Module 14 Flashcards
What is neuropharmacology?
Neuropharmacology is the study of how drugs affect the function of the central nervous system.
In most disorders affecting the CNS, there is a component that is mediated by what?
a biochemical imbalance
In neuropharmacology we attempt to treat this biochemical imbalance with what?
Drugs
Unfortunately, the drugs treat the symptoms of disease but not the cause.
What is a neuron?
Neurons are cells in the brain that act to process and transmit signals and information.
In a neuron, where does the start of information transfer happen?
the dendrite, which receives a signal from another neuron (this causes action potentials to propagate along the axon of the neuron)
Define neurotransmitter
Neurotransmitters are chemicals that transmit a signal across a synapse.
What is the resting membrane potential of cells?
approximately -70 mV
List the classes of neurotransmitters
- Monoamines (norepinephrine, epinephrine, dopamine, serotonin)
- Amino acids (excitatory - glutamate and aspartate; inhibitory - GABA and glycine)
- Other (Acetylcholine - Alzheimer’s and Parkinson’s)
(there are 100s of neurotransmitters but we’re just going to focus on a few in this class)
What are the five basic mechanisms, in which CNS drugs can mediate their actions?
- Replacement – the drug acts to replace neurotransmitters that are low in diseases.
- Agonists/Antagonist – A drug that 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.
- Nerve stimulation – The drug directly stimulates the nerve causing it to release more neurotransmitter.
What is Parkinson’s disease?
A chronic movement disorder.
Parkinson’s disease is a brain disorder that causes unintended or uncontrollable movements, such as shaking, stiffness, and difficulty with balance and coordination.
Parkinson’s disease (PD) is caused by what?
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.
What are the characteristic symptoms of PD?
- 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.
Describe the pathophysiology of PD
- 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, 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.
The etiology of PD is largely what?
idiopathic (unknown)
However, there are some factors thought to be associated with the development of PD.
What are some factors thought be be associated with the development of PD?
- 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 induced oxidative damage and PD.
What would be the ideal treatment for PD?
- 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 what?
- Increasing dopamine
- Decreasing acetylcholine
What are the 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
What are the 1 major class of drugs that act by decreasing acetylcholine neurotransmission?
- Cholinergic antagonists or anticholinergic drugs
What is the most effective drug for treating PD?
Levodopa (L-Dopa)
L-Dopa is a dopamine replacement.
Unfortunately, the beneficial effects of L-DOPA decrease over time as the disease progresses.
How does L-Dopa cross the blood brain barrier?
By an active transport protein
L-Dopa is inactive on its own but is converted to dopamine where?
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.
Why can’t we just give a patient dopamine as treatment?
In contrast to L-DOPA, dopamine:
- Does not cross the blood brain barrier.
- Has a very short half-life in blood.
List the adverse/side effects of L-Dopa
o Nausea and vomiting – due to dopamine mediated activation of the chemoreceptor trigger zone in the medulla.
o Dyskinesias – abnormal involuntary movements.
o Cardiac dysrhythmias – conversion of L-DOPA to dopamine in the periphery can result in activation of cardiac beta 1 receptors. (review Module 8)
o Orthostatic hypotension – rapid drop in blood pressure when a patient stands up.
o Psychosis – 20% of patients will develop hallucinations, vivid dreams/nightmares and paranoid thoughts.
How much L-Dopa reaches the brain?
- Only approximately 1% of the total L-DOPA dose reaches the brain.
- The remaining L-DOPA is metabolized in the peripheral tissue (mostly in the intestine) before reaching the brain.
Because L-DOPA is metabolized largely in peripheral tissue, what is L-DOPA almost always given with?
Carbidopa
Carbidopa is a decarboxylase inhibitor that inhibits the peripheral metabolism of L-DOPA. When Carbidopa is combined with L-DOPA, approximately 10% of L-DOPA reaches the brain. Carbidopa allows a lower dose of L-DOPA to be administered and decreases the incidence of cardiac dysrhythmias and nausea and vomiting.
Patients taking L-DOPA may experience which two types of loss of effect?
1) Wearing Off – Gradual loss of effect.
2) On-Off – Abrupt loss of effect.
Describe the “wearing-off” effect experienced by patients taking L-DOPA
- 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.
Describe the “on-off” effect experienced by patients taking L-DOPA
- 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.
Describe dopamine agonist drugs (used to treat PD)
- 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.
What are the adverse (side) effects of dopamine antagonist drugs?
