Cholinergic Agonists Flashcards
List the different classes of cholinergic agonists
1. Direct-acting agonists: bind to and activate muscarinic or nicotinic receptors.
- Some are selective for muscarinic or nicotinic receptors. Others have effects on both receptors.
- Theraputically useful drugs preferntially activate muscarinic receptors.
2. Indirect-acting agonists: inhibit acetylcholinesterase
Describe the muscarinic and nicotinic actions of acetylcholine
Discuss the actions of acetylcholine on the cardiovascular system.
Direct effects of Acetylcholine include:
- Vasodilation through NO synthesis
- Decrease in cardiac rate (M2 effect)
- Decrease in rate of conduction in the SA and AV nodes (M2 effect)
- Decrease in force of contraction (M2 effect)
IV injection of small doses of acetylcholine cause a fall in blood pressure due to vasodilation (M3 effect) usually accompanied by reflex tachycardia.
IV injections of large doses of acetylcholine cause vasodilation, a fall in blood pressure (M3 effect) and bradycardia (M2 effect)
Discuss the effects of acetylcholine on various organ systems
Describe the nicotinic effects of Acetylcholine
If muscarinic effects are blocked by a muscarinic antagonist such as atropine, large doses of acetylcholine produce nicotinic effects:
- Increase in blood pressure and vasoconstriction
- hese effects are due to stimulation of
List the classes of Direct Cholinergic Agonists
Describe the main drugs, mechanism of action, uses and adverse effects of choline ester drugs.
The main choline ester drugs are:
- Acetylcholine
- Methacholine
- Carbachol
- Bethanechol
Choline esters are quaternary ammoniums and are poorly absorbed and distributed into the CNS. They differ in their susceptibility to hydrolysis by cholinesterase. Acetylcholine is very rapidly hydrolyzed. Methacholine, Carbachol and Bethanechol are more resistant to hydrolysis by cholinesterase.
1. Acetylcholine
Has no systemic theraputic applications due to multiplicity of actions, and rapid hydrolysis by both acetylcholinesterase and plasma butyrylcholinesterase.
USES
- Used to obtain rapid miosis after delivery of the lens in cataract surgery and other procedures where rapid miosis is required.
- Methacholine
A muscarinic agonist (worsens Asthma effects)
USES
- Diagnosis of bronchial airway hyperactivity in subjects who do not have clinically apparent asthma.
- Carbachol
Both muscarinic and nicotinic agonist.
USES
- Miosis during surgery
- Reduces intraocular pressure after cataract surgery.
- Bethanchol
Muscarinic agonist.
USES
- Postoperative and postpartum urinary retention.
- Atony of the eurinary bladder.
Describe the main drugs, mechanism of action, uses and adverse effects of natural alkaloid drugs.
The main natural alkaloids are:
1. Pilocarpine
2. Nicotine
- Pilocarpine
Partial muscarini agonist. Tertiary amine (noncharged so enters CNS freely). Stable to hydrolysis by acetylcholinesterase.
USES
- Second line agent for open angle glaucoma
- Management of acute angle-closure glaucoma
- Treatment of dry mouth due to radiotherapy for cancer of head and neck
- Treatment of dry mouth caused by Sjogren’s Syndrome
ADVERSE EFFECTS
The adverse effects mimic the effects of generalized cholinergic stimulation:
- Sweating
- Salivation
- Flushing
- Low blood pressure
- Nausea
- Abdominal pain
- Diarrhea
- Bronchospasm
- Nicotine
Tertiary amine. Selective agonist of the nicotinic receptor. Depending on the dose, nicotine depolarizes autonomic ganglia, resulting first in stimulation and then in paralysis.
USES
- Smoking cessation therapy
ACTIONS
- At low doses: ganglionic stimulation by depolarization
- The response resembles simultaneous discharge of both parasympathetic and sympathetic nervous systems.
- CV system: Mainly sympathomimetic effects. Increase HR and BP due to catecholamine release from nerve terminals and adrenal medulla
- GI & Urinary tracts: Mainly parasympathomimetic effects: nausea, vomiting, diarrhea, voiding of urine.
- Secretions: Stimulation of salivary and bronchial secretions
- At high doses: ganglionic blockade and neuromuscular blockage.
