Autonomic Nervous System😊

Autonomic Nervous System

Origin: Neurotransmitters

• Preganglionic always Ach

• Parasympathetic always Ach

• Postganglionic sympathetic → Norepinephrine
• Except → Sweat glands → Ach

Actions: Location Parasympathetic Sympathetic

• Mnemonic:
• Sympathy → only in heart → only stimulate heart
• Sexual → Point (Erection → parasympathetic) and shoot (Ejaculation → Symp)

Erection	ㅤ	ㅤ
Mechanism	Parasympathetic (S2, S3, S4 roots)	Non-adrenergic non-cholinergic (NANC) system
Mediated by	Acetylcholine	Nitric oxide • Dilatation of arterioles • Compression of outflow veins • Engorgement & erection (Acts via cGMP)
Ejaculation	ㅤ	ㅤ
Mechanism	Sympathetic	ㅤ

PARASYMPATHETIC SYSTEM

• Major neurotransmitter is ACh.

• It works on cholinergic receptors.

Cholinergic Receptors

• Botulinum toxin → Prevent release of Acetyl choline → ↓ Acetyl choline at synapse

• Physostigmine → Inhibit acetylcholine esterase → ↑ Acetyl choline at synapse

• Mnemonic:
• Ach = Parasympathetic
• Boatil → Cola kittilla (Ach ↓↓) → ↓↓ Parasympathetic
• Flight → Cola kittum (Ach ↑↑) → ↑↑ Parasympathetic

Significance

• Respiratory Failure causing conditions
• Action on Neuromuscular Receptors:
• Aminoglycosides:
• Muscular Contraction (Lower Ach)
• Neuromuscular Toxicity
• DOC: Ca2+
• Krait Bite:
• β bungarotoxin
• Mnemonic: There was a krait () in Bunglow (bungarotoxin)
• Myasthenia Crisis
• Cobra Toxin
• Food Poisoning: Botulinism
• Flappy Infant Syndrome
• Mnemonic: Floppy Boat
• Mx: Ventilation

Uses of Botulinum:

• Tardive Dyskinesia (Torticollis/Cervical Dystonia):
• Injected into SCM

• Urge Incontinence/Overactive Bladder

• Cosmetic:
• To remove glabellar lines

• Unrelaxed LES:
• Achalasia

• Migraine Prophylaxis:
• D/T ↓ CGRP (Calcitonin gene-related peptide) Release

Mnemonic:

• Nicotine (Nicotinic) adich Music (Muscarinic) keett nadakkunnavar → Para

• α and β males → Sympathetic

CHOLINERGIC DRUGS:

Directly Acting Cholinergic Drugs:

• Mnemonic: pILOCarpine → COLI → Cholinergic

Indirectly Acting Cholinergic Drugs

• Acetylcholinesterase (AChE) Inhibitors
• Reversible AChE inhibitors are used clinically
• irreversible AChE inhibitors are toxic.

1. Reversible AChE Inhibitors

• Atropine = Antimuscarinic

Uses of Neostigmine

• Neostigmine → Nicotine vachal
1. Public place urination → Post op urinary retention
2. Walk showing My Ass → Myasthenia Gravis
3. Catch cobra → Cobra bite

Edrophonium Test (Tensilon Test)

• Used to differentiate between Myasthenia and Cholinergic crisis.

• IV Edrophonium given.
  → Very short acting [<10 min]

• If the condition improves for 10 min
• Myasthenia gravis.

• If the condition worsens for 10 min
• Cholinergic crisis.

• Mnemonic: Tension ollapo Edraa phone → 10 minitil

2. Irreversible AChE Inhibitors

• Organophosphates
• Malathion
• Parathion
• Sarin
• Sabin

• Carbamates
• Carbaryl
• Propoxur

Organophosphate Poisoning

• Competitive Irreversible inhibition of Acetylcholine esterase

Clinical Features

• Note:
• Nicotinic symptoms are extremely rare.
• Pinpoint pupil with increase in secretions usually indicates OP poisoning.

Treatment

1. Atropine

• Drug of choice for OP and Carbamate poisoning.
• Note: Atropine is not used in organochlorine (endrin) poisoning.
• Can reverse Muscarinic effects of OP
• Cannot reverse Nicotinic action → muscle weakness.

