Cholinergic Receptors Flashcards
Ach Synthesis:
What are the substrates?
What is the enzyme?
- Choline and Acetyl CoA
2. Choline acetyltransferase
Ach Transmission:
Before synthesis, choline is first sequestered into the neuron by a ______ transport.
Carrier mediated transport,
specifically Na-Choline symport.
Ach Transmission:
What is the Rate Limiting Step of this transmission?
The entry of Choline into the neuron via Na-Choline symport
Ach Transmission:
After synthesis, Ach is packed into small vesicles via ______ transport
Carrier mediated transport.
Ach Transmission:
What triggers the fusion of the Ach-filled vesicles with the cell membrane for exocytosis?
Entry of Ca2+ ions into the neuron via Voltage-gated ion channels.
Ach Transmission:
Ach can now bind to 2 kinds of Cholinergic receptors. What are they? What are their characteristics
- Nicotinic -ligand gated ion channel, fast,
2. Muscarinic - GPCR, slow
Ach Transmission:
To end the signal transmission, Ach can now be degraded by what enzyme?
Acetylcholinesterase
Nicotinic vs. Muscarinic:
Where are they usually found?
How many receptor subtypes?
Nicotinic: found at Ganglia/CNS and Neuromuscular jxn; 2 subtypes (ganglionic and neuromuscular)
Muscarinic: found at <3, vascular endothelium, smooth muscles and EXOcrine glands; 5 subtypes (M1-M5)
What are the drugs/toxins that are responsible for blocking the Nicotinic receptors?
- Hexamethonium (blocks ganglionic nicotrinic receptor)
2. Tubocurarine and alpha-bungarotoxin (blocks neuromuscular nicotinic receptor)
Nicotinic receptors:
Ganglionic Nicotinic Receptors are usually found where?
How bout Neuromuscular Nicotinic Receptors?
Ganglionic N.R. usually found at Autonomic, and sensory ganglia, including CNS (basta nerves)
Neuromuscular N.R.usually found at Neuromuscular Junction.
What are the common agonists for Nicotinic receptors?
Both Ganglionic and Neuromuscular N.R. respond to Acetylcholine and Carbamylcholine (also called Carbachol).
Bungarotoxin blocks the Neuromuscular N.R.
There are 2 types of bungarotoxin. What are they? How are they different?
Alpha-Bungarotoxin: blocks POSTsynaptic N.R.
Beta-Bungarotoxin: blocks Neurotransmitter release at the PREsynaptic cell membrane by preventing fusion of the vesicle w/ the cell membrane
Muscarinic Receptors:
There are 5 types of Muscarinic Receptors (M.R.). Where are they usually found?
M1: NERVES
M2: HEART, nerves, smooth muscles
M3: EXOcrine GLANDS
M4 and M5: CNS
Muscarinic Receptors:
What are the Mechanisms of these subtypes?
M1, M3, M5: promote IP3 and DAG cascade (Gq, phospholipase C)
M2 and M4: ihibits cAMP production (Gs, adenylyl cyclase)
What are Cholinomimetic Drugs?
Types? Divisions?
They are drugs that has the same action with Ach. AGONISTIC.
They are divided into 2: Direct and Indirect-Acting drugs.
Are there any subtypes of Direct acting drugs?
Yes. Direct-Acting drugs are further divided into 2: those acting on Muscarinic and those acting on Nicotinic receptors.
Direct-Acting Muscarinic Cholinomimetic Drugs:
There are two main examples of this - CHOLINE ESTERS and ALKALOIDS. What are the characteristics of these two?
Choline Esters:
- lipid insoluble, presence of BETA-METHYL group prevents its hydrolysis in GIT hence not given orally.
Alkaloids:
- easily absorbed at site of admin., excreted in the kidneys, of plant origin,
Direct-Acting Muscarinic Cholinomimetic Drugs:
Give an example of a choline ester and an alkaloid.
Direct Acting Cholinomimetic Drugs:
Is this for Nicotinic, Muscarinic or both receptors?
1. Acetylcholine & Carbamylcholine/Carbachol
2. Bethanechol & Pilocarpine
3. Nicotine & Varenicline
- Both
- Muscarinic
- Nicotinic
Direct Acting Cholinomimetic Drugs:
When is Bethanecol used?
used for spastic bladders/atony
Promotes MICTURITION
Direct Acting Cholinomimetic Drugs:
Patient has GLAUCOMA. What drug will you give?
