Autonomic Pharmacology

Overview of Autonomic Pharmacology

Objectives

1. Describe the origin of the sympathetic and parasympathetic systems from the central nervous system (CNS):

   • Cranio-sacral: The parasympathetic nervous system originates from cranial nerves III (oculomotor), VII (facial), IX (glossopharyngeal), and X (vagus) as well as sacral spinal nerves S2-S4. This system primarily focuses on restorative processes, promoting a state of calmness and energy conservation.

   • Thoraco-lumbar: The sympathetic nervous system arises from the thoracic and lumbar regions of the spinal cord (T1-L2). This division is responsible for initiating the ‘fight or flight’ response, preparing the body for stressful situations by mobilizing energy and enhancing alertness.

2. List synapses for acetylcholine (ACh) and norepinephrine (NE) release:

   • Acetylcholine (ACh): Released from preganglionic neurons in both the SNS and PSNS to bind to nicotinic receptors on postganglionic neurons. In the PSNS, ACh is further released at the target organ, binding to muscarinic receptors.

   • Norepinephrine (NE): Released from postganglionic sympathetic neurons to activate adrenergic receptors (α and β receptors) on target tissues, influencing various physiological responses including increased heart rate and mobilization of energy stores.

3. Identify neurotransmitters from the adrenal medulla:

   • The adrenal medulla, acting as an endocrine organ, releases epinephrine (80%) and norepinephrine (20%). These catecholamines circulate in the bloodstream, enhancing the sympathetic response by increasing heart rate, blood pressure, and blood glucose levels, effectively preparing the body for immediate action.

4. List precursors for ACh, NE, and epinephrine synthesis:

   • ACh: Synthesized from Acetyl CoA (derived from glucose metabolism) and Choline (obtained through diet and synthesized in the body). Initial synthesis occurs in the cytoplasm of nerve terminals where ACh is packaged into vesicles for release.

   • Norepinephrine/Epinephrine: Both are catecholamines synthesized from the amino acid Tyrosine, which undergoes hydroxylation to form Dopa, then decarboxylation to produce Dopamine. Subsequently, dopamine is converted to norepinephrine in the sympathetic nerve terminals. The adrenal medulla converts norepinephrine into epinephrine through the enzyme phenylethanolamine N-methyltransferase (PNMT).

5. Identify main autonomic nervous system (ANS) receptor subtypes in target organs:

   • Cholinergic Receptors (PSNS):

     • Muscarinic receptors (M1-M5): Affect various physiological processes, such as smooth muscle contraction (M3 in bronchial tissues) and glandular secretion (M1 in salivary glands), highlighting PSNS's role in digestion and sexual function.

   • Adrenergic Receptors (SNS):

     • Alpha (α) Receptors:

       • α1: Mediates vasoconstriction in blood vessels, leading to increased blood pressure.

       • α2: Functions in feedback inhibition of NE release; decreasing sympathetic outflow to manage stress responses.

     • Beta (β) Receptors:

       • β1: Primarily affects cardiac tissue, increasing heart rate and contractility leading to enhanced cardiac output.

       • β2: Found in bronchial tissue causing bronchodilation, promoting airflow - essential during stress or exercise.

6. Explain physiological and clinical responses of target organs to activation of the ANS divisions (SNS and PSNS):

   • Understanding how these divisions interact is critical in clinical settings to address conditions such as hypertension (excess sympathetic activity) or heart failure (reduced sympathetic support). For instance, activation of PSNS lowers heart rate and facilitates digestion through enhanced gastrointestinal motility; conversely, SNS activation can lead to increased heart rate, reduced GI motility, and dilation of airways to support heightened activity, such as during a stress response.

7. Understand the concept of dominant tone in the ANS:

   • Dominant tone refers to the prevailing control exerted by either the PSNS or SNS under resting conditions on organ function. In the heart, for example, the PSNS typically predominates, resulting in lower heart rates and promoting recovery and digestion. Disruptions to this balance can have clinical implications, such as in panic attacks where SNS dominance escalates heart rate, breathing, and stress hormones, impacting overall health.

8. Describe actions, side effects, and clinical uses of drugs affecting autonomic neurotransmitters:

   • Pharmacological agents can act as agonists or antagonists for the receptors in the ANS, facilitating treatments for various conditions:

     • Agonists: Mimic neurotransmitter activity, enhancing functions (e.g., β-agonists to alleviate asthma via bronchodilation).

     • Antagonists: Block neurotransmitter action, reducing effects (e.g., β-blockers to manage hypertension and reduce heart load). Potential side effects must be carefully considered to avoid complications like bradycardia, hypotension, or gastrointestinal disturbance.

Agenda

1. Introduction to Autonomic Nervous System

2. Parasympathetic Nervous System (PSNS)

3. Sympathetic Nervous System (SNS)

4. Neuromuscular Junction

5. Summary/Cases

Overview of Nervous System Divisions:

• Central Nervous System (CNS): Comprising the brain and spinal cord, the CNS processes sensory information and coordinates responses, integrating input from various body systems.

• Peripheral Nervous System (PNS):

  • Efferent Division:

    • Somatic: Controls voluntary movements through direct innervation of skeletal muscles, allowing conscious control over actions.

