Pharmacology I: Module 2 - Autonomic Pharmacology: Cholinergic Agonists and Antagonists
Knowledge Application Questions: Cholinergic Pharmacology After four years of ipratropium (Atrovent) (two puffs four times daily), a COPD patient is referred to a pulmonologist who has decided to change the drug treatment to tiotropium (Spiriva). Which of the following statements are correct? *(Select all that apply)* A. The medication that the patient has been receiving for the past four years is a short-acting antimuscarinic (anticholinergic) bronchodilator. B. Tiotropium (Spiriva) is a LAMA. C. Based on its structure, tiotropium would be expected to have extraordinarily high rates of constipation, urinary retention, and other anticholinergic adverse effects compared to other drugs in this pharmacological class.
A, B
Knowledge Application Questions: Cholinergic Pharmacology A 28-year-old female experiences troublesome nausea and dizziness when traveling by car or air for long periods. Which of the following drug products are options for this patient? A. OTC meclizine (Bonine) 25 mg or prescription meclizine (Antivert) 50 mg one hour before travel B. OTC dimenhydrinate (Dramamine) 50 mg one hour before travel C. prescription scopolamine bromide 72-hour transdermal system (Transderm-Scop)
A, B, C
Knowledge Application Questions: Cholinergic Pharmacology: An 80-year-old female with a history of chronic constipation, early cognitive impairment, and poorly controlled hypertension complains of urinary accidents and urinary urgency. The patient reports the need to wear an adult absorptive product. After examination, the physician establishes a diagnosis of OAB. Which of the following are correct regarding this scenario? *(Select all that apply)* A. A urinary anticholinergic, such as tolterodine (Detrol LA) or oxybutynin, may worsen the cognitive impairment and constipation in this patient. B. Mirabegron (Myrbetriq) may worsen the hypertension in this patient. C. There is not an optimal prescription drug option to manage OAB in this patient.
A, B, C
Knowledge Application Questions: Cholinergic Pharmacology: Which of the following are options for smoking cessation upon initiation of Chantix therapy? *(Select all that apply)* A. Fixed quit approach: Start Chantix, and then quit smoking after one week. B. Flexible quit approach: Start Chantix, and then quit smoking within one month. C. Gradual quit approach: Start Chantix, and then gradually reduce smoking to quit within 12 weeks. D. Gradual quit approach: Start Chantix in combination with a nicotine replacement product, and then gradually reduce smoking to quit within 12 weeks.
A, B, C
Classic anticholinergic drug actions: CNS effects: amnesia, ataxia, ____________ (more common in elderly), dizziness, drowsiness, excitement, fatigue, hallucination, headache, insomnia, nervousness, psychosis, and speech disturbance: drugs with anticholinergic activity should be avoided or used with caution in _________ patients and/or those with preexisting cognitive ______________.
*confusion*, elderly, dysfunction
Muscarinic Receptor Agonists - Classification of Muscarinic Receptor Agonists by Origin: Naturally Occurring Muscarinic Agonist:
*pilocarpine (Isopto Carpine, Pilopine HS, Salagen)*
Anticholinesterase Agents (Cholinesterase Inhibitors): Irreversible organophosphate (covalent) inhibitors (1):
-*Echothiophate iodide (Phospholine iodide) (indicated for glaucoma)*
Muscarinic Receptor Agonists - Classification of Muscarinic Receptor Agonists by Origin: Synthetic Choline Ester Muscarinic Agonists (4):
-*acetylcholine (Miochol-E)* -*bethanechol (Urecholine)* -*carbachol (Isopto Carbachol)* -cevimeline (Evoxac)
Knowledge Application: A Case Study in Organophosphate Toxicity: A 36-year-old farm worker is transported to the ER after spending the morning applying chemical pesticides to the fields. Paramedics noted drooling, sweating, wheezing, abdominal cramping, one episode of vomiting, highly constricted pupils, hypotension, muscle weakness, facial twitching, slurred speech, and ataxia. On board the ambulance, paramedics were instructed to give an intramuscular injection of atropine followed by initiation of an intravenous line and a second administration of atropine. Upon evaluation in the ER, physicians elected to repeat the atropine injection and to also administer 2-PAM (pralidoxime). What is the pharmacological basis of using atropine as an antidote to organophosphate toxicity? What is the pharmacological basis of using 2-PAM (pralidoxime) as an antidote to organophosphate toxicity?