Pilocarpine
Direct Acting Cholinomimetic Drugs:
A PARTIAL agonist of N.R. which comes in the form of Nicotine patches.
Varenicline
Used in patients to reduce their longing for nicotine.
What are the effects of the Direct-Acting Cholinergic Agents to the body?
May technique dito HAHAHA:
Generally, almost all will constrict in response to cholinomimetic agents EXCEPT for Arteries, Veins and Sphincters (first 2 will dilate at low dose but constrict at high dose). Glands will be stimulated.
What are the effects of the Direct-Acting Cholinergic Agents to the Heart?
@ the heart, these drugs will affect SA node (dec <3 rate), Atrium and Ventricle (dec contractile strength) and AV node (dec conduction velocity)
What do these terms mean?
Negative Chronotropy?
Negative Inotropy?
Negative Dromotropy?
All of these are the effects of cholinergic agents in the heart.
(-) Chronotropy = dec <3 rate
(-) Inotropy = dec contractile strength
(-) Dromotropy = dec conduction velocity
CNS contains BOTH muscarinic and nicotinic receptors. Brain has more ____ receptors and Spinal cord has more ____ receptors.
- Muscarinic
- Nicotinic
* *@ low doses = mild alerting effects
* *@ larger doses = tremors, emesis, etc
Peripherally Acting Cholinesterase (acts on PNS):
Their site of action is in the degradation of Ach which will enhance cholinergic transmission.
Give 2 examples of cholinesterase.
- Acetylcholinesterase - found primarily IN THE BLOOD and RBC membranes, NMJs and neural synapses
- Buterylcholinesterase - produced in liver, found IN THE PLASMA
Indirect Acting Cholinomimetic Drugs:
Anticholinesterases are considered cholinomimetic since they enhance Ach effect. Anticholinesterases are divided into 3 groups, what are they?
- Short acting Anti-ACHesterases (drug Edrophonium)
- Medium acting Anti-ACHesterases (drugs Neostigmine, Pyridostigmine, Physostigmine)
- Long acting/Irreversible Anti-ACHesterases (Organophosphates)
Characteristics of Indirect Acting drugs:
What are some of the characteristics of Edrophonium (short-acting Anti-Achesterase)
- a quarternary alcohol
- binds reversibly, very weak ionic bond with ACHesterases
- used in Myasthenia Gravis diagnosis
How is Edrophonium used in Myasthenia Gravis diagnosis?
Edrophonium is short acting (10mins). Giving this drug to patient w/ MG will enable him to raise his arms for more than 2 mins and his ptosis will disappear. If this effects are seen and expires after ~10 mins, then a diagnosis of MG is made.
What are some of the characteristics of Neostigmine, and other -stigmines (medium-acting Anti-Achesterase)?
- a carbamic acid ester of alcohol
- forms cabomylated covalent bond with enzyme
- persists for hours, maintenance drug for MG.
What are some of the characteristics of Organophosphates (Irreversible Anti-Achesterase)?
- forms a phosphorylated covalent bond w/ enzyme
- the longer they bond, the stronger they become (parang may “ageing” effect)
- inactivates ACHesterases, need to produce new ones
- can cause severe type of Peripheral Nerve Demyelination
2 Important Signs of Organophosphate toxicity!!!
- Salivation
2. Seizures
What is Pralidoxime?
- an ACHesterase regenerator; antidote to organophosphate poisoning
- most effective before the “ageing effect” of the phosphorylated covalent bond starts
What is Malathion?
An parasympathomimetic organophosphate that binds irreversible to cholinesterase
Symptoms of Toxicity for Indirect Acting Cholinomimetic Agents:
Hint: DUMBELS
DUMBELS:
Diarrhea, Urination, Myosis, Bronchoconstriction, Excitation, Lacrimation, Salivation
Centrally Acting Cholinesterase Inhibitors:
What are their characteristics?
Used in what conditions?
Give examples.
- orally active, lipid soluble, enter CNS
- used in the symptomatic treatment of Alzheimer’s and dementia
- ex. Rivastigmine, Galantamine, Donepezil
Ganglion Stimulants are agonists or the ganglionic N.R.
Effects?
Give an example
- generalized stimulation of autonomic ganglia (tachycardia, inc BP, Inc in secretions)
- Dimethylphenylpiperazinium (DMPP):
Cholinoceptor Blockers:
Enumerate the 4 MOAs for cholinoceptor blockers.