• Given via IV route every 5 minutes
• until atropinization signs appear
• Signs of Atropinization
• Decreased Secretions (Most reliable, Most specific).
• Mydriasis (Most commonly used sign).
• Tachycardia (Heart Rate > 100 bpm).

• Atropin also used in mushroom poisoning

2. AChE Reactivators (Oximes)

• Not drug of choice.
• Pralidoxime [PAM]
• PAM → peripherally
• Mnemonic: P for P
• Di AcetylMonoxime [DAM]
• DAM → both central and peripheral actions
• Mnemonic: D for Di action → 2 action → peripheral and central

• Only effective in OP poisoning.
• Mnemonic: OOO → oximes only in OP poisoning
• Not uses in Carbamate poisoning

Note

• Oximes not used

• Intermediate syndrome is seen

• No aging

• Less CNS toxicity

Anticholinergic Drugs

Atropine Poisoning: (Anticholinergic Poisoning)

• Patient presents with history of taking wild fruit (Dhatura/Belladonna).

• Signs/Symptoms (DRYD HEAT)
• D - Dry mouth, Delirium
• H - Hyperthermia
• A - Agitation
• T - Tachycardia
• U - Urinary Retention
• R - Restlessness
• A - Accommodation lost (Blurred vision, Photophobia)

• DOC for treatment: Physostigmine.

Sympathetic Nervous System

• Major neurotransmitter: Noradrenaline.

Adrenergic Receptors

Beta Receptors

• Beta → Think of Child birth
• 1st → Janikkum (JG) → HR nokkum (Heart)
• 2nd → Baaki ellam nokkum
• 3rd → weight kurayunnundo (Lipolysis) → Urine pass cheyyunnundo (Prostatic urethra)

• β3 stimulant → given for overactive bladder → Mirabegron

• Mnemonic: Mera bladder gone

Effect on Hypoglycemia

• Mnemonic:
• Beta Beta Mone 123

• Sympathetic system protects from hypoglycemia by two mechanisms:

1. Warning Symptoms	2. Hypoglycemia Reversal
Tachycardia (β1)	By changing metabolism (β2) Glycogenolysis Gluconeogenesis
Palpitations (β1)	ㅤ
Tremor (β2)	ㅤ
Sweating (M3)	ㅤ

• Beta blockers
• Mask hypoglycemia warning symptoms
• Prevent reversal of hypoglycemia.
• Contraindicated in diabetic patients.
• Sweating is the only reliable symptom

Adrenergic Drugs

• Divided into:
• Indirectly Acting Drugs
• Directly Acting Drugs

Indirectly Acting Drugs

Cocaine

• Acts by inhibiting reuptake of Noradrenaline.

• 2 actions
1. Local anaesthetic
• Causes vasoconstriction and hypertension.
• all other LA → vasodilation
2. Addictive drug.
• Tactile hallucinations ("cocaine bugs"): Scratching of skin.
• Causes palatine perforation.
• Overdose characterized by:
• Agitation
• Ulcers or scratch marks on skin
• Sympathetic symptoms
• Tachycardia,
• Mydriasis,
• Hypertension,
• MI

Directly Acting Drugs

1. Catecholamines

2. Non Catecholamines

1. Catecholamines

• Not effective orally.

Endogenous	Exogenous
Adrenaline (α1, α2, β1, β2) Mnemonic: A for all ()	Dobutamine (β1) Mnemonic: ButtamOne → β1
NA (α1, α2, β1) Mnemonic: NA → Not all	Isoprenaline (β1, β2) Mnemonic: Isoprenaline → half of adrenaline
Dopamine (D1, β1, α1) Mnemonic: DoBaOne (D1, β1, α1)	Fenoldopam (D1) For Dopa → always D1

Adrenaline uses

1. Anaphylactic Shock
• DOC
• Route of choice: IM or SC.
• Concentration: 1:1000
• 0.5 ml

2. Cardiac Arrest
• CPR is done first.
• Adrenaline is useful.
• Concentration: 1:10,000 (0.1 mg/mL)
• 10 mL in cardiac arrest
• 1 mL in Anaphylaxis
• Preferred routes: IV > Intraosseous > ET.