-Anticholinergic -Cholinesterase reactivator
A traditional mnemonic for remembering the signs and symptoms of organophosphate toxicity is SLUDGE and the Three Killer Bees. Based on the mechanism of action and pharmacological effects, identify the sign or symptom for each letter. SLUDGE: Three Killer Bees:
-Salivation, lacrimation, urination, diarrhea, gastrointestinal upset (cramping/pain), emesis (vomiting) -Bradycardia (low HR), bronchospasm (constriction), bronchorreha (mucus)
Anticholinergic Drugs (Muscarinic Receptor Antagonists): Semi-synthetic or synthetic congeners/analogs of atropine and related drugs - Inhalation for COPD (5):
-aclidinium bromide (Tudorza Pressair) -ipratropium (Atrovent) -glycopyrrolate (Seebri Neohaler) -tiotropium bromide (Spiriva) -umeclidinium bromide (Incruse Ellipta)
Anticholinesterase Agents (Cholinesterase Inhibitors) - Reversible, competitive (non-covalent) inhibitors (4):
-ambenonium (Mytelase) -*donepezil (Aricept, Aricept ODT) (indicated for Alzheimer's disease)* -edrophonium (Enlon) -galantamine (Razadyne, Razadyne ER) (indicated for Alzheimer's disease)
Competitive (non-depolarizing) neuromuscular blockers utilized clinically (6):
-atracurium (Tracrium) intravenous injection -cisatracurium (Nimbex) intravenous injection -mivacurium (Mivacron) intravenous injection -pancuronium (Pavulon) intravenous injection -rocuronium (Zemuron) intravenous injection -vecuronium (Norcuron) intravenous injection
Anticholinergic Drugs (Muscarinic Receptor Antagonists): Naturally occurring alkaloids (3):
-atropine (d,l-hyoscyamine) (also found in jimson weed, Datura stramonium) -hyoscyamine (Anaspaz, HyoMax, Levbid, Levsin, Levsinex) -scopolamine (Scopace, Transderm-Scop, Isopto Hyoscine)
Examples of drugs with high rates of anticholinergic activity - Antihistamines (6):
-chlorpheniramine (Chlor-Trimeton) -cyproheptadine (Periactin) -diphenhydramine (Benadryl) -doxylamine (Unisom) (commonly used as a sleep aid) -hydroxyzine (Atarax) -meclizine (Bonine) (commonly used for motion and travel sickness)
Examples of drugs with high rates of anticholinergic activity - Antipsychotics (5):
-chlorpromazine (Thorazine) -clozapine (Clozaril) -olanzapine (Zyprexa) -quetiapine (Seroquel) -thioridazine (Mellaril)
Anticholinergic Drugs (Muscarinic Receptor Antagonists): Semi-synthetic or synthetic congeners/analogs of atropine and related drugs - Ophthalmic diagnostic agents for inducing mydriasis (pupil dilation) and cycloplegia for visualization of the retina (3):
-cyclopentolate (Cyclogyl) -homatropine (Isopto Homatropine) -tropicamide (Mydriacyl)
Anticholinergic Drugs (Muscarinic Receptor Antagonists): Semi-synthetic or synthetic congeners/analogs of atropine and related drugs - Urinary Anticholinergics for Urinary Incontinence Due to Overactive Bladder (OAB) (6):
-darifenacin (Enablex) -fesoterodine (Toviaz) -oxybutynin (Ditropan XL, Gelnique and Oxytrol Transdermal) -solifenacin (Vesicare) -tolterodine (Detrol, Detrol LA) -trospium (Sanctura, Sanctura XR)
Urinary anticholinergics: treatment of overactive bladder (OAB) with symptoms of urinary incontinence, urgency, and frequency (6):
-darifenacin (Enablex) extended-release tablets -fesoterodine (Toviaz) extended-release tablets -*oxybutynin* (Ditropan) tablets, extended-release tablets, transdermal gel and patch* -solifenacin (Vesicare) tablets -*tolterodine (Detrol, Detrol LA) tablets, extended-release capsules* -trospium (Sanctura, Sanctura XR) tablets, extended-release capsules
Anticholinergic/anti-spasmodic agents for irritable bowel syndrome (IBS) (2):
-dicyclomine (Bentyl) -hyoscyamine (Levsin)
Anticholinesterase agents used in the treatment of Alzheimer's disease (3):
-donepezil (Aricept, Aricept ODT) tablets, orally disintegrating tablets -galantamine (Razadyne, Razadyne ER) tablets, extended-release capsules, solution -rivastigmine (Exelon, Exelon Patch) capsules, solution, transdermal patch
Newer Therapeutic Options for Functional GI Disorders (3):
-eluxadoline (Viberzi) -linaclotide (Linzess) -lubiprostone (Amitiza)
Anticholinesterase Agents (Cholinesterase Inhibitors) - Slowly reversible carbamate (covalent) inhibitors ('stigmines') (4):
-neostigmine (Prostigmin) -physostigmine -pyridostigmine (Mestinon) -*rivastigmine (Exelon) (indicated for Alzheimer's disease)*
Anticholinergic Drugs (Muscarinic Receptor Antagonists): Semi-synthetic or synthetic congeners/analogs of atropine and related drugs - Older anticholinergics for adjunctive treatment of peptic ulcer by reducing gastric acid secretion (2):
-pirenzepine (Gastrozepin) -propantheline (Pro-Banthine)
Examples of drugs with high rates of anticholinergic activity - Urinary Anticholinergics (1):
-tolterodine (Detrol)
Efficacy of varenicline: Varenicline trials indicate that ____% of patients report smoking cessation after 9 to 12 weeks of treatment. The abstinence rate for varenicline at 1 year was ____% versus ___% for placebo.
44, 37, 8
Knowledge Application Questions: Cholinergic Pharmacology: A 78-year-old with early-stage Alzheimer's disease is prescribed to pick up donepezil 10 mg, one capsule daily in the evening. The patient's caregiver arrives to pick up the prescription. Which of the following statements is appropriate and accurate counseling statements? A. The most common side effects of this medication are dry mouth, constipation, and urinary retention. B. This medication will greatly improve memory, as well as everyday function, and will slow the progression of Alzheimer's disease. C. This medication may cause loose stools, diarrhea, nausea, and cramping. Although these side effects usually lessen or resolve in 1 to 3 weeks, if there is worsening diarrhea and vomiting, please contact the doctor immediately.
C
Knowledge Application Questions: Cholinergic Pharmacology: Paramedics are called to a case of suspected organophosphate pesticide toxicity. After paramedics communicate the signs and symptoms to the ER, the physician orders immediate treatment. Which of the following is the appropriate antidote for this patient? A. physostigmine injection B. epinephrine injection C. atropine injection alone or combination atropine/pralidoxime (DuoDote) injection D. beta blocker injection
C
Knowledge Application Questions: Cholinergic Pharmacology: Paramedics respond to a 63-year-old female who feels faint. The pulse is 46 and irregular, the blood pressure is 82/50, the skin is pale, cool, and clammy, and the patient is having difficulty understanding questions. The ECG displays second-degree AV block (Mobitz Type II) with 3:1 conduction. The paramedics establish an IV line and await orders from the ER physician. Which of the following drugs is considered the treatment of choice? A. metoprolol (Lopressor) injection B. neostigmine (Prostigmin) injection C. atropine injection
C
Muscarinic Receptor Agonists - Selected Uses of Muscarinic Receptor Agonists: _____________ (_____________________) Ophthalmic Solution - Indicated for lowering intraocular pressure in _____________: administration of an ophthalmic muscarinic agonist promotes pupil _____________, which then ___________ the flow of aqueous humor from the eye leading to ____________ intraocular pressure.
