Vasopressin and Analogues Pharmacology

Quick Answer

Vasopressin (arginine vasopressin, AVP), also known as antidiuretic hormone (ADH), is an endogenous nonapeptide synthesised in the hypothalamic supraoptic and paraventricular nuclei and released from the posterior pituitary. It acts through three G-protein coupled receptor subtypes: V1a (vascular smooth muscle, Gq-coupled, causing vasoconstriction via IP3/Ca²⁺ pathway), V1b (anterior pituitary, ACTH release), and V2 (renal collecting duct, Gs-coupled, increasing cAMP and aquaporin-2 insertion for water reabsorption). In anaesthesia and critical care, exogenous vasopressin is used for catecholamine-resistant vasodilatory shock at a fixed dose of 0.03 units/min, where it provides non-adrenergic vasoconstriction and demonstrates a catecholamine-sparing effect. Importantly, ARC/ANZCOR guidelines no longer recommend vasopressin for cardiac arrest, as evidence does not support improved neurological outcomes. Terlipressin is a V1a-selective analogue used for hepatorenal syndrome (with albumin) and acute variceal bleeding due to potent splanchnic vasoconstriction. Desmopressin (DDAVP) is a V2-selective agonist lacking vasopressor activity, used to treat central diabetes insipidus, von Willebrand disease type 1, and mild haemophilia A by releasing vWF and Factor VIII from endothelial stores. Key adverse effects include mesenteric ischaemia (V1a), hyponatraemia (V2), and coronary vasoconstriction. [1-8]

Vasopressin Physiology

Synthesis and Storage

Arginine vasopressin is a cyclic nonapeptide (9 amino acids: Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH₂) with a disulfide bridge between the two cysteine residues forming a ring structure essential for biological activity. The molecular weight is 1084 Da. [1,2]

Site of Synthesis: Vasopressin is synthesised in magnocellular neurosecretory neurons located in two hypothalamic nuclei:

• Supraoptic nucleus (SON): Primary site, neurons project directly to posterior pituitary
• Paraventricular nucleus (PVN): Also contains parvocellular neurons projecting to the median eminence and brainstem

Biosynthesis Pathway:

1. Gene transcription produces prepro-vasopressin mRNA
2. Translation yields prepro-vasopressin polypeptide (164 amino acids) containing:
   • Signal peptide (cleaved during ER entry)
   • AVP (9 amino acids)
   • Neurophysin II (carrier protein, 93-95 amino acids)
   • Copeptin (glycopeptide, 39 amino acids)
3. Processing and packaging into neurosecretory granules
4. Axonal transport down the hypothalamo-hypophyseal tract (the unmyelinated axons extending from hypothalamus to posterior pituitary)
5. Storage in Herring bodies (axon terminal swellings) in the posterior pituitary (neurohypophysis)

Copeptin is co-released with AVP in equimolar amounts and serves as a stable surrogate marker for AVP secretion (AVP itself has a very short half-life making measurement difficult). Copeptin has become valuable for diagnosing diabetes insipidus. [3,9,10]

Regulation of Secretion

AVP release is controlled by two primary mechanisms:

1. Osmotic Regulation (Most Sensitive):

• Osmoreceptors in the circumventricular organs (organum vasculosum of the lamina terminalis [OVLT] and subfornical organ [SFO]) detect plasma osmolality changes
• Set point: ~285-290 mOsm/kg - above this threshold, AVP release increases linearly with osmolality
• Sensitivity: 1-2% increase in plasma osmolality triggers detectable AVP release
• The osmotic threshold for thirst is slightly higher than for AVP release

2. Haemodynamic (Non-Osmotic) Regulation:

• Baroreceptors in the carotid sinus, aortic arch, and left atrium monitor blood pressure and volume
• Requires >10-15% decrease in blood volume or pressure to stimulate AVP release
• When activated, produces much larger AVP release than osmotic stimuli (can override osmotic regulation)
• This explains why hypovolaemic patients may have high AVP levels despite low plasma osmolality

Other Stimuli for AVP Release:

• Nausea (potent non-osmotic stimulus)
• Pain
• Stress
• Angiotensin II (synergistic with osmotic stimulation)
• Hypoglycaemia
• Certain drugs (morphine, nicotine, cyclophosphamide)

Inhibitors of AVP Release:

• Alcohol (ethanol)
• Atrial natriuretic peptide (ANP)
• Cold exposure
• Alpha-adrenergic agonists [11,12]

Normal Plasma Levels and Half-Life

Receptor Pharmacology

Vasopressin exerts its effects through three G-protein coupled receptor (GPCR) subtypes, each with distinct tissue distribution, signalling mechanisms, and physiological effects.

