Autonomic Pharmacology Part 1 Flashcards
What are some of the things that occur in response to the parasympathetic activation
Reduced blood pressure
Reduced heart rate
Acts on M2 receptors on the heart
There is nitric oxide release leading to dilation of the blood vessels(acts on M3receptors in blood vessels)
Increased secretions(saliva and gastric juice)
Increased peristalsis
Decreased sphincter tone
Acts on M3 receptors in the Gi
Constricts bronchioles and increased secretions in the lungs
(Acts on M3 receptors)
Eye-there is miosis (eye is small) and accommodation for near vision
Eye doesn’t get wide cuz eye gets wide when you want to see far and run away from something (sympathetic)
Saliva becomes plenty and watery
Reduced sphincter tone and increased detrusor
Acts on M3 receptors on the bladder
How does acetylcholine synthesis occur and how does botulinum toxin stops the release of Ach
Synthesis:
•Cholinergic neurons contain large numbers of small membrane-bound vesicles (containing ACh) concentrated near the synaptic portion of the cell membrane.
•ACh is synthesized in the cytoplasm from acetyl-CoA and choline by the catalytic action of Choline acetyltransferase (ChAT).
•Acetyl-CoA is synthesized in mitochondria, which are present in large numbers in the nerve ending.
•Choline is transported from the extracellular fluid into the neuron terminal by a Na+-dependent membrane choline cotransporter (Carrier A).
•This carrier can be blocked by a group of drugs called hemicholiniums.
•The action of the choline transporter is the rate-limiting step in ACh synthesis
Choline is taken into the cell along with sodium using a transporter
It combines w Acetyl coA when it gets into the cell and the enzyme responsible is ChAt
This forms acetylcholine
This enters into the vesicle (ATP and other peptides are already in the vesicles)
When there is action potential transmission and it gets to the terminal
There is opening of a calcium channel located at the terminal allowing extra cellular calcium to enter the cell. When it enters it causes the exocytosis of the vesicle . Ach then comes out into the synaptic space
Looking for it’s receptors ( Muscarinic receptors)
Acetyl cholinesterase breaks down acetylcholine into choline and acetate
Botulinum toxin stops interaction between the SnAPs and Vamps (this interaction is caused by the release of calcium into the cell and the interaction causes exocytosis of the vesicle)
Importance of the auto receptor which is also a muscarinic receptors
When there is too much of Ach there’s a negative feedback effect so it regulates further release of the Ach
So when ACh binds to it it’ll tell the vesicle not to release more Ach into the synapse
How is Ach released and destroyed
Cholinergic Transmission –
Release:
•Synthesized, ACh is transported from the cytoplasm into the vesicles by an antiporter that removes protons(carrier B). This transporter can be blocked by vesamicol
•Release is dependent on extracellular Ca2+ and occurs when an action potential reaches the terminal and triggers sufficient influx of Ca2+ ions
•The increased Ca2+ concentration “destabilizes” the storage vesicles by interacting with special proteins: the vesicular associated membrane proteins (VAMPs) and synaptosome associated protein (SNAP)
•Fusion of the vesicular membranes with the terminal membrane results in exocytotic expulsion of ACh into the synaptic cleft
•The ACh vesicle release process is blocked by botulinum toxin through the enzymatic removal of two amino acids from one or more of the fusion proteins.
After release - ACh molecules may bind to and activate an ACh receptors
•Eventually, all of the ACh released will diffuse within range of an acetylcholinesterase (AChE) molecule
•AChE splits ACh into choline and acetate, neither of which has significant transmitter effect, and thereby terminates the action of the transmitter.
•Most cholinergic synapses are richly supplied with AChE;
•the half-life of ACh in the synapse is therefore very short.
•AChE is also found in other tissues, eg, red blood cells.