Carbachol (Isopto Carbachol), glaucoma, constriction, enhances, lowered
Knowledge Application Questions: Cholinergic Pharmacology: A physician treating a farmer in the ER contacts a local pharmacist to identify the potential cause of toxicity in a patient with salivation, lacrimation, urinary frequency, diarrhea, gastrointestinal upset, emesis, bradycardia, bronchospasm, and bronchial congestion. What is the etiology (cause) of the symptoms and what is the appropriate antidote? Cause A. Accidental ingestion of deadly nightshade leading to belladonna alkaloid poisoning. B. Toxic exposure to a cholinesterase inhibiting organophosphate pesticide. C. Overdose with a beta blocker. D. Accidental ingestion of the poisonous mushroom, Amanita muscaria, which contains high concentrations of the naturally occurring muscarinic agonist muscarine. Antidote A. The appropriate antidote for this patient is atropine. B. The appropriate antidote for this patient is a cholinesterase inhibitor, such as physostigmine.
Cause: B Antidote: A
Knowledge Application Questions: Cholinergic Pharmacology: A child is transported to the ER after playing in a nearby wooded area. The child has become increasingly listless and confused. The child complains of blurred vision, severe dry mouth, and the inability to urinate. In the ER, the skin is hot and dry to the touch, the pupils are dilated, and the ECG shows tachycardia. What is the cause of the patient's symptoms and what would be the appropriate antidote? Cause A. The child has accidentally ingested Amanita muscaria mushrooms, which contain high concentrations of the naturally occurring muscarinic agonist muscarine. B. The child has been exposed to an organophosphate pesticide. C. The child has accidentally ingested the leaves of the Pilocarpus plant resulting in toxic exposure to pilocarpine. D. The child has accidentally ingested berries from the Atropa belladonna plant resulting in toxic exposure to belladonna alkaloids. Antidote A. The appropriate antidote for this patient is a cholinesterase inhibitor, such as physostigmine. B. The appropriate antidote for this patient is atropine.
Cause: D Antidote: A
Muscarinic Receptor Agonists - Selected Uses of Muscarinic Receptor Agonists: _________________ (__________) oral capsules - Indicated for the treatment of ____ mouth (xerostomia) in patients with ____________ syndrome (an autoimmune condition in which autoantibodies injure salivary and lacrimal glands) and related dry mouth syndromes.
Cevimeline (Evoxac), dry, Sjogren's
Knowledge Application Questions: Cholinergic Pharmacology: A 28-year-old is referred to a gastroenterologist with complaints of abdominal pain and discomfort, bloating, and frequent loose stools that began 6 months previously. The patient reports that symptoms become worse under psychosocial stress. The patient has a history of generalized anxiety disorder treated with escitalopram (Lexapro) and Sjogren's syndrome with chronic dry eyes treated with lifitegrast (Xiidra) opthalmic solution. No obvious gastrointestinal pathology or abnormalities were identified by laboratory testing, imaging, and endoscopy. Testing for celiac disease was negative. The physician informs the patient that the most likely diagnosis is IBS-D. Of the choices below, which is the most appropriate drug option for this patient? A. linaclotide (Linzess) B. lubiprostone (Amitiza) C. dicyclomine (Bentyl) or hyoscyamine (Levsin) D. eluxadoline (Viberzi)
D
Knowledge Application Questions: Cholinergic Pharmacology: A patient is diagnosed with chronic idiopathic (functional) constipation. Which of the following approaches is NOT an ideal option for this patient? A. Daily use of polyethylene glycol (MiraLAX), an OTC laxative. B. Increased dietary fiber and water intake. C. Daily treatment with linaclotide (Linzess), a drug which enhances intestinal secretions. D. Daily treatment with hyoscyamine (Levsin) or dicyclomine (Bentyl).
D
Knowledge Application Questions: Cholinergic Pharmacology: Paramedics respond to a 63-year-old female who feels faint. The pulse is 46 and irregular, the blood pressure is 80/50, the skin is pale, cool, and clammy. The ECG displays third-degree AV block (complete heart block). The paramedics establish an IV line and await orders from the ER physician. Which of the following drugs is considered the treatment of choice? A. neostigmine (Prostigmin injection) B. beta blocker injection C. muscarinic agonist injection D. atropine injection
D
Drug-disease state interactions and contraindications - representative of anticholinergics: ________________ should be avoided in patients with obstructive diseases of the GI tract, severe ulcerative colitis, GERD (reflux esophagitis), obstructive uropathy, severe benign prostatic hyperplasia (BPH), and glaucoma.
