Coagulation pathway & related drugs , anaesthetic relevance & ASRA Guidelines - MD Anaesthesia PG exam

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ASRA 5th edition 2022 anticoagulation guidelines table summary heparin LMWH warfarin DOACs time intervals neuraxial

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I now have all the material needed. Here is the comprehensive MD Anaesthesia PG-exam answer:

Coagulation Pathway, Related Drugs, Anaesthetic Relevance & ASRA Guidelines

Source: Miller's Anesthesia 10e (Chapters 46, 60, 77) | ASRA PM Evidence-Based Guidelines, 5th Edition (2022)

PART 1 - THE COAGULATION CASCADE

The Classic Model (Waterfall/Cascade)

The traditional model divides haemostasis into three pathways:

Classic coagulation cascade - extrinsic and intrinsic pathways

Coagulation factors are synthesised in the liver and circulate as inactive zymogens. Each activated factor carries the suffix "a" (e.g., Factor IIa = thrombin). Activation requires assembly of membrane-bound complexes on phospholipid surfaces (platelets/microparticles) with: enzyme + substrate + cofactor + calcium. This confines clot formation to sites of injury.

A. Extrinsic Pathway (Initiation Phase)

Step	Detail
Trigger	Vascular injury exposes subendothelial Tissue Factor (TF)
Key complex	TF + Factor VIIa + Ca²+ on phospholipid surface
Products	Activates Factor X → Xa AND Factor IX → IXa (cross-talk with intrinsic)
Inhibitor	TFPI (Tissue Factor Pathway Inhibitor) rapidly extinguishes TF/VIIa activity
Lab test monitored by	PT / INR (prothrombin time)

Small amounts of Factor VIIa normally circulate in plasma; this is why the extrinsic pathway can be activated immediately after injury.

B. Intrinsic Pathway (Amplification Phase)

Step	Detail
Classic trigger	Contact activation - Factor XII activated by negatively charged surfaces
Modern understanding	Primarily an amplification system - propagates thrombin generation begun by extrinsic pathway
Sequence	XII → XIIa → XI → XIa → IX → IXa
Key activation complex	Tenase complex: FIXa + FVIIIa + Ca²+ + phospholipid → activates Factor X
Lab test monitored by	aPTT (activated partial thromboplastin time)

Note for exams: Factor XII, prekallikrein, and HMWK deficiencies prolong aPTT but do NOT cause clinical bleeding - this is why the intrinsic pathway is an amplifier, not the initiator.

C. Common Pathway

Step	Detail
Tenase complexes (intrinsic + extrinsic)	Both converge to activate Factor X → Xa
Prothrombinase complex	FXa + FVa + Ca²+ + phospholipid converts Prothrombin (II) → Thrombin (IIa)
Thrombin actions	Cleaves fibrinopeptides A & B from fibrinogen → fibrin monomers → polymerize
Stabilization	Factor XIIIa (activated by thrombin) cross-links fibrin strands → insoluble clot
Lab tests	Both PT and aPTT

Thrombin is the master regulator - it also activates platelets, activates Factors V and VIII (positive feedback), activates Factor XI, and activates Factor XIII.

Clot formation at vascular injury: initiation, propagation, stabilization

D. Natural Anticoagulant Mechanisms (Counter-Regulatory Pathways)

Four major systems prevent excess clot propagation:

System	Mechanism
Fibrinolysis	Plasmin (from plasminogen via t-PA/urokinase) degrades fibrin; limited by alpha-2-antiplasmin and PAI-1
TFPI	Complexes with FXa → inhibits TF/FVIIa → downregulates extrinsic pathway
Protein C system	Thrombin + Thrombomodulin (TM) activates Protein C; Protein C + Protein S degrade FVa and FVIIIa
SERPINs	Antithrombin (AT-III) inhibits thrombin, FXa, FIXa; heparin 1000x potentiates AT-III

Fibrinolytic pathway: plasminogen, plasmin, t-PA, PAI-1, antifibrinolytics

PART 2 - DRUGS AFFECTING COAGULATION & THEIR SITES OF ACTION

A. Anticoagulants

1. Unfractionated Heparin (UFH)

Mechanism: Binds antithrombin (AT-III), potentiates inhibition of thrombin (IIa), FXa, FIXa (ratio ~1:1 anti-IIa:anti-Xa). Requires AT-III to work.
Monitoring: aPTT (target 60-100s for therapeutic), ACT (intraoperative cardiac surgery)
Reversal: Protamine sulfate (1 mg per 100 units UFH)
Anaesthetic relevance: Used for intraoperative anticoagulation in cardiac/vascular surgery; IV onset immediate, subcutaneous onset ~1 hour

2. Low Molecular Weight Heparin (LMWH - Enoxaparin, Dalteparin)

Mechanism: Preferentially inhibits FXa (anti-Xa:anti-IIa ratio ~4:1); less effect on thrombin because chains too short to bridge AT-III to thrombin
Monitoring: Anti-Xa levels (ASRA recommends against routine anti-Xa testing as no safe level established for neuraxial procedures)
Reversal: Protamine (partial - ~60% reversal of anti-Xa activity)
Advantage over UFH: More predictable pharmacokinetics, less HIT risk

3. Fondaparinux (Selective Factor Xa Inhibitor)

Synthetic pentasaccharide, selectively inhibits FXa via AT-III
No reversal agent (andexanet alfa now available)
Half-life ~17-21 hours; renal excretion

4. Warfarin (Vitamin K Antagonist)

Mechanism: Inhibits Vitamin K epoxide reductase → depletes vitamin K-dependent factors: II, VII, IX, X, Protein C, Protein S
Factor VII has the shortest half-life (6h) → PT/INR rises first
Protein C depletie first → transient procoagulant state when initiating
Monitoring: PT/INR (target 2-3 for most indications)
Reversal: Vitamin K (slow, 12-24h), FFP (immediate), PCC (4-factor, fastest)

5. Direct Oral Anticoagulants (DOACs)

Drug	Target	Half-life	Renal excretion	Reversal
Dabigatran	Direct thrombin (IIa) inhibitor	12-17h	>80%	Idarucizumab
Rivaroxaban	Direct FXa inhibitor	5-9h	66%	Andexanet alfa
Apixaban	Direct FXa inhibitor	8-15h	27%	Andexanet alfa
Edoxaban	Direct FXa inhibitor	10-14h	50%	Andexanet alfa

6. Argatroban / Bivalirudin (Direct Thrombin Inhibitors - Injectable)

Direct thrombin inhibitors; used when HIT is diagnosed
Argatroban: hepatic metabolism (safe in renal failure); monitor aPTT
Bivalirudin: bivalent DTI; used in PCI/cardiac surgery

