Lecture 34/35 Flashcards
Antimuscarinic
Chol. Acute Symptoms
-Cholinergic direct and indirect agonist: DUMBELS & 3 Bs
Anticholinergic Symptoms
Opposite of DUMBELS
DUMBELS + 3 Bs
D - Diarrhea ==> Constipation (Dicyclomine, bowel syndromes)
U - Urinary Frequency ==> Urinary retention (Oxybutynin, Tolterodine)
M - Miosis ==> Mydriasis (Tropicamide, dilate pupil)
B - Bradycardia ==> Tachycardia (Atropine, AtroPEN)
Bronochorrhea ==> Decreased lung secretions (COPD, Asthma)
Bronchoconstriction ==> Bronchodilation (Ipratropium, Tiotropium)
E - Emesis ==> Less GI effects (help in treatment of bowel syndromes)
L - Lacrimation ==> Dry eyes (side effect)
S - Salivation ==> Dry mouth (side effect)
Anticholinergic CNS Uses
- Parkinson’s and Antipsychotic drugs (Benztropine)
- Motion sickness (Scopolamine)
- Deter drug abuse (Atropine)
Cholinergic Antagonists
- AKA Anticholinergics
- Bind to ACh-esterase, does NOT trigger receptor effect
- Prevents cholinergic drug binding
- Muscarinic antagonists, ganglionic blockers, and neuromuscular blockers are all examples
Muscarinic Antagonists
- Wise therapeutic use
- Selectively blocks muscarinic synapses of parasympathetic NS and CNS
- Tissues innervated by both sym. and parasym. will show increased sym. NS activity
Ganglionic Blockers
- Antagonizes nicotinic receptors on symp. and parasymp. ganglion
- Few clinical uses
Neuromuscular Blockers
- Block ACh effects on skeletal muscles
- Muscle relaxants, intubation agents, and surgery uses
Atropine Origin
- Prototype muscarinic antagonist
- Tertiary amine from Atropa belladonna
- Increase pupil size and rosy cheeks
- All parts of the plant are poisonous
- Anticholinergic compounds in Belladonna: Atropine (d, l-hyoscamine) and Scopolamine (hyoscine)
Antimuscarinic Agents
- Atropine
- Scopolamine
- Ipratropium
- Cyclopentolate
- Tropicamide
Long-Acting
- Tiotropium
- Aclindium
Jimson Weed
- Potentially abused by teens and adolescents
- Active ingredients: Atropine and Scopolamine
- Benefits: treats cough, asthma, intestinal cramps, diarrhea, bedwetting
- Side effects: Mydriasis, hallucinogen, delirium, anticholinergic crisis, death
Types of Muscarinic Receptor Antagonist
- Naturally occurring alkaloids; Atropine and Scopolamine
- Semisynthetic - derivatives of alkaloids, differ from parent by body disposition or duration of action. Examples: Homatropine and Tropicamide (Mydriacyl) - shorter duration; Ipratropium, Tiotropium, Aclindinium - Quaternary amines and don’t cross BBB
- Synthetic compounds, some selectivity for subtypes of muscarinic receptors. Examples: Pirenzepine - treat GI ulcers in some countries; Tolterodine, Oxybutynin, and other - urinary incontinence
Selectivity of Muscarinic Receptor Antagonist
- Little or no blockage at nicotinic receptor sites
- Parasympathetic muscarinic receptors in different organs vary in their sensitivity to muscarinic receptor antagonist
Atropine + Doses
- Low doses - depresses salivation/bronchial secretions and sweating
- Moderate doses - pupil dilates, heart rate increases, accommodation for vision (far vision)
- Large doses - Antagonize bladder, GI control, inhibits peeing an decreases motility/tone of gut (constipation)
- Highest dose - greater inhibition of gastric motility/secretion
Atropine Doses + Effects
- Doses of Atropine and most related muscarinic receptor antagonists that decrease gastric motility and secretion ALSO affect:
1. Salivary secretion (Dry mouth)
2. Ocular accommodation (blurred vision)
3. Micturition (difference in urination)
4. GI tone (constipation)
5. Heart rate (especially unopposed sympathetic)
Differences in sensitivities NOT due to differing affinities of muscarinic receptors since Atropine is NOT selective to muscarinic subtypes. More likely due to degree that various organ are regulated by parasympathetic tone.