•Another cholinesterase with a lower specificity for ACh, butyrylcholinesterase [pseudo cholinesterase], is found in blood plasma, liver, glial, and many other tissues
Where is M1 located and what is its effect on the locations when activated
Autonomic ganglion Cells, Gastric glands and Central Neurons (cortex, hippocampus, corpus striatum)
– Physiological Role: Mediation of Gastric acid secretion and relaxation of LES (vagal)
• Learning, memory and motor functions
So when there are diseases that bother learning and memory functions such as Dementia and Alzheimer’s you can cause the activation of M1 receptors to increase learning and memory
Where is M2 receptors found and what is it’s effect when activated
M2: Cardiac Muscarinic receptors
– Mediate vagal bradycardia
– Also auto receptors in cholinergic nerve endings
– CNS – Tremor, analgesia
When activated-the G protein here is Gi in the M2 receptor
It inhibits adenylyl cyclase and decreased cyto something d and there’s k channel activation causing slowing of diastolic depolarization causing slowed contractions by receptors on SA node,
Where is M3 receptors located and what is it’s effect when activated
M3: Visceral smooth muscles, glands and vascular endothelium. Also Iris and Ciliary muscles
If activated-there’s increased phospholipase C and that causes increased calcium in cytosol causing contraction of muscles or increased muscle tone
There is a protein(G couple something )that causes increased production of phospholipase C which causes the increased calcium in cytosol and increased secretions
What is the location,function,mode of action,it’s agonists of the NN receptor (ganglion type)(nicotinic receptors) And antagonist
Location-in autonomic ganglion of all types (sympathetic,para,adrenal medulla)
In the ganglion Ach had to activate a nicotinic receptor and when activated it causes the release of the neurotransmitters depending on the type of system either para or sympa or adrenal medulla(causes production of 80 percent adrenaline and 20 percent noradrenaline)
Function-depolarization and post ganglionic impulse,stimulates all autonomic ganglion,adrenal medulla,catecholamines release
Mode of action- sodium ,potassium,calcium channels opening
Agonists-acetylcholine,carbachol(CCh),nicotine
Selective stimulation of NN receptors
Dimethyl phenyl piperazinium (DMPP)
Antagonist-Trimethaphan,Mecamylamine,hexamethonium
What is the location,function,mode of action,it’s agonists of the NM receptor (muscle type)(nicotinic receptors) And antagonist
Location- skeletal muscle end plates
Function- stimulate skeletal muscle contraction
Mode of action-postsynaptic and excitatory (opening of actions potassium,sodium)
Agonists-acetylcholine,carbachol,suxamethonium
Selective stimulation by phenyl trimethyl anmonium(PTMA)
Antagonist-tubocurarine ,atracurium,vecuronium,pancuronium
Name two muscarinic agonists
Pilocarpine
Bethanechol
Acetylcholine is not used clinically cuz it has a short action
Name some Nicotinic receptor agonists
Succinylcholine
Nicotine
Anticholinesterase
Nome some anti cholinesterase to prevent the degradation of the acetylcholine to let it stay long
Edrophonium
Neostigmine
Distigmine
Pyridostigmine(organophosphate compounds)
Name some ganglion blockers
Trimetaphan (not ever used clinically) cuz it leads to the collapse of the cardiovascular system
Excess nicotine
(Depolarizing block)
At high doses nicotine causes block of the ganglion
Name some muscarinic antagonist
Atropine Hyoscine Ipratropium Tropicamide Benzatrophine
Name the types of cholinergic agonists and two main targets of these drugs actions
Acrtylcholine (ACh) is too rapidly hydrolyzed and inactivated by acetycholinesterases to be of any therapeutic use.
Its action can be replicated by other substances namely:
- Direct cholinergic agonists
- Indirect Cholinomimetics (cholinesterase inhibitors).
Two main targets of drug action:
- The postsynaptic receptor and
- The acetylcholinesterase enzyme, which breaks down acetylcholine.
NB: Some drugs are specific for the muscarinic receptor; others are specific for the nicotinic receptor
Name the two classes of direct cholinergic agents and give examples of each class and the side effects of these drugs
Esters: - structurally related to acetylcholine, e.g.
•Bethanechol (used in the treatment of urinary retention)
•Carbachol (The choline ester of carbamic acid, used in the treatment of glaucoma)
Esters form stronger bonds making it hard for acetylcholinesterase to break it
These are long acting as compared to acetylcholine
- Alkaloids: pilocarpine; muscarine(it’s a mushroom, it activates muscarinic receptors.it’s a poison. Not used clinically); arecoline
- The effects of all of these agents are exclusive muscarinic.