B. Antiplatelet Drugs

Drug	Mechanism	Anaesthetic Note
Aspirin	Irreversible COX-1 inhibition → reduced TXA2	Hold 7 days for neuraxial; continue for cardiac risk patients
Clopidogrel / Ticlopidine	Irreversible P2Y12 (ADP) receptor antagonist	Hold 7 days (clopidogrel), 10 days (ticlopidine)
Prasugrel	Irreversible P2Y12 antagonist (more potent)	Hold 7-10 days
Ticagrelor	Reversible P2Y12 antagonist	Hold 5-7 days
Cangrelor	IV reversible P2Y12	Hold 3 hours
Abciximab (GPIIb/IIIa inhibitor)	Irreversible GPIIb/IIIa blockade	Hold 24-48 hours
Tirofiban / Eptifibatide	Reversible GPIIb/IIIa blockade	Hold 4-8 hours

C. Thrombolytics (Fibrinolytics)

t-PA (Alteplase), Streptokinase, Urokinase
Convert plasminogen → plasmin → lyse fibrin
Contraindicated with neuraxial techniques; wait 10 days post-thrombolysis before neuraxial

D. Antifibrinolytics

Tranexamic Acid (TXA): Lysine analogue; blocks plasminogen binding to fibrin → inhibits fibrinolysis; widely used perioperatively to reduce blood loss
Epsilon-aminocaproic acid (EACA): Similar mechanism
Aprotinin: Serine protease inhibitor; also inhibits kallikrein (withdrawn due to renal toxicity concerns)

PART 3 - ANAESTHETIC RELEVANCE OF COAGULATION

Monitoring in Theatre

Test	Measures	Normal
PT / INR	Extrinsic + common pathway (F VII, X, V, II, fibrinogen)	INR <1.5 for neuraxial
aPTT	Intrinsic + common pathway	25-38 seconds
ACT	Bedside heparin monitoring in cardiac/vascular surgery	400-480s on bypass
Platelet count	Platelet number	>80,000 for neuraxial
TEG/ROTEM	Viscoelastic - clot formation dynamics	Guides product replacement
Anti-Xa	LMWH/fondaparinux levels	No established "safe" level for neuraxial

Coagulation & Cardiac Surgery (CPB)

CPB circuits cause: hemodilution, thrombocytopenia, platelet dysfunction, hyperfibrinolysis, factor dilution, hypothermia-induced coagulopathy
UFH 300-400 units/kg given before CPB; target ACT >400-480s
Protamine reversal 1:1 at end; heparin rebound possible 30-90 min later
Antifibrinolytics (TXA) routinely used to reduce surgical blood loss

DIC (Anaesthetic Relevance)

Lab hallmarks: low platelets + prolonged PT + prolonged aPTT + elevated D-dimer + low fibrinogen Triggered by: obstetric emergencies, massive transfusion, sepsis, trauma Management: treat underlying cause + selective blood component transfusion

PART 4 - ASRA GUIDELINES (5th Edition, 2022)

Regional Anaesthesia in the Patient Receiving Antithrombotic or Thrombolytic Therapy

The risk of spinal/epidural haematoma varies from 1:22,000 (elderly women, spinal for hip fracture) to 1.38:10,000 (epidural in orthopaedic surgery). ASRA principles:

Timing of needle/catheter insertion and removal must reflect pharmacokinetics of the specific anticoagulant
Neurologic monitoring is essential - maintain dilute LA concentrations to permit neurologic assessment
Concurrent use of multiple anticoagulants additively increases bleeding risk
If neuraxial haematoma suspected: urgent MRI and neurosurgical decompression within 8 hours

Table: ASRA 5th Edition Time Intervals - Neuraxial Procedures

Drug	Before needle/catheter	Resume after block/catheter removal	Notes
UFH SC 5000u q8-12h	4-6h + normal aPTT	1h	Check platelets if >4 days
UFH SC 7500-10,000u BD	12h + normal aPTT	1h
UFH SC >10,000u/dose or >20,000u/day	24h + normal aPTT	1h
UFH IV infusion	4-6h + normal aPTT	1h
Intraoperative heparinization (vascular surg)	Minimum 1h after needle placement before IV heparin	1h after catheter removal
LMWH prophylactic (enoxaparin 40mg/dalteparin 5000u)	12h	4h after block/12h after catheter removal	No concurrent hemostasis drugs
LMWH therapeutic (enoxaparin 1mg/kg BD or 1.5mg/kg OD)	24h	4h after block/24h after catheter removal
Fondaparinux	36-42h	6-12h	Single-needle pass only; no catheter
Warfarin	Stop 5 days; INR <1.5	12-24h after block	Check INR before catheter removal
Dabigatran	CrCl ≥80: 72h; CrCl 50-79: 96h; CrCl 30-49: 120h; unknown: 120h	6h	Contraindicated with indwelling catheter
Rivaroxaban	High dose (20mg): 72h; Low dose (10mg): 24h	6h	No catheter with standard dose
Apixaban	High dose (5mg BD): 72h; Low dose (2.5mg BD): 36h	6h
Edoxaban	72h	6h
Aspirin	OK to proceed (no mandatory hold)	Immediate	Continue for cardiac patients
Clopidogrel	7 days	Immediate (no LD) / 6h (with LD)	Contraindicated with catheter in situ
Ticlopidine	10 days	Same
Prasugrel	7-10 days	Same
Ticagrelor	5-7 days	Same
Cangrelor	3 hours	Same
Abciximab	24-48h	Contraindicated
Tirofiban/Eptifibatide	4-8h	Contraindicated
Thrombolytics (full dose)	10 days	Contraindicated	No neuraxial during therapy
Thrombolytics (1mg catheter clearance)	Contraindicated	-

Peripheral Nerve Blocks & ASRA

Superficial/compressible blocks (e.g., femoral, interscalene): generally lower risk; time intervals less strict
Deep/non-compressible blocks (e.g., paravertebral, psoas compartment, infraclavicular): same recommendations as neuraxial apply
Risk stratification: consider site, compressibility, proximity to neuraxis, and patient factors

Special Situations

Obstetric patients on LMWH:

Prophylactic LMWH: wait 12h before neuraxial
Therapeutic LMWH: wait 24h
Do NOT give LMWH within 4h of block or catheter removal

Patients on dual antiplatelet therapy (e.g., post-stent):

Stopping P2Y12 inhibitors carries risk of stent thrombosis
Balance thrombotic vs haematoma risk; multidisciplinary discussion mandatory

Patients with HIT:

Heparin absolutely contraindicated
Use argatroban or bivalirudin (DTIs) as alternatives
Argatroban: check aPTT; hepatic metabolism

Quick Exam Memory Aids

"Five things Warfarin inhibits": II, VII, IX, X + Protein C & S (mnemonic: 1972 = factors 1,9,7,2 + PC/PS)

DOAC "3 days rule" for high-dose neuraxial: all standard-dose DOACs need 72h (3 days) before neuraxial block

LMWH "12 and 24": 12h for prophylactic dose; 24h for therapeutic dose before neuraxial

Restart timing: Most agents restart 6-12h after neuraxial (block or catheter removal)

aPTT monitors: Intrinsic pathway (XII, XI, IX, VIII) + UFH therapy PT/INR monitors: Extrinsic pathway (VII) + warfarin therapy

Sources: Miller's Anesthesia 10th Edition, Chapter 46 (Hemostasis/Coagulation), Chapter 60 (Orthopedic Anaesthesia), Chapter 77 (Epidural Analgesia) | ASRA 5th Edition Guidelines (2022) | NYSORA ASRA Summary

Platelet mechanism and anti platelet drugs

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I have comprehensive data from Braunwald's Heart Disease, Barash's Clinical Anesthesia 9e, Harrison's, and Goodman & Gilman's. Now let me compile the full answer.

