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2060B: Pharmacology > Module 14: CNS Drugs (Part 1) > Flashcards

Module 14: CNS Drugs (Part 1) Flashcards

1
Q

Define neuropharmacology

A

Neuropharmacology is the study of how drugs affect the function of the central nervous system.

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2
Q

T/F
There are many disorders of the central nervous system and most of them have a component that is mediated by a biochemical imbalance

A

True

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3
Q

How is drug imbalance treated in neuropharmacology?

- What is important to note about treatment?

A

Drugs

- Drugs treat symptoms not the cause*

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4
Q

What is the brain composed of?

- What do they do?

A

The brain is composed of literally millions of neurons.

  • Neurons are cells in the brain that act to process and transmit signals and information.
  • Neurons are excitable cells that transmit information by electrical and chemical signaling
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5
Q

How do neurons transit a signal in the brain? (3)

A

1) The start of information transfer begins at the dendrite, which receives a signal from another neuron.
2) This causes action potentials (electrical signaling) to propagate along the axon of the neuron.
3) When the action potential reaches the pre-synaptic nerve terminal, it causes release of neurotransmitters (chemical signaling) which pass the signal along to the next neuron.

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6
Q

What is the action potential?

- Describe the process (4):

A

Action potentials play a key role in cell-to-cell communication in neurons.

1) The resting membrane potential of cells is approximately -70 mV.
- This means that the inside of the cell is negative with respect to the outside.

2) During depolarization, positively charged Na+ ions enter the cell through voltage gated Na+ channels.
3) The Na+ channels then close and potassium channels open allowing potassium to leave the cell during repolarization.
4) The current overshoots resting membrane potential and then returns to baseline (-70 mV).

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7
Q

What occurs at the synapse (4)?

A

1) Once an action potential reaches the pre-synaptic nerve terminal, it causes influx of calcium.
2) Calcium influx causes vesicles containing neurotransmitters to fuse with the pre-synaptic membrane.
3) The vesicles release neurotransmitters into the synaptic cleft (the space between the neurons).
4) The neurotransmitters bind to receptors on the post-synaptic nerve membrane and the signal continues.

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8
Q

What are neurotransmitters?

A

Neurotransmitters are chemicals that transmit a signal across a synapse.

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9
Q

What are the (3) classes of neurotransmitters?

A

1) Monoamines
- Norepinephrine – Depression and Anxiety
- Epinephrine – Anxiety
- Dopamine – Parkinson’s and Schizophrenia
- Serotonin – Depression and Anxiety

2) Amino Acids
- Excitatory – glutamate (Alzheimer’s) and aspartate (Alzheimer’s).
- Inhibitory – GABA (Anxiety) and glycine (Anxiety).

3) Other
- Acetylcholine – Alzheimer’s and Parkinson’s.

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10
Q

What are the (5) basic mechanisms of drugs to treat CNS disorders?

A
  1. Replacement – the drug acts to replace neurotransmitters that are low in diseases.
  2. Agonists/Antagonist – A drug that directly binds to receptors on the post-synaptic membrane.
  3. Inhibiting neurotransmitter breakdown – Neurotransmitter metabolism is inhibited.
  4. Blocking Reuptake – Neurotransmitter reuptake into the pre-synaptic neuron is blocked.
  5. Nerve stimulation – The drug directly stimulates the nerve causing it to release more neurotransmitter.
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11
Q

Parkingson’s:

  • What is it?
  • Cause?
  • What neurons do they lose?
  • Without treatment?
A
  • PD is a chronic movement disorder
  • We now know that Parkinson’s disease is caused by a progressive loss of dopaminergic neurons in the substantia nigra of the brain.
  • Although progressive loss of dopaminergic neurons is a normal process of aging, patients with PD lose 70-80% of their dopaminergic neurons.
  • Without treatment, PD progresses in 5-10 years to a state where patients are unable to care for themselves.
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12
Q

Symptoms of Parkingson’s (6):

A
  1. Tremor – mostly in the extremities including hands, arms, legs, jaw and face.
  2. Rigidity – due to joint stiffness and increased muscle tone.
  3. Bradykinesia – slowness of movement, especially slow to initiate movements.
  4. Masklike face – patients can’t show facial expression and have difficulty blinking and swallowing.
  5. Postural Instability – balance is impaired, patients have difficulty balancing while walking.
  6. Dementia – Often develops later in disease.
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13
Q

Pathophysiology of Parkinson’s:

  • Caused by an imbalance between?
  • Unhealthy imbalance results in?
  • Symptoms arise because (3)?
A
  • PD is a chronic movement disorder that is caused by an imbalance between acetylcholine and dopamine in the brain.
  • Unhealthy imbalance of acetylcholine and dopamine, which results in abnormal GABA release

