Chemistry and Pharmacodynamics

Atropine is the prototypical anticholinergic drug owing to its antagonism ofacetylcholineAcetylcholineA 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 (AChAChA 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)receptorsReceptorsReceptors 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

• Also called:
  • Antimuscarinics/muscarinicreceptorReceptorReceptors 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 antagonists
  • Cholinergic blockers
  • Parasympatholytics
• Chemistry of anticholinergics:
  • Have a primary point of attachment to cholinergicreceptorsReceptorsReceptors 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 through their cationic (positively charged)nitrogenNitrogenAn element with the atomic symbol n, atomic number 7, and atomic weight [14. 00643; 14. 00728]. Nitrogen exists as a diatomic gas and makes up about 78% of the earth’s atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells.Urea Cycle atom
  • Are eithertertiary aminesTertiary AminesTricyclic Antidepressants or quaternary ammonium compounds
  • A hydroxyl group enhances antimuscarinic activity over that of similar compounds without a hydroxyl group.
• Anticholinergic actions of chemicals:
  • Block the activity ofAChAChA 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 CNSreceptorsReceptorsReceptors 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 → prevent transmission of signals through certain parts of thenervous systemNervous systemThe 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
  • Atropine (prototypical drug) antagonizesAChAChA 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 CNSreceptorsReceptorsReceptors 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 (anticholinergic).

Mechanism of action and physiologic effects

• Mechanism of action:
  • Competitively inhibit the neurotransmitterAChAChA 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 atreceptorReceptorReceptors 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 within the cholinergic system 
  • This inhibition leads to blockade of the parasympatheticnervous systemNervous systemThe 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.
• Physiologic effects:
  • Decreased production of secretions:
    • Salivary glandsSalivary glandsThe 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
    • Bronchial treeBronchial treeThe collective term “bronchial tree” refers to the bronchi and all of their subsequent branches. The bronchi are the airways of the lower respiratory tract. At the level of the 3rd or 4th thoracic vertebra, the trachea bifurcates into the left and right main bronchi. Both of these bronchi continue to divide into secondary or lobar bronchi that bifurcate further and further.Bronchial Tree: Anatomy
    • GI tract
  • Bronchodilation
  • Smooth muscle relaxation in the GI tract andbladderBladderA musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters, and is held there until urination.Pyelonephritis and Perinephric Abscess
• Drug classes used for their anticholinergic activity:
  • Antispasmodics for GI conditions:
    • AntagonizeAChAChA 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 atmuscarinic receptorsMuscarinic ReceptorsAsthma Drugs
    • Relax smooth muscle
    • Inhibit histamine-inducedspasmsSpasmsAn involuntary contraction of a muscle or group of muscles. Spasms may involve skeletal muscle or smooth muscle.Ion Channel Myopathy
  • Urinary antispasmodics:
    • AntagonizeAChAChA 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 atmuscarinic receptorsMuscarinic ReceptorsAsthma Drugs
    • RelaxbladderBladderA musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters, and is held there until urination.Pyelonephritis and Perinephric Abscess smooth muscle
    • Inhibit involuntarydetrusor muscleDetrusor muscleUrinary Incontinence contractions
  • Inhaled long-acting muscarinic antagonists (LAMAs):
    • Bronchodilation
    • Decrease bronchial secretions
    • Used for individuals with chronic obstructivepulmonary diseasePulmonary diseaseDiseases involving the respiratory system.Blastomyces/Blastomycosis (COPDCOPDChronic 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))
  • Mydriatics in ophthalmology (eye drops):
    • Inhibit response of iris sphincter
    • Inhibit response of theciliary bodyCiliary bodyA ring of tissue extending from the scleral spur to the ora serrata of the retina. It consists of the uveal portion and the epithelial portion. The ciliary muscle is in the uveal portion and the ciliary processes are in the epithelial portion.Eye: Anatomy muscles
  • 1st-generationantihistaminesAntihistaminesAntihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation.Antihistamines:
    • Act onhistamine receptorsHistamine ReceptorsAntihistamines
    • Inhibitmuscarinic receptorsMuscarinic ReceptorsAsthma Drugs and have anticholinergic effects (used therapeutically for motion sickness)
  • Antiparkinson drugsAntiparkinson drugsMedications for the management of Parkinson’s disease improve the symptoms of tremor, rigidity, and postural instability by increasing dopamine levels in the brain. While levodopa is the drug of choice in individuals of any age with moderate or severe symptoms, other agents can be used as monotherapy for milder symptoms or in conjunction with levodopa–carbidopa for symptom control.Parkinson’s Disease Drugs (largely replaced by newer medications)
  • Acetylcholinesterase (AChE) regenerators stimulate the breakdown ofacetylcholineAcetylcholineA 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 → anticholinergic effect on cholinergic excess:
    • PralidoximePralidoximeVarious salts of a quaternary ammonium oxime that reconstitute inactivated acetylcholinesterase, especially at the neuromuscular junction, and may cause neuromuscular blockade. They are used as antidotes to organophosphorus poisoning as chlorides, iodides, methanesulfonates (mesylates), or other salts.General Principles of Toxidromes (2-pyridine aldoxime methylchlorideChlorideInorganic compounds derived from hydrochloric acid that contain the Cl- ion.Electrolytes (2-PAM)):antidoteAntidoteAn antidote is a substance that counteracts poisoning or toxicity. Substances that can cause poisoning include heavy metals (from occupation, treatments, or diet), alcohols, environmental toxins, and medications.Antidotes of Common Poisonings for organophosphatetoxicityToxicityDosage Calculation seen withinsecticide poisoningInsecticide PoisoningInsecticides are chemical substances used to kill or control insects, to improve crop yields, and to prevent diseases. Human exposures to insecticides can be by direct contact, inhalation, or ingestion. Important insecticides that can affect humans include organochlorines (dichlorodiphenyltrichloroethane (DDT)), organophosphates (malathion and parathion), and carbamates (carbaryl, propoxur, aldicarb, and methomyl).Insecticide Poisoning and nerve agents inbioterrorismBioterrorismThe use of biological agents in terrorism. This includes the malevolent use of bacteria; viruses; or other biological toxins against people, animals; or plants.Anthrax (AChE inhibitorsAChE inhibitorsCholinomimetic Drugs)
    • Because AChE breaks downAChAChA 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, theAChE inhibitorsAChE inhibitorsCholinomimetic Drugs cause cholinergic poisoning and AChE regenerators (antidoteAntidoteAn antidote is a substance that counteracts poisoning or toxicity. Substances that can cause poisoning include heavy metals (from occupation, treatments, or diet), alcohols, environmental toxins, and medications.Antidotes of Common Poisonings) → net decrease inAChAChA 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

