Inotropes and Vasopressors
An inotrope increase the rate and force of cardiac contraction.
A vasopressor increases vascular smooth muscle tone.
G-proteins
Gs ↑ Adenyl Cyclase
Gi ↓ Adenyl Cyclase
Adenyl Cyclase catalyses ATP → cAMP
cAMP → ↑ Ca → ↑ contractility/rate
cAMP broken down by PDE to AMP
GQ → ↑ PLC which catalyses PIP2 → DAG + IP3 → ↑Ca
α1
Gq
Vascular smooth muscle contraction
Bladder contraction
Intestinal relax
Pancreas ↓ secretion
α2
Gi
Presynaptic membranes ↓ norad release
PLT aggregation
ß1
Gs
Heart ↑ rate/contractility
JGA ↑ renin
Fat lipolysis
ß2
Gs
Heart ↑ rate/contractility (1/3 no of ß1)
Smooth muscle relax
Liver glycogenolysis
Pancreas ↑ secretion
ß3
Omentum and brown fat obesity control
D1
CNS modulates extra pyramidal activity
Periph renal and mesenteric vasodilatation
D2
CNS ↓ pit output
Periph inhibits norad release
Phenylalanine → tyrosine → dopa → dopamine → noradrenaline → adrenaline
Sympathomimetics act on adreno or dopamine receptors directly or indirectly
Based on a benzene ring
Catecholamine if have a hydroxyl group
Adrenaline
Uses
Asystole, shock, anaphylaxis, upper airway obstruction, with LA
Action
α and ß – more ß at low dose; α at high dose
CVS
Vasodilatation at v. low dose; constriction higher doses
↑ rate and contractility
↑O2 demand
RS
Bronchodilator
↓ secretions
↑ PVR
Metabolic
↑ glucose
↑ renin
↑ lactate (glycolysis)
K into cells
CNS
↑ MAC
Renal
Blood flow ↑ or ↓ (renal vasoconstriction but ↑ CO)
Metabolism
MAO in mitochondria
COMT in liver, kidney, blood
T1/2 2 min.
Noradrenaline
α > ß
Metabolism
Reuptake into nerve terminal where metab by MAOI
In circulation by COMT
Taken up in lungs
T1/2 2 mins
Dopamine
α, ß and D recs
ß at low dose; α at high
α1 agonists
Phenylephrine
α2 agonists
Clonidine
ß agonists
Dobutamine
ß1 > ß2
Vasodilatation reflex to ↑CO rather than ß2 action
Dopexamine
ß2 and D1
Isoprenaline
ß1 + 2
Salbutamol
ß2 > ß1
Mixed α and ß
Ephedrine
Direct α and ß and indirect action by stimulating norad release from sympathetic nerve endings (gets used up → tachyphylaxis)
Metaraminol
Mainly α1
Phosphodiesterase inhibitors
↑ cAMP by inhibition of its breakdown by PDE
→ inotropy, slight chronotropy and smooth muscle dilatation
Aminophyline
Used as a bronchodilator
CVS SEs and not recommended by BTS for asthma so don’t use
Enoximone and Milrinone
Selective PDEi – CVS only.
Theoretically good for heart failure as inotrope and vasodilator.
Often cause hypotension in critically ill.
Other
Glucagon
Acts on glucagon recs to ↑ cAMP → inotrope
Calcium
Use only if hypocalcaemia, Ca antag OD, ↑K
T3
Upregulates ß recs in heart
Digoxin
Inhibits Na/K ATPase → ↑ intracellular Na → ↓ exchange of intracellular Ca for extracellular Na → ↑ IC Ca
Vasopressin
Neuropeptide synthesised in hypothalamus and transported to posterior pituitary from which it is secreted.
Regulates plasma osmolality and volume, vascular tone and coagulation.
4 types of receptor all G-protein coupled:
V1
Vascular smooth muscle, myometrium and PLT
Vasoconstriction except in lungs where vasodilatation
V2
Collecting ducts
- Open aquaporin channels
- Release of vWF and factor 8
Pituitary
- ACTH release
- Temperature regulation
- Memory
Effects
Increased permeability of renal collecting ducts → reabsorption of water.
Vasoconstriction by a direct effect on vascular smooth muscle.
↑ levels factor 8 and vWF.
Released in response to:
↑ plasma osmolality (main stimulus) – osmoreceptors in hypothalamus.
↓ ECF volume – baroreceptors.
Stress, hypoxia, acidosis.
Drugs – morphine.
Angiotensin 2.
Therapy
Desmopressin
Minimal vasoconstrictor activity
DI (0.5-2mcg)
Haemophilia and vW
Terlipressin
Prodrug of vasopressin with milder SEs
↓ bleeding in varices (↓ portal blood flow)
Vasopressin
↑ BP in resistant vasodilatory shock
Varices
Cardiac arrest
A multi-centre randomised double-blinded trial showed better outcomes than with adrenaline in asystolic cardiac arrest with no difference in PEA or VT/VF.
Septic shock
Vasopressin levels initially ↑ but by 6h are inappropriately low for the degree of shock.
Noradrenaline exerts ↑ SEs with ↑ dose (↑ O2 demand, ↓mesenteric and renal blood flow, pulmonary hypertension and arrhythmias) and also inhibits vasopressin release in high doses.
A trial with 48 patients comparing norad alone and combined with vasopressin showed improved CI and gut mucosal blood flow and ↓ tachyarrythmias.
Vasopressin and noradrenaline are believed to work synergistically.
In high doses vasopressin → ↓ myocardial blood flow.
In low doses there is minimal effect on splanchnic blood flow.
The VASST trial compared vasopressin with noradrenaline – blinded, randomised 778 patients.
No difference in mortality.
Equal safety.