ANS-1 Flashcards
In a ganglion the receptors are of which subtype
Nn
Nicotinic receptor of neuronal subtype
The parts of the body when the neurotransmitter of post ganglionic sympathetic system is not norepinephrine
- Sweat glands (beta blockers cannot affect sweating)- Acetyl choline
- Adrenals- Acetyl choline
- Renal blood vessels- dopamine
Synthesis of Acetyl choline
Acetyl CoA from mitochondria + choline from systemic circulation
By choline-acetyl transferase
ACE Acetyl choline esterase
Two sites: 1. Esteratic site: Breaks down the ester bond 2. Anionic site: Choline’s + is attracted by this site
RDS of Acetyl choline synthesis
Reuptake of choline after action of ACE
Drugs which competes with choline for intake into the pre synaptic neuron
Hemicholinium
Used mostly in animal experiments
Drugs which inhibits the uptake of choline into the vesicle
Vesamicol
Used mostly in animal experiments
Drugs which block the pre synaptic Ca channel
Aminoglycosides
Produce neuromuscular toxicity by indirectly inhibiting Acetyl choline release
Drugs which directly inhibit Acetyl choline release into the synaptic cleft
Bungarotoxin
Botulinum toxin
Botulism: the patient dies by respiratory failure
Botox: migraine prophylaxis
Floppy infant
Muscle tone is lost
Infant with botulism
Acetyl choline is not released
Therapeutic uses of botulinum toxin
As Botox injection: 1. Migraine prophylaxis By decreasing CGRP (calcitonin gene related peptide) release 2. Achalasia 3. Dystonia (abnormal movement) 4. Cosmetology
Receptors of the parasympathetic nervous system
1. Muscarinic GPCR: A) Gq: Ca release M1, M3, M5 B) Gi/o: relaxation by opening potassium channel M2, M4 2. Nicotinic: A) muscular (Nm): myasthenia gravis B) neuronal (Nn): Adrenals, ganglions, CNS
Neurotransmitter of adrenals
Acetyl choline
M1 receptor
Being Gq, it increases Ca release CNS: Increases action potential Increases cognition Prevents Alzheimer’s syndrome Agonist: Taclifensin
GIT:
Increases secretion
M3 receptors
- GIT: muscular contraction
- Glands: increased secretion
- Bronchoconstriction
- Detruser: contraction
- Iris: contraction or miosis
- Blood vessels:
A) Endothelium (major effect)
Stimulates Ca dependent ENOS producing NO ➡️ vasodilation
B) Smooth muscle: minor vasocontraction
M5 and M4
Present in CNS
no clinical significance
M2 receptors
Heart
Block of SAN and AVN
i.e, bradycardia and block of AV conduction
A slight decrease in contraction of atrium greater than ventricle (clinically insignificant)
Classification of direct cholinergics
- Nicotinic
- Muscarinic:
A) amides:
All are lipid soluble except muscarine
Can cross BBB
Topical use
B) choline esters:
All are lipid insoluble
No central side effects
Examples of direct cholinergics
Nicotinic: Nicotine, Varenicline-smoking dependence Muscarinic: 1. Amides Pilocarpine- c.a. glaucoma,... Cevimeline- xerostomia 2. Choline esters Acetyl choline, esmolol, succinyl choline Bethanechol, carbachol, methacholine
Pilocarpine
Treatment of: 1. xerostomia 2. Miotic agent for closed angle glaucoma Along with physostigmine, echothiophate Increases trabecular outflow
Adverse effects (miotic agents):
- Accommodation spasm (all M3 receptor) leads to
- Head ache
- Retinal detachment
Cevimeline
Drug of choice for xerostomia
Acetyl choline is metabolised in plasma by
Pseudocholinesterase
Very short acting like esmolol, succinyl choline
So no systemic use
Uses of Acetyl choline
Miotic agent in ocular surgeries
Bethanechol and carbochol
Resistant to both ACE and pseudocholinesterase
M1,3 more than M2
1. Bethanechol has 0 nicotinic effect, hence preferred for bladder atony and gastroparesis (M3)
2. Carbochol has maximum nicotinic effect so no systemic and topical use
Miotic agent in ocular surgery (like Acetyl choline)
Methacholine
