ANXIOLITYCS, SEDATIVES, HIPNOTICS, ANTISEIZURE DRUGS

o What is “anxiety”? Apprehensive anticipation of future danger Experienced as dysphoric (unpleasant)-

hence ego-dystonic Often accompanied by somatic/physical

symptoms (e.g., muscle tension, elevated heart rate, etc.)

Relationship Between Arousal (anxiety) and Performance

What is “anxiety”?

Apprehensive anticipation of future danger Experienced as dysphoric (unpleasant)- hence ego-

dystonic Often accompanied by somatic/physical

symptoms (e.g., muscle tension, elevated heart rate, etc.)

Is “Anxiety” Always Pathological? Some anxiety is advantageous

Helps in novel situations Helps mobilize individual for quick response- fight or

flight response for survival Anxiety can heighten one’s awareness/alertness,

prepare a defense to a threatening situation

Genesis of “anxiety”?

Limbic region - hippocamp and amigdala receives imput from the locus coeruleus and dorsal rafhe

And turn the projects to the subcortical and cortical nuclei

Dysfunction of neurotransmission in limbic region (hippocamp and amigdala) of brain underlies Exccesive excitatory neurotransmission

(serotoninergic and noradrenergic) in the limbic system

Deficient inhibition of limbic neurotransmission by GABA receptors

What Causes Anxiety?

- Some Fears are Innate- Some learned fears are adaptive and appropriate; others are not and result from faulty learning…

- Thru Classical Conditioning: pairing of a threatening stimulus with a non-threatening one

- Hence, safe or innocuous stimuli (e.g., situations, objects) acquire a meaning of danger

When anxiety is excessive, becomes generalized, or is inappropriate for the situation, it becomes pathological

Anxiety Disorders

Panic disorder (agoraphobia) Posttraumatic stress disorder Social Phobia Specific phobia Obsessive-compulsive disorder Generalized anxiety disorder

Anxiety Disorders

Generalized anxiety disorder (GAD): People suffering from GAD have general symptoms of motor tension, autonomic hyperactivity, etc. for at least one month.

Phobic anxiety: Simple phobias. Agoraphobia, fear of animals,

etc.Social phobias.

Panic disorders: Characterized by acute attacks of fear as compared to the chronic presentation of GAD.

Obsessive-compulsive behaviors: These patients show repetitive ideas (obsessions) and behaviors (compulsions).

Panic ATTACKDiscrete period of intense fear or discomfort accompanied by at least four of the following physical sensations…

- Accompanying Symptoms: Chest pain Palpitations Sweating Trembling or shaking Paresthesias (numbness, tingling) Dizzy, faint Derealization, depersonalization Fear losing control or going crazy Fear of dying Shortness of breath, choking, smothering Nausea or GI distress Chills or hot flashes

Panic Attack

Episodes have a sudden onset and peak rapidly (usually in 10 minutes or less)

Often accompanied by a sense of imminent danger or doom and an urge to escape

May present to ER with fear of catastrophic medical event (e.g., MI or stroke)

Generalized Anxiety Disorder

Excessive worries about real life problems such as school and work performance (“worry wort”)

Typically seek help for somatic concerns in primary care setting

Accompanying anxiety symptoms: Muscle tension Restlessness or feeling keyed-up or on edge Easy Fatigability Irritability Trouble Concentrating Sleep disturbance

Anxiety as a symptom of…

Anxiety Disorder due to a General Medical Condition Anxiety judged to be due to direct physiological effects of a

general medical condition such as: Tumors (ex. Pheocromocytoma) Hypoxia (from a Pulmonary Embolus, Chronic Obstructive

Pulmonary Disease) Hyperthyroidism (thyroid storm) Myocardial infarction, arrhythmias, mitral valve prolapse Hypoglycemia

Substance Induced Anxiety Disorder Anxiety judged to be due to direct physiological effects of a

substance (i.e., a drug of abuse, a medication, or toxin exposure) Alcohol/sedative withdrawal Cocaine/stimulant intoxication Cannabis intoxication Caffeine intoxication

Anxiolytics

Strategy for treatmentReduce anxiety without causing sedation.

1) Benzodiazepines (BZDs).2) Barbiturates (BARBs).3) 5-HT1A receptor agonists.4) 5-HT2A, 5-HT2C & 5-HT3 receptor antagonists.

