Cholinesrterase drugs Flashcards
Nicotinic Receptor location
Neuromuscular end plate, Skeletal muscle, Autonomic ganglion cells
Muscarinic Location
Nerve, heart and smooth muscle, Gelands and endothelium
Direct Acting CAg
Acetylcholine Bethanechol Carbachol Cevimeline Nicotine Pilocarpine
Indirect acting Rev CAg
Ambenonium Donepezil Edrophonium Galantamine Neostigmine Physostigmine Rivastigmine
Indirect Acting Irr CAg
Echothiophate
Cholinomimetic (cholinergic) Drugs Short acting
Edrophonium
Cholinomimetic (cholinergic) Drugs
Intermediate to long acting
Carbamates
Very long acting Cholinomimetic (cholinergic) Drugs
Parathion
ACETYLCHOLINE CL Susc, Musc, Nico
Very
intermediate
intermediare
Methacholine Susc, Musc, Nico
V Little, Very, Intermediate
CARBACHOL CL Susc, Musc, Nico
Neg, Little, intermediate
Betanechol Susc, Musc, nico
Neg, Little, none
Acetylcholine
Direct Acting (Muscarinic)
Metacholine (No nicotinic action, resistant to Ache, like carbachol and
bethanechol
Act on both M and N receptors. Activates M1-M3 receptors in all peripheral tissues
Miotic for Eye surgery
CNS stimulation, miosis, cyclospasm, bronchoconstriction, excessive GI
and GU smooth muscle contraction, increased secretory activity of
sweat gland, airway; vasodilation (arises from M3 activation and
requires intact endothelium – Nitric oxide mediated
Results to increased secretion, smooth muscle contraction (except in
vascular smooth muscles where it causes relaxation) and changes in
heart rate; very short-lived duration of action: 5-30 sec, rapidly
hydrolyzed by AChe
Bethanechol
Carbachol USP 0.01% W/V
1 ml vial
A pack of 1 vial
Direct Acting (Muscarinic)
Carbachol (act on both muscarinic and nicotinic receptors)
Act on both M receptors only. Activates M1-M3 receptors
Bladder and bowel atony (post-surgery or spinal cord injury); congenital
megacolon
Cyclospasm, Diarrhea, Urinary urgency, Vasodilation (similar MOA with
Ach), Reflex tachycardia, Sweating
Both are resistant to hydrolysis of Ache – longer duration of action
Carbachol – use for glaucoma as a miotic agent
Neostigmine (an indirect acting cholinomimetic) is also another drug
useful for bladder and bowel atony (non obstructive type)
Pilocarpine
Direct Acting (Muscarinic)
Cevimeline (M3 selective)
Activates M3 receptors in ciliary muscle causing contraction of ciliary
body to facilitate aqueous humor outflow and diminish its rate of
secretion; increase salivation
Glaucoma, Sjogren syndrome, Sicca Syndrome, head and neck
irradiation
Miosis, Blurring of vision, increase salivation, Hypertension (after brief
period of hypotension due to activation of sympathetic postganglionic
M1 receptors
No effect of nicotinic receptors
Nicotine
Direct Acting (Nicotinic)
Lobeline and Varenicline (selective partial agonist at nicotinic receptor with 12-24
hour duration of action)
Lobeline and Varenicline (selective partial agonist at nicotinic receptor with 12-24
hour duration of action)
Smoking cessation
Generalized ganglionic stimulation (hypertension, tachycardia, nausea, vomiting and diarrhea
Activates all autonomic post ganglionic neurons (both sympathetic and
parasympathetic, hence generalized ganglionic stimulation) and skeletal muscle nm endplates
Nicotine in the CNS is associated with greater release of dopamine in the mesolimbic system (addicting effect) Smoke with nicotine (non fatal dose); avoid eating (40mg/2 cigarette)
Low dose and initial high dose Nicotine
Stimulate receptors depolarization of membrane and influx of Na and Ca
Large dose Nicotine
Stimulation followed by prolonged blockade of repolarization
Receptor: becomes refractory to stimulation
Toxicity: convulsions, fasciculations, and paralysis
Treatment: Atropine for muscarinic; symptomatic
approach
Nicotine: PNS
Nicotine – same on both parasympathetic and sympathetic
•CARDIOVASCULAR –SYMPATHOMIMETIC
•GASTROINTESTINAL-PARASYMPATHOMIMETIC
•Prolonged exposure may result in depolarizing
blockade of the ganglia
Primary autoimmune autonomic failure –
example of effect suppression on nicotinic
receptor function at the autonomic ganglia
Nicotine: Abstinence Syndrome
Irritability, restlessness, anxiety, headache, insomnia, GIT upset increased appetite, irritability, restlessness, anxiety headache, insomnia, GIT upset, increased appetite, craving to start smoking.