Dicyclomine
Knowledge Application Questions: Cholinergic Pharmacology: The physician elects to prescribe linaclotide (Linzess) capsules, 290 mcg, once daily 30 minutes before the fits meal of the day on an empty stomach. What is the most common adverse effect of linaclotide (Linzess)? A. sinusitis B. dizziness C. headache D. fatigue E. diarrhea
E
Knowledge Application Questions: Cholinergic Pharmacology: Which of the following statements regarding anticholinergic drug strategies are correct? *(Select All That Apply)* A. Urinary anticholinergics, such as tolterodine (Detrol), are relatively selective for bladder muscarinic receptors and have a low rate of systemic anticholinergic effects. B. Atropine injection is effective for improving conduction in type II second-degree and third-degree atrioventricular (AV) block. C. Anticholinergics are effective drug options for the treatment of GERD. D. A LAMA is an appropriate option for rescue or quick-relief management of COPD or asthma exacerbations. E. Hyoscyamine (Levsin) and dicyclomine (Bentyl) are classified as gastrointestinal antispasmodics. F. Patients receiving oxybutynin (Ditropan) may experience a greater rate of dry mouth, blurring of near vision, and possible constipation compared to other drugs in the class.
E, F
Drug-disease state interactions with anticholinergics - Drugs with significant anticholinergic properties should be avoided in: 1) Patients with ________ or obstructive diseases of the ___________ or ulcerative ________ 2) Patients with severe _______. 3) Patients with ____________.
GERD, GI tract, colitis, BPH, glaucoma
Muscarinic Receptor Agonists - Selected Uses of Muscarinic Receptor Agonists: __________________ (_______________________________) - Ophthalmic Solution: Indicated for the treatment of open-angle glaucoma administration of an ophthalmic muscarinic __________ promotes pupil ______________, which then __________ the flow of aqueous humor from the eye leading to ____________ intraocular pressure.
Pilocarpine (Isopto Carpine, Salagen), agonist, constriction, enhances, lowered
Muscarinic Receptor Agonists - Selected Uses of Muscarinic Receptor Agonists: __________________ (_______________________________) - Oral tablets: Treatment of dry mouth (xerostomia) from salivary gland ________________ secondary to radiation therapy of head and neck ________, as well as dry mouth associated with ________ syndrome (an autoimmune condition in which autoantibodies injure salivary and lacrimal glands).
Pilocarpine (Isopto Carpine, Salagen), hypofunction, cancer, Sjögren
Muscarinic Receptor Agonists - Classification of Muscarinic Receptor Agonists by Origin: Naturally Occurring Muscarinic Agonist: _________________ is the major alkaloid obtained from the leaves of South American shrubs of the genus Pilocarpus. Historically, South American natives have chewed the leaves of Pilocarpus plants to promote ____________. Today, the chief use of pilocarpine is to promote pupil _______________ (miosis) in the glaucoma patient in order to _________ intraocular pressure (IOP).
Pilocarpine, salivation, constriction, reduce
Mechanism of action and pharmacological basis of using inhaled anticholinergics in the treatment of COPD (and asthma): Although predominately used in the treatment of COPD, the Spiriva ___________ formulation of tiotropium has recently been approved for maintenance treatment of __________. More clinical trials may begin to show the ___________ of LAMAs in the maintenance treatment of asthma.
Respimat, asthma, efficacy
Classification of neuromuscular blockers based on mechanism of action: _____________________ (___________) injection: a ________________ neuromuscular blocker
Succinylcholine (Anectine), depolarizing
Examples of drugs with high rates of anticholinergic activity - Tricyclic antidepressants (1):
amitriptyline (Elavil)
Reversal of the actions of competitive neuromuscular blockers: The most common strategy is the administration by injection of an _________________________ agent such as ________________ (______________) injection or ___________________ (_______).
anticholinesterase, neostigmine (Prostigmin), edrophonium (Enlon)
Selected therapeutic uses of the belladonna alkaloids as anticholinergic agents - Atropine Sulfate: IV or IM injection as an ____________ for _____________________ pesticide or ____________ poisoning
antidote, organophosphate, nerve gas
Selected therapeutic uses of the belladonna alkaloids as anticholinergic agents - Hyoscyamine sulfate (Anaspaz, HyoMax, Levbid, Levsin, Levsinex): Oral and injection dosage forms as a gastrointestinal and urinary __________________ to control gastric secretion, visceral spasm, hypermotility in spastic colitis, abdominal cramps, and spastic bladder
antispasmodic
Important patient counseling information: Inhaled anticholinergics, especially LAMAs, should NOT be used "___________" to manage exacerbations of COPD symptoms or as a _______-relief or _________ inhaler for acute breathing problems (in COPD or asthma). For flare-ups/exacerbations and quick-relief, inhaled ____________ (a short-acting selective ________ agonist) is preferred.
as needed, quick, rescue, albuterol, beta2
Selected therapeutic uses of the belladonna alkaloids as anticholinergic agents - Atropine Sulfate: IV injection for the treatment of __________________ (__) heart block (impaired conduction from _____ to ____________) and/or severe _______________; ineffective for Type II ________-degree or ________-degree atrioventricular heart block
atrioventricular, AV, atria, ventricles, bradycardia, second, third
Anticholinergic Drugs (Muscarinic Receptor Antagonists): Classification of anticholinergic drugs by origin - Naturally occurring alkaloids (_____________ alkaloids) from the Atropa belladonna (Solanaceae) plants (deadly ______________)
belladonna, nightshade
Anticholinergic Drugs (Muscarinic Receptor Antagonists) - Drugs that ________ muscarinic receptors and _________ parasympathetic responses
block, inhibit
Mechanism of action and pharmacological basis of using inhaled anticholinergics in the treatment of COPD (and asthma): Inhaled anticholinergic agents ______________ antagonize the binding of acetylcholine to muscarinic receptors and __________ the actions of acetylcholine at muscarinic receptors in bronchial smooth muscle (that is, inhibition of bronchial smooth muscle contraction). These agents __________ bronchodilation, _____________ airway resistance, and ___________ airflow in the obstructed airways. Inhaled anticholinergics are most effective in the diseased, constricted airway. When used daily as a maintenance treatment, LAMAs appear to promote a ______________ opening of the airways.
