Cholinomimetic Drugs

Chemistry and Pharmacodynamics

Acetylcholine Acetylcholine A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS ( ACh ACh A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS) is a prototype direct-acting cholinergic drug. Cholinomimetics are direct activators of both the muscarinic and nicotinic cholinergic receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors.

Overview

• A neurotransmitter at various synapses, nerves, and motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology endplates in muscles:
  • Nerve impulse → ACh ACh A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS stored in the vesicles Vesicles Female Genitourinary Examination is released into the synaptic cleft Synaptic cleft Synapses and Neurotransmission → binds to a postsynaptic receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors → depolarization Depolarization Membrane Potential
  • ACh ACh A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS is degraded by the acetylcholinesterase (AChE) enzyme (present at tissue receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors sites and on RBCs RBCs Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes: Histology)
• ACh ACh A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS is released from sympathetic and parasympathetic neuronal terminals on:
  • Lacrimal glands Lacrimal Glands Dacryocystitis 
  • Salivary glands Salivary glands The salivary glands are exocrine glands positioned in and around the oral cavity. These glands are responsible for secreting saliva into the mouth, which aids in digestion. There are 3 major paired salivary glands: the sublingual, submandibular, and parotid glands. Salivary Glands: Anatomy
  • Sweat glands Sweat glands Sweat-producing structures that are embedded in the dermis. Each gland consists of a single tube, a coiled body, and a superficial duct. Soft Tissue Abscess
• Overall effects are “wet”: tearing, sweating, and salivation

Mechanism of action and physiologic effects

• Muscarinic cholinergic receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors:
  • All 5 types (M1, M2, M3, M4, and M5) are G protein-coupled receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors → increased intracellular levels of calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes, which lead to:
    • Glandular secretion Secretion Coagulation Studies at exocrine glands Exocrine glands Glands of external secretion that release its secretions to the body’s cavities, organs, or surface, through a duct. Glandular Epithelium: Histology
    • Vascular smooth muscle relaxation
    • ↓ Heart rate Heart rate The number of times the heart ventricles contract per unit of time, usually per minute. Cardiac Physiology and contractility
• Muscarinic receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors locations → effects:
  • Autonomic ganglia and exocrine glands Exocrine glands Glands of external secretion that release its secretions to the body’s cavities, organs, or surface, through a duct. Glandular Epithelium: Histology: ↑ salivary/ gastric acid Gastric acid Hydrochloric acid present in gastric juice. Gastroesophageal Reflux Disease (GERD) secretion Secretion Coagulation Studies and diaphoresis
  • Blood vessel endothelium Endothelium A layer of epithelium that lines the heart, blood vessels (vascular endothelium), lymph vessels (lymphatic endothelium), and the serous cavities of the body. Arteries: Histology: M3 receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors → smooth muscle relaxation → vasodilation Vasodilation The physiological widening of blood vessels by relaxing the underlying vascular smooth muscle. Pulmonary Hypertension Drugs
  • Respiratory: M3 receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors → smooth muscle contraction → bronchoconstriction
  • Stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach: Anatomy: M1 receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors → increase gastric acid Gastric acid Hydrochloric acid present in gastric juice. Gastroesophageal Reflux Disease (GERD) secretion Secretion Coagulation Studies 
  • Intestine: M3 receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors → increase peristalsis Peristalsis A movement, caused by sequential muscle contraction, that pushes the contents of the intestines or other tubular organs in one direction. Gastrointestinal Motility, contract the gastroesophageal sphincter, and relax the pyloric sphincter
  • Eye: M3 receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors → pupillary constriction ( miosis Miosis Pupil: Physiology and Abnormalities)
  • Heart: M2 receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors lead to:
    • ↓ Heart rate Heart rate The number of times the heart ventricles contract per unit of time, usually per minute. Cardiac Physiology due to sinoatrial (SA) node suppression Suppression Defense Mechanisms
    • ↓ Conduction velocity and increased refractory period in the atrioventricular (AV) node
    • ↓ Contractility (negative inotropy)
  • Genitourinary:
    • Contraction of the detrusor muscle Detrusor muscle Urinary Incontinence
    • Relaxation of the trigone Trigone Urinary Tract: Anatomy and internal urethral sphincter
    • Men and women: erectile tissue stimulation
• Nicotinic cholinergic receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors:
  • Ionotropic: act on ion channel receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (e.g., calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes channels Channels The Cell: Cell Membrane) (do not confuse with inotropic):
    • Receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors is activated →  ion channel opens → net Na⁺ influx → depolarization Depolarization Membrane Potential at the postsynaptic membrane Postsynaptic membrane Synapses and Neurotransmission 
    • Action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential in muscle fiber → muscle contracts
  • Located at the neuromuscular junction Neuromuscular junction The synapse between a neuron and a muscle. Skeletal Muscle Contraction → skeletal muscle contraction Skeletal muscle contraction Skeletal muscle is striated muscle containing organized contractile structures known as sarcomeres that are made up of overlapping myofilaments: actin and myosin. When a nerve impulse arrives from a motor neuron, the signal triggers an action potential (AP) in the sarcolemma (muscle cell membrane), resulting in the release of Ca ions from the sarcoplasmic reticulum (SR) within the muscle cell. Skeletal Muscle Contraction

