CAP 21 INTRODUCCION A LA FARMACOLOGÍA DE MEDICAMENTOS DEL SNC- KATZUNG-MEDICINA

Introduction to Pharmacology of Nervous System Drugs

Overview of CNS Drugs

• The discussion begins with the historical significance of drugs affecting the central nervous system (CNS), noting that they were among the first discovered by early humans.

• These drugs have been utilized for psychiatric conditions and analgesic purposes, highlighting their dual role in treatment.

Mechanisms of Action

• Advances in research allow for a deeper understanding of how these drugs interact at the neuronal level, particularly regarding neurotransmitter receptors.

• The impact of substances like alcohol and general anesthetics is noted, emphasizing their non-specific effects on neuronal communication.

Role in Disease Understanding

• Medications not only aid in treating diseases but also play a crucial role in diagnosing and understanding conditions such as schizophrenia through dopamine receptor interactions.

• Research on neurotransmitters like GABA has led to new insights into anxiety and epilepsy.

Structure and Function of the Central Nervous System

Components of CNS

• The CNS comprises the brain and spinal cord, which work together to process sensory information and generate responses necessary for interaction with the environment.

• The brain contains approximately 100 billion neurons organized into nuclei or structures like the cerebellum and hippocampus.

Neuronal Communication

• Neurons function similarly to factory workers, processing and transmitting information via electrochemical processes known as action potentials.

• Dendrites receive signals from other neurons while axons transmit signals; myelin sheaths enhance signal transmission speed.

Supporting Cells: Glial Cells

Functions of Glial Cells

• Glial cells act as supervisors within this complex system, maintaining an optimal environment for neuron function.

• Oligodendrocytes are responsible for forming myelin sheaths around axons, facilitating faster signal transmission.

Blood-Brain Barrier: Protection Mechanism

Importance of Blood-Brain Barrier

• The blood-brain barrier serves as a protective shield for the brain against circulating substances in the blood, including medications.

• Only specific hydrophobic substances or those utilizing particular transporters can cross this barrier; an example is L-DOPA used in Parkinson's treatment.

Neuronal Membrane Channels

Types of Ion Channels

• Neuronal membranes contain voltage-gated channels that respond to electrical changes and ligand-gated channels activated by neurotransmitter binding.

Neurotransmitter Receptors

• Neurotransmitters act as messengers binding to two types of receptors: ionotropic (fast response) and metabotropic (slower but prolonged effects).

Synaptic Transmission: Key Processes

Synapse Functionality

• Synapses are critical sites where neuronal communication occurs primarily through chemical synapses involving neurotransmitter release following action potential arrival at synaptic terminals.

Drug Interaction with Synaptic Transmission

Neurotransmitter Dynamics and Pharmacological Interactions

Neurotransmitter Synthesis and Storage

• Blocking neurotransmitter synthesis reduces their availability for release, impacting neural communication.

• Reserpine inhibits the storage of neurotransmitters in vesicles, leading to decreased release.

Metabolism and Release of Neurotransmitters

• Some drugs can prevent the breakdown of neurotransmitters, increasing their availability for release.

• Amphetamines promote catecholamine release, while tetanus toxin blocks neurotransmitter release.

Postsynaptic Actions and Receptor Interaction

• Opiates mimic enkephalins at receptors; strychnine acts as an antagonist by blocking glycine receptors, causing excitatory effects.

• Ketamine blocks NMDA receptor ion channels, affecting glutamate signaling.

Retrograde Signaling Mechanisms

• Retrograde signaling allows postsynaptic neurons to send signals back to presynaptic neurons to modulate neurotransmitter release.

• Endocannabinoids and nitric oxide serve as retrograde messengers in the central nervous system.

Pharmacological Selectivity in Neurotransmission

• The effectiveness of medications depends on specific neurotransmitters and receptors involved in various neuronal systems.

• Different types of receptors allow for targeted drug design that can treat specific conditions effectively.

Cellular Organization of the Brain

Hierarchical Neural Systems

• Hierarchical systems are crucial for sensory perception and motor control with clearly defined pathways formed by myelinated fibers.

• Information processing occurs sequentially through relay nuclei before reaching the cerebral cortex.

Neuron Types in Hierarchical Systems

• Projection neurons have large cell bodies and long axons that transmit signals over distances; they typically use glutamate as a transmitter.