If ANS symptoms are prominent:• ß-Adrenoreceptor antagonists. 2-AR agonists (clonidine).

Anxiolytics

Other Drugs with anxiolytic activity. TCAs (Fluvoxamine). Used for

Obsessive compulsive Disorder. MAOIs. Used in panic attacks. Antihistaminic agents. Present in over

the counter medications. Antipsychotics (Ziprasidone).

Sedative/Hypnotics

A hypnotic should produce, as much as possible, a state of sleep that resembles normal sleep.

By definition all sedative/hypnotics will induce sleep at high doses.

Normal sleep consists of distinct stages, based on three physiologic measures: electroencephalogram, electromyogram, electronystagmogram.

Two distinct phases are distinguished which occur cyclically over 90 min:

1) Non-rapid eye movement (NREM). 70-75% of total sleep. 4 stages. Most sleep stage 2.

2) Rapid eye movement (REM). Recalled dreams

Properties of Sedative/Hypnotics

1) The latency of sleep onset is decreased (time to fall asleep).2) The duration of stage 2 NREM sleep is increased.3) The duration of REM sleep is decreased.4) The duration of slow-wave sleep (when somnambulism and

nightmares occur) is decreased.Tolerance occurs after 1-2 weeks.

Some sedative/hypnotics will depress the CNS to stage III of anesthesia.

Due to their fast onset of action and short duration, barbiturates such as thiopental and methohexital are used as adjuncts in general anesthesia

Sedative/Hypnotics

1) Benzodiazepines (BZDs):

Alprazolam, diazepam, oxacepam, triazolam

2) Barbiturates:

Pentobarbital, phenobarbital

3) Alcohols:

Ethanol, chloral hydrate, paraldehyde, trichloroethanol,

4) Imidazopyridine Derivatives:

Zolpidem

5) Pyrazolopyrimidine

Zaleplon

Sedative/Hypnotics

6) Propanediol carbamates:Meprobamate

7) PiperidinedionesGlutethimide

8) AzaspirodecanedioneBuspirone

9) -Blockers**Propranolol

10) 2-AR partial agonist**Clonidine

Sedative/Hypnotics

Others:11) Antyipsychotics **

Ziprasidone12) Antidepressants **

TCAs, SSRIs13) Antihistaminic drugs **

Dephenhydramine

Sedative/Hypnotics

All of the anxiolytics/sedative/hypnotics should be used only for symptomatic relief.

************* All the drugs used alter the normal sleep cycle and should be administered only for days or weeks, never for

months.************USE FOR

SHORT-TERM TREATMENT

ONLY!!

SEDATIVE/HYPNOTICSANXYOLITICS

BEN ZO D IAZEPIN ES BAR BITU R ATES

GABAergic SYSTEM

GABAergic SYNAPSE

GABA

glutamate

glucose

Cl-

GAD

GABA-A Receptor Oligomeric (abdgepr)

glycoprotein. Major player in

Inhibitory Synapses. It is a Cl- Channel. Binding of GABA

causes the channel to open and Cl- to flow into the cell with the resultant membrane hyperpolarization.

GABA AGONISTS

BDZs

BARBs

GABA-A ReceptorBenzodiazepines acts

at three specific binding sites: 1 - omega 1, 2 - omega 2, 3 - omega 3

subtypes receptors

GABA AGONISTS

BDZs

BARBs

Benzodiazepines

- are the most important sedative hypnotics.- developed to avoid undesirable effects of barbiturates

(abuse liability).

Diazepam Chlordiazepoxide Triazolam Lorazepam Alprazolam Clorazepate => nordiazepam Halazepam Clonazepam Oxazepam Prazepam

Benzodiazepines - Mechanisms of Action

Enhance GABAergic Transmission

frequency of openings of GABAergic channels. Benzodiazepines

opening time of GABAergic channels. Barbiturates

receptor affinity for GABA. BDZs and BARBS

2) Stimulation of 5-HT1A receptors.

3) Inhibit 5-HT2A, 5-HT2C, and 5-HT3 receptors.

Pharmacokinetics of Benzodiazepines

Although BDZs are highly protein bound (60-95%), few clinically significant interactions.*

High lipid solubility high rate of entry into CNS rapid onset.

*The only exception is chloral hydrate and warfarin Hepatic metabolism. Almost all BDZs undergo microsomal oxidation (N-dealkylation and aliphatic hydroxylation) and conjugation (to glucoronides).