3. With LA
• decrease systemic toxicity and increase duration of action.
• 1:1,00,000 - 1:2,00,000.

Noradrenaline uses

• Septic Shock: DOC.

• Effect monitored by checking mean blood pressure.

Summary

• Vasoconstriction → BP ↑ → Vagal stimulation → Reflex ↓ HR

• Adrenaline → ↑ HR and ↑ BP
• Direct ↑ cardiac contractility (β1)
• so it overcomes Reflex bradycardia
• DOC in anaphylactic shock

• NA → ↑BP and ↓HR
• Potent vasoconstriction (α1)
• Reflex bradycardia result in ↓ HR
• But in denervated or atropinised heart
• No reflex bradycardia → ↑↑ HR
• Used in Medical ICU → In shock (except anaphylactic shock)

• Isoprenaline → ↓BP and ↑HR
• In CHB
• Used in Cardiac ICU

Dopamine

• Acts on: DoBBAAOne

Dose (mcg/kg/min)	Receptor	Organ	Action	Mnemonic
< 2	D1	Blood vessels	Vasodilation (↑ in Renal flow)	Do → DIlate
2-10	β1	Heart	HR ↑↑	Ba→ Pa → Pump
> 10	α1	Blood vessels	Vasoconstriction	Mine → constrict

• Uses:
• CHF → Cardiogenic shock
• Dobutamine → First-line if BP adequate
• Dopamine → If mild hypotension
• Norepinephrine → If severe hypotension
• Shock + Oliguria (DOC)

• Drug with ‘dopa’ in their name acts on D1, others do not
• So Dopa in name → D1 stmulation → ↑ Urine O/p

Drug	Mechanism of Action	Clinical Use
Dobutamine	Acts on β₁ receptors	Used for CHF
Dopexamine	Stimulates D₁, β₁, and β₂ receptors; inhibits reuptake of NA	Used for CHF
Fenoldopam	Stimulates only D1 receptors	Used in hypertensive emergencies

Dobutamine – Drug of Choice in

• Cardiogenic shock with low cardiac output and normal or high BP

• Acute decompensated heart failure (ADHF)

• Stress echocardiography (pharmacologic stress test)

2. Non-Catecholamines

• Note: Beta-2 agonists can cause following adverse effects:
• T - Tremors
• T - Tachycardia
• T - T-wave changes in ECG (due to hypokalemia)
• Pulmonary edema (by ritodrine)
• Hyperglycemia
• However, β2 agonists do not cause hypoglycemia.

Clonidine

• Mnemonic: Clonidine → Clutch → Brake

• Brake poyapo (Clonidine withdrawal) → Vandi idich → Pantilu Thola veenu (Phentolamine)

• Mechanism
• Central acting alpha 2 agonist
• ↓ Sympathetic outflow → ↓ Blood pressure

• Uses
• Hypertension
• Opioid withdrawal
• Smoking cessation
• Withdrawal symptom relief:
• ↓ Cravings
• ↓ Anxiety
• ↓ Irritability

• Rebound Hypertension
• Cause
• Abrupt discontinuation of clonidine
• Leads to:
• Upregulation of alpha-1 receptors
• Reduced alpha-2 receptor activity
• ↑ Sympathetic activity → No BRAKE → ↑↑ BP
• Symptoms
• Sudden, marked rise in BP
• Headache
• Dizziness
• Confusion
• DOC: Phentolamine

Norepinephrine Displacers

Mechanism of Action

• Drug (Similar to NE) enters neuron

• NE molecule displaced from vesicle → Synaptic space → Alpha & Beta stimulation → Sympathomimetic effect

• Eg: Tyramine in cheese and wine

Dosing

• Intermittent Dosing
• NE acts on Alpha & Beta receptors
• Sympathomimetic effects

• Continuous Dosing
• Depletion of NE
• Failure of drug & sympatholysis

Metabolism

• NE is metabolised by monoamine oxidase.

