerate. When converting to IV from a once daily dose of an oral extended relaease preparation, divided doses should be given to avoid fluctuations in serum concentrations. (TID)

Phenytoin

(Dilantin)

 PHT

Administraton

Oral suspension

Phenytoin

(Dilantin)

 PHT

Neurologic Toxicity

1. Cognitive impairment

2. Sedation, nystagmus (eyes move around) >20 mcg/ml

    ataxia (lack of muscle coordination)>30 mcg/ml

    mental changes: delirium, psychosis, depression >40

3. make make petit mal seizures worse.

Phenytoin

(Dilantin)

 PHT

Systemic toxicity

1. Gingival hypertrophy: minimized by good oral hygeine, although reversible, if permanent teeth grow through the "hyperplastic" gums, teeth will be out of place requiring orthodontry correction.

2. Skin rashes: can progress to Steven-Johnsons syndrome or toxic epidermal necrosis which may be fatal

3. Hirsutism, coarsening of facial features, and a long list of infrequent toxicities.

4. Cardiac arrythmias and/or hypotension if injected IV too quickly.

Phenytoin

(Dilantin)

 PHT

DRUG INTERACTIONS

Disulfiram

Phenytoin

(Dilantin)

 PHT

DRUG INTERACTIONS

Isoniazid

Phenytoin

(Dilantin)

 PHT

DRUG INTERACTIONS

Theophylline

Phenytoin

(Dilantin)

 PHT

DRUG INTERACTIONS

Fosohenytoin

is converted to phenytoin after absorption

it is water soluble and can be injected faster than phenytoin, causes less phlebitis and tissue damage at injection site. It is also more expensive

Phenobarbital

Solfoton

Mechanism of Action

Phenobarbital

Solfoton

Half-life

very long - up to 96 hours (stick around for a long time)

Need a loading dose.

Phenobarbital

Solfoton

Toxicity

1. hyperactivity and inattention in children

2. sedation- tolerance develops.

3. Cognitive skill impairment (may continue as long as patient is on therapy)

4. may make petit mal (absense) seizures worse.

Phenobarbital

Solfoton

Patient Related Variables

1. it stimulates the metabolism of many drugs.

2. Severe liver disease: doasage adjustment is needed

3. Resp depression

Primidone

Mysoline

not used a lot. metabolized into phenobarbital. Everything same as phenobarbital

Carbamazepine

Tegretol, Tegretol XR

ADMINISTRATION

exposing this drug to moisture will decrease their bioavailability by 30% (do not store in medicine cabinet near a shower)

Carbamazepine

Tegretol, Tegretol XR

METABOLISM

it stimulates its own metabolism as well as that of over drugs. so over time the blood level drifts downward. This autoinduciton takes 21-28 days to fully develop. If the dose is increased slowly over 2 to 3 weeks, this effect will not be noticed.

Carbamazepine

Tegretol, Tegretol XR

toxicity

OXCARBAZEPINE

Trileptal

more expensive, better tolerated. same as carbamazepine

VALPROIC ACID

Depakene, Depacon

DIVALPROEX Sodium

Depakote

Does it come in a few or a lot of ways to administer?

*Comes in a variety of ways to administer. they come in different doses. different products

VALPROIC ACID

Depakene, Depacon

DIVALPROEX Sodium

Depakote

Administration

-Give with food to decrease the GI effects

-Valproic acid sprinkle capsules can be opened and placed on food DO NOT CHEW.

VALPROIC ACID

Depakene, Depacon

DIVALPROEX Sodium

Depakote

toxicity

1. Liver Disease: baseline lft's, more common in children than older patients but still rare in both. mild elevations in LFT's are common.

2. Causes little sedation, does not affect cognitive skills. good thing about this drug

3. Weight gain (control with diet) diet training before you start the drug

ETHOSUXIMIDE

Zarontin

What kind of seizure is this the drug of choice for?

PETIT MAL

thats all its used for

BENZODIAZEPINES

Diazepam

When do you administer this drug?

during status epilepticus. After the patient has had a seizure and befor they are going to have another one

-problem with chronic use of this drug is patients develop a tolerance.

FELBAMATE

Felbatol

What severe toxicity does this drug cause?