V1a Receptor (Vascular)

Mechanism of Vasoconstriction:

1. AVP binds V1a receptor on vascular smooth muscle
2. Gq activation stimulates phospholipase C (PLC)
3. PLC hydrolyses PIP₂ to produce IP₃ and DAG
4. IP₃ releases Ca²⁺ from sarcoplasmic reticulum
5. DAG activates protein kinase C (PKC)
6. ↑Ca²⁺ activates calmodulin-dependent myosin light chain kinase (MLCK)
7. Myosin light chain phosphorylation → smooth muscle contraction
8. Additional: V1a inhibits ATP-sensitive K⁺ channels (K_ATP), which are pathologically open in sepsis, restoring vascular tone [4,13,14]

V1b (V3) Receptor (Pituitary)

The V1b receptor acts synergistically with corticotropin-releasing hormone (CRH) to stimulate ACTH secretion from anterior pituitary corticotrophs, linking the hypothalamic-pituitary-adrenal (HPA) axis to the vasopressin system during stress. [15]

V2 Receptor (Renal)

Mechanism of Antidiuresis:

1. AVP binds V2 receptor on basolateral membrane of collecting duct principal cells
2. Gs activation stimulates adenylyl cyclase
3. ↑cAMP activates protein kinase A (PKA)
4. PKA phosphorylates aquaporin-2 (AQP2) water channels
5. Phosphorylated AQP2 translocates from cytoplasmic vesicles to apical (luminal) membrane
6. Water moves through AQP2 channels down osmotic gradient into hypertonic medullary interstitium
7. Water exits cell through constitutively expressed AQP3/AQP4 on basolateral membrane
8. Net effect: concentrated urine, free water retention

Haemostatic Effects (Extrarenal V2):

• V2 receptors on vascular endothelium stimulate release of:
  • von Willebrand factor (vWF) from Weibel-Palade bodies
  • Factor VIII (carried by vWF in circulation)
  • Tissue plasminogen activator (tPA)
• This mechanism is exploited therapeutically by desmopressin in bleeding disorders [5,16,17]

Oxytocin Receptor

Vasopressin has structural homology with oxytocin (differs by only 2 amino acids) and demonstrates weak affinity for oxytocin receptors, explaining some uterine effects. Conversely, oxytocin has weak V1a and V2 activity. [18]

Receptor Selectivity Summary

Exogenous Vasopressin (Argipressin)

Pharmacokinetics

Cardiovascular Effects

Haemodynamic Profile:

• Systemic vascular resistance: ↑↑ (potent V1a-mediated vasoconstriction)
• Mean arterial pressure: ↑↑
• Heart rate: ↔ or ↓ (no direct chronotropic effect; reflex bradycardia may occur)
• Cardiac output: ↔ or ↓ (afterload increase may reduce CO in heart failure)
• Pulmonary vascular resistance: ↑ (may worsen RV dysfunction)

Regional Vascular Effects:

Unique Mechanism in Vasodilatory Shock: In sepsis and other vasodilatory states, vasopressin provides vasoconstriction through mechanisms independent of adrenergic receptors:

1. V1a-mediated smooth muscle contraction (described above)
2. Inhibition of K_ATP channels: These channels are pathologically activated in sepsis by NO and hypoxia; vasopressin inhibits them, restoring vascular tone
3. Inhibition of nitric oxide (NO)-mediated vasodilation: Vasopressin attenuates excessive NO signalling
4. Catecholamine potentiation: Restores responsiveness to norepinephrine

This explains why vasopressin is effective in catecholamine-resistant shock. [6,19,20]

Clinical Uses in Anaesthesia and Critical Care

1. Vasodilatory (Distributive) Shock: The primary indication for vasopressin in critical care is as an adjunct to norepinephrine in septic and other vasodilatory shock states.