- Hallucinations
- Daytime drowsiness
- Orthostatic hypotension
Describe dopamine releaser drugs (used to treat PD)
- Act to stimulate release of dopamine from dopaminergic neurons and in addition, it also blocks dopamine re-uptake 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.
What are the adverse (side) effects of dopamine releaser drugs?
Adverse effects include dizziness, nausea, vomiting, lethargy and anticholinergic side effects.
What is another name (short form) for Catecholamine-O-Methyltransferase Inhibitor?
COMT inhibitor
Describe COMT Inhibitors
- COMT is an enzyme that adds a methyl group to both dopamine and L-DOPA.
- Methylated dopamine and L-DOPA are inactive and do not activate dopamine receptors.
- Inhibiting COMT results in a greater fraction of L-DOPA that is available to be converted into dopamine.
COMT inhibitors are only moderately effective in treating symptoms of PD so they are often combined with what?
L-DOPA
What are the adverse (side) effects of COMT inhibitors?
Adverse effects are similar to those experienced with L-DOPA including nausea, orthostatic hypotension, vivid dreams, and hallucinations.
What is MAO-B?
- MAO-B is an enzyme that metabolizes dopamine and L-DOPA through oxidation, therefore inactivating them.
- MAO-B is present in both the periphery and in the brain.
What is another (short form) name for Monoamine oxidase-B inhibitor?
MAO-B inhibitor
MAO-B inhibitors are only moderately effecting in treating symptoms of PD, so they are often combined with what?
L-DOPA
What are the adverse (side) effects of MAO-B inhibitors?
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 (review Module 11).
Describe MAO-B inhibitors
MAO-B inhibitors are a class of drugs that inhibit the activity of MAO-B. 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.
The relative excess of acetylcholine in PD causes what?
diaphoresis, salvation, and urinary incontinence
Describe anticholinergic drugs
- 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.
- In the figure you can see anticholinergic drugs (orange dots) are blocking the binding of acetylcholine (yellow dots) to the receptor.
What are the adverse (side) effects of 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 so anticholinergic drugs are usually reserved for younger patients only.
What is Alzheimer’s disease?
Alzheimer’s disease is an irreversible form of progressive dementia and is the most common form of dementia.
- Over 500,000 Canadians have Alzheimer’s disease.
- Approximately 1 in 11 people over the age of 65 has Alzheimer’s disease.
- Women account for almost 75% of all current cases of Alzheimer’s.
- Alzheimer’s costs Canadian’s over $15 billion dollars per year.
What are the symptoms of Alzheimer’s disease?
- Symptoms of Alzheimer’s disease include memory loss, problems with language, judgment, behaviour, and intelligence.
- 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.
Describe the pathophysiology of Alzheimer’s disease
- 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.
- Patients with advanced Alzheimer’s have only 10% of the cholinergic function of healthy subjects.
What are the hallmarks of Alzheimer’s disease?
Neurofibrillary tangles and Neuritic plaques
Can a definitive diagnosis of Alzheimer’s be made?
Yes, but not until after patient death when a brain sample can be analyzed.
Describe 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.
Describe 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.
What is the cause (etiology) of Alzheimer’s disease?
The cause is usually unknown; however:
- Approximately 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.
- 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 also a risk factor for developing Alzheimer’s.
True or False: Drug treatment of Alzheimer’s disease shows only minimal improvement in symptoms.
True
What are the two classes of drugs currently used to treat Alzheimer’s?
- Cholinesterase inhibitors - Inhibit the breakdown of acetylcholine.
- NMDA receptor antagonists – Block NMDA mediated increases in intracellular calcium.
Describe cholinesterase inhibitors and how they work on patients with Alzheimer’s disease
- 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 approximately 25% of patients.
What are the adverse (side) effects of cholinesterase inhibitors?
o Nausea and vomiting
o Diarrhea
o Insomnia
Describe NMDA receptor antagonists and how they work on patients with Alzheimer’s disease
- The NMDA receptor is a calcium channel that is blocked by magnesium at rest.
- When glutamate 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.
- At rest a magnesium molecule blocks the NMDA receptor not allowing calcium to enter the post-synaptic neuron.
- Binding of glutamate causes dissociation of magnesium allowing calcium to enter the post-synaptic neuron.
- In Alzheimer’s disease, excess glutamate is released from neurons. This causes prolonged opening of the NMDA receptor and excess calcium influx into the post-synaptic neuron. NMDA receptor antagonists block calcium influx into the post-synaptic neuron.
Excess calcium is detrimental in which two ways?
- It is actually detrimental to learning and memory (it overpowers the normal calcium signal).
- It causes degradation of neurons (too much calcium is toxic)
Schitzophrenia