Pharmacokinetics

The pharmacokinetic properties of anticholinergic drugs are diverse, as they are available in many forms for different medical uses, such as IV atropine for severebradycardiaBradycardiaBradyarrhythmia 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, oral tablets for GI andbladderBladderA musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters, and is held there until urination.Pyelonephritis and Perinephric AbscessantispasmodicAntispasmodicAntispasmodics are a group of medications used to reduce excessive GI smooth muscle contractility and spasm. These medications may be helpful in those with abdominal pain due to conditions such as irritable bowel syndrome, although their efficacy is controversial.Antispasmodics use, inhaled forms of LAMAs for bronchodilation, and eye drops for cycloplegia. 

Eye drops

• Short-acting mydriatics dilate the pupils (e.g., cyclopentolate, tropicamide) and are preferred for ophthalmic diagnostic procedures.
• Cycloplegics producemydriasisMydriasisDilation of pupils to greater than 6 mm combined with failure of the pupils to constrict when stimulated with light. This condition may occur due to injury of the pupillary fibers in the oculomotor nerve, in acute angle-closure glaucoma, and in adie syndrome.Glaucoma, but they also paralyze the ciliary muscle in the treatment ofuveitisUveitisUveitis is the inflammation of the uvea, the pigmented middle layer of the eye, which comprises the iris, ciliary body, and choroid. The condition is categorized based on the site of disease; anterior uveitis is the most common.Diseases of the Uvea and other painful ophthalmic conditions.

