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in

Autonomic nervous system

Sympathetic
Neurotransmitter is NE

T1-L3

1:20-1:100 ratio

Preganglionic shorter, postganglionic longer

Parasympathetic

Ach

Cranio sacral outflow

3,7,9,10

S2,3,4

1:1 for preganglionic to postganglionic fiber

Preganglionic longer than postganglionic fiber

Cholinergic system

Acetylcholine
Synthesis, storage, metabolism

Synthesis
Choline and sodium

Symport

Choline plus acetyl co A

Acetylcholine

Vesicular uptake

Stored in vesicles

Ca enters

Release of Ach

Muscarinic and nicotinic receptor

Metabolism by cholinesterase

True cholinesterase located at synapse

Pseudo cholinesterase is in plasma

1. Rate limiting step hemicholinium

2. Vesamicol

3. Botulinum toxin, spider venom, inhibits release

4. Lambert eaton syndrome

Sites of release of Ach as neurotransmitter

All the preganglionic fibers of sympathetic and parasympathetic release

Ach

Fibers to Adrenal medulla

NMJ

Postganglionic parasympathetic fiber

Postganglionic sympathetic fiber release NE

Exception

Sweat glands, M3, Ach

Renal blood vessel, dopamine

In the medulla, NE methylated to epi , N methyl transferase

Neuro humoral transmission in medulla

Methylation is a phase 2 reaction

Usually sympathetic system uses NE

Botulinum A toxin

Inhibits release of Ach release from vesicles

Plastic surgery

Correction of blepharospasm

Strabismus

Onabotulinum toxin is a sub type of A, useful for prophylaxis of migraine

Botulinum toxin B

Skeletal ms relaxant

Saxitoxin, shellfish infected, produced by dinoflagellates

Tetradoxin also

Na channel blocker

Cause loss of sensation

Alpha bungarotoxin

Component of venom of banded krait or King cobra

Irreversible antagonist of Nm receptor( nicotinic muscle)

Thus a paralytic type of poison

Thus treated by

Cholinesterase inhibitor: neostigmine given with atropine

Ach accumulates

Atropine counteracts the muscarinic receptors activation and not the

nicotinic

Cholinoceptors

Muscarinic
Nicotinic

Muscarinic
M1,2,3,4,5

All muscarinic are G protein coupled receptors

Phospholipase C pathway is called Gq, produces IP3/ DAG as second
messenger
M1,3,5 go through Gq pathway

M2,4
Go through Gi pathway
Second messenger is cAMP

Receptor mechanism
Locations
Cell surface
Cytoplasm
Nucleus
Cell surface receptors
3 categories

1. Ligand gated receptors, fastest acting

2. G protein coupled
3. Enzyme linked receptor

Ligand gated receptor

Located within or near the ionic channel
Blocks the channel if activated
Eg. Receptor for lignocaine

GABA A receptor is ligand gated

Opening of chloride channel
BZD and barbiturates acts on this
Barbiturates act on surface of Alpha and subunits

Alpha and Y unit related to BZD

Similarily
When
Nm receptor acted on by Ach
Na and Ca channel open
Thus Nm receptor is also ligand gated
G protein pulped receptor

Serpentine shape
7 membrane structure

G protein normally seen as GDP

Has three sub units
Alpha, , Y
When drug acts on receptor
GDP changes to GTP
Alpha remains attached, and Y leave
Thus GTP alpha unit is the active most

Can go through
Gq, IP3/ DAG, M1,3,5 and alpha 1
Or
Gi or Gs, cAMP, M2, alpha 2 and
Enzyme linked receptor

Cell membrane receptor

Connected with an enzyme at the lower end
Transmembrane receptor

Eg. Receptor for insulin, enzyme linked is Tyrosine kinase

Non receptor action of tyrosine kinase

CML
Imatinib is the tyrosine kinase inhibitor
Imatinib resistant CML
New drugs
Dasatinib
Nilotinib