• Begins 24 hrs and last for weeks
Muscarinic Toxicity
Seen in overdosage of muscarinic agonist and in types of
mushroom (Inocybe); Amanita muscaria
Atropine (Cholinergic antagonist)
CNS stimulation, miosis, blurring of vision, bronchoconstriction,
excessive gastrointestinal and genitourinary smooth muscle
activity, increase secretory activity of the sweat glands, airway,
gastrointestinal tract, lacrimal glands; vasodilation
Symptoms of muscarinic poisoning is essentially similar with
organophosphate poisoning minus symptoms of nicotinic excess
In organophosphates: they are long acting acetylcholinesterase
inhibitor or indirect acting cholinomimetic
Mushroom Poisoning Rapid oneset
RAPID ONSET 15-30 MIN AFTER INGESTION SIGNS OF MUSCARINIC EXCESS OR MUSCARINIC SUPPRESSION ATROPINE 1-2 MG IS RECOMMENDED
MP Delayed onset
6-12 HRS
HEPATIC AND RENAL CELL INJURY ATROPINE NOT RECOMMENDED
Edrophonium
Cholinomimetic (Indirect acting – Alcohol)
Inhibits acetylcholinesterase. Amplified endogenously released acetylcholine
Myasthenia gravis (diagnosis: tensilon test)
Differentiation of cholinergic crisis and myasthenic crisis
Reversal of neuromuscular blockade
Miosis, Salivation, Nausea, Vomiting, Diarrhea,
Bradycardia
IV, very short lived; 5-15 mins duration of action
Neostigmine
Cholinomimetic (Indirect acting – Alcohol)
Pyridostigmine, Physostigmine, Ambenonium, echothiophate
(organophosphate)
Indirect acting
Inhibits acetylcholinesterase. Amplifies endogenously released acetylcholine
Myasthenia gravis (treatment); reversal of nondepolarizing neuromuscular
blockade (Neostigmine), Glaucoma (Physostigmine, Echothiophate), Bladder
and Bowel atony (Neostigmine)
Miosis, Salivation, Nausea, Vomiting, Diarrhea, Bradycardia (need to coadministering Atropine in toxicity)
Muscarinic effects are blocked by Atropine
Neostigmine: poor lipid solubility, oral. DOA: 30mins-2 hours
Pyridostigmine: poor lipid solubility, oral. DOA: 4-8 hours
Echothiophate: moderate lipid solubility. DOA: 2-7 days
Myasthenia Gravis
Autoimmune destruction of nicotinic Ach receptors characterized by
fluctuating muscle weakness, ocular symptoms, bulbar symptoms
and proximal muscle weakness
Myasthenic Crisis
acute worsening of symptoms due to infection,
stress or undermedication
Cholinergic Crisis
excessive activation of cholinoceptors (skeletal
muscle weakness and parasympathetic signs) due to overmedication
Muscarinic excess:
Nausea, vomiting, diarrhea, urinary urgency,
vasodilation, reflex tachycardia, sweating, salivation
and bronchoconstriction
Rivastigmine
Cholinomimetic (Indirect acting – Alcohol)
Galantamine, Donezepil, Tacrine
Inhibits acetylcholinesterase. Amplifies endogenously released
acetylcholine
Alzheimer’s Disease
Miosis, Salivation, Nausea, Vomiting, Diarrhea, Bradycardia (need
to co-administer Atropine in toxicity)
Rivastigmine as transdermal patch
Donezepil combined with Memantine for Alzheimer’s Disease
Organophosphate poisoning
Diarrhea Urination Miosis Bronchospasm Bradycardia Excitation (Skeletal muscle and CNS) Lacrimation Sweating Salivation
Pralidoxime: for Organophosphate Poisoning
Cholinesterase regenerator, Antidote
Binds phosphorus of organophosphate. Breaks
organophosphate bond with cholinesterase. (regenerates
active acetylcholinesterase)
Antidote for early stage cholinesterase inhibitor poisoning
