9 - CNS Pharmacology 1 Flashcards
1
Q
What is Neuropharmacology?
A
Neuropharmacology: the study of how
drugs affect the function of the central
nervous system.
- disorders of the CNS have a
component that is mediated by a
biochemical imbalance. - this biochemical imbalance is treated with drugs.
→ drugs treat the symptoms of disease but not the cause
2
Q
What are Neurons and how do they Work?
A
- Neurons are cells in the brain that process and transmit signals and
information. - Neurons are excitable cells that transmit information by electrical and chemical
signaling.
Information Transfer
1) Begins at the dendrite, which receives a signal from another neuron.
2) 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, via a synapse
3
Q
Action Potentials
A
- Action potentials play a key role in
cell-to-cell communication in
neurons. - The resting membrane
potential of cells is approx -70mV
→ the inside of the cell is negative is more negative than the outside. - During depolarization, positively charged Na+ ions enter the cell through Na+ channels.
- The Na+ channels then close and potassium channels open allowing
potassium to leave the cell during repolarization. - The current overshoots resting membrane potential and then returns to baseline (-70 mV).
4
Q
Phases of an Action Potential
A
1) Resting
- few K channels are open
- K moves in/out of cells
→ for every K that moves in, 1 K moves out
- membrane potential does not change
2) Threshold
- if depolarizing stimulus is received, it opens few Na channels; allowing Na to enter cell
- Na is + charged so when more enters the cell, it depolarizes (membrane potential is closer to threshold
3) Rising
- if threshold is achieved, other Na channels open and Na rushes in
- membrane potential increases further
4) Falling
- Na channels close
- K channels open
- K rushes out of cell and membrane potential decreases
- as membrane potential approaches resting potential even more, K channels open
5) Recovery/Hyper-polarization
- membrane potential undershoots resting membrane potential due to excess K leaving the cell
5
Q
The Synapse
A
- Once an action potential reaches the presynaptic nerve terminal, it causes influx of calcium.
- Calcium influx causes vesicles containing neurotransmitters to fuse with the pre-synaptic membrane.
- The vesicles release neurotransmitters into the synaptic cleft (the space between the neurons).
- The neurotransmitters (after released) bind to receptors on the post-synaptic nerve membrane and the signal continues.
6
Q
Neurotransmission
A
1) AP propagates down the nerve
2) Causes Ca channel to open and ca rush into cell
3) Causes vesicle to fuse with pre-synaptic membrane
4) NT’s are released and bind to receptors on syntactic neuron
5) Once NT’s come off the receptors on synaptic neuron, they are taken back up into pre-synaptic nerve terminal and repackaged in to vesicles (so they can be used again)
7
Q
Neurotransmitters in the CNS
A
- Neurotransmitters are chemicals that transmit a signal across a synapse.
- Neurotransmitters can be broken down into classes as summarized below:
Monoamines
1. Norepinephrine – Depression and Anxiety
2. Epinephrine – Anxiety
3. Dopamine – Parkinson’s and Schizophrenia
4. Serotonin – Depression and Anxiety
Amino Acids
1. Excitatory – glutamate (Alzheimer’s) and aspartate (Alzheimer’s).
2. Inhibitory – GABA (Anxiety) and glycine (Anxiety).
Other
1. Acetylcholine – Alzheimer’s and Parkinson’s.
8
Q
Basic Mechanisms of CNS Drug Action
A
Drugs can act to treat CNS disorders in several ways.
These include:
1. Replacement – the drug acts to replace neurotransmitters that are
low in diseases (ie. parkinsons)
- Agonists/Antagonist – A drug that enters synaptic cleft and directly binds to receptors on the post-synaptic membrane.
- Inhibiting neurotransmitter breakdown – Neurotransmitter metabolism is inhibited.
- Blocking Reuptake – Neurotransmitter reuptake into the pre-synaptic neuron is blocked.
→ blocking allows the NT to stay in the synaptic cleft for longer (and mediate effect for longer) - Nerve stimulation – The drug directly stimulates the nerve causing it
to release more neurotransmitter.
9
Q
Parkinson’s Disease
A
- Parkinson’s disease (PD) was first
described in 1817 by James Parkinson. - 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.
10
Q
Symptoms of Parkinsons Disease
A
- PD is a chronic movement disorder.
- Symptoms include:
1. Tremor – mostly in the extremities including hands, arms, legs, jaw and
face.
- Rigidity – due to joint stiffness and increased muscle tone.