Platelet Mechanism & Antiplatelet Drugs

Sources: Barash Clinical Anesthesia 9e | Braunwald's Heart Disease | Harrison's 22e | Goodman & Gilman's

PART 1 - PLATELET STRUCTURE & OVERVIEW

Platelets are anucleate disc-shaped cells (2-4 µm diameter), derived from megakaryocytes in bone marrow. Normal count: 150,000-400,000/µL. They are the cornerstone of primary haemostasis - forming the initial platelet plug at sites of vascular injury.

Platelet granules:

Granule Type	Contents	Function
Dense granules (δ)	ADP, ATP, serotonin, Ca²+	Amplify platelet activation (ADP is major recruiter)
Alpha granules (α)	vWF, fibrinogen, Factor V, PF4, P-selectin, fibronectin, clotting factors	Coagulation support, inflammation
Lysosomes	Hydrolases	Clot remodelling

PF4 (Platelet Factor 4) from alpha granules binds and neutralises heparin - the heparin-PF4 complex is the target antigen in HIT (Heparin-Induced Thrombocytopenia)

PART 2 - PLATELET MECHANISM: FOUR SEQUENTIAL STEPS

Platelet pathway: adherence, activation, stabilization, inhibition - full signaling diagram (Barash Clinical Anesthesia)

STEP 1 - ADHESION

Endothelial disruption exposes the subendothelial matrix, triggering platelet adhesion via two mechanisms depending on shear conditions:

Shear Condition	Adhesion Molecule	Platelet Receptor	Example Vessel
High shear (arterial)	von Willebrand Factor (vWF) from endothelium/subendothelium	GP Ib/IX/V complex	Arteries
Low shear (venous)	Collagen (subendothelial)	GP Ia/IIa (integrin α2β1) and GP VI	Veins

Key point: In high-shear arterial flow, vWF acts as a "molecular bridge" between subendothelial collagen and the platelet GPIb receptor. Anemia reduces platelet margination (RBCs normally push platelets to vessel wall periphery), impairing adhesion.

STEP 2 - ACTIVATION

Activation is triggered by multiple platelet agonists acting on G-protein coupled receptors (GPCRs), all converging on Phospholipase C (PLC):

Agonist	Receptor	Source
Thrombin (most potent)	PAR-1 (primary), PAR-4	Coagulation cascade
ADP	P2Y1 (shape change), P2Y12 (amplification/aggregation)	Dense granules
Thromboxane A2 (TXA2)	TP receptor	Arachidonic acid/COX-1 pathway
Serotonin	5-HT2A	Dense granules
Epinephrine	α2-adrenergic	Systemic circulation
Collagen (direct)	GP VI, GP Ia/IIa	Subendothelium

Intracellular signalling cascade (PLC pathway):

Agonist → GPCR → PLC activation
                    ↓
         IP3 → Ca²+ release from stores
                    ↓
         Dense granule & α-granule secretion (ADP, serotonin, vWF, PF4...)
         Ca²+ → PLA2 → Arachidonic acid → COX-1 → TXA2
         DAG → PKC → GP IIb/IIIa shape change ("inside-out signalling")
         Ca²+ → platelet shape change: disc → spiky (pseudopods)

Additional activation effects: Surface P-selectin expression, CD40 ligand release, microparticle release, leukocyte activation

STEP 3 - AGGREGATION (Stabilization)

Platelet aggregation is the final common pathway and depends entirely on GP IIb/IIIa (αIIbβ3 integrin) - the most abundant receptor on platelet surface (~80,000 copies/platelet).

Activated PLC → DAG → PKC → "inside-out signalling" changes the conformation of GP IIb/IIIa
Activated GP IIb/IIIa binds fibrinogen (low shear) and vWF (high shear)
Divalent fibrinogen bridges adjacent GP IIb/IIIa receptors on neighbouring platelets → platelet-platelet crosslinking
Fibrin strands (from the coagulation cascade) then weave through these aggregates to form the stable platelet plug

STEP 4 - PHYSIOLOGICAL INHIBITION

To prevent excessive clotting, endothelium actively inhibits platelets:

Inhibitor	Mechanism	End result
Prostacyclin (PGI2)	Binds IP receptor → ↑cAMP → PKA activation	Inhibits vWF adhesion, TXA2, PLC
Nitric oxide (NO)	↑cGMP → PKG activation	Inhibits TXA2 receptor
cAMP phosphodiesterase (PDE)	Degrades cAMP	Removes inhibitory cAMP signal

Pharmacological note: Dipyridamole and cilostazol inhibit PDE, thereby sustaining cAMP levels and potentiating PGI2's inhibitory effect.

PART 3 - ANTIPLATELET DRUGS (Full Classification)

Sites of action of antiplatelet drugs - from plaque disruption to platelet aggregation

CLASS 1 - COX-1 INHIBITORS

Aspirin (Acetylsalicylic Acid)

Feature	Detail
Mechanism	Irreversibly acetylates COX-1 → prevents arachidonic acid → TXA2 conversion → reduced platelet activation and recruitment
COX-2 effect	Only at high doses (~1g/day) - inhibits prostacyclin synthesis in endothelium (potentially pro-thrombotic at high doses)
Dose	75-325 mg/day; loading dose 160-300 mg (non-enteric-coated) for rapid effect
Duration of action	7-10 days (lifetime of platelet - anucleate, cannot synthesise new COX)
Monitoring	Bleeding time (no routine lab test)
Reversal	Platelet transfusion (1-2 units sufficient, as transfused platelets have intact COX)
Resistance	~25% of patients ("aspirin resistance") - CYP polymorphisms, non-compliance
Anaesthetic relevance	Continue for most procedures (cardiac stents); hold 7 days for neuraxial (ASRA)

CLASS 2 - ADP (P2Y12) RECEPTOR ANTAGONISTS

The P2Y12 receptor is the key ADP receptor that mediates platelet aggregation and amplification. ADP also binds P2Y1 (causes shape change only).