Classification and Pharmacokinetics

Cholinomimetic drugs either act directly on cholinergic receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors or inhibit AChE (the enzyme breaking down ACh ACh A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS). Important points about the pharmacokinetic properties of the medications include onset, duration, metabolism, and availability.

Classification

• ACh ACh A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS:
  • Both muscarinic and nicotinic actions
  • Rapidly hydrolyzed by AChE
• Some agents stimulate either the nicotinic or the muscarinic receptors Muscarinic Receptors Asthma Drugs.
• Direct-acting cholinomimetics:
  • Choline esters
    • ACh ACh A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS
    • Bethanechol
    • Methacholine
  • Plant alkaloids:
    • Nicotine Nicotine Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. Stimulants
    • Muscarine
    • Pilocarpine
• AChE inhibitors are indirect-acting cholinomimetics (AChE inhibiting, causing a net-positive cholinergic effect):
  • Reversible:
    • Donepezil and rivastigmine (used in the treatment of Alzheimer disease Alzheimer disease As the most common cause of dementia, Alzheimer disease affects not only many individuals but also their families. Alzheimer disease is a progressive neurodegenerative disease that causes brain atrophy and presents with a decline in memory, cognition, and social skills. Alzheimer Disease)
    • Neostigmine and physostigmine (used to reverse the effects of anesthesia Anesthesia A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. Anesthesiology: History and Basic Concepts/ neuromuscular blockade Neuromuscular Blockade The intentional interruption of transmission at the neuromuscular junction by external agents, usually neuromuscular blocking agents. It is distinguished from nerve block in which nerve conduction (neural conduction) is interrupted rather than neuromuscular transmission. Neuromuscular blockade is commonly used to produce muscle relaxation as an adjunct to anesthesia during surgery and other medical procedures. It is also often used as an experimental manipulation in basic research. It is not strictly speaking anesthesia but is grouped here with anesthetic techniques. The failure of neuromuscular transmission as a result of pathological processes is not included here. Aminoglycosides)
    • Pyridostigmine (used in the treatment of myasthenia gravis Myasthenia Gravis Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles caused by dysfunction/destruction of acetylcholine receptors at the neuromuscular junction. MG presents with fatigue, ptosis, diplopia, dysphagia, respiratory difficulties, and progressive weakness in the limbs, leading to difficulty in movement. Myasthenia Gravis)
  • Irreversible:
    • Malathion (antiparasitic for lice)
    • Isoflurophate (in eyedrops for glaucoma Glaucoma Glaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP). Glaucoma)
    • Sarin (used in nerve gas Nerve Gas Insecticide Poisoning for bioterrorism Bioterrorism The use of biological agents in terrorism. This includes the malevolent use of bacteria; viruses; or other biological toxins against people, animals; or plants. Anthrax)

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

Clinical Indications

Cholinomimetic drugs are used to treat many conditions, including dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders, glaucoma Glaucoma Glaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP). Glaucoma, and as an aid in smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases cessation.