- Bradykinesia – slowness of movement, especially slow to initiate
movements. - Masklike face – patients can’t show facial expression and have difficulty
blinking and swallowing. - Postural Instability – balance is impaired, patients have difficulty balancing while walking.
- Dementia – Often develops later in disease.
11
Q
Pathophysiology of PD
A
- PD is a chronic movement disorder that is caused by an imbalance
between acetylcholine and dopamine in the brain. - In healthy patients there is a normal balance of acetylcholine and
dopamine, which results in normal GABA release. - The symptoms of Parkinson’s arise because:
1. Dopamine release is decreased (dopaminergic neurons are decreased), therefore there is not enough dopamine present to inhibit GABA release.
- There is a relative excess of acetylcholine compared to dopamine,
which results in increased GABA release.
→ GABA = inhibitory NT - Excess GABA release causes the movement disorders observed in
PD
- Dopaminergic neurons have inhibitory effect on GABA
- When dopamine neuron fires, causes decreased GABA release
- When cholinergic releases acetylcholine, it causes increased GABA release
- Normally, these are in balance
○ Equal balance of Acetylcholine and dopamine - In PD, dopamine neuron hardly fires and acetylcholine neuron takes over
○ Causes increased release of GABA and uncontrolled movement
12
Q
Etiology of PD
A
- The etiology of PD is idiopathic (i.e. unknown) but there are some
factors thought to be associated with development of the disorder:
- Drugs – A by-product of illicit street drug synthesis produces the
compound MPTP. MPTP causes irreversible death of dopaminergic
neurons. - Genetics – Mutation in 4 genes (alpha synuclein, parkin, UCHL1, and
DJ-1) is known to predispose patients to PD. - Environmental Toxins – Certain pesticides have been associated with
PD. - Brain Trauma – Direct brain trauma from injury (i.e. boxing, accidents)
is linked with increased risk for developing PD. - Oxidative Stress – Reactive oxygen species are known to cause
degeneration of dopaminergic neurons.
- There is a link between
diabetes (which produces ROS) induced oxidative damage and PD.
13
Q
Drug Treatment of Parkinson’s Disease
A
- Ideal treatment for PD would be to reverse the degeneration of
dopaminergic neurons. this does not exists. - symptoms to 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
14
Q
Agents that Increase Dopamine Neurotransmission
A
- There are 5 different major classes of drugs that act by increasing
dopamine neurotransmission:
- Dopamine Replacement
- Dopamine Agonist
- Dopamine Releaser
- Catecholamine-O-Methyltransferase Inhibitor
- Monoamine oxidase-B (MAO-B) inhibitor
15
Q
- Dopamine Replacement – Levodopa (L-Dopa)
A
- Levodopa is the most effective drug for treating PD.
-the beneficial effects of L-DOPA decrease over time as the
disease progresses.
- L-DOPA crosses the blood brain barrier by an active transport protein.
- L-DOPA is inactive on its own but is converted to dopamine in
dopaminergic nerve terminals. - Conversion of L-DOPA to dopamine is mediated by decarboxylase
enzymes in the brain. - The cofactor pyridoxine (vitamin B6) speeds up this reaction.
16
Q
L- Dopa: Mechanism of Action
A
- L-Dopa; black circles
- BB restricts entry
1) L-dopa gets transported into the brain
2) Decarboxylase enzymes convert it into dopamine which can be packed into vesicles
3) This increase the dopamine present in dopaminergic neurons
4) When an AP is fired by this neuron, more dopamine gets released
17
Q
Why not just give dopamine?
A
In contrast to L-DOPA, dopamine:
1. Does not cross the blood brain barrier.
2. Has a very short half-life in blood.
→ even if it crossed BBB, not enough will get to the neuron to be active bc of its shirt half-life
18
Q
L-Dopa – Adverse Effects
A
L-DOPA has several side effects including:
1) Nausea and vomiting
→ due to dopamine mediated activation of the chemoreceptor trigger zone in the medulla.
2) Dyskinesias
→ abnormal involuntary movements.
3) Cardiac dysrhythmias
→ conversion of L-DOPA to dopamine in the periphery can result in activation of cardiac beta 1 receptors on cardiac cells of heart
4) Orthostatic hypotension
→ rapid drop in blood pressure when a patient stands up.
5) Psychosis
→ 20% of patients will develop hallucinations, vivid dreams/nightmares and paranoid thoughts.
19
Q
L-Dopa – Peripheral Metabolism
A
- Only approximately 1 % of the total L-DOPA dose reaches the brain.