Thienopyridines (Prodrugs - require hepatic activation)

Drug	Generation	Mechanism	Reversibility	Key features
Ticlopidine	1st	Irreversible P2Y12 blockade	Irreversible (7-10 days)	Withdrawn due to TTP/agranulocytosis; hold 10 days pre-neuraxial
Clopidogrel	2nd	Prodrug - activated by CYP2C19 (hepatic) → irreversible P2Y12 block	Irreversible (7 days)	Variable response due to CYP2C19 polymorphisms; most widely used; hold 7 days
Prasugrel	3rd	Prodrug - faster, more complete activation by CYP3A4/esterases → irreversible P2Y12 block	Irreversible (7-10 days)	More potent than clopidogrel; higher bleeding risk; avoid in age >75y, weight <60kg, prior CVA; hold 7-10 days

Clopidogrel resistance: Due to CYP2C19 loss-of-function polymorphisms (PM phenotype) - ~30% of population cannot adequately activate clopidogrel. PPIs (especially omeprazole) may further inhibit CYP2C19. Testing with platelet function assay or genotyping recommended in high-risk cases.

Non-thienopyridines (Direct - no prodrug activation needed)

Drug	Mechanism	Route	Reversibility	Half-life	Key features
Ticagrelor	Allosteric, reversible P2Y12 blockade	Oral	Reversible	7-9h	Does NOT require CYP activation; faster onset/offset than clopidogrel; preferred in ACS; causes dyspnoea (adenosine reuptake inhibition) and bradycardia; platelet transfusion NOT effective for reversal (drug binds transfused platelets); hold 5-7 days
Cangrelor	Direct, reversible P2Y12 blockade	IV only	Reversible	3-5 min	Immediate onset; offset within 1 hour; used perioperatively when oral P2Y12 must be held; hold only 3 hours pre-neuraxial

CLASS 3 - GP IIb/IIIa ANTAGONISTS (Platelet Aggregation Inhibitors)

These block the final common pathway of platelet aggregation - inhibit fibrinogen/vWF binding to activated GP IIb/IIIa.

Drug	Type	Half-life	Reversibility	Key features
Abciximab (ReoPro)	Fab fragment of humanised monoclonal antibody against activated GPIIb/IIIa	Dissociation t½: days (drug-receptor complex persists on platelet for up to 2 weeks)	Functionally irreversible	Also blocks αvβ3 (vitronectin receptor) and MAC-1 on leukocytes; IV use during PCI
Eptifibatide (Integrilin)	Synthetic cyclic peptide (KGD sequence - mimics fibrinogen)	2.5h	Reversible (within hours of stopping)	Renal excretion; used in UA/NSTEMI and PCI
Tirofiban (Aggrastat)	Non-peptide RGD mimetic	2h	Reversible	IV use in ACS

ASRA: Hold 24-48 hours (abciximab) or 4-8 hours (eptifibatide/tirofiban) before neuraxial.

CLASS 4 - cAMP PHOSPHODIESTERASE (PDE) INHIBITORS

Drug	Mechanism	Uses	Notes
Dipyridamole	Inhibits PDE3 + adenosine reuptake → ↑cAMP/cGMP → PKA/PKG → platelet inhibition; also inhibits TXA2 synthesis	TIA/stroke prevention (with aspirin - Aggrenox)	Also causes vasodilation; used in stress echo; half-life 10h
Cilostazol	Inhibits PDE3A → ↑cAMP → platelet inhibition; also vasodilatory	Peripheral artery disease (claudication)	Contraindicated in heart failure; hold 48h before neuraxial (ASRA)

CLASS 5 - PAR-1 (THROMBIN RECEPTOR) ANTAGONIST

Drug	Mechanism	Use	Notes
Vorapaxar (Zontivity)	Competitive PAR-1 inhibitor → blocks thrombin-mediated platelet activation	Secondary prevention post-MI (with aspirin/clopidogrel)	Long half-life (8 days); irreversible in clinical practice; contraindicated in prior stroke/TIA

PART 4 - COMPARISON TABLE OF P2Y12 INHIBITORS

Feature	Clopidogrel	Prasugrel	Ticagrelor	Cangrelor
Class	Thienopyridine	Thienopyridine	Cyclopentyl-triazolopyrimidine	ATP analogue
Prodrug?	Yes	Yes	No	No
Activation	CYP2C19	CYP3A4/esterases	Direct	Direct
Binding	Irreversible	Irreversible	Reversible	Reversible
Route	Oral	Oral	Oral	IV only
Loading dose	300-600 mg	60 mg	180 mg	Bolus + infusion
Maintenance	75 mg OD	10 mg OD	90 mg BD	Infusion
Offset	7 days	7-10 days	5 days	1 hour
CYP interaction	Major (CYP2C19)	Minor	CYP3A4 substrate	None
PPI interaction	Yes (omeprazole)	No	No	No
Dyspnoea	No	No	Yes (15%)	Possible
Hold before neuraxial	7 days	7-10 days	5-7 days	3 hours
Reversal	Platelet transfusion	Platelet transfusion	Ineffective (transfused platelets also inhibited)	Stop infusion (1h)

PART 5 - ANTIPLATELET DRUGS - ANAESTHETIC RELEVANCE

Perioperative Management

Indication	Decision
Aspirin alone	Generally continue (especially for cardiac/stent patients); hold only for neuraxial per ASRA
Dual antiplatelet therapy (DAPT) post-coronary stent	Risk stratification essential: stopping P2Y12 inhibitor within 30 days (BMS) or 12 months (DES) risks catastrophic stent thrombosis; multidisciplinary discussion mandatory
Elective surgery	Defer if within recommended hold period
Emergency surgery	Accept bleeding risk; consider platelet transfusion

Platelet Transfusion

Drug	Transfusion Effective?
Aspirin	Yes - residual aspirin diluted by new platelets with intact COX
Clopidogrel / Prasugrel	Yes - irreversible binding only to existing platelets; transfused platelets unaffected
Ticagrelor	No - circulating free drug will bind and inhibit transfused platelets
GP IIb/IIIa inhibitors	Abciximab: partially effective (drug redistributes to new platelets); Eptifibatide/Tirofiban: effective after drug level drops

Platelet Function Testing

Bleeding time (Ivy's method): not recommended routinely (poor correlation with surgical bleeding)
PFA-100: detects aspirin and clopidogrel effect; rapid, bedside-suitable
TEG/ROTEM: viscoelastic tests - detect platelet dysfunction in MA (maximum amplitude)
VerifyNow assay: specific for aspirin (ARU) and P2Y12 (PRU)
Light transmission aggregometry (LTA): gold standard for platelet function

Quick Exam Memory Aid

Steps of platelet activation: A-A-A-I (Adhesion → Activation → Aggregation → Inhibition)

Agonists that activate platelets: "TATS-E" - Thrombin, ADP, TXA2, Serotonin, Epinephrine

GP IIb/IIIa inhibitors: "Abcixi-Eptifi-Tirofi" → "AET" - all IV, all block final common pathway

Irreversible P2Y12 blockers: Ticlopidine, Clopidogrel, Prasugrel (all thienopyridines) Reversible P2Y12 blockers: Ticagrelor, Cangrelor (direct - no prodrug)

Clopidogrel resistance pathway: Clopidogrel → CYP2C19 (liver) → active metabolite → P2Y12 blockade. Omeprazole inhibits CYP2C19 → reduced efficacy.