Muscarinic Antagonists affect following tissues:
- CNS
- Eye
- CV System
- Circulatory
- Respiratory Tract
- GI Tract
- Urinary Tract
CNS Antimuscarinics
- Atropine: clinical doses have little effects, high doses cause CNS excitation (hallucinations, delirium) and eventual depression which can result in cardiac and respiratory failure
- Scopolamine: clinical doses - CNS depression with drowsiness, amnesia, fatigue
CNS Therapeutic Uses
- Benztropine (Cogentin, Trihexyphenidyl (Artane)
- Help correct imbalance of too little dopamine and excess ACh (Parkinsons, after antipsychotic treatment)
- Side effects: Antichol. in PNS, confusion, memory problems
Scopolamine Therapeutic Uses
- 1 mg patch/3 days
- Prevents N/V from:
1. Motion sickness - apply to hairless area behind ear 4 hours before needed effect
2. Recovering from anesthesia and surgery - apply patch evening before surgery
Scopolamine Side Effects/Warning
-Dry mouth (66%)
-Drowsiness (16%)
WARNING: Chronic open-angle glaucoma patients should be monitored since mydriatic effect could increase IOP
Eye Antimuscarinics
- Tropicamide (Mydriacyl)
- Blocks cholinergic effect on papillary sphincter muscles of iris which:
1. Dilates pupil producing mydriasis
2. Paralyzes ciliary muscles - near objects are blurred (cycloplegia)
3. Abolishes normal papillary reflex constriction to light
Tropicamide Therapeutic Uses
- Examination of retina and optic disc
2. Decrease in painful ciliary muscle spasm
Tropicamide Side Effects
- Photophobia - intolerance of bright light
- Transient stinging and slight increase in IOP
- Rare: causes an attack of acute angle-closure glaucoma
Accomodation
Process by which eye changes focus to see objects at various distances
-Antimus. limits focusing to distant objects
Miosis
Constriction of sphincter muscle
-Need to constrict ciliary muscle for near vision
CV - Heart + Antimus. Dosing
- Moderate doses - progressive inccrease in heart rate by blocking M2 receptor on SA node
- Atropine can abolish vagal cardiac slowing or asystole produced by pressure on eyeballs, peritoneal stimulation, injection of contrast dye during cardiac catheterization
- Prevent/abolish bradycardia or asystole from ACh inhibitors - AtroPEN (injection, 0.5-2 mg)
Abboject
- Atropine
- Limited use to ICU for short-term intravenous
1. Used to blunt the increased vagal tone (lower pulse/BP) produced by intra-abdominal tract of ocular muscle manipulations
2. Increase heart rate or decrease AV-block when judged to be hemodynamically significant due to excess vagal tone (temporary fix)
Circulatory Effects
- Completely counteracts peripheral vasodilation and sharp fall in BP from systemic ACh agonist
- No effect when given alone due to lack of cholinergic innervation in blood vessels
Respiratory Tract Effects
- ACh acts on M3 receptors on airway to produce bronchoconstriction
- ACh increases secretions of nose, mouth, pharynx, and bronchi (bronochorrhea)
- Therefore, Anti-Ch inhibit these 2 effects leading to:
1. Dilation of bronchi (useful in asthma and COPD)
2. Inhibition of secretions (useful in anesthesia and exposure to cholinergic enhancing compounds)
Ipratropium
- Atrovent
- Short acting anticholinergic
- Inhalation
- Major anticholinergic therapy for COPD and asthma
- Quaternary ammonium, poorly absorbed
- Metabolized by ester hydrolysis
- No penetration of BBB
- Non-selective antagonists at M1, M2, and M3 receptors