- Of this group, only pilocarpine enjoys therapeutic use, which is almost exclusively by local application to the eye in glaucoma
- Side effects often listed for these drugs include sweating (increased secretion), salivation, GI distress, and cramps (due to increased motility).
What are pseudo cholinesterases and where are they abundant in the body
Pseudocholinesterases
There are other cholinesterases that also metabolize Ach and drugs with related structures.
These other cholinesterases are sometimes called pseudocholinesterases or nonspecific cholinesterases, and they are abundant in the liver.
Which drug is a direct agonist at nicotinic receptors and how is nicotine used therapeutically
Nicotine is a direct agonist at nicotinic receptors. nicotine is used therapeutically to help patients stop smoking.
How?
If person tries to stop smoking completely it’ll cause withdrawal syndrome
So you give the person a nicotine patch so nicotine is released small small so person doesn’t have withdrawal syndrome
What is the use of bethanechol,carbachol,cemiveline,pilocarpine
Bethanechol-non obstructive urine retention
Carbachol-glaucoma
Cemiveline-dry mouth from Sjögren’s syndrome
Pilocarpine-glaucoma
During surgery apart from a local anaesthetic what is given to cause muscle relaxation
Nicotinic antagonist (muscle type not ganglion type)
Name the classes under indirect cholinesterase inhibitors and give examples
They could be
Reversible (water soluble e.g. Physostigmine, Neostigmine) and Irreversible inhibitors (lipid soluble e.g. organophosphates-very poisonous so aren’t used therpaeuticaly so are used as biological weapons)
What do indirect cholinesterase inhibitors do
They act by blocking the metabolism of Ach by cholinesterases.
They effectively increase the concentration of Ach at all cholinergic synapses.
The enzyme that is specific for Ach is called acetylcholinesterase, and it is found on both the pre- and postsynaptic membranes.
Acetylcholine has more affinity ormuscarinic receptors as compared to nicotinic but acts on both of em
Anti cholinesterase has some effect on nicotinic receptors but prefers miscarinic receptors to nicotinic receptors true or false. Give an example of this
True
When you give acetylcholine low dose it’ll cause Bradycardia
But when you give a drug that blocks muscarinic receptors examples atropine and you give more acetylcholine it’ll cause increased heart rate and blood pressure
Cuz the acetylcholine at low dose acted on the muscarinic receptors but once those receptors are blocked and you add more acetylcholine it’ll act on nicotinic receptors in the ganglion leading to productions of norepinephrine and Acetylcholine since the muscarinic receptors are blocked norepinephrine action will be seen instead of acetylcholine action causing high bp and increased heart rate
Name some examples of carbamates and how reversible inhibitors works
They include the quaternary amines and the carbamates.
They compete with acetylcholine for the active site on the cholinesterase enzyme.
This group includes the drugs with names ending in “-stigmine” and “-nium.”
Chemically, these agents include esters of
•Carbamic acid (carbamates such as physostigmine, neostigmine)
The reversible cholinestrease (AchE) inhibitors
They have similar actions and side effects as the direct acting drugs (muscarinic).
In addition, because they increase the concentration of Ach, they have effects at the neuromuscular junction (nicotinic).
These drugs cause similar side effects as the direct cholinergic agonists.
They also affect nicotinic receptors, primarily at the neuromuscular junction.
Reversible cholinestrease inhibitors can have effects on the cholinergic system in the CNS, if the drug can cross the blood-brain barrier.
The effects range from tremor, anxiety, and restlessness to coma.
How is AchE(reversible cholinesterase inhibitors) used in myasthenia gravis
Myasthenia gravis
Myasthenia gravis is an immune disease in which there is loss of acetylcholine receptors at the neuromuscular junction, resulting in weakness and fatigability of skeletal muscle.
Ach receptors are bound by immune agents in the end plates of skeletal muscles so Ach can’t act on those muscles so the patient gets skeletal muscle weakness
The AchE increases the Ach and the Ach will compete w the immune agents and surmount those agents
More common in women 20 to 40 with possible line to thymus gland tumors.
