Cholinergic Agonists and Antagonists Flashcards
Direct acting cholinergic agonists MOA
Bind to and activate muscarinic and nicotinic receptors –> many have effects on both receptors
Therapeutically useful drugs preferentially activate muscarinic receptors (located at parasympathetic effector organs and sweat glands)
Can be divided into choline esters (acetylcholine, methacholine, carbacol, bethanechol) and alkaloids
Direct effects of acetylcholine on cardiovascular system
Effect of small vs large doses of ACh on CVS
Vasodilation: endothelial M3 effect –> release of NO
Decrease in heart rate, rate of conduction in the SA and AV nodes and force of contraction - M2 effect
IV injection of small dose - vasodilation (M3) will cause fall in peripheral vascular resistance which will decrease the MAP –> will lead to reflex tachycardia (increased HR because the blood pressure is falling so the baroreceptors change the direct action of the drug)
IV injection in larger doses - vasodilation –> fall in PVR –> fall in MAP –> bradycardia M2 effect also occurs in addition to vasodilation and hypotension mediated by endothelial M3 receptors
Effect of acetylcholine on various organ systems (8)
Vasculature: release of NO and vasodilation –> decrease in BP (M3)
Iris: miosis
Ciliary muscle: accommodation of lens to near vision
Salivary, lacrimal and sweat glands: Increased secretions
Lungs: Bronchoconstriction and increased secretions
GI tract: Increased tone (M3), peristaltic activity and secretions and relaxation of sphincters
Urinary bladder: contraction of detrusor muscle and relaxation of sphincter –> voiding of urine
Heart: decreased heart rate, force of contraction and conduction velocity
Nicotinic effects of acetylcholine
If muscarinic effects are blocked by a muscarinic antagonist like atropine, last doses of ACh will produce nicotinic effects only (nothing will happen at low doses of ACh even when M receptors are blocked)
Increase in blood pressure and vasoconstriction due to stimulation of sympathetic ganglia and release of epinephrine from adrenal medulla
Choline Esters MOA and PK
Acetylcholine
Methacholine
Carbachol
Bethanechol
Are direct acting cholingeric agonists
Quaternary ammoniums –> poorly absorbed and distributed into CNS
Acetylcholine is rapidly hydrolysed by AChE but the other 3 are more resistant to hydrolysis by cholinesterase
Acetylcholine uses
No systemic therapeutic applications due to multiplicity of actions and rapid hydrolysis by both AChE and plasma BChE
Used to obtain rapid miosis after delivery of the lens in cataract surgery and other procedures where paid miosis is needed
Bethanechol MOA and uses
Direct acting muscarinic agonist
Used to treat
- post-operative and postpartum urinary retention
- atony of the urinary bladder
Carbachol MOA and uses
Direct acting muscarinic and nicotinic agonist
Used to treat miosis during surgery
Reduces intraocular pressure after cataract surgery
Methacholine MOA and uses
Direct acting muscarinic agonist
Used in diagnosis of bronchial airway hyperactivity in patients who do not have clinically apparent asthma –> It may be performed if a patient’s symptoms and spirometry do not clearly establish a diagnosis of asthma. The patient breathes in nebulized methacholine. The main result is the provocation concentration of methacholine that causes FEV1 to drop by 20%
Pilocarpine MOA and uses
Direct acting partial muscarinic agonist
Natural alkaloid and tertiary amine –> can enter the CNS
Stable to hydrolysis by AChE
Uses:
- Second line agent for open angle glaucoma
- Management of acute-angle closure glaucoma
- Treatment of dry mount due to radiotherapy for cancer of head and neck
- Treatment of dry mount caused by Sjogren’s syndrome
Adverse effects of muscarinic agonists
Increased sweating, salivation
Flushing (due to vasodilation of skin vessels)
Low blood pressure
Nausea
Abdominal pain and diarrhea
Bronchospasm
Pilocarpine can enter brain and cause CNS distrubances
Nicotine MOA and effects of different doses and uses
Natural alkaloid –> direct acting selective agonist of nicotinic receptor
Tertiary amine –> can enter brain
Use: smoking cessation therapy
Low dose: ganglionic stimulation by depolarisation. Response resembles simultaneous discharge of both parasympathetic and sympathetic nervous systems:
- CVS: Mainly sympathomimetic effects. Increase HR and BP due to catecholamine release from nerve terminals and adrenal medulla