Evidence Base:

• VASST Trial (2008): Landmark multicentre RCT comparing vasopressin (0.01-0.03 U/min) vs norepinephrine in septic shock. No overall mortality difference, but subgroup analysis suggested benefit in "less severe" shock (norepinephrine requirement 5-15 mcg/min at baseline). [21]
• VANISH Trial (2016): Early vasopressin vs norepinephrine showed no difference in kidney-failure-free days but reduced need for renal replacement therapy. [22]
• Surviving Sepsis Campaign (2021): Recommends adding vasopressin (0.03 U/min) when norepinephrine dose reaches 0.25-0.5 mcg/kg/min to achieve MAP target. [23]

Dosing:

Important: Vasopressin is typically used at a fixed low dose (0.03 U/min) as an adjunct, NOT as a first-line vasopressor or for titration.

2. Cardiac Arrest:

Historical Context: Vasopressin was previously used in cardiac arrest algorithms based on:

• Higher endogenous vasopressin levels in cardiac arrest survivors
• Theoretical benefits of non-adrenergic vasoconstriction
• Early observational studies suggesting benefit

Current ARC/ANZCOR Guidelines (2021): Vasopressin is NO LONGER recommended for cardiac arrest.

The evidence does not support improved survival or neurological outcomes:

• No RCT has demonstrated superiority over epinephrine
• AHA 2020 guidelines removed vasopressin from ACLS algorithm
• May be considered as alternative if epinephrine unavailable, but not routine use [24,25]

3. Other Indications:

• Hepatorenal syndrome: Terlipressin preferred (see below)
• Variceal bleeding: Terlipressin or octreotide preferred
• Posterior pituitary hormone replacement: Rarely used; desmopressin preferred for DI
• Bleeding oesophageal varices: Largely replaced by terlipressin

Terlipressin

Overview and Structure

Terlipressin (triglycyl-lysine-vasopressin) is a synthetic vasopressin analogue with three glycine residues attached to the N-terminus. It is a prodrug that is slowly converted to lysine-vasopressin (lypressin) by tissue peptidases. This slow conversion provides a prolonged duration of action suitable for bolus dosing. [26,27]

Receptor Selectivity

Terlipressin and its active metabolite lypressin demonstrate V1a selectivity with minimal V2 activity:

This selectivity profile produces potent vasoconstriction (particularly splanchnic) with minimal antidiuretic effect, making it suitable for hepatorenal syndrome and variceal bleeding. [7,28]

Pharmacokinetics

The prolonged effect allows for intermittent bolus dosing (every 4-6 hours) rather than continuous infusion.

Clinical Applications

1. Hepatorenal Syndrome (HRS-AKI):

Hepatorenal syndrome occurs in advanced cirrhosis due to splanchnic vasodilation reducing effective arterial blood volume, triggering intense renal vasoconstriction. Terlipressin causes splanchnic vasoconstriction, redistributing blood to the central circulation and improving renal perfusion.

Evidence:

• CONFIRM Trial (2021): Phase 3 RCT demonstrating terlipressin + albumin superior to placebo + albumin for HRS reversal (29% vs 16%). FDA approved terlipressin based on this trial. Important caution: increased respiratory adverse events (including respiratory failure) in terlipressin group. [29]
• Cavallin et al. (2015): Terlipressin superior to midodrine + octreotide for HRS reversal. [30]
• Continuous vs bolus: Continuous infusion (2-4 mg/24h) equally effective with fewer adverse events than bolus dosing. [31]

Dosing for HRS:

2. Acute Variceal Bleeding:

Terlipressin reduces portal pressure through splanchnic vasoconstriction, decreasing blood flow to varices.

Evidence:

• Cochrane review: Only vasoactive drug demonstrating mortality reduction in acute variceal bleeding vs placebo. [32]
• As effective as somatostatin and more effective than octreotide. [33]
• International guidelines (Baveno VII) recommend as first-line vasoactive therapy.