Adverse Effects and Contraindications

The primary adverse effects of cholinergic drugs are the consequence of overstimulation of the parasympathetic nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. Nervous System: Anatomy, Structure, and Classification. Symptoms result from excessive levels of ACh ACh A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS in the synapses, glands, smooth muscles Smooth muscles Unstriated and unstriped muscle, one of the muscles of the internal organs, blood vessels, hair follicles, etc. Contractile elements are elongated, usually spindle-shaped cells with centrally located nuclei. Smooth muscle fibers are bound together into sheets or bundles by reticular fibers and frequently elastic nets are also abundant. Muscle Tissue: Histology, and motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology endplates.

Adverse effects

• Cholinomimetic hyperactivity Hyperactivity Attention Deficit Hyperactivity Disorder may result in cholinergic crisis Cholinergic Crisis Myasthenia Gravis = the same signs and symptoms seen with cholinesterase Cholinesterase Liver Function Tests inhibitor poisoning ( nerve gas Nerve Gas Insecticide Poisoning):
  • Organophosphates inhibit AChE.
  • Reversed by atropine Atropine An alkaloid, originally from atropa belladonna, but found in other plants, mainly solanaceae. Hyoscyamine is the 3(s)-endo isomer of atropine. Anticholinergic Drugs 
  • Symptoms are more severe than the usual side effects of medications:
    • Decreased blood pressure
    • GI: abdominal cramps Cramps Ion Channel Myopathy, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, and vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
    • Blurred vision Blurred Vision Retinal Detachment
    • Pallor
    • Twitching of the facial muscles Facial muscles The facial muscles (also called mimetic muscles) control facial expression and are supplied by the facial nerve. Most of them originate from the skull and attach to the skin around the facial openings, which serve as a method to group or classify them. Facial Muscles: Anatomy
• Mnemonics to remember cholinergic effects:
  • Cholinomimetic muscarinic agonists exert side effects remembered by the mnemonic “SLUDGE“:
    • Salivation                                     
    • Lacrimation
    • Urination                             
    • Defecation/ diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
    • Gastric Emptying
  • Also “BBB“:
    • Bradycardia
    • Bronchoconstriction
    • Bronchorrhea (excess mucus discharge)
• Side effects of AChE inhibitors (e.g., donepezil):
  • Most common: diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • AV block AV block Atrioventricular (AV) block is a bradyarrhythmia caused by delay, or interruption, in the electrical conduction between the atria and the ventricles. Atrioventricular block occurs due to either anatomic or functional impairment, and is classified into 3 types. Atrioventricular block (AV block)
  • Bradycardia Bradycardia Bradyarrhythmia is a rhythm in which the heart rate is less than 60/min. Bradyarrhythmia can be physiologic, without symptoms or hemodynamic change. Pathologic bradyarrhythmia results in reduced cardiac output and hemodynamic instability causing syncope, dizziness, or dyspnea. Bradyarrhythmias
  • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • GI bleed
  • Headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess
  • Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia
  • Mood disturbance (e.g., depression and anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder)

Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation

• AChE inhibitors:
  • Cardiac conduction defects (risk of QT prolongation causing ventricular tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children)
  • Asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma or chronic obstructive pulmonary disease Pulmonary disease Diseases involving the respiratory system. Blastomyces/Blastomycosis ( COPD COPD Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD))
  • Urinary tract Urinary tract The urinary tract is located in the abdomen and pelvis and consists of the kidneys, ureters, urinary bladder, and urethra. The structures permit the excretion of urine from the body. Urine flows from the kidneys through the ureters to the urinary bladder and out through the urethra. Urinary Tract: Anatomy obstruction
  • Seizure history or risk
  • GI bleed history or risk
• Pilocarpine: Use eye drops to treat glaucoma Glaucoma Glaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP). Glaucoma and oral tablets to treat xerostomia Xerostomia Decreased salivary flow. Sjögren’s Syndrome (e.g., Sjögren syndrome Sjögren Syndrome Rheumatoid Arthritis):
  • Contraindicated in angle-closure glaucoma Angle-Closure Glaucoma Glaucoma
  • Acute iritis Iritis Inflammation of the iris characterized by circumcorneal injection, aqueous flare, keratotic precipitates, and constricted and sluggish pupil along with discoloration of the iris. Leprosy 
  • Acute asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma
  • Use caution with hepatic impairment.

Comparison Table