Causes aplastic anemia (1:2,500) not reported in children under 13 years old. Generally presents during the first 5 months of therapy. Primarily reported in womend with autoimmune diseases. 3rd line therapy when others don't work

LAMOTRIGINE

Lamictal

BLACK BOX WARNING

1:100, Rash 10% potentially life threatening (adults 3/1000; children 1/100-1/200) Most reported cases of life-threatening rash have been reported within 2-8 weeks of starting therapy (isolated cases after 6 months of therapy) Discontinue therapy at first sign of rash. Not used as a first line drug for kids. Steven Johnson's syndrome. FDA only approved use for kids 16 and under for Lennox-Gastaut syndrome.

SEDATIVES, HYPNOTICS, AND ANXIOLYTICS

GENERAL

These agents are indicated for short-term management of insomnia and for sedation prior to medical/diagnostic procedures. Anxiolytics may also be used for anxiety disorders such as panic disorder, generalized anxiety disorder, and social anxiety disorder.
a. Sedatives/anxiolytics – reduce anxiety, produce a calming effect
b. Hypnotics – induce sleep

Both very similar

Consider non-pharmacologic therapy for insomnia

(avoid medication)

1. Establish regular sleep/wake up times
2. Avoid long periods of wakefulness in bed (get out of bed, do not watch tv in bed)
3. Avoid daytime naps (sleep apnea)
4. Exercise regularly (but not just before bedtime)

Remove drug related causes of insomnia:

think these things before giving a medication

1. Decongestant at bedtime

2. SSRIs given at bedtime
3. Diuretics given at bedtime
4. Caffeine use at bedtime
5. Alcohol use at bedtime
6. Heavy meal before bedtime
7. Other

Treatment of insomnia

(Criteria for ideal hypnotic agents)

1. Rapid onset
2. Sufficient duration to last through the night
3. No residual daytime sedation
4. No disturbance of normal sleep patterns
5. No tolerance or withdrawal
The ideal hypnotic has not yet been discovered!

present a risk of respiratory and/or cardiovascular collapse.(Consult local policies and procedures for specifics) SAfety issue

1. Description for when sedative procedure should be used
2. Description of personnel training requirements
3. Baseline measurements of vital signs and CNS status
4. Monitoring requirements (should include use of pulse oximeter)
5. Description of resuscitation equipment that should be immediately available
6. Criteria for discontinuing close monitoring

Benzodiazepine Receptor Agonists (BZDRA’s)

Mechanism of action

Benzodiazepine Receptor Agonists (BZDRA’s)

Examples of Drugs

Zolpidem (Ambien), zaleplon (Sonata), eszopiclone (Lunesta)

withdrawal symptoms can occur with abrupt disconinuation

*BZDs have the following 4 properties:

Benzodiazepine Receptor Agonists (BZDRA’s)

How lethal are they when a lot are taken at once?

-Unlike CNS depressants, BZD's are less toxic, i.e. fetal overdose with oral BZD is very uncommon. They can be lethal when taken with other CNS depressants like ethanol, barbiturates, etc.

-Abrupt disconinuaiton can lead to withdrawal-- anxiety, insominia, increased CNS excitablility that can lead to seizure activity.

can be lethal in overdose. more pronounced depressive effect on the CNS than BNZ's

Active ingredient in most OTC sedatives

they are also anticholinergicss: dry mouth, tachycardia, urinary retention, and constipation. Not great for older people for a sleeper drug

-good for jet lag

-melatonin indongenous that peaks as we are going to sleep.

- Hypnotic that acts as an agonist at melatonin receptors.

-expensive

-not a controlled substance. CAM (complimentarl and alternative) no regulation on it from FDA.

Clinical Use of Sedatives and Hypnotics

BZD's with long 1/2 life

BZD's with long T1/2's (e.g flurazapam-Dulmane) can cause significant daytime sedation an impaired psychomotor performance. DO NOT USE METABOLITES WITH LONG HALF LIFE. Cause daytime sedation

What is the first line of therapy for sedation/hypnotics?

