Vasopressin
Chemical
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
MoA
Vasopressin receptors = all GPCR
- V1 – vascular smooth m. of systemic, splanchnic, renal, coronary, myometrium & platelets
Gq → activates phospholipid C → ↑IP3 & DAG → ↑intrac Ca2+ → mass VC
- V1b – adenohypophysis → stimulates release of adrenocorticotropin 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 → vWF protects F VIII from break down in plasma → vWF also helps platelets adhere to site of bleeding
- V3 – pituitary
Gq → activates phospholipase C → ↑IP3 & DAG → ↑intrac Ca2+ → ACTH release → memory & temp regulation
Vasopressin
Chemical
Vasopressin
Synthetic peptide hormone
Terlipressin
Synthetic vasopressin analogue (most sensitive for V1 receptor)
Desmopressin
Synthetic vasopressin analogue
(V2 selective)
Use
Vasopressin
- Cranial DI (ineffective for renal DI)
- Platelet dysfunction
(F VIII & vWF deficiency)
- Oesophageal variceal haemorrhage
- NA sparing in septic shock
Terlipressin
- Acute variceal bleeding
- Hepatorenal sysdrome
Desmopressin
- Mx haemphilia & vWF deficiency
- Bleeding post cardiac sx
- Antidiuretic (DI of any cause)
- 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: 500 mcg BD
Presentation
Vasopressin
Clear colourless vial
20U/ml
Terlipressin
Powder. Must be mixed
Desmopressin
Route
Vasopressin
IV
Terlipressin
IV
Desmopressin
PO/IV/Intranasal
Onset/Offset
Vasopressin
Fast – 30mins
Terlipressin
Delayed – 6hrs
Desmopressin
8 – 12hrs
MoA
Vasopressin
Vasopressin receptor agonist (all GPCR)
V1 – vascular smooth m.
Gq → intense VC
V2 – BASOLATERAL MEMB. Of distal tubules & collecting duct → ↑H2O resorption
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 memb. of tubule cells → ↑aquaporin 2 insertion → ↑H2O reabsorption
G5 → endothelial cells → ↑vWF release → promotes platelet adherence → protects F VIII from
break down in plasma
PD
Vasopressin
CVS
- ↑SVR
- ↑circulating volume
- ↑CO
- CA VC & ↑afterload = ↓myocardial O2 delivery
GI
- Marked splanchnic VC
- ↑glycogenolysis
Renal – ↑H2O reabsorption
Haem
- ↑platelet aggregation
- ↑vWF, ↑F VIII
Terlipressin
GI – ↓↓↓portal pressure
Desmopressin
Renal – ↑H2O reabsorption
Haem
- ↑platelet aggregation
- ↑vWF, ↑F VIII
Side Effects
Vasopressin
Hyponatraemia
Hypertensive crisis
Terlipressin
Abdo pain
Colic
HTN
Headache
Desmopressin
↓Na+
Headache
Insomnia
Contraindications
Vasopressin
- H2O retention
- IHD
- Cerebral vasospasm
- Pregnancy → oxytocin like effect → prem. 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
VD 0.3L/kg
M
Vasopressin
65% unchanged by kidneys
35% liver + kidney peptidases
Terlipressin
Endothelial peptidases
Desmopressin
No liver metabolism
E
Vasopressin
Renally excreted
t ½ B 30 mins
Terlipressin
65% unchanged in urine
35% endothelial peptidases
Desmopressin
65% unchanged in kidneys