competitively, inhibit, promote, decrease, enhance, sustained
Linaclotide (Linzess) oral capsules: Linaclotide (Linzess) is approved for the treatment of chronic idiopathic ________________ in adults and irritable bowel syndrome with ______________ (IBS-___) in adults. Linaclotide and its active metabolite bind and agonize guanylate cyclase-C on the luminal surface of intestinal epithelium, which increases chloride and bicarbonate secretion into the intestinal lumen. Increased extracellular cGMP may decrease visceral pain by reducing pain sensing nerve activity. ____________ (20%) is the most commonly reported adverse effect of linaclotide.
constipation, constipation, C, diarrhea
Lubiprostone (Amitiza) oral capsules: Lubiprostone (Amitiza) is approved for the treatment of chronic idiopathic ________________ in adults, irritable bowel syndrome with ________________ (IBS-__) in in women 18 years and older, and opioid-induced constipation in adults with chronic non-cancer pain. Lubiprostone is a locally acting chloride channel activator that enhances a chloride-rich intestinal fluid secretion. ___________ (29%), ______________ (12%), and headache (11%) are the most commonly reported adverse reactions.
constipation, constipation, C, nausea, diarrhea
Classic anticholinergic drug actions: Urinary system: _______________ bladder tone and __________ of the outlet (urinary ___________).
decreased, closure, retention
Classic anticholinergic drug actions: Salivary gland and thermoregulatory sweat gland: ______________ salivary gland secretion (_____ mouth, ____ throat) and _____________ sweating (____ skin and ___________ body temperature).
decreased, dry, dry, decreased, dry, elevated
Succinylcholine has a very high affinity for nicotinic muscle receptors and (similar to acetylcholine) produces ___________________ of the motor end-plate at the neuromuscular junction. However, because of a relatively high _______________ to acetylcholinesterase, succinylcholine produces a more ________________ and sustained depolarization at the motor end-plate than does acetylcholine. After a single IV dose of succinylcholine, transient twitching or fasciculation of the skeletal muscles occurs secondary to sustained __________________ (phase I block). However, very quickly after prolonged ___________________ has occurred, phase II neuromuscular block begins and the skeletal muscle fibers are no longer _____________ to endogenous acetylcholine (desensitization). Interestingly, in patients with _______________________, succinylcholine produces an _______________ phase II block without an initial phase I block. Succinylcholine has an ultra-_______ onset and duration and is useful for facilitating endotracheal _________________.
depolarization, resistance, prolonged, depolarization, depolarization, responsive, myasthenia gravis, immediate, short, intubation
Eluxadoline (Viberzi) oral tablets: Eluxadoline (Viberzi) is approved for the treatment of irritable bowel syndrome with __________ (IBS-__) in adults. Eluxadoline is a mixed mu opioid receptor agonist, delta opioid receptor antagonist, and kappa opioid receptor agonist which acts locally to reduce abdominal pain and ____________ in patients with IBS-__ without _______________ side effects. Warnings and precautions include possible sphincter of Oddi spasm resulting in pancreatitis or elevated hepatic enzymes; most often occurs during the first week of treatment and resolves with discontinuation of therapy.
diarrhea, D, diarrhea, D, constipating
Anticholinergic Drugs (Muscarinic Receptor Antagonists): Semi-synthetic or synthetic congeners/analogs of atropine and related drugs - Antispasmodic for Irritable Bowel Syndrome (IBS) (1):
dicyclomine (Bentyl)
Classic anticholinergic drug actions: Ophthalmic: pupil __________ (mydriasis) (bright light sensitivity), ciliary muscle ______________ (blurred near vision), and lacrimal gland ____________ (dry eyes)
dilation, relaxation, inhibition
Anticholinesterase Agents (Cholinesterase Inhibitors): Classification of anticholinesterase/cholinesterase inhibitors by mechanism of action - Reversible, competitive (non-covalent) inhibitors: Compete _________ with acetylcholine for ___________ to the active center of cholinesterase enzymes (competitive inhibition) leading to ________________ ACh _______________ and a significant ___________ in cholinergic activity
directly, binding, decreased, breakdown, increase
Adverse effect profile of dicyclomine and hyoscyamine: The most common adverse effects: dry mouth, constipation, urinary retention, and blurred vision. Additional adverse reactions: ___________, _____________ (may impair mental alertness), weakness, and nervousness. These CNS effects appear to be more common in the _______.
dizziness, drowsiness, elderly
Selected therapeutic uses of the belladonna alkaloids as anticholinergic agents - Mixed belladonna alkaloids with phenobarbital (Donnatal): Compounded oral tri-mix "green or purple lizard" (Donnatol elixir, lidocaine viscous, and an antacid/anti-gas suspension) for the treatment of severe ____________ and oral dosage forms for the treatment of irritable bowel syndrome and acute enterocolitis
dyspepsia
Anticholinergic Drugs (Muscarinic Receptor Antagonists): Semi-synthetic or synthetic congeners/analogs of atropine and related drugs - Older agent for symptomatic relief in various spastic urinary tract conditions (1):
flavoxate (FlavoxATE)
Therapeutic uses of dicyclomine and hyoscyamine: For the treatment of ______________ bowel disorders/_____ and other gastrointestinal motility disturbances associated with spasms, cramping, and pain.
functional, IBS
Irritable bowel syndrome (IBS) is a _____________ disorder of the gastrointestinal tract. After a thorough examination, there is no evidence of ____________ in this disorder (thus the term functional). Signs and symptoms include abdominal _______________, cramping, pain, complaints of bloating and fullness, and diarrhea and/or constipation. Patients with predominant ____________ are characterized as having IBS-D. Patients with predominant _________________ are characterized as having IBS-C. Note that although anti-spasmodic/anticholinergics may lessen cramping and pain, these agents are ____ ideal for IBS-C or idiopathic constipation because these drugs will __________ the constipation. IBS is a chronic condition that fluctuates with ______ and psychosocial ________. Many IBS patients have a history of _______________ or __________ disorders.