Dosing for Variceal Bleeding:

• Initial: 2 mg IV bolus
• Maintenance: 1-2 mg IV every 4-6 hours for up to 5 days
• Combine with endoscopic therapy (band ligation/sclerotherapy) and prophylactic antibiotics

Adverse Effects of Terlipressin

Contraindications:

• Severe coronary artery disease
• Peripheral vascular disease
• Pregnancy (causes uterine contractions)
• Uncontrolled hypertension

Desmopressin (DDAVP)

Overview and Structure

Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) is a synthetic vasopressin analogue with two key structural modifications:

1. Deamination at position 1 (removal of amino group from Cys)
2. D-arginine substitution at position 8 (instead of L-arginine)

These modifications confer:

• V2 selectivity: 3000-fold greater V2:V1a affinity ratio than native AVP
• Prolonged half-life: Resistant to enzymatic degradation
• Negligible vasopressor activity: Safe for chronic use [8,34]

Receptor Selectivity

Pharmacokinetics

Desmopressin's resistance to aminopeptidases (deamination) and the D-configuration at position 8 (resists carboxypeptidases) provide significantly prolonged activity compared to native AVP. [35]

Clinical Applications

1. Central Diabetes Insipidus:

Desmopressin is the treatment of choice for central (cranial) diabetes insipidus, where ADH deficiency causes failure to concentrate urine.

Dosing:

Important considerations:

• NOT effective for nephrogenic DI (V2 receptor dysfunction)
• Risk of hyponatraemia from excessive water retention—fluid restriction required
• In post-pituitary surgery patients, use cautiously to avoid masking the SIADH phase of triphasic response [36,37]

2. Von Willebrand Disease (vWD):

Desmopressin releases vWF and Factor VIII from endothelial Weibel-Palade bodies, typically producing 3-5 fold increases in plasma levels within 30-60 minutes.

Effectiveness by vWD Type:

Dosing for vWD/Haemophilia:

• IV: 0.3 mcg/kg diluted in 50 mL saline over 30 minutes
• Intranasal (Stimate®): 150 mcg per nostril (300 mcg total) for adults >50 kg

DDAVP Trial: Before surgical use, perform a test dose and measure vWF and FVIII response to ensure adequate therapeutic rise. [38,39]

3. Mild Haemophilia A:

Desmopressin can raise Factor VIII levels sufficiently to manage minor bleeding or surgery in patients with mild haemophilia A (FVIII >5%). It avoids the need for blood products.

Limitations:

• Ineffective for moderate-severe haemophilia A
• NOT effective for Haemophilia B (Factor IX deficiency)—desmopressin does not affect FIX levels
• Tachyphylaxis occurs with repeated doses (24-48 hours apart minimum) [40]

4. Other Indications:

• Primary nocturnal enuresis: Reduces urine production overnight
• Uremic bleeding: Shortens prolonged bleeding time
• Platelet dysfunction: May improve platelet adhesion

Adverse Effects of Desmopressin

Hyponatraemia Warning: The most serious adverse effect is hyponatraemia leading to seizures, particularly in:

• Children (smaller fluid tolerance)
• Elderly (impaired thirst regulation)
• Patients receiving IV fluids
• Repeat dosing within 24 hours

Mandatory: Fluid restriction for 24 hours after desmopressin administration for bleeding indications. [41]

Drug Interactions

Vasopressin/Terlipressin Interactions

Desmopressin Interactions

Special Populations

Critically Ill Patients

Vasopressin Deficiency in Sepsis: Endogenous vasopressin levels are initially elevated in early sepsis but become depleted in prolonged shock states, contributing to "relative vasopressin deficiency." This provides rationale for exogenous supplementation.