Sources: Barash's Clinical Anesthesia 9e (Chapter 17, Primary Haemostasis) | Braunwald's Heart Disease 12e (Chapter 95, Antiplatelet Drugs) | Harrison's 22e (Chapter 123) | Goodman & Gilman's Pharmacological Basis of Therapeutics

ANS - anaesthesia relavant anatomy and physiology with changes in ANS during anaesthesia- MD ANAESTHETIA PG EXAM 30 marks answer

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I now have comprehensive data from all sources. Let me compile the complete 30-mark MD Anaesthesia PG exam answer.

Autonomic Nervous System (ANS) - Anaesthesia-Relevant Anatomy & Physiology, and Changes During Anaesthesia

Sources: Barash's Clinical Anesthesia 9e (Chapter 14) | Braunwald's Heart Disease | Guyton & Hall | Ganong's Physiology | Katzung's Pharmacology

SECTION 1 - FUNCTIONAL ANATOMY OF THE ANS

The ANS is the part of the CNS and peripheral nervous system concerned with the involuntary regulation of cardiac muscle, smooth muscle, and glandular and visceral functions. It maintains homeostasis through two major divisions and a third (enteric) system.

Central Autonomic Organisation

The hypothalamus is the highest integrating centre of the ANS. It coordinates:

Anterior hypothalamus: parasympathetic functions (heat dissipation, cardiodeceleration)
Posterior/lateral hypothalamus: sympathetic functions (heat conservation, the "defence reaction")

Other central centres:

Nucleus tractus solitarius (NTS): primary integration of baroreceptor and chemoreceptor afferents
Rostral ventrolateral medulla (RVLM): main vasomotor centre; maintains resting sympathetic tone
Dorsal motor nucleus of vagus: parasympathetic outflow to thoracic and abdominal viscera
Locus coeruleus: noradrenergic nucleus; modulates arousal and sympathetic tone
Periaqueductal grey (PAG): descending modulation of pain and ANS activity

Peripheral ANS Organization - The Two-Neuron Arc

All ANS efferent pathways consist of two neurons in series:

Preganglionic neuron: cell body in CNS → myelinated (B fibre) → synapse in ganglion
Postganglionic neuron: cell body in ganglion → unmyelinated (C fibre) → effector organ

Schematic distribution of craniosacral parasympathetic and thoracolumbar sympathetic systems (Barash Clinical Anesthesia 9e)

Efferent ANS schematic - pre and postganglionic neurotransmitters (Barash)

SECTION 2 - SYMPATHETIC NERVOUS SYSTEM (SNS)

Anatomy

Feature	Detail
Origin	Intermediolateral grey column of spinal cord, T1-L3
Alternative name	Thoracolumbar division
Preganglionic fibre	Short, myelinated (B-fibre), 3mm diameter; speed 3-15 m/s
Ganglia location	Paravertebral chain (22 paired ganglia) OR unpaired collateral ganglia (celiac, superior/inferior mesenteric)
Postganglionic fibre	Long, unmyelinated (C-fibre); speed <2 m/s
Divergence ratio	1 preganglionic → many postganglionic → diffuse, widespread response
Neurotransmitter	Pre: ACh (nicotinic receptor); Post: Norepinephrine (adrenergic receptors)
Exception 1	Sweat glands and sympathetic vasodilator fibres: postganglionic releases ACh
Exception 2	Adrenal medulla - directly innervated by preganglionic fibers; chromaffin cells (modified postganglionic neurons) release 80% EPI + 20% NE directly into blood

Sympathetic Chain - Three Courses of Preganglionic Fibre

Synapse in ganglia at level of exit
Course up/down the chain to synapse at other levels
Pass through chain without synapsing → prevertebral (collateral) ganglia

Key Sympathetic Ganglia and Clinical Relevance

Ganglion	Level	Relevant Anaesthesia Point
Cervicothoracic (Stellate)	C7-T1	Stellate block for CRPS, arrhythmias, Horner's syndrome when blocked
Celiac plexus	T12-L1 (prevertebral)	Celiac plexus block for upper abdominal cancer pain
Superior hypogastric plexus	L5-S1	Pelvic pain procedures

SECTION 3 - PARASYMPATHETIC NERVOUS SYSTEM (PNS)

Anatomy

Feature	Detail
Origin	Craniosacral outflow: CN III, VII, IX, X + S2-S4
Alternative name	Craniosacral division
Preganglionic fibre	Long, myelinated; synapse near or within the target organ
Postganglionic fibre	Very short, unmyelinated
Convergence	Limited distribution → discrete, localised responses
Neurotransmitter	Pre: ACh (nicotinic); Post: ACh (muscarinic receptors)

Cranial Parasympathetic Outflow

Nerve	Ganglion	Target
CN III (Oculomotor)	Ciliary ganglion	Pupil constriction (miosis), accommodation
CN VII (Facial)	Pterygopalatine + Submandibular ganglia	Lacrimal, nasal, salivary glands
CN IX (Glossopharyngeal)	Otic ganglion	Parotid gland
CN X (Vagus)	Ganglia in/near organs	Heart, lungs, GI tract to splenic flexure - 75% of all PNS activity

Sacral Parasympathetic Outflow (S2-S4)

Via pelvic splanchnic nerves (nervi erigentes)
Innervates: descending colon, rectum, bladder, genitalia
Mediates erection (NO-mediated); bladder detrusor contraction

SECTION 4 - NEUROTRANSMITTERS AND RECEPTORS

Cholinergic Neurotransmission (ACh)

Synthesis: Choline + Acetyl-CoA → ACh (enzyme: Choline acetyltransferase) Storage: Synaptic vesicles Release: Ca²+-dependent exocytosis Degradation: Acetylcholinesterase (AChE) → choline + acetic acid (choline recycled)

Cholinergic Receptors

Receptor	Type	Location	Effect	Antagonist
Muscarinic M1	GPCR (Gq)	Brain, gastric glands	CNS excitation, acid secretion	Atropine
Muscarinic M2	GPCR (Gi)	Heart (SA, AV nodes)	↓HR, ↓conduction velocity	Atropine
Muscarinic M3	GPCR (Gq)	Smooth muscle, glands	Bronchoconstriction, secretion, GI motility	Glycopyrrolate
Nicotinic Nn	Ligand-gated ion channel (α3β4)	Autonomic ganglia	Ganglionic transmission	Hexamethonium, trimethaphan
Nicotinic Nm	Ligand-gated ion channel (α1β1δε)	Neuromuscular junction	Muscle contraction	Neuromuscular blockers

Anaesthetic note: Volatile anaesthetics and ketamine potently inhibit both ganglionic (α3β4) and CNS (α4β2) nicotinic receptors.

