Module 14 - CNS Drugs Part 1 Flashcards
What is Neuropharmacology
Neuropharmacology is the study of how drugs affect the function of the central nervous system.
There are many disorders of the central nervous system and most of them have a component that is mediated by a biochemical imbalance.
In neuropharmacology we attempt to treat this biochemical imbalance with drugs.
Unfortunately the drugs treat the symptoms of disease but not the cause.
The Brain
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.
The start of information transfer begins at the dendrite, which receives a signal from another neuron.
This causes action potentials (electrical signaling) to propagate along the axon of the neuron.
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 (see below)
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.
The start of information transfer begins at the dendrite, which receives a signal from another neuron.
This causes action potentials (electrical signaling) to propagate along the axon of the neuron.
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 (see below)
Action Potentials
Action potentials = communication in neurons
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.
During depolarization, positively charged Na+ ions enter the cell through voltage gated 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).
Synapse
Once an action potential reaches the pre-synaptic 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 bind to receptors on the post-synaptic nerve membrane and the signal continues.
Neurotransmitters in the CNS
Neurotransmitters are chemicals that transmit a signal across a synapse
Classes of neurotransmitters =
- monoamines
- amino acids
- other
Monoamines
Norepinephrine – Depression and Anxiety
Epinephrine – Anxiety
Dopamine – Parkinson’s and Schizophrenia
Serotonin – Depression and Anxiety
Amino Acids
Excitatory – glutamate (Alzheimer’s) and aspartate (Alzheimer’s).
Inhibitory – GABA (Anxiety) and glycine (Anxiety).
Other Neurotransmitters
Acetylcholine – Alzheimer’s and Parkinson’s.
Basic Mechanisms of CNS Drug Action
- 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.
Parkinson’s Disease
Parkinson’s disease (PD) was first described in 1817 by James Parkinson.
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.
Symptoms of Parkinson’s Disease
- 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.
Pathophysiology of Parkinson’s
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. A relative excess of acetylcholine compared to dopamine results in increased GABA release.
3. Excess GABA release causes the movement disorders observed in PD.
Etiology of Parkinson’s
The etiology of PD is largely 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 induced oxidative damage and PD.
Drug Treatment of Parkinson’s Disease
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
Agents that Increase Dopamine Neurotransmission
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
Dopamine Replacement – Levodopa (L-Dopa)
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.
Why not just give dopamine?
In contrast to L-DOPA, dopamine:
- Does not cross the blood brain barrier.
- Has a very short half-life in blood.
L-Dopa – Adverse Effects
Nausea and vomiting – due to dopamine mediated activation of the chemoreceptor trigger zone in the medulla.
Dyskinesias – abnormal involuntary movements.
Cardiac dysrhythmias – conversion of L-DOPA to dopamine in the periphery can result in activation of cardiac beta 1 receptors. (review Module 8)
Orthostatic hypotension – rapid drop in blood pressure when a patient stands up.
Psychosis – 20% of patients will develop hallucinations, vivid dreams/nightmares and paranoid thoughts.
L-Dopa – Peripheral Metabolism
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.
For this reason, L-DOPA is almost always given with carbidopa, 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.
L-DOPA may experience two types of loss of effect
L-DOPA may experience two types of loss of effect:
1) Wearing Off – Gradual loss of effect.
2) On-Off – Abrupt loss of effect.
L-DOPA Wearing Off
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.
L-DOPA On-Off
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.
Dopamine Agonist
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