Pharmacokinetic Changes:

• Increased volume of distribution: Capillary leak, oedema
• Reduced clearance: Hepatic and renal dysfunction
• Variable response: Altered receptor expression/sensitivity

Hepatic Impairment

• Vasopressin and terlipressin clearance reduced in severe liver disease
• Use with caution; start with lower doses
• However, hepatorenal syndrome (where terlipressin is indicated) inherently involves severe liver disease
• Monitor for adverse effects closely

Renal Impairment

• Desmopressin clearance reduced in renal impairment
• Increased duration of effect
• Higher risk of hyponatraemia
• Reduce dose and monitor sodium carefully

Paediatric Considerations

• Children more susceptible to desmopressin-induced hyponatraemia
• Lower fluid tolerance relative to body size
• Fluid restriction critical
• Terlipressin use limited; less evidence in children

Pregnancy

Vasopressin/Terlipressin:

• Contraindicated in pregnancy (risk of uterine contractions, fetal hypoxia)
• V1a receptors present on myometrium
• Oxytocin receptor cross-reactivity

Desmopressin:

• Considered safe in pregnancy for diabetes insipidus
• Minimal oxytocic activity
• Does not cross placenta significantly
• Used in gestational DI (where placental vasopressinase degrades endogenous AVP but not DDAVP) [42]

Elderly

• Increased sensitivity to antidiuretic effects
• Higher risk of hyponatraemia with desmopressin
• Impaired thirst mechanism
• Start with lower doses; monitor sodium closely

Australian/New Zealand Specific Considerations

TGA-Approved Formulations

PBS Listing

ANZCA and ANZICS Guidelines

Vasopressin in Shock:

• ANZICS Clinical Guidelines align with Surviving Sepsis Campaign
• Recommend vasopressin 0.03 U/min as adjunct to norepinephrine
• No specific ANZCA guideline on vasopressin

Cardiac Arrest:

• ARC/ANZCOR guidelines do NOT recommend routine vasopressin in cardiac arrest
• Epinephrine remains sole recommended vasopressor for ACLS

Australian Blood Products

For vWD and haemophilia, alternatives to desmopressin include:

• Biostate®: Plasma-derived vWF/FVIII concentrate (CSL Behring)
• Recombinant FVIII products: For haemophilia A when DDAVP inadequate

Indigenous Health Considerations

Aboriginal and Torres Strait Islander peoples and Māori populations may have specific considerations relevant to the clinical use of vasopressin and its analogues. Higher prevalence of chronic kidney disease (3-4 times non-Indigenous rates) affects desmopressin pharmacokinetics, reducing clearance and prolonging antidiuretic effect with increased hyponatraemia risk. Careful sodium monitoring and dose reduction are essential in Indigenous patients with known or suspected renal impairment. The elevated incidence of end-stage liver disease, including from hepatitis B and alcohol-related cirrhosis, means Indigenous patients may more commonly present with hepatorenal syndrome requiring terlipressin therapy. Close monitoring for ischaemic complications is critical given concurrent cardiovascular disease burden.

Cardiovascular comorbidities, including ischaemic heart disease and peripheral vascular disease, are substantially more prevalent in Indigenous Australian communities. These conditions increase the risk of coronary and mesenteric ischaemia with vasopressin and terlipressin. Lower thresholds for adverse effect monitoring and dose reduction should be considered. Remote and rural healthcare settings with high Indigenous populations may have limited access to intensive monitoring and specialist support. When using these agents in such settings, conservative dosing and early referral criteria should be established. Culturally safe care includes appropriate communication through Aboriginal Health Workers where available, involvement of family in treatment decisions consistent with Indigenous concepts of collective decision-making, and awareness of traditional medicine use that could affect fluid balance. Māori health principles of whakawhanaungatanga (building relationships) and manaakitanga (showing respect and care) should guide interactions in New Zealand practice.

Adverse Effects and Complications

Vasopressin Adverse Effects

Mesenteric Ischaemia is the most serious complication:

• Monitor for abdominal pain, distension, bloody stools, rising lactate
• More common at doses >0.04 U/min
• Discontinue vasopressin if suspected

Terlipressin Adverse Effects

See dedicated section above. Key concerns:

• Ischaemic events (mesenteric, cardiac, digital)
• Respiratory complications (highlighted in CONFIRM trial)
• Hyponatraemia (less than with desmopressin)

Desmopressin Adverse Effects

See dedicated section above. Key concerns:

• Hyponatraemia (most important)
• Water intoxication with seizures
• Tachyphylaxis

Management of Extravasation

Vasopressin extravasation can cause severe local tissue ischaemia.