SLUDGE (Muscarinic Stimulation Mnemonic)

Salivation, Lacrimation, Urination, Defecation, GI cramps, Emesis

Adrenergic Neurotransmission (NE/EPI)

Catecholamine Synthesis Pathway:

Tyrosine → DOPA → Dopamine → Norepinephrine → Epinephrine
    (tyrosine hydroxylase - rate-limiting step)

Termination of action: Primarily by neuronal reuptake (Uptake 1) back into the nerve terminal; metabolised by MAO (intraneuronal) and COMT (extraneuronal).

Adrenergic Receptors - Comprehensive Table

Receptor	Coupling	Location	Effect	Clinical Use
α1	Gq → IP3/DAG → ↑Ca²+	Peripheral vascular smooth muscle, myocardium, urethral sphincter	Vasoconstriction, +inotropy (minor), urinary retention	Phenylephrine (vasopressor)
α2 (pre)	Gi → ↓cAMP	Presynaptic terminals	Inhibit NE release (negative feedback)	Clonidine, dexmedetomidine
α2 (post)	Gi → ↓cAMP	CNS, coronaries, platelets	Sedation, analgesia, ↓MAC, platelet aggregation	Dexmedetomidine: ICU sedation
β1	Gs → ↑cAMP → PKA	SA node, AV node, myocardium, kidneys (JGA)	↑HR, ↑Inotropy, ↑Dromotropy, ↑Renin	Dobutamine (cardiac surgery)
β2	Gs → ↑cAMP → PKA	Bronchial, vascular, uterine smooth muscle; liver	Bronchodilation, vasodilation, glycogenolysis, uterine relaxation	Salbutamol, terbutaline
β3	Gs	Adipose tissue, bladder	Lipolysis, bladder relaxation	-
DA1	Gs	Renal, mesenteric, coronary vessels; renal tubule	Vasodilation, natriuresis, diuresis	Dopamine at 2-5 µg/kg/min, Fenoldopam
DA2	Gi	Presynaptic sympathetic terminals	↓NE release, secondary vasodilation	-

Receptor Up/Down-Regulation (Clinically Important)

Downregulation: Prolonged exposure to agonist → internalization of receptors → tachyphylaxis. E.g., chronic heart failure → β1 receptor downregulation (reduced inotropic response to catecholamines)
Upregulation: Chronic antagonist use → increased receptor numbers. E.g., chronic β-blocker therapy → up to 100% increase in β receptor numbers → β-blocker withdrawal syndrome (acute discontinuation = unopposed α stimulation + increased β receptors)
Clinical implication: Clonidine withdrawal follows the same mechanism

SECTION 5 - ANS REFLEXES (ANAESTHETIC RELEVANCE)

Baroreceptor Reflex

Pathway:

↑BP → Stretch of carotid sinus (CN IX) / aortic arch (CN X)
  → Nucleus Tractus Solitarius (NTS) in medulla
  → ↑Vagal tone (↓HR) + ↓Sympathetic vasomotor tone
  → BP returns to normal

Component	Location	Relevance
High-pressure sensors	Carotid sinus (CN IX), Aortic arch (CN X)	Major baroreceptors
Low-pressure sensors	Atria, pulmonary vessels, ventricles (Bainbridge reflex)	Volume sensing
Integration centre	NTS in medulla → RVLM → dorsal vagal nucleus	Drug targets (dexmedetomidine acts here)
Effectors	SA node (HR), peripheral vasculature (SVR)	Main cardiovascular determinants

Anaesthetic significance: Most anaesthetic agents blunt the baroreceptor reflex, explaining the haemodynamic instability seen during induction. Degree of blunting: Volatile agents > Propofol > Ketamine (maintains baroreflex).

Chemoreceptor Reflex

Peripheral: Carotid and aortic bodies (hypoxia, hypercapnia, acidosis) → ↑Ventilation + ↑Sympathetic tone
Central: Medullary chemoreceptors (CO2/H+) → ↑Ventilation
Volatile agents and opioids depress peripheral chemoreceptor response to hypoxia

Bainbridge Reflex

Atrial stretch receptor activation (volume overload) → reflex tachycardia via vagal afferents
Competes with baroreceptor reflex; the net HR response depends on the dominant reflex at the time

Bezold-Jarisch Reflex

Stimulation of ventricular C-fibres (serotonin, capsaicin, ischaemia) → bradycardia + hypotension + vasodilation (triad)
Mechanism: Vagal efferent activation + sympathetic withdrawal
Clinical relevance: Paradoxical bradycardia with spinal anesthesia, hypovolaemia in upright position, can cause vasovagal syncope

SECTION 6 - DIFFERENTIAL AUTONOMIC EFFECTS ON ORGANS

Organ	Sympathetic	Parasympathetic	Dominant Tone
Heart (SA node)	↑HR (β1)	↓HR (M2)	Parasympathetic (resting HR <100 due to vagal tone)
Heart (contractility)	+Inotropy (β1, β2)	Minimal	Sympathetic
Coronary arteries	Constriction (α1) / Dilation (β2, metabolic)	Dilation	Metabolic autoregulation
Peripheral vessels	Constriction (α1)	None (except vasodilator fibres in vessels)	Sympathetic
Bronchi	Bronchodilation (β2)	Bronchoconstriction (M3)	Parasympathetic
GI tract	↓Motility, ↑sphincter tone (α)	↑Motility, ↓sphincter tone (M)	Parasympathetic
Bladder detrusor	Relaxation (β2)	Contraction (M3)	Parasympathetic
Bladder sphincter	Contraction (α1)	Relaxation	Sympathetic
Pupil	Dilation - mydriasis (α1, dilator pupillae)	Constriction - miosis (M3, sphincter pupillae)	Equal tone
Salivary glands	Thick, viscid saliva (α)	Profuse, watery saliva (M)	Parasympathetic
Sweat glands	Diaphoresis (ACh via sympathetic!)	None	Sympathetic (cholinergic)
Adrenal medulla	EPI + NE release	None	Sympathetic
Liver	Glycogenolysis (α + β)	Glycogen synthesis	Sympathetic
Kidney	↑Renin (β1), vasoconstriction	None	Sympathetic
Eye ciliary muscle	Relaxation - far vision (β)	Contraction - near vision/accommodation (M3)	Parasympathetic

SECTION 7 - CHANGES IN ANS DURING ANAESTHESIA

This is the most important section for an MD Anaesthesia exam.

