Module 14: CNS Drugs Part II

Question 1

Epilepsy

Answer 1

Epilepsy is a neurological disorder that produces brief disturbances in the normal electrical activity in the brain.

Epilepsy is characterized by sudden, brief seizures, the nature and intensity of which vary from person to person.

Question 2

Seizure

Answer 2

A sudden alteration of behaviour that is caused by CNS dysfunction. Seizures are sudden and transient.

Question 3

Epileptic Seizure

Answer 3

A seizure that is caused by primary CNS dysfunction. This is due to excess depolarization and hypersynchronization of neurons.

Question 4

Non-Epileptic Seizure

Answer 4

A seizure-like episode that is not the result of abnormal electrical activity in the brain.

Question 5

Epilepsy definition

Answer 5

A tendency for recurrent spontaneous epileptic seizures

Question 6

Status Epilepticus

Answer 6

A single unremitting epileptic seizure of duration longer than 30 minutes OR frequent seizures without recovery of awareness in between. Status epilepticus is an emergency.

Question 7

Focal/Partial Seizures

Answer 7

These seizures arise in one area of the brain.

The terms focal seizure and partial seizure are interchangeable.

There are two types of focal/partial seizures:
1. Simple partial seizure
2. Complex partial seizure

Question 8

Simple Partial Seizure

Answer 8

Involve no loss of consciousness.

Symptoms depend on where the seizure activity is arising from.

Example Case

o 45 year old man
o Clonic movements of his right arm
o Progression to right face then right leg
o No impairment of consciousness
o Lasting ~ 45 seconds
o MRI – L motor strip oligodendroglioma

Question 9

Complex Partial seizure

Answer 9

A complex partial seizure involves loss of consciousness.

Patients may appear to be awake, but are not aware of surroundings.

Symptoms depend again on where the seizure activity is taking place.

Example Case:
- 37 year-old man with right temporal lobe epilepsy.
- Whistling; bicycling movements in left leg.
- Rising epigastric sensation with nausea.
- Normal ictal speech.
- No memory of the events post-ictally (i.e. after seizure).
- Duration: 30 – 45 seconds.

Question 10

Generalized Seizure

Answer 10

These seizures have a bilateral, diffuse onset, seeming to arise from all areas of the brain at once.

There are 5 different types of generalized seizures:

1. Absence seizures
2. Tonic/Clonic seizures
3. Myoclonic seizures
4. Tonic seizures
5. Atonic seizures

Question 11

Absence Seizures

Answer 11

Also called “petit-mal” (an older name).

Involve loss of consciousness, behavioural arrest and staring.

Are usually brief but may occur in clusters and can recur multiple times in a day.

Rarely associated with automatisms (unusual purposeless movements), usually minor if there are any.

More common in childhood.

Question 12

Tonic/Clonic Seizures

Answer 12

Tonic-clonic seizures involve:
An abrupt loss of consciousness
A tonic period (muscles become rigid), lasting ~ 1 minute
A clonic period (involuntary muscle contractions), lasting and additional 2-3 minutes

Patients may become incontinent and have tongue biting.

In the post-ictal phase patients may be drowsy, confused and frequently complain of headaches.

Used to be called “Grand-mal seizure”

Question 13

Myoclonic seizures

Answer 13

These seizures involve sudden, brief muscle contractions that can involve any muscle group.

Usually there is no loss of consciousness.

Sometimes they are associated with a later development of generalized tonic-clonic seizures.

Question 14

Tonic Seizures

Answer 14

Often involve sudden muscle stiffening (rigidity).
Often involve impaired consciousness.

Question 15

Atonic seizures

Answer 15

Involve sudden loss of muscle tone.
Usually brief, around 15 seconds.

Also known as “drop seizures”, as patients typically drop to the ground.

Potential for falling injuries.

Question 16

Secondary generalized seizure

Answer 16

A seizure that begins in one area of the brain (like a focal seizure) and then spreads throughout the brain.

The preliminary focal phase is sometimes referred to as an “aura”.