Begins with double vision & swallowing difficulties & progresses to paralysis of respiratory muscles
The quaternary carbamates (Neostigmine, Pyridostigmine) are used to overcome the relative ACh deficiency at the motor end plate in Myasthenia gravis
Additionally, steroids are used to reduce antibodies that bind to ACh receptors
How is AchE(reversible cholinesterase inhibitors) used in Alzheimer’s
In the early stages of Alzheimer disease, administration of centrally acting AchE inhibitors can bring about transient improvement in cognitive function or slow down deterioration in some patients.
•Suitable drugs include rivastigmine, donepezil, and galantamlne, which require slowly increasing dosage these cross bbb and inhibit acetylcholinesterase from destroying the little Ach produced by the remaining cholinergic neurons. Physostigmine and the other stigmines don’t cross the bbb so can’t be used in Alzheimer’s
•Peripheral side effects (inhibition of ACh breakdown) limit therapy.
•Donepezil and galantamine are not esters of carbamic acid and act by a different molecular action.
•Galantamine is also thought to promote the action of ACh at nicotinic cholinoceptors by an allosteric mechanism.
There is destruction of cholinergic neurons so there’s low production of Ach
So AchE helps in more Ach being there
How is AchE(reversible cholinesterase inhibitors) used in Other treatments
Uses of reversible AchE inhibitors are in the treatment of
•open-angle glaucoma and
•the reversal of nondepolarizing neuromuscular blockade after surgery (e.g. tubocurarine but not succinylcholine).
•Paralytic ileus or bladder atony (Neostigmine preferred)
What are the uses of these indirect acting cholinergic agents
Ambenonium- Myasthenia gravis
Edrophonium-diagnosis of myasthenia gravis (cuz it’s short acting as compared to ambenonium )
Neostigmine- myasthenia gravis,urine retention
Pyridostigmine- myasthenia gravis
Tacrine- Alzheimer’s disease
The irreversible inhibitors phosphorylate the enzyme and inactivate it.
Chemically, these agents include esters of
Phosphoric acid (very important while reversible inhibitors are esters of carbamic acid) (organophosphates such as paraoxon, and nitrostigmine or parathion).
These cholinesterase inhibitors are widely used as insecticides.
Because the organophosphates are lipid soluble, they rapidly cross all membranes, including skin and the blood-brain barrier.
True or false
And what drugs treat organophosphate poisoning
Pralidoxime (2-PAM) and Atropine are used to treat poisoning with organophosphates
Give examples of nerve gases (chemical warfare) and insecticides
Cholinesterase inhibitors are designed to be deadly = “NERVE GAS” (Military)
e.g., soman, sarin, tabun, VX
- Insecticides
e. g., diazinon (SPECTRACIDE), chlorpyrifos (DURSBAN), parathion, malathion
Accumulation of ACh at cholinergic receptors when using nerve gases produces effects reflecting stimulation of cardiac muscle, smooth muscles and glands. Such effects would be identical to those caused by muscarine poisoning.
•Bradycardia and hypotension occurs. However, in some cases, tachycardia may be observed, due to intense sympathetic discharge in response severe hypoxemia.
True or false
True
How do organophosphates work
Organophosphates As Nerve Gas Agents In Chemical Warfare
•Irreversible inhibition of acetylcholinesterase by these agents produces accumulation of ACh at the end plate of skeletal muscle fibers.
•This in turn leads to depolarizing blockade of the NM nicotinic receptor.
•Skeletal muscle paralysis occurs.
•Movement is impossible.
•The diaphragm is also paralyzed.
•The individual eventually dies due to respiratory paralysis.
–Persian gulf war syndrome
Name the classes of cholinergic antagonists
1.Muscarinic Antagonist
Selective
Non selective
- Antinicotinic
I.Ganglion Blockers (Nn)
II.Neuromuscular Blockers (Nm)
What are muscarinic antagonists and give examples
They block muscarinic receptors competitively, causing inhibition of all muscarinic functions
•They are effective in several clinical situations unlike cholinergic agonists
Drugs belonging to this group
a- Atropine & Hyoscine (scopolamine) (natural alkaloids)
b- Homatropine (synthetic comp.)
c- Atropine methonitrate (quaternary comp.)
d- Ipratropium (quaternary comp.)
e- Pirenzepine (selective M1 antagonist)
f- Cyclopentolate and tropicamide (tertiary amines developed for ophthalmic use)