The symptoms of Parkinson’s arise because:

  1. Dopamine release is decreased, therefore there is not enough dopamine present to inhibit GABA release.
  2. There is a relative excess of acetylcholine compared to dopamine, which results in increased GABA release.
  3. Excess GABA release causes the movement disorders observed in PD.
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14
Q

Etiology of Parkingson’s:

  • What causes it?
  • Factors associated with development?
A

The etiology of PD is largely idiopathic (i.e. unknown)

There are some factors thought to be associated with development of the disorder:

  1. Drugs – A by-product of illicit street drug synthesis produces the compound MPTP. MPTP causes irreversible death of dopaminergic neurons.
  2. Genetics – Mutation in 4 genes (alpha synuclein, parkin, UCHL1, and DJ-1) is known to predispose patients to PD.
  3. Environmental Toxins – Certain pesticides have been associated with PD.
  4. Brain Trauma – Direct brain trauma from injury (i.e. boxing, accidents) is linked with increased risk for developing PD.
  5. Oxidative Stress – Reactive oxygen species are known to cause degeneration of dopaminergic neurons. There is a link between diabetes induced oxidative damage and PD.
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15
Q

Treatments for Parkingson’s:

Ideally?

Realistically?

  • What would we increase?
  • What would we decrease?
A

The ideal treatment for PD would be to reverse the degeneration of dopaminergic neurons
- Unfortunately, no such treatment exists.

Therefore we treat the symptoms of PD by trying to improve the balance between dopamine and acetylcholine

  • Drug treatment of PD improves the dopamine acetylcholine balance by either:
    1. Increasing dopamine
    2. Decreasing acetylcholine
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16
Q

PD:

What are drugs that increase dopamine neurotransmission?

A

There are 5 different major classes of drugs that act by increasing dopamine neurotransmission:

  1. Dopamine Replacement
  2. Dopamine Agonist
  3. Dopamine Releaser
  4. Catecholamine-O-Methyltransferase Inhibitor
  5. Monoamine oxidase-B (MAO-B) inhibitor
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17
Q

Why can’t we just give dopamine to increase levels in a patient with PD?

A
  • Does not cross blood barrier

- Short half-life in blood

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18
Q

PD:

What does increase acetylcholine do?

A
  • Diaphoresis
  • Salivation
  • Urinary incontinence
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19
Q

PD:

  • How do anticholinergic drugs work?
  • What can they increase the effectiveness of?
A

Anticholinergic drugs block the binding of acetylcholine to its receptor and are also called cholinergic antagonists.
- Anticholinergic drugs may increase the effectiveness of L-Dopa.

20
Q

PD:

  • Adverse effects of anticholinergic drugs?
  • Why are these drugs reserved for younger patients?
A

Typical anticholinergic side effects include:
- Dry mouth, blurred vision, urinary retention, constipation, tachycardia.

Elderly patients may experience severe CNS side effects such as:

  • Hallucination, confusion and delirium
  • So, anticholinergic drugs are usually reserved for younger patients only.
21
Q

What is Alzheimer’s disease?

A

Alzheimer’s disease is an irreversible form of progressive dementia and is the most common form of dementia

22
Q

Early symptoms of Alzheimer’s disease?

- What occurs as the disease progresses?

A

Early symptoms of disease include confusion, memory loss and problems conducting routine tasks
- As disease progresses, patients have difficulty performing daily living activities including eating, bathing, speaking and controlling bowel and bladder function

23
Q 
Alzheimer's disease, pathophysiology:
- Characterized by?
- Followed by degeneration of?
- Linked to a decreased function of?
-
A
  • The pathophysiology of Alzheimer’s is characterized by a degeneration of cholinergic neurons in the hippocampus early in disease
  • Followed by degeneration of neurons in the in the cerebral cortex.
  • Alzheimer’s is linked to decreased cholinergic nerve function
24
Q

How is Alzheimers diagnosed?

- What are the hallmarks of the disease (2)?

A

A definitive diagnosis of Alzheimer’s cannot be given until after death when a brain sample is analyzed
- The hallmarks of Alzheimer’s are neurofibrillary tangles and neuritic plaques.