- Inhibit choline uptake/intake
- Inhibit Ach release
- Block Postsynaptic receptors
- Persistent postsynaptoc depolarization
An example of a Cholinoceptor blocker are muscarinic antagonists. Describe them.
Main examples: Atropine and Scopolamine
Chemistry of muscarinic antagonists:
1. natural alkaloids (atropine and scopolamine) - GIT absorbable
2. tertiary ammonium - GIT absorbable
3. quarternary ammonium - poor GIT absorption
Why do some antihistamine and antidepressant drugs have antimuscarinic effects?
Because their structures are similar to the tertiary ammonium that are muscarinic blockers
Atropine Toxicity symptoms?
Blind as a bat (cycloplegia/ near vision)
Dry as a bone (decreased sweating)
Red as a beet (thermoreg, blood vessels in skin dilate due to decreaseed sweating)
Mad as a hatter (hallucinations)
Hot as hell (thermoreg. fever becaus you dont perspire)
Presynaptic Cholinergic Inhibitor
Give MOA and site of Drug action.
Hemicholinium
Block transport of Choline into neuron for Ach synthesis;
Reuptake;
Presynaptic Cholinergic Inhibitor
Give MOA and site of Drug action.
Triethylcholine
Mimics choline, blocks transport of choline;
Synthesis;
Presynaptic Cholinergic Inhibitor
Give MOA and site of Drug action.
Vesamicol
Blocks Ach transport into vesicles;
Storage
Presynaptic Cholinergic Inhibitor
Give MOA and site of Drug action.
Botulinum toxin
Inhibit Ach release by blocking Ca2+ needed to release the vesicles.
Release
***active component is peptidase. causes parasympathetic and motor paralysis
Presynaptic Cholinergic Inhibitor
Give MOA and site of Drug action.
Apha and Beta-bungarotoxin
For Alpha: blocks post synaptic Ach receptors; Receptor of transmitter
For Beta: prevent fusion of vesicles with cell membrane; Release
Presynaptic Cholinergic Inhibitor
Give MOA and site of Drug action.
Aminoglycoside antibiotics
Blocks release of Ach.
CONTRAINDICATED in patients with M.G.
Drugs Affecting Autonomic Ganglia
Give MOA and site of Drug action.
Magnesium Ion
Competes with Ca2+;
Release
Drugs Affecting Autonomic Ganglia
Give MOA and site of Drug action.
Nicotine
Prolong depolarization
Receptor
Drugs Affecting Autonomic Ganglia
Give MOA and site of Drug action.
Hexamethonium, Trimetaphan, Tubocurarine
interference with postsynaptic action of Ach, blocked of nicotinic receptor
Ganglion blocking drugs block ALL AUTONOMIC and ENTERIC GANGLIA.
What are its clinical manifestations?
Mnemonic: HILIG Hypotension Inhibition of secretions Loss of cariovascular reflexes Impaired micturition Gastrointestinal paralysis
Neuromuscular blocking drugs:
What are the 2 ways of blocking neuromuscular transmission?
- Presynaptically - inhibit Ach synthesis
2. Postsynaptically - acto on receptor or ion channel
Neuromuscular blocking drugs:
What are its uses?
- Used in surgery, decreases the dose for anesthesia required
- For intubation (paralyze and sedate)
- muscle spasm control
- for STATUS EPILEPTICUS
What is status epilepticus?
uncontrolled and prolonged seizures of the respiratory muscles leading to zero breathing and hypoxia
Two types of Neuromuscular blocking drugs?
- Non depolarizing drugs
2. Depolarizing drugs
Non depolarizing drugs:
MOA? Effects?
- competitive antagonists,
- blocks the pore of the ion channel
- may also block prejunctional Na channels
- motor paralysis, consciousness and awareness of pain were normal
Non depolarizing drugs:
What is the sequence of motor paralysis?
- extrinsic eye muscles
- facial muscles
- limbs and pharynx
- respiratory muscles
Non depolarizing drugs: Drugs are always accompanied by unwanted effects. What are the unwanted effects of the ff: 1. Tubocurarine 2. Vecuronium 3. Gallamine/Pancuronium
- fall in BP due to ganglion block
- less ganglion block and release of histamine
- block muscarinic receptors in the <3
Depolarizing Drugs:
The MOA of these drugs has 2 phases Phase 1 (or depolarization block) and Phase II (desensitized). Give the characteristics of each phase.
- Phase 1: maintained depolarization at the endplate, loss of excitability, FASCICULATIONS,
