Cholinergic Drugs Flashcards
what receptor predominates in the heart
M2
Which neuronal pathways are specific to the sympathetic nervous system?
Specify the neurotransmitters and receptor types?
Sympathetic
Neurotransmitters: NE > Epi (DA); ACh
Receptors: α, β, (D), nAChR, mAChR
which neuronal pathways are unique to the parasympathetic nervous system?
which neurotransmiters?
which receptors?
Location, structural features, & MOA for M1 receptors
M1
Nerves
GPCR, Gq/11
IP3, DAG cascade
Location, structural features, & MOA for M2 receptors
M2
- Heart, nerves, smooth muscle
- GPCR, Gi/o
- Inhibition of cAMP production, activation of K+ channels
Location, structural features, & MOA for M3 receptors
M3
Glands, smooth muscle,endothelium
GPCR, Gq/11
IP3, DAG cascade
Location, structural features, & MOA for M4 receptors
M4
CNS
GPCR, Gi/o
Inhibition of cAMP production
Location, structural features, & MOA for M5 receptors
M5
CNS
GPCR, Gq/11
IP3, DAG cascade
Location, structural features, & MOA for NN receptors
NN
Postganglionic cell body, dendrites, CNS
α and β only
Examples: (α4)2(β4)3; (α7)5
Na+, K+ depolarizing ion channel
which receptors are predominate in smooth muscle?
M3, M2
predominate receptors in the eye
M3, M2
predominate receptors in the heart
predominate receptors in endothelium
M3
predominate receptors in glands
M3, M2
predominate receptors in the lungs
M3, M2
predominate receptors in GI/GU tracts
M3, M2
predominate receptors in CNS
M1-M5
role of cholinergic agonists
identify the subtypes and MOAs
mimic actions of ACh on nAChRs and mAChRs
Direct acting: directly stimulate muscarinic or nicotinic receptors
indirect acting: influence enzymes that then exert an effect on ACh
MOA for direct acting cholinergic agents
Identify 4 direct agonists
- MOA: agonists at cholinergic receptors
- Metabolized by acetylcholinesterase
- Acetylcholine
- Methacholine
- Carbachol
- Bethanechol
3 groups of AChE inhibitors
identify chemical traits of each
1) Alcohols
- reversible
- charged
- poorly absorbed
2) Carbamic acid esters
- reversible but longer lasting than alcohols
- charged
- poorly absorbed
3) Organophosphates
- irreversible (covalent)
- uncharged
- HIGHLY absorbed
what happens to eyes with direct parasympathetic stimulation?
Eye
Sphincter muscle of iris = Contraction (miosis)
Ciliary muscle = Contraction for near vision
what happens to the heart with direct parasympathetic stimulation?
Heart
Sinoatrial node = ↓ in rate (negative chronotropy)
Atria = ↓ in contractile strength (negative inotropy). ↓ in refractory period
AV node = ↓ in conduction velocity (negative dromotropy) & ↑ in refractory period
Ventricles = Small ↓ in contractile strength
what happens to the BVs with direct parasympathetic stimulation?
Blood vessels
Arteries = Dilation (via EDRF). Constriction (high-dose direct effect)
Veins = Dilation (via EDRF). Constriction (high-dose direct effect)
direct parasympathetic effect on the lungs
Lung
Bronchial muscle= Contraction (bronchoconstriction)
Bronchial glands = Stimulation
Direct parasympathetic effects on GI tract
Gastrointestinal tract
- Motility = Increase
- Sphincters = Relaxation
- Secretion = Stimulation
Direct parasympathetic effects on th GU tract
Urinary bladder
Detrusor = Contraction
Trigone and sphincter = Relaxation
Eye disorders treated using direct-acting cholinergic agonists
Diseases of the eye
- Glaucoma
- Accommodative esotropia: misalignment of the eyes caused by hypermetropic accomodative error
Primary pharmacological agent used to treat GI/GU disorders: GI/GU disorders
- Postoperative ileus
- Congenital megacolon
- Urinary retention
- Esophageal reflux
- Xerostomia d/t Sjögren syndrome
direct-acting cholinergic agonists
goal: stimulate parasympathetics
If a patient presents to the ED and there’s a suspicion of cholinergic agonist toxicity, what Sx might be present to confirm the Dx?