25
Q

AD:

  • What are neurofibrillary tangles?
  • What does it cause?
  • What are they responsible for?
A
  • Form inside neurons when microtubule arrangement is disrupted
  • The cause is abnormal production of a protein called tau
  • Tau is responsible for forming cross-bridges between microtubules keeping their structure
26
Q

AD:

  • Where are neuritic plaques found?
  • What are they composed of?
  • What does this result in?
A
  • Found outside of neurons
  • Are composed of a core of a protein fragments called beta amyloid
  • Beta amyloid has been shown to kill hippocampal cells and causes Alzheimer’s like symptoms when injected into monkeys.
27
Q

AD:

Etiology

  • Cause
  • Genetics?
  • Mutations?
  • Increased incidence in patients with?
  • What type of injury is a risk factor?
A

Cause is usually unknown

20% of cases run in families

Mutations in DNA can be a caused

  • For example, patients with two copies of the apolipoprotein E4 (ApoE4) are at increased risk for developing Alzheimer’s; It appears that ApoE4 promotes formation of neuritic plaques by binding to beta amyloid, therefore promoting deposition.
  • There is also an increased incidence of Alzheimer’s disease in patients with mutations in the amyloid precursor protein gene; This gene is involved in the production of beta-amyloid, a component of neuritic plaques.

Head injury is a risk factor

28
Q

Does drug treatment work in AD?

A

Drug treatment of Alzheimer’s disease shows only minimal improvement in symptoms.

29
Q

What two classes are known to treat AD?

A

There are currently only two classes of drugs used to treat Alzheimer’s:

  1. Cholinesterase inhibitors – Inhibit the breakdown of acetylcholine.
  2. NMDA receptor antagonists – Block NMDA mediated increases in intracellular calcium.
30
Q

What is schizophrenia?

  • What type of disease?
  • When does it begin?
A

Schizophrenia makes it hard to tell the difference between real and unreal experiences, to think logically, to have normal emotional responses, and to behave normally in social situations.

  • Schizophrenia is a common mental disease
  • Schizophrenia usually begins in adolescence or early adulthood (16-30 years old)
31
Q

T/F

Patients with schizophrenia usually have multiple personalities and are usually not violent.

A

False
In contrast to popular belief and this picture, patients with schizophrenia usually DO NOT have multiple personalities and are usually not violent.

32
Q

What are positive symptoms of schizophrenia?

A

Positive: Exaggerate or distort normal neurological function

  • Delusions
  • Hallucinations
  • Agitation
  • Paranoia
  • Combativeness
  • Disorganized speech/thinking
33
Q

What are negative symptoms of schizophrenia?

A

Negative: A loss of normal neurological function

  • Social withdrawal
  • Poverty of speech
  • Poor self-care
  • Poor insight
  • Poor judgement
  • Emotional withdrawal
  • Blunted affect
  • Lack of motivation
34
Q

Etiology of Schizo:

  • Cause
  • Increased risks (4)
A

The cause of schizophrenia is largely unknown.

Here are a few factors known to increase the risk for developing schizophrenia:

  1. Family history: 10% of schizophrenics have a parent with the disease. If both parents have schizophrenia, there is a 25% chance their children will have it.
  2. Drug abuse: Methamphetamine (crystal meth), phencyclidine (PCP – angel dust) and lysergic acid diethylamide (LSD) use are all known to cause schizophrenia.
  3. Low birth weight: Babies born at less than 5.5 pounds have an increased risk of developing schizophrenia.
  4. Low IQ: The lower a person’s IQ, the greater the risk they have of developing schizophrenia.
35
Q

What regions of the brain are affected by schizo (6)?

A

1) Basal Ganglia
- Movement and emotions

2) Frontal Lobe
- Decision making and insight

3) Limbic System
- Emotions

4) Auditory System
- Hallucinations

5) Occipital lobe
- Visual info processing

6) Hippocampus
- Learning and memory

36
Q

Pathphysiology of Schizo:

  • What is increased?
  • What drug decreases positive symptoms?
  • What disease is thought of as opposite of Schizo?
  • What other drugs should be considered?
A

Usually schizophrenia is thought of as a disorder with increased dopaminergic nerve transmission.

Drugs that block dopaminergic nerve function decrease some of the positive symptoms of schizophrenia.

Schizophrenia and Parkinson’s are often thought of as on the opposite ends of the dopamine continuum because in schizophrenia there is excess dopamine and in Parkinson’s there is too little dopamine.
- Further, drugs used to treat Parkinson’s disease may cause schizophrenia like side effects.

Although the dopamine hypothesis is helpful, it is too simple: The neurotransmitters 5-HT (also called serotonin) and glutamate also play a role in schizophrenia

  • 5-HT (serotonin) – Patients with schizophrenia have a decreased number of 5-HT2A and an increased number of 5-HT1A receptors in the frontal cortex. These changes are thought to play a role in the symptoms patients with schizophrenia experience.
  • Glutamate – Glutamate binds to and activates the NMDA receptor. PCP (angel dust) is a strong antagonist of the NMDA receptor and causes many of the symptoms of schizophrenia. Patients with schizophrenia have a decreased number of NMDA receptors in some regions of their brain.
37
Q

T/F
In schizophrenia there is increased dopaminergic neurotransmission and therefore increased binding of dopamine to D2 receptors.

A

True

38
Q

How is schizo diagnosed?

- What is evaluated?