Oral anticholinergic agents

• The lipophilicity of a drug correlates with itspenetrationPenetrationX-rays into the CNS; ↑ lipophilicity causesdizzinessDizzinessAn imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness.Lateral Medullary Syndrome (Wallenberg Syndrome), drowsiness, and cognitive impairment.
• GI antispasmodics: dicyclomine and hyoscyamine
  • Used forirritable bowel syndromeIrritable bowel syndromeIrritable bowel syndrome (IBS) is a functional bowel disease characterized by chronic abdominal pain and altered bowel habits without an identifiable organic cause. The etiology and pathophysiology of this disease are not well understood, and there are many factors that may contribute.Irritable Bowel Syndrome, biliary colic
  • Excretion: primarily in urine 
  • Half-lifeHalf-LifeThe time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity.Pharmacokinetics and Pharmacodynamics: 2–3.5 hours; extended-release form, 7.5 hours
  • Both are lipophilic.
  • Metabolism: hepaticcytochrome P450Cytochrome P450A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism.Drug-Induced Liver InjuryenzymesEnzymesEnzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules.Basics of Enzymes
• Urologic anticholinergic drugs/antispasmodics:
  • Used for overactivebladderBladderA musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters, and is held there until urination.Pyelonephritis and Perinephric Abscess
  • Excretion: mostly in urine

Atropine (IV)

• Nonselective muscarinic blocker
• Tertiary amine:
  • Lipid-soluble
  • Crosses theblood–brain barrierBlood–Brain BarrierMeningitis in Children (BBBBBBSpecialized non-fenestrated tightly-joined endothelial cells with tight junctions that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue.Nervous System: Histology)
• Used IV in advanced cardiac life support (ACLS) protocol for symptomaticbradycardiaBradycardiaBradyarrhythmia 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 to increase HR
• Onset of action: 30 seconds
• Duration of action: approximately 4 hours
• Maximum effect (IV): 2–6 minutes

Indications

Anticholinergic drugs are used in many forms. They are used via eye drops in ophthalmology as mydriatics/cycloplegics, included in inhalers asbronchodilatorsBronchodilatorsAsthma Drugs and to dry up secretions as LAMAs for individuals withCOPDCOPDChronic 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), and used in oral pill form as antispasmodics. Atropine is also used IV for severebradycardiaBradycardiaBradyarrhythmia 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 and is part of the ACLS protocol.