ACUTE POISONING
- Symptoms of acute, severe poisoning: nausea, salivation, abdominal pain, vomiting, diarrhea, cold sweat, mental confusion and weakness.
- Blood pressure fall, the pulse is weak.
- Death may occur from paralysis of respiratory muscles and/or central respiratory failure.
List the classes of Indirect-Acting Cholinergic Agents (Anticholinesterases)
1. Edrophonium
2. Carbamates
A. Physostigmine
B. Neostigmine
C. Pyridostigmine
3. Organophosphates
A. Echothiophate
B. Parathion and Malathion
C. Sarin
Describe the mechanism of action and organ system effects of the indirect-acting cholinergic agents
MOA: Cholinesterase inhibitors act by inhibiting acetylcholinesterase: they increase concentration of endogenous acetylcholine.
- Edrophonium binds reversibly to the active site of the enzyme.
- Carbamates form a covalent bond with the enzyme.
-
Organophosphates phosphorylate the enzyme. The covalent bond formed is extremely stable and hydrolyzes very slowly.
- The phosphorylated enzyme may undergo a process called ageing.
- This process strengthens the phosphorous-enzyme bond.
Describe the organ system effects of acetylcholinesterases
Anticholinesterases amplify the action of endogenous acetylcholine. Therefore their effects are similar (but not always identical) to the effects of the direct-acting cholinomimetic agonists.
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.
EYE/RESPIRATORY TRACT/GI TRACT & URINARY TRACT: These systems are well innervated by the parasympathetic system. The effects of cholinesterase inhibitors are similar to the effects of the direct-acting cholinomimetics.
NMJ: Cholinesterase inhibitors increase the strength of contraction. Useful to reverse action of nondepolarizing neuromuscular blockers. Useful in Myasthenia Gravis.
Describe the system effects of acetylcholinesterases on the Cardiovascular System
- Cholinesterase inhibitors can activate both sympathetic and parasympathetic ganglia supplying the heart.
- They can also activate acetylcholine receptors on cardiac and vascular smooth muscles that receive cholinergic innervation.
- In the heart, parasympathetic effects predominate. Negative chronotropic, dromotropic, and ionotropic effects: cardiac output falls.
- In the vascular smooth muscle, cholinesterase inhibitors have minimal effects because most vascular beds lack cholinergic innervation.
- At moderate doses they cause an increase in systemic vascular resistance and blood pressure.
- This is due to activation of sympathetic ganglia and central sympathetic centers.
- The net CV effects of moderate doses of cholinesterase inhibitors consist of:
- Modest bradycardia
- Fall in cardiac output
- Increased vascular resistance
- Increase in blood pressure
- Toxic doses of cholinesterase inhibitors cause marked bradycardia, significant derease of cardiac output and hypertension
- Edrophonium
Quaternary ammonium. Does not enter CNS.
USES
- Used in the diagnosis of myasthenia gravis. Edrophonium IV leads to rapid increase in muscle strength.
- Used to reverse the neuromuscular block produced by non-depolarizing muscular blockers.
2A Physostigmine
Tertiary amine. Can enter and stimulate the CNS.
USES
- Treatment of overdoeses of anticholinergic drugs
2B Neostigmine
Quaternary ammonium. Does not enter CNS.
USES
- Postoperative urinary retention.
- Reversal of effects of non-depolarizing neuromuscular blockers after surgery.
- Treatment of mysathenia gravis.
2C Pyridostigmine
Quaternary ammonium. Does not enter CNS.
USES
- Treatment of Myasthenia Gravis.
3A Echothiophate
USES
- Rarely used for glaucoma.
3B Parathion and Malathion (Insecticides)
USES
- Insecticides
3C Sarin (Nerve agents)
Among the most potent synthetic toxic agents known.
Describe the AChE Inhibitors used in Alzheimer Disease
- The mainstay of therapy for patients with Alzheimer disease is the use of centrally acting acetylcholinesterase inhibitors.
- Donepezil
- Rivastigmine
- Galantamine
Describe the mechanism by which Pralidoxime reactivates phosphorylated acetylcholinesterases.
- If given before ageing has occured, drugs like pralidoxime split the phosphorous-enzyme bond.
- Pralidoxime can be used as a cholinesterase regenerator for organophosphate insecticide poisoning.