- GI and urinary tracts: Mainly parasympathetic effects: nausea, vomiting, diarrhoea and voiding of urine
- Secretions: stimulation of salivary and bronchial secretions
High doses: Ganglionic and neuromuscular blockage due to sensitisation of receptors by prolonged depolarisation –> paralysis
Acute nicotine poisoning
Nausea, salivation, abdominal pain, vomiting, diarrhea, cold sweat, mental conduction and weakness
Decreased blood pressure and weak pulse
Death may occur from paralysis of respiratory muscles and/or central respiratory failure
Differences in MOA of indirect acting cholinergic agents
All inhibit acetylcholinesterase and increase concentration of endogenous acetylcholine
Edrophonium:
Binds reversibly to active site of AChE –> Enzyme-inhibitor complex doesn’t involve a covalent bond and is short-lived (only 2 to 10 minutes)
Carbamates:
Form a colavent bond with AChE –> enzyme-inhibitor bond spontaneously hydrolyses within 30 minutes to 6 hours
Organophosphates:
Phosphorylate AChE –> covalent bond formed is extremely stable and hydrolyses very slowly –> phosphorylated enzyme may undergo a process called ageing –> strengths the phosphorous-enzyme bond so it becomes irreversible
Effects of cholinesterase inhibitors on CNS, NMJ, eyes, glands, GI and urinary tracts
CNS: In low concentrations, liposoluble cholinesterase inhibitors cause CNS activation. In higher concentrations, they cause convulsions which may be followed by coma and respiratory arrest
NMJ: Increase strength of skeletal muscle contraction (Nm receptors)
Eyes: miosis and accommodation of lens to near vision
Salivary, lacrimal and sweat glands: Increased secretions
Lungs: Bronchoconstriction and increased secretions
GI tract: Increased tone (M3), peristaltic activity and secretions and relaxation of sphincters
Urinary bladder: contraction of detrusor muscle and relaxation of sphincter –> voiding of urine
Effects of cholinesterase inhibitors on cardiovascular system
Can activate both sympathetic and parasympathetic ganglia supplying the heart
Heart: parasympathetic effects predominate –> decreased heart rate, contractility and conduction velocity –> cardiac output falls
Vascular smooth muscle: Minimal effect because vascular beds lack cholingeric innervation. At moderate doses, they cause an increase in systemic vascular resistance and blood pressure due to the activation of sympathetic ganglia and central sympathetic centers
Cardiovascular effects of moderate doses of cholinesterase inhibitors (4)
Modest bradycardia
Fall in cardiac output
Increased vascular resistance
Increase in blood pressure
Cardiovascular effects of toxic doses of cholinesterase inhibitors
The accumulation of acetylcholine at the ganglia is initially excitatory on nicotinic receptors, but at higher concentrations, ganglionic blockade ensues as a result of persistent depolarization
Causes marked bradycardia, significant decrease of cardiac output and hypotension
Edrophonium MOA and uses
Reversible acetylcholinesterase inhibitor –> indirect acting cholingeric antagonist
Quaternary ammonium - does not enter CNS
Uses:
- Diagnosis of myasthenia gravis. Edrophonium IV leads to rapid increase in muscle strength
- Used to reverse the neuromuscular block produced by non-depolarising muscular blockers
Physostigmine MOA and uses
Carbamate –> Form a colavent bond with acetylcholinesterase –> indirect acting cholingeric antagonist
Tertiary amine –> can enter and stimulate CNS
Used to treat overdoses of anticholinergic drugs (eg: atropine)
Neostigmine MOA and uses
Carbamate –> Form a colavent bond with acetylcholinesterase –> indirect acting cholingeric antagonist
Quaternary ammonium - does not enter CNS
Uses:
- Postoperative urinary retention
- Reversal of effects of non-depolarizing neuromuscular blockers after surgery
- Treatment of myasthenia gravis
Pyridostigmine MOA and uses
Carbamate –> Form a colavent bond with acetylcholinesterase –> indirect acting cholingeric antagonist
Quaternary ammonium - does not enter CNS
Treatment of myasthenia gravis
Echothiophate MOA and use
Organophosphate –> covalently bond forms via phosphorylation of acetylcholinesterase and inhibits enzyme –> indirect acting cholinergeric antagonist
Rarely used for glaucoma
Malathion and Parathion
Organophosphate insecticides
Activated in the body by conversion to oxygen analogs.