Benzodiazepine Receptor Agonists (BZDRA’s)

BXD's, Barbituates, and antihistamines

ADVERSE EFFECTS

1. Sedation: day time

2. Amnesia: most common: midazolam, temazepam, & triazolam.

3. Resp depression: most notably with IV/ combo with fentanyl.

4. Dependance and withdrawal. WITHDRAWAL FROM BARBITURATES CAN BE FATAL. S/S include: anxiety, tremor insomnia, agitation, tachycardia, vomiting, diaphoresis, seizures. usually not fatal

5. Paradoxical agitation/rage (patients go nuts)

6. Flumazenil (Romazicon) is a benzodiazepine antagonits: (same as how narcan is to opiod)

7. OSA (don't want to give them a BZD)

8. Rebound Insomnia: rebound , makes you sleep lighter, keep use of these short term. Once stop patient will have trouble sleeping for a few nights.

IMPORTANT DRUG INTERACTION

midazolam and protease inhibitors

 benzodiazepines

Onset of Action

0.5-1 hours thus atleast one hour should lapse prior to redosing og prn BZD for sleep.

TREATMENT of ANXIETY

General Anxiety Disorder
 Acute treatment (short term)

TREATMENT of ANXIETY

General Anxiety Disorder

Chronic Therapy

Anti-anxiety

Buspirone

(Buspar)

Mixed reviews: can't take 1-3 weeks to start working.

Nonbenzodiazepine with anxiolytic properties. Has no anticonvulsant, sedative or muscle relaxant property. (Inconsistent reports of efficacy) Activity at serotonin receptors. Buspirone is effective as an antianxiety medication but is ineffective in treating panic disorders.
i. Onset of action is slow; may take 1 to 3 weeks for maximal effects; thus, is never used on a prn basis.
ii. Does not have sedative properties; therefore, does not produce additive sedation with alcohol or other CNS depressants.
iii. Questionable effectiveness particularly in the elderly.

Social Anxiety Disorders

and

Panic Disorders

*SSRI's are the drug of choice

-Benzodiasepines are effective but are generally not used as monotherapy. Patients find it difficult to stop taking these medication because of rebound anxiety.

Stage Fright

Beta blockers

 maybe useful in patients with peformance anxiety who present primarily with cardiovascular symptoms of anxiety (palpitations/tremors) NOT GOOD FOR SOCIAL ANXIETY DISORDER

HEADACHE

2 GENERAL DIVISIONS

ORGANIC

1. Infections: Meningitis, sinus

2. Diseases of eyes, ears, nose, throat, teeth

3. Mass lesions: tumors edema, hematomas, cerebral hemorrhage.

4. Cranial Neuralgias (trigeminal, glossopharyngeal )

HEADACHE

2 GENERAL DIVISIONS

Non-Organic

1. With aura

2. Without aura

3. Migraine variants ("complicated migraine")

         a. Hemiplegic: paralysis/weakness on one side of the body

         b. opthalmoplegic: paralysis of eye muscles

         c. Basilar artery: dizzyness, vertigo, ataxia

Migraine variants ("complicated migraine")

has a headache with these things

KNOW the 3 and what drug is contraindicated when these are present

a. Hemiplegic: paralysis/weakness on one side of the body

b. opthalmoplegic: paralysis of eye mus

c. Basilar artery: dizzyness, vertigo, ataxia

TRIPTANS

CLUSTER HEADACHES

(1) Prevalence 0.08% in women and 0.4% in men; onset in late 20’s
(2) Severe, unilateral pain that is retro-orbital; often described as “searing burning pain behind one eye.”
(3) Not associated with an aura
(4) Usually associated with one or more of the following symptoms on the side of the head where the patient has pain: lacrimation, conjunctival injection, rhinorrhea, forehead of facial swelling, miosis, ptosis.
(5) Treatment/prevention:
(a) Therapy similar to migraine therapy
(b) Abortive therapy can include Oxygen 5-8L/min

Tension Headache

Hypertensive Headache

BP must be very high to cause a HA ( a bad HA can cause mild hypertension) treat HA by treating cause of high blood pressure.