SLUDGE CRITERIA
S - salivation
L- lacrimation
U- urinary frequency
D- diaphoresis/diarrhea
G-GI cramps/pain
E- emesis
- or
DUMBBELs criteria
D- diaphoresis/diarrhea
U- urinary frequency
M - Miosis (pupil constriction)
B - Bronchospasm/bronchorrhea
E - Emesis
L - Lacrimation
S- Salivation
nausea, vomiting, diarrhea, urinary urgency, salivation, sweating, cutaneous vasodilation, bronchial constriction, increase in glandular secretion (SLUDGE)
SLUDGE Criteria
SLUDGE CRITERIA
S - salivation
L- lacrimation
U- urinary frequency
D- diaphoresis/diarrhea
G-GI cramps/pain
E- emesis
–signs of toxicity from direct acting cholinergic agonists targing mAChRs
DUMBBELS Criteria
DUMBBELS criteria
D- diaphoresis/diarrhea
U- urinary frequency
M - Miosis (pupil constriction)
B - Bronchospasm/bronchorrhea
E - Emesis
L - Lacrimation
S- Salivation
-signs of mAChR agonist toxicity
In what situations will use of muscarinic stimulants be contraindicated?
Muscarinic stimulants
- Predictable - nausea, vomiting, diarrhea, urinary urgency, salivation, sweating, cutaneous vasodilation, bronchial constriction, increase in glandular secretion (SLUDGE)
- Contraindicated in patients who have asthma, hyperthyroidism, coronary insufficiency, acid-peptic disease
If a patient presents with nicotine toxicity, what would you predict to uncover as the source during H&P?
What Sx would concern you the most and require emergent action?
If they do have nicotinic overstimulation from a direct-acting cholinergic agonist, how will you treat them?
Nicotinic stimulants
- Nicotine poisoning: from cigarettes and insecticides
- Acute toxicity includes CNS stimulation, skeletal muscle end plate depolarization, respiratory paralysis, hypertension, cardiac arrhythmias
Tx: atropine and parenteral anticonvulsants (diazepam, a benzodiazepine)
pt presents with dry mouth and gritty feeling eyes
Dx and Tx?
Dx: Sjögren syndrome
Tx with direct acting cholinergic agonists
Tx option 1: Cevimeline
•Oral tablet used to treat dry mouth (xerostomia) in patients with Sjögren syndrome
Tx option 2: Pilocarpine
•Approved for xerostomia treatment in patients with Sjögren syndrome or head and neck cancer treatment related xerostomia (PO), miosis during ophthalmic procedures (topical), and for glaucoma (topical)
Pure mAChR agoni
Drug of choice to induce miosis during eye surgery
use a direct acting cholinergic agonist
Acetylcholine
Approved for intraocular use during surgey, causes miosis (reduction in pupil size)
Carbachol
•Nonspecific cholinergic agonist that is used for the treatment of glaucoma or to produce miosis during surgery or ophthalmic examination
Indications and adverse effects for use of Bethanechol
Bethanechol: direct acting cholinergic agonist
- Selective mAChR agonist that primarily affects the urinary and GU tracts
- Tx: patients with urinary retention and heartburn
- Pro: Little cardiovascular stimulation
- Con: May produce urinary tract infection if sphincter fails to relax
Indications and adverse effects for use of Verencicline
Varenicline (Chantix)
- Use: FDA approved for smoking cessation
- Partial agonist that binds with high affinity and selectivity to α4β2 nAChRs (NN)
- MOA: stimulation and subsequent moderate, sustained release of mesolimbic dopamine are thought to reduce craving and withdrawal symptoms associated with smoking cessation
- Side Effects: Nausea is most common adverse effect;
Serious adverse effects: neuropsychiatric sx such as behavior change, agitation, depressed mood, suicidal ideation, and attempted and completed suicide
Most common clinical indications for use of INDIRECT acting cholinergic agonists
Use #1: Glaucoma
•Stimulation of mAChRs on the ciliary body facilitates aqueous humor outflow and reduces intraocular pressure (replaced by β-blockers, prostaglandins)
Use #2: Dementia (Alzheimer and Parkinson Diseases)
•Patients with Alzheimer Disease dementia have a deficiency of intact cholinergic neurons (particularly those extending from subcortical areas such as the nucleus basalis of Meynert)
Use #3: Antidote to anticholinergic poisoning
- From atropine, antihistamines, TCAs, sleep aids, cold preparations
- Sx – cutaneous vasodilation, anhidrosis, anhydrotic hyperthermia, nonreactive mydriasis, delirium, hallucinations, reduction/elimination of the desire to urinate
Use #4: Reversal of neuromuscular paralysis
Use #5: Myasthenia gravis
Sx and Tx for AChE inhibitor Toxicity
- AChE inhibitor toxicity
- Sx: SLUDGE or DUMBBELS, effects on NMJ
- Combination Tx needed:
- atropine (central & peripheral effects)
- maintenance of vital signs (respiratory is key)
- decontamination (remove clothing, wash skin)
- pralidoxime (cholinesterase regenerator)
Contrast effects of cholinergic agonists vs cholinergic antagonists
explain subgroups of cholinergic antagonists
which are most clinically useful?