(organophosphate poisoning and nerve gas poisoning); can
relieve skeletal muscle and endplate block
Address both muscarinic and nicotinic symptoms
Must be administered before 6-8 hours of
organophosphate bond with cholinesterase occurs (before
the bond has aged (AGING) or turned into covalent bond:
Has oxime group which has high affinity for phosphorus
Atropine for Organophosphate Poisoning
Cholinergic antagonist (muscarinic)
Competitively blocks all muscarinic receptors
Mydriatic, cycloplegic, antidote for organophosphate poisoning
(first choice), Bradycardia, Hypersalivation, Decreased airway
secretion during general anesthesia
Mydriasis, Tachycardia, Cycloplegia, Skin Flushing, Delirium,
Hallucinations, Urinary retention, Constipation
Only muscarinic symptoms are reversed. No effect on the nicotinic
signs of toxicity
Notorious for causing hyperthermia in susceptible patients because
Atropine suppressed thermoregulatory sweating
Antimuscarinic Agents
Atropine Benztropine Cyclopentolate Darifenacin Fesoterodine Ipratropium Oxybutynin Scopolamine Solifenacin Tiotropium Tolterodine Trihexyphenidyl Tropicamide Trospium chloride
Ganglionic
Blockers
Nicotine
Hexamthonium
Mecamylamine
Neuromuscular
Blockers
Cisatracurium Pancuronium Rocuronium Succinylcholine Vecuronium
Antimuscarinic M1 selective
Pirenzepine
Nonselective Antimuscarinic
Atropine
Antinicotinic Ganglionic blocker
Hexamethonium
Neuromuscular blockers Antinicotinic
Tubocurarine
AChE Regenerator oximes
Pralidoxime
Atropine
ATROPA BELLADONA
DATURA STRAMONIUM
Cholinergic antagonist (muscarinic)
Homatropine, Cyclopentolate, Tropicamide
Competitively blocks all muscarinic receptors (salivary, bronchial
and sweat glands)
Mydriatic – from unopposed sympathetic dilator activity
Cycloplegia – due to weakness of ciliary muscle contraction; loss of
accommodation – no near vision focus
Antidote for organophosphate poisoning (1st choice, addressing
muscarinic excess), Bradycardia, Hypersalivation
Mydriasis, Tachycardia, Cycloplegia, Skin Flushing, Delirium,
Hallucinations, Urinary retention, Constipation, Dry eyes “Sandy
Eyes”
Cross BBB, just like physostigmine (an indirect-acting cholinomimetic)
Atropine Effects
CVS
• Low doses: Initial bradycardia (autoreceptors, M3)
• Moderate to high: tachycardia
• Little effect on blood pressure
LUNGS
• Limited use: Block of M2 receptors in postganglionic
parasympathetic fibers versus block in the M3
receptors in airway smooth muscle
• Valuable in some patients with asthma and in many
COPD patients
Benztropine
Cholinergic antagonist (muscarinic)
Biperiden, Trihexylphenidyl
Competitive blocks all muscarinic receptors
Restores neurotransmitter balance in the basal ganglia
Parkinson’s Disease
Blurring of vision, Dry eyes, Constipation, Dry mouth, Urinary
retention
The tremors associated with Parkinson disease is a result of relative
excess of cholinergic activity due to the deficiency of dopamine
activity in the basal ganglia stratum system. The role of cholinergic
antagonism is for tremor/rigidity improvement
Ipratropium
M receptor antagonist
Tiotropium, Glycopyrronium, Aclidinium, Umeclidinium
Blocks muscarinic receptors in bronchial smooth muscle.
Prevents vagal-stimulated bronchoconstriction
Acute asthma, COPD
Dry mouth, Blurred vision, includes all anti-cholinergic effects
Less toxic than beta agonist
Tiotropium and Umeclidinium have longer DOA.
