Pain 😪 Flashcards
What is the process of neurotransmission in the Central Nervous System?
Using a provided diagram, describe the neurotransmission process in the Central Nervous System, focusing on the events at the synapse. Begin with the arrival of an action potential at the presynaptic neuron and trace the sequence of events that lead to the transmission of a neural message to the postsynaptic neuron. Highlight the critical molecular and cellular events involved in this process and discuss the role of neurotransmitters, receptors, and other relevant components. Support your explanation with a clear and labelled illustration of the synaptic transmission process.
1) Arrival of action potential: An action potential reaches the axon terminal of the presynaptic neuron. This depolarisation causes voltage-gated calcium (Ca**) channels in the membrane to open.
2) Calcium influx: Calcium ions (Ca?) enter the presynaptic terminal from the extracellular space due to the concentration gradient. The increased intracellular Ca” concentration acts as a signal to initiate the next steps.
3) Neurotransmitter release: The influx of Ca”* triggers synaptic vesicles containing neurotransmitters (e.g., glutamate, GABA dopamine) to move toward the presynaptic membrane. Vesicles fuse with the presynaptic membrane via a process called exocytosis, releasing neurotransmitters into the synaptic cleft.
The neurotransmitters diffuse across the synaptic cleft and bind to specific receptors on the postsynaptic membrane (e.g., ligand-gated ion channels or G-protein-coupled receptors).
4) Postsynaptic response and termination of signal:
Depending on the type of receptor and neurotransmitter: Excitatory neurotransmitters (e.g., glutamate) cause an influx of positive ions (e.g., Na), leading to depolarization and the generation of an excitatory postsynaptic potential (EPSP).
Inhibitory neurotransmitters (e.g., GABA) cause an influx of negative ions (e.g., CI) or efflux of K, leading to hyperpolarization and the generation of an inhibitory postsynaptic potential (IPSP). If the summation of EPSs reaches the threshold, an action potential is initiated in the postsynaptic neuron.
The signal is terminated by: Reuptake: Neurotransmitters are taken back into the presynaptic terminal via transporter proteins.
Enzymatic Degradation: Enzymes (e.g., acetylcholinesterase) break down neurotransmitters in the synaptic cleft.
Diffusion: Neurotransmitters diffuse away from the synaptic cleft.
What is the relationship between neurotransmission and pain pathways (ascending and descending pathways), including nociceptive and neuropathic pain, in the development and perpetuation of chronic pain?
What is the general structure of a neuron?
Dendrite: the input region, receives input from other neurons (excitatory - generate an electrical impulse - or inhibitory - keep the neuron from firing)
Cell body: nucleus, stores DNA abs rough ER, which builds protein abs mitochondria. It maintains the nerve cell and is involved in the growth and development of the nerve cell.
Axon: main conduction unit, carries info in the form of electrical signal known as the action potential. It transmits electrical signals to other neurons, muscles or glands.
Axon terminals: the output region, release of neurotransmitter.
What is the role of neurotransmission in the development and maintenance of chronic pain?
Provide a detailed overview of the pain pathways, including key neurotransmitters, receptors, and brain regions. Additionally, discuss how changes in neural plasticity may contribute to the transition from acute to chronic pain.
How do analgesics affect neurotransmission in the Central Nervous System?
Briefly describe how the drugs below affect neurotransmission in the CNS
Why is it recommended not to use an electric blanket or sit under direct sunshine when wearing these patches
Increased vasoldilation
The recommendation to avoid using an electric blanket or sitting in direct sunlight while wearing fentanyl patches is based on the risk of increased skin temperature, which can significantly impact the patch’s performance:
Accelerated Drug Release: Fentanyl patches are designed to release the drug at a controlled and constant rate over approximately 72 hours. Elevated skin temperature can enhance skin permeability, accelerating the release and absorption of fentanyl into the bloodstream, potentially leading to unintended overdose and dangerously high fentanyl concentrations.
Altered Pharmacokinetics: Localized heating of the skin can disrupt the drug’s pharmacokinetics, compromising both the safety and the effectiveness of the patch.
Skin Irritation and Adhesion Issues: Excessive heat can cause skin irritation and weaken the patch’s adhesion to the skin. This may result in uneven drug delivery and reduce the patch’s therapeutic effectiveness.
Explain how Fentanyl reaches systemic circulation once leaving the patch at a constant rate of delivery.
Fentanyl, when delivered via a transdermal patch, enters systemic circulation through transdermal absorption, providing a controlled and continuous release of the active pharmaceutical ingredient (API) into the bloodstream through the following steps:
Application: The patch should be applied to clean, dry, and hairless skin, such as the upper arm or chest. The adhesive layer ensures the patch remains securely attached to the skin.
Skin Penetration: Fentanyl, uniformly distributed within the adhesive layer, passes through the outermost skin layer (stratum corneum) into the underlying tissues via passive diffusion, driven by a concentration gradient. This process is facilitated by fentanyl’s lipophilic nature.
Systemic Absorption: After reaching the dermis, fentanyl diffuses through the capillary walls into the bloodstream, bypassing the intestinal and hepatic first-pass metabolism.
Distribution: Once in the bloodstream, fentanyl is distributed to tissues and organs, including the central nervous system, where it binds to mu-opioid receptors, producing potent analgesic effects for chronic pain management.