Anticholinergic drugs

• Antimuscarinic agents:
  • Atropine: used IV in ACLS protocol for symptomaticbradycardiaBradycardiaBradyarrhythmia 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
  • Glycopyrrolate:
    • Used as ananesthesiaAnesthesiaA 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 adjunct
    • Used as an antisialagogue
• Medications fordystoniaDystoniaDystonia is a hyperkinetic movement disorder characterized by the involuntary contraction of muscles, resulting in abnormal postures or twisting and repetitive movements. Dystonia can present in various ways as may affect many different skeletal muscle groups.Dystonia/Parkinson diseaseParkinson diseaseParkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder. Although the cause is unknown, several genetic and environmental risk factors are currently being studied. Individuals present clinically with resting tremor, bradykinesia, rigidity, and postural instability.Parkinson’s Disease (largely replaced by newer drugs):
  • Benztropine: antagonizesAChAChA 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 andhistamine receptorsHistamine ReceptorsAntihistamines
  • Trihexyphenidyl: antagonizesAChAChA 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 CNSreceptorsReceptorsReceptors 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
• GI antispasmodics: used in the treatment ofirritable bowel syndromeIrritable bowel syndromeIrritable bowel syndrome (IBS) is a functional bowel disease characterized by chronic abdominal pain and altered bowel habits without an identifiable organic cause. The etiology and pathophysiology of this disease are not well understood, and there are many factors that may contribute.Irritable Bowel Syndrome (IBSIBSIrritable bowel syndrome (IBS) is a functional bowel disease characterized by chronic abdominal pain and altered bowel habits without an identifiable organic cause. The etiology and pathophysiology of this disease are not well understood, and there are many factors that may contribute.Irritable Bowel Syndrome)
• Urinary antispasmodics: used in the treatment of overactivebladderBladderA musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters, and is held there until urination.Pyelonephritis and Perinephric Abscess (OAB)
• Anticholinergics in eye drops:
  • Drugs that cause pupillary dilation (mydriatics):
    • Affect only the iris, not the ciliary muscle
    • Used duringophthalmic examOphthalmic examA comprehensive examination of the eyes and their functions is important for all individuals with ocular symptoms, and to screen for visual acuity, glaucoma, and retinal pathology. A routine examination includes testing for visual acuity, peripheral vision, and color vision, plus an examination of the external eye, conjunctiva, sclera, iris, pupil, and extraocular movements.Ophthalmic Exam of the posterior segment andfundusFundusThe superior portion of the body of the stomach above the level of the cardiac notch.Stomach: Anatomy
  • Drugs that cause ciliary muscle paralysis and inhibitaccommodationAccommodationRefractive Errors or focusing ability: cycloplegic
    • Used in ophthalmic exams and the evaluation ofhyperopiaHyperopiaRefractive Errors
    • Used for prevention and release of posteriorsynechiaeSynechiaeScar tissue from prior surgery.Infertility in individuals withuveitisUveitisUveitis is the inflammation of the uvea, the pigmented middle layer of the eye, which comprises the iris, ciliary body, and choroid. The condition is categorized based on the site of disease; anterior uveitis is the most common.Diseases of the Uvea
    • TreatpainPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways associated withciliary bodyCiliary bodyA ring of tissue extending from the scleral spur to the ora serrata of the retina. It consists of the uveal portion and the epithelial portion. The ciliary muscle is in the uveal portion and the ciliary processes are in the epithelial portion.Eye: Anatomy spasm in the eye
  • Also used to treatamblyopiaAmblyopiaA nonspecific term referring to impaired vision. Major subcategories include stimulus deprivation-induced amblyopia and toxic amblyopia. Stimulus deprivation-induced amblyopia is a developmental disorder of the visual cortex. A discrepancy between visual information received by the visual cortex from each eye results in abnormal cortical development. Strabismus and refractive errors may cause this condition. Toxic amblyopia is a disorder of the optic nerve which is associated with alcoholism, tobacco smoking, and other toxins and as an adverse effect of the use of some medications.Strabismus (lazy eye) in infants
  • Names of ophthalmic preparations:
    • Cyclopentolate
    • Homatropine
    • Tropicamide 
• BronchodilatorsBronchodilatorsAsthma Drugs: used in the treatment ofCOPDCOPDChronic 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)