A

There is no definitive test for schizophrenia.
- Diagnosis is usually made by a psychiatrist after interviewing the patient and family.

The psychiatrist may evaluate several things before diagnosing schizophrenia:

  1. Changes in function from before illness.
  2. Developmental background.
  3. Family history.
  4. Response to medication.
  5. Brain scans – some changes are typical in schizophrenics.
    - In the top image the schizophrenic twin has enlarged ventricles.
    - In the bottom image the schizophrenic twin has decreased frontal lobe brain activity.
39
Q

What treatments are used for schizo?

  • How are they classified?
  • Conventional vs. atypical?
  • What is used today?
A

The basis for treating the symptoms of schizophrenia is blocking dopamine and/or serotonin neurotransmission in the brain.

  • Drugs used to treat schizophrenia can be classified as conventional antipsychotics or atypical antipsychotics.
  • Conventional and atypical antipsychotics differ in their mechanism of action and side effect profile.
  • Although it was once thought the atypical antipsychotics would take over the market, both conventional and atypical antipsychotics are in use today.
40
Q

Schizo:

How do conventional anti-psychotics work?

A
  • Conventional antipsychotics act primarily by blocking dopamine 2 (D2) receptors primarily in the mesolimbic area of the brain.
  • To a lesser degree, they also block receptors for acetylcholine, histamine, and norepinephrine.
  • The potency of conventional antipsychotics is directly proportional to their ability to inhibit D2 receptors.
  • These drugs are more effective at treating the positive symptoms of schizophrenia than the negative symptoms.
  • Initial effect of drugs may be seen in as few as 1 or 2 days but substantial improvement in symptoms usually takes between 2 and 4 weeks.
41
Q

Schizo:

  • How do conventional antipsychotics work?
  • What is the potency proportional to?
  • Do they treat positive, negative, or both symptoms?
  • Duration until effect?
A

Conventional antipsychotics act primarily by blocking dopamine 2 (D2) receptors primarily in the mesolimbic area of the brain.
- To a lesser degree, they also block receptors for acetylcholine, histamine, and norepinephrine.

The potency of conventional antipsychotics is directly proportional to their ability to inhibit D2 receptors.

These drugs are more effective at treating the positive symptoms of schizophrenia than the negative symptoms.

Initial effect of drugs may be seen in as few as 1 or 2 days but substantial improvement in symptoms usually takes between 2 and 4 weeks.

42
Q

Schizo:

- Adverse affects of conventional antipsychotics (6)

A

There are several adverse effects of conventional antipsychotics including:

  1. Extrapyramidal Symptoms
  2. Sudden high fever
  3. Anticholinergic effects
  4. Orthostatic Hypotension
  5. Sedation
  6. Skin reactions
43
Q

Schizo:

- What are extra-pyramidal symptoms? (4)

A 
Extrapyramidal symptoms (EPS) deserve special mention
- They are movement disorders that resemble the symptoms of Parkinson’s disease.

EPS are due to blockade of D2 receptors and four types of EPS occur:

  1. Acute dystonia – Involuntary spasm of the muscles in the face, tongue, neck or back. Typically occurs early in therapy.
  2. Parkinsonism – Bradykinesia, mask-like faces, rigidity, and stooped posture are common. May treat with an anticholinergic drug to help relieve these symptoms. L-Dopa must be avoided.
  3. Akathesia – Pacing, squirming, and a desire to continually be in motion. Typically occurs early in treatment.
  4. Tardive Dyskinesia – Occurs in about 20% of patients on long-term therapy. Is irreversible so early detection is essential. Symptoms include involuntary twisting and writhing of the face and tongue along with lip-smacking. Patients developing tardive dyskinesia should be switched to an atypical antipsychotic.
44
Q

Schizo:

  • How do atypical antipsychotics work?
  • Affinity?
  • Therapeutic action?
A

Atypical antipsychotics block both dopamine D2 receptors and 5-HT1A and 5-HT2A receptors.

  • Despite having some activity to block D2 receptors, the affinity is very low.
  • Therapeutic action is attributed to blockade of 5-HT receptors.
45
Q

Schizo:

Compared to conventional antipsychotics, atypical antipsychotics have (3):

A
  1. The same efficacy versus positive symptoms of schizophrenia,
  2. A much greater efficacy versus negative symptoms of schizophrenia.
  3. A much lower risk of developing extrapyramidal symptoms, especially tardive dyskinesia. This is attributable to decreased D2 receptor blocking activity.
46
Q

Schizo:

- Adverse affects of atypical anti-psychotics (5)?

A
  • Sedation
  • Orthostatic hypotension
  • Weight gain (sometimes severe)
  • Risk of developing type II diabetes
  • Anticholinergic effects

2060B: Pharmacology (18 decks)

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