Question 17

Localizing Focal Seizures

Answer 17

The location of a focal seizure can be determined by evaluating the patient’s symptoms and what we know about the various regions of the brain

Question 18

Frontal Lobe

Answer 18

Simple repetitive motor movements involving a localized muscle group are associated with seizure activity in the contralateral (opposite side of the brain) primary motor cortex.

Tonic posturing affecting the entire side of the body are associated with seizure activity in the contralateral Supplemental Motor Area (SMA) and other higher level motor structures.

Very complex behavioural automatisms that involve bilateral movement such as swimming or bicycle riding movements are associated with seizure activity in higher areas of the frontal cortex. These behaviours often involve vocalizations, laughter and/or crying.

Question 19

Temporal Lobe

Answer 19

Emotions such as anger, fear, euphoria and psychic symptoms such as déjà vu, jamais vu or amnesia are associated with seizure activity in the temporal lobe.

Auditory (hearing) hallucinations of buzzing or voices talking, and olfactory (smell) and gustatory (taste) hallucinations are associated with the temporal lobe.

More complex sensory phenomena, involving visual distortions, paresthesias (i.e. numbness) and autonomic disturbances can also be associated with temporal lobe seizures.

Question 20

Parietal Lobe

Answer 20

Localized paresthesias, such as numbness and “pins and needles”, are associated with seizure activity in the contralateral somatosensory cortex.

More complex and widespread paresthesias are associated with seizure activity in the somatosensory association cortex.

Seizure activity in the higher order sensory association areas in the parietal lobe can be associated with complex multi-sensory hallucinations and illusions. Can be hard to distinguish from temporal lobe seizure activity, which is more common.

Question 21

Occipital Lobe

Answer 21

Visual hallucinations, such as flashing or a repeated pattern in the environment, are associated with seizure activity in the occipital lobe. The hallucinations are less likely to be of organized objects such as people or faces.

Seizure activity in the occipital lobe can also produce temporary blindness or decreased vision, as well as the sensation of eye movement. Patients may have reflex nystagmus (involuntary eye movement).

Simple partial seizures in the occipital lobe can be mistaken for migraine headaches, as many of the symptoms are similar to common migraine auras.

Question 22

Epileptogenesis

Answer 22

There are three main classifications for the etiology of epilepsy:

1. Symptomatic epilepsy - Epilepsy arising from an identified physical cause, such as a brain tumor, stroke, infection, or other injury.
2. Idiopathic Epilepsy - Epilepsy that does not have an identifiable cause; there is often a family history of seizures, and genetics likely play a role.
3. Cryptogenic epilepsy - Epilepsy that is likely to have an underlying cause that has not been identified.

Question 23

The Seizure Threshold

Answer 23

Seizures are caused by spontaneous, uncontrollable discharges from hyperexcitable areas of the brain.

The seizure threshold can be thought of as the balance between excitable and inhibitory forces in the brain.

Everybody has a seizure threshold and the seizure threshold affects how susceptible a patient is to having a seizure.

Keep in mind that seizures are mediated by changes in electrical activity, so the ability to reach threshold and fire an action potential is important in the generation of a seizure.

Some factors that may affect the seizure threshold are: stroke, head injury, drug/alcohol withdrawal, infection, tumour, severe fever, visual stimuli (flashing lights).

Question 24

Antiepileptic Drugs (AED’S)

Answer 24

Antiepileptic drugs work by four distinct mechanisms of action:

1. Blocking sodium channels.
2. Blocking voltage-dependent calcium channels.
3. Glutamate antagonists
4. Potentiating the actions of GABA.

Question 25

Blocking Sodium Channels

Answer 25

Remember that sodium influx into the cell is a critical step in the generation of an action potential.

After sodium enters the cell, the sodium channel enters an inactive state during which time further sodium entry to the cell is prevented.

In normal cases, the sodium channel very quickly returns to the active state to allowing more sodium to enter the cell to generate another action potential.

Sodium channel blocker AEDs act to prolong the inactivation state of the sodium channel and therefore don’t allow neurons to fire at a high frequency.

Question 26

Phenytoin

Answer 26

Is the most widely used AED and acts by blocking sodium channels.