A. PREOPERATIVE / STRESS RESPONSE

Before induction, surgical anxiety activates the HPA axis and SNS:

↑Plasma catecholamines (NE and EPI)
↑HR, ↑BP, ↑cardiac output
Pupil dilation, dry mouth, diaphoresis
Premedication with midazolam, alpha-2 agonists (dexmedetomidine, clonidine) attenuates this

B. INDUCTION OF ANAESTHESIA

Propofol

Strong SNS depression: reduces muscle sympathetic nerve activity (MSNA)
Blunts baroreceptor reflex → ↓SVR and ↓HR → significant hypotension
Reduces cardiac output
Mechanism: facilitates GABA-A, inhibits NE release centrally

Thiopentone/Barbiturates

Inhibits sympathetic outflow from brainstem (reduces MSNA)
Blunts baroreflex → hypotension
Despite lower BP, reflex tachycardia may be seen (baroreceptors partly functional)
Mechanism: GABA-A potentiation + direct myocardial depression

Etomidate

Cardiovascular stability: minimal effect on SNS
Does NOT significantly blunt baroreceptor reflex
Neither heart rate nor blood pressure change significantly
Drug of choice in haemodynamically unstable patients

Ketamine - Unique Dissociative Profile

Indirect sympathomimetic: inhibits reuptake of NE into sympathetic nerve terminals → ↑plasma catecholamines
Net effect: ↑HR, ↑BP, ↑cardiac output, ↑SVR, ↑myocardial O2 demand
Centrally: direct myocardial depression (masked by SNS stimulation in healthy patients)
Important: In catecholamine-depleted patients (e.g., prolonged haemorrhagic shock, burns), the direct myocardial depressant effect is unmasked → cardiovascular collapse possible
Baroreflex maintained with ketamine (unlike most agents)
S(+)-ketamine: increases MSNA despite ↑BP; racemic ketamine does not significantly increase generalised SNS outflow

Midazolam/Benzodiazepines

Mild SNS depression
Minimal baroreceptor blunting
Cardiovascular stability maintained

C. LARYNGOSCOPY AND TRACHEAL INTUBATION

This represents the most powerful acute sympathetic stimulus in routine anaesthesia:

Mechanism:

Mechanical stimulation of pharynx/larynx → afferents via CN IX, X
Activates NTS → massive sympathetic discharge
Releases EPI and NE from adrenal medulla and sympathetic terminals
Response: ↑HR (up to 30-50%), ↑MAP (up to 20-30 mmHg), ↑intracranial pressure, ↑intraocular pressure

At-risk patients: Coronary artery disease, cerebrovascular disease, aortic aneurysm, hypertensive patients

Attenuation strategies:

Drug	Mechanism	Dose
Opioids (fentanyl 2-3 µg/kg)	Central sympatholytic + blunts laryngeal reflexes	Pre-induction
Lidocaine IV (1.5 mg/kg)	Blunts laryngeal afferents	90s before laryngoscopy
Esmolol (1-2 mg/kg)	β1 blockade	Pre-induction bolus
Labetalol	α+β blockade
Dexmedetomidine (0.5-1 µg/kg)	α2 agonist - central sympatholysis	Pre-induction infusion
Clonidine	α2 agonist	Premedication
Deep anaesthesia	↑volatile concentration	Must balance against cardiovascular depression

D. VOLATILE ANAESTHETIC AGENTS

All volatile agents cause dose-dependent depression of sympathetic nervous activity:

Agent	Primary ANS Effect	Baroreceptor Effect	HR Effect	BP Effect	Special Feature
Halothane	↓SNS activity; ↑vagal tone	Markedly blunted	Bradycardia	↓↓↓BP	Sensitizes myocardium to catecholamines → arrhythmias; do NOT use with epinephrine
Enflurane	↓SNS activity	Blunted	↑HR (reflex)	↓↓BP	Less sensitization to catecholamines than halothane
Isoflurane	↓SNS activity (central); ↓SVR	Blunted	↑HR (reflex tachycardia due to ↓BP)	↓↓BP	Dilates coronary vasculature
Sevoflurane	↓SNS activity	Moderately blunted	Minimal change	↓BP (less than isoflurane)	Safest for bronchospasm; cardiac conduction stable
Desflurane	↓SNS activity at steady state	Special: rapid ↑ in concentration → acute SNS stimulation → ↑HR, ↑BP (catecholamine surge)	Tachycardia with rapid ↑	Transient ↑BP with rapid ↑	"Sympathetic response to desflurane" on rapid concentration increase

Mechanism of volatile agent SNS depression:

Inhibit ganglionic transmission (nicotinic α3β4 receptors)
Depress RVLM vasomotor centre
Blunt baroreceptor and chemoreceptor reflexes
Reduce NE release from sympathetic terminals
Direct myocardial depression (decrease calcium availability)

Halothane sensitization to catecholamines (HIGH YIELD):

Mechanism: Halothane + catecholamines → re-entrant cardiac arrhythmias
Maximum safe dose of epinephrine with halothane: 2 µg/kg (vs 10 µg/kg with isoflurane/sevoflurane)

E. OPIOIDS AND ANS

Effect	Detail
Central vagomimetic	Opioids stimulate vagal nucleus → bradycardia (especially morphine, fentanyl, remifentanil)
↓SNS activity	Reduce NE release from sympathetic terminals at supraspinal level
Histamine release	Morphine (not fentanyl/remifentanil) → histamine release → peripheral vasodilation
Blunt stress response	High-dose opioids (cardiac anaesthesia: 50-100 µg/kg fentanyl) significantly attenuate sympathoadrenal response to surgical stimulation
Respiratory depression	Blunts peripheral chemoreceptor response to hypoxia
Remifentanil	Most potent vagomimetic → severe bradycardia; use with glycopyrrolate

F. NEURAXIAL ANAESTHESIA (SPINAL/EPIDURAL)

Neuraxial block produces a "chemical sympathectomy" proportional to the level and density of block.

Cardiovascular effects - depend on level:

Block Level	SNS Blocked	Cardiovascular Effect
Below T10	Only lumbar/sacral sympathetics	Minimal cardiovascular change
T4-T6	Most splanchnic sympathetics	↓SVR, ↓preload, ↓BP (major)
Above T4 (cardiac accelerator fibres)	T1-T4 cardiac sympathetics blocked	Bradycardia + ↓contractility + ↓BP
High spinal (above T1)	All SNS + phrenic nerve	Cardiovascular collapse possible; Bezold-Jarisch reflex precipitated

Mechanism of hypotension in spinal anaesthesia:

Sympathetic efferent block → arterial vasodilation (↓SVR)
Venous dilation → venous pooling → ↓preload → ↓cardiac output
If T1-T4 blocked: cardiac accelerators blocked → bradycardia

Bezold-Jarisch Reflex in Spinal Anaesthesia:

Occurs with hypovolaemia + upright position
Vigorous "empty" ventricle contracts against low volume → stimulates ventricular mechanoreceptors
Results in: paradoxical bradycardia + hypotension (reflex vagal activation + sympathetic withdrawal)
Management: Atropine + fluid/vasopressor + Trendelenburg