- M2 blockage increases the release of presynaptic ACh which partially antagonizes the bronchodilation effect
- Quat. ammonium dissociates more slowly from M3 than M2
Tiotropium
- Spiriva
- Long acting inhalant
- Also Aclindium, Umeclindium
- Major anticholinergic therapies for COPD and asthma
- Second generation anticholinergic
- Quat. ammonium, decreased systemic absorption, no CNS effects
- Antagonist at M1, M2, and M3 receptors but dissociates MUCH more slowly at M3 than Ipratropium
- More selective antagonist of M3 which prolongs its activity
Ipratropium Bromide (Atrovent)
- Sympathetic relief of rhinorrhea occurring with common cold or seasonal allergies
- DOESN’T relieve nasal congestion or sneezing
GI Tract Effects
- Chol. input controls sphincter activity, GI motility, and acid secretions via vagal input
- Vagus = NOT EXCLUSIVE CONTROL OF GI
Other Regulators of GI
- Hydrochloric acid secretion - histamine and gastrin
- GI motility is highly regulated by the enteric plexus made up of neurons and cells including 5-HT, dopamine, and peptides (motilin, cholecystolenin, VP)
Belladonna and Opium Rectal Suppositories
- Active ingredients: morphine, atropine, and scopolamine
- Relieve moderate to severe pain associated with:
1. Rectal or bladder tenesmus (painful straining) that may occur post-op
2. Urethral spasms
Donnatol Extentabs
- Phenobarbital (sedative), hyoscyamine, atropine, scopolamine
- FDA: “Possible effective”
1. Adjunct therapy for IBS
2. Adjunctive therapy for duodenal ulcer
Dicyclomine
-Bentyl
-Treats functional bowel disorder and IBS
-Relieves smooth muscle spasms by 2 mechanisms:
1. Antimus. effect on smooth muscle
2. Direct effect on smooth muscle - antagonizes bradykinin and histamine-induced spasms in isolated ileum tissues
Side Effects - Anticholinergic (dry mouth, tachycardia, constipation….)
Urinary Tract Effects
- Mus. antagonists decreases normal tone and amplitudes of contractions of ureter and bladder
- Antichol. treat overactive bladder
- Non-pharmacological approaches - urge suppression and retraining of bladder
Urinary Tract Antimuscarinics
- Oxybutynin (Ditropan)
- Tolterodine (Detrol)
- *First line treatment for overactive bladder**
Symptoms of Overactive Bladder
- Urgency - sudden, compelling desire to pass urine
- Urgent urinary incontinence - involuntary leakage
- Frequency - voiding 7+ times per day
- Nocturia - voiding 4+ times per night
Oxybutynin
- Ditropan
- Various forms: gel, ER tablets, tablets, syrup, patch
- Patch may have decreases antichol. side effects
Tolterodine
- Detrol
- Tablets
- Treat overactive bladder
Overactive Bladder Antimuscarinic Precautions
- Care when treating patients at risk of urinary or gastric retention
- Care when patients have decreased GI motility
Side Effects: Dry mouth, urinary retention, constipation, blurred vision, and CNS effects (somnolence, confusion)
Overactive Bladder Facts
- Prevalence- 7-67% of men and 9-43% of women
- D/C of anticholinergics occurs in 4-31%
- Increased rates of D/C in first 30 days (43-83%), over half never refill medication due to side effects
NEED TO COUNSEL PATIENTS ON SE AND ADVERSE INTERACTIONS
Anesthesia Antimuscarinic Uses
-Used as a premedication for anesthesia
Uses
- Prevent/treat bradycardia
- Decrease salivary secretions
- Promotes bronchodilation
- Prevent vagus nerve induced bradycardia
Anesthesia Antimus. Contraindications
- Tachycardia patients
- Elderly patients or patients with conditions like CHF that can’t handle tachycardia