    • Autonomic: Regulates involuntary processes (heart rate, digestion) and is further divided into the SNS and PSNS.

Functions of the Autonomic Nervous System (ANS)

The ANS governs functions that are not under conscious control, including:

• Heart Rate: Modulates based on physiological and emotional stimuli to maintain homeostasis.

• Respiration: Increases or decreases in rate and depth according to metabolic demands, heavily influenced by CO2 levels in blood.

• Digestion: Coordinates digestive processes such as gastric motility and enzyme secretion through its influences on various organ systems.

Two Subdivisions:

• Sympathetic Nervous System (SNS):

  • Prepares the body for high-energy demands, enhancing blood flow to muscles and oxygen delivery. Major effects include:

    • Increases heart rate: achieved via β1-receptor activation.

    • Bronchodilation to enhance airflow: allows greater oxygen uptake during exertion.

    • Inhibition of gastrointestinal motility: diverts resources away from digestion to immediate physical demands.

• Parasympathetic Nervous System (PSNS):

  • Focuses on maintaining energy, regulating non-emergency bodily functions:

    • Decreases heart rate: Achieved through ACh binding to muscarinic receptors.

    • Bronchoconstriction to reduce airflow: Helps in maintaining normal resting respiratory function.

    • Promotes gastrointestinal motility and digestive processes: Facilitated through increased enzyme secretion and muscle contractions, promoting a balanced state.

Both systems influence most organs, typically demonstrating an antagonistic relationship, with one division often dominating, termed dominant tone.

Receptor Nomenclature

• PSNS:

  • Cholinergic:

    • Primarily utilizing ACh with major receptor types:

      • Muscarinic receptors (M1-M5): Influence various physiological responses including smooth muscle contraction, endothelial function, and glandular secretion which are crucial for digestive processes and fluid balance.

• SNS:

  • Adrenergic:

    • Response mediated through epinephrine and norepinephrine, divided into:

      • Alpha (α) Receptors:

        • α1: Involved in vascular smooth muscle contraction, increasing peripheral resistance and blood pressure.

        • α2: Functions primarily in central nervous system feedback, inhibiting NE release and managing stress levels.

      • Beta (β) Receptors:

        • β1: Target cardiac tissues; increasing the force and frequency of contractions.

        • β2: Present in smooth muscles of the airways and blood vessels; causing relaxation and vasodilation.

Effects of ANS Pharmacology on the Eye

• Sympathetic Effects: Activation of α1 receptors in the iris dilator muscle leads to pupil dilation (mydriasis), enhancing vision under low-light conditions.

• Parasympathetic Effects: M3 receptor activation in the sphincter muscle of the iris leads to pupil constriction (miosis) for improved focus on near objects.

• Glaucoma Management:

  • Increased intraocular pressure is a leading cause of blindness; treatment strategies include:

    • Increasing drainage of aqueous humor via prostaglandin analogs, promoting outflow through the trabecular meshwork or uveoscleral pathway.

    • Decreasing production of aqueous humor via beta-blockers, reducing fluid secretion at the ciliary body.

Neuromuscular Junction (NMJ) Overview

The NMJ is the connection between motor neurons and skeletal muscle tissue, integral for voluntary muscle movement. Key events include:

• ACh Binding: ACh released at the NMJ binds to nicotinic receptors on the muscle cell membrane, initiating depolarization.

• Sodium Influx: Leads to muscle membrane depolarization and muscle contraction through a series of action potentials along the muscle fibers.

Types of Neuromuscular Blockers:

• Non-depolarizing blockers: (e.g., Rocuronium) function by competitively inhibiting ACh from binding with nicotinic receptors, resulting in muscle paralysis.

• Depolarizing blockers: (e.g., Succinylcholine) initially cause muscle contractions (fasciculations) but lead to prolonged paralysis due to receptor desensitization.

Indirect-acting Cholinergic Drugs

• Mechanisms: These drugs enhance available ACh levels by inhibiting cholinesterase, which breaks down ACh, thereby prolonging its action at the synapse.

• Types of Reactions:

  • Acetylation: Rapid recovery of cholinergic function, commonly observed with reversible inhibitors.

  • Carbamylation: Slower recovery; often seen with carbamate inhibitors that have a longer half-life.

  • Phosphorylation: Leads to irreversible binding to cholinesterase, as seen with organophosphates, resulting in toxic accumulation of ACh.

Summary of Cases Related to ANS Effects

• Understanding drug effects on key systems such as heart, gastrointestinal (GI), and respiratory systems is crucial for effective clinical practice. Case discussions involve analyzing ECG changes post-sympathetic activation, understanding the treatment of anticholinergic poisoning, and recognizing the effects of autonomic imbalance in conditions such as diabetic autonomic neuropathy.

Concluding Remarks

• A comprehensive, in-depth understanding of pharmacology related to the autonomic nervous system is essential for healthcare providers.

• A thorough review of receptor types, their mechanisms, and clinical applications is key to appreciating pharmacological agents' roles in treating autonomic dysfunction, managing chronic diseases, and optimizing patient care.

Establishing a solid foundation in autonomic pharmacology will enhance clinical decision-making, promote safe medication practices, and improve patient outcomes in various medical scenarios.