U2vii / 17A20: Describe the pharmacology of vasopressin (70 marks) and its analogues (30 marks)

17A20: Exam Report

Describe the pharmacology of vasopressin (70% of marks) and its analogues (30% of marks).

28% of candidates passed this question.

A pharmacology answer template outlining pharmacokinetics and dynamics was required. Candidates failed to score marks for describing the physiology of vasopressin secretion. A number of answers demonstrated limited knowledge about its  indications for use and its potential adverse effects.

U2vii / 17A20: Describe the pharmacology of vasopressin (70 marks) and its analogues (30 marks)

  • A NONAPEPTIDE HORMONE formed in hypothalamus & released from PPG
  • 1° function is to regulate Plasma Osmolality & Volume → however, is also a potent vasoconstrictor

Synthesis

  • In cell bodies of supraoptic & paraventricular nuclei of hypothalamus
  • Transported down axons in neurosecretory granules
  • Stored in nerve terminals of PPG

Release

↑ Plasma Osmolality

  • Detected by osmoreceptors in Ant. Hypothalamus (outside BBB)
  • OsmoR generates electrical impulse → travels axon length → stimulates Vasopressin release by PPG

↓ECF Volume

  • Hypovolaemia → ↓atrial P → stretch receptors of atria ↓firing rate → afferent fibres of atrial stretch receptors synapse with NTS of Medulla → communicates with Hypothalamus → controls its release by PPG
    • AII (by AII receptor on hypothalamus)
    • Pain
    • Nausea
    • Stress
    • Hypoxaemia
    • Acidosis
    • IPPV
    • Catecholamines → at low levels, activate α1 receptor → stimulates vasopressin release

↓ Release → ↓plasma osmolality / ↑plasma volume

Mechanism of Action

Vasopressin Receptors = all GPCR

  • V1 – Vascular smooth m. of systemic, splanchnic, renal, coronary, myometrium & platelets
    • Gq → activates Phospholipid C → ↑IP3 & DAG → ↑Intracellular Ca2+ → Mass VC
  • V1b – Adenohypophysis → stimulates release of adenocorticotropin from APG

 

  • V2 – Distal tubules & collecting duct → BASOLATERAL MEMBRANE
    • GS → activates AC → ↑cAMP → ↑Ca2+ → AQUAPORIN 2 channels insert on APICAL MEMBRANE → ↑H2O reabsorption
    • RECALL: Aquaporins insert on Apical membrane
    • Aquaporins = family of 5 water channels. Only one is vasopressin sensitive = AqP2
  • Endothelial cells
    • GS → induces release of vWF
    • cWF protects F VIII from breakdown in plasma
    • vWF also helps platelets adhere to site of bleeding
  • V3 – Pituitary
    • Gq → activates Phospholipase C → ↑IP3 & DAG → ↑Intracellular Ca2+ → ACTH release → memory & temp regulation

Vasopressin Analogues

Vasopressin Analogues

Chemical

Vasopressin

Synthetic peptide hormone

Terlipressin

Synthetic vasopressin analogue (Most selective for V1 receptor)

Desmopressin

Synthetic vasopressin analogue (V2 selective)

Use

Vasopressin

  1. Cranial DI (ineffective for Renal DI)
  2. Platelet dysfunction (F VIII & vWF deficiency)
  3. Oesophageal variceal haemorrhage
  4. NA sparing in Septic Shock

Terlipressin

  1. Acute variceal bleeding
  2. Hepatorenal syndrome

Desmopressin

  1. Mx haemophilia & vWF deficiency
  2. Bleeding post cardiac sx
  3. Antidiuretic (DI of any cause)
  4. Nocturnal enuresis

Dose

Vasopressin

0.01 – 0.1 units/min

Terlipressin

1 – 2mg QID

Desmopressin

IV 2 – 4mcg BD

IN 10 – 40mcg in 24hr

PO 500mcg BD

Presentation

Vasopressin

Clear colourless vial

20U/mL

Terlipressin

Powder. Most be mixed

Desmopressin

Route

Vasopressin

IV

Terlipressin

IV

Desmopressin

PO/IV/Nasally

Onset

Vasopressin

Fast

Terlipressin

Delayed

Desmopressin

Offset

Vasopressin

~30mins

Terlipressin

6hrs

Desmopressin

8 – 12hrs

MoA

Vasopressin

Vasopressin receptor agonist (all GPCR)

  • V1 – vascular smooth m.
  • Gq – intense VC
  • V2 – BASOLATERAL MEMBRANE of distal tubules & collecting duct → ↑H2O reabsorption
  • V2 – endothelial cells → ↑vWF release

Terlipressin

The most selective V1 receptor agonist

  • Gq – intense VC
  • Especially selective for splanchnic circulation

Desmopressin

Selective V2 receptor agonist

  • G5 – basolateral membrane of tubule cell → ↑Aquaporin 2 insertion – ↑H2O reabsorption
  • G5 – endothelial cells → ↑vWF release
  • Promotes platelet adhesion
  • Protects F VIII from breakdown in plasma

PD

CVS

Vasopressin

  • ↑SVR
  • ↑Circulating vol
  • ↑CO
  • CA vc & ↑afterload = ↓Myocardial O2­ delivery

Terlipressin

Desmopressin

GI

Vasopressin

  • Marked splanchnic VC
  • ↑Glycogenolysis

Terlipressin

↓↓↓ portal pressure

Desmopressin

Renal

Vasopressin

↑H2O reabsorption

Terlipressin

Desmopressin

↑water reabsorption

HAEM

Vasopressin

  • ↑platelet aggregation
  • ↑vWF, ↑F VIII

Terlipressin

Desmopressin

  • ↑Platelet aggregation
  • ↑vWF, ↑F VIII

Side Effects

Side Effects​

Vasopressin

  • Hyponatraemia
  • Hypertensive crisis

Terlipressin

  • Abdominal pain
  • Colic
  • HTN
  • Headache

Desmopressin

  • ↓Na+
  • Headache
  • Insomnia

Contraindication

Vasopressin

  1. H2O retention
  2. IHD
  3. Cerebral vasospasm
  4. Pregnancy → oxytocin like effect → premature uterine contractions

Terlipressin

Desmopressin

PK

A

Vasopressin

0% OBA

Terlipressin

IV only

Desmopressin

0.1% OBA

D

Vasopressin

30% PPB. VD 0.2L/kg

Terlipressin

PPB 30%

Desmopressin

0.3L/kg

M

Vasopressin

  • 65% unchanged by kidneys
  • 35% liver + kidney peptidases

Terlipressin

  • Endothelial peptidases
  • 65% unchanged in urine
  • 35% endothelial peptidases

Desmopressin

  • No liver metabolism

E

Vasopressin

  • Renally
  • t½ B 30 mins  

Terlipressin

  • 65% unchanged in urine

Desmopressin

  • 65% unchanged in kidneys