Rapid tissue redistribution long acting long half lives and elimination half lives (from 10 to > 100 hrs).

All BDZs cross the placenta detectable in breast milk may exert depressant effects on the CNS of the lactating infant.

Pharmacokinetics of Benzodiazepines

Many have active metabolites with half-lives greater than the parent drug. Prototype drug is diazepam (Valium), which has active

metabolites (desmethyl-diazepam and oxazepam) and is long acting (t½ = 20-80 hr).

Differing times of onset and elimination half-lives (long half-life => daytime sedation).

Keep in mind that with formation of active metabolites, the kinetics of the parent drug may not reflect the time course of the pharmacological effect.

Estazolam, oxazepam, and lorazepam, which are directly metabolized to glucoronides have the least residual (drowsiness) effects.

All of these drugs and their metabolites are excreted in urine.

Properties of Benzodiazepines

• BDZs have a wide margin of safety if used for short periods. Prolonged use may cause dependence.

• BDZs have little effect on respiratory or cardiovascular function compared to BARBS and other sedative-hypnotics.

• BDZs depress the turnover rates of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in various brain nuclei.

Side effects• CNS depression: drowsiness, excess sedation, impaired

coordination, nausea, vomiting, confusion and memory loss. Tolerance develops to most of these effects.

• Dependence with these drugs may develop.• Serious withdrawal syndrome can include convulsions

and death.

Toxicity/Overdose with Benzodiazepines• Drug overdose is treated with flumazenil (a BDZ receptor

antagonist, short half-life), but respiratory function should be adequately supported and carefully monitored.

• Seizures and cardiac arrhythmias may occur following flumazenil administration when BDZ are taken with TCAs.

• Flumazenil is not effective against BARBs overdose.

Drug-Drug Interactions with BDZs• BDZ's have additive effects with other CNS depressants

(narcotics), alcohol => have a greatly reduced margin of safety.• BDZs reduce the effect of antiepileptic drugs.• Combination of anxiolytic drugs should be avoided.• Concurrent use with ODC antihistaminic and anticholinergic

drugs as well as the consumption of alcohol should be avoided.• SSRI’s and oral contraceptives decrease metabolism of BDZs.

Barbiturates

Phenobarbital Pentobarbital Amobarbital Mephobarbital Secobarbital Aprobarbital

Pharmacokinetics of Barbiturates

Rapid absorption following oral administration. Rapid onset of central effects. Extensively metabolized in liver (except

phenobarbital), however, there are no active metabolites.

Phenobarbital is excreted unchanged. Its excretion can be increased by alkalinization of the urine.

In the elderly and in those with limited hepatic function, dosages should be reduced.

Phenobarbital and meprobamate cause autometabolism by induction of liver enzymes.

Properties of Barbiturates

Mechanism of Action.• They increase the duration of GABA-gated

channel openings.• At high concentrations may be GABA-mimetic.

Less selective than BDZs, they also:• Depress actions of excitatory neurotransmitters.• Exert nonsynaptic membrane effects.

Toxicity/Overdose

Strong physiological dependence may develop upon long-term use.

Depression of the medullary respiratory centers is the usual cause of death of sedative/hypnotic overdose. Also loss of brainstem vasomotor control and myocardial depression.

Withdrawal is characterized by increase anxiety, insomnia, CNS excitability and convulsions.

Drugs with long-half lives have mildest withdrawal Drugs with quick onset of action are most abused. No medication against overdose with BARBs. Contraindicated in patients with porphyria

Miscellaneous Drugs

Buspirone Chloral hydrate Hydroxyzine Meprobamate (Similar to

BARBS) Zolpidem (BZ1 selective) Zaleplon (BZ1 selective)

BUSPIRONE

Mechanism of Action:

• Acts as a partial agonist at the 5-HT1A

receptor presynaptically inhibiting serotonin release.

• The metabolite 1-PP has 2 -AR blocking action.

BUSPIRONE

• Most selective anxiolytic currently available.• The anxiolytic effect of this drug takes several

weeks to develop => used for GAD.• Buspirone does not have sedative effects and

does not potentiate CNS depressants.• Has a relatively high margin of safety, few side

effects and does not appear to be associated with drug dependence.

• No rebound anxiety or signs of withdrawal when discontinued.

• Not effective in panic disorders.