functional, pathology, discomfort, diarrhea, constipation, not, worsen, diet, stress, depressive, anxiety
Adverse actions of succinylcholine include: mast cell histamine release (risk of bronchospasm, hypotension), rapid release of intracellular K+ (risk of hyperkalemia), risk of malignant ________________* when combined with a general anesthetic (muscle rigidity, hyperthermia, metabolic acidosis, and tachycardia due to intense Ca2+ from muscle): *Treatment of choice for malignant hyperthermia is IV administration of ______________ (___________), which blocks _______ release from skeletal muscle.
hyperthermia, dantrolene (Dantrium), Ca2+
Mechanism of action of anticholinergics in the treatment of overactive urinary bladder: Urinary ______________ (difficulty with voluntary prevention of urination) secondary to _____________ urinary bladder (due to excessive parasympathetic tone and muscarinic receptor stimulation) is the most common cause of urinary _________________ in later middle-age and elderly patients. This condition can be successfully managed with muscarinic receptor _____________. By _____________ urinary tract muscarinic receptors and _____________ excessive parasympathetic tone, these agents ___________ intravesicular (internal bladder) pressure, increase bladder ___________, and ________ the frequency of detrusor smooth muscle contractions in the bladder wall. Anticholinergics may also diminish bladder sensation during filling and thus decrease the sense of ___________. It should be noted that anticholinergics may be used to treat similar conditions: nocturnal enuresis (bed wetting) in children and patients with spastic paraplegia (a complication of paralysis) by reducing urinary frequency and increasing bladder capacity.
incontinence, overactive, incontinence, antagonists, blocking, reducing, decrease, capacity, reduce, urgency
Classic anticholinergic drug actions: Cardiovascular: _____________ heart rate, conduction velocity, and contractility (_______________ and ______________).
increased, tachycardia, palpitations
Anticholinesterase Agents (Cholinesterase Inhibitors) - Drugs that __________ promote cholinergic receptor _______________ (both muscarinic and nicotinic) by inhibiting acetylcholinesterase (AChE) to _______ acetylcholine levels and activity
indirectly, stimulation, raise
Pharmacological basis for use of cholinesterase inhibitors in Alzheimer's disease: Anticholinesterase (cholinesterase inhibitors) ____________ the enzymatic breakdown of acetylcholine and ___________ cholinergic transmission at residual synapses in the Alzheimer's brain. Most clinical trials demonstrate that treatment with an anticholinesterase agent results in a modest, but statistically significant, ___________ of the decline in cognitive test performance, although there is *no evidence for __________ or slowing of pathological progression of disease.*
inhibit, enhance, slowing, reversal
Classic anticholinergic drug actions: Gastrointestinal: ____________of gastrointestinal motility, peristalsis, and secretion (__________________).
inhibition, constipation
Strategies for reversing the effects of neuromuscular blockers: Reversal of the actions of succinylcholine (depolarizing neuromuscular blocker) and the curious scenario of plasma pseudocholinesterase deficiency - Although, in theory, cholinesterase _____________ should have the ability to at least ___________ reverse the effects of succinylcholine, in practice, due to the ____________ duration of succinylcholine (6-11minutes), physicians allow patients to continue to receive _______________ support until the drug is eliminated by endogenous cholinesterase. However, although relatively rare, patients with an inherited pseudocholinesterase ________________ can experience greatly _____________ paralysis from succinylcholine due to a much slower rate of metabolic ________________.
inhibitors, partially, ultrashort, respiratory, deficiency, sustained, breakdown
Inhaled muscarinic receptor antagonist bronchodilators used in the treatment of chronic obstructive pulmonary disease (COPD) - Short-acting inhaled muscarinic antagonist (anticholinergic) (SAMA): ________________________ inhalation aerosol, inhalation solution, intranasal solution: short-acting (_______ times daily) inhalation aerosol and solution as a bronchodilator for the maintenance treatment of _________; intranasal solution for the relief of rhinorrhea associated with allergic rhinitis
ipratropium (Atrovent), four, COPD
Selected therapeutic uses of the belladonna alkaloids as anticholinergic agents - Hyoscyamine sulfate (Anaspaz, HyoMax, Levbid, Levsin, Levsinex): Oral and injection dosage forms to relieve symptoms in intestinal disorders, including _____________________________ (_____), diverticulitis, infant colic, and biliary colic
irritable bowel syndrome, IBS
Anticholinesterase Agents (Cholinesterase Inhibitors): Classification of anticholinesterase/cholinesterase inhibitors by mechanism of action - Irreversible organophosphate (covalent) inhibitors: Organophosphates from a stable, _____-lasting _________________________ (covalent modification) of the active center of AChE leading to virtually ____________ inactivation of enzyme activity and significantly sustained ____________ of cholinergic activity
long, alkylphosphorylation, irreversible, elevations
Muscarinic Receptor Agonists - Drugs that directly stimulate muscarinic receptors resulting in effects that ________ physiological parasympathetic/cholinergic responses
mimic
Adverse effects and warnings for varenicline: The most common adverse reactions reported for varenicline include ________ (30%), abnormal __________ (e.g., vivid, unusual, or strange), constipation, flatulence, and vomiting.
nausea, dreams
Most common adverse effects reported for anticholinesterase agents in the treatment of Alzheimer's disease: Gastrointestinal adverse effects including __________, __________, abdominal __________, and ___________ can be significant and at times severe at higher than the recommended dose. This is particularly true for the 23 mg daily dose of ______________ (__________). In most patients, the nausea, abdominal distress, and loose stools are more frequent upon ________ therapy, however, the frequency and intensity of these adverse effects usually diminish over _______.