Treatment:

1. Stop infusion immediately
2. Aspirate residual drug if possible
3. Infiltrate area with phentolamine 5-10 mg in 10-15 mL saline
4. Apply warm compresses
5. Elevate affected area
6. Consult vascular/plastic surgery if severe

ANZCA Primary Exam Focus

Common MCQ Themes

1. Receptor pharmacology: V1a (Gq, IP₃/Ca²⁺, vasoconstriction) vs V2 (Gs, cAMP, AQP2/water reabsorption)
2. Structure-activity relationships: Why desmopressin lacks V1a activity (deamination, D-arginine)
3. Terlipressin mechanism: V1a-selective prodrug; splanchnic vasoconstriction
4. Desmopressin indications: Central DI (not nephrogenic), vWD type 1 (not 2B), mild haemophilia A (not B)
5. Vasopressin in cardiac arrest: NO longer recommended (ARC/ANZCOR)
6. Adverse effects: Mesenteric ischaemia (vasopressin/terlipressin), hyponatraemia (desmopressin)
7. Physiological secretion: Osmotic (sensitive) vs haemodynamic (threshold >10% volume change)

Primary Viva Question Patterns

• "Compare the receptor pharmacology of vasopressin, terlipressin, and desmopressin"
• "Describe the mechanism by which vasopressin is useful in septic shock"
• "A patient with vWD type 2B needs surgery—can you use desmopressin?"
• "Why is vasopressin no longer recommended in cardiac arrest?"
• "What are the risks of desmopressin and how do you mitigate them?"

Key Calculations

Vasopressin Infusion:

• Standard dose: 0.03 units/min
• Preparation: 20 units in 100 mL (0.2 units/mL)
• Rate for 0.03 U/min: 0.03 ÷ 0.2 = 0.15 mL/min = 9 mL/hr

Desmopressin for vWD:

• Dose: 0.3 mcg/kg IV
• 70 kg patient: 0.3 × 70 = 21 mcg
• Using 4 mcg/mL solution: Draw up 5.25 mL, dilute in 50 mL saline, infuse over 30 minutes

Assessment Content

SAQ Practice Question (20 marks)

Question:

A 55-year-old man with decompensated alcoholic cirrhosis is admitted to ICU with oliguric acute kidney injury. He has tense ascites, jaundice, and encephalopathy. His serum creatinine has risen from 95 to 280 μmol/L over 5 days despite volume resuscitation with albumin. There is no evidence of sepsis or nephrotoxin exposure. Urinalysis shows no protein or casts.

(a) Outline the pathophysiology of hepatorenal syndrome and explain how terlipressin addresses this. (6 marks)

(b) Compare the receptor pharmacology and clinical applications of terlipressin versus desmopressin in a structured format. (6 marks)

(c) Describe the dosing of terlipressin for hepatorenal syndrome and the mandatory co-therapy. What monitoring is required? (4 marks)

(d) List four contraindications or precautions for terlipressin use. (4 marks)

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Model Answer:

(a) Pathophysiology of HRS and Terlipressin Mechanism (6 marks)

Hepatorenal Syndrome Pathophysiology: In advanced cirrhosis with portal hypertension, splanchnic vasodilation occurs due to increased nitric oxide, carbon monoxide, and other vasodilators. [1 mark]

This splanchnic vasodilation causes:

• Reduced effective arterial blood volume (EABV) [0.5 mark]
• Activation of renin-angiotensin-aldosterone system (RAAS) [0.5 mark]
• Sympathetic nervous system activation [0.5 mark]
• Endogenous vasopressin release [0.5 mark]

The result is intense renal vasoconstriction (afferent arteriolar) leading to reduced renal perfusion and GFR, despite relatively preserved tubular function (hence bland urinalysis). [1 mark]

How Terlipressin Addresses This: Terlipressin is a V1a-selective vasopressin analogue that causes potent splanchnic vasoconstriction. [1 mark]

This:

• Increases effective arterial blood volume by redistributing blood from splanchnic to central circulation [0.5 mark]
• Reduces RAAS and sympathetic activation [0.5 mark]
• Improves renal perfusion pressure and GFR [0.5 mark]
• Combined with albumin, further expands plasma volume [0.5 mark]