If a receptor is associated with JAK Janus kinase:

Growth hormone receptor
Pegvisoment : growth hormone receptor blocker

Intracellular receptors
Cytoplasmic
Nuclear
Cytoplasmic
Eg. Corticosteroids

Nucleus
Eg. Thyroid hormone, estrogen, testosterone, vit A and D
All amine hormone act on cell surface except thyroid hormone

M1 receptor

Present in stomach
Cholinergic stimulation causes gastritis
Vagotomy or M1 blocker
Selective M1 blocker useful for gastritis
Pirenzipine
Telenzipine
Agonist is Oxotermorine

M2 receptors

Selective M2 agonist is Methacholine

Vagal or M2 stimulation will cause
Delay in the conduction velocity

Ventricular rate controlled in AF by Methacholine

It delays the conduction rate
Although Digoxin is used instead of Methacholine
Usually digoxin inhibits Na K ATPase
Ca accumulates Intracellularily
Increased force of contraction,thus used in heart failure

Although in AF the action is vagomimetic on AVN

The ventricular rate gets controlled

In atrial flutter
It converts flutter to AF
Digoxin can only be used for atrial arrythmias

All antiarrythmics cause bradycardia

Except some which are antivagal
Thus cause ventricular tachycardia
Class 1a
Quinidine
Procainamide
Disopyramide: highest antivagal action
Thus prior administration of digoxin inhibits quinidine induced
tachycardia

These 3 drugs can cause constipation and retention of urine

Thus contraindicated in BPH

Selective M2 blocker are

Methoctramine
Triptramine

In patients prone for asthma, Methacholine acts on M3 in the

bronchus causing spasm, precipitating Asthma
Thus, it is Methacholine challenge test for diagnosis of Asthma

M3 receptor

3 different areas
Smooth ms
Eye
Gland( exocrine)
Smooth muscles
Vascular endothelium has only M3 receptor but no cholinergic
innervation
Thus exogenous Ach will show response
Release EDRF
Decrease in BP

In visceral organs
Smooth muscles of bronchi, GIT , genitourinary tract

In lungs, bronchospasm
In GIT, stimulation of peristalsis
Useful for paralytic ileus: Bethanecol
Similarily act on urinary tract to relive post OP urinary retention

Eye
Pupil is surrounded by circular or sphincter or constrictor ms
These have M3 receptor

Radial ms or longitudinal ms or dilator pupilae

These have alpha 1 receptor

Pilocarpine
Ecothiophate: organophosphate , irreversible anticholinesterase

Above two when used

Miosis
If phenylephrine is used
Alpha 1 stimulant
Pupillary dilation
Mydriasis

Mydriasis can also be produced by M3 blocker

Timolol has no effect on pupil size as it is a blocker

Oculomotor nerve stimulation will cause Miosis as it is a
parasympathetic nerve
Thus pilocarpine will reverse the Mydriasis produced by occulomotor
nerve injury as the receptors still present

Pilocarpine and ecothiophate

Used in glaucoma
By promoting drainage
Through canal of. Schlemm

Common side effect of topical ecothiophate is cataract

Exocrine glands

Lacrimal
Salivary
Sweat
M3 stimulation produces Lacrimation, sweating, salivation

Cevimeline is a M3 agonist useful in Sjogren syndrome

Xerotomia can also be caused by radiation
Amifostine is a radio protective, used in such cases
Cisplatin causes nephrotoxic , Amifostine is nephroprotective in such
cases

Nicotinic receptor

Nm: muscle
Nn: neuronal ganglia

Nm
Cholinergic drugs thus used in MG as it increases the muscle strength
Thus to produce ms relaxation during Sx,
We need to block Nm receptor
Ach causes ms contraction or depolarization
D tubocurarine competes for Nm receptor
Thus the depolarization does not happen
Thus called non depolarizing
Competitive antagonism is always reversible
Neostigmine is used
Sugammadex is a new drug for
Vecuronium: cardio friendly
Pancuronium: anti vagal property
Rocuronium: fastest acting