• Local circuit neurons are smaller with limited axonal reach; they often inhibit activity using GABA or glycine.

Feedback Mechanisms in Neural Pathways

• Recurrent feedback pathways allow information to return to presynaptic neurons for activity adjustment; direct feedforward pathways convey information through networks efficiently.

Diffuse Neural Systems

Characteristics of Non-Specific Neural Systems

Neurotransmitters and Their Functions

Characteristics of Neurotransmitter Systems

• Neurotransmitters are produced by a limited number of neurons located in discrete nuclei, often within the brainstem. They exhibit diffuse projections throughout the brain and spinal cord.

• These neurons have extensive and divergent axonal branching, impacting multiple areas of the brain and spinal cord simultaneously.

• Key neurotransmitters include norepinephrine (produced in the locus coeruleus), serotonin (originating from raphe nuclei), and acetylcholine, all with widespread effects on various brain functions.

Mechanisms of Action

• Neurotransmitters typically act through metabotropic receptors, leading to long-lasting modulatory effects rather than localized actions. This results in their involvement in global functions such as sleep, wakefulness, appetite, and emotional states.

Major Neurotransmitters: Glutamate

• Glutamate serves as an excitatory neurotransmitter released into the synaptic cleft, acting on postsynaptic receptors.

• There are several types of ionotropic glutamate receptors: AMPA (permeable to sodium and potassium), Kainate (similar to AMPA but less uniformly distributed), and NMDA (highly permeable to sodium, potassium, and calcium; requires glutamate and glycine binding for activation).

• NMDA receptors play a crucial role in long-term potentiation associated with learning and memory.

Major Neurotransmitters: GABA

• GABA (gamma-Aminobutyric acid) is a primary inhibitory neurotransmitter in the central nervous system with two receptor types: GABA_A (ionotropic; allows chloride influx for rapid inhibition) and GABA_B (metabotropic; mediates slower inhibition affecting calcium and potassium channels).

Other Important Inhibitory Neurotransmitters

• Glycine acts as an inhibitory neurotransmitter primarily in the spinal cord and brainstem. Its receptors are pentameric chloride-permeable channels that can be blocked by strychnine.

Criteria for Identifying Neurotransmitters

• Three key criteria for identifying neurotransmitters include:

• Localization: Must be present at presynaptic terminals.

• Release: Should be released in response to neuronal activity dependent on calcium levels.

• Mimetism: Application should mimic natural neurotransmitter action; antagonists must inhibit this response.

Acetylcholine's Role

• Acetylcholine is recognized as the first identified neurotransmitter with significant roles in central synapses. It has nicotinic receptors (fast response; blocked by nicotinic antagonists) and muscarinic receptors (mediating slower responses).

Subtypes of Muscarinic Receptors

Neurotransmitters and Their Functions in the Brain

The Role of Neostriatum and Other Nuclei

• The neostriatum and other nuclei are linked to cognitive functions and memory; loss of these neurons is associated with Alzheimer's disease.

• Dopamine, a catecholamine, is involved in the reward system and movement regulation, while noradrenaline affects attention and arousal through its excitatory or inhibitory receptors.

Monoamines: Key Players in Brain Function

• Serotonin plays a crucial role in mood regulation, sleep control, and hemostasis; it acts via metabotropic receptors and ionotropic receptor 5-HT3.

• Histamine, primarily found in the tuberomammillary nucleus of the posterior hypothalamus, modulates arousal, tension, feeding behavior, and memory through various receptor types (H1-H4).

Neuropeptides: Modulators of Various Functions

• Neuropeptides act as neurotransmitters within the central nervous system; they are stored in large dense vesicles and can have local or long-distance effects.

• Examples include substance P (linked to nociception) found in unmyelinated sensory neurons and orexin (involved in wakefulness and energy homeostasis).

Endocannabinoids: Retrograde Signaling Molecules

• Endocannabinoids like anandamide function as retrograde synaptic messengers affecting neurotransmitter release; they influence memory, cognition, and pain perception.

Nitric Oxide & Purines: Emerging Signaling Molecules

• Nitric oxide may serve as a retrograde messenger implicated in synaptic plasticity; it responds to NMDA receptor activation.