(b) Comparison of Terlipressin vs Desmopressin (6 marks)

[1 mark per 2 correct entries, maximum 6 marks]

(c) Dosing and Monitoring (4 marks)

Terlipressin Dosing for HRS:

• Bolus regimen: 0.5-2 mg IV every 4-6 hours [0.5 mark]
• Continuous infusion: 2-4 mg over 24 hours (lower adverse events) [0.5 mark]
• Duration: Continue until serum creatinine normalises or for maximum 14 days [0.5 mark]

Mandatory Co-therapy:

• Intravenous albumin: 20-40 g per day [0.5 mark]
• Albumin expands plasma volume and enhances terlipressin efficacy [0.5 mark]

Monitoring Required:

• Serum creatinine (daily) - assess response [0.5 mark]
• Serum sodium (daily) - hyponatraemia risk [0.25 mark]
• Haemodynamics (heart rate, blood pressure) [0.25 mark]
• Oxygen saturation - respiratory complications (CONFIRM trial) [0.25 mark]
• Clinical assessment for ischaemia (abdominal pain, chest pain, digital pallor) [0.25 mark]

(d) Contraindications/Precautions for Terlipressin (4 marks)

1. Severe coronary artery disease - risk of myocardial ischaemia from coronary vasoconstriction [1 mark]
2. Peripheral vascular disease - risk of digital/limb ischaemia [1 mark]
3. Pregnancy - causes uterine contractions; risk of fetal hypoxia [1 mark]
4. Uncontrolled hypertension - systemic vasoconstriction worsens hypertension [0.5 mark]
5. Known hypersensitivity to terlipressin or vasopressin analogues [0.5 mark]

[Maximum 4 marks]

Total: 20 marks

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Primary Viva Scenario (15 marks)

Opening Stem:

You are called to the cardiothoracic ICU to review a 68-year-old man who is 4 hours post-coronary artery bypass grafting. He is hypotensive (MAP 55 mmHg) despite norepinephrine at 0.4 mcg/kg/min. He is warm and peripherally vasodilated. The surgical team suspects post-cardiotomy vasoplegia.

Expected Viva Progression:

Examiner: What vasopressor would you consider adding, and why?

Candidate Response (4 marks):

"I would consider adding vasopressin at a fixed dose of 0.03 units/minute as an adjunct to norepinephrine.

Post-cardiotomy vasoplegia is a vasodilatory shock state characterised by low systemic vascular resistance despite adequate cardiac output. It occurs in 5-25% of cardiac surgery patients, particularly after prolonged cardiopulmonary bypass.

The rationale for vasopressin includes:

1. Non-adrenergic mechanism: Vasopressin acts through V1a receptors, independent of adrenergic pathways, which may be desensitised or downregulated after CPB
2. Catecholamine-sparing effect: Allows reduction of norepinephrine dose
3. Relative vasopressin deficiency: Endogenous vasopressin stores may be depleted in prolonged shock states
4. K_ATP channel inhibition: Vasopressin inhibits pathologically open ATP-sensitive potassium channels that contribute to vasodilation in sepsis and post-CPB vasoplegia"

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Examiner: Describe the mechanism of action of vasopressin at the cellular level.

Candidate Response (4 marks):

"Vasopressin produces vasoconstriction through activation of V1a receptors on vascular smooth muscle cells.

Signal Transduction Pathway:

1. Vasopressin binds to V1a receptor (a G-protein coupled receptor)
2. V1a is coupled to Gq proteins
3. Gq activation stimulates phospholipase C (PLC)
4. PLC hydrolyses phosphatidylinositol 4,5-bisphosphate (PIP₂)
5. This produces inositol triphosphate (IP₃) and diacylglycerol (DAG)
6. IP₃ releases calcium from sarcoplasmic reticulum stores
7. DAG activates protein kinase C (PKC)
8. Increased intracellular calcium activates calmodulin-dependent myosin light chain kinase (MLCK)
9. MLCK phosphorylates myosin light chains → smooth muscle contraction

Additional Mechanism in Shock: Vasopressin also inhibits ATP-sensitive potassium (K_ATP) channels, which are pathologically activated in sepsis and vasoplegia by nitric oxide and hypoxia. This restores vascular smooth muscle membrane potential and contractile responsiveness."