- The remaining L-DOPA is metabolized in the peripheral tissue (mostly in intestine) before reaching the brain.
For this reason, L-DOPA is almost always given with carbidopa - a
decarboxylase inhibitor that inhibits the peripheral metabolism of L-DOPA (allows more L-dopa to reach the site of action)
- When carbidopa is combined with L-DOPA, approximately 10% of LDOPA reaches the brain (in contrast to 1% of L-dopa is administered only)
- Carbidopa allows a lower dose of L-DOPA to be administered and
decreases the incidence of cardiac dysrhythmias and nausea and
vomiting.
20
Q
L-Dopa Alone Vs. L-Dopa with Carbidopa
A
L-Dopa Alone
- L-Dopa enters peripheral tissues, and decarboxyalse enzymes metabolize most of it to dopamine and only a little bit (1%) of L-dopa reached the target
L-Dopa + Carbidopa
- inhibit peripheral decarboxyalse enzymes to some degree
- when L-dopa enters, only some gets metabolized, and 10% will reach the brain
21
Q
L-Dopa - Loss of Effect
A
- Patients taking L-DOPA may experience two types of loss of effect:
1) Wearing Off – Gradual loss of effect
→ Usually occurs at the end of the dosing interval and indicates that drug
levels might be low.
→ Can be minimized by:
1. Shortening the dosing interval.
2. Give a drug that inhibits L-DOPA metabolism (i.e. a COMT
inhibitor).
3. Add a dopamine agonist to the therapy.
2) On-Off – Abrupt loss of effect
→ Can occur even when drug levels are high.
→ Can be minimized by:
1. Dividing the medication into 3-6 doses per day.
2. Using a controlled release formulation.
3. Moving protein-containing meals to the evening.
22
Q
- Dopamine Agonist (increase dopamine in the brain)
A
- Produce their effects by directly
activating dopamine receptors on the
post-synaptic cell membrane. - Not as effective as L-DOPA but
are often used as first line treatment
for patients with milder symptoms - in contrast to L-Dopa which enters the pre-synaptic nerve terminal, dopamine agonists cross the BBB and bind to dopamine receptors on post-synaptic membrane and mediate their effect
Adverse Effects
- Hallucinations
- Daytime drowsiness
- Orthostatic hypotension
23
Q
- Dopamine Release
A
- Acts to stimulate release of dopamine from dopaminergic neurons and also blocks dopamine reuptake into pre-synaptic nerve
terminals. It also blocks NMDA receptors. - Response develops rapidly, usually within 2-3 days.
- Not as effective as L-Dopa, so usually used in combination with L-Dopa or
alone only in mild PD. - Blockade of NMDA receptors is thought to decrease dyskinesia side effect of L-Dopa
→ dopamine releasers are given to ppl who have dyskinesia/movements SE with L-Dopa - Adverse effects include dizziness, nausea, vomiting, lethargy and
anticholinergic side effects.
2 MOA of Dopamine Releasers
- cross the BB and stimulate release of dopamine from pre-synaptic nerve terminal and block dopamine uptake transporter
- does not allow dopamine to get back into pre-synaptic neuron and allows it to stay in syanptic cleft and act for longer
24
Q
- Catecholamine-O-Methyltransferase Inhibitor (COMT)
A
- COMT is an enzyme that adds a methyl group to both dopamine and LDOPA to inactivate them
- Methylated dopamine and L-DOPA are inactive and do not activate
dopamine receptors. - Inhibiting COMT results in a greater fraction of L-DOPA available to
be converted into dopamine - COMT inhibitors are only moderately effective in treating symptoms of PD
and are often combined with L-Dopa. - Adverse effects are similar to those experienced with L-DOPA including
nausea, orthostatic hypotension, vivid dreams and hallucinations.
25
5. Monoamine oxidase-B (MAO-B) inhibitor
- MAO-B is an enzyme that metabolizes dopamine and L-DOPA through oxidation, therefore inactivating them
- MAO-B oxidatively metabolizes L-Dopa and dopamine to inactive form (unable to activate dopamine receptors)
- MAO-B is present in both the periphery and in the brain.
- Inhibiting oxidative metabolism of L-DOPA allows more conversion to
dopamine in the brain.
- Similarly, inhibition of dopamine metabolism allows more dopamine to
remain in nerve terminals and be released following an action potential.
- MAO-B inhibitors are only moderately effective in treating symptoms of PD and are often combined with L-Dopa.
- Adverse effects include insomnia, orthostatic hypotension and dizziness.