Resistant to pseudocholinesterase only
M2 more than M1,3
Moderate nicotinic effect
Used in bronchial challenge test in diagnosis of bronchial asthma
Examples of indirect cholinergics
1. Organophosphates •Warfare agents •Echothiophate, Fluostigmine •Insecticides 2. Carbamate •Physostigmine •Donepezil, Rivastigmine, Galantamine •Pyridostigmine, Neostigmine-Myasthenia gravis •Edrophonium
Organophosphates
Original uses
Binds to the esteratic site of ACE Irreversible binding(after ageing) Warfare agents (nerve gas) like Sarin, cyclosarin, tabun, Soman, Vx
Ageing of ACE
After the binding and breakage of the bond between esteratic site and organophosphates ,
the esteratic site forms stronger irreversible bonds
ACE reactivators
Oximes
They have positive charge and bind to the anionic site thus removing organophosphate from the esteratic site
Organophosphates clinical uses
Echothiophate Fluostigmine Miotic agent in closed angle glaucoma (no more preferred) Side effects: 1. Common miotic agent side effects 2. Iris cysts (echothiophate)
Organophosphates as insecticides and pesticides
Induce spastic paralysis (increased stimulation)
For suicide cases of cholinergic poisoning:
1. Agitation
2. Increased secretions: patient drowns in his own secretions
3. Pin point pupil:
due to severe miosis
opioid toxicity or pontine myelinosis
Organophosphate poisoning treatment
Atropine is the drug of choice (saves the life)
Then to treat nicotinic symptoms oximes are used like:
1. pralidoxime (most commonly used oxime in India)
2. obidoxime
3. diacetyl monoxime
Most specific drug in organophosphate poisoning is
Oximes
Because it reverses the effect of organophosphates (reactivation of ACE)
Though it is not the life saving drug (atropine)
Carbamates
Mechanism
Binds to both esteratic site and anionic site
(So in case of carbamate poisoning oximes are useless
Drug of choice is atropine)
This binding is reversible after a long time or pseudoirreversible
Exception:
Edrephonium-
binds only to anionic site via ionic bonds
So it is short acting
Carbamates
Examples of drugs
1. Tertiary amines: Lipid soluble Like physostigmine, donepezil, rivastigmine, galantamine 2. Quaternary amines: Lipid insoluble 3. Herbicides, fungicides, pesticides
Physostigmine
Example of tertiary amine of carbamate Use: 1. Closed angle glaucoma (miotic agent) 2. Atropine toxicity (both crosses BBB) Belladonna poisoning/ datura poisoning Sources: physostigma venenosum (calabar beans)
Donepezil, rivastigmine, galantamine are used in
Alzheimer’s disease
They are tertiary amine (carbamates) that can cross BBB
Myasthenia gravis
Anti Nm antibodies which competitively inhibit Ach
Drug of choice is Edrephonium for Tensilon test, diagnosis
Neostigmine for both diagnosis and treatment
Pyridostigmine DoC for treatment (usually)
Premedication of atropine required for removing muscarinic side effects
Edrephonium
Edrephonium ,unlike other carbamates ,binds only to anionic site via ionic bonds
So it is short acting
Hence used for
1. Tensilon test, diagnosis of myasthenia gravis
2. Differential diagnosis of myasthenia gravis and cholinergic crisis
3. Treatment of PVST (paraoxysmal supraventricular tachycardia)
Neostigmine
Quaternary amine (carbamate)
- Treatment and diagnosis of myasthenia gravis with atropine as premedication
- NDMR (non depolarising muscle relaxants) reversal which also competitively inhibit Nm receptor
- Cobra bite treatment: damaged post synaptic membrane
- Bladder stone
- Gastroparesis
Pyridostigmine
Oral long acting drug in quaternary amine of carbamate
Uses:
1. DoC for treatment of myasthenia gravis
2. Postural hypotension
Myasthenia gravis treatment