Phenytoin is useful in the treatment of all types of epileptic seizures except absence seizures.

The metabolic capacity of the liver to metabolize phenytoin is limited. Therefore phenytoin displays non-linear kinetics, i.e. a small increase in dose may produce a large increase in plasma concentration.

Phenytoin has a narrow therapeutic range and often undergoes therapeutic drug monitoring.

Question 27

Adverse effects of phenytoin

Answer 27

Adverse effects of phenytoin include sedation, gingival hyperplasia, skin rash.

Phenytoin is teratogenic.

Question 28

Blocking voltage-dependent calcium channels

Answer 28

Influx of calcium through voltage-dependent calcium channels promotes neurotransmitter release from the pre-synaptic nerve terminal.

Inhibition of calcium channels suppresses neurotransmitter release

Question 29

Glutamate antagonists

Answer 29

Glutamate is an excitatory CNS neurotransmitter.

Blocking glutamate decreases CNS excitation and is therefore a treatment target for AED’s.

Glutamate mediates its effects by binding to either:
1) the NMDA receptor or 2) the AMPA receptor.

Glutamate antagonists used to treat epilepsy block both the NMDA and AMPA receptors, preventing excitation in the CNS.

Question 30

GABA Receptor

Answer 30

GABA is an inhibitory CNS neurotransmitter.

Binding of GABA to its receptor causes negatively charged Cl- ions to rush into the cell.

Remember the action potential? Increased negative charge in the cell will make it more difficult for threshold to be reached and therefore more difficult to have an action potential.

Question 31

Potentiating the Actions of GABA

Answer 31

Drugs that potentiate the actions of GABA increase inhibitory stimuli in the CNS and therefore suppress seizure activity.

Drugs that potentiate the actions of GABA can mediate their effect 4 different ways:

1. Enhancing binding of GABA to its receptor.
2. Stimulating GABA release.
3. Inhibiting GABA reuptake.
4. Inhibiting GABA metabolism.

Question 32

Antiepileptic Drugs

Answer 32

AEDs can be classified as either traditional (phenytoin, valproic acid) or newer AEDs (lamotrigine).

The effectiveness of traditional vs. newer AEDs appears to be similar.

Newer AEDs tend to have decreased side effects and a decreased propensity to induce hepatic drug metabolizing enzymes.

Question 33

Depression

Answer 33

Occasional feelings of depression are normal, as are grief and sadness following any form of loss.

When these symptoms are prolonged and interfere with everyday life, depression may be diagnosed.

Depression is thought to occur to one third of people at some time in their life.

Current estimates suggest that 3% of Canadian’s currently have depression.

Question 34

Diagnosis of Depression

Answer 34

For a diagnosis of depression, at least five of the following symptoms must occur for at least two weeks:

• Depressed mood most of the day, nearly everyday.
• Loss of interest or pleasure in all or almost all activities.
• Significant weight loss (without dieting) or weight gain.
• Insomnia or hypersomnia.
• Psychomotor agitation or retardation.
• Fatigue and energy loss.
• Feelings of worthlessness or excessive guilt.
• Decreased ability to think, concentrate, or excessive indecisiveness.
• Recurrent thoughts of death or suicidal ideations.

Question 35

Types of Depression

Answer 35

Depression can be classified into two major types: exogenous or endogenous.

Exogenous depression is triggered by external stimuli, whereas endogenous depression may or may not be related to external events.

Question 36

Exogenous Depression

Answer 36

Pathological grief – Prolonged grieving coupled with excessive guilt. Psychotherapy is usually more effective in terms of treatment than drugs.

Adjustment disorder– Prolonged depression following failure or rejection (i.e. losing your job, failing out of school). Common symptoms include hypersomnia (excess sleep) and hyperphagia (overeating). Psychotherapy is often more effective than drug therapy.

Question 37

Endogenous Depression

Answer 37

7
Major depression – Common symptoms include loss of interest and lack of response to positive stimuli. Symptoms are usually worse in the morning. Insomnia and weight loss are also typical.