(Which came first)

Migraine Headache

Wolf Theory )Vascular Hypothesis

NOT SUPPORTED BY CURRENT EVIDENCE

a) Vasospasm is initiating pathology
b) Ischemia – cause of aura
c) Release of vasospasm – aura ends
d) Vasodilatation – cause of throbbing headache

migraine headache

Neurogenic Theory

PREVAILING CURRENT HYPOTHESIS

a) Two current theories of the root cause of migraines: Dysfunction originates in brainstem and spreads to the cortex or the other way around – currently a debated point
b) Cortical Spreading Depression (wave of intense nerve cell activity)
(1) When wave of activity involves the sensory cortex, an aura occurs.
(2) Neuronal dysfunction involves the brain stem resulting in dysinhibition of the trigeminovascular system causing the release of neurotransmitters (glutamate and nitric oxide), which in turn cause release calcitonin gene-related peptide (CGRP), which in turn causes inflammation and pain (headache).
(3) Aura is not associated with ischemia
(4) Headache is not associated with vasodilatation

Serotonin is a key neurotransmitter regulating the trigeminovascular system: serotonin stimulation inhibitors CGRP release

International Headache Society

definition of a headache

“a familial disorder characterized by recurrent attacks of headache of variable frequency, duration, and intensity, which are usually unilateral and associated with anorexia, nausea, and vomiting; these attacks may be preceded or accompanied by neurological or visual symptoms”

Migraine headaches

Prodrome

occurs in approximately 60% of the patients

can last hours to days.

symptoms include: depression, difficulty concentrating, feeling weary and tired, stiff neck.

Migraine headache

Aura

occurs in approx 30% of patients

evolves over 5-20 minutes

can be visual, sensory, or motor

headache usually follows within 60 minutes.

they are typically unilateral, gradual onset, and throbbing.

Variable in durationL 4-72 hours in adults, 1-72 hours in children (shorter)

bilateral pain in 40% pf patients

anoerxia, N/V are common

Migraine headache

Postdrone

occurs approximately in 70% of patients

feeling tired washed out, impaired concentration, scalp tenderness, depression, malaise

some patients can feel refreshed or euphoric

Diet: chocolate, alcohol, monosodium glucomate, menstration, sleep deprevation, tyramine contained foods (aged cheeses) nitrates (processed food, hot dogs), skipped meals

Drugs: theophylline, nitroglycerine, drug induced intracranial pressure (NSAID, esp indomethacin), OCP, steroids, TMP-SMX (Bactrim), tetracycline (esp minocycline)

Enviromental

Emotional

cocaine (give patients permission to tell us the truth)

alcholol withdrawal, caffeine withdrawal

Decongestants

Treatments for a headache

ABORTIVE THERAPY

first few things you do

-Move to cool, quiet dark enviroment

-Start therapy promptly with adequate dose: GI motility is still adequate for oral therapy, Gastric stasis is associated with migraines.

Treatments for a headache

ABORTIVE THERAPY

NSAIDS

a) First line therapy for mild to moderate HA – must take early, and don't be wimpy give effective dose
(1) Aspirin 900mg (adult)
(2) Naproxen Sodium
(a) Anaprox one or two 550mg tabs q12h
(b) Aleve 450mg q12h
(3) Ibuprofen (a) 800mg q4h x 2 doses (b) 5-10mg/kg/ dose x 2 doses
b) Overuse can cause rebound headache; avoid regular use (may be used regularly at time of menstruation for menstruation related HA). Max 2-3 days/week.

-Rebound headache when withdrawal

Treatments for a headache

ABORTIVE THERAPY

Acetaminophen

NOT EFFECTIVE placebo controlled trials have not shown oral acetaminophen to be effective.

Treatments for a headache

ABORTIVE THERAPY

NARCOTICS

a) Because of potential of overuse (ADDICTIVE), narcotics are generally reserved for rescue therapy when other therapies have not worked.
b) Butorphanol nasal spray (Stadol NS) may use in emergency situation.

