Untitled Quiz

Drugs Acting on Autonomic Nervous System

The nervous system is composed of all the nerves in the body, and it works with the endocrine system to control and coordinate bodily functions.
Nerve tissues receive stimuli, transmit them to nerve centers, and initiate responses.
The nervous system is divided into two parts: the Peripheral Nervous System (PNS) and the Central Nervous System (CNS).
The PNS contains afferent (sensory) and efferent (motor) neurons
The CNS consists of the brain and spinal cord.
The autonomic nervous system (ANS) is part of the efferent division of the PNS, controlling involuntary bodily functions.
The ANS is further divided into sympathetic and parasympathetic systems, generally working in opposition.
The sympathetic system is active in emergencies, activating “fight-or-flight” responses.
The parasympathetic system is active during non-emergency situations, promoting "rest and digest" functions.
The ANS innervates smooth muscle, cardiac muscle, and exocrine glands.
The somatic nervous system controls voluntary functions, like skeletal muscle contractions and sensory neurons in the skin.
The autonomic nervous system uses two types of neurons to send signals: preganglionic and postganglionic neurons.
Acetylcholine (ACh) is the neurotransmitter at most preganglionic synapses and some postganglionic synapses of the parasympathetic system.
Norepinephrine (NE) is the neurotransmitter at most postganglionic sympathetic synapses, and in the adrenal medulla causes release of epinephrine (E).
Neurotransmission in the PNS occurs at preganglionic synapses, postganglionic synapses, and all somatic motor end plates.
Key neurotransmitters in the autonomic nervous system include acetylcholine, norepinephrine, epinephrine, and serotonin (5-HT).

Autonomic Neurotransmitters

The peripheral nervous system (PNS) uses neurotransmitters to carry nerve impulses across synapses.
Key neurotransmitters include ACh, NE, epinephrine, and serotonin (5-HT).
Neurotransmission occurs at preganglionic synapses, postganglionic synapses, and all somatic motor end plates.

Cholinergic Neurons

Cholinergic neuron release acetylcholine (ACh).
ACh interacts with specific receptors at postsynaptic sites.
Drugs mimicking ACh action are cholinomimetics.
Drugs hindering ACh breakdown are also cholinomimetics.
ACh is a neurotransmitter that is released from the presynaptic nerve ending that interacts with specific receptors at the postsynaptic site and causes a receptor-mediated response.
Drugs that mimic the actions of ACh are termed cholinomimetic, or parasympathomimetic.
Drugs that mimic the actions of epinephrine and norepinephrine are termed adrenomimetic or sympathomimetic.

Cholinergic Receptors

Cholinergic receptors come in two main types, muscarinic and nicotinic receptors.
Muscarinic receptors are G-protein coupled receptors that activate various second messenger systems.
Nicotinic receptors are ligand-gated ion channels that directly alter ion flow across the membrane.
Muscarinic receptors are located postsynaptically on smooth muscle, glands, and effector organs of cholinergic sympathetic fibers. They're stimulated by the alkaloid muscarine and they are metabotropic, activating G proteins with 5 subtypes (M1, M2, M3, M4, M5).
Located in ganglia of both parasympathetic and sympathetic systems, nicotinic receptors are ionotropic receptors, enabling sodium channels
The neurotransmitter ACh acts on both muscarinic and nicotinic receptors to initiate various responses in the body.

Autonomic Neurotransmitters cont.

Acetylcholine is the key transmitter at the preganglionic synapses in both the parasympathetic and sympathetic nervous systems
Norepinephrine is the chief transmitter at postganglionic synapses within the sympathetic nervous system.
Epinephrine is the chief transmitter at the adrenal medulla .

Cholinergic Drugs

Cholinergic agonists mimic the effects of ACh.
Direct-acting agonists have similar qualitative action to ACh.
Indirect-acting agonists block the breakdown of ACh.
Acetylcholine is a vital neurotransmitter, exerting its functions through diverse mechanisms, impacting various organs within the body.

Structure-Activity Relationships (SAR) of Acetylcholine

Analyzing lead compounds is crucial for drug development, determining which parts of molecules contribute to activity.
Key groupings of ACh are broken down—acyl, ethylene, and ammonium groups—to assess structural changes affecting activity, and for potential new drug development.
Modification of the quaternary ammonium group affects muscarinic activity significantly.
The quaternary ammonium structure of ACh is essential for muscarinic activity; removing or substituting with less positive groups leads to less activity.
Structure-activity relationship studies focus on modifications to the ACh structure to alter activity profile and enhance or diminish function.
The size of the substituents and the resulting properties define the effect on the molecule.

Cholinesterase Inhibitors (ChE Inhibitors)

Cholinesterases are enzymes that break down acetylcholine (ACh).
There are two main types in humans: Acetylcholinesterase (AChE) and Butyrylcholinesterase (BuChE).
Cholinesterase inhibitors affect nerve function by increasing the amount of ACh at synapses, causing prolonged effects.
Irreversible inhibitors permanently halt cholinesterase activity, while reversible inhibitors temporarily halt cholinesterase activity.
AChE inhibitors are used in treating certain conditions, but they carry potential side effects, making use cautious and selective.

Agents Approved for the Treatment of Alzheimer's Disease

Tacrine, Donepezil, and Rivastigmine are approved drugs for treating Alzheimer's disease, aiming to increase levels of acetylcholine to alleviate symptoms.