Severe depression – Similar symptoms to major depression with the addition of severe suicidal ideation and psychoses.

Atypical depression - Similar symptoms to major depression but patients have the atypical symptoms of hypersomnia and hyperphagia. Often patients with atypical depression are obese.

Dysthymia - The patient’s mood is regularly low but symptoms are not as severe as major depression. Symptoms are usually more noticeable to family members/close friends than they are to the patient. Usually responds better to psychotherapy than to drugs.

Seasonal Affective Disorder (SAD) - Mild or moderate symptoms of depression related to the lack of sunlight. Usually only affects people in the winter months.

Postpartum Depression – Moderate to severe depression in women after they give birth. Usually occurs within 3 months of delivery but may occur up to a year after birth.

Bipolar Disorder – Alternating periods of elevated or irritable mood and periods of depression.

Question 38

The Monoamine Hypothesis

Answer 38

The exact cause and pathophysiology of depression are unknown.

The major hypothesis with regard to the biochemical basis for depression is the monoamine hypothesis.

This hypothesis suggests that altered monoamine release, receptor sensitivity, or post-synaptic function lead to symptoms of depression.

An example in support of this hypothesis:
Jim, a twenty-year-old university student, goes to a rave Saturday night and takes ecstasy, a drug that depletes the neurotransmitter serotonin (5-HT). Jim has a great time at the rave. The next week Jim lacks motivation to study for his classes, doesn’t leave his couch, and thinks his life is going nowhere.

Question 39

Antidepressants

Answer 39

Antidepressant drugs act to increase the synaptic levels of one or more monoamine neurotransmitters.

The efficacy of antidepressants is difficult to assess since it often takes months for effects to occur.

Results from placebo-controlled clinical trials also suggest that as much as 40% of the effects observed may be attributed to the placebo effect.

Antidepressant drugs mediate their effects by one of two major mechanisms:

1. Inhibiting monoamine reuptake.
2. Inhibiting monoamine metabolism.

Question 40

Classes of Antidepressant Drugs

Answer 40

There are four major classes of drugs used to treat depression:

1. Tricyclic Antidepressants
2. Selective Serotonin Reuptake Inhibitors (SSRIs)
3. Selective Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs)
4. Monoamine Oxidase Inhibitors (MAOIs)

Question 41

Tricyclic Antidepressants

Answer 41

Their name stems from their chemical structure which has three rings, hence tricyclic.

TCAs act by inhibiting the reuptake of both serotonin and norepinephrine.

Effective in the treatment of major depression.

Question 42

Adverse effects of Tricyclic Antidepressants

Answer 42

Anticholinergic effects
Sedation
Orthostatic hypotension
Decreased seizure threshold
Cardiac toxicity – rare but potentially serious.
Weight gain
Sexual dysfunction

Question 43

Selective Serotonin Reuptake Inhibitors (SSRIs)

Answer 43

Similar mechanism of action to TCA’s but they only block serotonin reuptake.

SSRIs are thought to have similar efficacy to TCA’s but the incidence of side effects is lower.

SSRIs are the most commonly used treatment of depression and are most commonly used in major depression.

Question 44

Selective Serotonin Reuptake Inhibitors (SSRIs) Adverse effects

Answer 44

Weight gain

Sexual dysfunction

Insomnia

Serotonin syndrome – increased serotonin transmission can result in agitation, confusion, anxiety, hallucinations and incoordination. Symptoms may appear within 3 days of initial therapy and disappear when the drug is stopped

Question 45

Selective Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs)

Answer 45

SNRIs block the re-uptake of both norepinephrine and serotonin and are effective treatments of major depression.

Their main advantage is the faster onset of action.

How are they different than TCAs? They do not have the characteristic three ring structure that TCAs have. The mechanism of action of SNRIs is very similar to TCAs.

Question 46

Selective Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) adverse effects

Answer 46

Nausea
Diastolic hypertension
Sexual dysfunction

Question 47

Monoamine Oxidase Inhibitors (MAOIs)

Answer 47

Monoamine oxidase (MAO) is an enzyme that inactivates monoamine neurotransmitters.