nausea, vomiting, distress, diarrhea, donepezil, Aricept, initial, time
Pharmacological basis for use of cholinesterase inhibitors in Alzheimer's disease: A major pathological feature of Alzheimer's disease is the progressive development of *_________________ tangles and __________ plaques* in brain tissue, particularly in the ___________ cortex. In concert with these changes, *there is also __________ and __________________ of the cholinergic neurons that normally support higher order _____________ functions (reasoning, analyzing, sequencing, memory, critical thinking, personality) in the cerebral cortex.* This leads to a major neurochemical disturbance in Alzheimer's disease: a *deficiency of ________________ and ______________ function.* It is thought that an acetylcholine deficiency in the cerebral cortex contributes to the development of ___________ (neurocognitive disorder) in Alzheimer's patients. *Alzheimer's disease is the most common cause of dementia in our society.*
neurofibrillary, amyloid, cerebral, atrophy, degeneration, cognitive, acetylcholine, cholinergic, dementia
Warning for serious _________________ events for Chantix: Advise patients and caregivers that the patient should _______ taking Chantix and contact a healthcare provider immediately if agitation, hostility, depressed mood, or changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior while __________ Chantix or shortly after _________________ Chantix.
neuropsychiatric, stop, taking, discontinuing
Patients should not use ___________ replacement products while taking Chantix.
nicotine
Mechanism of action of varenicline: Because of partial agonist activity, varenicline stimulates these neuronal __________ receptors, but at a significantly _______ level than nicotine: in the presence of varenicline, the stimulatory actions of nicotine are _______________ and the patient is ______ likely to experience the sense of pleasure-reward and reinforcement from nicotine use. The goal is for the patient to stop using ____________ products.
nicotinic, lower, diminished, less, tobacco
Therapeutic uses of neuromuscular blocking agents: Neuromuscular blockers are drugs that bind to ___________ receptors on __________ muscle, inhibit neuromuscular transmission, and induce skeletal muscle relaxation (______________________); used for inpatients and outpatients as an adjunct to general ____________, to facilitate tracheal intubation, and to provide skeletal muscle relaxation during surgery or ______________ ventilation in the ICU.
nicotinic, skeletal, flaccid paralysis, anesthesia, mechanical
Neuromuscular Blockers: Drugs that block ___________ receptors on __________ muscle in order to induce skeletal muscle ___________ as an aid to ____________ procedures
nicotinic, skeletal, paralysis, surgical
Possible approaches to quitting and Chantix therapy: FIXED QUIT APPROACH: Begin Chantix, and then quit smoking after _____________. FLEXIBLE QUIT APPROACH: Begin Chantix, and then quit smoking within ______________. GRADUAL QUIT APPROACH: Begin Chantix, and then gradually reduce smoking to quit within ____________.
one week, one month, 12 weeks
Urinary anticholinergics: *Note: _____________ OTC (__________ for Women) 4-day transdermal system is only indicated for women due to concerns of OTC access, which may place males with benign prostatic hyperplasia (BPH) at risk for ______________ urinary retention if taking an _________________.
oxybutynin, Oxytrol, worsening, anticholinergic
Mechanism of action of varenicline: Varenicline is a nicotinic receptor __________ agonist indicated for use as an aid in smoking cessation treatment. Varenicline is a partial agonist at a nicotinic neuronal receptor subtype (Nneuronal) in the CNS that contributes to _______________ release in the pleasure-reward and reinforcement system. When using tobacco products, nicotine rapidly __________ the blood-brain barrier and provokes strong pleasure-reward actions through ______________ the release of dopamine and excitatory amino acid neurotransmitters in the CNS (this is the basis of nicotine _________________).
partial, dopamine, crosses, promoting, dependence
Selected therapeutic uses of the belladonna alkaloids as anticholinergic agents - Scopamine bromide (Scopace, Transderm-Scop, Isopto Hyoscine): Transdermal patch for the ____________ of nausea and vomiting associated with _______________________ as well as prevention of postoperative nausea and vomiting; off-label use for sialorrhea (excessive drooling)
prevention, motion sickness
Classic anticholinergic drug actions: Respiratory: ____________ of bronchial smooth muscle (____________________) and ________________ bronchial mucous secretion (inhaled anticholinergics are used in COPD).
relaxation, bronchodilation, decreased
Anticholinesterase Agents (Cholinesterase Inhibitors): Classification of anticholinesterase/cholinesterase inhibitors by mechanism of action - Slowly reversible carbamate (covalent) inhibitors ('___________'): Binding of these agents results in covalent modification (_________________) of AChE, which ___________ the enzyme from actively _______________ acetylcholine leading to a significant _____________ in cholinergic activity
stigmines, carbamoylation, prevents, hydrolyzing, increase
Competitive neuromuscular blockers compete with ACh at skeletal muscle nicotinic receptors and block ACh from _____________ skeletal muscle, which leads to _____________ and flaccid paralysis; these agents are based structurally on the natural product tubocurarine, which is an alkaloid and active principle found in curare; curare is a relatively generic term used to describe various South American arrow poisons. Note: ______________ (______________) is the only available _______________________ short-acting agent: alternative to succinylcholine for endotracheal intubation.