- Conditions like constipation and ileus will worsen
Opioid Abuse
- Atroine like compounds are added to some opioids to prevent abuse of compounds
- If taken in excess, the antichol. side effects make it unpleasant and potentially toxic
Hydrocodone
- Analgesic
- Relief of cough, nasal congestion, and moderate pain
- High abuse potential
Hycodan
- Hydrocodone + Homatropine
- Tablet and liquid form
Diphenoxylate (Lomotil)
- Schedule V
- Tablets and liquid
- Prescription - oral administration of treat diarrhea
- Dophenoxylate (schedule II) has abuse potential so they add Atropine to made the Lomotil
COPD
- Major cause of chronic morbidity/mortality
- 4th leading cause of death
- Definition: preventable, treatable pulmonary disease, airflow limits not FULLY reversible, progressive decline of airflow with abnormal inflammatory response of lung
Mechanisms of Airflow Limitation
- Small airway disease - inflammation, airway remodeling
2. Parenchymal destruction - destruction of alveolar, decrease in elastic recoil
COPD Risk Factors
- Genetic - polygenic disease, best document factor is alpha-1 antitrypnea, inhibits serine proteases
- Tobacco smoke - most common risk factor, pregnancy smoking can also affect lung growth in fetus
- Other inhalation exposure - chemicals, vapors, irritants, oxidative stress, age, respiratory infections, nutrition, comorbidities
COPD Stages
- Mild - chronic cough and sputum
- Moderate - SOB
- Severe - increased SOB, decreased exercise capacity, fatigue, repeated exacerbation
- Very severe - respiratory failure (PP of oxygen - <60 mmHg)
COPD Treatment - Mild to Very Severe
- Bronchodilators - cornerstone
- Short acting and as needed (inhalation)
Drugs
- Albuterol - B2 selective agonist, dilates bronchi
- Ipratropium - Antichol. antagonist of constriction by ACh
- Combinations (Duoneb, Combivent)
Combivent/Duoneb
- Ipratropium is minimally absorbed, quarternary ammonium
- Albuterol - selective B2 receptor agonist, little effect on B1 cardiac receptors if absorbed
WARNINGS: Caution with other anticholinergic drug use, patients with CV disorders (hypertension, arrhythmias)
COPD Treatment - Moderate to Very Severe
-Add long-acting bronchodilators
Drugs
- B2 selective agonists - Salmeterol (Serevent), Formoterol (Foradil)
- Cholinergic Antagonists - Tiotropium (Spiriva, dry powder), Incruse Ellipta)
- Combo LABA/LAAC - once daily: Vilanterol/Umeclindium (Anoro Ellipta), Olodaterol/Tiotropium (Stiolto Respimat)
COPD Treatment: Severe to Very Severe
- Add inhaled corticosteroids
- Inhaled anti-inflammatories with or without B2 agonists
- Fluticasone (Flovent), Fluticasone + Salmeterol (Advair HFA), Budesonide + Formoterol (Symbicort), Fluticasone + Vilanterol (Breo Ellipta)
- Oral corticosteroids in severe cases greatly increase side effects
- Can also add Theophylline (Theolair), an adenosine receptor antagonist (adenosine constricts bronchi) for those who need additional symptom control
Do you use lower or higher doses of inhaled corticosteroids when co-administered with CYP34A inhibitors?
Lower
Which drugs are <1% absorbed by the body?
- Mometasone
- Fluticasone
Roflumilast
- Daliresp
- Selective inhibitor of PDE4, a cAMP metabolizing enzyme in the lungs
- Decreases risk of COPD exacerbations in severe COPD with bronochorrhea
- NOT a bronchodilator, not indicated for relief of acute bronchospasm
- Side effects: diarrhea, weight loss, nausea, psychiatric reactions like depression, anxiety, etc.