Controlled Release: The matrix design of the patch ensures a constant drug release rate over a typical duration of 72 hours. This steady release helps maintain consistent drug levels, providing sustained pain relief while minimizing fluctuations.
4 stages of nociception
Pregabalin effect on neurotransmission
Bind to presynaptic alpha2-delta subunits of voltage-gated calcium channels in the CNS.
This inhibits the influx of calcium ions and the release of excitatory neurotransmitters such as glutamate, substance P, and CGRP (Calcitonin Gene-Related Peptide) on the primary afferent neuron
This prevents the activation of the receptor on the secondary afferent neuron and the propagation of pain signals to the brain.
Among the designs presented above, which one was discontinued for the transdermal delivery of Fentanyl, and what were the two main reasons for its discontinuation?
The reservoir transdermal patch was recalled and subsequently removed from the market after extensive testing. It was replaced by the matrix-type fentanyl patch due to several health and safety concerns:
Dosing Errors: Reservoir patches were associated with a higher risk of dosing errors, leading to either overdose or subtherapeutic dosing. Both scenarios carry severe health consequences, including the potential for fatalities. Narrow therapeutic index. Dose doubling : Damaging the patch (e.g., cutting it) can lead to the rapid release of the entire drug reservoir, effectively “doubling” or significantly increasing the intended dose.
This risk was one of the reasons reservoir patches for Fentanyl were discontinued.
Variability in Drug Delivery: Minor changes in body temperature or skin conditions could significantly affect drug absorption from reservoir patches, resulting in unpredictable and potentially unsafe variations in drug delivery.
Risk of Misuse and Overdose: The design of reservoir patches allowed for tampering, as the fentanyl could be easily separated from the drug reservoir. This facilitated misuse, such as extracting and injecting or ingesting the concentrated fentanyl gel, leading to rapid and dangerous doses.
The matrix-type fentanyl patch addresses these issues by incorporating the drug directly into the adhesive layer, preventing unauthorized extraction and minimizing the risk of misuse. This design enhances patient safety and reduces the likelihood of adverse events.
Matrix drug delivery system patch: Why do you think this design is more suitable for delivering Fentanyl?
Consistent Drug Distribution: The adhesive matrix ensures fentanyl is evenly distributed across the patch, enabling uniform delivery of the drug to the skin throughout its surface.
Controlled and Sustained Release: This design allows for a steady release of fentanyl over a prolonged period, typically 72 hours, maintaining stable therapeutic drug levels in the bloodstream and reducing the risk of dose dumping, which can lead to safety concerns.
Drug Stability: The patch provides a stable environment for fentanyl, preventing degradation and ensuring reliable drug release.
Simplified Manufacturing: The matrix design requires fewer components compared to reservoir patches, making it easier to manufacture.
Patient Comfort and Safety: Its thin and flexible design ensures comfort and ease of use, with minimal risk of overdose or subtherapeutic dosing, both of which pose significant health risks, including fatalities.
Misuse Prevention: By integrating fentanyl within the adhesive layer, the design prevents unauthorized extraction or tampering, enhancing patient safety and reducing the likelihood of misuse or adverse events.
In the original study from which the pharmacokinetic and pharmacodynamic parameters were taken, it was noticed that there was a slight time delay between the maximum plasma concentration of the drug and the maximum reduction in pain score. What would explain such a time delay?
Time is required for: the drug to move from the bloodstream to target tissues / conversion into active metabolites / to bind to receptors
The therapeutic effect of a drug may not align with its peak plasma concentration due to factors like receptor interaction and downstream signaling delays.
Drug distribution to target receptors is influenced by tissue perfusion, lipophilicity, and active transport mechanisms, causing a time lag.
Receptor binding and signaling kinetics can delay the onset of the physiological response.
Indirect effects, such as modulation of secondary messengers or neurotransmitters, may introduce additional delays.
Adaptive body responses, including receptor desensitization, feedback mechanisms, and counter-regulatory effects, can affect the timing of drug action.
Individual differences in genetics, metabolism, and health contribute to variability in drug response timing.
Prodrugs require time for metabolic activation, leading to delays between plasma concentration peaks and therapeutic effects.
LG had a baseline pain score 9, measured using the Lickert Pain score. The relationship between pain score and concentration of a drug that she was taking was best described by the following model:
Where E is the measured pain score, E0 is the baseline pain score, C is drug concentration in µg/L, and Emax is the maximum reduction in pain score (from baseline), which was 8. The C50 was 0.1µg/L.
Using the information provided, determine the plasma concentration that would produce a 30% reduction in pain score from baseline for LG.
E = E0 - Emax x C/( C + C50)
0.3 x 9 = 2.7
9 - 2.7 = 6.3 (E)
6.3 = 9 - (8 x C / C + 0.1)
9 - 6.3 =( 8 x C )/ (C + 0.1)
2.7 = 8C /( C + 0.1)
2.7 x (C + 0.1) = 8C
2.7C + 0.27 = 8C
0.27 = 8C - 2.7C
0.27 = 5.3C
C = 0.27 / 5.3
= 0.051mcg/L
Type of headache: medication overuse
Headache type: giant cell (temporal) arteritis