- At therapeutic doses, MAO-B inhibitors used to treat Parkinson’s do not inhibit MAO-A in the liver and therefore do not cause hypertensive crisis when patients eat tyramine-containing foods (huh???)
26
What about Acetylcholine?
- symptoms of PD are due to the relative imbalance of dopamine (to little) and acetylcholine (too much).
- The relative excess of acetylcholine in PD causes diaphoresis (excess
sweating), salivation and urinary incontinence.
27
Anticholinergic Drugs
- anticholinercis drugs helps treat the excess acetylcholine that occurs in PD
- 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
→ In doing so these drugs decrease the incidence of diaphoresis, salivation,
and incontinence.
1) anticholinergic binds to cholinergic receptors
2) any acetylcholine releases from vesicles are unable to bind and mediate effects
28
Adverse Effects - Anticholinergic Drugs
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
→ avoid anticholinergic drugs in elderly patients
29
Alzheimer’s Disease
- Alzheimer’s disease is an
irreversible form of progressive dementia and is the most common form of
dementia.
- predominantly affects
people over the age of 65
has Alzheimer’s disease.
- Women account for majority of all current cases of
Alzheimer’s.
Symptoms
→ memory loss
→ problems with language, judgment, behavior and intelligence.
Early symptoms of disease
→confusion
→memory loss
→problems conducting routine tasks
As disease progresses, patients have difficulty:
→performing daily living
activities including eating, bathing, speaking
→ controlling bowel and
bladder function
30
Alzheimer’s Pathophysiology
- 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 (decrease acetylcholine release)
- Patients with advanced
Alzheimer’s have only 10% of
the cholinergic function of
healthy subjects
31
Alzheimers Diagnosis
- 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
32
Neurofibrillary tangles VS Neuritic Plaques
Neurofibrillary tangles
- 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 (disrupted micrortubule arrangement)
Neuritic Plaques
- Found outside of neurons and 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.
33
Alzheimers Etiology
- The cause of Alzheimer’s disease is usually unknown.
- Suggestive familial linkage (~20% of cases are thought to run in families (i.e. genetically determined).
- There is some evidence that mutations in DNA can be a cause for
developing Alzheimer’s disease.
→ Ex. patients with two copies of the apolipoprotein E4 (ApoE4)
are at increased risk for developing Alzheimer’s
→ 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 also a risk factor for developing Alzheimer’s
34
Drug Treatment of Alzheimer’s Disease
- Drug treatment of Alzheimer’s disease shows only minimal improvement
in symptoms.
- There are currently only 2 classes of drugs used to treat Alzheimer’s:
1. Cholinesterase inhibitors – Inhibit the breakdown of acetylcholine (more acetyhcoline remains in neurons)
2. NMDA receptor antagonists – Block NMDA mediated increases in
intracellular calcium
35
1. Cholinesterase inhibitors
- These drugs inhibit the metabolism of acetylcholine by the enzyme
acetylcholinesterase.
- This allows more acetylcholine to remain in the synaptic cleft to exert its
actions.
- Cholinesterase inhibitors are only able to enhance cholinergic neurotransmission in the remaining healthy neurons.
- Cholinesterase inhibitors display minimal benefit on some measures of
memory.
- Cholinesterase inhibitors are only effective in ~ 25% of patients
36
Adverse Effects of Cholinesterase inhibitors
Common adverse effects of cholinesterase inhibitors include:
o Nausea and vomiting
o Diarrhea
o Insomnia
37
2. NMDA receptor antagonists
- The NMDA receptor is a calcium channel that is blocked by magnesium at rest.
- When glutamate (is released from pre synaptic nerves), it binds to the NMDA receptor, the magnesium dissociates
allowing calcium to enter the post-synaptic neuron.
- When the glutamate leaves the receptor, magnesium returns to block the entry of calcium.
- Normal calcium influx is thought to be important in the process of learning
and memory.
- In Alzheimer’s disease, there is excess glutamate release so the NMDA
receptor remains open allowing excess calcium to enter the cell.
38
Why is excess calcium detrimental?
1) It is actually detrimental to learning and memory (it overpowers the
normal calcium signal)
2. It causes degradation of neurons (too much calcium is toxic)
39
NMDA Receptor (Healthy)
- glutamate in pre-synaptic neuron
- glutamate gets released, magnesium dissociates, and Ca enters the cell
- when glutamate leaves receptor, magnesium comes back and fills the channel in, disabling excess Ca from entering the cell
40
NMDA Receptor (Alzheimers)
- excessive glutamate release from pre-synaptic neurons
- when excess glutamate enters synaptic cleft it stays bound, causes Mg to dissociate, and allows excessive Ca to enter cell
To treat excess release of glutamate
- NMDA receptor antagonist allows excess glutamate to release, and mg to dissociate; HOWEVER
- NMDA antagonist fills the pore before excess Ca enters the cell and prevents degradation of cholinergic neurons
41
Adverse Effects of NMDA
- NMDA antagonists are well tolerated.