1. Generalised MG: DoC pyridostigmine If not steroids if not immunomodulators 2. Ocular MG: DoC pyridostigmine if not immunomodulators 3. Myasthenic crisis: DoC IV Ig (IV Ig is also used in Guillain barre syndrome, Kawasaki disease) If not plasmapheresis
Anti cholinergic drug classification
- Muscarinic inhibitors
- Nicotinic inhibitors
A. Nn inhibitors:
ganglionic blockers
2nd line drugs in hypertension
(side effects: postural hypertension)
B. Nm inhibitors- muscle relaxants
Examples of Nn blockers /ganglioside blockers (anti cholinergic)
- Tetra ethyl ammonium-research
- Mecamylamine-Taurette syndrome
- Trimethaphan-HTN emergency
- Hexamethonium
These drugs are used as second line anti hypertensive drugs
Examples of muscarinic receptor blockers
- Tropicamide (shortest acting)
- Atropine (most potent)
- Homatropine
- Cyclopentolate
Tetraethyl ammonium
Nn blockers
So anti hypertensive
Used only as a research drug as it causes potassium channel blockage
Trimethaphan
Nn inhibitors (anti cholinergic) Used by intravenous route for treatment of hypertensive emergency
Mecamylamine
Nn inhibitor (anti cholinergic)
Treatment of Tourette syndrome
Adjunct to nicotine patch in smoking dependence
Effects of anti muscarinic drugs (anti cholinergics)
- CNS: (M1) decreased cognition
- Pupils: (M3) mydriasis and cycloplegia
- Oropharyngeal secretions: decrease
- Lungs: bronchodilatation
- Heart:
increase HR and AVN conduction - GIT: decrease HCl secretions, decrease contraction
- Bladder: decrease detruser concentration
Why is scopolamine called truth serum
Anti muscarinic drugs decrease cognition (M1 receptor inhibition)
So it is used for narcoanalysis
Though the drug of choice for narcoanalysis is thiopentone
The drug of choice for narcoanalysis is
Thiopentone
Uses of mydriatics
And their examples
Examples: muscarinic receptor blockers like:
- Tropicamide: shortest acting so preferred for adults
- Atropine: most potent so preferred in children
- Fundus examination
- To prevent synechae formation for patients with uveitis, corneal ulcer
The anti muscarinic drugs used as pre anaesthetic medication
Why
Glycopyrrolate is used as a pre anaesthetic medication to decrease oropharyngeal secretion (preventing aspiration pneumonia as the cough reflex is suppressed)
It is a quaternary amine so it does not cross the BBB
Uses of muscarinic acid blockers wrt cycloplegia
- Decreases pain in iridocyclitis
2. Refractive error test
Uses of anti muscarinic drugs wrt lungs
- DoC for COPD
2. Bronchial asthma treatment
Drug of choice for COPD is
Anti muscarinic drugs cause bronchoconstriction
Other effects like fibrosis and sclerosis are not reversible
1. Ipratropium: short acting, QID
2. Oxitropium and Aclidineum:
intermediate action, BD
3. ‘Tiotropium’, Umeclidineum, Revefenacin:
Long acting (so DoC), OD
Atropine and heart
- Treatment of bradyarrythmia
- AVN block reversal
Atropine is an anti arrhythmic drug
Side effects of the DoC for COPD
Anti muscarinic drugs Side effects: 1. Dry mouth 2. Glaucoma 3. Urine retention
Anti muscarinic drugs and stomach
Decrease HCl secretions so used in treatment of peptic ulcer disease
Pirenzepine
Tesenzepine
It also decreases contractility
Anti muscarinic drugs used as anti spasmodics
They decrease contraction
Glycopyrrolate
Dicyclomine
Scopolamine (hyoscine)
DoC for motion sickness
Scopolamine (hyoscine)
It is given as transdermal patch
Applied atleast 4-5 hours before journey (acts for 2-3 days)
Also used as an anti-spasmodic
Anti muscarinic drugs and bladder
Effect
Decrease detruser concentration
Used against overactive bladder/ detruser instability ➡️ spontaneous contraction ➡️ urge incontinence
The various examples of drugs used in treating urge incontinence of bladder
Anti muscarinic drugs 1. Non selective anti muscarinic: FFOTT Flavoxate Fesoterodine Oxybutinin (very toxic so used as transdermal patch) Tolterodine Trospium-only quaternary amine (so does not cross BBB) 2. Selective M3 blockers: DS ‘Darifenacin’-most selective so DoC Solifenacin