Cheese Reaction

• Patient eats together
1. Tyramine containing food
• (Cheese, wine, etc.)
• Displacement of NE
2. MAO Inhibitors
• (Anti-depressants)
• NE not metabolised

• Accumulation of NE
• Hypertensive crisis

• DOC: Phentolamine

• Mnemonic: A depressed patient taking MAO I → celebrates New year (cheese and wine) → comes to EM with ↑ BP

Anti-Adrenergic Drugs

• Alpha blockers

• β - Blockers

ALPHA BLOCKERS

1. Non-selective (α 1 + α 2) blockers

2. Selective α 1 blockers

Adverse Effect

• First Dose → cause Postural Hypotension

• α1 blockers always started at bed-time.

Benign Prostatic Hyperplasia: (BPH)

BETA (β) BLOCKERS

1. Beta-1 + Beta-2 # (First Generation)
• Cardiac and non-cardiac uses.
• Contraindicated in:
• Asthma
• DM
• PVD

2. Beta-1 # (Second Generation)
• Only cardiac uses.
• Relatively safe.

1. Cardio-Selective or 2nd Generation Beta

• New → Nebivolol

• Beta → Betaxolol

• Blockers → Bisoprolol

• Act → Acebutolol

• Exclusively → Esmolol

• At → Atenolol

• Myo → Metoprolol

• Cardium → Celiprolol

• These are relatively safe in:
• Asthma
• PVD
• DM

2. Intrinsic Sympathomimetic Activity [ISA] or Partial Agonists

• Less chances of causing severe bradycardia
• Contain → Celiprolol
• Partial → Pindolol
• Agonist → Alprenolol (Alpam)
• Activity → Acebutolol

1st generation

• 1st generation doctors → Proper Sota Time Nahi
• Propranolol
• Sotalol
• Timolol
• Nadolol

Other Mnemonic:

• LABetolol → Alpha and β blocker

• TILisolol → Tile Potti Open ayi (Potassium opener)

• Sotalol → Close to Pottan (Close Potassium) → QT Prolongation

• Propanolol → Proper Sodium → Proper anasthesia

• NO releasing → Nebi Cealingilkude (celiprolol) Nadannu → Nebivolol, Nadalol

Vasodilation via

Indications

Other Applied Aspects

Hypertrophic Obstructive Cardiomyopathy (HOCM)

• MOA of drug:
• ↓↓ heart contraction →
• ↓↓ LVOT obstruction.

• Treatment (Rx):
• Medical:
• Metoprolol
• If no response, consider CCBs:
• Verapamil or Diltiazem.
• If no response, try Ranolazine.
• Surgical:
• Septal resection.
• Contraindication (C/I):
• Digoxin:
• Increases force of contraction
• Worsens HOCM

Adverse Effects and Contra-indications

• Due to β 1 Blockade
1. ↓ Rate → Bradycardia (C/I in Sick sinus syndrome)
2. ↓ Conduction → AV Block
3. ↓ Contractility → Acute CHF

• Due to β 2 Blockade
1. Asthma
2. Peripheral vascular Disease
3. Diabetes mellitus
4. Variant angina.

Carvedilol

• Non selective

• Cardioprotective antioxidant

• Maximum Plasma Protein binding
• Minimum: Celiprolol

• Used in hepatic venous pressure reduction
• Alpha ⛔ activity
• Intra hepatic vasodilatation
• NonSelective BetaBlocker of choice for prophylaxis of variceal bleeding in high-risk cases.

• Mnemonic: Carvedilol crave for proteins

• MOA: Ca channel blocker

Nebivolol

• Most cardioselective & Cardioprotective

• 3rd generation

• MOA: ↑ NO

Esmolol

• Half-Life (T½)
• Longest: Nadolol
• Mnemonic: Kore Nadannu
• Shortest: Esmolol
• Mnemonic:
• Esmolol → Esterases, Small
• Esma → Asthma, Surgery

• Metabolised by esterases

• DOC in
• Intraoperative blocker
• Aortic dissection as combination therapy
• β blocker in Asthmatics
• Less risk of bronchoconstriction

Aortic Dissection

• Advantage of Treatment:
• ↓ BP
• Reduces risk of aneurysmal rupture.

• Treatment (Rx):
• Esmolol
• Plus Nitroprusside.
• Monotherapy (either alone) is avoided.
• Causes reflex tachycardia.