Drugs with major anticholinergic side effects

• Low-potency 1st-generationantipsychoticAntipsychoticAntipsychotics, also called neuroleptics, are used to treat psychotic disorders and alleviate agitation, mania, and aggression. Antipsychotics are notable for their use in treating schizophrenia and bipolar disorder and are divided into 1st-generation antipsychotics (FGAs) and atypical or 2nd-generation antipsychotics.First-Generation Antipsychotics drugs (FGAsFGAsAntipsychotics, also called neuroleptics, are used to treat psychotic disorders and alleviate agitation, mania, and aggression. Antipsychotics are notable for their use in treating schizophrenia and bipolar disorder and are divided into 1st-generation antipsychotics (FGAs) and atypical or 2nd-generation antipsychotics.First-Generation Antipsychotics):
  • Work primarily ondopamineDopamineOne of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement.Receptors and Neurotransmitters of the CNSreceptorsReceptorsReceptors 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
  • Also have an affinity formuscarinic receptorsMuscarinic ReceptorsAsthma Drugs → anticholinergic side effects
  • Examples oflow-potency FGAsLow-potency FGAsFirst-Generation Antipsychotics:
    • ChlorpromazineChlorpromazineThe prototypical phenothiazine antipsychotic drug. Like the other drugs in this class chlorpromazine’s antipsychotic actions are thought to be due to long-term adaptation by the brain to blocking dopamine receptors. Chlorpromazine has several other actions and therapeutic uses, including as an antiemetic and in the treatment of intractable hiccup.First-Generation Antipsychotics 
    • ThioridazineThioridazineA phenothiazine antipsychotic used in the management of psychosis, including schizophrenia.First-Generation Antipsychotics
• Tricyclic antidepressantsTricyclic antidepressantsTricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain.Tricyclic Antidepressants: inhibitnorepinephrineNorepinephrinePrecursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus.Receptors and Neurotransmitters of the CNS andserotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS reuptake 
• AntihistaminesAntihistaminesAntihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation.Antihistamines (1st generation):
  • Used for motion sickness (nauseaNauseaAn unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses.Antiemetics),allergic rhinitisAllergic rhinitisAn inflammation of the nasal mucosa triggered by allergens.Rhinitis, anddizzinessDizzinessAn imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness.Lateral Medullary Syndrome (Wallenberg Syndrome)/vertigoVertigoVertigo is defined as the perceived sensation of rotational motion while remaining still. A very common complaint in primary care and the ER, vertigo is more frequently experienced by women and its prevalence increases with age. Vertigo is classified into peripheral or central based on its etiology.Vertigo
  • Examples of 1st-generationantihistaminesAntihistaminesAntihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation.Antihistamines:
    • ChlorpheniramineChlorpheniramineA histamine h1 antagonist used in allergic reactions, hay fever, rhinitis, urticaria, and asthma. It has also been used in veterinary applications. One of the most widely used of the classical antihistaminics, it generally causes less drowsiness and sedation than promethazine.Antihistamines
    • DimenhydrinateDimenhydrinateA drug combination that contains diphenhydramine and theophylline. It is used for treating vertigo, motion sickness, and nausea associated with pregnancy.Antihistamines (Dramamine)
    • DiphenhydramineDiphenhydramineA histamine h1 antagonist used as an antiemetic, antitussive, for dermatoses and pruritus, for hypersensitivity reactions, as a hypnotic, an antiparkinson, and as an ingredient in common cold preparations. It has some undesired antimuscarinic and sedative effects.Antihistamines 
    • DoxylamineDoxylamineHistamine h1 antagonist with pronounced sedative properties. It is used in allergies and as an antitussive, antiemetic, and hypnotic. Doxylamine has also been administered in veterinary applications and was formerly used in parkinsonism.Antihistamines
    • HydroxyzineHydroxyzineA histamine h1 receptor antagonist that is effective in the treatment of chronic urticaria, dermatitis, and histamine-mediated pruritus. Unlike its major metabolite cetirizine, it does cause drowsiness. It is also effective as an antiemetic, for relief of anxiety and tension, and as a sedative.Antihistamines 
    • Ipratropium bromideIpratropium BromideAsthma Drugs (Atrovent nasal spray)
    • MeclizineMeclizineA histamine h1 antagonist used in the treatment of motion sickness, vertigo, and nausea during pregnancy and radiation sickness.Antihistamines (Antivert)
    • PromethazinePromethazineA phenothiazine derivative with histamine h1-blocking, antimuscarinic, and sedative properties. It is used as an antiallergic, in pruritus, for motion sickness and sedation, and also in animals.Antihistamines
    • ScopolamineScopolamineAn alkaloid from solanaceae, especially datura and scopolia. Scopolamine and its quaternary derivatives act as antimuscarinics like atropine, but may have more central nervous system effects. Its many uses include an anesthetic premedication, the treatment of urinary incontinence and motion sickness, an antispasmodic, and a mydriatic and cycloplegic.Antiemetics (patchPatchNonpalpable lesion > 1 cm in diameterGeneralized and Localized Rashes)
• Centrally actingskeletal muscle relaxantsSkeletal muscle relaxantsSpasmolytics are skeletal muscle relaxants medications which reduce forceful, involuntary muscle contraction. These medications have a variety of mechanisms, and can either act centrally to inhibit somatic motor neuron signals, or peripherally to prevent calcium release from the sarcoplasmic reticulum.Spasmolytics:
  • CyclobenzaprineCyclobenzaprineSpasmolytics
  • Metaxalone
  • MethocarbamolMethocarbamolA centrally acting muscle relaxant whose mode of action has not been established. It is used as an adjunct in the symptomatic treatment of musculoskeletal conditions associated with painful muscle spasm.Spasmolytics
  • Orphenadrine
  • TizanidineTizanidineSpasmolytics

Adverse Effects, Contraindications, Drug–Drug Interactions, and Toxicity

Adverse effects are due to effects on the CNS and also to reduced activity of the parasympatheticnervous systemNervous systemThe 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. Anticholinergics must be used with caution or avoided in the elderly owing to the risks of side effects.

