Chapter 14: Basic Principles of Neuropharmacology

Definition of Neuropharmacology: Neuropharmacology is the study of drugs that alter processes controlled by the nervous system.
Clinical Significance: Neuropharmacologic agents have widespread clinical applications due to the broad spectrum of physiological processes controlled by the nervous system and the substantial clinical benefits obtained by manipulating those processes. More than $25\%$ of fundamental pharmacological study is dedicated to these agents.
Divisions of the Nervous System and Neuropharmacologic Drugs:
- The nervous system is divided into two main components: the Central Nervous System (CNS) and the Peripheral Nervous System (PNS).
- Neuropharmacologic agents are similarly categorized into two broad classes: peripheral nervous system drugs and central nervous system drugs.
Physiological Scope of Regulation: Because the nervous system participates in regulating practically all bodily processes, virtually all physiological functions can be influenced by drugs that alter neuronal regulation. By mimicking or blocking neuronal regulation, neuropharmacologic drugs can modify diverse processes including:
- Skeletal muscle contraction
- Cardiac output
- Vascular tone
- Respiration
- Gastrointestinal (GI) function
- Uterine motility
- Glandular secretion
- Functions unique to the CNS: ideation, mood, and perception of pain.

Basic Cellular Communication: Neurons elicit responses from target cells via intercellular communication. A target postsynaptic cell can be:
- Another neuron
- A muscle cell
- A cell within a secretory gland
Two Basic Steps of Neuronal Function:
1. Axonal Conduction: The process of propagating an electrical impulse along the axon of a neuron.
2. Synaptic Transmission: The process by which information is carried across the synaptic gap separating the neuron from the postsynaptic cell.

Drugs Altering Axonal Conduction:
- The process of conducting an impulse along an axon is fundamentally identical in all neurons.
- A drug that alters axonal conduction affects conduction indiscriminately in all nerves to which it has access.
- Consequently, drugs acting on axonal conduction cannot produce selective effects.
- Example: Local anesthetics work by producing nonselective inhibition of axonal conduction, thereby suppressing signal transmission in any nerve they reach.
- Very few pharmacologic agents act by altering axonal conduction.
Drugs Altering Synaptic Transmission:
- The vast majority of neuropharmacologic agents operate by altering synaptic transmission.
- Unlike axonal conduction, synaptic transmission allows drugs to produce effects that are highly selective.
- High selectivity is possible because individual synapses differ structurally and functionally from one another:
- Synapses at different anatomical locations employ different neurotransmitters.
- The body utilizes more than one receptor type for most neurotransmitters.
- Utilizing a drug that selectively influences a specific neurotransmitter or receptor type permits the targeted modification of one neurally regulated process while leaving most other physiological processes unaffected.

Sequence of Synaptic Transmission:
- Requires the release of neurotransmitter molecules from the presynaptic axon terminal.
- Neurotransmitter molecules diffuse across the synaptic gap and bind to specific receptors on the postsynaptic target cell.
- Transmitter-receptor binding initiates a cascade of intracellular events, leading to a change in the behavior of the postsynaptic cell.
Postsynaptic Behavioral Alterations:
- Neuron Target: Increases or decreases its firing rate.
- Muscle Target: Contracts or relaxes.
- Glandular Target: Increases or decreases secretion.
Receptor Activation Principles:
- A neuron's ability to influence target cell behavior depends strictly on altering receptor activity on that target cell.
- If a target cell lacks receptors for a released neurotransmitter, the neuron cannot affect that cell.
- Central Concept: Regardless of its precise mechanism of action, any neuropharmacologic drug ultimately works by influencing receptor activity on target cells.

Five Basic Steps of Synaptic Transmission:
1. Transmitter Synthesis: Synthesis of neurotransmitter molecules within the neuron.
2. Transmitter Storage: Storage of neurotransmitter molecules within presynaptic vesicles.
3. Transmitter Release: Release of neurotransmitters into the synaptic gap upon presynaptic activation.
4. Receptor Binding: Binding of neurotransmitter molecules to receptors on the postsynaptic target cell.
5. Termination of Transmitter Action: Dissociation of the neurotransmitter from its receptor, followed by termination via transmitter reuptake or enzymatic degradation.
Drug Effects on Receptor Function:
- Drugs alter receptor function via two primary mechanisms:
- Increasing receptor activation.
- Decreasing receptor activation.
- Example: Drugs that increase neurotransmitter synthesis cause an increase in transmitter availability, leading directly to increased receptor activation.
Selectivity in Neuropharmacology:
- Selectivity is one of the most desirable properties of a drug, enabling it to alter a specific disease process while leaving other physiological processes largely unaffected.
- High drug selectivity is achievable because the nervous system employs multiple distinct receptor types to regulate its functions.

Three Essential Information Requirements: To predict the major physiological effects of any PNS drug, three key pieces of information must be identified:
1. The type or types of receptors through which the drug acts.
2. The normal physiological response to activation of those specific receptors.
3. The exact effect of the drug on receptor function (whether it increases or decreases activation).

All neuropharmacologic drugs act by altering synaptic transmission EXCEPT local anesthetics
Impact of a drug on a neuronally regulated process depends on drug’s ability to directly or indirectly alter receptor activity on target cells
- Drugs acting on receptor function: increase or decrease activation
- Drugs that increase transmitter synthesis increase receptor activation
- Drugs that decrease transmitter synthesis decrease receptor activation
- Drugs that promote synthesis of “super” transmitters increase receptor activation
- Drugs that impede transmitter storage decrease receptor activation
- Drugs that promote transmitter release increase receptor activation
- Drugs that suppress transmitter release decrease receptor activation
- Agonists increase receptor activation
- Antagonists decrease receptor activation
- Drugs that bind receptors and enhance actions of the natural transmitter at the receptor increase receptor activation
- Drugs that block transmitter reuptake increase receptor activation
Presence of multiple receptor types increases our ability to produce selective drug effects
For PNS drugs, learn:
- Identity of the receptor
- Normal response to activation of the receptor
- Whether the drug increases or decreases receptor activation