Classification of sympathomimetics
1. Catecholamines A. Endogenous B. Exogenous 2. Non catecholamines 3. Norepinephrine depletors
Epinephrine
Agonist of α and β1 and β2 (vasodilation) receptors
So more potent cardiac stimulator
1. DoC for cardiac arrest
2. DoC for anaphylactic shock (IM route with multiple dose, if no effect then IV)
3. DoC for brittle asthma
4. Local vasoconstrictor to reduce bleeding
5. Used along with local anaesthetics to increase the duration of action
6. Glaucoma
Norepinephrine
Agonist of α and only β1 receptors More potent vasoconstrictor, so: 1. DoC for vasodilatory shock (sepsis) 2. Cardiogenic shock Side effects: If given via IM route causes muscle necrosis
1:1000 dilution for epinephrine
Used for systemic effect Used via: 1. IM 2. Subcutaneous 3. Endotracheal
1:10,000 dilution for epinephrine
For systemic effect
- IV
- Intracardiac route
- Intraosseous route
1:100,000 dilution for epinephrine
When used as a local vasoconstrictor
1:200,000 dilution for epinephrine is used
Used along with local anaesthetics
Dale’s phenomenon
When epinephrine is given to a living system:
Initially epinephrine acts on α1, so bp increases
Then epinephrine gets metabolised, so bp falls to normal
Then epinephrine acts on β2 receptors, so the bp decreases
The body then produces catecholamines to bring the level back to normal
VMAT2
Inhibitors of it
Vesicular mono amine transporter of the vesicle
It transports dopamine of the axon endings into the vesicle
Inhibitors are:
1. Reserpine
2. Tetrabenazine
3. Derivatives of tetrabenazine like:
Deutetrabenazine
ValbenazineExogenous catecholamines
- Dobutamine- acute CHF, stress ECG
- Fenoldopam and Dopexamine- hypertensive emergency
- Isoprenaline (isoproterenol)-bradycardia, AV Nodal block, bronchial asthma
- Droxidopa-postural hypotension
RDS of norepinephrine or dopamine formation
Inhibitor of this step is
The first step of hydroxylation of tyrosine to DOPA by tyrosine hydroxylase
Metyrosine is an analog of tyrosine which inhibits this step
Formation of norepinephrine occurs in
How
Vesicle
The dopamine is converted into norepinephrine in the vesicle by Dopamine β hydroxylase
Fate of norepinephrine after it stimulates the receptors
- Reuptake back into the pre synaptic neuron (most common 95%)
- Can be metabolised MAO, COMT
- Diffusion from the synaptic cleft
Metyrosine is used in
Analogue of tyrosine Inhibits the RDE Used in: 1. Hypertension 2. Pheochromocytoma as an add on drug
Reserpine is used in
Treatment of tardive dyskinesia
Treatment of hypertension
Tetrabenazine
Inhibitor of VMAT2 of norepinephrine synthesis pathway (like Reserpine, Deutetrabenazin, Valbenazine)
- DoC in Huntington’s chorea
- Treatment of tics associated with Taurette syndrome
Deutetrabenazine and valbenazine
Longer-acting Tetrabenazine derivatives
Inhibitor of VMAT2 of norepinephrine synthesis pathway (like Reserpine, tetrabenazine)
DoC in Tardive dyskinesia
Dopamine β hydroxylase is inhibited by
Disulfiram
No clinical significance
Drugs which inhibit reuptake of norepinephrine
- TCA (Tricyclic antidepressants)
- SNRI (Serotonin norepinephrine reuptake inhibitors)
- Cocaine
Increased norepinephrine ➡️
- Increased blood pressure
- Arrhythmia
DoC for deaddiction of cocaine
Bromocriptine stimulates D2 receptors and gives similar effect
The kick of cocaine is due to increased dopamine ➡️ D2 receptor stimulation (brain)
Cocaine also inhibitors reuptake of norepinephrine
Common side effects of drugs like metyrosine, reserpine, tetrabenazine, deutetrabenazine, valbenazine
These drugs inhibit norepinephrine (depression, hypotension) and dopamine synthesis (Parkinsonism).