Treatments for a headache

ABORTIVE THERAPY

METACLOPRAMIDE (REGLAN)

Treatments for a headache

ABORTIVE THERAPY

Fiorinal (ASA, butalbital, caffeine)

a) Fiorinal – No placebo controlled trials are available to prove or disprove its efficacy.
b) Caffeine
(1) May help in cases of caffeine withdrawal
(2) May inhibit sleep
c) Barbiturates
(1) May be habit forming (NOT A FAN)

Treatments for a headache

ABORTIVE THERAPY

MIDRIN

(combo: isometheptene, dichloraphenazone, acetaminophen)

a) Studies demonstrate only borderline effectiveness
b) Used in mild to moderate headache
c) Mild vasoconstriction, sedative, analgesic
d) Take 2 caps at onset, then 1qh, max 5 q12h
e) Makes patient sleepy

Treatments for a headache

ABORTIVE THERAPY

TRIPTANS

(NSAIDS and these are first line)

-this drug stimulate the serotonin receptor (5-HT) 1D/1B receptors (without stimulating any other serotonin receptors) which in turn interrupts the release of calcitonin gene-related peptide (CGRP) which decreases pain and inflammation

-Efficacy in children is not clear, probably because untreated migraines in children are relatively short compared to adults.

-Does not prevent the aura

Treatments for a headache

ABORTIVE THERAPY

TRIPTANS

CONTRAINDICATIONS

They can cause ischemia

(1) Complicated Migraines
    (a) Hemiplegic – paralysis/weakness on one side of the body
    (b) Opthalmoplegic – paralysis of eye muscles
    (c) Basilar artery – Dizziness, vertigo, ataxia
(2) Ischemic Heart Disease (acute MI is rare)
(3) Prior MI
(4) Pregnancy
DO NOT COMBINE ERGOTS AND OTHER TRIPTANS ( too much serotonin stimulation)

Treatments for a headache

ABORTIVE THERAPY

TRIPTANS

TOXICITIES

(may want patient to try first dose in your office)

(1) Pressure, tightness, or warmth in chest, neck, throat, jaw – can mimic angina. Mechanism is secondary to motility changes of esophagus and not secondary to ischemia.
(2) Nausea / Vomiting
(3) Bad taste from nasal product (Sumatriptan)

Treatments for a headache

ABORTIVE THERAPY

TRIPTANS

DRUG INTERACTIONS

(1) SSRI – weakness, hyperreflexia, incoordination
(2) Ergots + Other triptans – excessive vasoconstriction

Treatments for a headache

ABORTIVE THERAPY

 EROGOTS

(Non specific Serotonin agonist)

What can be a life threatening controindication for combination with another medication?

getting away from using them

Life threatening peripheral ischemia has been associated with the coadministration of Caforgot and potent CYP 3A4 inhibitors (protease inhibitors and erythromycin inhibit that enzyme and cause ergots to become toxic and even fatal)

Treatments for a headache

ABORTIVE THERAPY

DHE- Dihydroergotamine

WILL MAKE YOU FEEL LIKE YOUR GOING TO DIE/ MUST BABYSIT THE PATIENT/ Acute anxiety last maybe 10 minutes

transient cerebral ischemia

Treatments for a headache

ABORTIVE THERAPY

Antiemetics

a) IV prochlorperazine (Compazine) and ondansetron (Zofran) have been shown to be useful adjuvant therapy as a first-line antiemetic in the setting of a provider’s office or emergency department.

Treatments for a headache

ABORTIVE THERAPY

Drugs shown NOT to work

a) Acetaminophen alone
b) Intranasal lidocaine
c) IV corticosteroids
d) Clonidine

Treatments for a headache

ABORTIVE THERAPY

Drugs without good studies supporting efficacy.

a) Feverfew
b) SSRI (with exception of fluoxetine where there is evidence for modest effectiveness)

Migraine Headaches

PROPHYLACTIC THERAPY

(may take 2-6 months to show full therapeutic benefit)

CRITERIA FOR USE

a) Three for more migraine headaches per month
b) Migraine HA >48hours
c) Extreme HA severity

Migraine Headaches

PROPHYLACTIC THERAPY

(may take 2-6 months to show full therapeutic benefit)

DRUGS USED

-Propranolol 40-120 mg tid

- Cyproheptidine (Periactine) 2-18 mg qd
a) Very poor choice for children / adolescents (even though the only FDA approved for kids) b) causes Sedation, weight gain

- (GOOD) Amitryptyline (Elavil) 10-100 mg qhs (10mg qhs, incr. by 10mg/day/wk) small dose, also treats depressiona) Dry mouth, constipation b) Good choice for adolescents (note next item)c) Keep out of reach of small children* d) Weight gain in some patients.

- Verapamil (Calan)

-Valprioric acid (Divalproex)