Succinylcholine
Structurally and functionally similar to Ach
Post OP Muscle fasciculation and pain is side effect of Sch
Duration of action is 5-7 min
Undergo metabolism by pseudo cholinesterase
But genetically abnormality
Atypical pseudo cholinesterase
Action more than 5-7 minutes
Leading to Sch apnea
Flaccid paralysis

Treatment for Sch apnea

Ventilatory support
Fresh blood transfusion as pseudo cholinesterase present in plasma

Dibucaine no. is used to differentiate

More than 80% hydrolysis: pseudo
Less than 20%: atypical
Nn receptor

Nn receptor seen on sympathetic , parasympathetic and medullary

ganglia
The drug/ neurotransmitter stimulating is Ach
Thus Ganglionic stimulation will cause HT as too much NE
Ganglionic blocker/ Nn blocker can be used to control HT
Hexamethonium
Trimethaphan
Mecamylamine

Trimethaphan is used to produce controlled hypotension

Mecamylamine is used to control smoking
Anti smoking drugs
First line therapy
Vareniciline- nicotine agonist, suicidal ideation
Nicotine patch: available as gum, patch, lozenges, oral and nasal
inhaler but no tablet
Bupropion, best drug,atypical antidepressant, norepinephrine
dopamine reuptake inhibitor, also used in wt loss,ADHD in adult
( in children, methylphenidate and atomoxetine)
Side effect is seizure

Second line therapy

Clonidine
Nortyptaline
Misc
Rimonabant: cannabinoid 1 antagonist, wt loss,prevents craving of
alcohol
Side effects: psychiatry problems, withdrawn
Topiramate, side effect of nephrolothiasis and wt loss
Mecamylamine

Treatment of atropine poisoning( belladonna poisoning)

Doc is Physostigmine
Neostigmine does not cross BBB
Ach not used therapeutically as metabolized

Side effects of Ach

D
U
M
B
B
E
L
S
S
Drugs that undergo metabolism by pseudo cholinesterase
Plasma
Sch, 25 min
Mivacurium( shortest acting among non depolarizing), day care Sx
Ester LA( except cocaine)
All ester linked undergo metabolism by esterase
Cocaine in liver by cyto P 450 enzyme
Esmolol, 5-15 minutes, only IV administration,used for emergency
control of HT
Remifentanil, analgesic agent, shortest acting opioid
4 fentanyls in opioid
Fentanyl, 100 X, 30 min
Sufentanil, 1000X, 30 min
Alfentanil, 5 X, 5-10 min
Remifentanil, 100 X, 3-5 min( shortest acting)

All are more potent than morphine

Least potent opioid

Pethidine and propoxyphene ( 1/10 X)

Fentanyl + droperidol = neuroleptic analgesia

Femtanyl + droperidol + N2O = neuroleptic anesthesia
Most common side effect: post OP truncal rigidity
Anticholinesterase
Reversible
Carbamates
Physostigmine, plant product, lipid soluble, doc for atropine
poisoning
Neostigmine, direct Nm stimulatory activity, thus used in MG, curare
poisoning, cobra bite
Pyridostigmine, also used for MG as duration of action is long
Edrophonium, very short acting, diagnostic purpose of MG,
ameliorative test( Tensilon test)
All are water soluble
Rivastigmine
Donepezil
Galantamine
All are cerebro selective anticholinesterase, thus used for Alzheimer's

Tacrine( acridine) is not used anymore, due to hepatotoxicity

Irreversible anticholinesterase
Organophosphate

Diflos
Ecothiophate, useful for glaucoma , causing cataract
Parathion
Malathion, used for pediculosis, lice infestation
Diazinon
Tabun, slow acting
Sarin, 3-5 hrs
Soman, fastest acting,2 min
All 3 are nerve gas poison
Treatment is by atropine and oxime
But oxime causes HT which can be treated by
phentolamine( reversible non selective alpha blocker)
Nerve gas cause convulsion, treated by diazepam