Has no effect of the chronic inflammation aspect of asthma
Glycopyrronium – for COPD; anti-spasmodic and reduce salivation
Tiotropium – adjunct in pulmo rehab (increase exercise tolerance)
Scopolamine
Cholinergic antagonist (muscarinic)
Competitively blocks all muscarinic receptors Antagonizes histamine and serotonin
Motion sickness (M3 and M4 receptors), Decrease acid secretion in the GIT, Nausea and Vomiting
Drowsiness, Amnesia, Sedation, Blurring of vision, Dry
eyes, Constipation, Dry mouth, Urinary retention
For motion sickness, available in patch
Other name: hyoscine
Highest propensity to cause CNS symptoms compared to
all other anticholinergics
Scopolamine: Indication
MOTION SICKNESS
- Certain vestibular disorder and production of endolymph
- Scopolamine is one of the oldest remedies
- Given by IV or oral
- Patch with 48 to 72 hr effect
- Sedation and dry mouth
- OPHTHALMOLOGIC DISORDER
- EXAMINATION OF RETINA (Mydriasis)
- FUNDOSCOPIC EXAM (Cycloplegia)
- Eye drops or ointment
- RESPIRATORY
- Pre medication: atropine or scopolamine
- Ipratropium: synthetic analog of atropine
- tiotropium
Dicyclomine
Cholinergic antagonist (muscarinic)
Hyoscyamine, Glycopyrrolate
Competitively blocks muscarinic (M3) receptors
Inflammatory bowel disease, diarrhea, decrease acid secretion in GIT
Tachycardia, confusion, urinary retention, relative contraindicated
in patients with Glaucoma (increase intraocular pressure)
Quarternary amines, action remains on the periphery Unlike tertiary amines, like atropine, scopolamine can act centrally
as the cross the BBB
Oxybutynin
Cholinergic antagonist (muscarinic)
Darifenacin, Solifenacin, Tolterodine, Trospium, Imipramine, Fesoterodine
Slightly blocks M3 receptors
Reduces detrusor muscle tone
Urge incontinence, Post-operative bladder spasms (Prostatectomy)
Tachycardia, Constipation, Xerostomia, Increased IOP
May cause pruritus (available in patch)
Imipramine – tricyclic antidepressant with strong antimuscarinic Darifenacin and Solifenacin – M3 greater selectivity
Scopolamine: Indication Gut
INFLAMMATORY BLADDER DISORDER • BLADDER SPASM(Oxybutinin:M3) • UROLITHIASIS • Involuntary voiding in children • Trospium (nonselective) • Darifenacin and Solifenacin • Tolterodine and Fesoterodine • Urinary incontinence
Atropine Toxicity
- Signs/Symptoms – Hot as a hare, Dry as a bone, Red as a beet, blind as a bat and Mad as a hatter
- Caution use in infants (sensitive to atropine, hyperthermia effect)
- Can aggravate acute angle-closure glaucoma (mydriasis effect)
• Can precipitate further retention in patients with benign prostatic hyperplasia (relaxation of smooth muscle of
ureter and bladder wall
Hexamethonium
Cholinergic antagonist (Nicotinic)
Trimetaphan (blocks the receptor), Mecamylamine
Competitively blocks Nn nicotinic receptors
Hypertension (obsolete), Hypertensive emergencies
Postural hypotension, Dry mouth, Blurred vision,
Constipation, Sexual dysfunction, Tachycardia
Hemicholinium – blocks choline uptake (synthesis)
Hexamethonium – blocks the ion channel
Neuromuscular Blocking Drugs
Skeletal muscle relaxants
Nondepolarizing Drugs NMB
- Tubocurarine
- Pancuronium
- Atracurium
- Vecuronium
Depolarizing Drugs NMB
Succinylcholine
Succinylcholine
Depolarizing neuromuscular blocker
Short acting
6-11 mins in duration; 60-90 seconds in onset
Agonist at Ach-N receptors causing initial twitch (transient
contractions) then persistent depolarization (flaccid
paralysis) then followed by repolarization (paralysis)
Skeletal muscle relaxant during intubation and GA
Postop muscle pain, increased intragastric pressure
(aspiration risk) increased IOP; Malignant Hyperthermia
Dantrolene - antidode
Antimuscarinic Agents
Atropine Benztropine Cyclopentolate Darifenacin Fesoterodine Ipratropium Oxybutynin Scopolamine Solifenacin Tiotropium Tolterodine Trihexyphenidyl Tropicamide Trospium chloride
Ganglionic
Blockers
Nicotine
Hexamthonium
Mecamylamine
Neuromuscular
Blockers
Cisatracurium Pancuronium Rocuronium Succinylcholine Vecuronium