Beta-Blockers with Special Properties

Water Soluble β Blockers

• Mnemonic: BANANAS CHIPS
• Betaxolol
• Atenolol
• Nebivolol
• Acebutolol
• Nadolol
• Sotalol
• Bisoprolol
• Celiprolol

• Contraindication (CI)
• Renal failure

GLAUCOMA

• It may be due to:
• ↑ Aqueous humor production
• ↓ Aqueous humor drainage

DRUG OF CHOICE

• POAG – Latanoprost

• Angle closure glaucoma – Acetazolamide

• Acute congestive glaucoma – Mannitol

MOA OF DRUGS USED IN GLAUCOMA

Adverse Effects

MiotiCS

• Cataract

• Stenosis of NLD

PGF2α Analogues (Latanoprost)

• Pigmentation of Iris (Heterochromia Iridis)

• Growth of eyelashes (Hypertrichosis)

• Fluid in macula (Macular edema)

• Mnemonic: PGF

• Contra-indicated in uveitis

ApracLonIDine Q

• Lid retraction

Brimonidine Q

• Causes Brain suppression and ocular hypotension in Infants (Leads to Apnea)

• C/I in children < 2yrs

Netarsudil (Rho-kinase inhibitor)Q

• Cornea verticillata.

ANS PRACTICALS

1. Ileum graphQ

• Cholinergic drug → Acetyl choline

• Adrenergic drug → Epinephrine

2. Atropine & Acetylcholine experiment

1. (A) + (B): ACh Action
• Vasodilation (m3) → ↓ BP

2. (C): ACh + Atropine
• Atropine blocks m3 receptors.
• Results in no effect on blood pressure.

3. (D): High Doses of ACh + Atropine
• Stimulate Preganglionic Nn receptors.
• Releases norepinephrine → Vasoconstriction (Nn) → ↑ BP

• Summary
• Acetylcholine alone → ↓ BP
• Acetylcholine (low dose) + Atropine → No change in BP
• Acetylcholine (high dose) + Atropine → ↑↑ BP
• Nicotinic/sympathetic action appear

3. Dale's Phenomenon

• Epinephrine administration → biphasic effect on blood pressure (BP).
• Mnemonic: ACBD
• AC → High price → high dose adrenaline → ↑↑ BP → a curve
• BD → Beedi → Low price → low dose → ↓↓ BP → b curve
• High concentrations of adrenaline:
• α1 receptors → vasoconstriction → ↑↑ BP.
• a curve
• Low concentrations of adrenaline:
• β2 receptors → vasodilation → ↓↓ BP.
• b curve

4. Vasomotor Reversal of Dale

• Epinephrine + α-blocker (Phentolamine):
• Only β action observed → vasodilation → ↓ BP

5. Vasomotor Re-reversal of Dale

• Epinephrine + β-blocker:
• Unopposed α action observed → ↑↑ vasoconstriction
• Steep rise in BP.

• Applied aspect:
• In Pheochromocytoma,
• Alpha before β Blocker

6. Effect on Heart Rate (HR) and Blood Pressure (BP)

• Factors influencing:
• Systolic BP
• Directly proportional
• to cardiac contractility.
• to preload (increased by vasoconstriction).
• Diastolic BP
• Directly proportional to
• tone of peripheral blood vessels.

2. Dog Blood Pressure Experiment

• Ephedrine given → BP ↑ → Same dose is repeated → Less ↑ in BP → Called Tachyphylaxis

Autonomic Drugs and Clinical Uses Summary

Bronchodilation: Inhalation Route of Administration

Pressurized Metered Dose Inhaler (PMDI)

• Gas:
• HydroxyFluoro Alkali (HFA)

• Mechanism
• Placed in mouth
• Canister pressed
• Release of drug
• Coincides with inspiration

• S/E:
• Drug deposition in the oropharynx

Nebulizer (Ipratropium)

• Application
• Inhalable mist
• For acute exacerbation of asthma/COPD

• Components
• High air flow
• Container for drug solution

Side Effect: Paradoxical Bronchoconstriction

• Causes
1. Hypotonic solution
• Avoid
• Use isotonic solution
2. Bromide
3. Blocking of presynaptic m2 (autoreceptor)
• Increases Ach
• Stimulates postsynaptic m3
• Leads to bronchoconstriction
4. Excipients like EDTA and Benzalkonium chloride