Receptors of sympathetic system are which type of receptors
GPCR
Both α and β
α1, α2 and β2 have hyperglycaemic effects via different mechanisms
α1 receptors
Gq subtype of receptors of post-synaptic membrane
Increases Ca
1. Vasoconstriction
2. Contraction of prostatic urethra and bladder sphincter
3. Contraction of radial muscles of iris ➡️ mydriasis
4. Relaxation of GIT smooth muscle due to Ca-dependent K-channels opening
5. Increased glycogenolysis and gluconeogenesis in liver and muscle
α2 receptors
explain
Gi subtype of receptors on the pre synaptic
Exception:
1. Post synaptic and Gq subtype in blood vessels ➡️ vasoconstriction
2. β islet cells is post synaptic Gi subtype ➡️ decreases insulin release ➡️ hyperglycaemia
Stimulated at high concentration
Blocks the release of norepinephrine (autoreceptor)
Clonidine is an agonist
Auto receptors
examples
They reduce the secretion of their own neurotransmitter
- α2 receptors of sympathetic
- M2 of parasympathetic system
- H3 of histaminergic system
- 5HT1 of serotonergic system
Clonidine
α2 receptor agonist given for hypertension patients via IV route
Slow infusion of oral:
presynaptic receptor ➡️ decreases norepinephrine ➡️ vasodilation
Fast infusion (contraindicated):
Post synaptic receptor ➡️ vasoconstriction
β receptors
All are Gs subtype of GPCR
β1,2,3
β1 receptor
Gs subtype
1. Heart:
cAMP increases ➡️ Ca channel phosphorylation ➡️ Increased Ca ➡️ increased CO, HR and conduction
2. JG cells (kidney)
Increased renin ➡️ increased blood pressure
β2 receptors
explain
Gs subtype of receptors on the pre synaptic neuron
Stimulated at low concentrations
Stimulates norepinephrine release
β2 receptor functions and locations
1. Smooth muscle: cAMP➡️ activates MLCP, inhibits MLCK, opens K+ channels ➡️ relaxation: Vasodilation Bronchodilation Relaxation of uterus 2. Cardiac and skeletal muscles: increased cAMP ➡️ phosphorylation of Ca channels ➡️ increased contractility (palpitations, tremors) 3. Hyperglycaemia
β2 receptor and blood glucose level
Gs subtype of GPCR ➡️ increases cAMP:
- Induces glycogenolysis and gluconeogenesis (liver and muscle) ➡️ hypoglycaemic
- Increases insulin release
Predominantly hyperglycaemic
β3 receptors
- Detruser muscle:
Increased cAMP ➡️ relaxation - Adipocytes:
Increased cAMP ➡️ activates hormone sensitive lipase HSL➡️ lipolysis
Treatment of obesity