There are two major types of MAO:

1. MAO-A: metabolizes serotonin and norepinephrine
2. MAO-B: metabolizes dopamine

MAO inhibitors used to treat depression are non-selective, inhibiting MAO-A and MAO-B.

MAO inhibitors are helpful in the treatment of atypical depression and dysthymia.

MAO inhibitors mediate their effects by inhibiting the metabolism of monoamines in the pre-synaptic neuron.

Question 48

Monoamine Oxidase Inhibitors (MAOIs) adverse effects

Answer 48

CNS excitation – anxiety, insomnia, agitation.
Orthostatic hypotension
Hypertensive crisis if taken with tyramine containing foods.

Question 49

Bipolar Disorder

Answer 49

Is a severe illness characterized by recurrent fluctuations between episodes of mania and depression.

Symptoms usually begin in adolescence or early adulthood.

The manic phase consists of symptoms such as:
Irritation
- Inflated self-esteem (delusions of grandeur)
- Little need for sleep
- Poor control of temper
- Reckless behaviour (binge eating, drinking, drug use)
- Easily distracted

The symptoms experienced during the depressive phase are similar to the ones described in the depression section of this module.

Question 50

Pattern of Mood Episodes

Answer 50

Not all patients cycle repeatedly between episodes of mania and depression.

Some patients may experience repeated mania with occasional depression and others may experience repeated depression with occasional mania.

The duration of each episode can also vary substantially from a day to over a year.

On average, patients with bipolar disorder experience approximately 2 episodes every 5 years.

Question 51

Drug Treatment of Bipolar

Answer 51

Bipolar disorder is treated with three major groups of drugs:

1. Mood Stabilizers
2. Antipsychotics
3. Antidepressants

Question 52

Mood Stabilizers

Answer 52

1. Relieve symptoms during manic or depressive episodes,
2. Prevent recurrence of manic or depressive episodes,
3. Do not worsen symptoms of mania or depression and do not alter the rate of cycling.

The primary drugs used as mood stabilizers are lithium and the antiepileptic drug valproic acid.

Although the mechanism of action of lithium is not clear, it is thought to work by altering the uptake and release of glutamate and blocking the binding of serotonin.

Lithium has a narrow therapeutic range and plasma concentrations may be altered by sodium.

Agents that increase sodium loss from the body (i.e. diuretics) increase lithium concentrations and may produce toxicity including GI upset, tremor, sedation and hypotension.

Question 53

Antipsychotics

Answer 53

Are used in bipolar disorder acutely to control symptoms during manic episodes and long term to help stabilize mood.

Antipsychotic drugs benefit patients with bipolar disorder even if they don’t have psychotic symptoms.

Atypical antipsychotics are preferred over conventional antipsychotics largely due to the their lower risk of extrapyramidal symptoms.

Question 54

Antidepressants

Answer 54

Antidepressants are used in bipolar disease to treat depressive episodes.

Antidepressants are always combined with a mood stabilizer.

It is thought that if antidepressants were used alone, they may precipitate a manic episode.

At the moment, there is not good evidence for which antidepressant works best in bipolar disorder.

Question 55

Anxiety

Answer 55

Anxiety is a normal physiological response to stress.

It is normal for people to be nervous before an exam or to have “butterflies” in their stomach before a first date.

In contrast, an anxiety disorder exists when the symptoms of anxiety create a functional impairment in a patient’s daily living.

Anxiety and depression are closely linked so patients that have an anxiety disorder are likely to also suffer from depression.

Question 56

Types of Anxiety

Answer 56

1. General anxiety disorder – Patient is overwhelmed with uncontrollable worrying. The hallmark is an unrealistic or excessive worry about several activities that lasts 6 months or longer.
2. Panic Disorder – Patients have a sense of impending doom that is unrelated to stressors. They experience panic attacks, which are sudden in onset and may include symptoms like heart palpitations, chest pain, shortness of breath, dizziness. They are often confused for a heart attack.
3. Agoraphobia – An anxiety where the patient feels judged or situational anxiety where escaping would be difficult or embarrassing.
4. Obsessive-compulsive disorder – Persistent obsession and compulsions that interfere with daily life (i.e. handwashing, checking locks).
5. Social anxiety disorder – Anxiety in social situations. Patients may not be able to talk (or stop talking), eat in front of others, or use public washrooms.
6. Post-traumatic stress disorder – Anxiety that occurs after experiencing a traumatic event. Symptoms may include re-experiencing the event and severe insomnia.
7. Simple Phobia – Symptoms are related to a specific fear (i.e. spiders, elevators).