- Side effects observed in clinical trials had the same incidence as patients
taking placebo.
42
Schizophrenia
- 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.
- patients with schizophrenia
usually do not have multiple personalities and are usually not violent.
- Schizophrenia is a common mental disease that affects approximately 1%
of the world’s population.
- Schizophrenia usually begins in adolescence or early adulthood (16-30
years old).
43
Schizophrenia Symptoms
Symptoms of schizophrenia can be divided into positive or negative
symptoms.
1) Positive symptoms: exaggerate or distort normal neurological
function
→ Delusions
→ Hallucinations
→ Agitation
→ Paranoia
→ Combativeness
→ Disorganized Speech
2) Negative symptoms: where there is a loss of normal neurological
function
→ Social Withdrawal
→ Poverty of Speech
→ Poor Self Care
→ Poor Insight
→Poor Judgement
→ Emotional Withdrawal
44
Schizophrenia Etiology
- The cause of schizophrenia is largely unknown
- 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.
45
Brain Regions Affected by Schizophrenia
1) Basal Ganglia
→ involved in movement and emotions
→ in Schizophrenia, abnormal activity causes paranoia and hallucinations
2) Frontal Lobe
→ problem solving and insight
→ involved in difficulty planning actions and organizing thoughts
3) Limbic System
→emotions
→ in schizophrenia, contributes to agitation
4) Auditory System
→ Overactivity contributes to hallucinations
5) Occipital Love
→ processes visual information
→ involved in interpreting images, reading emotion on others faces and recognizing motion
6) Hippocampus
→ mediates learning and memory which are decreased in schizophrenia
46
Schizophrenia Pathophysiology
- schizophrenia is 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 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.
- drugs used to treat Parkinson’s disease may cause schizophrenia
like side effects.
- 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 play a role in the symptoms patients with schizophrenia experience.
- 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.
47
Normal Dopamine Neurotransmission
- limited amount of dopamine is released from the nerve and binds to dopamine receptors on post-synaptic nerve terminal
48
Dopaminergic Transmission in Schizophrenia
- excess release of dopamine
- excess binding of dopamine to its receptors mediates the symptoms of schizophrenia
49
Schizophrenia Diagnosis
- 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.
**Brain scans do not provide a definitive diagnosis of schizophrenia
50
Drug Treatment of Schizophrenia
- The basis for treating the symptoms of schizophrenia is blocking dopamine and/or serotonin neurotransmission in the brain.
- Drugs used to treat schizophrenia are: conventional
antipsychotics or atypical antipsychotics.
- Conventional and atypical antipsychotics differ in their mechanism of action and side effect profile
51
Conventional Antipsychotics
- 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
- Conventional antipsychotics block the binding of dopamine to D2 receptors; disables dopamine from binding and disables dopaminergic nerve transmission
52
Adverse Effects of Conventional Antipsychotics
1. Extrapyramidal Symptoms
2. Sudden high fever
3. Anticholinergic effects
4. Orthostatic Hypotension
5. Sedation
6. Skin reactions
53
Extrapyramidal Symptoms of Conventional Antipsychotics
- Extrapyramidal symptoms (EPS) are
movement disorders that resemble the symptoms of Parkinson’s disease.
- EPS are due to blockade of D2 receptors
4 types of EPS occur:
1. Acute dystonia
→Involuntary spasm of the muscles in the face, tongue, neck or back.
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 (L-Dopa would promote schizophrenic like symptoms)
3. Akathesia
→ Pacing, squirming, and a desire to continually be in motion
4. Tardive Dyskinesia (more severe)
→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
→ occurs LATER in therapy
* cute dystonia, Parkinsonism, and Akathesia occur early in therapy*
54
Atypical Antipsychotics
- 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.
Compared to conventional antipsychotics, atypical antipsychotics have:
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
→due to low affinity they have for blocking D2 receptors/activity
55
Adverse Effects of Atypical Antipsychotics
1. Sedation
2. Orthostatic hypotension
3. Weight gain (sometimes severe)
4. Risk of developing type II diabetes
5. Anticholinergic effects.