G. SPECIFIC DRUGS AFFECTING ANS - ANAESTHESIA PHARMACOLOGY

Drug Class	Drug	ANS Effect	Anaesthesia Use
α2-Agonists	Dexmedetomidine	↓NE release (presynaptic α2) → sedation, analgesia, ↓MAC (70-90%), ↓sympathetic tone, bradycardia, ↓BP initially	ICU sedation, adjunct to GA, awake fibreoptic intubation
α2-Agonists	Clonidine	Same mechanism, longer acting	Premedication, neuraxial adjuvant
β-Blockers	Esmolol	β1 blockade → ↓HR, ↓BP	Blunt laryngoscopy response; SVT
Anticholinesterases	Neostigmine	↑ACh → muscarinic effects: bradycardia, bronchospasm, ↑secretions, gut motility	Reversal of NMB; always with anticholinergic
Anticholinergics	Atropine	Blocks muscarinic M2 (heart) → ↑HR, ↓secretions	Bradycardia, premedication
Anticholinergics	Glycopyrrolate	Quaternary amine - does NOT cross BBB; longer acting; potent antisecretory	Preferred with neostigmine reversal
Vasopressors	Phenylephrine	α1 agonist → vasoconstriction, reflex bradycardia	Spinal hypotension (preserves uteroplacental flow)
Vasopressors	Ephedrine	Indirect α+β → ↑HR + ↑BP	Spinal hypotension (preferred in obstetrics - older teaching)
Sympatholytics	Labetalol	α1+β blocker	Hypertension control perioperatively

H. REGIONAL AND LOCAL ANAESTHETIC EFFECTS ON ANS

Epidural adrenaline (epinephrine) with LA: systemic absorption → β2 effects (tachycardia, ↓K+), local vasoconstriction prolongs block, absorption test marker
Interscalene block: proximity to sympathetic chain → ipsilateral Horner's syndrome (miosis, ptosis, anhidrosis, enophthalmos) in up to 100% - due to stellate ganglion block
Stellate ganglion block: deliberate therapeutic use for CRPS, hot flushes, arrhythmias

SECTION 8 - AUTONOMIC SYNDROMES RELEVANT TO ANAESTHESIA

Syndrome	Mechanism	Anaesthetic Implication
Horner's Syndrome	Interruption of oculosympathetic pathway (T1 → superior cervical ganglion → eye)	Expected after interscalene block; concerning if new post-intubation
Autonomic Dysreflexia	Spinal cord injury above T6: uncontrolled SNS below lesion with exaggerated responses	Triggered by surgical/bladder stimulation; severe hypertension + bradycardia; requires deep anaesthesia
Orthostatic Hypotension	Failure of sympathetic vasoconstriction on standing	Treat with position, fluids, phenylephrine; common post-spinal
Diabetic Autonomic Neuropathy	Loss of sympathetic regulation + vagal tone	"Silent MI", gastroparesis (aspiration risk), labile BP, resting tachycardia, orthostatic hypotension
MAO Inhibitors	↑Synaptic catecholamines (block MAO)	Avoid indirect sympathomimetics (ephedrine, tyramine foods → "hypertensive crisis"); avoid pethidine (serotonin syndrome); use direct-acting vasopressors only
Tricyclic Antidepressants	Block NE reuptake + anticholinergic	Exaggerated response to indirect vasopressors; anticholinergic effects
Carcinoid Syndrome	Tumour secretes serotonin, bradykinin, histamine, tachykinins	Perioperative carcinoid crisis (flushing, bronchospasm, hypotension); treat with Octreotide
Phaeochromocytoma	Catecholamine-secreting tumour	Pre-operative α-blockade (phenoxybenzamine 10-14 days) → then β-blockade; intraoperative hypertensive crisis on tumour handling

SECTION 9 - SUMMARY TABLE: ANS EFFECTS OF COMMON ANAESTHETIC AGENTS

Agent	HR	BP	SVR	Cardiac Output	Baroreflex	Special ANS Note
Propofol	↓	↓↓	↓↓	↓	Blunted	Vagomimetic; hypotension via SNS depression
Thiopentone	↑ (reflex)	↓	↓	↓	Blunted	Reflex tachycardia common
Etomidate	NC	NC	NC	NC	Maintained	Cardiovascular stability; choice in shock
Ketamine	↑↑	↑↑	↑	↑	Maintained	Indirect sympathomimetic; catecholamine release
Halothane	↓↓	↓↓	↓	↓↓	Blunted	Sensitizes myocardium to catecholamines
Isoflurane	↑ (reflex)	↓↓	↓↓	NC/↑	Blunted	Reflex tachycardia from vasodilation
Sevoflurane	NC	↓	↓	NC/↓	Moderate blunting	Safest for cardiac; minimal HR change
Desflurane	↑↑ (rapid ↑)	↑ (rapid ↑)	↑ (rapid ↑)	NC	Blunted	Sympathetic surge with rapid concentration ↑
Morphine	↓	↓	↓	↓	Blunted	Histamine release; vagomimetic
Fentanyl	↓↓	NC	NC	NC	Blunted	Potent vagomimetic; no histamine
Remifentanil	↓↓↓	↓	↓	↓	Blunted	Most potent bradycardia of all opioids
Dexmedetomidine	↓↓	↓	↑ (initial) then ↓	↓	Maintained	Biphasic BP; profound α2 agonism; ↓MAC 70-90%
Spinal (T4-T6)	↓ (if above T4)	↓↓	↓↓	↓	Bypassed	Chemical sympathectomy

QUICK EXAM MNEMONICS

Cranial nerve parasympathetic outflow: "3, 7, 9, 10" (OIII, OVII, OIX, OX)

Sympathetic thoracolumbar levels: T1-L3 (or T1-L2/L3)

All preganglionic fibers release: ACh (both SNS and PNS preganglionic = nicotinic)

Adrenal medulla exception: Preganglionic SNS fiber → ACh (nicotinic on chromaffin cells) → EPI + NE release

Sweat glands exception: Sympathetic innervation but ACh (muscarinic) is the neurotransmitter

Ketamine vs all others: Only anaesthetic that ↑HR + ↑BP (indirect sympathomimetic)

Desflurane: Only volatile that causes acute SNS surge with rapid concentration increase

Halothane sensitisation: Avoid epinephrine-containing LA solutions during halothane; maximum 2 µg/kg adrenaline

Sources: Barash, Cullen & Stoelting's Clinical Anesthesia 9e (Chapter 14 - Anesthesia and the Autonomic Nervous System) | Braunwald's Heart Disease 12e | Guyton & Hall Medical Physiology | Katzung's Basic & Clinical Pharmacology 16e | ANS Sympathetic Review - Anesthesiology 2008

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