Malathion is rapidly metabolized to inactive products in birds and mammals, but not
in insects. It is considered safe enough for sale to the general public.
Parathion is not detoxified effectively in vertebrates; thus it is considered more dangerous than malathion to humans and livestock and is not available for general public use.
Can lead to poisoning
Sarin
Organophosphate nerve gas
Poisoning with these agents includes an important component of CNS toxicity.
AChE inhibitors used in Alzeihmer Disease
Donepezil
Rivastigmine
Galantamine
Patients with Alzheimer disease have reduced cerebral production of choline acetyl transferase, which leads to a decrease in acetylcholine synthesis and impaired cortical cholinergic function.
The mainstay of therapy for patients with Alzheimer disease is the use of centrally acting cholinesterase inhibitors to slow down progression of disease.
Pralidoxime use
REactivator of AChE –> can be used as a cholinesterase regenerator for organophosphate insecticide poisoning
If given before ageing has occured, it can split the phosphorus-enzyme bond.
Antidote to organophosphate insecticide poisoning
First give atropine to block the muscarinic receptors so the excess acetylcholine cannot act
Give pralidoxime to regenerate the cholinesterase. Need to give it before ageing because if it occurs, then it is irreversible
Atropine MOA
Reversible competitive muscarinic receptor antagonist –> prevents acetylcholine from binding at the receptors
Tertiary amine - both a central and peripheral muscarinic blocker
Atropine effects (5)
Eye: mydriasis and cycloplegia (loss of accommodation)
GI: Reduces gastric motility
Urinary system: Decreases hypermotility of the bladder
Cardiovascular system:
- Low doses: Bradycardia due to blockade of presynaptic M2 receptors that normally inhibit ACh release
- Moderate to high therapeutic doses: Blockade of atrial M2 receptors –> tachycardia
- High doses may cause cutaneous vasodilation: “atropine flush”
Secretions: Sweat, salivary and lacrimal glands are blocked. Inhibition of sweat glands may cause high body temperature (due to inability to thermoregulate)
Uses of atropine (4)
Antispasmodic - to relax GI tract and bladder
Antidote for cholinergic agonists
- eg: To alleviate the muscarinic side effects of anticholinesterase drugs (eg
neostigmine) used for reversal of neuromuscular blockade
To block respiratory tract secretions prior to surgery
To increase heart rate or decrease AV-block when bradycardia or AV-block are hemodynamically significant and thought to be due to excess parasympathetic tone.
Atropine adverse effects (7)
Dry mouth
Blurred vision
Sandy eyes - due to decrease lacrimation
Tachycardia
Constipation
Urinary retention
CNS effect: Restlessness, confusion, hallucinations, delirium which pay progress to depression, collapse of circulatory and respiratory systems and death
Scopolamine MOA and uses
Muscarinic receptor antagonist
Uses:
- Prevents motion sickness (inhibits M1 receptors in the vomiting centres in the brain)
- To block short-term memory: sometimes used in anaesthetic procedures
Irpratropium and tiotropium MOA and uses
Quaternary ammonium muscarinic antagonists
Used as inhalation drugs in treatment of COPD and asthma
Homatropine and tropicamide MOA and uses
Tertiary amine muscarinic antagonists
Used as mydriatic for fundoscopy.