Adverse effects

• Neuropsychiatric:
  • Drowsiness
  • HallucinationsHallucinationsSubjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real. They may be of organic origin or associated with mental disorders.Schizophrenia
  • MemoryMemoryComplex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory.Psychiatric Assessment impairment 
• Exocrine glandularsecretionSecretionCoagulation Studies → dry mouth
• Smooth muscle contractionSmooth muscle contractionSmooth muscle is primarily found in the walls of hollow structures and some visceral organs, including the walls of the vasculature, GI, respiratory, and genitourinary tracts. Smooth muscle contracts more slowly and is regulated differently than skeletal muscle. Smooth muscle can be stimulated by nerve impulses, hormones, metabolic factors (like pH, CO2 or O2 levels), its own intrinsic pacemaker ability, or even mechanical stretch.Smooth Muscle Contraction →:
  • Urinary retentionUrinary retentionInability to empty the urinary bladder with voiding (urination).Delirium
  • ConstipationConstipationConstipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency< 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic.Constipation
• Pupils →:
  • Blurred visionBlurred VisionRetinal Detachment
  • PhotophobiaPhotophobiaAbnormal sensitivity to light. This may occur as a manifestation of eye diseases; migraine; subarachnoid hemorrhage; meningitis; and other disorders. Photophobia may also occur in association with depression and other mental disorders.Migraine Headache

Warnings/contraindicationsContraindicationsA 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

• Beers criteriaBeers CriteriaGeriatric Care and Screening (medications be used with caution or avoided in elderly individuals):
  • Includes many strong, systemically acting anticholinergics; inhaled LAMAs forCOPDCOPDChronic 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) are exceptions when indicated.
  • Elderly individuals are more vulnerable to anticholinergic adverse effects due to:
    • Increased permeability of theBBBBBBSpecialized non-fenestrated tightly-joined endothelial cells with tight junctions that form a transport barrier for certain substances between the cerebral capillaries and the brain tissue.Nervous System: Histology 
    • Decreased ACh-induced transmission within the CNS
• Strong anticholinergics have a cumulative dose–response relationship with the development of AlzheimerdementiaDementiaMajor 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.

Comparison of adverse effects,contraindicationsContraindicationsA 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, and drug–drug interactions

ToxicityToxicityDosage Calculation/overdose

Acholinergic crisisCholinergic CrisisMyasthenia Gravis may occur with an overdose or with using multiple drugs that have cholinergic effects.

• Mnemonic: “Dry as aboneBoneBone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy.Bones: Structure and Types, hot as a pistol, red as a beet, mad as a hatter”
  • Dry: excess of the antisialagogue effect
  • Hot: anhidrosis and inability to regulatebody temperatureBody TemperatureThe measure of the level of heat of a human or animal.Heatstroke → hyperthermia
  • Red: due to peripheralvasodilationVasodilationThe physiological widening of blood vessels by relaxing the underlying vascular smooth muscle.Pulmonary Hypertension Drugs
  • Mad: psychosis
• Treatment:physostigminePhysostigmineA cholinesterase inhibitor that is rapidly absorbed through membranes. It can be applied topically to the conjunctiva. It also can cross the blood-brain barrier and is used when central nervous system effects are desired, as in the treatment of severe anticholinergic toxicity.Cholinomimetic Drugs (antidoteAntidoteAn antidote is a substance that counteracts poisoning or toxicity. Substances that can cause poisoning include heavy metals (from occupation, treatments, or diet), alcohols, environmental toxins, and medications.Antidotes of Common Poisonings)

Comparison of Mechanism of Action and Indications in Different Anticholinergics

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