Question 57

Treatment drugs for anxiety

Answer 57

The major classes of drugs used to treat anxiety include:

1. Benzodiazepines (BDZs)
2. Buspirone
3. Antidepressants

Question 58

Benzodiazepines (BDZs)

Answer 58

Benzodiazepines are the first line therapy for anxiety.

They act by potentiating the actions of GABA at the GABA receptor.

Note that benzodiazepines are NOT GABA agonists. They bind to a different site on the GABA receptor and cause increased binding of GABA to the receptor.

When GABA binds to the receptor, it opens a channel and chloride ions move into the cell. This causes CNS depression.

Because BDZs amplify the actions of endogenous GABA and are not GABA agonists, there is limit to how much CNS depression they may produce. This makes them much safer than GABA agonist drugs such as barbiturates.

Question 59

Therapeutic uses of Benzodiazepines

Answer 59

Benzodiazepines have several therapeutic actions. They are used clinically to treat:

1. Anxiety
2. Seizures
3. Insomnia
4. Alcohol withdrawal
5. Muscle spasm

Different dosages are used to produce different effects. For example, a higher dose of BDZ is used to treat insomnia than anxiety.

In terms of anxiety, BDZs are effective in treating generalized anxiety disorder and social anxiety disorder

Question 60

Adverse effects of Benzodiazepines

Answer 60

CNS depression – drowsiness, difficulty concentrating.

Anterograde amnesia – impaired memory of events that occur following dosing.

Respiratory depression – is rare with BDZ’s however more common if combined with alcohol.

Teratogenic

Tolerance – occurs to some effects but not others. No tolerance to anxiolytic effects or sedative effects but tolerance does develop to the effect on seizures.

Withdrawal – the dose of BDZ’s should be tapered slowly to avoid withdrawal.

Question 61

Buspirone

Answer 61

Buspirone is not a CNS depressant and acts to treat anxiety in a mechanism distinct from BDZs.

Although the mechanism of action for buspirone is unclear, it appears to involve modulation of serotonergic and/or dopaminergic neurotransmission.

Since buspirone is not a CNS depressant, it is useful in treating anxiety in patients who use alcohol.

Buspirone is indicated for the treatment of generalized anxiety disorder but appear to be ineffective in the treatment of other types of anxiety (i.e. panic disorder, obsessive compulsive disorder).

Buspirone shows no signs of tolerance or physical dependence.

Its major disadvantage is that its anxiolytic effects develop slowly, therefore it is ineffective at treating symptoms that require immediate relief.

In terms of adverse effects buspirone is well tolerated and is non-sedating. The adverse effects most commonly reported include dizziness, lightheadedness and excitement.

Question 62

Antidepressants are useful in the treatment of certain types of anxiety =

Answer 62

Generalized anxiety disorder – SSRIs and SNRIs are effective, but like buspirone are slow to generate their effect.

Panic Disorder/Agoraphobia – SSRIs, TCAs and MAO inhibitors are useful but effects take 6-12 weeks to appear. SSRIs are preferred because they are better tolerated than TCAs and MAO inhibitors.

Obsessive Compulsive Disorder (OCD) – SSRIs are the first line therapy. Patients with OCD also require behavioural therapy, which is a very important component of treatment.

Social Anxiety Disorder – SSRIs are the first line therapy although BDZ’s may also be used. BDZ’s provide immediate relief from symptoms whereas SSRIs require time for the effect to occur.

Post-Traumatic Stress Disorder – There is no good evidence that antidepressants or other drugs are effective in treating PTSD.