Produces mydriasis with cycloplegia
Preferred to atropine because of shorter duration of action
Benztropine and trihexyphenidyl MOA and uses
Tertiary amine muscarinic antagonists
Used to treat Parkinson’s disease and the extrapyramidal effects of antipsychotic drugs
In the basal ganglia, there is dopaminergic input and cholinergic input and there is a balance between these
two. In Parkinson’s the dopaminergic input starts to die so the cholinergic effects predominate –> tremors, tardive dyskinesia. Block the action of the extra cholinergic input using these drugs to stop these symptoms
Glycopyrrolate MOA and uses
Muscarinic antagonist
Used orally to inhibit GI motility
Used parentally to prevent bradycardia during surgical procedures
Tolterodine MOA and uses
Muscarinic antagonist
Used for overactive bladder
Contraindications of antimuscarinic agents (3)
Contraindicated in patients with angle-closure glaucoma –> obstructs drainage of acqeous humour even more due to mydriasis
Should be used with caution in patients with prostatic hypertrophy - can cause even more stasis of urine in the bladder and it can lead to infections
Should be used in caution in the elderly –> can enter CNS –> adverse effects caused by anticholinergic drugs in the elderly may include acute encephalopathy (delirium, confusional state), falls, urinary retention, constipation, and exacerbation and decompensation of underlying cognitive, functional, and behavioral deficits (particularly in patients with dementia).
Nicotinic receptor antagonists that are ganglion blockers
Nicotine: ganglion blocker due to prolonged depolarisation of nicotinic receptors
Hexamethomium and mecamylamine: antagonism of nicotinic receptors
Effects of ganglion blockers
Effect is to remove the predominant control
Arterioles (S)–> vasodilation and hypotension
Veins (S) –> ventilation
Heart (PS) –> increased heart rate
Iris (PS) –> Mydriasis
Ciliary muscle (PS) –> cycloplegia (focus for far vision)
GI tract (PS) –> reduced tone and motility, constipation and decreased secretions
Urinary bladder (PS) –> urine retention
Salivary glands (PS) –> Dry mouth
Sweat glands (S) –> Anhydrosis
Tubocurarine MOA and uses
Competitive antagonist of Nm receptors –> prevent acetylcholine from binding –> non-depolarizing blockers –> prevent depolarization and inhibit muscular contraction
Adjuvant drugs in anaesthesia during surgery to relax skeletal muscle
Reversing non-depolarizing blockade
Action can be overcome by increasing concentration of acetylcholine in synaptic cleft, for example with cholinesterase inhibitors such as neostigmine or edrophonium.
Succinylcholine MOA and use
Depolarizing neuromuscular blocker –> Binds to nicotine receptor and depolarises the NMJ –> persists in the synaptic cleft and stimulates the receptor –> receptor desensitisation –> flaccid paralysis
Given IV by continuous infusion. Rapidly hydrolysed by plasma cholinesterase. Extremely brief duration of action (5-10 min) and rapid onset (1-1.5 min).
Uses:
- Rapid endotracheal intubation
- ECT: last line of treatment for patients with drug refractory depression
Adverse effects of depolarising neuromuscular blockers
Malignant hyperthermia due to excessive release of Ca2+ from the DR –> high fever, muscle breakdown, acidosis
Most incidents due to combination of succinylcholine and a halogenated aesthetic
Antidote to malignant hyperthermia
Dantrolene –> blocks release of Ca2+ from DR
Reversal of adverse effects caused by depolarisation blockers
Hemicholinum-3
Blocks CHT –> Prevents uptake of choline required for acetylcholine synthesis
Used as a research tool
Vesamicol
Blocks Ach-H+ antiporter (VAchT) –> prevents storage of acetylcholine
Used as a research tool
Botulinum Toxin MOA and uses
A potent neurotoxin –> prevents synaptic vesicle fusion with the axon
terminal membrane –> inhibiting acetylcholine release.
Injected locally into muscles for treatment of several disease involving muscle spasms (torticollis, achalasia, strabismus,
blepharospasm, and other focal dystonias
Approved for cosmetic treatment of facial wrinkles