Muscarinic and nicotinic subgroups
Antinicotinic agents
- Neuromuscular junction (skeletal muscle relaxants)
- Ganglia (rarely used)
Antimuscarinic agents
- CNS, nerves, heart, smooth muscle, glands, endothelium
- Block the effects of parasympathetic autonomic discharge
•The most clinically useful cholinergic antagonists
Prototype antimuscarinic agent: atropine
What are the following drugs used for?
Scopolamine
Drugs used for motion sickness
•Scopolamine
route: PO, injection, transdermal
What are the following drugs used for?
- Atropine
- Dicyclomine
- Glycopyrrolate
- Hyoscyamine
Drugs for gastrointestinal disorders (hypermobility, traveller’s diarrhea)
- Atropine**
- Dicyclomine
- Glycopyrrolate
- Hyoscyamine
Often combined w/opioid antidiarrheal drug to discourage abuse of the opioid agent
•Example: Lomotil - combination of atropine and diphenoxylate
What are the following drugs used for?
- Atropine
- Cyclopentolate
- Homatropine
- Scopolamine
- Tropicamide
Drugs used in ophthalmology
- Atropine
- Cyclopentolate
- Homatropine
- Scopolamine
- Tropicamide
Prob: prevent synechia formation in uveitis and iritis ( iris sticks to lens or cornea)
Tx: Homatropine & atropine
- Pros: Long-acting agents
- Mydriasis may last 6 hours to 12 days and cycloplegia persists about 10 hours to 14 days
ONLY use mAChR antagonists when cycloplegia or prolonged mydriasis (pupil dilation) is required.
Example: Refractive eye surgery (LASIK)
Otherwise: Use α-adrenergic receptor agonists are shorter-acting and produce less adverse effects
What are the following drugs used for?
- Ipratropium
- Tiotropium
Drugs used for respiratory disorders
- Ipratropium: 1st line therapy for asthma
- Tiotropium (longer acting): COPD Tx bc longer bronchodilator action
Both are inhalation mAChR antagonists (anticholinergic drugs)
side effect: dry mouth/throat
What are the following drugs used for?
- Darifenacin
- Oxybutynin
- Solifenacin
- Tolterodine
- Trospium
Drugs used for urinary disorders
•Oxybutynin
- selective M3 antagonist
- side effects: dry mouth/eyes (xerostomia), dizziness, constipation, blurred vision
These are M3 but have longer half-life and lower side effects
- Darifenacin
- Solifenacin
- Tolterodine
- Trospium
What are the following drugs used for?
•Atropine (+ pralidoxime)
Drugs used for cholinergic poisoning
•Atropine (+ pralidoxime): must use both together!
Causes:
- cholinesterase inhibitor insecticides
- wild mushrooms
- chemical warfare nerve gasses
- Antimuscarinic agents (atropine) are given to reduce mAChR stimulation
- No effective treatment at nAChR (pralidoxime)
- Atropine is useless in delayed-onset mushroom poisoning
- characterized by vomiting and nausea 6-12 hrs after ingestion and causes hepatic/renal cellular injury by amatoxins that inhibit RNA polymerase
What are the following drugs used for?
- Benztropine
- Biperiden
- Orphenadrine
- Procyclidine
- Trihexyphenidyl
Drugs used for movement disorders: Parkinson’s Ds
note: not as effective as dopaminergic tx
- Benztropine (3o amine)
- Biperiden
- Orphenadrine
- Procyclidine (3o amine)
- Trihexyphenidyl (3o amine)
what is the general effect of anticholinergic drugs
increase sympathetic tone
What effect would use anti-cholinergic drugs have on the following systems?
CNS
Eye
Cardio
Respiratory
GI
GU
Sweat Glands
CNS = Sedation, drowsiness, amnesia, hallucinations, tremor reduction
Eye = Pupil dilation, cycloplegia (ciliary muscle paralysis), loss of accommodation, secretion reduction
Cardio= Tachycardia
Respiratory =Bronchodilation and secretion reduction
GI tract = Reduce salivation, gastric secretion, prolonged gastric emptying time
GU tract = Urinary retention
Sweat glands = Suppression of thermoregulatory sweating by inhibiting sympathetic cholinergic nerve fibers (remember: no parasympathetic innervation of sweat glands)
Anticholinergics: adverse effects
Anticholinergics adverse effects if used to reduce GI secretions
mydriasis
cycloplegia
High systemic concentrations lead to block of parasympathetic function:
dry as a bone, blind as a bat, red as a beet, mad as a hatter, hot as a hare
•Tx: AChE inhibitors or symptomatically
Anticholinergics: contraindications
Anti-cholinergic Use Contraindications/caution:
don’t use in patient’s with the following:
- Glaucoma
- Prostatic hyperplasia
- Acid-peptic disease