stimulating, relaxation, mivacurium (Mivacron), non-depolarizing
Drugs that target nicotinic receptors: _____________(Chantix) oral tablets: a major smoking ____________ treatment
varenicline, cessation
Knowledge Application Questions: Cholinergic Pharmacology: A 29-year-old female who has tried on multiple occasions to stop smoking by using nicotine replacement products, receives a prescription for varenicline (Chantix). The patient has informed the physician of plans to conceive and asks about safety of the medication in pregnancy and lactation. Which of the following are appropriate patient counseling points for this patient? *(Select all that apply)* A. The patient may begin Chantix, and then quit smoking after one week. B. The patient may begin Chantix, and then quit smoking within one month. C. The patient may begin Chantix, and then gradually quit smoking within 12 weeks. D. The most common side effects of Chantix are nausea, unusual (e.g., vivid, strange) dreams, constipation, flatulence, and vomiting. E. If agitation, hostility, changes in mood, changes in behavior or thinking, abnormal thoughts, or thoughts that include self-harm, then contact the physician immediately. F. The patient may use a nicotine replacement product, such as nicotine gum or patches, while being treated with Chantix. G. The incidence of adverse pregnancy outcomes following maternal use of varenicline is not greater in comparison to pregnancy outcomes of pregnant patients who smoke. H. It is not known if varenicline is present in breast milk. According to the manufacturer, the decision to breastfeed during treatment should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Infants exposed via breast milk should be monitored for seizures or excessive vomiting.
A, B, C, D, E, G, H
Knowledge Application Questions: Cholinergic Pharmacology: An 82-year-old with moderate-stage Alzheimer's disease is prescribed a combination of memantine extended-release, 7 mg, and donepezil, 10 mg, (Namzaric), one capsule daily in the evening. The patient's caregiver arrives to pick up the prescription. Which of the following statements are appropriate and accurate counseling statements? *(Select all that apply)* A. "This medication can be taken without regard to meals. The medication should not be crushed, but the capsule can be broken open and the contents sprinkled on a soft food like applesauce." B. "The most common side effects of this medication are dry mouth, constipation, and urinary retention." C. "This medication may cause loose stools, diarrhea, nausea, and cramping. Although these side effects usually lessen or resolve in 1 to 3 weeks, if there is worsening diarrhea and vomiting, please contact the doctor immediately." D. "There are two medicines in this product. One of the medications may cause dizziness, feelings of being anxious or agitated, or increased confusion. Please contact the doctor if these effects occur." E. "This medication will greatly improve memory, as well as everyday function."
A, C, D
Inhaled muscarinic receptor antagonist bronchodilators used in the treatment of chronic obstructive pulmonary disease (COPD) - Inhaled long-acting muscarinic antagonists (anticholinergic) (LAMAs): ______________ bromide (Tudorza Pressair) inhalation powder: indicated for ______-daily long-term, maintenance treatment of bronchospasm associated with COPD ___________________ (Seebri Neohaler) inhalation powder: indicated for _______-daily long-term, maintenance treatment of bronchospasm associated with COPD ______________ bromide (Spiriva Handihaler) inhalation powder and (Respimat) inhalation aerosol: indicated for the long-term, ______-daily maintenance treatment of bronchospasm associated with COPD. Respimat only: Maintenance treatment of _________ in patients 12 years and older. _________________ bromide (Incruse Ellipta) inhalation powder: indicated for ______-daily maintenance treatment of airflow obstruction in patients with COPD
Aclidinium, twice, glycopyrrolate, twice, tiotropium, once, asthma, umeclidinium, once
Knowledge Application Questions: Cholinergic Pharmacology: A 22-year-old college student visits a clinic with complaints of abdominal pain and discomfort, bloating, and constipation. Bowel movements are only once every 10-12 days, and the stools are hard and painful to pass. The patient reports that symptoms become worse under psychosocial stress. The patient admits to having a poor diet, little physical activity, poor sleep habits, and anxiety related to a personal relationship. After examination and testing, the physician establishes a diagnosis of IBS-C. Which of the following drug products are an option for this patient? *(Select all that apply)* A. hyoscyamine (Levsin) B. linaclotide (Linzess) C. dicyclomine (Bentyl) D. lubiprostone (Amitiza) E. eluxadoline (Viberzi)
B, D
Knowledge Application Questions: Cholinergic Pharmacology: A healthy-appearing 46-year-old female visits with a physician regarding sudden urinary urgency, frequent urination, decreased urinary control, and what the patient describes as "wetting accidents". Since the patient has a strong family history of type 2 diabetes, the physician orders blood glucose testing. The patient's fasting glucose and posprandial (after a meal) glucose are in the normal range. The patient's vital signs are normal and there is nothing remarkable in the past medical history. The physician determines that this patient is experiencing overactive bladder (OAB) and explains to the patient that OAB is the most common cause of urinary incontinence in middle and older ages. Which of the following are appropriate pharmacological strategies to manage OAB in this patient? (*Select All That Apply*) A. treatment with an alpha blocker B. treatment with an anticholinergic C. treatment with a PDE V inhibitor D. treatment with a beta3 agonist
B, D
Knowledge Application Questions: Cholinergic Pharmacology: A patient receives a diagnosis of COPD. When discussing treatment options, the patient requests a once-daily medication because the patient is already taking multiple medications for other conditions. Which of the following COPD strategies are best for this patient? A. ipratropium (Atrovent) inhalation aerosol B. tiotropium (Spiriva) Handihaler or Respimat C. glycopyrrolate (Seebri Neohaler) inhalation powder D. aclidinium (Tudorza Pressair) inhalation powder E. umeclidnium (Incruse Ellipta) inhalation powder
B, E
Muscarinic Receptor Agonists - Selected Uses of Muscarinic Receptor Agonists: ____________________ (______________) Oral Tablets - Indicated for the treatment of postoperative (after abdominal or pelvic surgery) and postpartum (after childbirth) non-obstructive (functional) urinary ___________/difficult urination, secondary to temporary autonomic nerve ________ and neurogenic _______ (lack of tone) of the urinary bladder (resulting in a _____________ ability of the bladder smooth muscle to ___________).
Bethanechol (Urecholine), retention, injury, atony, decreased, contract