OPC poisoning
Atropine takes care of muscarinic receptor actions
Pralidoxime will reactivated the cholinesterase
Oxime binds with Anionic site since OPC bind with esteric site
Thus oxime is not useful for carbamate poisoning as they bind to
both sites

Irinotecan: anti cancer drug

Topoisomerase 1 inhibitor
It has anticholinesterase activity
Diarrhea is the drug limiting side effect

Mushroom poisoning
Amantoxine acts by inhibiting mRNA

Muscarinic type: into bye and related species, atropine useful

Anticholinergic/ hallucinogenic type: isoxazole compound in A.
Muscaria, atropine CI
Phalloidin type: peptide toxin( amatoxin), A phalloides, inhibits
mRNA and protein
Toxicity of GIT, liver, kidney
Only supportive therapy
Thiotic acid
Penicillin( non infective use of penicillin)
Herbal products
Silibinin

Herbal products

Ephedra: cold, wt loss, abused by athletes

Garlic: lipid lowering, inhibit HMG Co A reductase
Ginkgo biloba: dementia( neuronal glycoside)
Milk thistle( silybin): mushroom poisoning
St. John's wort: active compound is Hyperforin, mono
amine( serotonin, NE) reuptake inhibitor, natural antidepressant
It's a strong enzyme inducer
Drug interaction common

Saw palmetto: BPH , similar to finasteride

Coenzyme Q: statin induced myopathy
Glucosamine: osteoarthritis
Melatonin: jet lag, remelteon is melatonin like molecule used to treat
insomnia
Echinacea: improves immune function
Terminalis Arjuna: heart failure
Myaesthenia gravis

Autoimmune disease
Ab against Nm receptor

Ameliorative test
Provocative test
Both are non specific
Specific test : show the Ab, by biopsy

Neostigmine: direct Nm activity

Pyridostigmine : longer acting
Plasmapheresis
Thymectomy
Steroids( anti inflammatory, anti cancer,
Steroid inhibiting phospholipase A2 have anti inflammatory activity
Apoptosis of lymphocytes is the anti cancer action
Immunosuppressant activity is due to the T helper cells,inhibit IL 1
and 6

Azathioprine( anti metabolites: anti purine group) and cyclosporine

All anti metabolites have anti cancer and immunosuppressant activity
Mtx: CHORIOCARCINOMA and RA, psoriasis
Azathioprine only has immunosuppressive activity
All anti metabolites have myelo suppression

Immunosuppressants
Cyclosporine
Tacrolimus FK506
Sirolimus
Everolimus

Activation of T cell
Intracellular increase of Ca
Activation of Calcineurin
NFATc moves from cytoplasm to nucleus
IL-2 released
Acts on mTOR receptor

Cyclosporine binds to cyclophilin

While tacrolimus binds to FKBP12
Both inhibit Calcineurin , Calcineurin inhibitors
Both cause nephrotoxicity, tacrolimus more than cyclosporine
Tacrolimus is a macrolide antibiotic
Cyclosporine has side effects not seen with tacrolimus
Hypertrophy of gums
Hirsuitism
Hypertension: treated by CCB

Sirolimus and everolimus are IL-2 receptor blocker

Useful for cardiac transplant
For preparing coronary stent , drug eluting
Renal angiomyolipoma with tuberous sclerosis
Post menopausal breast cancer
Side effect
Thrombocytopenia
Hyperlipidemia
HUS

Quinine has a skeletal ms relaxing activity, thus CI in MG

Thus used in nocturnal leg cramps
Other Abx having ms relaxant activity
Amino glycosides
Tetracycline
Polypeptide Abx