Pharmacokinetics of BUSPIRONE

• Rapidly absorbed orally.• Undergoes extensive hepatic

metabolism (hydroxylation and dealkylation) to form several active metabolites (e.g. 1-(2-pyrimidyl-piperazine, 1-PP)

• Well tolerated by elderly, but may have slow clearance.

• Analogs: Ipsapirone, Gepirone, Tandospirone.

BUSPIRONE

Side effects:

• Tachycardia, palpitations, nervousness, GI distress and paresthesias may occur.

• Causes a dose-dependent pupillary constriction.

Zolpidem

• Structurally unrelated but as effective as BDZs.

• Minimal muscle relaxing and anticonvulsant effect.

• Rapidly metabolized by liver enzymes into inactive metabolites• Dosage should be reduced in patients with hepatic

dysfunction, the elderly and patients taking cimetidine.

Properties of Zolpidem

Mechanism of Action:

• Binds selectively to BZ1 receptors - 1 .

• Facilitates GABA-mediated neuronal inhibition.

• Actions are antagonized by flumazenil

Properties of Other drugs.

Chloral hydrate Is used in institutionalized patients. It

displaces warfarin (anti-coagulant) from plasma proteins.

Extensive biotransformation.

Properties of Other Drugs

2-Adrenoreceptor Agonists (eg. Clonidine)• Antihypertensive.• Has been used for the treatment of panic

attacks.• Has been useful in suppressing anxiety during the

management of withdrawal from nicotine and opioid analgesics.

• Withdrawal from clonidine, after protracted use, may lead to a life-threatening hypertensive crisis.

Properties of Other Drugs

-Adrenoreceptor Antagonists (eg. Propranolol)

• Use to treat some forms of anxiety, particularly when physical (autonomic) symptoms (sweating, tremor, tachycardia) are severe.

• Adverse effects of propranolol may include: lethargy, vivid dreams, hallucinations.

ANTIEPILEPTIC DRUGS

A group of chronic CNS disorders characterized by recurrent seizures.

Seizures are sudden, transitory, and uncontrolled episodes of brain dysfunction resulting from abnormal discharge of neuronal cells with associated motor, sensory or behavioral changes.

Epilepsy - pathophysiology

Local imbalance amongs excitatory and inhibitory influence on the electrical activity across the cell membrane of neuronesThe brain of epileptics patients has been found:

A reduction in the activity of membrane – bound ATP aze linked to neuronal transmembrane ion pumps

A reduction in the activity of the inhibitory GABA – ergic neurons

Causes for Acute Seizures

Trauma Encephalitis Drugs Birth trauma Withdrawal from

depressants Tumor

High fever Hypoglycemia Extreme

acidosis Extreme

alkalosis Hyponatremia

Hypocalcemia Idiopathic

Partial (focal) SeizuresI. Simple Partial SeizuresII. Complex Partial Seizures

Generalized SeizuresI. Absence SeizuresII. Tonic-Clonic seizuresIII. Tonic SeizuresIV. Atonic SeizuresV. Clonic and Myoclonic SeizuresVI. Infantile Spasms

Classification of Seizures

Treatment of Epilepsies

Goals: Block repetitive neuronal firing. Block synchronization of neuronal

discharges. Block propagation of seizure.

Minimize side effects with the simplest drug regimen.

MONOTHERAPY IS RECOMMENDED IN MOST CASES

Treatment of Epilepsies

Strategies: Modification of ion conductances.

Increase inhibitory (GABAergic) transmission.

Decrease excitatory (glutamatergic) activity.

Actions of Phenytoin on Na+ Channels

A. Resting State

B. Arrival of Action Potential causes depolarization and channel opens allowing sodium to flow in.

C. Refractory State, Inactivation

Na+

Na+

Na+

Sustain channel in this conformation

GABAergic SYNAPSE

Drugs that Act at the GABAergic

Synapse

GABA agonists GABA antagonists Barbiturates Benzodiazepines GABA uptake

inhibitors

GLUTAMATERGIC SYNAPSE

Excitatory Synapse. Permeable to Na+, Ca2+

and K+. Magnesium ions block

channel in resting state. Glycine (GLY) binding

enhances the ability of GLU or NMDA to open the channel.