Cholinergic Blocking Agents

Cholinergic blocking agents prevent acetylcholine (ACh)'s action, influencing various bodily functions.
Anticholinergic drugs competitively block ACh receptors, reducing ACh's effects in the parasympathetic nervous system.
Different types of blockers (antagonists) target different cholinergic receptors and nerve junctions.
Anticholinergic drugs produce several responses, including dry mouth and difficulties with vision and reduced secretion in the GI tract and the genitourinary tract, as well as eye issues. These effects vary depending on usage and dosage.

Anti-Muscarinic Agents

Antimuscarinic drugs block muscarinic receptors, reducing the effects of acetylcholine on target organs.
These agents are found in cold and flu remedies, reducing nasal and respiratory tract secretions.
Different chemical structures of anti-muscarinic agents are used depending on the desired effect and activity.

Natural Tropine Esters

Atropine and scopolamine are naturally occurring tropine esters that block muscarinic receptors and have various effects on the body.
They cause dryness of the mouth, dilation of the pupils, decreased stomach activity, and are used to treat motion sickness.

Synthetic Non-Tropine Esters

Synthetic non-tropine esters, such as cyclopentolate and dicyclomine, are anticholinergic drugs with various effects.
They block muscarinic receptors and can be used for treating spasms in the gastrointestinal tract, reducing secretions.

Aminoalcohol Ethers

Aminoalcohol ethers are anticholinergic drugs related to antihistamines, used to treat Parkinson's disease.
They are effective in blocking muscarinic receptors centrally and cause fewer peripheral-related side effects.
Several compounds are used in Parkinson's treatment and other related medical issues, including antisecretory agents.

Aminoamides

Structurally, certain aminoamides are represented by types of anticholinergics molecules, replacing hydroxide (OH) groups with amide groups (-NH₂).
Used as antisecretory agents
Contain functional groups similar to the structural building blocks of acetylcholine (ACh).

General Structure of Muscarinic Antagonists

Muscarinic antagonists contain certain components (e.g., ring structures, carbon lengths) to create a highly potent and selective block on muscarinic receptors.
Important features include substituents on carbon atoms, nitrogen substitution, and the distance between nitrogen groups and carbon bonding.

Therapeutic Actions of Cholinergic Blocking Agents

Cholinergic blocking agents have clinical use in constricting the pupils (mydriasis) decreasing secretions, controlling nausea during and post-operative situations, as antispasmodics (treating GI or urinary tract spasms), as well as other medical conditions.

Nicotinic Antagonists

Nicotinic antagonists block the effects of acetylcholine (ACh) at nicotinic receptors in the autonomic ganglia and neuromuscular junctions—especially in skeletal muscle.
These agents are commonly used as muscle relaxants, to reduce or block autonomic responses, and are typically not given orally.

Neuromuscular Blockers

Neuromuscular blockers are substances that interrupt acetylcholine (ACh)'s actions at the neuromuscular junction, causing muscle relaxation.
They are mainly used as muscle relaxants in surgical procedures.
Different types exist (e.g., depolarizers and non-depolarizers), with differing mechanisms of action, and some have more limited clinical use and side effects

Irreversible Inhibitors of Cholinesterase

Irreversible cholinesterase inhibitors inhibit the breakdown of acetylcholine causing an increase in synaptic acetylcholine levels.
These substances are commonly used as insecticides but are also capable of poisoning mammals.
Irreversible inhibitors like organophosphates are often used to overcome muscle relaxants caused by depolarizing effects.

Adrenergic Drugs

Adrenergic drugs are chemical agents producing effects like sympathetic nervous stimulation.
These agents are often used in treating circulatory system complications, asthma, and other conditions, however they frequently have side effects.
They could be further classified as adrenergic agonists or antagonists.

Catecholamines

Catecholamines, including norepinephrine, epinephrine, and dopamine, are neurotransmitters in the body.
They contain an amine group and catechol structure/parts. These substances are responsible for several effects within the body, although they frequently have side effects.

Biosynthesis, Storage, & Release of Catecholamines

Catecholamines (NE, epinephrine, dopamine) are synthesized from the amino acid tyrosine, a complex process.
These substances are stored in vesicles within nerve endings and released into the synapse under stimulated conditions to promote numerous functions.
The enzymes required to synthesize catecholamines are crucial, with MAO (monoamine oxidase) and COMT (catechol-O-methyl-transferase) being important for catecholamine metabolism. The end product of their metabolisms contributes to physiological effects within the body.

Adrenergic Receptors (Adrenoceptors)

Adrenergic receptors are sites for catecholamine binding that trigger numerous cellular responses, influencing both the peripheral and central nervous systems.
Different subtypes (alpha and beta) and their particular effects, alongside their location, and functions are all categorized. This ensures a comprehensive understanding of the actions.
Alpha and beta receptors are implicated in numerous bodily functions, with significant impact on heart rate, blood pressure, respiration, and blood flow.

Sympathomimetic Agents

Sympathomimetic agents mimic effects of NE or epinephrine, mimicking actions of the sympathetic nervous system.
These drugs interact directly with receptors (agonists) or indirectly by releasing or altering catecholamine levels (indirect-acting sympathomimetics).
Some drugs are selective, targeting particular receptor subtypes, whereas others work on multiple receptors. Types include direct acting, mixed acting, and indirect acting.