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Examiner: What are the key differences between vasopressin and its analogues terlipressin and desmopressin?

Candidate Response (4 marks):

The structural modifications of desmopressin (deamination at position 1 and D-arginine at position 8) dramatically shift receptor selectivity toward V2, eliminating vasopressor activity. Terlipressin is a prodrug with glycine residues that is slowly converted to the active V1a-selective compound."

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Examiner: What adverse effects would you monitor for with vasopressin infusion?

Candidate Response (3 marks):

"The key adverse effects to monitor include:

1. Mesenteric ischaemia (most serious):

   • Due to splanchnic V1a-mediated vasoconstriction
   • Monitor for abdominal pain, distension, bloody stools, rising lactate
   • More common at doses >0.04 U/min

2. Coronary vasoconstriction:

   • Risk of myocardial ischaemia, particularly in this post-CABG patient
   • Monitor ECG, troponin trends
   • Use lowest effective dose

3. Peripheral ischaemia:

   • Digital and cutaneous vasoconstriction
   • Monitor for pallor, mottling, digital cyanosis

4. Hyponatraemia:

   • V2-mediated water retention
   • Less common at low doses but monitor sodium daily

5. Bradycardia:

   • From reduced cardiac output and possible reflex mechanisms
   • Usually well-tolerated but monitor

For this post-cardiac surgery patient, I would maintain the lowest effective dose (0.03 U/min), closely monitor for myocardial ischaemia given his coronary disease, and wean as soon as haemodynamics stabilise."

Total: 15 marks

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12. PMID: 2465351 (Share L - Cardiovascular receptors and AVP)
13. PMID: 15175255 (Michelotti GA - Vasopressin receptor signaling)
14. PMID: 11307133 (Landry DW - Vasopressin deficiency in shock)
15. PMID: 15017013 (Serradeil-Le Gal C - V1b receptor pharmacology)
16. PMID: 26162397 (Fenton RA - Aquaporin regulation)
17. PMID: 10657513 (Knepper MA - Collecting duct water transport)
18. PMID: 11571490 (Bankir L - Vasopressin water retention)
19. PMID: 23143615 (Barrett JS - Vasopressin pharmacokinetics in shock)
20. PMID: 34605881 (Evans L - Surviving Sepsis Campaign 2021)
21. PMID: 18305265 (Russell JA - VASST trial)
22. PMID: 27483063 (Gordon AC - VANISH trial)
23. PMID: 34605881 (Surviving Sepsis Campaign 2021)
24. ARC/ANZCOR Guideline 11.5 - Medications in Adult Advanced Life Support 2021
25. PMID: 33081539 (AHA 2020 ACLS Guidelines)
26. PMID: 12137652 (Ioannou G - Cochrane variceal bleeding)
27. PMID: 22114250 (Seo YS - Terlipressin vs somatostatin)
28. PMID: 22314516 (Wells M - Vasoactive drugs variceal bleeding)
29. PMID: 33656486 (Wong F - CONFIRM trial HRS)
30. PMID: 25747274 (Cavallin M - Terlipressin vs midodrine/octreotide)
31. PMID: 26725434 (Cavallin M - Terlipressin bolus vs infusion)
32. PMID: 12137652 (Cochrane - Terlipressin mortality benefit)
33. PMID: 22114250 (Seo YS - Terlipressin variceal bleeding)
34. PMID: 17403361 (Federici AB - vWD guidelines)
35. PMID: 9198124 (Mannucci PM - DDAVP bleeding disorders)
36. PMID: 23413554 (Di Iorgi N - Diabetes insipidus management)
37. PMID: 14607067 (Juul KV - DDAVP safety)
38. PMID: 8462524 (Lethagen S - DDAVP for vWD)
39. PMID: 17403361 (Federici AB - vWD management guidelines)
40. PMID: 9198124 (Mannucci PM - DDAVP in haemophilia)
41. PMID: 14607067 (Juul KV - Desmopressin hyponatraemia)
42. PMID: 23349251 (Christ-Crain M - Diabetes insipidus diagnosis)

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