Agonists: NMDA, AMPA, Kainate.Mg++

Na+

AGONISTS

GLU

Ca2+

K+

GLY

Treatment of Epilepsies

1) Hydantoins: phenytoin2) Barbiturates: phenobarbital3) Oxazolidinediones: trimethadione4) Succinimides: ethosuximide5) Acetylureas: phenacemide

Treatment of Epilepsies1) Structurally dissimilar:

1) carbamazepine2) valproic acid3) BDZs.

2) As are the new compounds:1) Felbamate (Japan)2) Gabapentin3) Lamotrigine4) Tiagabine5) Topiramate6) Vigabatrin

Pharmacokinetic Parameters

PHENYTOIN (Dilantin) Oldest nonsedative

antiepileptic drug. Useful for partial all types of

epilepsia, except absences Fosphenytoin, a more

soluble prodrug is used for parenteral use.

“Fetal hydantoin syndrome” It alters Na+, Ca2+ and K+

conductances. Inhibits high frequency

repetitive firing. Alters membrane potentials. Alters a.a. concentration. Alters NTs (NE, ACh, GABA)

Toxicity:•Ataxia and nystagmus.•Cognitive impairment.•Hirsutism•Gingival hyperplasia.•Coarsening of facial features.•Dose-dependent zero order kinetics.•Exacerbates absence seizures.

CARBAMAZEPINE (Tegretol)

Tricyclic, antidepressant (bipolar) 3-D conformation similar to

phenytoin. Useful for partial all types of epilepsia,

except mioclonic epilepsy Mechanism of action, similar to

phenytoin. Inhibits high frequency repetitive firing.

Decreases synaptic activity presynaptically.

Binds to adenosine receptors (?). Inh. uptake and release of NE, but not

GABA. Potentiates postsynaptic effects of

GABA. Metabolite is active.

Toxicity:•Autoinduction of metabolism.•Nausea and visual disturbances.•Granulocyte supression.•Aplastic anemia.•Exacerbates absence seizures.

OXCARBAZEPINE (Trileptal)

Closely related to carbamazepine.

With improved toxicity profile. Less potent than

carbamazepine. Active metabolite. Mechanism of action, similar to

carbamazepine It alters Na+

conductance and inhibits high frequency repetitive firing.

Toxicity:•Hyponatremia•Less hypersensitivityand induction of hepaticenzymes than with carb.

PHENOBARBITAL (Luminal)

Except for the bromides, it is the oldest antiepileptic drug.

Although considered one of the safest drugs, it has sedative effects.

Many consider them the drugs of choice for seizures only in infants.

Acid-base balance important. Useful for partial, generalized

tonic-clonic seizures, and febrile seizures

Prolongs opening of Cl- channels. Blocks excitatory GLU (AMPA)

responses. Blocks Ca2+ currents (L,N).

Inhibits high frequency, repetitive firing of neurons only at high concentrations.

Toxicity: Sedation. Cognitive

impairment. Behavioral

changes. Induction of liver

enzymes. May worsen

absence and atonic seizures.

PRIMIDONE (Mysolin)

Metabolized to phenobarbital and phenylethylmalonamide (PEMA), both active metabolites.

Effective against partial and generalized tonic-clonic seizures.

Absorbed completely, low binding to plasma proteins.

Should be started slowly to avoid sedation and GI problems.

Its mechanism of action may be closer to phenytoin than the barbiturates.

Toxicity:•Same as phenobarbital•Sedation occurs early.•Gastrointestinal complaints.

VALPROATE (VALPROIC ACID)

Fully ionized at body pH, thus active form is valproate ion.

One of a series of carboxylic acids with antiepileptic activity. Its amides and esters are also active.

Mechanism of action, similar to phenytoin.

levels of GABA in brain. May facilitate Glutamic acid

decarboxylase (GAD). Inhibits GAT-1. [aspartate]Brain?

May increase membrane potassium conductance.

Useful for partial all types of epilepsia

Toxicity:•Elevated liver enzymes including own.•Nausea and vomiting.•Abdominal pain and heartburn.•Tremor, hair loss, •Weight gain.•Idiosyncratic hepatotoxicity.•Negative interactions with other antiepileptics.•Teratogen: spina bifida

ETHOSUXIMIDE (Zarontin)

Drug of choice for absence seizures.

High efficacy and safety. Not plasma protein or fat binding Mechanism of action involves

reducing low-threshold Ca2+ channel current (T-type channel) in thalamus.

At high concentrations: Inhibits Na+/K+ ATPase. Depresses cerebral metabolic rate. Inhibits GABA aminotransferase.

Phensuximide = less effective

Methsuximide = more toxic

Toxicity:•Gastric distress, including, pain, nausea and vomiting•Lethargy and fatigue•Headache•Hiccups•Euphoria•Skin rashes•Lupus erythematosus (?)

CLONAZEPAM (Klonopin)

A benzodiazepine. Long acting drug with efficacy

for absence seizures. One of the most potent

antiepileptic agents known. Also effective in some cases of

myoclonic seizures. Has been tried in infantile

spasms. Doses should start small. Increases the frequency of Cl-

channel opening.

Toxicity:

•Sedation is prominent.

VIGABATRIN (-vinyl-GABA)

Absorption is rapid, bioavailability is ~ 60%, T 1/2 6-8 hrs, eliminated by the kidneys.

Use for partial seizures and West’s syndrome.

Contraindicated if preexisting mental illness is present.

Irreversible inhibitor of GABA-aminotransferase (enzyme responsible for metabolism of GABA) => Increases inhibitory effects of GABA.

S(+) enantiomer is active.

Toxicity:•Drowsiness•Dizziness•Weight gain

•Agitation•Confusion•Psychosis

LAMOTRIGINE (Lamictal)

Presently use as add-on therapy with valproic acid (v.a. conc. are be reduced).

Almost completely absorbed T1/2 = 24 hrs Low plasma protein binding Suppresses sustained rapid firing

of neurons and produces a voltage and use-dependent inactivation of sodium channels, thus its efficacy in partial seizures.

Also effective in myoclonic and generalized seizures in childhood and absence attacks.

Toxicity:•Dizziness•Headache•Diplopia•Nausea•Somnolence•Rash

FELBAMATE (Felbatrol)

Effective against partial seizures but has severe side effects.

Because of its severe side effects, it has been relegated to a third-line drug used only for refractory cases.

Toxicity:•Aplastic anemia•Severe hepatitis

TOPIRAMATE Rapidly absorbed, bioav. is > 80%,

has no active metabolites, excreted in urine.T1/2 = 20-30 hrs

Blocks repetitive firing of cultured neurons, thus its mechanism may involve blocking of voltage-dependent sodium channels

Potentiates inhibitory effects of GABA (acting at a site different from BDZs and BARBs).

Depresses excitatory action of kainate on AMPA receptors.

Teratogenic in animal models. It is used as an ad-on treatment for

drug-resistant partial or generalised seizures

Toxicity: Somnolence Fatigue Dizziness Cognitive

slowing Paresthesias Nervousness Confusion Urolithiasis

TIAGABINE (Gabatril)

Derivative of nipecotic acid. 100% bioavailable, highly protein

bound. T1/2 = 5 -8 hrs Effective against partial and

generalized tonic-clonic seizures.

GABA uptake inhibitor GAT-1. Potentiates inhibitory effects of

GABA (acting at a site different from BDZs and BARBs).

Depresses excitatory action of kainate on AMPA receptors.

Teratogenic in animal models.

Toxicity:•Dizziness•Nervousness•Tremor•Difficulty concentrating•Depression•Asthenia•Emotional lability•Psychosis•Skin rash

GABAPENTIN (Neurontin) Used as an adjunct in partial and

generalized tonic-clonic seizures. Does not induce liver enzymes. not bound to plasma proteins. drug-drug interactions are negligible. Low potency. An a.a.. Analog of GABA that does not

act on GABA receptors, it may however alter its metabolism, non-synaptic release and transport.

Toxicity:•Somnolence.•Dizziness.•Ataxia.•Headache.•Tremor.

ZONISAMIDE

Sulfonamide derivative. Marketed in Japan. Good bioavailability, low pb. T1/2 = 1 - 3 days Effective against partial and

generalized tonic-clonic seizures.

Mechanism of action involves voltage and use-dependent inactivation of sodium channels (?).

May also involve Ca2+ channels.

Toxicity:•Drowsiness•Cognitive impairment•High incidence of renal stones (?).

ANTIEPILEPTIC DRUG INTERACTIONS

With other drugs:antibiotics phenytoin, phenobarb,

carb.anticoagulants phenytoin and phenobarb

met.cimetidine displaces pheny, v.a. and

BDZsisoniazid toxicity of phenytoinoral contraceptives antiepileptics metabolism.salicylates displaces phenytoin and v.a.

theophyline carb and phenytoin may effect.